Embryology - User contributions [en-gb]

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2023-10-23T23:13:02Z

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2023-10-17T22:40:55Z

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2023-08-05T10:19:52Z

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2019-12-30T21:01:40Z

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{{Header}}
[[File:Amniocentesis.jpg|300px|right]]
==Introduction==
'''How and why do things go wrong in development?'''

[[File:child smallpox.jpg|thumb|Mother with child, face and body showing smallpox scars.]]

These notes cover abnormalities that can occur during development ({{abnormal development}}) often described as {{congenital abnormalities}} or {{birth defects}}. There are many different ways that developmental abnormalities can occur the 3 major types are '''Genetic''' (inherited), '''Environmental''' (maternal) and '''Idiopathic''' (unknown, not determined) derived abnormalities. The environmental factors that cause or lead to any of these abnormalities are described as teratogens. Congenital abnormalities are classified under the system called the [[International Classification of Diseases]] ({{ICD-11}}) that version updated in 2018.

Note that genetic and environmental effects can also interact and it is this and the group, now classified as idiopathic or "unknown causes", that require further research to place them in either or both of the two real categories. Furthermore developmental organizer genes, for example Hedgehog, have been recently implicated in adult carcinogenesis.

{{#pmid:19782018|reload}}

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2019-12-30T20:53:00Z

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2019-12-30T20:46:38Z

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''A draft page designed to be used only for testing.''

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RichardTest

2019-04-15T10:21:02Z

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2018-02-14T05:43:10Z

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2018-02-14T05:41:52Z

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Endocrine - Thyroid Development

2016-11-07T20:23:48Z

Z3486783:

{{Header}}
==Introduction==
[[File:Pharyngeal_pouches.jpg|thumb|Embryonic origins of the endocrine organs of the neck]]
The boundary endoderm in the floor region forms a pocket (marked by the foramen cecum) that separates from the surface and forms the thyroid. Cells originate on the surface of the floor and descend into mesoderm above aortic sac and into the hypopharyngeal eminence as "cords". These cells continue to descend until they reach their final destination in the neck adjacent to the thyroid cartilage.

This pathway forms a temporary duct (thyroglossal duct). There are abnormalities of incomplete or excessive descent of these thyroid precursor cells. The thyroid is one of the earliest endocrine organs to differentiate and has an important hormonal role in embryonic development. The early bundle of cells then forms the thyroid by first dividing to form 2 lobes separated by a narrow connecting isthmus.

* '''Maternal thyroid hormone''' - required for early stages of brain development ([[#Maternal Thyroid|Maternal Thyroid]] recent studies show both high and low thyroid hormone impact)
* '''Fetal functions from week 10''' - required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)
* '''Fetal fully functional 16 - 18 weeks''' - ({{GA}} 18-20 weeks)
* '''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)
.

[[#Maternal Thyroid|Maternal thyroid]] function also changes in early pregnancy, through pituitary changes, resulting in thyroid stimulating hormone (TSH) levels decreasing during the transition from pre-pregnancy to early pregnancy.<ref><pubmed>22436200</pubmed></ref> This change in TSH was less predictable in women with thyroid antibodies. Maternal thyroid hormone crosses the placenta.<ref name=PMID17574007><pubmed>17574007</pubmed></ref>

Hyperthyroidism in adults is generally treated with antithyroid drugs (ATDs), some of these drugs have been identified as teratogens during pregnancy. (More? [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|Antithyroid Drugs]])

Iodine deficiency disorders (IDD) is the single most common cause of preventable mental retardation and brain damage in the world. Iodine (Greek, ioeides = violet) is required for the synthesis of thyroid hormone, a key regulator of neurological development. IDD causes goiters and decreases the production of hormones vital to growth and development. (More? [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]])

{{Endocrine Links}} | [[Lecture - Head Development]] | [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]] | [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|AbnormalDevelopment - Antithyroid Drugs]]

==Some Recent Findings==
[[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
{|
|-bgcolor="F5FAFF"
|
* '''Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembl'''y<ref name=PMID27068110><pubmed>27068110</pubmed></ref> "Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes."
* '''Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections'''<ref name=PMID25458181><pubmed>25458181</pubmed></ref> "To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross-sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. ...Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae."
* '''Early thyroid development requires a Tbx1-Fgf8 pathway'''<ref><pubmed>19389367</pubmed></ref>"The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. ... a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid."

* '''Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.'''<ref><pubmed>19088150</pubmed></ref> "The World Health Organization (WHO) recently increased their recommended iodine intake during pregnancy from 200 to 250 microg/d and suggested that a median urinary iodine (UI) concentration of 150-249 microg/L indicates adequate iodine intake in pregnant women. Thyrotropin concentrations in blood collected from newborns 3-4 d after birth may be a sensitive indicator of even mild iodine deficiency during late pregnancy; a <3% frequency of thyrotropin values >5 mU/L indicates iodine sufficiency."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: ''Thyroid Embryology''

<pubmed limit=5>Thyroid Embryology</pubmed>
|}
== Reading ==
* '''Human Embryology '''(2nd ed.) Larson
* '''The Developing Human: Clinically Oriented Embryology '''(6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347
* Before We Are Born (5th ed.) Moore and Persaud
* Essentials of Human Embryology Larson
* Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

{| class="wikitable mw-collapsible mw-collapsed"
! Thyroid
|-
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| '''Endocrinology - An Integrated Approach''' Stephen Nussey and Saffron Whitehead

St. George's Hospital Medical School, London, UK Oxford: BIOS Scientific Publishers; 2001. ISBN-10: 1-85996-252-1

Copyright © 2001, BIOS Scientific Publishers Limited. [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf]
|-
| colspan=2|[http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A246 Iodine intake]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A248 Anatomical features of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A249 Iodine trapping and thyroid function]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A278 Synthesis of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A280 Actions of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A289 Control of thyroid hormone synthesis and secretion]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A292 Hyperthyroidism — Graves' disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A332 Primary hypothyroidism — Hashimoto's disease and myxedema]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A362 Secondary hypothyroidism]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A364 Hypothyroidism in infancy and childhood]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A375 Thyroid hormone resistance]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A376 Non-thyroid illness (‘sick euthyroid’ syndrome)]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A393 Transport and metabolism of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A394 Biochemical measurements of thyroid hormone status]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A399 Thyroid growth]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A400 Nodular thyroid disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A402 Thyroid cancer]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A435 Clinical case questions]
|}

==Development Overview==
{|
| [[File:Tongue1.png|foramen caecum|300px]]
| [[File:Stage13 and 22 thyroid development a.jpg|600px|Stage 13 and Stage 22 thyroid development]]
|-
| Foramen Caecum
| Stage 13 and Stage 22 thyroid development
|}
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg thyroglossal duct]
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus

==Thyroid Timeline==
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis growth factors (insulin-like, epidermal) stimulates follicular growth

===Stage 13===

[[File:Stage 13 image 058.jpg|400px]] [[File:Stage 13 image 058.jpg|400px]]

:'''Links:''' [[Carnegie_stage_13_-_serial_sections|Stage 13 Sections]] | [[Carnegie stage 13]]

===Stage 22===
[[File:Stage 22 image 068.jpg|400px]] [[File:Stage 22 image 166.jpg|400px]]

:'''Links:''' [[Carnegie_stage_22_-_serial_sections|Stage 22 Sections]] | [[Carnegie stage 22]]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|600px]]

:'''Links:''' [[Neural System Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]]

==Fetal Thyroid Hormone==
[[File:Pituitary thyroid pathway.jpg|thumb|Endocrine Pituitary-Thyroid Pathway]]
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

== Thyroid Hormone ==
Thyroid hormone is synthesized in the thyroid gland by the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin.

{| width="600px"
| [[File:Thyroxine.jpg|300px]]

'''Thyroxine''' (T4) molecular structure showing iodine positions (red rings).
| [[File:Triiodothyronine.jpg|300px]]

'''Triiodothyronine''' (T3)
|-
| '''Thyroxine''' (T4) - (Mr 777) majority of thyroid hormone derived from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.
| '''Triiodothyronine''' (T3) - synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4), though T3 is mainly used by tissues. Derived mainly from peripheral monodeiodination of T4 (at the 5' position of the outer ring of the iodothyronine nucleus).
|}
[[File:HPT_axis.jpg|300px]]

===Deiodinases===
{|
| A group of enzymes that can modify the thyroid prohormone secreted by the thyroid gland either activating ([[D#deiodinase 2|deiodinase 2]]) or deactivating ([[D#deiodinase 3|deiodinase 3]]) thyroid hormone. Their role is thought to regulate the amount of active hormone available locally in a tissue.

'''Deiodinase 2'''
* (Dio2) A [[D#deiodinase|deiodinating enzyme]] that activates thyroid hormone by clipping the 5'-iodine off of the T4 prohormone to create T3, which is the preferred ligand for thyroid receptors. The enzyme has 5'- outer ring (5'-) catalytic activity.

'''Deiodinase 3'''
* (Dio3) A [[D#deiodinase|deiodinating enzyme]] that inactivates thyroid hormone by removing the 5-iodine from either the T4 prohormone or the T3 active hormone. The enzyme has 5- inner ring (5-) catalytic activity.

| [[File:Thyroid hormone homeostasis.jpg|300px]]

Thyroid hormone homeostasis
|}
'''Links:''' [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5819 PubChem - T4] | [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5920 PubChem - T3]

==Calcitonin==
Calcitonin is synthesized by parafollicular cells (C cells) interspersed in the connective tissue between the follicles and the blood capillary network.<ref name=PMID18012><pubmed>18012</pubmed></ref>

==Maternal Thyroid==
Maternal thyroid related changes during pregnancy<ref><pubmed>10447005</pubmed></ref>:
* stimulation of maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG)
* occurs mainly near end of first trimester associated with a transient lowering in serum TSH
* increase in serum thyroxine-binding globulin levels
* small decrease in free hormone concentrations (in iodine-sufficient conditions) significantly amplified in iodine restriction or overt iodine deficiency
* trend toward a slight increase in basal thyrotropin (TSH) values between first trimester and term
* modifications of the peripheral metabolism of maternal thyroid hormones

Maternal thyroid hormone crosses the placenta possibly by 3 transport protein family mechanisms<ref name=PMID17574007><pubmed>17574007</pubmed></ref>
# thyoorganic anion-transporting polypeptide
# L-type amino acid transporter
# monocarboxylate transporter

A recent study has identified an association of maternal thyroid function during early pregnancy with child brain morphology and IQ<ref name="PMID26497402"><pubmed>26497402</pubmed></ref>

* Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume
• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume
• Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology

In the placenta, the inner ring placental deiodinase inactivates most of the maternal T4 to reverse T3 (rT3). During fetal development to term, up to 30% of the fetal thyroid hormones are of maternal origin.

==Abnormalities==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>]]
There are structural anatomical variations and thyroid under and over development, there are a number of abnormalities associated with the persistence of the embryological path of thyroid cell descent, the thyroglossal duct.

In addition there are abnormalities due to low iodine environmental conditions of growth and development. This has subsequent effects upon neural and renal development.

===Lingual thyroid gland===
The failure of thyroid descent.

{|
| [[File:Ectopic thyroid - lingual 01.jpg|300px]]
| [[File:Ectopic_thyroid_-_sublingual,_suprahyoid_and_subhyoid.jpg|sublingual, suprahyoid and subhyoid|250px]]
| [[File:Ectopic thyroid - sublingual and suprahyoid.jpg|sublingual and suprahyoid|250px]]
|-
| '''Ectopic thyroid - lingual'''<ref><pubmed>21765986</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134180 PMC3134180]</ref>
| Sublingual, suprahyoid and subhyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
| Sublingual and suprahyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
|}

===Thyroglossal Cyst===
The persistence of the thyroglossal duct.

===Thyroglossal fistula===
The partial degeneration of the thyroglossal duct.

===Abnormal development of the thyroid===

Incomplete or excessive descent.

===Pyramidal Lobe===
{|
| [[File:Thyroid_pyramidal_lobe.jpg|200px|Thyroid pyramidal lobe]]
|

This additional lobe is formed from the isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
|}
===Agenesis of Isthmus===
{|
| [[File:Thyroid-agenesis of isthmus.jpg|200px|Thyroid agenesis of isthmus<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>]]
| An absence of the isthmus with the lateral lobes positioned independently on either side of the trachea. The normal isthmus measures about 1.25 cm transversely as well as vertically and is located anterior to the second and third tracheal cartilages.<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>
|}

=== Congenital Hypothyroidism ===
[[File:Congenital hypothyroidism.jpg|thumb|Infant with congenital hypothyroidism<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>]]
[[File:Human thyroid system and neural development.jpg|thumb|Human thyroid system and neural development]]
Occurs approximately 1 in 3000 births, associated with neurological abnormalities. This abnormality can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. The condition can be classified as a permanent and transient form.

'''American Academy of Pediatrics 2006''' - Update of newborn screening and therapy for congenital hypothyroidism<ref><pubmed>16740880</pubmed></ref> "Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis."

===Congenital Hypothyroidism Classification===
{|
|-bgcolor="CEDFF2"
| width=150px|'''Classification'''
| '''Etiology'''
|-
| Primary
| Thyroid dysgenesis (developmental anomaly)

Thyroid dyshormonogenesis (impaired hormone production)

Resistance to TSH binding or signaling
|-bgcolor="F5FAFF"
| Central
| Isolated TSH deficiency

Thyrotropin-releasing hormone deficiency

Thyrotropin-releasing hormone resistance

Deficiency in pituitary development transcription factors
|-
| Peripheral
| Resistance to thyroid hormone

Abnormalities of thyroid hormone transport

|-bgcolor="F5FAFF"
| Syndromic
| Pendred syndrome

Bamforth-Lazarus syndrome

Ectodermal dysplasia

Hypothyroidism

Kocher - Deber - Semilange syndrome

Benign chorea - hypothyroidism

Choreoathetosis

Obesity - colitis
|-
| Transient
| Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma
|-bgcolor="F5FAFF"
|
| Based on Table 3 from review on congenital hypothyroidism.<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>
|}

==Iodine Deficiency==
Iodine deficiency disorder (IDD) is the single most common cause of preventable mental retardation and brain damage in the world (More? Abnormal Development - Iodine Deficiency). It is required for synthesis of thyroid hormone, which in turn regulates aspects of neural development.

Worldwide:

1.6 billion people are at risk
IDD affects 50 million children
100,000 cretins are born every year
It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women cause miscarriage, stillbirth and mentally retarded children.

A teaspoon of iodine is all a person requires in a lifetime, but because iodine cannot be stored for long periods by the body, tiny amounts are needed regularly. In areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace, food fortification and supplementation have proven highly successful and sustainable interventions.

Iodized salt programs and iodized oil supplements are the most common tools in the fight against IDD.

(Data: ICCIDD)

Prolonged intake of large amounts (excess) of iodide can increase the incidence of goiter and/or hypothyroidism in humans. African Congo appears to be the only country that appears to have a dietary excess.

:'''Links:''' [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]]

== Maternal Abnormalities ==
[[File:Thyroid_uptake_scans_.jpg|400px|left]]

Thyroid uptake scan images of normal and abnormal thyroids
'''(A)''' Normal

'''(B)''' Graves disease: diffuse increased uptake in both thyroid lobes.

'''(C)''' Toxic multinodular goiter (TMNG): "hot" and "cold" areas of uneven uptake.

'''(D)''' Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid.

'''(E)''' Thyroiditis: decreased or absent uptake.

Thyroid uptake scans image<ref><pubmed>16363909</pubmed></ref> Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy."

Graves' disease in mothers can cause '''thyrotoxic fetus''' - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

'''Maternal Hashimoto's Thyroiditis''' (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

'''Links:''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 NIH Genes & Disease - Chapter 41 - Endocrine] | [http://www.epa.gov/radiation/radionuclides/technetium.htm EPA (USA) - Radiation Technetium]

== Environmental Thyroid Disruptors ==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>
]]
There are several environmental compounds (chemicals) that are suspected of being thyroid disruptors including:

* halogenated phenolic compounds (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl)
* phenol compounds (pentachlorophenol, 2,4,6-triiodophenol)

They have been demonstrated to induce partial agonistic and/or complex competitive/uncompetitive antagonistic responces in cell culture.

Bisphenol A - monomer used to manufacture polycarbonate plastic, possibly disrupts thyroid hormone function and affects neocortical development (accelerating neuronal differentiation/migration). (More? [http://www.ehponline.org/members/2005/7713/7713.html EHP - Bisphenol A Need for a New Risk Assessment])

== Genes ==
[[File:Mouse_E14.5_Titf1_gene_expression.jpg|thumb|Mouse (E14.5) Titf1 gene expression<ref><pubmed>21267068</pubmed>| [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000582 PLoS Biol.] | [http://www.eurexpress.org Eurexpress transcriptome atlas]</ref>]]
* Thyroid Transcriptor Factors (TTF) - TTF-1, TTF-2, PAX-8
* Fetal hypothyroidism from low levels of these transcription factors- Pit-1, Prop-1, LHX-3
* Thyrotropin-releasing hormone (TRH)
* Thyroid-stimulating hormone (TSH)

[[File:Mouse thyroid Hes1 model.jpg]]

'''Mouse thyroid Hes1 model'''<ref><pubmed>21364918</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752 PLoS One.]</ref>

==Thyroid Images==
===Adult Histology===
<gallery>
File:Thyroid_histology_001.jpg|Adult Thyroid (low power)
File:Thyroid_histology_002.jpg|Adult Thyroid (high power)
File:Parathyroid_histology_001.jpg|Adult Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Adult Parathyroid (high power)
</gallery>

===Anatomy===
<gallery>
File:Gray1174.jpg|The thyroid gland and its relations
</gallery>

== References ==
<references/>

=== Journals ===
* '''Thyroid''' [http://www.liebertpub.com/publication.aspx?pub_id=55 Thyroid] The official journal of the [http://www.thyroid.org/ American Thyroid Association].

=== Online Textbooks ===
'''Endocrinology: An Integrated Approach''' Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=endocrin.TOC&depth=1 table of Contents]

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.235 The Thyroid Gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.364 Hypothyroidism in infancy and childhood]

'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Endocrine]

'''Developmental Biology''' (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5434#5437 Is the endostyle the precursor of the thyroid gland?]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5198#5206 Environmental thyroid hormone disruptors]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.table.3110 table 13.1. Some derivatives of the neural crest]

'''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

* [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.table.2803 table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP]

'''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books&cmd=search&doptcmdl=TOCView&term=thyroid+development+AND+hstat%5Bbook%5D Thyroid Gland search Results]

===Reviews===
<pubmed>12432093</pubmed>
<pubmed>15863666</pubmed>
<pubmed>15231702</pubmed>
<pubmed>12566717</pubmed>

===Articles===
<pubmed>20976176</pubmed>
<pubmed>16093324</pubmed>
<pubmed>10902817</pubmed>

===Search PubMed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=thyroid%20development thyroid development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Congenital%20Hypothyroidism Congenital Hypothyroidism]

==Additional Images==
<gallery>
File:Minot1897 436.jpg|1897 Minot Fig 436 Pig thyroid
File:Minot1897 437.jpg|1897 Minot Fig 437 Human thyroid
File:Sudler1902-fig03.jpg|1902 Sudler Fig 3 Human pharynx
File:Sudler1902-fig04.jpg|1902 Sudler Fig 4 Human pharynx
File:Keith1902 fig030.jpg|1902 Keith Fig 30
Gray1174.jpg|1918 Gray Fig 1174
</gallery>
==Terms==

== External Links ==
{{External Links}}

* [http://www.iccidd.org/ International Council for the Control of Iodine Deficiency Disorders]
* [http://www.who.int/nut/idd.htm World Health Organization- Micronutrient deficiencies Eliminating iodine deficiency disorders]
* [http://www.british-thyroid-association.org/ British Thyroid Association] The official site of the British Thyroid Assocation, a non-profit making Learned Society of professional clinical specialist doctors and scientists in the United Kingdom who manage patients with thyroid disease and/or are researching into the thyroid and its diseases in humans.
* [http://w3.whosea.org/techinfo/nutri.htm#Iodine WHO Nutrition Guidelines]
* [http://www.thyroid.org/ American Thyroid Association] [http://www.thyroid.org/patients/index.html%20 American Thyroid Association - Patient Information]
* [http://www.clark.net/pub/tfa/index.html Thyroid Foundation of America]
* [http://www.endo-society.org/ Endocrine Society (USA)]
* [http://www.eurothyroid.com/ European Thyroid Association]
* [http://www.lats.org/ Latin-American Thyroid Association]
* [www.aota.or.kr Asia and Oceana Thyroid Association]
* [http://www.endocrinology.org/ Society for Endocrinology (UK)]
* [http://www.BAES.org/ British Association of Endocrine Surgeons]
* [www.aace.com American Association of Clinical Endocrinologists]
* [http://www.thyroidmanager.org/ Thyroid Disease Manager USA] -- this site includes textbook on the Thyroid. .
* [www.synthroid.com Knoll Pharmaceuticals]- makers of SYNTHROID
* Gray's Anatomy - [http://www.bartleby.com/107/272.html The Ductless Glands] | [http://www.bartleby.com/107/Images/large/image1174.gif The thyroid gland and its relations] | [http://www.bartleby.com/107/Images/large/image979.gif Floor of pharynx of human embryo about twenty-six days old. ](From model by Peters) | [http://www.bartleby.com/107/273.html 4b. The Parathyroid Glands]

{{Glossary}}

{{Footer}}

[[Category:Endocrine]] [[Category:Thyroid]]

Endocrine - Thyroid Development

2016-11-07T20:02:59Z

Z3486783:

{{Header}}
==Introduction==
[[File:Pharyngeal_pouches.jpg|thumb|Embryonic origins of the endocrine organs of the neck]]
The boundary endoderm in the floor region forms a pocket (marked by the foramen cecum) that separates from the surface and forms the thyroid. Cells originate on the surface of the floor and descend into mesoderm above aortic sac and into the hypopharyngeal eminence as "cords". These cells continue to descend until they reach their final destination in the neck adjacent to the thyroid cartilage.

This pathway forms a temporary duct (thyroglossal duct). There are abnormalities of incomplete or excessive descent of these thyroid precursor cells. The thyroid is one of the earliest endocrine organs to differentiate and has an important hormonal role in embryonic development. The early bundle of cells then forms the thyroid by first dividing to form 2 lobes separated by a narrow connecting isthmus.

* '''Maternal thyroid hormone''' - required for early stages of brain development ([[#Maternal Thyroid|Maternal Thyroid]] recent studies show both high and low thyroid hormone impact)
* '''Fetal functions from week 10''' - required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)
* '''Fetal fully functional 16 - 18 weeks''' - ({{GA}} 18-20 weeks)
* '''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)
.

[[#Maternal Thyroid|Maternal thyroid]] function also changes in early pregnancy, through pituitary changes, resulting in thyroid stimulating hormone (TSH) levels decreasing during the transition from pre-pregnancy to early pregnancy.<ref><pubmed>22436200</pubmed></ref> This change in TSH was less predictable in women with thyroid antibodies. Maternal thyroid hormone crosses the placenta.<ref name=PMID17574007><pubmed>17574007</pubmed></ref>

Hyperthyroidism in adults is generally treated with antithyroid drugs (ATDs), some of these drugs have been identified as teratogens during pregnancy. (More? [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|Antithyroid Drugs]])

Iodine deficiency disorders (IDD) is the single most common cause of preventable mental retardation and brain damage in the world. Iodine (Greek, ioeides = violet) is required for the synthesis of thyroid hormone, a key regulator of neurological development. IDD causes goiters and decreases the production of hormones vital to growth and development. (More? [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]])

{{Endocrine Links}} | [[Lecture - Head Development]] | [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]] | [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|AbnormalDevelopment - Antithyroid Drugs]]

==Some Recent Findings==
[[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
{|
|-bgcolor="F5FAFF"
|
* '''Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembl'''y<ref name=PMID27068110><pubmed>27068110</pubmed></ref> "Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes."
* '''Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections'''<ref name=PMID25458181><pubmed>25458181</pubmed></ref> "To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross-sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. ...Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae."
* '''Early thyroid development requires a Tbx1-Fgf8 pathway'''<ref><pubmed>19389367</pubmed></ref>"The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. ... a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid."

* '''Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.'''<ref><pubmed>19088150</pubmed></ref> "The World Health Organization (WHO) recently increased their recommended iodine intake during pregnancy from 200 to 250 microg/d and suggested that a median urinary iodine (UI) concentration of 150-249 microg/L indicates adequate iodine intake in pregnant women. Thyrotropin concentrations in blood collected from newborns 3-4 d after birth may be a sensitive indicator of even mild iodine deficiency during late pregnancy; a <3% frequency of thyrotropin values >5 mU/L indicates iodine sufficiency."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: ''Thyroid Embryology''

<pubmed limit=5>Thyroid Embryology</pubmed>
|}
== Reading ==
* '''Human Embryology '''(2nd ed.) Larson
* '''The Developing Human: Clinically Oriented Embryology '''(6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347
* Before We Are Born (5th ed.) Moore and Persaud
* Essentials of Human Embryology Larson
* Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

{| class="wikitable mw-collapsible mw-collapsed"
! Thyroid
|-
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| '''Endocrinology - An Integrated Approach''' Stephen Nussey and Saffron Whitehead

St. George's Hospital Medical School, London, UK Oxford: BIOS Scientific Publishers; 2001. ISBN-10: 1-85996-252-1

Copyright © 2001, BIOS Scientific Publishers Limited. [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf]
|-
| colspan=2|[http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A246 Iodine intake]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A248 Anatomical features of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A249 Iodine trapping and thyroid function]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A278 Synthesis of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A280 Actions of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A289 Control of thyroid hormone synthesis and secretion]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A292 Hyperthyroidism — Graves' disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A332 Primary hypothyroidism — Hashimoto's disease and myxedema]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A362 Secondary hypothyroidism]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A364 Hypothyroidism in infancy and childhood]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A375 Thyroid hormone resistance]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A376 Non-thyroid illness (‘sick euthyroid’ syndrome)]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A393 Transport and metabolism of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A394 Biochemical measurements of thyroid hormone status]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A399 Thyroid growth]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A400 Nodular thyroid disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A402 Thyroid cancer]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A435 Clinical case questions]
|}

==Development Overview==
{|
| [[File:Tongue1.png|foramen caecum|300px]]
| [[File:Stage13 and 22 thyroid development a.jpg|600px|Stage 13 and Stage 22 thyroid development]]
|-
| Foramen Caecum
| Stage 13 and Stage 22 thyroid development
|}
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg thyroglossal duct]
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus

==Thyroid Timeline==
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis growth factors (insulin-like, epidermal) stimulates follicular growth

===Stage 13===

[[File:Stage 13 image 058.jpg|400px]] [[File:Stage 13 image 058.jpg|400px]]

:'''Links:''' [[Carnegie_stage_13_-_serial_sections|Stage 13 Sections]] | [[Carnegie stage 13]]

===Stage 22===
[[File:Stage 22 image 068.jpg|400px]] [[File:Stage 22 image 166.jpg|400px]]

:'''Links:''' [[Carnegie_stage_22_-_serial_sections|Stage 22 Sections]] | [[Carnegie stage 22]]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|600px]]

:'''Links:''' [[Neural System Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]]

==Fetal Thyroid Hormone==
[[File:Pituitary thyroid pathway.jpg|thumb|Endocrine Pituitary-Thyroid Pathway]]
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

== Thyroid Hormone ==
Thyroid hormone is synthesized in the thyroid gland by the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin.

{| width="600px"
| [[File:Thyroxine.jpg|300px]]

'''Thyroxine''' (T4) molecular structure showing iodine positions (red rings).
| [[File:Triiodothyronine.jpg|300px]]

'''Triiodothyronine''' (T3)
|-
| '''Thyroxine''' (T4) - (Mr 777) majority of thyroid hormone derived from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.
| '''Triiodothyronine''' (T3) - synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4), though T3 is mainly used by tissues. Derived mainly from peripheral monodeiodination of T4 (at the 5' position of the outer ring of the iodothyronine nucleus).
|}
[[File:HPT_axis.jpg|300px]]

===Deiodinases===
{|
| A group of enzymes that can modify the thyroid prohormone secreted by the thyroid gland either activating ([[D#deiodinase 2|deiodinase 2]]) or deactivating ([[D#deiodinase 3|deiodinase 3]]) thyroid hormone. Their role is thought to regulate the amount of active hormone available locally in a tissue.

'''Deiodinase 2'''
* (Dio2) A [[D#deiodinase|deiodinating enzyme]] that activates thyroid hormone by clipping the 5'-iodine off of the T4 prohormone to create T3, which is the preferred ligand for thyroid receptors. The enzyme has 5'- outer ring (5'-) catalytic activity.

'''Deiodinase 3'''
* (Dio3) A [[D#deiodinase|deiodinating enzyme]] that inactivates thyroid hormone by removing the 5-iodine from either the T4 prohormone or the T3 active hormone. The enzyme has 5- inner ring (5-) catalytic activity.

| [[File:Thyroid hormone homeostasis.jpg|300px]]

Thyroid hormone homeostasis
|}
'''Links:''' [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5819 PubChem - T4] | [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5920 PubChem - T3]

==Calcitonin==
Calcitonin is synthesized by parafollicular cells (C cells) interspersed in the connective tissue between the follicles and the blood capillary network.<ref name=PMID18012><pubmed>18012</pubmed></ref>

==Maternal Thyroid==
Maternal thyroid related changes during pregnancy<ref><pubmed>10447005</pubmed></ref>:
* stimulation of maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG)
* occurs mainly near end of first trimester associated with a transient lowering in serum TSH
* increase in serum thyroxine-binding globulin levels
* small decrease in free hormone concentrations (in iodine-sufficient conditions) significantly amplified in iodine restriction or overt iodine deficiency
* trend toward a slight increase in basal thyrotropin (TSH) values between first trimester and term
* modifications of the peripheral metabolism of maternal thyroid hormones

Maternal thyroid hormone crosses the placenta possibly by 3 transport protein family mechanisms<ref name=PMID17574007><pubmed>17574007</pubmed></ref>
# thyoorganic anion-transporting polypeptide
# L-type amino acid transporter
# monocarboxylate transporter

A recent study has identified an association of maternal thyroid function during early pregnancy with child brain morphology and IQ<ref name="PMID26497402"><pubmed>26497402</pubmed></ref>

* Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume
• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume
• Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology

In the placenta, the inner ring placental deiodinase inactivates most of the maternal T4 to reverse T3 (rT3). During fetal development to term, up to 30% of the fetal thyroid hormones are of maternal origin.

==Abnormalities==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>]]
There are structural anatomical variations and thyroid under and over development, there are a number of abnormalities associated with the persistence of the embryological path of thyroid cell descent, the thyroglossal duct.

In addition there are abnormalities due to low iodine environmental conditions of growth and development. This has subsequent effects upon neural and renal development.

===Lingual thyroid gland===
The failure of thyroid descent.

{|
| [[File:Ectopic thyroid - lingual 01.jpg|300px]]
| [[File:Ectopic_thyroid_-_sublingual,_suprahyoid_and_subhyoid.jpg|sublingual, suprahyoid and subhyoid|250px]]
| [[File:Ectopic thyroid - sublingual and suprahyoid.jpg|sublingual and suprahyoid|250px]]
|-
| '''Ectopic thyroid - lingual'''<ref><pubmed>21765986</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134180 PMC3134180]</ref>
| Sublingual, suprahyoid and subhyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
| Sublingual and suprahyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
|}

===Thyroglossal Cyst===
The persistence of the thyroglossal duct.

===Thyroglossal fistula===
The partial degeneration of the thyroglossal duct.

===Abnormal development of the thyroid===

Incomplete or excessive descent.

===Pyramidal Lobe===
{|
| [[File:Thyroid_pyramidal_lobe.jpg|200px|Thyroid pyramidal lobe]]
|

This additional lobe is formed from the isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
|}
===Agenesis of Isthmus===
{|
| [[File:Thyroid-agenesis of isthmus.jpg|200px|Thyroid agenesis of isthmus<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>]]
| An absence of the isthmus with the lateral lobes positioned independently on either side of the trachea. The normal isthmus measures about 1.25 cm transversely as well as vertically and is located anterior to the second and third tracheal cartilages.<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>
|}

=== Congenital Hypothyroidism ===
[[File:Congenital hypothyroidism.jpg|thumb|Infant with congenital hypothyroidism<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>]]
[[File:Human thyroid system and neural development.jpg|thumb|Human thyroid system and neural development]]
Occurs approximately 1 in 3000 births, associated with neurological abnormalities. This abnormality can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. The condition can be classified as a permanent and transient form.

'''American Academy of Pediatrics 2006''' - Update of newborn screening and therapy for congenital hypothyroidism<ref><pubmed>16740880</pubmed></ref> "Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis."

===Congenital Hypothyroidism Classification===
{|
|-bgcolor="CEDFF2"
| width=150px|'''Classification'''
| '''Etiology'''
|-
| Primary
| Thyroid dysgenesis (developmental anomaly)

Thyroid dyshormonogenesis (impaired hormone production)

Resistance to TSH binding or signaling
|-bgcolor="F5FAFF"
| Central
| Isolated TSH deficiency

Thyrotropin-releasing hormone deficiency

Thyrotropin-releasing hormone resistance

Deficiency in pituitary development transcription factors
|-
| Peripheral
| Resistance to thyroid hormone

Abnormalities of thyroid hormone transport

|-bgcolor="F5FAFF"
| Syndromic
| Pendred syndrome

Bamforth-Lazarus syndrome

Ectodermal dysplasia

Hypothyroidism

Kocher - Deber - Semilange syndrome

Benign chorea - hypothyroidism

Choreoathetosis

Obesity - colitis
|-
| Transient
| Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma
|-bgcolor="F5FAFF"
|
| Based on Table 3 from review on congenital hypothyroidism.<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>
|}

==Iodine Deficiency==
Iodine deficiency disorder (IDD) is the single most common cause of preventable mental retardation and brain damage in the world (More? Abnormal Development - Iodine Deficiency). It is required for synthesis of thyroid hormone, which in turn regulates aspects of neural development.

Worldwide:

1.6 billion people are at risk
IDD affects 50 million children
100,000 cretins are born every year
It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women cause miscarriage, stillbirth and mentally retarded children.

A teaspoon of iodine is all a person requires in a lifetime, but because iodine cannot be stored for long periods by the body, tiny amounts are needed regularly. In areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace, food fortification and supplementation have proven highly successful and sustainable interventions.

Iodized salt programs and iodized oil supplements are the most common tools in the fight against IDD.

(Data: ICCIDD)

Prolonged intake of large amounts (excess) of iodide can increase the incidence of goiter and/or hypothyroidism in humans. African Congo appears to be the only country that appears to have a dietary excess.

:'''Links:''' [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]]

== Maternal Abnormalities ==
[[File:Thyroid_uptake_scans_.jpg|400px|left]]

Thyroid uptake scan images of normal and abnormal thyroids
'''(A)''' Normal

'''(B)''' Graves disease: diffuse increased uptake in both thyroid lobes.

'''(C)''' Toxic multinodular goiter (TMNG): "hot" and "cold" areas of uneven uptake.

'''(D)''' Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid.

'''(E)''' Thyroiditis: decreased or absent uptake.

Thyroid uptake scans image<ref><pubmed>16363909</pubmed></ref> Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy."

Graves' disease in mothers can cause '''thyrotoxic fetus''' - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

'''Maternal Hashimoto's Thyroiditis''' (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

'''Links:''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 NIH Genes & Disease - Chapter 41 - Endocrine] | [http://www.epa.gov/radiation/radionuclides/technetium.htm EPA (USA) - Radiation Technetium]

== Environmental Thyroid Disruptors ==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>
]]
There are several environmental compounds (chemicals) that are suspected of being thyroid disruptors including:

* halogenated phenolic compounds (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl)
* phenol compounds (pentachlorophenol, 2,4,6-triiodophenol)

They have been demonstrated to induce partial agonistic and/or complex competitive/uncompetitive antagonistic responces in cell culture.

Bisphenol A - monomer used to manufacture polycarbonate plastic, possibly disrupts thyroid hormone function and affects neocortical development (accelerating neuronal differentiation/migration). (More? [http://www.ehponline.org/members/2005/7713/7713.html EHP - Bisphenol A Need for a New Risk Assessment])

== Genes ==
[[File:Mouse_E14.5_Titf1_gene_expression.jpg|thumb|Mouse (E14.5) Titf1 gene expression<ref><pubmed>21267068</pubmed>| [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000582 PLoS Biol.] | [http://www.eurexpress.org Eurexpress transcriptome atlas]</ref>]]
* Thyroid Transcriptor Factors (TTF) - TTF-1, TTF-2, PAX-8
* Fetal hypothyroidism from low levels of these transcription factors- Pit-1, Prop-1, LHX-3
* Thyrotropin-releasing hormone (TRH)
* Thyroid-stimulating hormone (TSH)

[[File:Mouse thyroid Hes1 model.jpg]]

'''Mouse thyroid Hes1 model'''<ref><pubmed>21364918</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752 PLoS One.]</ref>

==Thyroid Images==
===Adult Histology===
<gallery>
File:Thyroid_histology_001.jpg|Adult Thyroid (low power)
File:Thyroid_histology_002.jpg|Adult Thyroid (high power)
File:Parathyroid_histology_001.jpg|Adult Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Adult Parathyroid (high power)
</gallery>

===Anatomy===
<gallery>
File:Gray1174.jpg|The thyroid gland and its relations
</gallery>

== References ==
<references/>

=== Journals ===
* '''Thyroid''' [http://www.liebertpub.com/publication.aspx?pub_id=55 Thyroid] The official journal of the [http://www.thyroid.org/ American Thyroid Association].

=== Online Textbooks ===
'''Endocrinology: An Integrated Approach''' Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=endocrin.TOC&depth=1 table of Contents]

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.235 The Thyroid Gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.364 Hypothyroidism in infancy and childhood]

'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Endocrine]

'''Developmental Biology''' (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5434#5437 Is the endostyle the precursor of the thyroid gland?]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5198#5206 Environmental thyroid hormone disruptors]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.table.3110 table 13.1. Some derivatives of the neural crest]

'''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

* [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.table.2803 table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP]

'''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books&cmd=search&doptcmdl=TOCView&term=thyroid+development+AND+hstat%5Bbook%5D Thyroid Gland search Results]

===Reviews===
<pubmed>12432093</pubmed>
<pubmed>15863666</pubmed>
<pubmed>15231702</pubmed>
<pubmed>12566717</pubmed>

===Articles===
<pubmed>20976176</pubmed>
<pubmed>16093324</pubmed>
<pubmed>10902817</pubmed>

===Search PubMed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=thyroid%20development thyroid development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Congenital%20Hypothyroidism Congenital Hypothyroidism]

==Additional Images==
<gallery>
File:Minot1897 436.jpg|1897 Minot Fig 436 Pig thyroid
File:Minot1897 437.jpg|1897 Minot Fig 437 Human thyroid
File:Sudler1902-fig03.jpg|1902 Sudler Fig 3 Human pharynx
File:Sudler1902-fig04.jpg|1902 Sudler Fig 4 Human pharynx
File:Keith1902 fig030.jpg|1902 Keith Fig 30
Gray1174.jpg|1918 Gray Fig 1174
</gallery>
==Terms==

== External Links ==
{{External Links}}

* [http://www.iccidd.org/ International Council for the Control of Iodine Deficiency Disorders]
* [http://www.who.int/nut/idd.htm World Health Organization- Micronutrient deficiencies Eliminating iodine deficiency disorders]
* [http://www.british-thyroid-association.org/ British Thyroid Association] The official site of the British Thyroid Assocation, a non-profit making Learned Society of professional clinical specialist doctors and scientists in the United Kingdom who manage patients with thyroid disease and/or are researching into the thyroid and its diseases in humans.
* [http://w3.whosea.org/techinfo/nutri.htm#Iodine WHO Nutrition Guidelines]
* [http://www.thyroid.org/ American Thyroid Association] [http://www.thyroid.org/patients/index.html%20 American Thyroid Association - Patient Information]
* [http://www.clark.net/pub/tfa/index.html Thyroid Foundation of America]
* [http://www.endo-society.org/ Endocrine Society (USA)]
* [http://www.eurothyroid.com/ European Thyroid Association]
* [http://www.lats.org/ Latin-American Thyroid Association]
* [www.aota.or.kr Asia and Oceana Thyroid Association]
* [http://www.endocrinology.org/ Society for Endocrinology (UK)]
* [http://www.BAES.org/ British Association of Endocrine Surgeons]
* [www.aace.com American Association of Clinical Endocrinologists]
* [http://www.thyroidmanager.org/ Thyroid Disease Manager USA] -- this site includes textbook on the Thyroid.
* [www.synthroid.com Knoll Pharmaceuticals]- makers of SYNTHROID
* Gray's Anatomy - [http://www.bartleby.com/107/272.html The Ductless Glands] | [http://www.bartleby.com/107/Images/large/image1174.gif The thyroid gland and its relations] | [http://www.bartleby.com/107/Images/large/image979.gif Floor of pharynx of human embryo about twenty-six days old. ](From model by Peters) | [http://www.bartleby.com/107/273.html 4b. The Parathyroid Glands]

{{Glossary}}

{{Footer}}

[[Category:Endocrine]] [[Category:Thyroid]]

Endocrine - Thyroid Development

2016-11-07T20:01:45Z

Z3486783:

{{Header}}
==Introduction==
[[File:Pharyngeal_pouches.jpg|thumb|Embryonic origins of the endocrine organs of the neck]]
The boundary endoderm in the floor region forms a pocket (marked by the foramen cecum) that separates from the surface and forms the thyroid. Cells originate on the surface of the floor and descend into mesoderm above aortic sac and into the hypopharyngeal eminence as "cords". These cells continue to descend until they reach their final destination in the neck adjacent to the thyroid cartilage.

This pathway forms a temporary duct (thyroglossal duct). There are abnormalities of incomplete or excessive descent of these thyroid precursor cells. The thyroid is one of the earliest endocrine organs to differentiate and has an important hormonal role in embryonic development. The early bundle of cells then forms the thyroid by first dividing to form 2 lobes separated by a narrow connecting isthmus..

* '''Maternal thyroid hormone''' - required for early stages of brain development ([[#Maternal Thyroid|Maternal Thyroid]] recent studies show both high and low thyroid hormone impact)
* '''Fetal functions from week 10''' - required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)
* '''Fetal fully functional 16 - 18 weeks''' - ({{GA}} 18-20 weeks)
* '''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)
.

[[#Maternal Thyroid|Maternal thyroid]] function also changes in early pregnancy, through pituitary changes, resulting in thyroid stimulating hormone (TSH) levels decreasing during the transition from pre-pregnancy to early pregnancy.<ref><pubmed>22436200</pubmed></ref> This change in TSH was less predictable in women with thyroid antibodies. Maternal thyroid hormone crosses the placenta.<ref name=PMID17574007><pubmed>17574007</pubmed></ref>

Hyperthyroidism in adults is generally treated with antithyroid drugs (ATDs), some of these drugs have been identified as teratogens during pregnancy. (More? [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|Antithyroid Drugs]])

Iodine deficiency disorders (IDD) is the single most common cause of preventable mental retardation and brain damage in the world. Iodine (Greek, ioeides = violet) is required for the synthesis of thyroid hormone, a key regulator of neurological development. IDD causes goiters and decreases the production of hormones vital to growth and development. (More? [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]])

{{Endocrine Links}} | [[Lecture - Head Development]] | [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]] | [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|AbnormalDevelopment - Antithyroid Drugs]]

==Some Recent Findings==
[[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
{|
|-bgcolor="F5FAFF"
|
* '''Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembl'''y<ref name=PMID27068110><pubmed>27068110</pubmed></ref> "Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes."
* '''Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections'''<ref name=PMID25458181><pubmed>25458181</pubmed></ref> "To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross-sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. ...Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae."
* '''Early thyroid development requires a Tbx1-Fgf8 pathway'''<ref><pubmed>19389367</pubmed></ref>"The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. ... a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid."

* '''Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.'''<ref><pubmed>19088150</pubmed></ref> "The World Health Organization (WHO) recently increased their recommended iodine intake during pregnancy from 200 to 250 microg/d and suggested that a median urinary iodine (UI) concentration of 150-249 microg/L indicates adequate iodine intake in pregnant women. Thyrotropin concentrations in blood collected from newborns 3-4 d after birth may be a sensitive indicator of even mild iodine deficiency during late pregnancy; a <3% frequency of thyrotropin values >5 mU/L indicates iodine sufficiency."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: ''Thyroid Embryology''

<pubmed limit=5>Thyroid Embryology</pubmed>
|}
== Reading ==
* '''Human Embryology '''(2nd ed.) Larson
* '''The Developing Human: Clinically Oriented Embryology '''(6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347
* Before We Are Born (5th ed.) Moore and Persaud
* Essentials of Human Embryology Larson
* Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

{| class="wikitable mw-collapsible mw-collapsed"
! Thyroid
|-
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| '''Endocrinology - An Integrated Approach''' Stephen Nussey and Saffron Whitehead

St. George's Hospital Medical School, London, UK Oxford: BIOS Scientific Publishers; 2001. ISBN-10: 1-85996-252-1

Copyright © 2001, BIOS Scientific Publishers Limited. [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf]
|-
| colspan=2|[http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A246 Iodine intake]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A248 Anatomical features of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A249 Iodine trapping and thyroid function]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A278 Synthesis of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A280 Actions of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A289 Control of thyroid hormone synthesis and secretion]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A292 Hyperthyroidism — Graves' disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A332 Primary hypothyroidism — Hashimoto's disease and myxedema]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A362 Secondary hypothyroidism]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A364 Hypothyroidism in infancy and childhood]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A375 Thyroid hormone resistance]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A376 Non-thyroid illness (‘sick euthyroid’ syndrome)]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A393 Transport and metabolism of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A394 Biochemical measurements of thyroid hormone status]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A399 Thyroid growth]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A400 Nodular thyroid disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A402 Thyroid cancer]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A435 Clinical case questions]
|}

==Development Overview==
{|
| [[File:Tongue1.png|foramen caecum|300px]]
| [[File:Stage13 and 22 thyroid development a.jpg|600px|Stage 13 and Stage 22 thyroid development]]
|-
| Foramen Caecum
| Stage 13 and Stage 22 thyroid development
|}
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg thyroglossal duct]
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus

==Thyroid Timeline==
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis growth factors (insulin-like, epidermal) stimulates follicular growth

===Stage 13===

[[File:Stage 13 image 058.jpg|400px]] [[File:Stage 13 image 058.jpg|400px]]

:'''Links:''' [[Carnegie_stage_13_-_serial_sections|Stage 13 Sections]] | [[Carnegie stage 13]]

===Stage 22===
[[File:Stage 22 image 068.jpg|400px]] [[File:Stage 22 image 166.jpg|400px]]

:'''Links:''' [[Carnegie_stage_22_-_serial_sections|Stage 22 Sections]] | [[Carnegie stage 22]]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|600px]]

:'''Links:''' [[Neural System Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]]

==Fetal Thyroid Hormone==
[[File:Pituitary thyroid pathway.jpg|thumb|Endocrine Pituitary-Thyroid Pathway]]
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

== Thyroid Hormone ==
Thyroid hormone is synthesized in the thyroid gland by the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin.

{| width="600px"
| [[File:Thyroxine.jpg|300px]]

'''Thyroxine''' (T4) molecular structure showing iodine positions (red rings).
| [[File:Triiodothyronine.jpg|300px]]

'''Triiodothyronine''' (T3)
|-
| '''Thyroxine''' (T4) - (Mr 777) majority of thyroid hormone derived from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.
| '''Triiodothyronine''' (T3) - synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4), though T3 is mainly used by tissues. Derived mainly from peripheral monodeiodination of T4 (at the 5' position of the outer ring of the iodothyronine nucleus).
|}
[[File:HPT_axis.jpg|300px]]

===Deiodinases===
{|
| A group of enzymes that can modify the thyroid prohormone secreted by the thyroid gland either activating ([[D#deiodinase 2|deiodinase 2]]) or deactivating ([[D#deiodinase 3|deiodinase 3]]) thyroid hormone. Their role is thought to regulate the amount of active hormone available locally in a tissue.

'''Deiodinase 2'''
* (Dio2) A [[D#deiodinase|deiodinating enzyme]] that activates thyroid hormone by clipping the 5'-iodine off of the T4 prohormone to create T3, which is the preferred ligand for thyroid receptors. The enzyme has 5'- outer ring (5'-) catalytic activity.

'''Deiodinase 3'''
* (Dio3) A [[D#deiodinase|deiodinating enzyme]] that inactivates thyroid hormone by removing the 5-iodine from either the T4 prohormone or the T3 active hormone. The enzyme has 5- inner ring (5-) catalytic activity.

| [[File:Thyroid hormone homeostasis.jpg|300px]]

Thyroid hormone homeostasis
|}
'''Links:''' [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5819 PubChem - T4] | [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5920 PubChem - T3]

==Calcitonin==
Calcitonin is synthesized by parafollicular cells (C cells) interspersed in the connective tissue between the follicles and the blood capillary network.<ref name=PMID18012><pubmed>18012</pubmed></ref>

==Maternal Thyroid==
Maternal thyroid related changes during pregnancy<ref><pubmed>10447005</pubmed></ref>:
* stimulation of maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG)
* occurs mainly near end of first trimester associated with a transient lowering in serum TSH
* increase in serum thyroxine-binding globulin levels
* small decrease in free hormone concentrations (in iodine-sufficient conditions) significantly amplified in iodine restriction or overt iodine deficiency
* trend toward a slight increase in basal thyrotropin (TSH) values between first trimester and term
* modifications of the peripheral metabolism of maternal thyroid hormones

Maternal thyroid hormone crosses the placenta possibly by 3 transport protein family mechanisms<ref name=PMID17574007><pubmed>17574007</pubmed></ref>
# thyoorganic anion-transporting polypeptide
# L-type amino acid transporter
# monocarboxylate transporter

A recent study has identified an association of maternal thyroid function during early pregnancy with child brain morphology and IQ<ref name="PMID26497402"><pubmed>26497402</pubmed></ref>

* Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume
• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume
• Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology

In the placenta, the inner ring placental deiodinase inactivates most of the maternal T4 to reverse T3 (rT3). During fetal development to term, up to 30% of the fetal thyroid hormones are of maternal origin.

==Abnormalities==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>]]
There are structural anatomical variations and thyroid under and over development, there are a number of abnormalities associated with the persistence of the embryological path of thyroid cell descent, the thyroglossal duct.

In addition there are abnormalities due to low iodine environmental conditions of growth and development. This has subsequent effects upon neural and renal development.

===Lingual thyroid gland===
The failure of thyroid descent.

{|
| [[File:Ectopic thyroid - lingual 01.jpg|300px]]
| [[File:Ectopic_thyroid_-_sublingual,_suprahyoid_and_subhyoid.jpg|sublingual, suprahyoid and subhyoid|250px]]
| [[File:Ectopic thyroid - sublingual and suprahyoid.jpg|sublingual and suprahyoid|250px]]
|-
| '''Ectopic thyroid - lingual'''<ref><pubmed>21765986</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134180 PMC3134180]</ref>
| Sublingual, suprahyoid and subhyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
| Sublingual and suprahyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
|}

===Thyroglossal Cyst===
The persistence of the thyroglossal duct.

===Thyroglossal fistula===
The partial degeneration of the thyroglossal duct.

===Abnormal development of the thyroid===

Incomplete or excessive descent.

===Pyramidal Lobe===
{|
| [[File:Thyroid_pyramidal_lobe.jpg|200px|Thyroid pyramidal lobe]]
|

This additional lobe is formed from the isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
|}
===Agenesis of Isthmus===
{|
| [[File:Thyroid-agenesis of isthmus.jpg|200px|Thyroid agenesis of isthmus<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>]]
| An absence of the isthmus with the lateral lobes positioned independently on either side of the trachea. The normal isthmus measures about 1.25 cm transversely as well as vertically and is located anterior to the second and third tracheal cartilages.<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>
|}

=== Congenital Hypothyroidism ===
[[File:Congenital hypothyroidism.jpg|thumb|Infant with congenital hypothyroidism<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>]]
[[File:Human thyroid system and neural development.jpg|thumb|Human thyroid system and neural development]]
Occurs approximately 1 in 3000 births, associated with neurological abnormalities. This abnormality can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. The condition can be classified as a permanent and transient form.

'''American Academy of Pediatrics 2006''' - Update of newborn screening and therapy for congenital hypothyroidism<ref><pubmed>16740880</pubmed></ref> "Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis."

===Congenital Hypothyroidism Classification===
{|
|-bgcolor="CEDFF2"
| width=150px|'''Classification'''
| '''Etiology'''
|-
| Primary
| Thyroid dysgenesis (developmental anomaly)

Thyroid dyshormonogenesis (impaired hormone production)

Resistance to TSH binding or signaling
|-bgcolor="F5FAFF"
| Central
| Isolated TSH deficiency

Thyrotropin-releasing hormone deficiency

Thyrotropin-releasing hormone resistance

Deficiency in pituitary development transcription factors
|-
| Peripheral
| Resistance to thyroid hormone

Abnormalities of thyroid hormone transport

|-bgcolor="F5FAFF"
| Syndromic
| Pendred syndrome

Bamforth-Lazarus syndrome

Ectodermal dysplasia

Hypothyroidism

Kocher - Deber - Semilange syndrome

Benign chorea - hypothyroidism

Choreoathetosis

Obesity - colitis
|-
| Transient
| Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma
|-bgcolor="F5FAFF"
|
| Based on Table 3 from review on congenital hypothyroidism.<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>
|}

==Iodine Deficiency==
Iodine deficiency disorder (IDD) is the single most common cause of preventable mental retardation and brain damage in the world (More? Abnormal Development - Iodine Deficiency). It is required for synthesis of thyroid hormone, which in turn regulates aspects of neural development.

Worldwide:

1.6 billion people are at risk
IDD affects 50 million children
100,000 cretins are born every year
It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women cause miscarriage, stillbirth and mentally retarded children.

A teaspoon of iodine is all a person requires in a lifetime, but because iodine cannot be stored for long periods by the body, tiny amounts are needed regularly. In areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace, food fortification and supplementation have proven highly successful and sustainable interventions.

Iodized salt programs and iodized oil supplements are the most common tools in the fight against IDD.

(Data: ICCIDD)

Prolonged intake of large amounts (excess) of iodide can increase the incidence of goiter and/or hypothyroidism in humans. African Congo appears to be the only country that appears to have a dietary excess.

:'''Links:''' [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]]

== Maternal Abnormalities ==
[[File:Thyroid_uptake_scans_.jpg|400px|left]]

Thyroid uptake scan images of normal and abnormal thyroids
'''(A)''' Normal

'''(B)''' Graves disease: diffuse increased uptake in both thyroid lobes.

'''(C)''' Toxic multinodular goiter (TMNG): "hot" and "cold" areas of uneven uptake.

'''(D)''' Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid.

'''(E)''' Thyroiditis: decreased or absent uptake.

Thyroid uptake scans image<ref><pubmed>16363909</pubmed></ref> Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy."

Graves' disease in mothers can cause '''thyrotoxic fetus''' - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

'''Maternal Hashimoto's Thyroiditis''' (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

'''Links:''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 NIH Genes & Disease - Chapter 41 - Endocrine] | [http://www.epa.gov/radiation/radionuclides/technetium.htm EPA (USA) - Radiation Technetium]

== Environmental Thyroid Disruptors ==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>
]]
There are several environmental compounds (chemicals) that are suspected of being thyroid disruptors including:

* halogenated phenolic compounds (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl)
* phenol compounds (pentachlorophenol, 2,4,6-triiodophenol)

They have been demonstrated to induce partial agonistic and/or complex competitive/uncompetitive antagonistic responces in cell culture.

Bisphenol A - monomer used to manufacture polycarbonate plastic, possibly disrupts thyroid hormone function and affects neocortical development (accelerating neuronal differentiation/migration). (More? [http://www.ehponline.org/members/2005/7713/7713.html EHP - Bisphenol A Need for a New Risk Assessment])

== Genes ==
[[File:Mouse_E14.5_Titf1_gene_expression.jpg|thumb|Mouse (E14.5) Titf1 gene expression<ref><pubmed>21267068</pubmed>| [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000582 PLoS Biol.] | [http://www.eurexpress.org Eurexpress transcriptome atlas]</ref>]]
* Thyroid Transcriptor Factors (TTF) - TTF-1, TTF-2, PAX-8
* Fetal hypothyroidism from low levels of these transcription factors- Pit-1, Prop-1, LHX-3
* Thyrotropin-releasing hormone (TRH)
* Thyroid-stimulating hormone (TSH)

[[File:Mouse thyroid Hes1 model.jpg]]

'''Mouse thyroid Hes1 model'''<ref><pubmed>21364918</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752 PLoS One.]</ref>

==Thyroid Images==
===Adult Histology===
<gallery>
File:Thyroid_histology_001.jpg|Adult Thyroid (low power)
File:Thyroid_histology_002.jpg|Adult Thyroid (high power)
File:Parathyroid_histology_001.jpg|Adult Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Adult Parathyroid (high power)
</gallery>

===Anatomy===
<gallery>
File:Gray1174.jpg|The thyroid gland and its relations
</gallery>

== References ==
<references/>

=== Journals ===
* '''Thyroid''' [http://www.liebertpub.com/publication.aspx?pub_id=55 Thyroid] The official journal of the [http://www.thyroid.org/ American Thyroid Association].

=== Online Textbooks ===
'''Endocrinology: An Integrated Approach''' Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=endocrin.TOC&depth=1 table of Contents]

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.235 The Thyroid Gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.364 Hypothyroidism in infancy and childhood]

'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Endocrine]

'''Developmental Biology''' (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5434#5437 Is the endostyle the precursor of the thyroid gland?]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5198#5206 Environmental thyroid hormone disruptors]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.table.3110 table 13.1. Some derivatives of the neural crest]

'''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

* [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.table.2803 table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP]

'''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books&cmd=search&doptcmdl=TOCView&term=thyroid+development+AND+hstat%5Bbook%5D Thyroid Gland search Results]

===Reviews===
<pubmed>12432093</pubmed>
<pubmed>15863666</pubmed>
<pubmed>15231702</pubmed>
<pubmed>12566717</pubmed>

===Articles===
<pubmed>20976176</pubmed>
<pubmed>16093324</pubmed>
<pubmed>10902817</pubmed>

===Search PubMed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=thyroid%20development thyroid development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Congenital%20Hypothyroidism Congenital Hypothyroidism]

==Additional Images==
<gallery>
File:Minot1897 436.jpg|1897 Minot Fig 436 Pig thyroid
File:Minot1897 437.jpg|1897 Minot Fig 437 Human thyroid
File:Sudler1902-fig03.jpg|1902 Sudler Fig 3 Human pharynx
File:Sudler1902-fig04.jpg|1902 Sudler Fig 4 Human pharynx
File:Keith1902 fig030.jpg|1902 Keith Fig 30
Gray1174.jpg|1918 Gray Fig 1174
</gallery>
==Terms==

== External Links ==
{{External Links}}

* [http://www.iccidd.org/ International Council for the Control of Iodine Deficiency Disorders]
* [http://www.who.int/nut/idd.htm World Health Organization- Micronutrient deficiencies Eliminating iodine deficiency disorders]
* [http://www.british-thyroid-association.org/ British Thyroid Association] The official site of the British Thyroid Assocation, a non-profit making Learned Society of professional clinical specialist doctors and scientists in the United Kingdom who manage patients with thyroid disease and/or are researching into the thyroid and its diseases in humans.
* [http://w3.whosea.org/techinfo/nutri.htm#Iodine WHO Nutrition Guidelines]
* [http://www.thyroid.org/ American Thyroid Association] [http://www.thyroid.org/patients/index.html%20 American Thyroid Association - Patient Information]
* [http://www.clark.net/pub/tfa/index.html Thyroid Foundation of America]
* [http://www.endo-society.org/ Endocrine Society (USA)]
* [http://www.eurothyroid.com/ European Thyroid Association]
* [http://www.lats.org/ Latin-American Thyroid Association]
* [www.aota.or.kr Asia and Oceana Thyroid Association]
* [http://www.endocrinology.org/ Society for Endocrinology (UK)]
* [http://www.BAES.org/ British Association of Endocrine Surgeons]
* [www.aace.com American Association of Clinical Endocrinologists]
* [http://www.thyroidmanager.org/ Thyroid Disease Manager USA] -- this site includes textbook on the Thyroid.
* [www.synthroid.com Knoll Pharmaceuticals]- makers of SYNTHROID
* Gray's Anatomy - [http://www.bartleby.com/107/272.html The Ductless Glands] | [http://www.bartleby.com/107/Images/large/image1174.gif The thyroid gland and its relations] | [http://www.bartleby.com/107/Images/large/image979.gif Floor of pharynx of human embryo about twenty-six days old. ](From model by Peters) | [http://www.bartleby.com/107/273.html 4b. The Parathyroid Glands]

{{Glossary}}

{{Footer}}

[[Category:Endocrine]] [[Category:Thyroid]]

Immune System Development

2016-11-07T11:10:56Z

Z3486783:

{{Header}}
==Introduction==
[[File:Lymphatic_vessel_development.jpg|thumb|alt=Lymphatic vessel development cartoon|Lymphatic vessel development<ref name=PMID19138383><pubmed>19138383</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646268 PMC2646268] | [http://genomebiology.com/2008/9/12/243 Genome Biology]</ref>]]

[[File:Stage 22 image 169.jpg|thumb|alt=Developing Human Thymus (Carnegie stage 22)|Developing Human Thymus ([[Carnegie stage 22|stage 22]])]]
Development of the immune system will also link to cardiovascular development notes (blood and vessel) and bone marrow development. Two organs which also relate to this system are the thymus and spleen, which have in the past been included in endocrine and gastrointestinal tract development respectively. There are now also movies showing lymphocyte (B and T cells) traffic within adult lymph nodes.

The maternal immune system also has specialised functions and cells associated with [[implantation]], [[Placenta Development|placenta development]] and pregnancy.

* '''During prenatal development''', maternal IgG antibodies are transferred from about {{GA}} week 13 from maternal blood across the placenta. Placenta syncytiotrophoblast cell endosomes bind IgG, in maternal blood lacunae, through neonatal Fc receptors.
* '''During early postnatal development''', maternal IgA, IgM, IgG antibodies are transferred from [[Normal_Development_-_Milk|breast milk]] into the infant gastrointestinal tract.
* '''During postnatal development''', the immune system matures..

{{Immune Links}}

==Some Recent Findings==
{|
|-bgcolor="F5FAFF"
|
* '''Tie1 is required for lymphatic valve and collecting vessel development'''<ref name=PMID25576926><pubmed>25576926</pubmed></ref> "Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. Reduction of Tie1 levels in mouse embryos with a hypomorphic Tie1 allele resulted in abnormal lymphatic patterning and architecture, decreased lymphatic draining efficiency, and ultimately, embryonic demise. ... Our findings reveal a fundamental role for Tie signaling during lymphatic vessel remodeling and valve morphogenesis and implicate it as a candidate gene involved in primary lymphedema."
* '''The Nobel Prize in Physiology or Medicine''' [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/ 2011] Bruce A. Beutler and Jules A. Hoffmann ''for their discoveries concerning the activation of innate immunity'' and the other half to Ralph M. Steinman ''for his discovery of the dendritic cell and its role in adaptive immunity''.
* '''Regulation of lymphatic-blood vessel separation by endothelial Rac1.'''<ref><pubmed>19906871</pubmed></ref> "Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown."
* '''The development of intestinal lymphoid tissues at the interface of self and microbiota'''<ref><pubmed>19741595</pubmed></ref> "(postnatal) Intestinal lymphoid tissues face the challenging task of inducing adaptive immunity to pathogens, yet maintaining homeostasis with the enormous commensal microbiota. To that aim, the ancient partnership between self and flora has resulted in the generation of a unique set of lymphoid tissues capable of constant large-scale reformatting. A first set of lymphoid tissues, the mesenteric lymph nodes and Peyer's patches, are programmed to develop in the sterile environment of the fetus, whereas a second set of lymphoid tissues, the tertiary lymphoid tissues, are induced to form by the microbiota and inflammation."
* '''Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways.'''<ref><pubmed>20231472</pubmed></ref>"Here, we show a similar divergence in human B-cell development pathways between the Pax5(+)TdT(-) pre/pro-B differentiation pathway that gives rise to infant B-lineage leukemias and the early-B pathway."
* '''Epithelial cells in fetal intestine produce chemerin to recruit macrophages.'''<ref><pubmed>19443732</pubmed></ref> "Macrophages are first seen in the fetal intestine at 11-12 wk and rapidly increase in number during the 12- to 22-wk period of gestation. The development of macrophage populations in the fetal intestine precedes the appearance of lymphocytes and neutrophils and does not require the presence of dietary or microbial antigens."
* '''Ontogeny of reticular framework of white pulp and marginal zone in human spleen: immunohistochemical studies of fetal spleens from the 17th to 40th week of gestation.''' <ref><pubmed>19255788</pubmed></ref> "The reticular framework of the periarteriolar lymphoid sheath (PALS), lymph follicle (LF), and marginal zone (MZ) is thus heterogeneous in the fetal spleen, and the development of the heterogeneity is related to the ontogeny of the PALS, LF, and MZ."

|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Immune+System+Development ''Immune System Development'']

<pubmed limit=5>Immune System Development</pubmed>
|}
== Spleen Development==

{| class="prettytable"
| [[File:Stage_13_image_074.jpg|300px]]
| The human spleen arises in week 5 within the [[D#dorsal mesogastrium|dorsal mesogastrium]] as proliferating [[M#mesenchyme|mesenchyme]] overlying the dorsal pancreatic endoderm. Cells required for its hemopoietic function arise from the yolk sac wall and near dorsal aorta.

The spleen generates both red and white cells in the 2nd trimester. Note that many embryonic RBCs remain nucleated.
|-
| [[:File:Stage_13_image_074.jpg|D4]] Dorsal Mesogastrium ([[Carnegie stage 13|stage 13)]]
|
|}

:'''Links:''' [[Cardiovascular_System_-_Spleen_Development|Spleen Development]]
==Thymus Development==

{| class="prettytable"
| [[File:Stage_22_image_071.jpg|alt=Embryonic thymus|300px]]
| The thymus has a key role in the development of an effective immune system as well as an endocrine function.
The thymus has two origins for the lymphoid thymocytes and the thymic epithelial cells. The thymic epithelium begins as two flask-shape endodermal diverticula that form from the third pharyngeal pouch and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta.
|-
| [[:File:Stage_22_image_071.jpg|D4]] Developing Thymus ([[Carnegie stage 22|stage 22)]]
|
|}

:'''Links:''' [[Thymus Development]]

==Lymph Node Development==

[[File:Lymph_node_cartoon_01.jpg|alt=Lymph node cartoon|300px]]

:'''Links:''' [[Lymph Node Development]]

==T Lymphocyte Development==

A study of cord blood from 19 early second and third trimester fetuses (GA 18-36 weeks) and 16 term newborns (GA 37-42 weeks).<ref><pubmed>12165087</pubmed></ref>
* Percentage of lymphocytes in fetal white blood cells was 79.3%, reducing to 40% by term birth
** higher than that of adults.
* Mononuclear cells (cord blood mononuclear cells (CBMC)
* fetal mononuclear cells were unable to produce IL-2, IL-4 or IFN-gamma.
* spontaneously secreted IL-10, IL-6 and TNF-alpha in vitro.
* fail to respond to mitogen (PHA) or allogeneic stimulation in vitro.
** Stimulation with PHA up-regulated the production of IL-10, IL-6 and TNF-alpha substantially.
**CD3+ T cells in fetal (40.1%) and neonatal (42.4%)
** lower than that of men (59.6%) and pregnant women (53.6%).
* CD8+ T cells (9.5%)
* gamma delta - T cells (0.5%)
* NK cells (4.8%)

==Gastrointestinal Tract==
Intraepithelial Lymphocytes

[[File:Intraepithelial lymphocyte differentiation 02.jpg|600px]]

Thymic and peripheral differentiation of natural and induced intraepithelial lymphocyte.<ref name=PMID21681197><pubmed>21681197</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140792 Nat Rev Immunol.]</ref>

See also [[:File:Intraepithelial lymphocyte differentiation 01.jpg|Intraepithelial lymphocyte differentiation]]

==Other Organs==

* '''Liver''' - The adult liver is a lymphoid organ with a predominantly innate immune system. NK cells are abundant in the normal liver (about one-third of intrahepatic lymphocytes), differs from other lymphoid organs and peripheral blood.

==Maternal Antibodies==

During prenatal development, maternal antibodies are transferred across the placenta to the fetus. Immunoglobulin G (IgG) is transferred across the syncytiotrophoblast cell layer is mediated by the Neonatal Fc receptor (FcRn). Once inside placental villi, immunoglobulins then need to enter fetal circulation by crossing the second cellular endothelial cell layer by an as yet unknown mechanism.

During postnatal development, maternal antibodies are transferred by maternal milk across the neonatal gastrointestinal tract epithelium by the Neonatal Fc receptor (FcRn).
(See Neonatal Fc receptor review<ref name=PMID25601863><pubmed25601863 </pubmed>| [http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00664/full Front Immunol.]</ref>)

:'''Links:''' [[Placenta Development]] | [[Normal_Development_-_Milk|Milk]]

==Additional Images==
<gallery>
File:Stage 22 image 169.jpg|Developing Human Thymus ([[Carnegie stage 22|stage 22]])
File:Stage_22_image_085.jpg|'''F1''' Developing Human Spleen ([[Carnegie stage 22|stage 22]])
File:Stage_22_image_086.jpg|'''F2''' Developing Human Spleen ([[Carnegie stage 22|stage 22]])
File:Stage_22_image_087.jpg|'''F3''' Developing Human Spleen ([[Carnegie stage 22|stage 22]])
File:Pharyngeal_pouches.jpg|Embryonic origins of the endocrine organs of the neck
File:Intraepithelial lymphocyte differentiation 03.jpg|IEL function
File:Intraepithelial lymphocyte differentiation 02.jpg|IEL differentiation
</gallery>

==Histology==

The images below are from adult immune Lymph Nodes.
<gallery>
File:Lymph_node_histology_01.jpg|Lymph Node - Subcapsular sinus = marginal sinus
File:Lymph_node_histology_02.jpg|Rabbit Lymph Node
File:Lymph_node_histology_03.jpg|Rabbit Lymph Node
File:Lymph_node_histology_04.jpg|Lymph Node - medullary sinuses and medullary cords
File:Lymph_node_histology_05.jpg|Lymph Node - high endothelial venules
File:Lymph_node_histology_06.jpg|Lymph Node - macrophages
</gallery>

==Immune Cells==

* Human natural killer cells (NK) - originate from CD34(+) hematopoietic progenitor cells.

===Adult Lymphocyte Histology===
{{Lymphocyte images}}

<gallery>
File:T_and_B_lymphocytes_EM09.jpg|T and B Lymphocytes TEM
File:T_and_B_lymphocytes_EM10.jpg|T and B Lymphocytes TEM
File:B lymphocytes EM08-10.jpg|B lymphocytes TEM
File:B lymphocyte EM08.jpg|B lymphocyte TEM
File:B lymphocyte EM09.jpg|B lymphocyte TEM
File:B lymphocyte EM10.jpg|B lymphocyte TEM
File:Lymphocyte rosettes EM012.jpg|B lymphocyte SEM
File:Plasma cell EM06.jpg|Plasma Cell TEM
File:T2 lymphocyte EM13.jpg|T2 Lymphocyte TEM
File:T2 lymphocyte EM14.jpg|T2 Lymphocyte TEM
File:Lymphocyte rosettes EM01-06.jpg|lymphocyte rosettes SEM
File:Lymphocyte rosettes EM01.jpg|T lymphocyte SEM
File:Lymphocyte rosettes EM02.jpg|T lymphocyte SEM
File:Lymphocyte rosettes EM03.jpg|T lymphocyte SEM
File:Lymphocyte rosettes EM04.jpg|T lymphocyte SEM
File:Lymphocyte rosettes EM05.jpg|T lymphocyte SEM
File:Lymphocyte rosettes EM06.jpg|T lymphocyte SEM
</gallery>

==Movies==
===Adult Lymphocyte Motility===
{{Adult Mouse Lymphocyte Motility movies}}

{{Thymus Movie 1}}
==References==

<references/>

===Reviews===
<pubmed>21071706</pubmed>
<pubmed>18946678</pubmed>
<pubmed>15804980</pubmed>
<pubmed>15376314</pubmed>
<pubmed>12669020</pubmed>

===Articles===

===Search Pubmed===

Search August 2010 "Immune System Development" All (90551) Review (15955) Free Full Text (28278)

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Immune%20System%20Development Immune System Development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=embryo%20Immune%20System%20Development Embryo Immune System Development]

==Terms==

{{Immune terms}}

{{Glossary}}

{{Footer}}

Endocrine - Thyroid Development

2016-11-07T10:15:35Z

Z3486783:

{{Header}}
==Introduction==
[[File:Pharyngeal_pouches.jpg|thumb|Embryonic origins of the endocrine organs of the neck]]
The boundary endoderm in the floor region forms a pocket (marked by the foramen cecum) that separates from the surface and forms the thyroid. Cells originate on the surface of the floor and descend into mesoderm above aortic sac and into the hypopharyngeal eminence as "cords". These cells continue to descend until they reach their final destination in the neck adjacent to the thyroid cartilage.

This pathway forms a temporary duct (thyroglossal duct). There are abnormalities of incomplete or excessive descent of these thyroid precursor cells. The thyroid is one of the earliest endocrine organs to differentiate and has an important hormonal role in embryonic development. The early bundle of cells then forms the thyroid by first dividing to form 2 lobes separated by a narrow connecting isthmus.

* '''Maternal thyroid hormone''' - required for early stages of brain development ([[#Maternal Thyroid|Maternal Thyroid]] recent studies show both high and low thyroid hormone impact)
* '''Fetal functions from week 10''' - required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)
* '''Fetal fully functional 16 - 18 weeks''' - ({{GA}} 18-20 weeks)
* '''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)
.

[[#Maternal Thyroid|Maternal thyroid]] function also changes in early pregnancy, through pituitary changes, resulting in thyroid stimulating hormone (TSH) levels decreasing during the transition from pre-pregnancy to early pregnancy.<ref><pubmed>22436200</pubmed></ref> This change in TSH was less predictable in women with thyroid antibodies. Maternal thyroid hormone crosses the placenta.<ref name=PMID17574007><pubmed>17574007</pubmed></ref>

Hyperthyroidism in adults is generally treated with antithyroid drugs (ATDs), some of these drugs have been identified as teratogens during pregnancy. (More? [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|Antithyroid Drugs]])

Iodine deficiency disorders (IDD) is the single most common cause of preventable mental retardation and brain damage in the world. Iodine (Greek, ioeides = violet) is required for the synthesis of thyroid hormone, a key regulator of neurological development. IDD causes goiters and decreases the production of hormones vital to growth and development. (More? [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]])

{{Endocrine Links}} | [[Lecture - Head Development]] | [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]] | [[Abnormal_Development_-_Drugs#Antithyroid_Drugs|AbnormalDevelopment - Antithyroid Drugs]]

==Some Recent Findings==
[[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
{|
|-bgcolor="F5FAFF"
|
* '''Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembl'''y<ref name=PMID27068110><pubmed>27068110</pubmed></ref> "Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes."
* '''Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections'''<ref name=PMID25458181><pubmed>25458181</pubmed></ref> "To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross-sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. ...Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae."
* '''Early thyroid development requires a Tbx1-Fgf8 pathway'''<ref><pubmed>19389367</pubmed></ref>"The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. ... a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid."

* '''Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.'''<ref><pubmed>19088150</pubmed></ref> "The World Health Organization (WHO) recently increased their recommended iodine intake during pregnancy from 200 to 250 microg/d and suggested that a median urinary iodine (UI) concentration of 150-249 microg/L indicates adequate iodine intake in pregnant women. Thyrotropin concentrations in blood collected from newborns 3-4 d after birth may be a sensitive indicator of even mild iodine deficiency during late pregnancy; a <3% frequency of thyrotropin values >5 mU/L indicates iodine sufficiency."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: ''Thyroid Embryology''

<pubmed limit=5>Thyroid Embryology</pubmed>
|}
== Reading ==
* '''Human Embryology '''(2nd ed.) Larson
* '''The Developing Human: Clinically Oriented Embryology '''(6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347
* Before We Are Born (5th ed.) Moore and Persaud
* Essentials of Human Embryology Larson
* Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

{| class="wikitable mw-collapsible mw-collapsed"
! Thyroid
|-
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| '''Endocrinology - An Integrated Approach''' Stephen Nussey and Saffron Whitehead

St. George's Hospital Medical School, London, UK Oxford: BIOS Scientific Publishers; 2001. ISBN-10: 1-85996-252-1

Copyright © 2001, BIOS Scientific Publishers Limited. [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf]
|-
| colspan=2|[http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A246 Iodine intake]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A248 Anatomical features of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A249 Iodine trapping and thyroid function]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A278 Synthesis of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A280 Actions of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A289 Control of thyroid hormone synthesis and secretion]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A292 Hyperthyroidism — Graves' disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A332 Primary hypothyroidism — Hashimoto's disease and myxedema]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A362 Secondary hypothyroidism]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A364 Hypothyroidism in infancy and childhood]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A375 Thyroid hormone resistance]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A376 Non-thyroid illness (‘sick euthyroid’ syndrome)]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A393 Transport and metabolism of thyroid hormones]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A394 Biochemical measurements of thyroid hormone status]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A399 Thyroid growth]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A400 Nodular thyroid disease]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A402 Thyroid cancer]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/#A435 Clinical case questions]
|}

==Development Overview==
{|
| [[File:Tongue1.png|foramen caecum|300px]]
| [[File:Stage13 and 22 thyroid development a.jpg|600px|Stage 13 and Stage 22 thyroid development]]
|-
| Foramen Caecum
| Stage 13 and Stage 22 thyroid development
|}
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg thyroglossal duct]
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus

==Thyroid Timeline==
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis growth factors (insulin-like, epidermal) stimulates follicular growth

===Stage 13===

[[File:Stage 13 image 058.jpg|400px]] [[File:Stage 13 image 058.jpg|400px]]

:'''Links:''' [[Carnegie_stage_13_-_serial_sections|Stage 13 Sections]] | [[Carnegie stage 13]]

===Stage 22===
[[File:Stage 22 image 068.jpg|400px]] [[File:Stage 22 image 166.jpg|400px]]

:'''Links:''' [[Carnegie_stage_22_-_serial_sections|Stage 22 Sections]] | [[Carnegie stage 22]]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|600px]]

:'''Links:''' [[Neural System Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]]

==Fetal Thyroid Hormone==
[[File:Pituitary thyroid pathway.jpg|thumb|Endocrine Pituitary-Thyroid Pathway]]
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

== Thyroid Hormone ==
Thyroid hormone is synthesized in the thyroid gland by the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin.

{| width="600px"
| [[File:Thyroxine.jpg|300px]]

'''Thyroxine''' (T4) molecular structure showing iodine positions (red rings).
| [[File:Triiodothyronine.jpg|300px]]

'''Triiodothyronine''' (T3)
|-
| '''Thyroxine''' (T4) - (Mr 777) majority of thyroid hormone derived from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.
| '''Triiodothyronine''' (T3) - synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4), though T3 is mainly used by tissues. Derived mainly from peripheral monodeiodination of T4 (at the 5' position of the outer ring of the iodothyronine nucleus).
|}
[[File:HPT_axis.jpg|300px]]

===Deiodinases===
{|
| A group of enzymes that can modify the thyroid prohormone secreted by the thyroid gland either activating ([[D#deiodinase 2|deiodinase 2]]) or deactivating ([[D#deiodinase 3|deiodinase 3]]) thyroid hormone. Their role is thought to regulate the amount of active hormone available locally in a tissue.

'''Deiodinase 2'''
* (Dio2) A [[D#deiodinase|deiodinating enzyme]] that activates thyroid hormone by clipping the 5'-iodine off of the T4 prohormone to create T3, which is the preferred ligand for thyroid receptors. The enzyme has 5'- outer ring (5'-) catalytic activity.

'''Deiodinase 3'''
* (Dio3) A [[D#deiodinase|deiodinating enzyme]] that inactivates thyroid hormone by removing the 5-iodine from either the T4 prohormone or the T3 active hormone. The enzyme has 5- inner ring (5-) catalytic activity.

| [[File:Thyroid hormone homeostasis.jpg|300px]]

Thyroid hormone homeostasis
|}
'''Links:''' [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5819 PubChem - T4] | [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5920 PubChem - T3]

==Calcitonin==
Calcitonin is synthesized by parafollicular cells (C cells) interspersed in the connective tissue between the follicles and the blood capillary network.<ref name=PMID18012><pubmed>18012</pubmed></ref>

==Maternal Thyroid==
Maternal thyroid related changes during pregnancy<ref><pubmed>10447005</pubmed></ref>:
* stimulation of maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG)
* occurs mainly near end of first trimester associated with a transient lowering in serum TSH
* increase in serum thyroxine-binding globulin levels
* small decrease in free hormone concentrations (in iodine-sufficient conditions) significantly amplified in iodine restriction or overt iodine deficiency
* trend toward a slight increase in basal thyrotropin (TSH) values between first trimester and term
* modifications of the peripheral metabolism of maternal thyroid hormones

Maternal thyroid hormone crosses the placenta possibly by 3 transport protein family mechanisms<ref name=PMID17574007><pubmed>17574007</pubmed></ref>
# thyoorganic anion-transporting polypeptide
# L-type amino acid transporter
# monocarboxylate transporter

A recent study has identified an association of maternal thyroid function during early pregnancy with child brain morphology and IQ<ref name="PMID26497402"><pubmed>26497402</pubmed></ref>

* Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume
• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume
• Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology

In the placenta, the inner ring placental deiodinase inactivates most of the maternal T4 to reverse T3 (rT3). During fetal development to term, up to 30% of the fetal thyroid hormones are of maternal origin.

==Abnormalities==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>]]
There are structural anatomical variations and thyroid under and over development, there are a number of abnormalities associated with the persistence of the embryological path of thyroid cell descent, the thyroglossal duct.

In addition there are abnormalities due to low iodine environmental conditions of growth and development. This has subsequent effects upon neural and renal development.

===Lingual thyroid gland===
The failure of thyroid descent.

{|
| [[File:Ectopic thyroid - lingual 01.jpg|300px]]
| [[File:Ectopic_thyroid_-_sublingual,_suprahyoid_and_subhyoid.jpg|sublingual, suprahyoid and subhyoid|250px]]
| [[File:Ectopic thyroid - sublingual and suprahyoid.jpg|sublingual and suprahyoid|250px]]
|-
| '''Ectopic thyroid - lingual'''<ref><pubmed>21765986</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134180 PMC3134180]</ref>
| Sublingual, suprahyoid and subhyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
| Sublingual and suprahyoid<ref name="PMID21713222"><pubmed>21713222</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109820 PMC3109820] | [http://www.ijnm.in/article.asp?issn=0972-3919;year=2010;volume=25;issue=4;spage=143;epage=146;aulast=Jain Indian J Nucl Med.]</ref>
|}

===Thyroglossal Cyst===
The persistence of the thyroglossal duct.

===Thyroglossal fistula===
The partial degeneration of the thyroglossal duct.

===Abnormal development of the thyroid===

Incomplete or excessive descent.

===Pyramidal Lobe===
{|
| [[File:Thyroid_pyramidal_lobe.jpg|200px|Thyroid pyramidal lobe]]
|

This additional lobe is formed from the isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
|}
===Agenesis of Isthmus===
{|
| [[File:Thyroid-agenesis of isthmus.jpg|200px|Thyroid agenesis of isthmus<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>]]
| An absence of the isthmus with the lateral lobes positioned independently on either side of the trachea. The normal isthmus measures about 1.25 cm transversely as well as vertically and is located anterior to the second and third tracheal cartilages.<ref name=PMID20181171"><pubmed>20181171</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827060 Cases J.]</ref>
|}

=== Congenital Hypothyroidism ===
[[File:Congenital hypothyroidism.jpg|thumb|Infant with congenital hypothyroidism<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>]]
[[File:Human thyroid system and neural development.jpg|thumb|Human thyroid system and neural development]]
Occurs approximately 1 in 3000 births, associated with neurological abnormalities. This abnormality can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. The condition can be classified as a permanent and transient form.

'''American Academy of Pediatrics 2006''' - Update of newborn screening and therapy for congenital hypothyroidism<ref><pubmed>16740880</pubmed></ref> "Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis."

===Congenital Hypothyroidism Classification===
{|
|-bgcolor="CEDFF2"
| width=150px|'''Classification'''
| '''Etiology'''
|-
| Primary
| Thyroid dysgenesis (developmental anomaly)

Thyroid dyshormonogenesis (impaired hormone production)

Resistance to TSH binding or signaling
|-bgcolor="F5FAFF"
| Central
| Isolated TSH deficiency

Thyrotropin-releasing hormone deficiency

Thyrotropin-releasing hormone resistance

Deficiency in pituitary development transcription factors
|-
| Peripheral
| Resistance to thyroid hormone

Abnormalities of thyroid hormone transport

|-bgcolor="F5FAFF"
| Syndromic
| Pendred syndrome

Bamforth-Lazarus syndrome

Ectodermal dysplasia

Hypothyroidism

Kocher - Deber - Semilange syndrome

Benign chorea - hypothyroidism

Choreoathetosis

Obesity - colitis
|-
| Transient
| Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma
|-bgcolor="F5FAFF"
|
| Based on Table 3 from review on congenital hypothyroidism.<ref><pubmed>20537182</pubmed>| [http://www.ojrd.com/content/5/1/17 Orphanet J Rare Dis.]</ref>
|}

==Iodine Deficiency==
Iodine deficiency disorder (IDD) is the single most common cause of preventable mental retardation and brain damage in the world (More? Abnormal Development - Iodine Deficiency). It is required for synthesis of thyroid hormone, which in turn regulates aspects of neural development.

Worldwide:

1.6 billion people are at risk
IDD affects 50 million children
100,000 cretins are born every year
It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women cause miscarriage, stillbirth and mentally retarded children.

A teaspoon of iodine is all a person requires in a lifetime, but because iodine cannot be stored for long periods by the body, tiny amounts are needed regularly. In areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace, food fortification and supplementation have proven highly successful and sustainable interventions.

Iodized salt programs and iodized oil supplements are the most common tools in the fight against IDD.

(Data: ICCIDD)

Prolonged intake of large amounts (excess) of iodide can increase the incidence of goiter and/or hypothyroidism in humans. African Congo appears to be the only country that appears to have a dietary excess.

:'''Links:''' [[Abnormal Development - Iodine Deficiency|Iodine Deficiency]]

== Maternal Abnormalities ==
[[File:Thyroid_uptake_scans_.jpg|400px|left]]

Thyroid uptake scan images of normal and abnormal thyroids
'''(A)''' Normal

'''(B)''' Graves disease: diffuse increased uptake in both thyroid lobes.

'''(C)''' Toxic multinodular goiter (TMNG): "hot" and "cold" areas of uneven uptake.

'''(D)''' Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid.

'''(E)''' Thyroiditis: decreased or absent uptake.

Thyroid uptake scans image<ref><pubmed>16363909</pubmed></ref> Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy."

Graves' disease in mothers can cause '''thyrotoxic fetus''' - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

'''Maternal Hashimoto's Thyroiditis''' (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

'''Links:''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 NIH Genes & Disease - Chapter 41 - Endocrine] | [http://www.epa.gov/radiation/radionuclides/technetium.htm EPA (USA) - Radiation Technetium]

== Environmental Thyroid Disruptors ==
[[File:Thyroid_hormone_homeostasis.jpg|thumb|Thyroid hormone homeostasis and disruptors.<ref name="PMID21918727"><pubmed>21918727</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170895 PMC3170895]</ref>
]]
There are several environmental compounds (chemicals) that are suspected of being thyroid disruptors including:

* halogenated phenolic compounds (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl)
* phenol compounds (pentachlorophenol, 2,4,6-triiodophenol)

They have been demonstrated to induce partial agonistic and/or complex competitive/uncompetitive antagonistic responces in cell culture.

Bisphenol A - monomer used to manufacture polycarbonate plastic, possibly disrupts thyroid hormone function and affects neocortical development (accelerating neuronal differentiation/migration). (More? [http://www.ehponline.org/members/2005/7713/7713.html EHP - Bisphenol A Need for a New Risk Assessment])

== Genes ==
[[File:Mouse_E14.5_Titf1_gene_expression.jpg|thumb|Mouse (E14.5) Titf1 gene expression<ref><pubmed>21267068</pubmed>| [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000582 PLoS Biol.] | [http://www.eurexpress.org Eurexpress transcriptome atlas]</ref>]]
* Thyroid Transcriptor Factors (TTF) - TTF-1, TTF-2, PAX-8
* Fetal hypothyroidism from low levels of these transcription factors- Pit-1, Prop-1, LHX-3
* Thyrotropin-releasing hormone (TRH)
* Thyroid-stimulating hormone (TSH)

[[File:Mouse thyroid Hes1 model.jpg]]

'''Mouse thyroid Hes1 model'''<ref><pubmed>21364918</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752 PLoS One.]</ref>

==Thyroid Images==
===Adult Histology===
<gallery>
File:Thyroid_histology_001.jpg|Adult Thyroid (low power)
File:Thyroid_histology_002.jpg|Adult Thyroid (high power)
File:Parathyroid_histology_001.jpg|Adult Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Adult Parathyroid (high power)
</gallery>

===Anatomy===
<gallery>
File:Gray1174.jpg|The thyroid gland and its relations
</gallery>

== References ==
<references/>

=== Journals ===
* '''Thyroid''' [http://www.liebertpub.com/publication.aspx?pub_id=55 Thyroid] The official journal of the [http://www.thyroid.org/ American Thyroid Association].

=== Online Textbooks ===
'''Endocrinology: An Integrated Approach''' Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=endocrin.TOC&depth=1 table of Contents]

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.235 The Thyroid Gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.329 Surgical anatomy and embryology of the thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.364 Hypothyroidism in infancy and childhood]

'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Endocrine]

'''Developmental Biology''' (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5434#5437 Is the endostyle the precursor of the thyroid gland?]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.box.5198#5206 Environmental thyroid hormone disruptors]
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.table.3110 table 13.1. Some derivatives of the neural crest]

'''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

* [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.table.2803 table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP]

'''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books&cmd=search&doptcmdl=TOCView&term=thyroid+development+AND+hstat%5Bbook%5D Thyroid Gland search Results]

===Reviews===
<pubmed>12432093</pubmed>
<pubmed>15863666</pubmed>
<pubmed>15231702</pubmed>
<pubmed>12566717</pubmed>

===Articles===
<pubmed>20976176</pubmed>
<pubmed>16093324</pubmed>
<pubmed>10902817</pubmed>

===Search PubMed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=thyroid%20development thyroid development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Congenital%20Hypothyroidism Congenital Hypothyroidism]

==Additional Images==
<gallery>
File:Minot1897 436.jpg|1897 Minot Fig 436 Pig thyroid
File:Minot1897 437.jpg|1897 Minot Fig 437 Human thyroid
File:Sudler1902-fig03.jpg|1902 Sudler Fig 3 Human pharynx
File:Sudler1902-fig04.jpg|1902 Sudler Fig 4 Human pharynx
File:Keith1902 fig030.jpg|1902 Keith Fig 30
Gray1174.jpg|1918 Gray Fig 1174
</gallery>
==Terms==

== External Links ==
{{External Links}}

* [http://www.iccidd.org/ International Council for the Control of Iodine Deficiency Disorders]
* [http://www.who.int/nut/idd.htm World Health Organization- Micronutrient deficiencies Eliminating iodine deficiency disorders]
* [http://www.british-thyroid-association.org/ British Thyroid Association] The official site of the British Thyroid Assocation, a non-profit making Learned Society of professional clinical specialist doctors and scientists in the United Kingdom who manage patients with thyroid disease and/or are researching into the thyroid and its diseases in humans.
* [http://w3.whosea.org/techinfo/nutri.htm#Iodine WHO Nutrition Guidelines]
* [http://www.thyroid.org/ American Thyroid Association] [http://www.thyroid.org/patients/index.html%20 American Thyroid Association - Patient Information]
* [http://www.clark.net/pub/tfa/index.html Thyroid Foundation of America]
* [http://www.endo-society.org/ Endocrine Society (USA)]
* [http://www.eurothyroid.com/ European Thyroid Association]
* [http://www.lats.org/ Latin-American Thyroid Association]
* [www.aota.or.kr Asia and Oceana Thyroid Association]
* [http://www.endocrinology.org/ Society for Endocrinology (UK)]
* [http://www.BAES.org/ British Association of Endocrine Surgeons]
* [www.aace.com American Association of Clinical Endocrinologists]
* [http://www.thyroidmanager.org/ Thyroid Disease Manager USA] -- this site includes textbook on the Thyroid.
* [www.synthroid.com Knoll Pharmaceuticals]- makers of SYNTHROID
* Gray's Anatomy - [http://www.bartleby.com/107/272.html The Ductless Glands] | [http://www.bartleby.com/107/Images/large/image1174.gif The thyroid gland and its relations] | [http://www.bartleby.com/107/Images/large/image979.gif Floor of pharynx of human embryo about twenty-six days old. ](From model by Peters) | [http://www.bartleby.com/107/273.html 4b. The Parathyroid Glands]

{{Glossary}}

{{Footer}}

[[Category:Endocrine]] [[Category:Thyroid]]

MediaWiki:Sidebar

2016-04-05T04:05:26Z

Z3486783: Undo revision 222315 by Z3486783 (talk)

MediaWiki:Sidebar

2016-04-05T04:04:48Z

Z3486783:

RichardTest

2016-02-23T01:11:57Z

Z3486783: Created page with "Test"

Test

Sandbox

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Z3486783:

Main Page

2015-04-04T06:40:46Z

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__NOTOC__
{|
| {{Header}}
|-
| <imagemap>Image:Front-page-image.jpg|thumb|left|500px|

rect 3 1 117 83 [[Reproductive_Cycles]]
rect 129 2 273 88 [[Fertilization]]
rect 279 2 501 131 [[Embryonic_Development]]
rect 328 136 499 276 [[Human_System_Development]]
rect 284 278 497 492 [[Fetal Development]]
rect 357 505 497 645 [[Human_Abnormal_Development]]
rect 131 519 353 644 [[Neonatal_Development]]
rect 0 521 124 647 [[Animal_Development]]

</imagemap>

[[File:Mark Hill.jpg‎|thumb|100px|Dr Mark Hill]]

{{CURRENTDAYNAME}} {{CURRENTMONTHNAME}} {{CURRENTDAY}} {{CURRENTYEAR}}
== Introduction ==
Welcome to the Embryology online education and research website. There are many ways to find what you are looking for. Click on the image term or use the lefthand menu items or use the search window at the top of the page.

{|
|-bgcolor="FAF5FF"
|
<big>[[Site Map]] - '''where''' the content is located</big>
|-bgcolor="F5FFFA"
|
<big>[[New]] - '''what''' is new on this Wiki</big>
|-bgcolor="F5FAFF"
|
<big>[[Contributors]] - '''who''' has contributed</big>
|}

'''Bookmark with:''' https://embryology.med.unsw.edu.au

[[File:facebook_32x32.png|link=http://www.facebook.com/sharer.php?u=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:delicious_32x32.png|link=http://del.icio.us/post?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:digg_32x32.png|link=http://digg.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:reddit_32x32.png|link=http://reddit.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:stumbleupon_32x32.png|link=http://www.stumbleupon.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:citeulike_32x32.png|link=http://www.citeulike.org/posturl?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]

{{Popular pages}}

Total number of views: '''{{NUMBEROFVIEWS}}'''

== Start Here ==
This is the [[Main_Page|Main Page]] of the website, clicking the top lefthand icon or the menu item will always bring you to here.

There are several different ways to find what you are looking for: click the [[#top|'''major topic''']] on the large left hand image, the [[Site Map|'''Site Map''']] also links to major topic sections, the [[:Special:Categories|'''Category''']] option will show related materials, or simply use the '''search''' box.
{|
| [[File:Chris.jpg|80px]]
| Designed to update the original UNSW Embryology website online since 1996. You should find this new site easier to navigate and search. I am always happy to receive [mailto:m.hill@unsw.edu.au feedback] on your learning experience.

Content has been derived under a number of different copyright restrictions, therefore do not assume that you can reuse content found on this current site without permission. Click on images and movies to get descriptions and full copyright information.
|}
|-
| <div id="News"></div>
{{Main Page News}}

{| class="wikitable mw-collapsible mw-collapsed"
! Author Comments
|-
| [[File:Mark_Hill.jpg|50px]]

Shown below is the original embryology main page content links, I removed this in the latest update to simplify the opening page appearance, but this also removed the google visibility.

== Human Embryology ==
[[File:Human Carnegie stage 1-23.jpg|thumb|Human Embryo, Carnegie stages 1-23]]
[[File:Stage14compare23.jpg|thumb|Human Embryo]]
* [[Reproductive Cycles]] - reproductive cycles of different species. [[:Category:Ovary|Category:Ovary]]
* [[Fertilization]] - the methods and events surrounding fertilization.
* [[Embryonic Development]] - in humans the first eight weeks of development. [[:Category:Human Embryo|Category:Human Embryo]]
* [[Fetal Development]] - in humans from week 9 to 36 of development. [[:Category:Human_Fetus|Category:Human Fetus]]
* [[Birth]] - the methods and events surrounding parturition or "birth". [[:Category:Birth|Category:Birth]]
* [[Timeline_human_development|Timeline]] - a general overview of human development.
* [[Prenatal Diagnosis]] - techniques to diagnose abnormal development. [[:Category:Prenatal_Diagnosis|Prenatal Diagnosis]]

== Movies ==
[[Movies]] There are many different animations showing developmental processes and research material [[Movies|Movies main page]] they currently being prepared in the MP4 format.

[[File:FlashVideo.jpg|90px|link= Flash Movies]] [[File:Quicktime-icon.jpg|90px|link=Movies]]

== Human System Development ==
* [[Human System Development]] - an introductory page describing the development of different systems and specialized organs. Use the links listed below to view specific topics.

{{Systems}}

== Human Neonatal ==
* [[Neonatal Development]] - the events of the first four weeks after birth (postnatal) of human development.

== Human Abnormal Development ==
* [[Human Abnormal Development]] - an introduction to the abnormalities of human development. [[:Category:Abnormal_Development|Category:Abnormal Development]]
* [[Prenatal Diagnosis]] - techniques to diagnose abnormal development. [[:Category:Prenatal_Diagnosis]]

Please note that abnormal development pages may contain clinical images not suitable for children.

== Class Notes ==

* [[Class Notes]] - a link to online undergraduate course materials.
** [[Medicine]] [[:Category:Medicine]]
** [[ANAT2341]] - the current undergraduate Science course in embryology. [[:Category:ANAT2341|Category:ANAT2341]]
* [[Embryology Textbooks]] - a list of textbooks generally designed for the undergraduate level.

==Animal Development==

* [[Animal Development]] - an introduction to the development in other species, including those that are used as research models of development.

==Textbooks/Journals ==
* [[Embryology Textbooks]] - a list of textbooks generally designed for the undergraduate level.
* [[Journals]] - embryology journals.
* RSS journal feeds - [http://dev.biologists.org/rss/current.xml Development] | [http://www3.interscience.wiley.com/rss/journal/38417 Developmental Dynamics] | [http://feeds2.feedburner.com/CellAndDevelopmentBiologyNews Cell And Development Biology News]
* [[Recent Papers]] - recent papers in embryology appearing in the journals.
* [[Embryology History]] - brief overview of some events in developmental history.

== Contributed Pages ==
* [[Contributed Pages]] - pages prepared by experts following a request to contribute. [[Contributors]] - who has contributed.
* [[Student Pages]] - pages prepared by students as part of their course work.
|}
|}
{{Glossary}}

{{Footer}}

[[File:ALTC_logo.jpg|250px|left]]

Main Page

2015-04-04T06:34:26Z

Z3486783:

__NOTOC__
{|
| {{Header}}
|-
| <imagemap>Image:Front-page-image.jpg|thumb|left|500px|

rect 3 1 117 83 [[Reproductive_Cycles]]
rect 129 2 273 88 [[Fertilization]]
rect 279 2 501 131 [[Embryonic_Development]]
rect 328 136 499 276 [[Human_System_Development]]
rect 284 278 497 492 [[Fetal Development]]
rect 357 505 497 645 [[Human_Abnormal_Development]]
rect 131 519 353 644 [[Neonatal_Development]]
rect 0 521 124 647 [[Animal_Development]]

</imagemap>

[[File:Mark Hill.jpg‎|thumb|100px|Dr Mark Hill]]

{{CURRENTDAYNAME}} {{CURRENTMONTHNAME}} {{CURRENTDAY}} {{CURRENTYEAR}}
== Introduction ==
Welcome to the Embryology online education and research website. There are many ways to find what you are looking for Click on the image term or use the lefthand menu items or use the search window at the top of the page.

{|
|-bgcolor="FAF5FF"
|
<big>[[Site Map]] - '''where''' the content is located</big>
|-bgcolor="F5FFFA"
|
<big>[[New]] - '''what''' is new on this Wiki</big>
|-bgcolor="F5FAFF"
|
<big>[[Contributors]] - '''who''' has contributed</big>
|}

'''Bookmark with:''' https://embryology.med.unsw.edu.au

[[File:facebook_32x32.png|link=http://www.facebook.com/sharer.php?u=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:delicious_32x32.png|link=http://del.icio.us/post?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:digg_32x32.png|link=http://digg.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:reddit_32x32.png|link=http://reddit.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:stumbleupon_32x32.png|link=http://www.stumbleupon.com/submit?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]
[[File:citeulike_32x32.png|link=http://www.citeulike.org/posturl?url=http://php.med.unsw.edu.au/embryology/index.php?title=Main_Page]]

{{Popular pages}}

Total number of views: '''{{NUMBEROFVIEWS}}'''

== Start Here ==
This is the [[Main_Page|Main Page]] of the website, clicking the top lefthand icon or the menu item will always bring you to here.

There are several different ways to find what you are looking for: click the [[#top|'''major topic''']] on the large left hand image, the [[Site Map|'''Site Map''']] also links to major topic sections, the [[:Special:Categories|'''Category''']] option will show related materials, or simply use the '''search''' box.
{|
| [[File:Chris.jpg|80px]]
| Designed to update the original UNSW Embryology website online since 1996. You should find this new site easier to navigate and search. I am always happy to receive [mailto:m.hill@unsw.edu.au feedback] on your learning experience.

Content has been derived under a number of different copyright restrictions, therefore do not assume that you can reuse content found on this current site without permission. Click on images and movies to get descriptions and full copyright information.
|}
|-
| <div id="News"></div>
{{Main Page News}}

{| class="wikitable mw-collapsible mw-collapsed"
! Author Comments
|-
| [[File:Mark_Hill.jpg|50px]]

Shown below is the original embryology main page content links, I removed this in the latest update to simplify the opening page appearance, but this also removed the google visibility.

== Human Embryology ==
[[File:Human Carnegie stage 1-23.jpg|thumb|Human Embryo, Carnegie stages 1-23]]
[[File:Stage14compare23.jpg|thumb|Human Embryo]]
* [[Reproductive Cycles]] - reproductive cycles of different species. [[:Category:Ovary|Category:Ovary]]
* [[Fertilization]] - the methods and events surrounding fertilization.
* [[Embryonic Development]] - in humans the first eight weeks of development. [[:Category:Human Embryo|Category:Human Embryo]]
* [[Fetal Development]] - in humans from week 9 to 36 of development. [[:Category:Human_Fetus|Category:Human Fetus]]
* [[Birth]] - the methods and events surrounding parturition or "birth". [[:Category:Birth|Category:Birth]]
* [[Timeline_human_development|Timeline]] - a general overview of human development.
* [[Prenatal Diagnosis]] - techniques to diagnose abnormal development. [[:Category:Prenatal_Diagnosis|Prenatal Diagnosis]]

== Movies ==
[[Movies]] There are many different animations showing developmental processes and research material [[Movies|Movies main page]] they currently being prepared in the MP4 format.

[[File:FlashVideo.jpg|90px|link= Flash Movies]] [[File:Quicktime-icon.jpg|90px|link=Movies]]

== Human System Development ==
* [[Human System Development]] - an introductory page describing the development of different systems and specialized organs. Use the links listed below to view specific topics.

{{Systems}}

== Human Neonatal ==
* [[Neonatal Development]] - the events of the first four weeks after birth (postnatal) of human development.

== Human Abnormal Development ==
* [[Human Abnormal Development]] - an introduction to the abnormalities of human development. [[:Category:Abnormal_Development|Category:Abnormal Development]]
* [[Prenatal Diagnosis]] - techniques to diagnose abnormal development. [[:Category:Prenatal_Diagnosis]]

Please note that abnormal development pages may contain clinical images not suitable for children.

== Class Notes ==

* [[Class Notes]] - a link to online undergraduate course materials.
** [[Medicine]] [[:Category:Medicine]]
** [[ANAT2341]] - the current undergraduate Science course in embryology. [[:Category:ANAT2341|Category:ANAT2341]]
* [[Embryology Textbooks]] - a list of textbooks generally designed for the undergraduate level.

==Animal Development==

* [[Animal Development]] - an introduction to the development in other species, including those that are used as research models of development.

==Textbooks/Journals ==
* [[Embryology Textbooks]] - a list of textbooks generally designed for the undergraduate level.
* [[Journals]] - embryology journals.
* RSS journal feeds - [http://dev.biologists.org/rss/current.xml Development] | [http://www3.interscience.wiley.com/rss/journal/38417 Developmental Dynamics] | [http://feeds2.feedburner.com/CellAndDevelopmentBiologyNews Cell And Development Biology News]
* [[Recent Papers]] - recent papers in embryology appearing in the journals.
* [[Embryology History]] - brief overview of some events in developmental history.

== Contributed Pages ==
* [[Contributed Pages]] - pages prepared by experts following a request to contribute. [[Contributors]] - who has contributed.
* [[Student Pages]] - pages prepared by students as part of their course work.
|}
|}
{{Glossary}}

{{Footer}}

[[File:ALTC_logo.jpg|250px|left]]

RG Test01

2014-10-29T03:37:24Z

Z3486783:

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer nec odio. Praesent libero. Sed cursus ante dapibus diam. Sed nisi. Nulla quis sem at nibh elementum imperdiet. Duis sagittis ipsum. Praesent mauris. Fusce nec tellus sed augue semper porta. Mauris massa. Vestibulum lacinia arcu eget nulla. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Curabitur sodales ligula in libero. Sed dignissim lacinia nunc. Curabitur tortor. Pellentesque nibh. Aenean quam. In scelerisque sem at dolor. Maecenas mattis. Sed convallis tristique sem. Proin ut ligula vel nunc egestas porttitor. Morbi lectus risus, iaculis vel, suscipit quis, luctus non, massa. Fusce ac turpis quis ligula lacinia aliquet. Mauris ipsum. Nulla metus metus, ullamcorper vel, tincidunt sed, euismod in, nibh. Quisque volutpat condimentum velit. Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Nam nec ante. Sed lacinia, urna non tincidunt mattis, tortor neque adipiscing diam, a cursus ipsum ante quis turpis. Nulla facilisi. Ut fringilla. Suspendisse potenti. Nunc feugiat mi a tellus consequat imperdiet. Vestibulum sapien. Proin quam. Etiam ultrices. Suspendisse in justo eu magna luctus suscipit. Sed lectus. Integer euismod lacus luctus magna. Quisque cursus, metus vitae pharetra auctor, sem massa mattis sem, at interdum magna augue eget diam. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Morbi lacinia molestie dui. Praesent blandit dolor. Sed non quam. In vel mi sit amet augue congue elementum. Morbi in ipsum sit amet pede facilisis laoreet. Donec lacus nunc, viverra nec.

RG Test01

2014-10-29T03:36:28Z

Z3486783:

RG Test01

2014-10-29T03:36:00Z

Z3486783:

RG Test01

2014-10-29T00:58:53Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=

==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

There are currently no known cures for DEB; however there are techniques to manage the clinical manifestations of the disease, which include:
*wound care<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*preventing factors that may cause blistering<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*using aqueous disinfectants - highly effective<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*dental care<ref name= PMID252845240><pubmed>25284524</pubmed></ref>:
:-use of topical fluoride
:-careful prophylaxis
:-use of topical antibiotics to prevent secondary infections<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

One study is currently exploring the potential of protein therapy as a treatment for DEB. Their results show that intradermal injection of recombinant human collagen 7 in mice with DEB led to “restoration of C7 and anchoring fibrils.”<ref name= PMID19018253><pubmed>19018253</pubmed></ref> Other techniques that aim to restore C7 include:
*bone marrow transplant- improved blistering in mice specimen and increase survival rates<ref name= PMID24860657><pubmed>24860657</pubmed></ref>
*hematopoietic cell transplant (HCT)- increased deposition of C7 in injured skin<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

===Congenital Alopecia Areata===
[[Image:Alopecia Areata.jpg|frame|right|middle|270x220px|Patches of hair loss: a sign of alopecia areata.<ref name="PMID23960401"><pubmed>23960401</pubmed></ref>]]
Alopecia areata (AA) is an abnormality of the hair affecting anagen hair follicles, characterised by well-demarcated patches of hair loss. It is non-scarring and can occur on the scalp and/or the body. 90% of AA cases occur on the scalp. 5%-10% of patients with AA lose all hair on their scalp; this is called alopecia totalis. While others lose all of their body hair, this is called alopecia universalis. <ref name= PMID17269961><pubmed>17269961</pubmed></ref> Its pathogenesis is considered to be both genetic and autoimmune. There is an abnormality with the genes related to the immune system and to the hair follicles. And histopathology shows signs of lymphatic infiltration of the hair follicles and the loss of these scalp lymphocytes allow hair follicles to recover.<ref name= PMID16338213><pubmed>16338213</pubmed></ref> High frequencies of catagen and telogen hair follicles are also present in areas affected by AA.<ref name= PMID17269961><pubmed>17269961</pubmed></ref>

-snip-

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-29T00:54:08Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=

==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

There are currently no known cures for DEB; however there are techniques to manage the clinical manifestations of the disease, which include:
*wound care<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*preventing factors that may cause blistering<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*using aqueous disinfectants - highly effective<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*dental care<ref name= PMID252845240><pubmed>25284524</pubmed></ref>:
:-use of topical fluoride
:-careful prophylaxis
:-use of topical antibiotics to prevent secondary infections<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

One study is currently exploring the potential of protein therapy as a treatment for DEB. Their results show that intradermal injection of recombinant human collagen 7 in mice with DEB led to “restoration of C7 and anchoring fibrils.”<ref name= PMID19018253><pubmed>19018253</pubmed></ref> Other techniques that aim to restore C7 include:
*bone marrow transplant- improved blistering in mice specimen and increase survival rates<ref name= PMID24860657><pubmed>24860657</pubmed></ref>
*hematopoietic cell transplant (HCT)- increased deposition of C7 in injured skin<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

===Congenital Alopecia Areata===
[[Image:Alopecia Areata.jpg|frame|right|middle|270x220px|Patches of hair loss: a sign of alopecia areata.<ref name="PMID23960401"><pubmed>23960401</pubmed></ref>]]
Alopecia areata (AA) is an abnormality of the hair affecting anagen hair follicles, characterised by well-demarcated patches of hair loss. It is non-scarring and can occur on the scalp and/or the body. 90% of AA cases occur on the scalp. 5%-10% of patients with AA lose all hair on their scalp; this is called alopecia totalis. While others lose all of their body hair, this is called alopecia universalis. <ref name= PMID17269961><pubmed>17269961</pubmed></ref> Its pathogenesis is considered to be both genetic and autoimmune. There is an abnormality with the genes related to the immune system and to the hair follicles. And histopathology shows signs of lymphatic infiltration of the hair follicles and the loss of these scalp lymphocytes allow hair follicles to recover.<ref name= PMID16338213><pubmed>16338213</pubmed></ref> High frequencies of catagen and telogen hair follicles are also present in areas affected by AA.<ref name= PMID17269961><pubmed>17269961</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:56:01Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

There are currently no known cures for DEB; however there are techniques to manage the clinical manifestations of the disease, which include:
*wound care<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*preventing factors that may cause blistering<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*using aqueous disinfectants - highly effective<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*dental care<ref name= PMID252845240><pubmed>25284524</pubmed></ref>:
:-use of topical fluoride
:-careful prophylaxis
:-use of topical antibiotics to prevent secondary infections<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

One study is currently exploring the potential of protein therapy as a treatment for DEB. Their results show that intradermal injection of recombinant human collagen 7 in mice with DEB led to “restoration of C7 and anchoring fibrils.”<ref name= PMID19018253><pubmed>19018253</pubmed></ref> Other techniques that aim to restore C7 include:
*bone marrow transplant- improved blistering in mice specimen and increase survival rates<ref name= PMID24860657><pubmed>24860657</pubmed></ref>
*hematopoietic cell transplant (HCT)- increased deposition of C7 in injured skin<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

===Congenital Alopecia Areata===
[[Image:Alopecia Areata.jpg|frame|right|middle|270x220px|Patches of hair loss: a sign of alopecia areata.<ref name="PMID23960401"><pubmed>23960401</pubmed></ref>]]
Alopecia areata (AA) is an abnormality of the hair affecting anagen hair follicles, characterised by well-demarcated patches of hair loss. It is non-scarring and can occur on the scalp and/or the body. 90% of AA cases occur on the scalp. 5%-10% of patients with AA lose all hair on their scalp; this is called alopecia totalis. While others lose all of their body hair, this is called alopecia universalis. <ref name= PMID17269961><pubmed>17269961</pubmed></ref> Its pathogenesis is considered to be both genetic and autoimmune. There is an abnormality with the genes related to the immune system and to the hair follicles. And histopathology shows signs of lymphatic infiltration of the hair follicles and the loss of these scalp lymphocytes allow hair follicles to recover.<ref name= PMID16338213><pubmed>16338213</pubmed></ref> High frequencies of catagen and telogen hair follicles are also present in areas affected by AA.<ref name= PMID17269961><pubmed>17269961</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:35:32Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

There are currently no known cures for DEB; however there are techniques to manage the clinical manifestations of the disease, which include:
*wound care<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*preventing factors that may cause blistering<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*using aqueous disinfectants - highly effective<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*dental care<ref name= PMID252845240><pubmed>25284524</pubmed></ref>:
:-use of topical fluoride
:-careful prophylaxis
:-use of topical antibiotics to prevent secondary infections<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

One study is currently exploring the potential of protein therapy as a treatment for DEB. Their results show that intradermal injection of recombinant human collagen 7 in mice with DEB led to “restoration of C7 and anchoring fibrils.”<ref name= PMID19018253><pubmed>19018253</pubmed></ref> Other techniques that aim to restore C7 include:
*bone marrow transplant- improved blistering in mice specimen and increase survival rates<ref name= PMID24860657><pubmed>24860657</pubmed></ref>
*hematopoietic cell transplant (HCT)- increased deposition of C7 in injured skin<ref name= PMID24860657><pubmed>24860657</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:30:44Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

There are currently no known cures for DEB; however there are techniques to manage the clinical manifestations of the disease, which include:
*wound care<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*preventing factors that may cause blistering<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*using aqueous disinfectants - highly effective<ref name= PMID19945622><pubmed>19945622</pubmed></ref>
*dental care<ref name= PMID252845240><pubmed>25284524</pubmed></ref>:
:-use of topical fluoride
:-careful prophylaxis
:-use of topical antibiotics to prevent secondary infections<ref name= PMID24860657><pubmed>24860657</pubme></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:20:35Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

===Dystrophic Epidermolysis Bullosa===
[[Image:Dystrophic Epidermolysis Bullosa lesions.jpg|frame|right|sub|270x230px|Severe skin lesions due to Dystrophic epidermolysis bullosa.<ref name="PMID23739692"><pubmed>23739692</pubmed></ref>]]
Dystrophic Epidermolysis Bullosa (DEB), a type of epidermolysis bullosa, is a genetic disease of the skin, usually present at birth or at an early age. Currently, around 400,000 - 500,000 people are affected with the disease<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is characterised by the fragility of the skin<ref name= PMID252845240><pubmed>25284524</pubmed></ref>, where it blisters upon minimal trauma and scars<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, usually at the extremities<ref name= PMID252845240><pubmed>25284524</pubmed></ref>. It is caused by a mutation in collagen VII gene (COL7A1)<ref name= PMID19945622><pubmed>19945622</pubmed></ref><ref name= PMID24860657><pubmed>24860657</pubmed></ref>, which is responsible for the the formation of anchoring fibrils<ref name= PMID19945622><pubmed>19945622</pubmed></ref>. Anchoring fibrils are responsible for dermal-epidermal adherence<ref name= PMID19945622><pubmed>19945622</pubmed></ref>, that is why it’s loss of function results to blistering of the skin. In some cases, even teeth and nails are affected. Teeth of patients with DEB have enamel defects and when combined with poor oral hygiene, it may lead to decay. Nails of DEB patients are often dystrophic and will eventually be lost.<ref name= PMID252845240><pubmed>25284524</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:12:12Z

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{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-28T03:03:30Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

==Abnormalities==

===Aplasia Cutis Congenita===
[[Image:Cutis aplasia.jpg|frame|right|middle|250x187px|Aplasia cutis congenita at the scalp]]
Aplasia cutis congenita (ACC) is a rare skin abnormality, characterised by the absence of all layers of the skin. It is most common to occur on the scalp (70%), specially the vertex. In severe cases, the defect can go as deep as the bone or the dura. Other sites of ACC include the skin of the limb regions. “ACC occurs in approximately 1 in 10000 live births, with a female-to-male ratio of 7:5.” The specific aetiologic agent for ACC is still unknown. It has been suggested to be genetic and/or environmental. The damage to the vertex is suggested to be the result of the biomechanical stretch at this area when the fetal brain is growing.<ref name= PMID22549580><pubmed>22549580</pubmed></ref>

Presently, ACC is managed via conservative treatments or surgical treatments. Conservative treatments refer to basic wound treatments and preventing infection with the use dressings and antibiotics. Surgical treatments, specifically scalp reconstruction procedures, aim to reconstruct the damage to the skin through skin grafts, local scalp flaps, and pericardial scalp flaps. Large defects are often treated using surgical treatments.<ref name= PMID23147310><pubmed>23147310</pubmed></ref>

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-27T04:53:45Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

===Teeth===
<ref name= PMID5267156><pubmed>5267156</pubmed></ref> -- <pubmed>5267156</pubmed>

{| class="wikitable mw-collapsible mw-collapsed"
! Historic: Textbook References - UNSW Embryology
|-
|
* [http://archive.org/details/odontographyort02owen Odontography; or, A treatise on the comparative anatomy of the teeth; their physiological relations, mode of development, and microscopic structure, in the vertebrate animals] (1840)
* [http://archive.org/details/philtrans06747998 On the Development and Homologies of the Molar Teeth of the Wart-Hogs (Phacochaerus), with Illustrations of a System of Notation for the Teeth in the Class Mammalia] (January 1, 1843)
* [http://archive.org/details/philtrans09292853 On the Development and Succession of the Teeth in the Marsupialia] (January 1, 1866)
* [On the Structure and Development of the Teeth of Ophidia http://archive.org/details/philtrans05838057] (January 1, 1874)
* [http://archive.org/details/philtrans06818652 On the Development of the Teeth of Fishes (Elasmobranchii and Teleostei)] (January 1, 1874)
* [http://archive.org/details/philtrans03024546 On the Development of the Teeth of the Newt, the Frog, and Certain Lizards] (January 1, 1874)
* [http://archive.org/details/philtrans08383999 On the Development of the Enamel of the Teeth of Vertebrates] (January 1, 1882)
* [http://archive.org/details/jstor-1758946 On the Development of Teeth in the Lamprey] (December 7, 1883)
* [http://archive.org/details/horsesteethtreat03clar Horses' teeth: a treatise on their mode of development, anatomy, microscopy, pathology, and dentistry] (1886)
* [http://archive.org/details/originformationo00legr The origin and formation of the dental follicle. The first memoir on the development of the teeth] (1880)
* [http://archive.org/details/jstor-2454366 Development of the Teeth in Rodents] (September 1, 1899)
* [http://archive.org/details/jstor-1623502 Recent Investigations Upon the Embryology and Pathology of Teeth] (November 22, 1895)
* [http://archive.org/details/anatlasskiagram00rankgoog An Atlas of skiagrams: Illustrating the Development of the Teeth with Explanatory Text] (1908)
* [http://archive.org/details/textbookofdenta00noye A text-book of dental histology and embryology, including laboratory directions] (1921)
|}

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-27T04:49:58Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

===Nail===

[[Image:Fetal Nail Development - Historic Timeline.jpg|frame|center|middle|135x115px|Week 9-10]]

Microscopy and staining techniques have been essential tools in study of nail development, anatomy and physiology. Thus, as such technology advances scientists have been able to uncover the morphological details of the nail and understand the changes that occur during nail development. A review of the history allows us to recognize the major contributor to this field. History of research on nail development also reveals the interesting debate on the origins of keratinized cells which migrate to form the nail palate in weeks 20-24 of fetal development.

* German scientists Unna and Pinkus were both highly reputable dermatologists who conducted a great deal of research on the structure and development of the skin and associated structures. (<ref name= PMID12581143><pubmed>12581143</pubmed></ref> <ref>Roberts, H. L., & Walker, N. (1929). PAUL GERSON UNNA. British Journal of Dermatology, 41(4), 157-160.</ref>)
* '''1883''' - Unna published a chapter on the anatomy and development of the human nail in the German textbook "Ziemsssen's Handbuch der Speciell Pathologie und Therapie" - Ziemsssen 's manual of special pathology and therapy. He provided some of the earliest insight into the development of the nail.
* '''1927''' - Pinkus conducted his investigations into fetal nail development. His findings were published in the "Handbuch Der Haut und Geschlechtskrankeiten” - Manual of Skin and Venerail Disease. Like Unna, these findings primarily focused on determining the cell types and structural feature
* Based on their findings both scientists proposed that the highly vascular nail matrix in the proximal nail fold gives rise to the nail plate during normal fetal development. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>

* '''1954''' - Barton and Lewis conducted further investigations on the microscopic features of the fetal and mature nail and surrounding soft tissue. Lewis challenged and developed the model proposed by Unna and Pinkus, suggesting the "tri-partite" origin of the nail plate from three distinct regions with in the proximal region of the nail (1) the proximal nail fold (2) the matrix and (3) bed. <ref name= PMID5556500><pubmed>5556500</pubmed></ref>
* Prior to the 1900’s it was difficulty in obtaining normal fetal specimens. Furthermore, the histological staining techniques used to prepare slides of nail tissue often damage the specimen and little detail could be seen during the microscopic examinations. Barton and Lewis conducted this investigation in hopes that a better understanding of the normal developmental anatomy and physiology would assist physicians in diagnosing and treating abnormalities. <ref name= PMID13206419><pubmed>13206419</pubmed></ref>

* '''1959''' - Samman carried out an investigation on the blood supply of the human toe nail. It was thought that a deeper understanding of morphology and distribution of nail vasculature might allows us to infer the mechanism of nail plate genesis. Samman found capillary loops through out the nail fold and concluded that this supports the theory of multiple sites giving rise to the nail plate. He also noted that in the case of damage to the the terminal nail plate blood supply to the nail bed is increased. <ref name= PMID14441224><pubmed>14441224</pubmed></ref>

* '''1963''' - Zaias conducted his study on the embryology of the human nail. Primarily though light microscopy techniques, Zaias was able to build on our understanding of finer changes in the structure of the nail. He proposed a timeline highlighting the morphological hallmarks in each stage of normal nail development. <ref name= PMID14003041><pubmed>14003041</pubmed></ref> A number of follow up studies were conducted using a primate model.

The current understanding of fetal nail development is a summation contributions of many researches in the international scientific community. Today research continues, technology allows exploration beyond macroscopic and microscopic morphological changes in the fetal nail. Now the aim is to understand the molecular signalling with in the epidermal cells which drives this process.

{| align="center" style="text-align:centre"
|-
| [[Image:Nail Plate Development - Pinkus .jpg|frame|center|middle|180x150px|Nail Plate Development - Pinkus]] || [[Image:Nail Plate Development -Lewis .jpg|frame|center|middle|180x150px|Nail Plate Development - Lewis]]
|}

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
<references/>

RG Test01

2014-10-27T04:47:02Z

Z3486783:

{{ANAT2341Project2014header}}
=Integumentary=
==Introduction==
This page concerns the development of the integumentary system in the fetal stage of development, particularly its organs i.e. the skin, glands, hair, teeth, and nails. It explores the mechanism of development as well as the timeline of development. This page also outlines some recent findings on the development of the integumentary system, as well as historic findings. Finally, this page also explores some of the congenital abnormalities of the integumentary system, its mechanism or pathogenesis, clinical manifestations, and how they are treated or managed.

{| class="wikitable mw-collapsible mw-collapsed"
! Objectives
|-
|
*Understand the development of the skin and its derivatives in the fetal stage of development.
*To be familiarised with current studies on the integumentary system.
*To be familiarised with previous understandings about the development of the integumentary system.
*Brief understanding of some abnormalities of the integumentary system.
|}

==Development Overview==
[[Image:Integumentary System Fetal Development Timeline.jpg|frame|centre|middle|375x312px|A timeline of the major events in the fetal stage of development of the major organs of the integumentary system.]]

===Skin===
The skin consists of 2 layers: the outer layer (epidermis) and a deeper connective tissue layer (dermis)<ref name="Moore & Persaud"/>.
*The epidermis is derived from the ectoderm. Initially it exists as only a single layer of ectodermal cells at 7-8 days of gestation<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. However, by about 13-14 weeks after gestation, a 3- layered structure of fetal epidermis exists<ref name= PMID2413039><pubmed>2413039</pubmed></ref>- consisting of the stratum basale, 1 or 2 intermediate layers and the periderm<ref name= PMID168272><pubmed>168272</pubmed></ref>. The peridermal cells eventually become desquamated and form part of the vernix cervix.
** The 5 definitive layers of the adult skin are evident in the human fetus after 22-24 weeks of gestation<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Indirect influences form the dermis help differentiate the epidermis into: stratum basale, stratum spinosium, stratum granulosum, stratum lucidum and stratum corneum<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>.
*The somatic mesoderm is the embryonic origin of the dermis. The mesoderm of the dermatones of the body, also contribute to the development of the dermis. Specifically though, in the head and neck region of the body, the dermis is derived from neural crest cells<ref name="BRS Embryology">Dudek, R.W. (2011). '''BRS Embryology''' (5th ed.). Lippincott Williams & Wilkins</ref>.
** The dermis is initially composed of just mesenchymal cells- loosely aggregated mesodermal cells. These mesenchymal cells later develop into fibroblasts- which function to secrete collagen and lay-down elastic fibers into the extracellular matrix<ref name="BRS Embryology"/>.

3 other specialised cells of the epidermis also exists<ref name="BRS Embryology"/> - these include melanoblasts, Langherhan cells and Merkel cells.
*'''Melanoblasts'''- are derived from neural crest cells that have migrated into the stratum basale. Mid-pregnancy, melanosomes are observed, differentiating the melanoblasts into melanocytes<ref name="BRS Embryology"/>.
*'''Langheran cells-''' are derived from bone marrow (originally form mesoderm) and migrate into the epidermis<ref name="BRS Embryology"/>. They have the function of antigen presentation.
*'''Merkel cells'''- still have an uncertain origin. They have a function related to mechanoreception.

{| style="width:60%; height:125px" border="1" align="center"
|-
! Week !! Description !! Phase Diagram
|-
| '''Weeks 6-8'''|| In an electron micrograph study of the epidermis<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, the periderm and and basal layer of the developing skin was observed. The basal cell keratins K5 and K14 were also observed from 8 weeks onwards<ref name= PMID2413039><pubmed>2413039</pubmed></ref> || [[Image:Human_embryo_skin_8-9_week_EGA.jpg|100x100px|Weeks 6-8]]
|-
| '''Weeks 7-9''' || In an electron micrograph study of the epidermis at weeks 7-9 of development, the stratified three-layer structure of the epidermis was observed<ref name= PMID2413039><pubmed>2413039</pubmed></ref>; with the stratum intermedium forming between the basal and periderm layers . Kertain filaments, such as K8 and K19 have been encircled- they feature during fetal skin development but are absent in the adult epidermis. || [[Image:Human_embryo_skin_9-11_week_EGA.jpg|100x100px| Weeks 7-9]]
|-
| '''Weeks 14-16''' || By week 14, the basal layer, the intermediate layer/s and the periderm 3-layered structure can be observed in the fetus<ref name= PMID2413039><pubmed>2413039</pubmed></ref>. By week 14, K17 can also be found in the basal and intermediate layers of the epidermis (In adult skin, K17 is not observed) <ref name= PMID19701759><pubmed>19701759</pubmed></ref>. Developing blood vessels were observed at the end of week 16<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. || [[Image:Fetal_integumentary_histology_14w.jpg|100x100px| Week 14]]
|-
| '''Weeks 20-22''' || By week 20, hair follicles can be already be seen in the epidermis. The total number of intermediate layers has also increased<ref name= PMID19701759><pubmed>19701759</pubmed></ref>. In an electron micrograph study at week 22 of development<ref name= PMID2413039><pubmed>2413039</pubmed></ref>, kertanised epidermis was analysed. It was observed that glycogen was abundantly present throughout all epidermal layers. (The included arrows, highlight the keratin filament bundles, which are now organised and peripherally placed.) || [[Image:Human_embryo_skin_24_week_EGA.jpg|100x100px| Week 22]]
|-
| '''Adult''' || In adult skin- a greater diversity of cells can be seen as more cells differentiate. Basal, spinous, granular and cornified cells are all example of such<ref name= PMID168272><pubmed>168272</pubmed></ref><ref name= PMID7039717><pubmed>17039717</pubmed></ref>. The fetal extra-cellular matrix also differs from that of the adult- mainly in terms of the collagen type<ref name= PMID8292556><pubmed>8292556</pubmed></ref>. and amount of glycosaminoglycans present<ref name= PMID2027330><pubmed>2027330</pubmed></ref>. || [[Image:Fetal_integumentary_histology_Adult.jpg|100x100px| Adult]]
|}

===Hair===
Hair originates from the ectoderm. At about 12 weeks, it is believed that specific signals from the dermis are released- signaling for the induction hair follicle formation <ref name= PMID1566372><pubmed>1566372</pubmed></ref><ref name= PMID20590427><pubmed>20590427</pubmed></ref>

{| style="width:80% border="1" align="center" style="text-align:left"
|-
! Stage !! Weeks !! Description
|-
| '''(a) Undifferentiated Epithelium''' || Weeks 8-12 || Through reciprocal interactions and ‘first dermal signaling’, cells from the stratum basale grow into the underlying dermis. The signaling pathway, however, has not been fully identified<ref name= PMID11841536><pubmed>11841536</pubmed></ref>
|-
| '''(b) Placode''' || Weeks 12-14 || The ‘first dermal signals’ influence epithelial cells to develop a placode- a thickening of the columnar cells. It is theorised that varying intrinsic dermal signals lead to the expression of various placodes and consequently, the differences in the expression of hair thickness/size throughout the body<ref name= PMID10529418><pubmed>10529418</pubmed></ref>. The specific combination of promoter and repressor activators for hair development, is also theorised to characterise for the regional differences in eventual hair expression<ref name= PMID10431226><pubmed>10431226</pubmed></ref>
|-
| '''(c) Germ''' || Weeks 13-16 || WNT Signalling is believed to have a role in the induction of the dermal condesate<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Platelet-derived growth factor-A molecules from the placode, also contributes to the induction of the dermal condensate. The development of the dermal condensate helps further induce the downward growth of the placode.
Through secreted proteins such as Sonic Hedgehog, the placode continues to proliferate and enclose the dermal condensate. This eventually forms a deep, club-shaped hair bud, with an invaginated dermal papillae <ref name= PMID11841536><pubmed>11841536</pubmed></ref>. These dermal papillae are rapidly infiltrated by blood vessels and nerve endings.
|-
| '''(d) Peg''' || Weeks 19-21 || Sonic Hedgehog and the induction of a ‘secondary dermal signal’ (characterisation unknown) leads to a significant down-growth and proliferation of the follilular epithelium<ref name= PMID9768360><pubmed>9768360</pubmed></ref>.
In this stage, it is also believed that the polarity of the hair follicle (the angle at which hair-follicles grow in relation to skin) and the architecture of the hair follicle itself (straight hair, wavy hair, etc) is regulated in part by Sonic Hedgehog and TGF-a signaling respectively<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
|-
| '''(e) Bulbous Peg''' || Weeks 23-28 || This stage is characterised by the appearance of the hair follicle bulb. Further and significant differentiation of the inner root sheeth and the hair shaft also characterises this stage<ref name= PMID11841536><pubmed>11841536</pubmed></ref>.
The epithelial cells within the hair bulb, begin to differentiate into the germinal matrix – which grow, proliferate and keratinise to form the hair shaft and internal root sheet<ref name= PMID11841536><pubmed>11841536</pubmed></ref>. Other epithelial cells outside of the hair bud, form the external hair sheeth. Mesodermal cells of the dermis that surround the invaginating hair follicle form the dermal root sheeth and the arrecrtor pili muscles for hairs.
Proteins such as Notch1 are believed to help regulate the phenotype of keratinocytes as they differentiate<ref name= PMID10804183><pubmed>10804183</pubmed></ref>.
|}

{| align="center" style="text-align:center"
|-
| [[Image:Fetal Hair Follicle Development - Week 8-12.JPG|frame|right|middle|180x150px| (a) Week 8-12]]||[[Image:Fetal Hair Follicle Development - Week 12-14.JPG|frame|right|middle|180x150px| (b) Week 12-14]]|| [[Image:Fetal Hair Follicle Development - Week 13-16.JPG|frame|right|middle|180x150px| (c) Week 13-16]] || [[Image:Fetal Hair Follicle Development - Week 19-21.JPG|frame|right|middle|180x150px| (d) Week 19-21]]|| [[Image:Fetal Hair Follicle Development - Week 23-28 .JPG|frame|right|middle|180x150px| (e) Week 23-28]]
|}

'''Lanugo Hair'''<ref name="Moore & Persaud"/>
*Appear at the end of week 12
*Abundant from weeks 17-20
*Shed 4 weeks before birth <ref>Cite this page: Hill, M.A. (2014) Embryology 2009 Lecture 18. Retrieved October 23, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_18</ref>
*Lanugo Hairs are the first fetal hairs. They are characterised by their soft, fine and unpigmented nature.
*Lanugo Hairs have a role in keeping the vernix caseosa intact to the fetus<ref name="Moore & Persaud"/>

===Nail===

Together, fingernails and toenails are modifications of the epidermis which are derived from the same embryonic origin, the ectoderm. <ref name="Pansky">Pansky, B. (1982). Review of Medical Embryology. Embryome Sciences, Inc 1301 Harbor Bay Parkway, Alameda, CA, 94502</ref>

{| style="width:100%" border="1" align="center" style="text-align:left"
|-
! Week !! Event
|-
| '''Week 9''' || The primitive finger nail beings to from. Preceding the morphological development, molecular signalling molecules being patterning the ectodermal layer. Signal molecules such as Bone Morphogentic Proteins (BMPs) allow communication between tissue layers and are involved in the initiating development of the nail. <ref name= PMID21387539><pubmed>21387539</pubmed></ref>
|-
| '''Week 10'''|| The primary nail field is establish, marked by a localised thickening of the epithelium. This primary nail fields initial from on the ventral surface of the digits and are repositioned to the dorsal side during development. <ref name="Moore & Persaud">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.</ref> The LIM-homeodomain protein (Lmx1b) is a signalling molecule involved in this process, it's localised expression allows the dorsal-vetral limb axis to be established. A mutation in the gene coding for Lmx1b correlates with abnormal development of the nail and other bony structures. <ref name= PMID9590288><pubmed>9590288</pubmed></ref>
|-
| '''Week 11''' || On the lateral edges of the primary nail field, ectodermal cells proliferate to from the shallow lateral nail folds. Similarly proliferation of the cells on the proximal end of the nail field gives rise to the deeper proximal nail fold. The nail field now appears as a distinct region on the digits. <ref name="Pansky"/>. In addition, the distal ridges of nail bed keratinise.
|-
| '''Week 13''' || Seen in cross-section, the early nail matrix begins to from, this marked region with in the proximal nail fold which undergoes localised cornification. The nail plate grows from the nail matrix as kertaised cells are flattened and compacted into dense nail tissue.
|-
| '''Week 14''' || The primitive toe nails being to from. This event usually occurs 4 weeks after development of the finger nails. The differential timing of these events is established by signalling molecules that establish the rostro-cauda sequence of development in the embryo and fetus.
|-
| '''Week 20''' || Nail plate begins to grow over the nail bed from the proximal nail matrix towards the distal direction.
|-
| '''Week 24''' || Free nail plate is visible to the naked eye. Initially the developing nail is covered by a thin layer of epidermis known as the eponychium (corneal layer of epidermis). At this stage in fetal development the eponychium declines, the cuticle remains over the proximal nail plate. Below the free end of the nail, epidermal cells aggregate to form the mass known as the hyponychium<ref name="Moore & Persaud"/>.
|-
| '''Week 32-36''' || The finger nails and toe nails respectively reach the tips of the digits and the toes.
|}

{| align="center" style="text-align:centre"
|-
| [[Image:Feta Nail Development - Week 9-10.jpg|frame|right|middle|135x115px|Week 9-10]]|| [[Image:Fetal Nail Development - Week 11-12.jpg|frame|right|middle|135x115px|Week 11-12 ]] || [[Image:Fetal Nail Development - Week 13-14 .jpg|frame|right|middle|135x115px|Week 13-14]]|| [[Image:Mature Nail .jpg|frame|right|middle|135x115px|Mature Nail]]
|}

===Glands===
{| style="width:75%" border="1" align="center" style="text-align:left"
|-
! Gland Type !! Description !! Image
|-
| '''Sebaceous Glands''' || Sebaceous glands develop from the epithelial wall of the hair follicle. They secrete the '''vernix caseosa'''

Vernix caseosa is a material secreted by sebaceous glands in the foetus in the last trimester of development (Week 21)<ref name="PMID15830002"><pubmed>15830002</pubmed></ref> and is characterised by it’s cheese-like appearance around the neonate at birth. The functions of vernix caseosa include:
*thermal regulation <ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*barrier to water loss (to keep fetal skin hydrated)<ref name="PMID21504444"><pubmed>21504444</pubmed></ref><ref name="PMID15830002"><pubmed>15830002</pubmed></ref>
*prevents the epidermis from water contact while epidermal cornification and formation of the stratum corneum occurs<ref name="PMID21504444"><pubmed>21504444</pubmed></ref>
*antioxidant<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*anti-infective<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*moisturises the skin<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
*assists in wound-healing<ref name="PMID19881987"><pubmed>19881987</pubmed></ref>
|| [[Image:Newborn - vernix caseosa.jpg|frame|center|middle|250x187px|Vernix caseosa on a neonate.<ref>Image source: JazlynRoseVernixByPhilKonstantin.jpg‎ http://en.wikipedia.org/wiki/File:JazlynRoseVernixByPhilKonstantin.jpg</ref>]]
|-
| '''Mammary Glands''' || Mammary glands develop from the mammary ridge- a downgrowth of the epidermis (ectoderm) into the underlying dermis (mesoderm). This occurs at about week 6 of development. Mammary glands first develop into primary mammary buds<ref name="Moore & Persaud"/>, which successively grow in length and complexity. Prior to puberty, the mammary glands are anatomically indistinguishable.<ref name= PMID23720046><pubmed>23720046</pubmed></ref> || [[Image:Hand-drawn_mammary_gland_during_fetal_development.jpg|frame|center|middle|250x187px|Mammary gland development during the fetal stage]]
|-
| '''Sweat Glands''' ||
There are two major kinds of sweat glands present in humans, both of which develop from downgrowths of the epidermis into the underlying dermis. Sweat glands have been histologically identified in studies from week 21 of development. They begin as cellular buds<ref name="Moore & Persaud"/>, which proliferate as solid, cylindrical down growths into mesenchyme. Central cells degenerate to form a lumen, while the terminal region coils to eventually form the body of the gland. As fetal development continues, peripheral cells eventually differentiate into secretory and myoepithelial cells<ref name="Moore & Persaud"/>.

Eccrine Sweat Glands
* Located in the skin with distributions throughout most of the body<ref name="Moore & Persaud"/>.
* Function in thermoregulation and excretion of excess electrolytes and water <ref name="Bolognia">Bolognia, J.L., Jorizzo, J.L. & Schaffer J.V. (2012). Dermatology (3rd ed.). Elsevier Limited.</ref>.
* Present at birth with function initiating shortly after birth<ref name="Moore & Persaud"/>.

Apocrine Sweat Glands
*Located in the skin of the axilla, pubic and perianal areas and nipple areolae<ref name="Moore & Persaud"/>.
* May function in a form of olfactory communication <ref name="Bolognia"/>.
* Present at birth with function originating at puberty<ref name="Moore & Persaud"/>.

|| [[Image:Hand-drawn_sweat_gland_development.jpg|frame|center|middle|250x187px|Sweat gland development during the fetal stage]]
|}

===Teeth===
The ectoderm and the associated underlying layer of neural crest cells, are the origin for teeth development. Teeth have the main function of processing food, but also frequently serve other functions in relation to defense, display of dominance and phonetic articulation in humans <ref name= PMID19266065><pubmed>19266065</pubmed></ref>.

{| class="wikitable"
|-
! Stage!! Week !! Description
|-
| '''(A) Lamina'''|| Week 6 || As the oral ectoderm grows and proliferates, it closely interacts and has a downward movement into the underlying neural crest ectomesenchyme<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. In the Lamina stage, teeth may grow only within the epithelium. This leads to the formation of the dental lamina. Morphological differences between the individual teeth arise due to the different expression of odontogenic genes that encode for different transcription factors that regulate the synthesis of various signaling factors<ref name= PMID7626420><pubmed>7626420</pubmed></ref>.
|-
| '''(B) Placode'''|| Week 7 || The dental lamina and the dental placodes arise, due to specific signals from adjacent epithelial cells. These dental placodes secrete molecules from all four growth and transcription factor families (BMPs, FGFs, SHH and WNTs) <ref name= PMID19266065><pubmed>19266065</pubmed></ref> to induce the expression of many genes in the mesenchyme and form tooth buds.
|-
| '''(C) Bud''' || Week 8 || The bud stage is characterised by the appearance of a tooth blastema and a highly un-organised arrangement of cells<ref name=PMID19266065><pubmed>19266065</pubmed></ref>. Tooth buds are formed, as the epithelium cells interact with the messenchyme. This occurs at the sides of the dental placodes<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. These tooth buds, later form and develop into enamel organs.
Also, as opposed to the earlier Lamina stage, in the Bud stage of tooth development, the odontogenic potential is lost from the epithelium and teeth may now only grow within the ectomesenchyme<ref name= PMID3478009 ><pubmed>3478009 </pubmed></ref>.
|-
| '''(D) Cap'''|| Week 11 || With further differential proliferation and epithelial infolding, the bud takes upon the shape of an inverted cap<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. Mesenchymal cells secrete various extracellular molecules that increase the concentration of growth factors- inducing shape changes and cellular differentiation for the developing tooth<ref name= PMID19266065><pubmed>19266065</pubmed></ref>.
|-
| '''(E) Bell'''|| Week 14 || The buds further develop and refold once again- this time forming an overall bell-shaped appearance<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The Bell stage of tooth development is characterised by the events of crown morphogenesis and cytodifferentiation<ref name= PMID1725872><pubmed>1725872</pubmed></ref>.
Also, during this stage, the cells differentiate in situ, and the crown takes its final shape<ref name= PMID19266065><pubmed>19266065</pubmed></ref>. The dental papilla, which forms from the neural crest cells that underlie the enamel organs <ref name= PMID3250849><pubmed>3250849</pubmed></ref> eventually give rise to the dental pulp and odontoblasts- which produce predentin and dentin, in the adult body.
With further development and immediate predentine deposition<ref name= PMID3250849><pubmed>3250849</pubmed></ref>, these cells then take a columnar shape and differentiate into ameloblasts that start synthesizing and depositing enamel.
|}

[[Image:Timeline - Fetal Tooth Development.jpg|frame|left|middle|300x175px|The stages of embryonic teeth development]]

===Video===
<html5media height="300" width="400">https://www.youtube.com/watch?v=nRH8M-arC58</html5media>

==Current Research ==
{|
|-bgcolor="F5FFFA"
|
* '''Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development:''' <ref name=PMID23377137><pubmed>23377137</pubmed></ref> In recognition of the vital roles of CASP-14 and CK-19 in human skin development and maturation, the purpose of this study was to primordially investigate the expression of these two molecular factors throughout the stages of human fetal skin development from gestation to the postnatal period in order to evaluate their singular and collective functions in epidermal and associated appendage maturation and processes of differentiation and re-modelling of human fetal skin. The results of the immunohistochemical study showed the expression of CASP-14 to be a biochemical marker of human epithelial differentiation during gestation, whilst CK-19 was a marker for epidermal stem cells nests of the stratum basale of the fetal epidermis and appendages. CASP-14 was concentrated within the more differentiated fetal epidermal layers, progressively declining from the basal layer toward term whilst CK-19 showed reduced expression with progressive epidermal development of the fetal stages and was a biochemical marker for epidermal stem cells nests of the stratum basale showing marginal conservation in basal cell nests at term and postnatally. Expression of CASP-14 within the epidermal appendages of the hair follicles and sebaceous glands were concentrated within the greater differentiated inner root sheath whilst CK-19 was greatly concentrated within the outer root sheath. Inconsistent patterns of expression of both molecules CASP-14 and CK-19 were demonstrated within eccrine sweat glands.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation:''' <ref name= PMID25066162><pubmed>25066162</pubmed></ref> Cellular signalling between mesencyhmal and epithelial layers of the developing skin initiate an assortment of morphogenetic events throughout embryogenesis, involving the formation of the skin and in particular, the development of hair follicles (HF). The aims of this study was to identify the specific signalling pathways associated with HF morphogenesis during the primary stages of mouse hair follicle development through the investigation of the precise expression patterns and role of the Cxcr4 receptor in two specialised cell types- mesenchymal dermal condensate (DC) cells and epithelial placode cells. Staining patterns of the Cxcr4 receptor in the budding HF revealed a high concentration within epithelial placode cells and later DC cells in developing HF’s, signifying a shift of expression between epithelial and mesenchymal layers during HF morphogenesis. The functionality of the Cxcr4 receptor was tested through Cxcr4 receptor ablation in both the mesenchymal and epithelial layers of the developing embryonic skin of conditional knockout mice (cKO) and was verified through immunofluorescence staining techniques. Normal HF development was still induced despite the absence of Cxcr4 expression in the skin of the cKO mice and numbers were comparable to those found in the wild-type (WT) control group in embryonic and postnatal skin groups demonstrating that the chemokine signalling through the Cxcr4 receptor is inessential for normal early HF development (Figure 1).
|}

[[Image: Eosin_staining_of_mouse_embryonic_skin.png|frame|250x250px|center|Figure 1: Hematoxylin/ eosin staining of embryonic skin sections and macroscopic view of external hair shafts of mouse. Cxcr4 receptor ablation in condensates and placodes show no effect on mouse HF morphogenesis. Hair follicle and shaft develop normally and in comparable numbers in both Tbx18cre (a) and Krt14-cre (b) Cxcr4fl/fl cKO mice<ref name= PMID25066162><pubmed>25066162</pubmed></ref>.]]
[[Image:- compound mouse mutants demonstrate partially rescued upper and lower molars.png|frame|center|middle|300px|Figure 2: Msx1-/--;Tbx2+/-mouse mutants showed rescue from bud to cap phase transition in embryonic dental development. Both upper and lower molars showed an enlargement in the tooth buds (H, K, L), with few upper molars progressing to cap stage (G). The arrowheads indicate enamel knots (E,G,I)<ref name= PMID23720046><pubmed>23720046</pubmed></ref>.]]

{|
|-bgcolor="F5FFFA"
|
* '''The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin:''' <ref name= PMID22804461><pubmed>22804461</pubmed></ref> In comparison to the characterization of the stem cell niche within the folliculosebaceous-apocrine unit, the local microenvironment of stem cells within the human nail organ is yet to be characterized. The aims of the current study was through immunohistochemical analysis to describe the expression pattern of six follicular stem cell markers; cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK-19), PHLDA1, CD200 and nestin within the developing human nail and compare it with the embryonic and fetal human hair follicle. In addition, locations of vast proliferative activity within the nail were assessed using labeling with Ki-67. The stem cell markers CK15 (both clones), CK19, PHLDA1, CD200 and nestin showed no staining within the nail and hair matrix samples, however were present within the central proximal nail fold and follicular bulge. The biochemical marker for proliferation, Ki-67 showed the highest concentration of proliferative cells within the hair germ, lower regions of the hair peg and in the hair matrix. In the developing human nail the expression of Ki-67 was most prominent within the nail bed epithelium and the later nail matrix. In contrast the lowest numbers of kI-67 positive staining cells were located in regions of stem cell niches of the follicular bulge and proximal ventral nail fold as stem cells divide infrequently. Throughout the course of embryonic development these stem cell markers exhibit a highly specific expression pattern both within the nail and the hair follicle. The results seem to suggest that during embryonic envelopment the proximal ventral nail fold is the niche for nail stem cells.
|}

{|
|-bgcolor="F5FFFA"
|
* '''Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud to cap stage transition in tooth development:''' <ref name= PMID23720046><pubmed>23720046</pubmed></ref> The expression of Bmp4 is essential for the bud to cap phase transition in embryonic dental development and is accordingly firmly regulated, with earlier stages of expression localised within the dental epithelial placode developing in to a later forms of expression in the dental mesenchyme. Numerous transcription factors including Pax 9, Osr2, Barx 1, Msx1, have been identified to prompt and maintain Bmp4 expression in these critical stages of tooth development. In particular Msx1 is one such transcription factor induced through epithelial Bmp4 expression and in turn is essential for the induction and regulation of dental mesencyhmal Bmp4 expression. The results of this investigation have demonstrated the expression of an additional transcription factor, Tbx2, induced through epithelial Bmp4, within the dental mesenchyme at bud stage of dental development. To determine a functional connection between the Msx1 and Tbx2 transcription factors, a cross was made between Tbx2 and Msx1 mutant mice. The data demonstrates that bud phase tooth arrest in Msx1-/- mice is moderately restored in Msx1-/-. Tbx2+/- compound mutants. The maintenance of Tbx2 expression in the Msx-/- arrested tooth buds exhibits that the expression of Tbx2 is not dependant on that of Msx1. This restoration in the developmental process is associated with the establishment of the enamel knot (EK) and the reinstatement of mesencyhmal Bmp4 expression (Figure 2). Knockout of Tbx2 resulted in an increase mesencyhmal Bmp4 expression. This data demonstrates that subsequent to the induction of epithelial Bmp4, both transcription factors Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that results in EK formation as well as mesenchymal Bmp4 expression at the vital bud to cap phase transition in embryonic dental development resulting in appropriate morphogenesis and patterning.

|}

{| class="wikitable mw-collapsible mw-collapsed"
! More Recent Papers
|-
|
<pubmed>23826487</pubmed>
<pubmed>22342389</pubmed>
<pubmed>24911066</pubmed>
<pubmed>25143675</pubmed>
<pubmed>23271751</pubmed>
<pubmed>25249463</pubmed>
<pubmed>23097355</pubmed>
|}

==Historic Findings==

Knowledge of the Integumentary expands in conjunction with technological developments that allow observation of microscopic structures. Historically animal models have been used to map the stages in the development of the fetal integumentary system.

===Skin===

* The fetal development of the skin has been investigated by in a targeted method by research scientists at large. In addition to this practising medical professionals ; both physicians and surgeons have had a significant contribution to our understanding of normal and abnormal fetal development.
* '''1900''' - Bardeen used the pig animal model to study the histogenesis of the dermomyotomes and nervous appratus. Bardeen and other scientists established that the human skin results from the union of the epithelial material derived from the ectoderm (epidermis) and the connective tissue origination from the mesoderm (dermis). <ref> http://journals.lww.com/plasreconsurg/Citation/1949/07000/CLINICAL_ASPECTS_OF_EMBRYOLOGICAL_SKIN.8.aspx Bardeen, C. R. (1900). The development of the musculature of the body wall in the pig, including its histogenesis and its relations to the myotomes and to the skeletal and nervous apparatus. Johns Hopkins Hosp. Rep, 9, 367-399.</ref>

===Hair===
The study of hair follicle development was primarily motivated by the need to understand abnormalities in development.

* '''1958''' - German dermatologist, Pinkus studied fetal hair follicle development using light microscopy techniques. Based on his observation he was able to propose four primary stages of hair follicle development: pre-germ, hair-germ, hair-peg and bulbous. <ref> Pinkus, H. (1958). Embryology of hair. The biology of .air growth, 1-32. </ref> <ref name= PMID14433089><pubmed>14433089</pubmed></ref>

* '''1959''' - Pinkus expanded his study of the hair follicle the development of the hair follicle in man, especially the infundibulum and the connective tissue part.

* '''1968''' - Breathnach and Smith conducted through investigations into the phases of early fetal development. The light microscope has been the greatest tool in the study of human hair follicle development. Electron microscopy was not commonly used until recently and so little was known about the ultrastructure of the skin and its appendages. In their 1968 study they focused primarily on the development of the

* Breathnach with a number of other researches then expanded their studies looking at the and understand the peripheral nerves, the sweat duct and nail development were also explored and the interrelationship of cells at particular foetal stages was deduced. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> These studies have provided information on the differentiation of cells and tissue of some functional importance and underline the role of cells and tissues.

* '''1968''' - Robins and Breathnatch investigated the development on the sebacious and apocrine swelling in the skin, which where closely associated with development of the hair follicle. They observed differentiation of desmosomes and development of cytoplasmic contents of the cell.

* '''1969''' - Chase and Eaton investigated fetal hair follicle development. Through their work they were able to stage the process. Hair follicle development begins with downwards growth fromt he level fo th dermis. Development begins with the downwards growth of the follicle structure from the level of the dermis. The follicle is a processes during the quiecent phase thought he adipose layer during gowth and differntiation. They also established that upward movement of hair inovlves the addition of next cells from the matrix of the follicle and an enlargement of each cell. Furthermore their research also showed that the epidermal and dermal layers were dynamic and interacting with each other. The most significant developments in the understanding of hair follicle development came from studies investigating the differentiation pattern of cells as the follicle develops. <ref name= PMID5656140><pubmed>5656140</pubmed></ref> <ref name= PMID4097391><pubmed>4097391</pubmed></ref> They were able to understand the cycling nature of hair follicle growth following development.

Determined that the hair fibre finally breaks through the epidermis and appres about the skin at around 19-21 weeks of development. The lanugo (foetal) hair is extremely fine with no medulla and a tip free of pigment.

-snip-

===Hypohidrotic Ectodermal Dysplasia===
[[Image:Oligodontia.jpg|frame|right|middle|250x187px|Oligodontia: a clinical manifestation of HED.<ref name="PMID21165248 "><pubmed>21165248 </pubmed></ref>]]
Hypohidrotic ectodermal dysplasia (HED) is the most of all ectodermal dysplasias, caused by an abnormality in the development of ectodermal tissues, which inlude skin, hair, teeth, sweat glands, and nails.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Patients with ectodermal dysplasia often have sparse hair and oligodontia, which is a condition where teeth are missing and are poorly developed.<ref name= PMID20682465><pubmed>20682465</pubmed></ref><ref name= PMID24678015><pubmed>24678015</pubmed></ref> Sweating is a very important function in the body in terms of thermoregulation. HED is mainly characterised by hypohidrosis due to the lack of sweat glands in the skin, which could lead to hyperpyrexia and sometimes death. In neonates, the mortality rate of HED reaches up to 30%, with the first year of life having the highest risk. <ref name= PMID20682465><pubmed>20682465</pubmed></ref> HED is caused by a genetic abnormality of the ectodysplasin A gene (EDA) and passed on by X-linked inheritance. The mutations of this gene results in the poor sweating ability or none at all in a person. The effects of this abnormality is usually more severe in males than in females. <ref name="PMID21357618"><pubmed>21357618</pubmed></ref><ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

There is currently no pharmacological therapies for HED but there are methods applied to prevent the disease from aggravating. Neonates with HED are placed in incubators and monitored to prevent them from overheating. Management of this disease gets easier as the patient ages. Adults with HED can control their thermoregulation by staying in cool environments or drinking cold drinks to lower the body temperature. Currently, there are studies that aim to find a cure for this abnormality, e.g. gene replacement therapy in animal models.<ref name="PMID24678015"><pubmed>24678015</pubmed></ref>

{| class="wikitable mw-collapsible mw-collapsed"
! More Abnormalities
|-
|
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Abnormalities| Abnormalities of the Skin and its derivatives]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Gland_Development#Abnormalities| Abnormalities of the Glands]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Nail_Development#Abnormalities| Abnormalities of the Nail]
*[https://embryology.med.unsw.edu.au/embryology/index.php/Integumentary_System_-_Tooth_Development#Abnormalities| Abnormalities of the Teeth]
|}

==References==
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