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http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464273/figure/F1/ the cochlear image

http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Cochlear_implant.JPG#filehistory

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464273/figure/F1/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464273/pdf/hippokratia-11-077.pdf

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2012-10-02T05:43:12Z

Z3333431: Created page with "http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464273/figure/F1/ the cochlear image http://embryology.med.unsw.edu.au/em..."

2012 Group Project 6

2012-10-02T04:08:37Z

Z3333431: /* Hearing aid */

[[File: z3333865.Ruby.jpeg | 450px| right]]
= Hearing Development=

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important sense and an inherent part of human life. It widens our scope of life and allows us to work, relax, communicate, learn and form memories. The sense of hearing has evolved through the years in vertebrates is inherent for both hunting and surviving. The sound energy produced has be converted into an electrical signal for us to make sense of it. For successful transmission the correct development of the ear is of utmost important. Not only formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will also talk about some abnormal processes and mutations which lead to various structural and functional diseases.

==History==

{| cellpadding=5 style="border:2px solid #08E8DE"
|- bgcolor= #00BFFF
|'''Date''' || '''Description'''
|- bgcolor=#87CEEB
|'''1536''' || The first clear distinction is made between the middle and inner ear. How to observe the middle ear ossicles is also explained. <ref><pubmed>4598483</pubmed></ref> <ref name="PMID6341584"><pubmed>6341584</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438986/?page=6 Nicola Massa.]
|- bgcolor=#ADD8E6
| '''1543''' || ''De fabrica'' by Andreas Vesalius was published which identified and named the incus and the malleus. Also identified the tensor tympani and the anatomical position of the oval window to the round window <ref><pubmed>22581496</pubmed></ref>. [http://www.ncbi.nlm.nih.gov/pubmed/22581496 Andreas Vesalius]
|- bgcolor=#87CEEB
|''' 1561''' || ''Observationes anatomicae'' is published and describes the tympanic membrane. The stapes ossicle is also discovered and named. <ref><pubmed>22965774</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/22965774 Gabriele Falloppio]
|- bgcolor=#ADD8E6
| '''1563''' || In the book ''De Auditus Organis'', it was proposed that the tympanic membrane is connected to the nasopharynx. This tube was named after the writer of the book. He also completed the diescritpion of the tensor tymapani: <ref><pubmed>7029021</pubmed></ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 Bartolomeo Eustachi]
|- bgcolor=#87CEEB
|'''17th Century'''|| The Metal ear was one of the first hearing aids created. It was placed over the ear to channel sound into the ear.
|- bgcolor=#ADD8E6
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#87CEEB
|'''1683''' || The bony labyrinth is described in more detail. It is determined the spiral lamina has a bony and membranous part, and it divides the spiral duct into an upper and lower compartment. <ref name="PMID6341584"/>[http://www.sciencedirect.com/science/article/pii/S1286011510000172 Duverney.]
|- bgcolor=#ADD8E6
|'''1704'''|| The book ''De aure humana tractatus'' with information regarding the anatomy, physiology and pathology of the ear is published.<ref name="PMC1142106"><pubmed>PMC1142106</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor= #87CEEB
|'''1707'''|| It is proposed that the labyrinth contains fluid instead of air. <ref name="PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor=#ADD8E6
| '''1772'''|| Antonio Scarpa discovers the ear labyrinth <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

==Adult Anatomy and Histology==

[[File:Anatomy_of_the_Ear.JPG|thumb|left|450px|Anatomy of the ear]]

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear. The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus. The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate. The malleus, which is in contact with the tympanic membrane, moves which in turn moves the other ossicles. The ossicles namely malleus, incus and stapes provide solid medium for the waves to travel through and act as a lever increasing the amplitude of the sound wave 20 times.

The oval window marks the boundary between the middle and the inner ear, which constitutes of an outer bony labyrinth and an inner membranous labyrinth. The cochlea which is a coil resembling a snail’s shell houses the organ of Corti, the peripheral receptor for hearing. Histologically the cochlea is divided into 3 parts scala vestibule, scala media and the scala tympani divided by the vestibular and basilar membrane respectively.

The sound waves are transmitted from the stapes into the oval window. The vibrations cause movement of the perilymph fluid in the scala vestibuli into the scala media causing movement of basilar membrane and bending of the hair cells. The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve. The nerve impulses travel from this neve through the brainstem to the thalamus to the primary auditory cortex, which is located on the transverse temporal gyrus.

The basilar membrane has a tonotopic organisation and human ears can hear sounds ranging from 20-20000 Hz. Near the apex of the cochlea the basilar membrane is wide and loose whereas near the base is narrow and tight hence enabling us to hear different frequencies.

==Development==

The development of outer ear is attributed to the first pharyngeal arch. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref>

The pharyngeal arches arise as a series of bulges arising laterally from the embryo head around 3-4 weeks of human development. The arches have a consistent organisation of the endoderm, ectoderm and mesoderm. The ectoderm forms the outer surface of the arch with the core made up of mesoderm. Next to the mesoderm core on the opposite the ectoderm is the endoderm. All three layers contribute to the formation of outer, middle and inner ear structures hence contributing to hearing. In between the arches the ectoderm and endoderm come in contact with each other forming a continuous sheath on either side of the mesoderm, forming groves externally and arches internally. Inside the mesoderm core of each arch lies a specific cell population that goes onto develop into a nerve, cartilage and artery.

===Outer Ear===

'''Pinna'''

[[File:Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages]]

Post development the anatomy of the external ear simply consists of the pinna or the auricle and external acoustic/auditory meatus. The auricle develops around the first and second pharyngeal arches as a series of auricular enlargements or hillocks around the 5th week of development. Gradually by the 6th week the hillocks grow in size and increase to six in number, three on the first arch and 3 on the second arch, the first of which starts at the bottom anterior side going in a clockwise direction. In the 7th week the hillocks enlarge further and each of the arches contributes to a specific part of the pinna. The first arch gives rise to the tragus, helix and cymba concha whereas arch 2 gives rise to concha, antihelix and antitragus. The differentiation starts around the neck region but as the mandible develops the pinna structures move more cranially. It is not until the 12th week that the fusion of these various parts occur and is completed by week 20th.

Various genetic markers and coordinated signalling mechanisms are required for normal development of the pinna. One of which is the EYA1 gene, which is imperative for formation of the pinna. Mice with a homologous Eya1 null gene either has malformed or absent ears and since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development, mutation in which causes malformation of the perichondrium and thus cartilage formation. Another gene important for early patterning of the pinna is the Hox2 gene, mutations in which leads to formation of a shapeless protuberance rather than a normal shaped pinna. Hox2 gene is expressed in the second pharyngeal arch and the malformations in the ear are contributed to the parts derived from the second pharyngeal arch like the antitragus, antihelix and concha.
<ref><pubmed>14674478</pubmed></ref> <ref><pubmed>17104502</pubmed></ref>

'''External Auditory Meatus'''

The External Auditory Meatus (EAM) is derived from ectoderm that forms the first pharyngeal groove situated between the 1st and the 2nd pharyngeal arches. At 8 weeks of gestation a c-shaped skeletal structure develops from ectoderm of the first pharyngeal cleft migrating and meeting the mesoderm of the first grove called the tympanic ring that controls and coordinates the invagination of the ectoderm. The tympanic ring is a transient embryological structure, which eventually gets integrated into the temporal bone and provides anchorage to the eardrum. Medial to the ring lays the endoderm of the first pharyngeal arch that contributes to the formation of the tympanic or middle ear cavity. At 12 weeks of gestation the tympanic ring begins to ossify in a sequential fashion via endomembranous ossification forming the bony part of the EAM. The ring starts to condense at the proximal end of the 1st pharyngeal arch, goes around the circumference of the cleft and invades the 2nd arch. Starting at the tip of the 1st pharyngeal cleft the ectodermal cells begin to proliferate filling the lumen of the meatus forming a meatal plug which medially extends in a disc like fashion during week 10. The proliferation follows the path of the tympanic ring with the mesoderm tissue between the ring and the meatus forming a fibrous layer. In week 13 of development the innermost part of the meatal plug makes a contact with malleus. This innermost part of the disc in week 15 splits leaving a thin endoderm layer behind which contributes to formation of the tympanic membrane. By the middle of 16th week the meatus although full in length is still narrow and curved and it is not until week 18 that it gets fully expanded and complete.

Since the correct development of EAM is heavily dependent on the tympanic ring, hence any mutation in the tympanic ring causes an abnormal growth of the EAM. Many genes are required to coordinate and control tympanic ring formation most prominent being the Gsc and Prx1 genes. Chimeric studies have revealed that tympanic ring in Gsc null mice fails to ossify whereas the ring whereas mice with null Prx1 gene have an over ossified tympanic ring. In both cases the meatus fails to form indicating a delicate balance between the expressions of both genes is required for proper ring development hence correct formation of EAM. Likewise for pinna formation Hox2 gene is also essential for differentiation of pharyngeal arch into the tympanic ring and the formation of EAM. <ref><pubmed>10976045</pubmed></ref> <ref><pubmed>14674478</pubmed></ref> <ref><pubmed>1441991</pubmed></ref>

===Middle Ear===

'''Tympanic Membrane'''

Tympanic membrane or the eardrum forms the boundary between the outer and middle ear and responsible for transmitting the soundwaves coming in from the EAM to the mechanical waves going into the ossicles. During 8th week of gestation the development of tympanic membrane begins when the first funnel shaped ectodermal cleft meets the endodermal pouch with the mesenchyme growing in-between. This mesenchyme eventually becomes thinner and forms the eardrum during week 12. The diameter of the membrane grows three fold between week 11 and 16 and the membrane fuses with the tympanic ring.

The 1st pharyngeal cleft (ectoderm) gives rise to the EAM and the tympanic membrane comes from the mesoderm from the 1s pharyngeal arch. The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week. During week 7 the 2nd pharyngeal arch constricts the tympanic recess dividing it into a medial portion that form the Eustachian tube and a lateral portion that forms the tympanic cavity. <ref><pubmed> 17346562</pubmed></ref> <ref><pubmed> 10976045</pubmed></ref> <ref><pubmed> 2921547</pubmed></ref>

'''The Ossicles'''

The middle ear constitutes of the skeletal structures called ossicles, which amplify and transmit sound to the inner ear.

The middle ear consists of the middle ear cavity and it are housed the 3 ossicles – the malleus, incus and stapes from lateral to medial. The mesenchymal tissue or the neural crest cells from 1st and 2nd pharyngeal arch contributes to the formation of the ossicular chain.

Two main theories underlie the formation of the ossicles. First is the classical theory according to which the malleus and incus develops from the first pharyngeal arch whereas stapes develops from the 2nd pharyngeal arch. Another theory proposes that malleal head and body of incus comes from the first pharyngeal arch while the second arch gives rise to stapes, handle of malleus and long process of incus. <ref><pubmed>18803631</pubmed></ref>.

[[File:normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology]]

===Inner Ear===

The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode.
The otic placode is a thickened portion of ectoderm located on the each side of the developing head of the embryo, next to the hindbrain. It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed. Invagination occurs next, which creates the otocyst - a vesicle which will develop into the different components of the inner ear: the cochlea, the semicircular canals with cristae, the utricle, the saccule and the vestibulo-acoustic ganglion. <ref name="PMID17891709"><pubmed>17891709</pubmed></ref>[[File:z3333865.stages development inner ear.jpg|thumb|300px|Developmental milestones in mouse inner ear formation]]

====The Otic Placode====

'''Induction of the otic placode'''

Experiments with molecular markers have revealed that several steps are needed for induction of the otic placode.

We will briefly consider the three major steps:

'''1''' ''Pre-placodal domain''

The pre-placodal domain is a narrow strip of the ectoderm adjacent to the anterior neural plate after gastrulation. Different placodes arise from the pre-placodal domain. All the craniofacial sensory organs, including the ear, develop from these different placodes located at the periphery of the neural plate.

Various evidence indicates the existence of this pre-placodal region:

* Morphology indicates a thickened band of ectoderm around the anterior neural plate in some species, including mice and humans. As time progresses, this thickening will only be present at the locations where the different craniofacial placodes differentiate - including the otic placode.<ref><pubmed>15531360</pubmed></ref>

* Experiments have also shown that the placodes will only develop in the correct location, if rotation of the ectoderm along the anteroposterior axis takes place at the open neural plate stage. If rotation takes place at a later time, the placodes will form at incorrect places.<ref><pubmed>14100031</pubmed></ref>

* Gene expression has also indicated that particular genes are present in the pre-placodal domain. These genes belong to the Dlx, Six, Eya, Iro, BMP, Foxi and Msx families. Glavic et al. (2004) has shown that 'loss and gain of function of some of these genes resulted in the widening or reduction of the pre-placodal field'. Linked to this was also the domain of expression of some placode-specific genes; which either enlarged or diminished.<ref><pubmed>15242793</pubmed></ref>

'''2''' ''Pre-otic field''
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

Once the general placodal state has been established, the identity of each placode is induced by local signals. The optic placode is induced by various signals, including Pax8, Pax2, Fibroblast Growth Factors (FGFs), and many transciption factors.

In particular the FGFs are significant otic inducers. Signalling occurs from various rhombomeres from the hindbrain and the cranial paraxial mesoderm located beneath the area of the otic placode. For example, in mice FGF3 is expressed in rhombomeres
5 and 6, whereas FGF10 is expressed in the underlying mesoderm.<ref><pubmed>7789270</pubmed></ref> <ref name="PMID12810586"><pubmed>12810586</pubmed></ref> Mutations of FGF3 and FGF10 have been investigated. Results showed that mice with a mutation of either FGF3 or FGF10 developed an abnormal otic vesicle, and a combination of the two mutants resulted in failure to form an otic vesicle.<ref name="PMID12810586"/>

''--> picture''

'''3''' ''Otic placode/epidermis fate decision''

In the presence of FGF signalling, Wnt signalling can significantly influence the next step, which is the otic placode/epidermis fate decision. According to the review article by Ohyama ''et al''. (2007) ‘Cells receiving high levels of Wnt signalling differentiate as otic placode, while cells receiving little or no Wnt signalling differentiate as epidermis.’<ref name="PMID17891709"/>

The first evidence regarding the contribution of Wnt signalling came from experiments with the otic ectoderm of chicks.
* Data showed that specific marker genes, such as Pax2, were induced to a greater extend with FGF19 and Wnt8c present as compared to FGF19 alone <ref><pubmed>11110663</pubmed></ref>. Ladher ''et al''.(2000) hypothesised that FGF19 induced Wnt8c, and together they induced the otic gene markers.

Another possibility is the independent action of FGFs and Wnt signalling.
* Studies have shown that Wnt signalling onto Pax2+ cells results in differentiation of those cells into otic placode tissue. Pax2+ cells that were not exposed to Wnt signalling differentiate as epidermis <ref name="PMID16452098"><pubmed>16452098</pubmed></ref>.
* Wnt signalling also suppresses Foxi2, resulting in a Foxi2-negative area of particular size, which then allows for FGFs to induce otic genes <ref name="PMID16452098"/>. In this case, Wnt signalling determined the size of the otic placode, yet acted independently from FGF signalling.
* Phillips et al. (2004) studied the role of FGF and Wnt signalling; specifically looking at FGF3, FGF8 and Wnt8. Their data showed that Wnt8 is not absolutely necessary for otic induction, however it is required for timely initiation of the otic field. <ref><pubmed>14757644</pubmed></ref>

'''The neural domain'''
[[File:neural domain.jpg|thumb|200px|The expression of Sox2 and Sox3 during development of the ear]]
During the early stages of embryonic development, a neural competent domain is established. This domain will eventually give rise to neurons and hair cells. Various signalling pathways are required to initially create this domain and to maintain it later on. <ref name="PMID19247974"><pubmed>19247974</pubmed></ref>

* ''FGF and Sox''
FGF signalling and the Sox genes are essential for the establishment of the neural competent domain. An important aspect of Sox genes is that they have a state of self-renewal, as well as a state of neural commitment. <ref><pubmed>15863505</pubmed></ref>
As investigated by Rex et al. (1997) and Pevny and Placzek (2005), "SoxB1 genes (Sox1, Sox2, Sox3) have been linked directly to ectodermal cells that are competent to acquire neural fate, and the commitment of cells to a neural fate".<ref><pubmed>9215646</pubmed></ref> <ref><pubmed>15721738</pubmed></ref>

Before the otic placode becomes distinct, Sox3 is already expressed in a broad area around the location of the future otic placode. Later in it will only be found in the proneural region of the otic placode. Based on this, the review by Alsina et al. (2009) suggests that a neural fate acquisition occurs prior to otic placode formation.<ref name="PMID19247974"/> During the early stages of development of the otocyst, Sox2 and Sox3 are found in proliferating cells within the proneural region. Both are expressed when neurons are generated, however, Sox3 switches off and only Sox2 remains during further development of the ear. This suggests that the ongoing expression of Sox2 plays a role in sensory cell development, as explained in the review by Alsina et al (2009).<ref name="PMID19247974"/>

-We will look into this in further detail when describing the development of the elementary sensory unit of the ear-

* ''Notch signalling''
Notch signalling is required for several developmental processes, including the maintenance of the neural competent domain.

In the notch signalling pathway, notch is the receptor, with most of its ligands being transmembrane proteins. Signalling is therefore restricted to neighbouring cells. Research by Daudet and Lewis (2005) reveiled how notch signalling plays a role in inner ear development, including:

- Notch signalling mediates lateral inhibition and thereby controls the differentiation of hair cells and supporting cells - in particular in the vestibular regions <ref name="PMID15634704"><pubmed>15634704</pubmed></ref>

- An early phase of Notch activity promotes formation of prosensory patches <ref name="PMID15634704"/>

- Other signalling pathways are likely to cooperate with Notch to specify prosensory regions of the otocyst <ref name="PMID15634704"/>

====The Otocyst====
[[File:neural fate.jpg|thumb|200px|Recent model related to sensory fate.]]

'''Patterning of the otocyst'''

The otocyst, also known as the otic vesicle, is present once invagination of the otic placode has occurred. Regionalisation of the otocyst results in the topological organisation of the ear. The neural tube affects the patterning of the otocyst, and FGF, Wnt and Hh signalling pathways are also known to play a role.
FGF and Wnt rely on signals from the hindbrain. <ref><pubmed>17891710</pubmed></ref>

Prosensory patches emerge within the otocyst. These develop as a differentiate from the neural competent domain.<ref name="PMID21266409"><pubmed>21266409</pubmed></ref>

- haircells (sensory patch)

- neurons (neural competent domain)

As proposed in recent models by Neves ''et al.'' (2011): Jagged 1 functions through lateral induction to activate Notch signalling. Notch signalling then functions through lateral inhibition and regulates Sox2 expression. Sox2 specifies sensory fate within the prosensory domains. "This confines sensory competence to the prosensory patches, ensuring the development of sensory organs of the correct size and location." <ref name="PMID21266409"/>

'''Establishing polarity and formation of inner ear structures'''
[[File:z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.]]

The different axis of the inner ear are fixed at different points in time. This means different signals are involved to establish the polarity and allow for development.<ref><pubmed>9389659</pubmed></ref>
The dorsal-ventral polarity is very significant in the development of inner ear structures. The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle.

The neural tube plays a role in patterning of the placode and it has been shown similar signals from the neural tube are also needed to establish the dorso-ventricular axis of the inner ear.<ref><pubmed>16325169 </pubmed></ref>

* ''Shh signalling''
The notochord produces Shh, which helps in patterning the dorso-ventricular axis of the neural tube. <ref><pubmed>18621990</pubmed></ref> This signal diffuses further and also affects the developing otocyst, where a gradient of Shh receptors is located from the dorsal to ventral aspect. <ref><pubmed>12231626</pubmed></ref>
Dorso-ventricular patterning and development of inner ear structures – in particular ventral structures – is achieved by the graded response to Shh.

As reviewed by Grooves and Fekete (2012) “data suggests that Shh acts on the ventral otocyst directly to regulate cochlear development, and that dorsal development can be regulated by signals from tissues adjacent to the otocyst that require Shh signaling for their normal development.”<ref name="PMID22186725"><pubmed>22186725</pubmed></ref>

* ''Wnt signalling''
Shh signalling for the ventral aspect is complemented by signals for the dorsal aspect of the inner ear. Wnt signalling takes places in the otic placode, as described above. This is initially as a gradient from medial to lateral <ref><pubmed>20171206 </pubmed></ref>, which later in the otocyst will be a gradient from doral to ventral <ref><pubmed>16452098</pubmed></ref>

As further suggested in the review by Grooves and Fekete (2012) “Wnt and Shh signals regulate different inner ear genes in different ways, with opposing gradients of Shh and Wnt signaling regulating the spatial localization of transcription factors, ultimately leading to the differentiation of a correctly patterned inner ear.” <ref name="PMID22186725"/>

* ''Hedgehog signalling''
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR'''
|- bgcolor=#E7FEFF
|
* Development of the inner ear: This starts out with the induction of the otic placode and consists of 3 major stages
'''1.''' Pre-placodal domain: After gastrulation, a pre-placodal domain is present adjacent to the anterior neural plate. The various placodes will arise from this domain.

'''2.''' Pre-otic field: Local signals establish the identity of each placode, including the otic placode. FGF signals from both rhombomeres and the cranial paraxial mesoderm are important otic inducers.

'''3.''' Otic placode/epidermis fate decision: signalling occurs to determine precisely which cells become the otic placode and which cells aquire the epidermal fate. FGF and Wnt signalling is necessary in this step, which could possibly be dependent or independent of each other.

* Neural component: During the early stages of embryonic development, a neural competent domain is established as part of the otic placode. FGF, Sox and Notch signalling play a role in creating and maintaining this domain. Once invagination occurs and an otocyst has formed, signalling pathways allow for patterning of the otocyst and formation of prosensory patches. Hair cells develop from the sensory patches and neurons develop from the remaining neural competent domain.

* Establishing polarity and formation of inner ear structures: The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle. For this reason, it is important for normal development of the inner ear to establish polarity, such as the dorso-ventral axis. Various signals are involved, including Shh and Wnt signalling. Hedgehog signalling needs to be suppressed.
|}

==Abnormal Hearing==

===Genetic===

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFA500"
|'''Genetic abnormality'''||'''Description'''||'''Image'''
|- bgcolor="#FFEFD5"
|''Mutation of GJB2 gene'' ||
* Approximately 60% of congenital deafness in developed nations is caused by genetic factors.
* More than 50 loci have been found to be responsible for the genetic causes of non syndromic deafness (isolated hearing loss with no affects to other parts of the body) called NSD and accounts for more than 80% of genetic related congenital deafness. GJB2 gene which instructs the protein Connexin 26 to be formed, is the most common cause of NSD.
* Connexin 26 is found all over the body, with a great number on the skin and in the inner ear.
*Over 90 of the GJB2 gene mutations have been associated with NSD. <ref><pubmed> 10980526 </pubmed></ref>

||
[[File:Mutation_on_GJB2_gene.jpg|x250px]]

|- bgcolor="#FFCC99"
|''Autosomal dominant hearing loss'' ||
* Autosomal dominant hearing loss is transferred directly though the previous generations and can usually be detected when reviewing at a family tree.
* There is a 50% probability that the child will also have hearing loss, and subsequently increases if both parents have the dominant gene. Research has shown that the phenotype due to GJB2 varies due to the great range of the degree of deafness in the patients.
* This alludes to the fact that other environmental causes have also contributed to the patients hearing impairment <ref><pubmed> 10980526 </pubmed></ref>.
* M34T missense mutation has been found in families where there are both affected and non affected people thus indicating its contribution to autosomal deafness both dominant and recessive deafness.
* Similarly, studies have shown additional missense mutations R75W, D66H and G59A are also causes of DNFA however they have been connected to other clinical manifestations <ref><pubmed> 11216656 </pubmed></ref>.

||
[[File:Dominant_diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Autosomal recessive hearing loss'' ||
* Autosomal recessive deafness is an inheritance of both the mother and father’s recessive genes of connexin 26 mutation.
* There is a 25% chance that the child will have hearing loss. However normally as both parents have normal hearing, it is difficult to foresee if the child will inherit hearing loss.
* The most prevalent connexin 26 gene mutation in the majority of ethnic groups for DNFB is the 35delG.
* Mutations in the connexin 26 genes equate to half of the DNFB cases <ref><pubmed> 14979964 </pubmed></ref>.

||
[[File:Autosomal_Recessive_Inheritance_Diagram.jpg|x250px]]

|- bgcolor="#FFCC99"
|''X linked hearing loss'' ||
* X linked hearing loss is carried by the mother and passed down to both the male and female children.
* Generally only the male children are affected if they receive the affected X chromosome while the daughters will be the carrier of the gene.
* The hearing loss can be a combination of both conductive (damage to the outer or middle ear) and sensorineural hearing loss (malfunction of the cochlea and or the hearing nerve) <ref><pubmed> 1163535 </pubmed></ref>.

||
[[File:X_Linked_Recessive_Diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Mitochondrial hearing loss'' ||
* Mitochondrial hearing loss is passed down solely through the mother.
* It is caused by mutations in either MT-RNR1 or MT-TS1 leading to moderate to profound hearing loss.
* MT RNR1 is generally correlated to aminoglycoside ototoxicity and sensorineural hearing loss independent of aminoglycoside ototoxicity occurring usually in the 20’s.
*Aminoglycoside ototoxicity refers to the increased chance of hearing loss after consuming antibiotics and is irreversible.
* MT-TS1 is sensorineural hearing loss occurring during childhood and is generally considered nonsyndromic <ref><pubmed> 20301595 </pubmed></ref>.

|}

NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS

'''Genetic Syndromes'''

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFF000"
|'''Syndrome'''||'''Description'''||'''Image'''
|- bgcolor="#FFFDD0"
|''Usher Syndrome'' ||
* Most common cause of congenital deafness due to defects in the inner ear and also causes vision loss
* Separated into 3 subgroups: USH1, USH2 and USH3<ref><pubmed> 16434480 </pubmed></ref>.

## USH1 - profound deafness at birth
## USH2 - Moderate level of deafness at birth
## USH3 - Hearing normal at birth but will gradually worsen as the child ages
* Various genes are thought to cause the disorder most recent is WHRN gene <ref><pubmed> 16452831 </pubmed></ref>.

||
[[File:Basal_Cochlear_Outer_Hair_Cells.jpg|x250px]]
|- bgcolor="#FBEC5D"
|''Pendred Syndrome'' ||
* Autosomal recessive disorder which causes progressive sensorineural hearing loss, and can also affect the thyroid gland, accounting for more than 10% of severe hearing impairment.
* Patients usually have structural malformations of the inner ear, in some cases a missing cochlear.
* The syndrome is caused by a variety of gene mutations, SLC26A4 gene causing more than half of all of the Pendred Syndrome cases.
* There is no current treatment option, and is most important that it is screened for in childhood hearing loss in order to teach differing ways of communication <ref><pubmed> 18285825 </pubmed></ref>.

'''All of these defects are suggestive of a developmental arrest at 7 weeks of human embryonic development. In addition, it has been noted that patients with Mondini malformations usually have reduced numbers of hair cells and spiral ganglion cells (11); these latter microscopic defects are thought to lead to the deafness. '''

||
[[File:Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px]]
|- bgcolor="#FFFDD0"
|''Goldenhar Syndrome'' ||
* There are a varying amount of malformations usually regarding the ears, mouth and jaw such as microtia and preauricular appendages.
* There is limited knowledge as to how this syndrome occurs, and there are currently no treatments for the subsequent hearing loss. <ref><pubmed>10829494 </pubmed></ref>
* It is thought that environment could play a role with an increased level of children developing this syndrome during the Golf War <ref><pubmed> 9408975 </pubmed></ref>.

||
[[File:MRI_of_Goldenhar_Syndrome.jpg]]

|}

===Environmental===

'''Infections'''

{| cellpadding=5 style="border:1px solid #74C365"
|- bgcolor="#009F6B"
|'''Organism'''||'''Description'''||'''
|- bgcolor="#F0FFF0"
|''Toxoplasmosis'' ||
* Toxoplasma gondii is an intracellular protozoan and can infect humans through undercooked meat containing bradyzoites or by legumes infected by oocysts (greatly infectious).
* A study published in 1988 collected data from 23,000 pregnancies which found mothers with an IgG antibody to toxoplasmosis during pregnancy doubled the incidence of deafness for the child. This was identified along with other symptoms such as microcephaly and low IQ scoring. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis.
* Congenital toxoplasmosis also results in mental retardation and deafness along with blindness and usually multiple organs affected such as Chorioretinitis. Notably, the infection risk differs during the gestation time: “1% at less than 6 weeks, 4–6% at 6–16 weeks, 20–40% at 16–25 weeks and 60–80% at 36 weeks of gestation” (http://www.marmaramedicaljournal.org/pdf/pdf_MMJ_446.pdf)
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref><pubmed> 3041362 </pubmed></ref>.
* Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 10356003 </pubmed></ref>.
*There have been inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>. Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 11561963 </pubmed></ref>.
* Notably, although this was an uncontrolled trial, this prenatal treatment was proven to be of some benefit <ref><pubmed> 10356003 </pubmed></ref> <ref><pubmed> 12618153 </pubmed></ref> <ref><pubmed> 1929726 </pubmed></ref> <ref><pubmed> 11821335 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article was published in the Lancet providing clear evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody.
* Studies have subsequently shown that the fetal infection risk will differ throughout the duration of the pregnancy. During week 1 to 10, there is a 100% fetal transmission rate, leading to an 81% rate during the first trimester, due to the immaturity of the fetal defense mechanisms and solely relying on maternal immunoglobulin G. This decreases throughout the second and third trimester, however the infection rate goes back to 100% in the last month of pregnancy. The sudden decrease is thought to be due by the maternal antibodies along with fetal cell mediated immune responses along with the humoral responses.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium. (G Tondury, DW Smith Fetal rubella pathology). As the cells appear desquamated within the vessel lumens, it is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli, which in turn leads to an increase in infection and damage to the developing fetal organs.
* Fetal organ development may be compromised by the virus prompting apoptosis. Studies indicate that the caspid protein dependent mechanism of the Rubella virus leads to apoptosis. (Rubella Virus Capsid Protein Induces Apoptosis in Transfected RK13 Cells, Robert Duncan). Rubella infected cells which do not undergo apoptosis result in a reduced growth rate and a shorten life span due to a decreased mitotic activity.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation.
* As Rubella has long been a known congential disease, through the Rubella vaccine, this has almost completely eliminated the disease in western countries. Thus as this is an entirely preventable disease, future programs should of Rubella prevention should lead to Rubella being a disease of the past.

(Rubella, the lancet, DWG Brown AND KV Pugachev, TK Frey Rubella virus induces apoptosis in culture cells)

(Onset and severity of hearing loss due to congenital rubella infection)

|- bgcolor="#F0FFF0"
|''Cytomegalovirus'' ||
* Cytomegalovirus (CMV) is an enveloped herpes virus which is passed to the fetus via vertical transmission.
* As 95% of pregnant women are asymptomatic, it is incredibly hard to diagnose.
* The virus can be classified into acute and non acute infections. Acute maternal infection can be verified by low IgG avidity levels.
* There are 2 methods to determine if the fetus has contracted CMV. A cordocentesis can be conducted to obtain fetal blood for sampling however issues have been raised regarding its safety and notably accessibility. (Weiner C.P.: Cordocentesis. Obstet Gynecol Clin North Am 15. 283-301.1988).
* Amniocentesis can also diagnose the CMV via PCR and is considered the better diagnostic tool due to the quick and reliable results it gives. High DNA copy numbers for the CMV infection relates to a greater severity of the disease and hence could indicate the hearing impairment outcome.
* A recent study has noted the role of CMV causing sensorineural hearing loss and subsequently being a high risk factor for hearing impairment. The results showed that more than half of the children participating had CMV IgG antibodies, with 20% being found as CMV DNA positive which indicates that the child has an active infection. (Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology, Eva Karltorp).
* There is no current treatment protocol for CMV, however a non random sampling trial has suggested the treatment of hyperimmune globulin giving promising results in the study. (Nigro G., Adler S.P., La Torre R., et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353. 1350-1362.2005; ).
* Another study showed that treatment of the symptomatic cases of CMV infection with intravenous ganciclovir (or Valganciclovir orally) for 6 weeks has indicated improvement in the child’s hearing. (Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46S:S22-S6.)

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''||'''
|- bgcolor="#FFA6C9"
|''Alcohol consumption during pregnancy'' ||
* Fetal Alcohol syndrome is a variety of conditions which occur in the fetus if the mother consumes alcohol during pregnancy. There is no safe level of alcohol consummation during pregnancy.
*Fetal Alcochol Syndrome is associated to 4 hearing impairment disorders:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss
(Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review. Church MW, Kaltenbach JA Alcohol Clin Exp Res 1997 May;21(3):495-512.)
*It is also associated with a variety of other malformations (skeletal and visceral), growth retardation and nervous system defects. The developmental delay of the auditory system is thought to be due to decreased growth of neurons and myelin and subsequently the synapses.
* Sensorineural hearing loss is thought to be caused by a greater amount of apoptosis during the inner ear development and thus leading to decreased levels of auditory nerve fibres and sensory receptor cells. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
*

|}

===Structural malformations of the ear===

{| cellpadding=5 style="border:1px solid #880085"
|- bgcolor="#9457EB"
|'''Structural malformation'''||'''Description'''||'''Image'''
|- bgcolor="#FAF5FF"
|''Stenosis'' ||
* Internal auditory canal stenosis is classified as someone who has an internal auditory canal 2mm or less.
* It is considered a rare disease with only 2.5% of patients with congenital hearing loss being affected by stenosis .
* It is thought to be as secondary to vestibulocochlear nerve hypoplasia <ref><pubmed> 9892864 </pubmed></ref>.

||
[[File:Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px]]
|- bgcolor="#E0CEF2"
|''Enlarged vestibular aqueduct'' ||
* Approximately 7% of all sensorineural hearing loss patients had an enlarged vestibular aqueduct.
* The most recognised cause of an enlarged vestibular aqueduct is due to a mutation on chromosome 7 on the SLC26A4 gene <ref><pubmed> 16570074 </pubmed></ref>.
* There is no current treatment and thus is important to identify it when the patient is a child so that alternative communicative methods can be taught.

(Sensorineural hearing loss in Patients with large vestibular aqueduct, Okumura)

||
[[File:Enlarged_Vestibular_aqueduct.jpg|x250px]]
|- bgcolor="#FAF5FF"
|''Microtia''||
* Deformation of the outer ear which can be with or without the external ear canal.
*There are 4-5 grades of microtia which range from a small ear to deformed outer ear to no ear present at all.
* Treatment involves the complete reconstruction of the outer ear and occasionally the middle ear depending on the level of hearing loss associated with it <ref><pubmed> 10890145 </pubmed></ref>.

||
[[File:Microtia_boy_surgery.jpg|x320px]]

|}

---------

==Technologies to detect==

The importance of having a neonatal screening test for hearing within the early days of life are important for the rest of that individual’s life. Screening is used to identify the children most at risk of having a congenital hearing problem. The importance of having an early diagnosis and having a method of intervention is crucial for the development of speech and language and learning of the child later in life, as reviewed by Oudesluys-Murphy ‘’et al’’. 1996. <ref name="PMID8789756"><pubmed>8789756</pubmed></ref>
Screening tests allow for the detection of hearing loss within the few days of life. This could be due to a dysfuctional cochlea or various other problems as discussed in our abnormal hearing section. Within Australia there are a few simple test that allow newborns to be tested fast, accurately and reliable <ref name="PMID8789756"/>.

===Oto-acoustic testing===
[[File: infant hearing test.jpg|thumb|300px| Testing the hearing of an infant]]

The oto-acoustic test measures the integrity of the inner ear. This involves the cochlea and its physiological effects - the production of an otoacoustic emission in response to sound <ref name="PMID8220282"><pubmed>8220282</pubmed></ref>. It involves inserting a probe into the ear canal, which then produces clicks or tones that are normally picked up by the cochlea. The function and healthiness of the cochlea can be measured, as the different parts of the cochlea respond to different forms of stimuli in terms on pitch and frequency <ref name="PMID8220282"/>.

For this test, there are two methods used for screening the hearing in newborns.

• The production of a single click or tone called the Transient Evoked Otoacoustic Emission test (TEOAE) <ref name="PMID8220282"/>

• The production of two simultaneous tones named the Distortion Product Otoacoustic Emissions Test (DPOAE) <ref name="PMID8220282"/>

===Auditory Brainstem Response===

The Auditory Brainstem Response tests the neurological function of the auditory brainstem. It is more so used as a referral test, rather than a screening test, as generally hearing loss is already suspected <ref name="PMID11667937"><pubmed>11667937</pubmed></ref>. This test uses a click or a tone, which causes the production of impulses by the neurons from the auditory nerve, travelling along the auditory pathway. This is then measured and detected by external electrodes that are on the scalp and the earlobe of the newborn. <ref name="PMID11667937"/>

===Automated Brainstem Response===

This cheaper and quicker method uses an ear cup that is fitted over the infant’s ear <ref name="PMID11343042"><pubmed>11343042</pubmed></ref>. This then sends out a stimulus and a response is measured through a series of electrodes that are connected to the earlobes, scalp, shoulders and neck<ref name="PMID11343042"/>. The automated brainstem response uses a computer to visualise and calculate the results, and produce a result of either ‘pass/refer’. Data of the patient are cross-referenced with a collection of results regarded as normal responses<ref name="PMID11343042"/>.

===OtoSCOPE===

A new genetic testing method called OtoSCOPE discovered in 2010 has greatly increased the efficiency for testing nonsyndromic hearing loss and Usher syndrome. It provides a great diagnostic tool, as all the genes related to hearing loss can be sequenced simultaneously thereby decreasing cost and time. The patients can be informed relatively early for any genetic abnormalities therefore providing early prognosis and genetic counselling. <ref><pubmed>21078986</pubmed></ref>

==Technologies to overcome the problems==
Depending on the hearing loss, there are different types of technologies to overcome this. Types of hearing lost are conductive and sensori-neutral . One type is the conductive, caused by the damage or blockage of the outer or middle ear, the other is sensori-neutral, where the damage is to the auditory pathway or nerve. In some cases there is a combination of the two. And there are two current technologies that overcome this problem and they are the the hearing aid and the cochlea ear implant.

===Hearing aid===
[http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx Hearing Aids] are a major advance in helping people hearing, they work by amplifying the sounds so they can be detected even by the damaged inner ear. This method of hearing relies on the healthiness or still relative functioning cochlea. The damage of the sensori-neural pathway is overcome by the amplication of sounds to compensate the loss of hearing cells or hair cells in the cochlea. This is proportionate to the amount of hair cells still functioning. This amplication of the sounds, helps the patient hear and listen and communicate with others. This however also amplifies background noise. They consists of the microphone, amplifier and a speaker. From the sound being received by the microphone, this converted by the microphone into electrical impulses and replays it to the amplifer. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref name="NIH">{{citation
|title= Hearing Aid Basics
|url=http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

===Cochlea Ear Implant===
[http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx Cochlea ear] implants help the hearing impaired to listen. This is through having a device to provide a sense of sound. The cochlea implants consists of a few major components in helping the patient hear. It consists of a microphone, which detects the environmental sounds, a small electronic processor that selects the sound produced from the microphone. There is also a transmitter and the stimulator. This converts the signal that comes off the electronic processor into electrical impulses, which leads up the final component which is the electrode array. This picks up the electrical impulses and delivers them to the correct region of the auditory nerve. These methods of hearing or sensing sound are used only in severer or profoundly hearing impaired who have a dysfunctioning cochlea. <ref><pubmed>PMID:6028666</pubmed></ref>

<ref name='cochlea_NPR'>{{cite=book| first=Hendrinkus| last=Dulfhuis|coauthors=| title=''Cochlea Mechanics: Introduction to a time Domain Analysis of Cochlea''| date=10-2-2012| publisher Springer Science+ Business Media|url=http://books.google.com.au/books?id=1UpECoc_q3UC&pg=PA5&lpg=PA5&dq=Gabriele+Falloppio+ear&source=bl&ots=mc9sb_0UR1&sig=WqdWXmDrJWV-2rqlWF3ihzMnWLE&hl=en&sa=X&ei=ozFoUPL8BoiQiQf_qoDYDw&ved=0CEEQ6AEwAw#v=onepage&q=Gabriele%20Falloppio%20ear&f=false| work=cochlea implant| pages = | accessdate = 20012-10-01 | language = }}</ref>

==Current Research==

* ''' ''Hair cell differentiation'' '''

A recently published paper by Pan ''et al.'' (2012) investigated the various levels and durations of expression of a particular transcription factor, which is necessary for hair cell differentiation. The ''Atoh1'' transcription factor was tested for by using conditional knock-out mice - ''Atoh1-cre'' <ref name="PMID22279587"><pubmed>22279587</pubmed></ref>. They determined that reduced levels of ''Atoh1'' resulted in the progressive loss of hair cells from the organ of Corti shortly after birth <ref name="PMID22279587"/>. Similar data was obtained when the deletion of the ''Atoh1'' transcription factor was delayed. Slight differences were noted between inner and outer hair cells: the loss of inner hair cells was more significant than the loss of outer hair cells. This indicates that ''Atoh1'' may play a role in the differential development of inner and outer hair cells.
[[File: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears.]]
[[File: Atoh1 hair cell loss.png|none|thumb|200px|Conditional deletion of Atoh1 results in death of organ of Corti cells and patchy Myo7a-positive presumptive hair cells which are innervated by many nerve fibers.]]

* ''' ''Stem cell therapy'' '''

The discovery of stem cells has led to an entirely new era in research, and the potential to prevent and treat conditions such as hearing loss.
It has been discovered that stem cells are present in the inner ear. In non-mammalian vertebrates, these stem cells allow the inner ear sensory epithelium to recover and function again after being damaged. This is not the case when it comes to mammals. Cells capable of regeneration are found in the vestibular sensory epithelium and in the neonatal cochlea. <ref><pubmed>8456285</pubmed></ref> However, only very limited regeneration may take place after damage has been done to the inner ear. Research is ongoing in various laboratories worldwide, such as at the University of Sheffield, as to how stem cells can be used to regain the sense of hearing. Early September 2012 there was an incredible breakthrough, as scientists from the university used [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx human embryonic stem cells to restore hearing in a common form of deafness.] This proves human stem cells could be used to repair the damaged ear and will hopefully lead to various other stem-cell based therapies.

[[File: aquaporins.png|thumb|200px|Aquaporins]]

* ''' ''Middle ear homeostasis'' '''

A recent article by Morris ''et al.'' (2012) investigated the mechanisms responsible for the ion homeostasis in the middle ear and how this relates to disease. They used BALB/c mice for immunohistochemistry of particular ion homeostasis factors of the middle and inner ear <ref name="PMID22720014"><pubmed>22720014</pubmed></ref>. This was then used to compare transport and barrier mechanisms and identify what is present in the tympanic cavity. Next, the middle ears received transtympanic injections with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation <ref name="PMID22720014"/>. Data shows that cellular hypertrophy occurred and localization of ion channels, such as aquaporins, was preserved within the inflamed middle ear epithelium<ref name="PMID22720014"/>. Morris ''et al.'' suggested that these channels could be used as a therapeutic target.

* ''' ''Molecular mechanisms - ongoing project'' '''

The HEARing Cooperative Research Centre ([http://www.hearingcrc.org/ CRC]) is involved in many ongoing research projects. Professor Doug Hilton supervises one of the projects: Genomic & molecular therapeutic approaches to environmental and age-related hearing loss.

A major public health issue is presbycusis - age-related hearing loss. It is known that apoptosis of cells within the cochlea plays a role; however, the many other factors involved and their molecular mechanisms are not yet fully understood. This research project is looking at the genes, proteins and regulatory pathways involved in both hearing and hearing-loss. The aim is to use this knowledge to identify molecules that can be targeted to [http://www.hearingcrc.org/research/projects/r122 prevent and/or treat hearing loss.]

==Glossary==

*'''Cristae''': the sensory organ of rotation located in the semicircular canal of the inner ear

*'''Ectoderm''': the outermost layer of the three primary germ cell layers in the very early embryo

*'''Epidermis''': surface epithelium of the skin, superficial to the dermis

*'''Gastrulation''': The inward migration of cells

*'''Hindbrain''': The lower part of the brainstem, comprising the cerebellum, pons, and medulla oblongata

*'''Lateral inhibition''': process whereby one cell takes on a state and the adjacent cells takes on the opposite state

*'''Mesoderm''': the middle layer of the three primary germ cell layers in the very early embryo

*'''Neural plate''': a thickened plate of ectoderm along the dorsal midline of the early vertebrate embryo that gives rise to the neural tube and crests

*'''Neural tube''': A hollow structure formed after gastrulation, from which the brain and spinal cord form

*'''Open neural plate stage''': stage of the neural plate before closure into the neural tube

*'''Otic placode''': a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops

*'''Otocyst – otic vesicle''': The structure formed by invagination of the embryonic ectodermal tissue that develops into the inner ear

*'''Pre-placodal domain''': An ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

*'''Proneural region – neural competent domain''': a region of the otic placode involved in neurogenesis

*'''Prosensory region''': region containing a population of cells that can develop into hair cells or or supporting cells

*'''Rhombomere''': a segment of the developing rhombencephalon (hindbrain segment)

*'''Saccule''': one of two otolith organs. The smaller of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Somite''': A segmental mass of mesoderm in the vertebrate embryo, occurring in pairs along the notochord

*'''Utricle''': one of two otolith organs. The larger of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Vestibular region''': the region of the inner ear close to the cochlea. Here the semicircular canals converge

*'''Vestibulo-acoustic ganglion''': The cranial ganglion of cranial nerve 8

==External Links==

[http://news.yale.edu/2012/02/16/yale-study-how-mitochondrial-dna-defects-cause-inherited-deafness|Yale study: how mitochondrial DNA defects cause inherited deafness]

== References ==
<references/>

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

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 6

2012-10-02T04:07:26Z

Z3333431: /* Cochlea Ear Implant */

[[File: z3333865.Ruby.jpeg | 450px| right]]
= Hearing Development=

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important sense and an inherent part of human life. It widens our scope of life and allows us to work, relax, communicate, learn and form memories. The sense of hearing has evolved through the years in vertebrates is inherent for both hunting and surviving. The sound energy produced has be converted into an electrical signal for us to make sense of it. For successful transmission the correct development of the ear is of utmost important. Not only formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will also talk about some abnormal processes and mutations which lead to various structural and functional diseases.

==History==

{| cellpadding=5 style="border:2px solid #08E8DE"
|- bgcolor= #00BFFF
|'''Date''' || '''Description'''
|- bgcolor=#87CEEB
|'''1536''' || The first clear distinction is made between the middle and inner ear. How to observe the middle ear ossicles is also explained. <ref><pubmed>4598483</pubmed></ref> <ref name="PMID6341584"><pubmed>6341584</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438986/?page=6 Nicola Massa.]
|- bgcolor=#ADD8E6
| '''1543''' || ''De fabrica'' by Andreas Vesalius was published which identified and named the incus and the malleus. Also identified the tensor tympani and the anatomical position of the oval window to the round window <ref><pubmed>22581496</pubmed></ref>. [http://www.ncbi.nlm.nih.gov/pubmed/22581496 Andreas Vesalius]
|- bgcolor=#87CEEB
|''' 1561''' || ''Observationes anatomicae'' is published and describes the tympanic membrane. The stapes ossicle is also discovered and named. <ref><pubmed>22965774</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/22965774 Gabriele Falloppio]
|- bgcolor=#ADD8E6
| '''1563''' || In the book ''De Auditus Organis'', it was proposed that the tympanic membrane is connected to the nasopharynx. This tube was named after the writer of the book. He also completed the diescritpion of the tensor tymapani: <ref><pubmed>7029021</pubmed></ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 Bartolomeo Eustachi]
|- bgcolor=#87CEEB
|'''17th Century'''|| The Metal ear was one of the first hearing aids created. It was placed over the ear to channel sound into the ear.
|- bgcolor=#ADD8E6
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#87CEEB
|'''1683''' || The bony labyrinth is described in more detail. It is determined the spiral lamina has a bony and membranous part, and it divides the spiral duct into an upper and lower compartment. <ref name="PMID6341584"/>[http://www.sciencedirect.com/science/article/pii/S1286011510000172 Duverney.]
|- bgcolor=#ADD8E6
|'''1704'''|| The book ''De aure humana tractatus'' with information regarding the anatomy, physiology and pathology of the ear is published.<ref name="PMC1142106"><pubmed>PMC1142106</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor= #87CEEB
|'''1707'''|| It is proposed that the labyrinth contains fluid instead of air. <ref name="PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor=#ADD8E6
| '''1772'''|| Antonio Scarpa discovers the ear labyrinth <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

==Adult Anatomy and Histology==

[[File:Anatomy_of_the_Ear.JPG|thumb|left|450px|Anatomy of the ear]]

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear. The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus. The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate. The malleus, which is in contact with the tympanic membrane, moves which in turn moves the other ossicles. The ossicles namely malleus, incus and stapes provide solid medium for the waves to travel through and act as a lever increasing the amplitude of the sound wave 20 times.

The oval window marks the boundary between the middle and the inner ear, which constitutes of an outer bony labyrinth and an inner membranous labyrinth. The cochlea which is a coil resembling a snail’s shell houses the organ of Corti, the peripheral receptor for hearing. Histologically the cochlea is divided into 3 parts scala vestibule, scala media and the scala tympani divided by the vestibular and basilar membrane respectively.

The sound waves are transmitted from the stapes into the oval window. The vibrations cause movement of the perilymph fluid in the scala vestibuli into the scala media causing movement of basilar membrane and bending of the hair cells. The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve. The nerve impulses travel from this neve through the brainstem to the thalamus to the primary auditory cortex, which is located on the transverse temporal gyrus.

The basilar membrane has a tonotopic organisation and human ears can hear sounds ranging from 20-20000 Hz. Near the apex of the cochlea the basilar membrane is wide and loose whereas near the base is narrow and tight hence enabling us to hear different frequencies.

==Development==

The development of outer ear is attributed to the first pharyngeal arch. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref>

The pharyngeal arches arise as a series of bulges arising laterally from the embryo head around 3-4 weeks of human development. The arches have a consistent organisation of the endoderm, ectoderm and mesoderm. The ectoderm forms the outer surface of the arch with the core made up of mesoderm. Next to the mesoderm core on the opposite the ectoderm is the endoderm. All three layers contribute to the formation of outer, middle and inner ear structures hence contributing to hearing. In between the arches the ectoderm and endoderm come in contact with each other forming a continuous sheath on either side of the mesoderm, forming groves externally and arches internally. Inside the mesoderm core of each arch lies a specific cell population that goes onto develop into a nerve, cartilage and artery.

===Outer Ear===

'''Pinna'''

[[File:Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages]]

Post development the anatomy of the external ear simply consists of the pinna or the auricle and external acoustic/auditory meatus. The auricle develops around the first and second pharyngeal arches as a series of auricular enlargements or hillocks around the 5th week of development. Gradually by the 6th week the hillocks grow in size and increase to six in number, three on the first arch and 3 on the second arch, the first of which starts at the bottom anterior side going in a clockwise direction. In the 7th week the hillocks enlarge further and each of the arches contributes to a specific part of the pinna. The first arch gives rise to the tragus, helix and cymba concha whereas arch 2 gives rise to concha, antihelix and antitragus. The differentiation starts around the neck region but as the mandible develops the pinna structures move more cranially. It is not until the 12th week that the fusion of these various parts occur and is completed by week 20th.

Various genetic markers and coordinated signalling mechanisms are required for normal development of the pinna. One of which is the EYA1 gene, which is imperative for formation of the pinna. Mice with a homologous Eya1 null gene either has malformed or absent ears and since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development, mutation in which causes malformation of the perichondrium and thus cartilage formation. Another gene important for early patterning of the pinna is the Hox2 gene, mutations in which leads to formation of a shapeless protuberance rather than a normal shaped pinna. Hox2 gene is expressed in the second pharyngeal arch and the malformations in the ear are contributed to the parts derived from the second pharyngeal arch like the antitragus, antihelix and concha.
<ref><pubmed>14674478</pubmed></ref> <ref><pubmed>17104502</pubmed></ref>

'''External Auditory Meatus'''

The External Auditory Meatus (EAM) is derived from ectoderm that forms the first pharyngeal groove situated between the 1st and the 2nd pharyngeal arches. At 8 weeks of gestation a c-shaped skeletal structure develops from ectoderm of the first pharyngeal cleft migrating and meeting the mesoderm of the first grove called the tympanic ring that controls and coordinates the invagination of the ectoderm. The tympanic ring is a transient embryological structure, which eventually gets integrated into the temporal bone and provides anchorage to the eardrum. Medial to the ring lays the endoderm of the first pharyngeal arch that contributes to the formation of the tympanic or middle ear cavity. At 12 weeks of gestation the tympanic ring begins to ossify in a sequential fashion via endomembranous ossification forming the bony part of the EAM. The ring starts to condense at the proximal end of the 1st pharyngeal arch, goes around the circumference of the cleft and invades the 2nd arch. Starting at the tip of the 1st pharyngeal cleft the ectodermal cells begin to proliferate filling the lumen of the meatus forming a meatal plug which medially extends in a disc like fashion during week 10. The proliferation follows the path of the tympanic ring with the mesoderm tissue between the ring and the meatus forming a fibrous layer. In week 13 of development the innermost part of the meatal plug makes a contact with malleus. This innermost part of the disc in week 15 splits leaving a thin endoderm layer behind which contributes to formation of the tympanic membrane. By the middle of 16th week the meatus although full in length is still narrow and curved and it is not until week 18 that it gets fully expanded and complete.

Since the correct development of EAM is heavily dependent on the tympanic ring, hence any mutation in the tympanic ring causes an abnormal growth of the EAM. Many genes are required to coordinate and control tympanic ring formation most prominent being the Gsc and Prx1 genes. Chimeric studies have revealed that tympanic ring in Gsc null mice fails to ossify whereas the ring whereas mice with null Prx1 gene have an over ossified tympanic ring. In both cases the meatus fails to form indicating a delicate balance between the expressions of both genes is required for proper ring development hence correct formation of EAM. Likewise for pinna formation Hox2 gene is also essential for differentiation of pharyngeal arch into the tympanic ring and the formation of EAM. <ref><pubmed>10976045</pubmed></ref> <ref><pubmed>14674478</pubmed></ref> <ref><pubmed>1441991</pubmed></ref>

===Middle Ear===

'''Tympanic Membrane'''

Tympanic membrane or the eardrum forms the boundary between the outer and middle ear and responsible for transmitting the soundwaves coming in from the EAM to the mechanical waves going into the ossicles. During 8th week of gestation the development of tympanic membrane begins when the first funnel shaped ectodermal cleft meets the endodermal pouch with the mesenchyme growing in-between. This mesenchyme eventually becomes thinner and forms the eardrum during week 12. The diameter of the membrane grows three fold between week 11 and 16 and the membrane fuses with the tympanic ring.

The 1st pharyngeal cleft (ectoderm) gives rise to the EAM and the tympanic membrane comes from the mesoderm from the 1s pharyngeal arch. The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week. During week 7 the 2nd pharyngeal arch constricts the tympanic recess dividing it into a medial portion that form the Eustachian tube and a lateral portion that forms the tympanic cavity. <ref><pubmed> 17346562</pubmed></ref> <ref><pubmed> 10976045</pubmed></ref> <ref><pubmed> 2921547</pubmed></ref>

'''The Ossicles'''

The middle ear constitutes of the skeletal structures called ossicles, which amplify and transmit sound to the inner ear.

The middle ear consists of the middle ear cavity and it are housed the 3 ossicles – the malleus, incus and stapes from lateral to medial. The mesenchymal tissue or the neural crest cells from 1st and 2nd pharyngeal arch contributes to the formation of the ossicular chain.

Two main theories underlie the formation of the ossicles. First is the classical theory according to which the malleus and incus develops from the first pharyngeal arch whereas stapes develops from the 2nd pharyngeal arch. Another theory proposes that malleal head and body of incus comes from the first pharyngeal arch while the second arch gives rise to stapes, handle of malleus and long process of incus. <ref><pubmed>18803631</pubmed></ref>.

[[File:normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology]]

===Inner Ear===

The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode.
The otic placode is a thickened portion of ectoderm located on the each side of the developing head of the embryo, next to the hindbrain. It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed. Invagination occurs next, which creates the otocyst - a vesicle which will develop into the different components of the inner ear: the cochlea, the semicircular canals with cristae, the utricle, the saccule and the vestibulo-acoustic ganglion. <ref name="PMID17891709"><pubmed>17891709</pubmed></ref>[[File:z3333865.stages development inner ear.jpg|thumb|300px|Developmental milestones in mouse inner ear formation]]

====The Otic Placode====

'''Induction of the otic placode'''

Experiments with molecular markers have revealed that several steps are needed for induction of the otic placode.

We will briefly consider the three major steps:

'''1''' ''Pre-placodal domain''

The pre-placodal domain is a narrow strip of the ectoderm adjacent to the anterior neural plate after gastrulation. Different placodes arise from the pre-placodal domain. All the craniofacial sensory organs, including the ear, develop from these different placodes located at the periphery of the neural plate.

Various evidence indicates the existence of this pre-placodal region:

* Morphology indicates a thickened band of ectoderm around the anterior neural plate in some species, including mice and humans. As time progresses, this thickening will only be present at the locations where the different craniofacial placodes differentiate - including the otic placode.<ref><pubmed>15531360</pubmed></ref>

* Experiments have also shown that the placodes will only develop in the correct location, if rotation of the ectoderm along the anteroposterior axis takes place at the open neural plate stage. If rotation takes place at a later time, the placodes will form at incorrect places.<ref><pubmed>14100031</pubmed></ref>

* Gene expression has also indicated that particular genes are present in the pre-placodal domain. These genes belong to the Dlx, Six, Eya, Iro, BMP, Foxi and Msx families. Glavic et al. (2004) has shown that 'loss and gain of function of some of these genes resulted in the widening or reduction of the pre-placodal field'. Linked to this was also the domain of expression of some placode-specific genes; which either enlarged or diminished.<ref><pubmed>15242793</pubmed></ref>

'''2''' ''Pre-otic field''
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

Once the general placodal state has been established, the identity of each placode is induced by local signals. The optic placode is induced by various signals, including Pax8, Pax2, Fibroblast Growth Factors (FGFs), and many transciption factors.

In particular the FGFs are significant otic inducers. Signalling occurs from various rhombomeres from the hindbrain and the cranial paraxial mesoderm located beneath the area of the otic placode. For example, in mice FGF3 is expressed in rhombomeres
5 and 6, whereas FGF10 is expressed in the underlying mesoderm.<ref><pubmed>7789270</pubmed></ref> <ref name="PMID12810586"><pubmed>12810586</pubmed></ref> Mutations of FGF3 and FGF10 have been investigated. Results showed that mice with a mutation of either FGF3 or FGF10 developed an abnormal otic vesicle, and a combination of the two mutants resulted in failure to form an otic vesicle.<ref name="PMID12810586"/>

''--> picture''

'''3''' ''Otic placode/epidermis fate decision''

In the presence of FGF signalling, Wnt signalling can significantly influence the next step, which is the otic placode/epidermis fate decision. According to the review article by Ohyama ''et al''. (2007) ‘Cells receiving high levels of Wnt signalling differentiate as otic placode, while cells receiving little or no Wnt signalling differentiate as epidermis.’<ref name="PMID17891709"/>

The first evidence regarding the contribution of Wnt signalling came from experiments with the otic ectoderm of chicks.
* Data showed that specific marker genes, such as Pax2, were induced to a greater extend with FGF19 and Wnt8c present as compared to FGF19 alone <ref><pubmed>11110663</pubmed></ref>. Ladher ''et al''.(2000) hypothesised that FGF19 induced Wnt8c, and together they induced the otic gene markers.

Another possibility is the independent action of FGFs and Wnt signalling.
* Studies have shown that Wnt signalling onto Pax2+ cells results in differentiation of those cells into otic placode tissue. Pax2+ cells that were not exposed to Wnt signalling differentiate as epidermis <ref name="PMID16452098"><pubmed>16452098</pubmed></ref>.
* Wnt signalling also suppresses Foxi2, resulting in a Foxi2-negative area of particular size, which then allows for FGFs to induce otic genes <ref name="PMID16452098"/>. In this case, Wnt signalling determined the size of the otic placode, yet acted independently from FGF signalling.
* Phillips et al. (2004) studied the role of FGF and Wnt signalling; specifically looking at FGF3, FGF8 and Wnt8. Their data showed that Wnt8 is not absolutely necessary for otic induction, however it is required for timely initiation of the otic field. <ref><pubmed>14757644</pubmed></ref>

'''The neural domain'''
[[File:neural domain.jpg|thumb|200px|The expression of Sox2 and Sox3 during development of the ear]]
During the early stages of embryonic development, a neural competent domain is established. This domain will eventually give rise to neurons and hair cells. Various signalling pathways are required to initially create this domain and to maintain it later on. <ref name="PMID19247974"><pubmed>19247974</pubmed></ref>

* ''FGF and Sox''
FGF signalling and the Sox genes are essential for the establishment of the neural competent domain. An important aspect of Sox genes is that they have a state of self-renewal, as well as a state of neural commitment. <ref><pubmed>15863505</pubmed></ref>
As investigated by Rex et al. (1997) and Pevny and Placzek (2005), "SoxB1 genes (Sox1, Sox2, Sox3) have been linked directly to ectodermal cells that are competent to acquire neural fate, and the commitment of cells to a neural fate".<ref><pubmed>9215646</pubmed></ref> <ref><pubmed>15721738</pubmed></ref>

Before the otic placode becomes distinct, Sox3 is already expressed in a broad area around the location of the future otic placode. Later in it will only be found in the proneural region of the otic placode. Based on this, the review by Alsina et al. (2009) suggests that a neural fate acquisition occurs prior to otic placode formation.<ref name="PMID19247974"/> During the early stages of development of the otocyst, Sox2 and Sox3 are found in proliferating cells within the proneural region. Both are expressed when neurons are generated, however, Sox3 switches off and only Sox2 remains during further development of the ear. This suggests that the ongoing expression of Sox2 plays a role in sensory cell development, as explained in the review by Alsina et al (2009).<ref name="PMID19247974"/>

-We will look into this in further detail when describing the development of the elementary sensory unit of the ear-

* ''Notch signalling''
Notch signalling is required for several developmental processes, including the maintenance of the neural competent domain.

In the notch signalling pathway, notch is the receptor, with most of its ligands being transmembrane proteins. Signalling is therefore restricted to neighbouring cells. Research by Daudet and Lewis (2005) reveiled how notch signalling plays a role in inner ear development, including:

- Notch signalling mediates lateral inhibition and thereby controls the differentiation of hair cells and supporting cells - in particular in the vestibular regions <ref name="PMID15634704"><pubmed>15634704</pubmed></ref>

- An early phase of Notch activity promotes formation of prosensory patches <ref name="PMID15634704"/>

- Other signalling pathways are likely to cooperate with Notch to specify prosensory regions of the otocyst <ref name="PMID15634704"/>

====The Otocyst====
[[File:neural fate.jpg|thumb|200px|Recent model related to sensory fate.]]

'''Patterning of the otocyst'''

The otocyst, also known as the otic vesicle, is present once invagination of the otic placode has occurred. Regionalisation of the otocyst results in the topological organisation of the ear. The neural tube affects the patterning of the otocyst, and FGF, Wnt and Hh signalling pathways are also known to play a role.
FGF and Wnt rely on signals from the hindbrain. <ref><pubmed>17891710</pubmed></ref>

Prosensory patches emerge within the otocyst. These develop as a differentiate from the neural competent domain.<ref name="PMID21266409"><pubmed>21266409</pubmed></ref>

- haircells (sensory patch)

- neurons (neural competent domain)

As proposed in recent models by Neves ''et al.'' (2011): Jagged 1 functions through lateral induction to activate Notch signalling. Notch signalling then functions through lateral inhibition and regulates Sox2 expression. Sox2 specifies sensory fate within the prosensory domains. "This confines sensory competence to the prosensory patches, ensuring the development of sensory organs of the correct size and location." <ref name="PMID21266409"/>

'''Establishing polarity and formation of inner ear structures'''
[[File:z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.]]

The different axis of the inner ear are fixed at different points in time. This means different signals are involved to establish the polarity and allow for development.<ref><pubmed>9389659</pubmed></ref>
The dorsal-ventral polarity is very significant in the development of inner ear structures. The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle.

The neural tube plays a role in patterning of the placode and it has been shown similar signals from the neural tube are also needed to establish the dorso-ventricular axis of the inner ear.<ref><pubmed>16325169 </pubmed></ref>

* ''Shh signalling''
The notochord produces Shh, which helps in patterning the dorso-ventricular axis of the neural tube. <ref><pubmed>18621990</pubmed></ref> This signal diffuses further and also affects the developing otocyst, where a gradient of Shh receptors is located from the dorsal to ventral aspect. <ref><pubmed>12231626</pubmed></ref>
Dorso-ventricular patterning and development of inner ear structures – in particular ventral structures – is achieved by the graded response to Shh.

As reviewed by Grooves and Fekete (2012) “data suggests that Shh acts on the ventral otocyst directly to regulate cochlear development, and that dorsal development can be regulated by signals from tissues adjacent to the otocyst that require Shh signaling for their normal development.”<ref name="PMID22186725"><pubmed>22186725</pubmed></ref>

* ''Wnt signalling''
Shh signalling for the ventral aspect is complemented by signals for the dorsal aspect of the inner ear. Wnt signalling takes places in the otic placode, as described above. This is initially as a gradient from medial to lateral <ref><pubmed>20171206 </pubmed></ref>, which later in the otocyst will be a gradient from doral to ventral <ref><pubmed>16452098</pubmed></ref>

As further suggested in the review by Grooves and Fekete (2012) “Wnt and Shh signals regulate different inner ear genes in different ways, with opposing gradients of Shh and Wnt signaling regulating the spatial localization of transcription factors, ultimately leading to the differentiation of a correctly patterned inner ear.” <ref name="PMID22186725"/>

* ''Hedgehog signalling''
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR'''
|- bgcolor=#E7FEFF
|
* Development of the inner ear: This starts out with the induction of the otic placode and consists of 3 major stages
'''1.''' Pre-placodal domain: After gastrulation, a pre-placodal domain is present adjacent to the anterior neural plate. The various placodes will arise from this domain.

'''2.''' Pre-otic field: Local signals establish the identity of each placode, including the otic placode. FGF signals from both rhombomeres and the cranial paraxial mesoderm are important otic inducers.

'''3.''' Otic placode/epidermis fate decision: signalling occurs to determine precisely which cells become the otic placode and which cells aquire the epidermal fate. FGF and Wnt signalling is necessary in this step, which could possibly be dependent or independent of each other.

* Neural component: During the early stages of embryonic development, a neural competent domain is established as part of the otic placode. FGF, Sox and Notch signalling play a role in creating and maintaining this domain. Once invagination occurs and an otocyst has formed, signalling pathways allow for patterning of the otocyst and formation of prosensory patches. Hair cells develop from the sensory patches and neurons develop from the remaining neural competent domain.

* Establishing polarity and formation of inner ear structures: The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle. For this reason, it is important for normal development of the inner ear to establish polarity, such as the dorso-ventral axis. Various signals are involved, including Shh and Wnt signalling. Hedgehog signalling needs to be suppressed.
|}

==Abnormal Hearing==

===Genetic===

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFA500"
|'''Genetic abnormality'''||'''Description'''||'''Image'''
|- bgcolor="#FFEFD5"
|''Mutation of GJB2 gene'' ||
* Approximately 60% of congenital deafness in developed nations is caused by genetic factors.
* More than 50 loci have been found to be responsible for the genetic causes of non syndromic deafness (isolated hearing loss with no affects to other parts of the body) called NSD and accounts for more than 80% of genetic related congenital deafness. GJB2 gene which instructs the protein Connexin 26 to be formed, is the most common cause of NSD.
* Connexin 26 is found all over the body, with a great number on the skin and in the inner ear.
*Over 90 of the GJB2 gene mutations have been associated with NSD. <ref><pubmed> 10980526 </pubmed></ref>

||
[[File:Mutation_on_GJB2_gene.jpg|x250px]]

|- bgcolor="#FFCC99"
|''Autosomal dominant hearing loss'' ||
* Autosomal dominant hearing loss is transferred directly though the previous generations and can usually be detected when reviewing at a family tree.
* There is a 50% probability that the child will also have hearing loss, and subsequently increases if both parents have the dominant gene. Research has shown that the phenotype due to GJB2 varies due to the great range of the degree of deafness in the patients.
* This alludes to the fact that other environmental causes have also contributed to the patients hearing impairment <ref><pubmed> 10980526 </pubmed></ref>.
* M34T missense mutation has been found in families where there are both affected and non affected people thus indicating its contribution to autosomal deafness both dominant and recessive deafness.
* Similarly, studies have shown additional missense mutations R75W, D66H and G59A are also causes of DNFA however they have been connected to other clinical manifestations <ref><pubmed> 11216656 </pubmed></ref>.

||
[[File:Dominant_diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Autosomal recessive hearing loss'' ||
* Autosomal recessive deafness is an inheritance of both the mother and father’s recessive genes of connexin 26 mutation.
* There is a 25% chance that the child will have hearing loss. However normally as both parents have normal hearing, it is difficult to foresee if the child will inherit hearing loss.
* The most prevalent connexin 26 gene mutation in the majority of ethnic groups for DNFB is the 35delG.
* Mutations in the connexin 26 genes equate to half of the DNFB cases <ref><pubmed> 14979964 </pubmed></ref>.

||
[[File:Autosomal_Recessive_Inheritance_Diagram.jpg|x250px]]

|- bgcolor="#FFCC99"
|''X linked hearing loss'' ||
* X linked hearing loss is carried by the mother and passed down to both the male and female children.
* Generally only the male children are affected if they receive the affected X chromosome while the daughters will be the carrier of the gene.
* The hearing loss can be a combination of both conductive (damage to the outer or middle ear) and sensorineural hearing loss (malfunction of the cochlea and or the hearing nerve) <ref><pubmed> 1163535 </pubmed></ref>.

||
[[File:X_Linked_Recessive_Diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Mitochondrial hearing loss'' ||
* Mitochondrial hearing loss is passed down solely through the mother.
* It is caused by mutations in either MT-RNR1 or MT-TS1 leading to moderate to profound hearing loss.
* MT RNR1 is generally correlated to aminoglycoside ototoxicity and sensorineural hearing loss independent of aminoglycoside ototoxicity occurring usually in the 20’s.
*Aminoglycoside ototoxicity refers to the increased chance of hearing loss after consuming antibiotics and is irreversible.
* MT-TS1 is sensorineural hearing loss occurring during childhood and is generally considered nonsyndromic <ref><pubmed> 20301595 </pubmed></ref>.

|}

NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS

'''Genetic Syndromes'''

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFF000"
|'''Syndrome'''||'''Description'''||'''Image'''
|- bgcolor="#FFFDD0"
|''Usher Syndrome'' ||
* Most common cause of congenital deafness due to defects in the inner ear and also causes vision loss
* Separated into 3 subgroups: USH1, USH2 and USH3<ref><pubmed> 16434480 </pubmed></ref>.

## USH1 - profound deafness at birth
## USH2 - Moderate level of deafness at birth
## USH3 - Hearing normal at birth but will gradually worsen as the child ages
* Various genes are thought to cause the disorder most recent is WHRN gene <ref><pubmed> 16452831 </pubmed></ref>.

||
[[File:Basal_Cochlear_Outer_Hair_Cells.jpg|x250px]]
|- bgcolor="#FBEC5D"
|''Pendred Syndrome'' ||
* Autosomal recessive disorder which causes progressive sensorineural hearing loss, and can also affect the thyroid gland, accounting for more than 10% of severe hearing impairment.
* Patients usually have structural malformations of the inner ear, in some cases a missing cochlear.
* The syndrome is caused by a variety of gene mutations, SLC26A4 gene causing more than half of all of the Pendred Syndrome cases.
* There is no current treatment option, and is most important that it is screened for in childhood hearing loss in order to teach differing ways of communication <ref><pubmed> 18285825 </pubmed></ref>.

'''All of these defects are suggestive of a developmental arrest at 7 weeks of human embryonic development. In addition, it has been noted that patients with Mondini malformations usually have reduced numbers of hair cells and spiral ganglion cells (11); these latter microscopic defects are thought to lead to the deafness. '''

||
[[File:Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px]]
|- bgcolor="#FFFDD0"
|''Goldenhar Syndrome'' ||
* There are a varying amount of malformations usually regarding the ears, mouth and jaw such as microtia and preauricular appendages.
* There is limited knowledge as to how this syndrome occurs, and there are currently no treatments for the subsequent hearing loss. <ref><pubmed>10829494 </pubmed></ref>
* It is thought that environment could play a role with an increased level of children developing this syndrome during the Golf War <ref><pubmed> 9408975 </pubmed></ref>.

||
[[File:MRI_of_Goldenhar_Syndrome.jpg]]

|}

===Environmental===

'''Infections'''

{| cellpadding=5 style="border:1px solid #74C365"
|- bgcolor="#009F6B"
|'''Organism'''||'''Description'''||'''
|- bgcolor="#F0FFF0"
|''Toxoplasmosis'' ||
* Toxoplasma gondii is an intracellular protozoan and can infect humans through undercooked meat containing bradyzoites or by legumes infected by oocysts (greatly infectious).
* A study published in 1988 collected data from 23,000 pregnancies which found mothers with an IgG antibody to toxoplasmosis during pregnancy doubled the incidence of deafness for the child. This was identified along with other symptoms such as microcephaly and low IQ scoring. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis.
* Congenital toxoplasmosis also results in mental retardation and deafness along with blindness and usually multiple organs affected such as Chorioretinitis. Notably, the infection risk differs during the gestation time: “1% at less than 6 weeks, 4–6% at 6–16 weeks, 20–40% at 16–25 weeks and 60–80% at 36 weeks of gestation” (http://www.marmaramedicaljournal.org/pdf/pdf_MMJ_446.pdf)
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref><pubmed> 3041362 </pubmed></ref>.
* Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 10356003 </pubmed></ref>.
*There have been inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>. Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 11561963 </pubmed></ref>.
* Notably, although this was an uncontrolled trial, this prenatal treatment was proven to be of some benefit <ref><pubmed> 10356003 </pubmed></ref> <ref><pubmed> 12618153 </pubmed></ref> <ref><pubmed> 1929726 </pubmed></ref> <ref><pubmed> 11821335 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article was published in the Lancet providing clear evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody.
* Studies have subsequently shown that the fetal infection risk will differ throughout the duration of the pregnancy. During week 1 to 10, there is a 100% fetal transmission rate, leading to an 81% rate during the first trimester, due to the immaturity of the fetal defense mechanisms and solely relying on maternal immunoglobulin G. This decreases throughout the second and third trimester, however the infection rate goes back to 100% in the last month of pregnancy. The sudden decrease is thought to be due by the maternal antibodies along with fetal cell mediated immune responses along with the humoral responses.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium. (G Tondury, DW Smith Fetal rubella pathology). As the cells appear desquamated within the vessel lumens, it is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli, which in turn leads to an increase in infection and damage to the developing fetal organs.
* Fetal organ development may be compromised by the virus prompting apoptosis. Studies indicate that the caspid protein dependent mechanism of the Rubella virus leads to apoptosis. (Rubella Virus Capsid Protein Induces Apoptosis in Transfected RK13 Cells, Robert Duncan). Rubella infected cells which do not undergo apoptosis result in a reduced growth rate and a shorten life span due to a decreased mitotic activity.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation.
* As Rubella has long been a known congential disease, through the Rubella vaccine, this has almost completely eliminated the disease in western countries. Thus as this is an entirely preventable disease, future programs should of Rubella prevention should lead to Rubella being a disease of the past.

(Rubella, the lancet, DWG Brown AND KV Pugachev, TK Frey Rubella virus induces apoptosis in culture cells)

(Onset and severity of hearing loss due to congenital rubella infection)

|- bgcolor="#F0FFF0"
|''Cytomegalovirus'' ||
* Cytomegalovirus (CMV) is an enveloped herpes virus which is passed to the fetus via vertical transmission.
* As 95% of pregnant women are asymptomatic, it is incredibly hard to diagnose.
* The virus can be classified into acute and non acute infections. Acute maternal infection can be verified by low IgG avidity levels.
* There are 2 methods to determine if the fetus has contracted CMV. A cordocentesis can be conducted to obtain fetal blood for sampling however issues have been raised regarding its safety and notably accessibility. (Weiner C.P.: Cordocentesis. Obstet Gynecol Clin North Am 15. 283-301.1988).
* Amniocentesis can also diagnose the CMV via PCR and is considered the better diagnostic tool due to the quick and reliable results it gives. High DNA copy numbers for the CMV infection relates to a greater severity of the disease and hence could indicate the hearing impairment outcome.
* A recent study has noted the role of CMV causing sensorineural hearing loss and subsequently being a high risk factor for hearing impairment. The results showed that more than half of the children participating had CMV IgG antibodies, with 20% being found as CMV DNA positive which indicates that the child has an active infection. (Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology, Eva Karltorp).
* There is no current treatment protocol for CMV, however a non random sampling trial has suggested the treatment of hyperimmune globulin giving promising results in the study. (Nigro G., Adler S.P., La Torre R., et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353. 1350-1362.2005; ).
* Another study showed that treatment of the symptomatic cases of CMV infection with intravenous ganciclovir (or Valganciclovir orally) for 6 weeks has indicated improvement in the child’s hearing. (Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46S:S22-S6.)

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''||'''
|- bgcolor="#FFA6C9"
|''Alcohol consumption during pregnancy'' ||
* Fetal Alcohol syndrome is a variety of conditions which occur in the fetus if the mother consumes alcohol during pregnancy. There is no safe level of alcohol consummation during pregnancy.
*Fetal Alcochol Syndrome is associated to 4 hearing impairment disorders:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss
(Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review. Church MW, Kaltenbach JA Alcohol Clin Exp Res 1997 May;21(3):495-512.)
*It is also associated with a variety of other malformations (skeletal and visceral), growth retardation and nervous system defects. The developmental delay of the auditory system is thought to be due to decreased growth of neurons and myelin and subsequently the synapses.
* Sensorineural hearing loss is thought to be caused by a greater amount of apoptosis during the inner ear development and thus leading to decreased levels of auditory nerve fibres and sensory receptor cells. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
*

|}

===Structural malformations of the ear===

{| cellpadding=5 style="border:1px solid #880085"
|- bgcolor="#9457EB"
|'''Structural malformation'''||'''Description'''||'''Image'''
|- bgcolor="#FAF5FF"
|''Stenosis'' ||
* Internal auditory canal stenosis is classified as someone who has an internal auditory canal 2mm or less.
* It is considered a rare disease with only 2.5% of patients with congenital hearing loss being affected by stenosis .
* It is thought to be as secondary to vestibulocochlear nerve hypoplasia <ref><pubmed> 9892864 </pubmed></ref>.

||
[[File:Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px]]
|- bgcolor="#E0CEF2"
|''Enlarged vestibular aqueduct'' ||
* Approximately 7% of all sensorineural hearing loss patients had an enlarged vestibular aqueduct.
* The most recognised cause of an enlarged vestibular aqueduct is due to a mutation on chromosome 7 on the SLC26A4 gene <ref><pubmed> 16570074 </pubmed></ref>.
* There is no current treatment and thus is important to identify it when the patient is a child so that alternative communicative methods can be taught.

(Sensorineural hearing loss in Patients with large vestibular aqueduct, Okumura)

||
[[File:Enlarged_Vestibular_aqueduct.jpg|x250px]]
|- bgcolor="#FAF5FF"
|''Microtia''||
* Deformation of the outer ear which can be with or without the external ear canal.
*There are 4-5 grades of microtia which range from a small ear to deformed outer ear to no ear present at all.
* Treatment involves the complete reconstruction of the outer ear and occasionally the middle ear depending on the level of hearing loss associated with it <ref><pubmed> 10890145 </pubmed></ref>.

||
[[File:Microtia_boy_surgery.jpg|x320px]]

|}

---------

==Technologies to detect==

The importance of having a neonatal screening test for hearing within the early days of life are important for the rest of that individual’s life. Screening is used to identify the children most at risk of having a congenital hearing problem. The importance of having an early diagnosis and having a method of intervention is crucial for the development of speech and language and learning of the child later in life, as reviewed by Oudesluys-Murphy ‘’et al’’. 1996. <ref name="PMID8789756"><pubmed>8789756</pubmed></ref>
Screening tests allow for the detection of hearing loss within the few days of life. This could be due to a dysfuctional cochlea or various other problems as discussed in our abnormal hearing section. Within Australia there are a few simple test that allow newborns to be tested fast, accurately and reliable <ref name="PMID8789756"/>.

===Oto-acoustic testing===
[[File: infant hearing test.jpg|thumb|300px| Testing the hearing of an infant]]

The oto-acoustic test measures the integrity of the inner ear. This involves the cochlea and its physiological effects - the production of an otoacoustic emission in response to sound <ref name="PMID8220282"><pubmed>8220282</pubmed></ref>. It involves inserting a probe into the ear canal, which then produces clicks or tones that are normally picked up by the cochlea. The function and healthiness of the cochlea can be measured, as the different parts of the cochlea respond to different forms of stimuli in terms on pitch and frequency <ref name="PMID8220282"/>.

For this test, there are two methods used for screening the hearing in newborns.

• The production of a single click or tone called the Transient Evoked Otoacoustic Emission test (TEOAE) <ref name="PMID8220282"/>

• The production of two simultaneous tones named the Distortion Product Otoacoustic Emissions Test (DPOAE) <ref name="PMID8220282"/>

===Auditory Brainstem Response===

The Auditory Brainstem Response tests the neurological function of the auditory brainstem. It is more so used as a referral test, rather than a screening test, as generally hearing loss is already suspected <ref name="PMID11667937"><pubmed>11667937</pubmed></ref>. This test uses a click or a tone, which causes the production of impulses by the neurons from the auditory nerve, travelling along the auditory pathway. This is then measured and detected by external electrodes that are on the scalp and the earlobe of the newborn. <ref name="PMID11667937"/>

===Automated Brainstem Response===

This cheaper and quicker method uses an ear cup that is fitted over the infant’s ear <ref name="PMID11343042"><pubmed>11343042</pubmed></ref>. This then sends out a stimulus and a response is measured through a series of electrodes that are connected to the earlobes, scalp, shoulders and neck<ref name="PMID11343042"/>. The automated brainstem response uses a computer to visualise and calculate the results, and produce a result of either ‘pass/refer’. Data of the patient are cross-referenced with a collection of results regarded as normal responses<ref name="PMID11343042"/>.

===OtoSCOPE===

A new genetic testing method called OtoSCOPE discovered in 2010 has greatly increased the efficiency for testing nonsyndromic hearing loss and Usher syndrome. It provides a great diagnostic tool, as all the genes related to hearing loss can be sequenced simultaneously thereby decreasing cost and time. The patients can be informed relatively early for any genetic abnormalities therefore providing early prognosis and genetic counselling. <ref><pubmed>21078986</pubmed></ref>

==Technologies to overcome the problems==
Depending on the hearing loss, there are different types of technologies to overcome this. Types of hearing lost are conductive and sensori-neutral . One type is the conductive, caused by the damage or blockage of the outer or middle ear, the other is sensori-neutral, where the damage is to the auditory pathway or nerve. In some cases there is a combination of the two. And there are two current technologies that overcome this problem and they are the the hearing aid and the cochlea ear implant.

===Hearing aid===
Hearing Aids are a major advance in helping people hearing, they work by amplifying the sounds so they can be detected even by the damaged inner ear. This method of hearing relies on the healthiness or still relative functioning cochlea. The damage of the sensori-neural pathway is overcome by the amplication of sounds to compensate the loss of hearing cells or hair cells in the cochlea. This is proportionate to the amount of hair cells still functioning. This amplication of the sounds, helps the patient hear and listen and communicate with others. This however also amplifies background noise. They consists of the microphone, amplifier and a speaker. From the sound being received by the microphone, this converted by the microphone into electrical impulses and replays it to the amplifer. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref name="NIH">{{citation
|title= Hearing Aid Basics
|url=http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

===Cochlea Ear Implant===
[http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx Cochlea ear] implants help the hearing impaired to listen. This is through having a device to provide a sense of sound. The cochlea implants consists of a few major components in helping the patient hear. It consists of a microphone, which detects the environmental sounds, a small electronic processor that selects the sound produced from the microphone. There is also a transmitter and the stimulator. This converts the signal that comes off the electronic processor into electrical impulses, which leads up the final component which is the electrode array. This picks up the electrical impulses and delivers them to the correct region of the auditory nerve. These methods of hearing or sensing sound are used only in severer or profoundly hearing impaired who have a dysfunctioning cochlea. <ref><pubmed>PMID:6028666</pubmed></ref>

<ref name='cochlea_NPR'>{{cite=book| first=Hendrinkus| last=Dulfhuis|coauthors=| title=''Cochlea Mechanics: Introduction to a time Domain Analysis of Cochlea''| date=10-2-2012| publisher Springer Science+ Business Media|url=http://books.google.com.au/books?id=1UpECoc_q3UC&pg=PA5&lpg=PA5&dq=Gabriele+Falloppio+ear&source=bl&ots=mc9sb_0UR1&sig=WqdWXmDrJWV-2rqlWF3ihzMnWLE&hl=en&sa=X&ei=ozFoUPL8BoiQiQf_qoDYDw&ved=0CEEQ6AEwAw#v=onepage&q=Gabriele%20Falloppio%20ear&f=false| work=cochlea implant| pages = | accessdate = 20012-10-01 | language = }}</ref>

==Current Research==

* ''' ''Hair cell differentiation'' '''

A recently published paper by Pan ''et al.'' (2012) investigated the various levels and durations of expression of a particular transcription factor, which is necessary for hair cell differentiation. The ''Atoh1'' transcription factor was tested for by using conditional knock-out mice - ''Atoh1-cre'' <ref name="PMID22279587"><pubmed>22279587</pubmed></ref>. They determined that reduced levels of ''Atoh1'' resulted in the progressive loss of hair cells from the organ of Corti shortly after birth <ref name="PMID22279587"/>. Similar data was obtained when the deletion of the ''Atoh1'' transcription factor was delayed. Slight differences were noted between inner and outer hair cells: the loss of inner hair cells was more significant than the loss of outer hair cells. This indicates that ''Atoh1'' may play a role in the differential development of inner and outer hair cells.
[[File: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears.]]
[[File: Atoh1 hair cell loss.png|none|thumb|200px|Conditional deletion of Atoh1 results in death of organ of Corti cells and patchy Myo7a-positive presumptive hair cells which are innervated by many nerve fibers.]]

* ''' ''Stem cell therapy'' '''

The discovery of stem cells has led to an entirely new era in research, and the potential to prevent and treat conditions such as hearing loss.
It has been discovered that stem cells are present in the inner ear. In non-mammalian vertebrates, these stem cells allow the inner ear sensory epithelium to recover and function again after being damaged. This is not the case when it comes to mammals. Cells capable of regeneration are found in the vestibular sensory epithelium and in the neonatal cochlea. <ref><pubmed>8456285</pubmed></ref> However, only very limited regeneration may take place after damage has been done to the inner ear. Research is ongoing in various laboratories worldwide, such as at the University of Sheffield, as to how stem cells can be used to regain the sense of hearing. Early September 2012 there was an incredible breakthrough, as scientists from the university used [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx human embryonic stem cells to restore hearing in a common form of deafness.] This proves human stem cells could be used to repair the damaged ear and will hopefully lead to various other stem-cell based therapies.

[[File: aquaporins.png|thumb|200px|Aquaporins]]

* ''' ''Middle ear homeostasis'' '''

A recent article by Morris ''et al.'' (2012) investigated the mechanisms responsible for the ion homeostasis in the middle ear and how this relates to disease. They used BALB/c mice for immunohistochemistry of particular ion homeostasis factors of the middle and inner ear <ref name="PMID22720014"><pubmed>22720014</pubmed></ref>. This was then used to compare transport and barrier mechanisms and identify what is present in the tympanic cavity. Next, the middle ears received transtympanic injections with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation <ref name="PMID22720014"/>. Data shows that cellular hypertrophy occurred and localization of ion channels, such as aquaporins, was preserved within the inflamed middle ear epithelium<ref name="PMID22720014"/>. Morris ''et al.'' suggested that these channels could be used as a therapeutic target.

* ''' ''Molecular mechanisms - ongoing project'' '''

The HEARing Cooperative Research Centre ([http://www.hearingcrc.org/ CRC]) is involved in many ongoing research projects. Professor Doug Hilton supervises one of the projects: Genomic & molecular therapeutic approaches to environmental and age-related hearing loss.

A major public health issue is presbycusis - age-related hearing loss. It is known that apoptosis of cells within the cochlea plays a role; however, the many other factors involved and their molecular mechanisms are not yet fully understood. This research project is looking at the genes, proteins and regulatory pathways involved in both hearing and hearing-loss. The aim is to use this knowledge to identify molecules that can be targeted to [http://www.hearingcrc.org/research/projects/r122 prevent and/or treat hearing loss.]

==Glossary==

*'''Cristae''': the sensory organ of rotation located in the semicircular canal of the inner ear

*'''Ectoderm''': the outermost layer of the three primary germ cell layers in the very early embryo

*'''Epidermis''': surface epithelium of the skin, superficial to the dermis

*'''Gastrulation''': The inward migration of cells

*'''Hindbrain''': The lower part of the brainstem, comprising the cerebellum, pons, and medulla oblongata

*'''Lateral inhibition''': process whereby one cell takes on a state and the adjacent cells takes on the opposite state

*'''Mesoderm''': the middle layer of the three primary germ cell layers in the very early embryo

*'''Neural plate''': a thickened plate of ectoderm along the dorsal midline of the early vertebrate embryo that gives rise to the neural tube and crests

*'''Neural tube''': A hollow structure formed after gastrulation, from which the brain and spinal cord form

*'''Open neural plate stage''': stage of the neural plate before closure into the neural tube

*'''Otic placode''': a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops

*'''Otocyst – otic vesicle''': The structure formed by invagination of the embryonic ectodermal tissue that develops into the inner ear

*'''Pre-placodal domain''': An ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

*'''Proneural region – neural competent domain''': a region of the otic placode involved in neurogenesis

*'''Prosensory region''': region containing a population of cells that can develop into hair cells or or supporting cells

*'''Rhombomere''': a segment of the developing rhombencephalon (hindbrain segment)

*'''Saccule''': one of two otolith organs. The smaller of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Somite''': A segmental mass of mesoderm in the vertebrate embryo, occurring in pairs along the notochord

*'''Utricle''': one of two otolith organs. The larger of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Vestibular region''': the region of the inner ear close to the cochlea. Here the semicircular canals converge

*'''Vestibulo-acoustic ganglion''': The cranial ganglion of cranial nerve 8

==External Links==

[http://news.yale.edu/2012/02/16/yale-study-how-mitochondrial-dna-defects-cause-inherited-deafness|Yale study: how mitochondrial DNA defects cause inherited deafness]

== References ==
<references/>

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

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 6

2012-10-02T04:06:14Z

Z3333431: /* Cochlea Ear Implant */

[[File: z3333865.Ruby.jpeg | 450px| right]]
= Hearing Development=

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important sense and an inherent part of human life. It widens our scope of life and allows us to work, relax, communicate, learn and form memories. The sense of hearing has evolved through the years in vertebrates is inherent for both hunting and surviving. The sound energy produced has be converted into an electrical signal for us to make sense of it. For successful transmission the correct development of the ear is of utmost important. Not only formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will also talk about some abnormal processes and mutations which lead to various structural and functional diseases.

==History==

{| cellpadding=5 style="border:2px solid #08E8DE"
|- bgcolor= #00BFFF
|'''Date''' || '''Description'''
|- bgcolor=#87CEEB
|'''1536''' || The first clear distinction is made between the middle and inner ear. How to observe the middle ear ossicles is also explained. <ref><pubmed>4598483</pubmed></ref> <ref name="PMID6341584"><pubmed>6341584</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438986/?page=6 Nicola Massa.]
|- bgcolor=#ADD8E6
| '''1543''' || ''De fabrica'' by Andreas Vesalius was published which identified and named the incus and the malleus. Also identified the tensor tympani and the anatomical position of the oval window to the round window <ref><pubmed>22581496</pubmed></ref>. [http://www.ncbi.nlm.nih.gov/pubmed/22581496 Andreas Vesalius]
|- bgcolor=#87CEEB
|''' 1561''' || ''Observationes anatomicae'' is published and describes the tympanic membrane. The stapes ossicle is also discovered and named. <ref><pubmed>22965774</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/22965774 Gabriele Falloppio]
|- bgcolor=#ADD8E6
| '''1563''' || In the book ''De Auditus Organis'', it was proposed that the tympanic membrane is connected to the nasopharynx. This tube was named after the writer of the book. He also completed the diescritpion of the tensor tymapani: <ref><pubmed>7029021</pubmed></ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 Bartolomeo Eustachi]
|- bgcolor=#87CEEB
|'''17th Century'''|| The Metal ear was one of the first hearing aids created. It was placed over the ear to channel sound into the ear.
|- bgcolor=#ADD8E6
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#87CEEB
|'''1683''' || The bony labyrinth is described in more detail. It is determined the spiral lamina has a bony and membranous part, and it divides the spiral duct into an upper and lower compartment. <ref name="PMID6341584"/>[http://www.sciencedirect.com/science/article/pii/S1286011510000172 Duverney.]
|- bgcolor=#ADD8E6
|'''1704'''|| The book ''De aure humana tractatus'' with information regarding the anatomy, physiology and pathology of the ear is published.<ref name="PMC1142106"><pubmed>PMC1142106</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor= #87CEEB
|'''1707'''|| It is proposed that the labyrinth contains fluid instead of air. <ref name="PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor=#ADD8E6
| '''1772'''|| Antonio Scarpa discovers the ear labyrinth <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

==Adult Anatomy and Histology==

[[File:Anatomy_of_the_Ear.JPG|thumb|left|450px|Anatomy of the ear]]

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear. The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus. The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate. The malleus, which is in contact with the tympanic membrane, moves which in turn moves the other ossicles. The ossicles namely malleus, incus and stapes provide solid medium for the waves to travel through and act as a lever increasing the amplitude of the sound wave 20 times.

The oval window marks the boundary between the middle and the inner ear, which constitutes of an outer bony labyrinth and an inner membranous labyrinth. The cochlea which is a coil resembling a snail’s shell houses the organ of Corti, the peripheral receptor for hearing. Histologically the cochlea is divided into 3 parts scala vestibule, scala media and the scala tympani divided by the vestibular and basilar membrane respectively.

The sound waves are transmitted from the stapes into the oval window. The vibrations cause movement of the perilymph fluid in the scala vestibuli into the scala media causing movement of basilar membrane and bending of the hair cells. The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve. The nerve impulses travel from this neve through the brainstem to the thalamus to the primary auditory cortex, which is located on the transverse temporal gyrus.

The basilar membrane has a tonotopic organisation and human ears can hear sounds ranging from 20-20000 Hz. Near the apex of the cochlea the basilar membrane is wide and loose whereas near the base is narrow and tight hence enabling us to hear different frequencies.

==Development==

The development of outer ear is attributed to the first pharyngeal arch. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref>

The pharyngeal arches arise as a series of bulges arising laterally from the embryo head around 3-4 weeks of human development. The arches have a consistent organisation of the endoderm, ectoderm and mesoderm. The ectoderm forms the outer surface of the arch with the core made up of mesoderm. Next to the mesoderm core on the opposite the ectoderm is the endoderm. All three layers contribute to the formation of outer, middle and inner ear structures hence contributing to hearing. In between the arches the ectoderm and endoderm come in contact with each other forming a continuous sheath on either side of the mesoderm, forming groves externally and arches internally. Inside the mesoderm core of each arch lies a specific cell population that goes onto develop into a nerve, cartilage and artery.

===Outer Ear===

'''Pinna'''

[[File:Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages]]

Post development the anatomy of the external ear simply consists of the pinna or the auricle and external acoustic/auditory meatus. The auricle develops around the first and second pharyngeal arches as a series of auricular enlargements or hillocks around the 5th week of development. Gradually by the 6th week the hillocks grow in size and increase to six in number, three on the first arch and 3 on the second arch, the first of which starts at the bottom anterior side going in a clockwise direction. In the 7th week the hillocks enlarge further and each of the arches contributes to a specific part of the pinna. The first arch gives rise to the tragus, helix and cymba concha whereas arch 2 gives rise to concha, antihelix and antitragus. The differentiation starts around the neck region but as the mandible develops the pinna structures move more cranially. It is not until the 12th week that the fusion of these various parts occur and is completed by week 20th.

Various genetic markers and coordinated signalling mechanisms are required for normal development of the pinna. One of which is the EYA1 gene, which is imperative for formation of the pinna. Mice with a homologous Eya1 null gene either has malformed or absent ears and since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development, mutation in which causes malformation of the perichondrium and thus cartilage formation. Another gene important for early patterning of the pinna is the Hox2 gene, mutations in which leads to formation of a shapeless protuberance rather than a normal shaped pinna. Hox2 gene is expressed in the second pharyngeal arch and the malformations in the ear are contributed to the parts derived from the second pharyngeal arch like the antitragus, antihelix and concha.
<ref><pubmed>14674478</pubmed></ref> <ref><pubmed>17104502</pubmed></ref>

'''External Auditory Meatus'''

The External Auditory Meatus (EAM) is derived from ectoderm that forms the first pharyngeal groove situated between the 1st and the 2nd pharyngeal arches. At 8 weeks of gestation a c-shaped skeletal structure develops from ectoderm of the first pharyngeal cleft migrating and meeting the mesoderm of the first grove called the tympanic ring that controls and coordinates the invagination of the ectoderm. The tympanic ring is a transient embryological structure, which eventually gets integrated into the temporal bone and provides anchorage to the eardrum. Medial to the ring lays the endoderm of the first pharyngeal arch that contributes to the formation of the tympanic or middle ear cavity. At 12 weeks of gestation the tympanic ring begins to ossify in a sequential fashion via endomembranous ossification forming the bony part of the EAM. The ring starts to condense at the proximal end of the 1st pharyngeal arch, goes around the circumference of the cleft and invades the 2nd arch. Starting at the tip of the 1st pharyngeal cleft the ectodermal cells begin to proliferate filling the lumen of the meatus forming a meatal plug which medially extends in a disc like fashion during week 10. The proliferation follows the path of the tympanic ring with the mesoderm tissue between the ring and the meatus forming a fibrous layer. In week 13 of development the innermost part of the meatal plug makes a contact with malleus. This innermost part of the disc in week 15 splits leaving a thin endoderm layer behind which contributes to formation of the tympanic membrane. By the middle of 16th week the meatus although full in length is still narrow and curved and it is not until week 18 that it gets fully expanded and complete.

Since the correct development of EAM is heavily dependent on the tympanic ring, hence any mutation in the tympanic ring causes an abnormal growth of the EAM. Many genes are required to coordinate and control tympanic ring formation most prominent being the Gsc and Prx1 genes. Chimeric studies have revealed that tympanic ring in Gsc null mice fails to ossify whereas the ring whereas mice with null Prx1 gene have an over ossified tympanic ring. In both cases the meatus fails to form indicating a delicate balance between the expressions of both genes is required for proper ring development hence correct formation of EAM. Likewise for pinna formation Hox2 gene is also essential for differentiation of pharyngeal arch into the tympanic ring and the formation of EAM. <ref><pubmed>10976045</pubmed></ref> <ref><pubmed>14674478</pubmed></ref> <ref><pubmed>1441991</pubmed></ref>

===Middle Ear===

'''Tympanic Membrane'''

Tympanic membrane or the eardrum forms the boundary between the outer and middle ear and responsible for transmitting the soundwaves coming in from the EAM to the mechanical waves going into the ossicles. During 8th week of gestation the development of tympanic membrane begins when the first funnel shaped ectodermal cleft meets the endodermal pouch with the mesenchyme growing in-between. This mesenchyme eventually becomes thinner and forms the eardrum during week 12. The diameter of the membrane grows three fold between week 11 and 16 and the membrane fuses with the tympanic ring.

The 1st pharyngeal cleft (ectoderm) gives rise to the EAM and the tympanic membrane comes from the mesoderm from the 1s pharyngeal arch. The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week. During week 7 the 2nd pharyngeal arch constricts the tympanic recess dividing it into a medial portion that form the Eustachian tube and a lateral portion that forms the tympanic cavity. <ref><pubmed> 17346562</pubmed></ref> <ref><pubmed> 10976045</pubmed></ref> <ref><pubmed> 2921547</pubmed></ref>

'''The Ossicles'''

The middle ear constitutes of the skeletal structures called ossicles, which amplify and transmit sound to the inner ear.

The middle ear consists of the middle ear cavity and it are housed the 3 ossicles – the malleus, incus and stapes from lateral to medial. The mesenchymal tissue or the neural crest cells from 1st and 2nd pharyngeal arch contributes to the formation of the ossicular chain.

Two main theories underlie the formation of the ossicles. First is the classical theory according to which the malleus and incus develops from the first pharyngeal arch whereas stapes develops from the 2nd pharyngeal arch. Another theory proposes that malleal head and body of incus comes from the first pharyngeal arch while the second arch gives rise to stapes, handle of malleus and long process of incus. <ref><pubmed>18803631</pubmed></ref>.

[[File:normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology]]

===Inner Ear===

The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode.
The otic placode is a thickened portion of ectoderm located on the each side of the developing head of the embryo, next to the hindbrain. It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed. Invagination occurs next, which creates the otocyst - a vesicle which will develop into the different components of the inner ear: the cochlea, the semicircular canals with cristae, the utricle, the saccule and the vestibulo-acoustic ganglion. <ref name="PMID17891709"><pubmed>17891709</pubmed></ref>[[File:z3333865.stages development inner ear.jpg|thumb|300px|Developmental milestones in mouse inner ear formation]]

====The Otic Placode====

'''Induction of the otic placode'''

Experiments with molecular markers have revealed that several steps are needed for induction of the otic placode.

We will briefly consider the three major steps:

'''1''' ''Pre-placodal domain''

The pre-placodal domain is a narrow strip of the ectoderm adjacent to the anterior neural plate after gastrulation. Different placodes arise from the pre-placodal domain. All the craniofacial sensory organs, including the ear, develop from these different placodes located at the periphery of the neural plate.

Various evidence indicates the existence of this pre-placodal region:

* Morphology indicates a thickened band of ectoderm around the anterior neural plate in some species, including mice and humans. As time progresses, this thickening will only be present at the locations where the different craniofacial placodes differentiate - including the otic placode.<ref><pubmed>15531360</pubmed></ref>

* Experiments have also shown that the placodes will only develop in the correct location, if rotation of the ectoderm along the anteroposterior axis takes place at the open neural plate stage. If rotation takes place at a later time, the placodes will form at incorrect places.<ref><pubmed>14100031</pubmed></ref>

* Gene expression has also indicated that particular genes are present in the pre-placodal domain. These genes belong to the Dlx, Six, Eya, Iro, BMP, Foxi and Msx families. Glavic et al. (2004) has shown that 'loss and gain of function of some of these genes resulted in the widening or reduction of the pre-placodal field'. Linked to this was also the domain of expression of some placode-specific genes; which either enlarged or diminished.<ref><pubmed>15242793</pubmed></ref>

'''2''' ''Pre-otic field''
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

Once the general placodal state has been established, the identity of each placode is induced by local signals. The optic placode is induced by various signals, including Pax8, Pax2, Fibroblast Growth Factors (FGFs), and many transciption factors.

In particular the FGFs are significant otic inducers. Signalling occurs from various rhombomeres from the hindbrain and the cranial paraxial mesoderm located beneath the area of the otic placode. For example, in mice FGF3 is expressed in rhombomeres
5 and 6, whereas FGF10 is expressed in the underlying mesoderm.<ref><pubmed>7789270</pubmed></ref> <ref name="PMID12810586"><pubmed>12810586</pubmed></ref> Mutations of FGF3 and FGF10 have been investigated. Results showed that mice with a mutation of either FGF3 or FGF10 developed an abnormal otic vesicle, and a combination of the two mutants resulted in failure to form an otic vesicle.<ref name="PMID12810586"/>

''--> picture''

'''3''' ''Otic placode/epidermis fate decision''

In the presence of FGF signalling, Wnt signalling can significantly influence the next step, which is the otic placode/epidermis fate decision. According to the review article by Ohyama ''et al''. (2007) ‘Cells receiving high levels of Wnt signalling differentiate as otic placode, while cells receiving little or no Wnt signalling differentiate as epidermis.’<ref name="PMID17891709"/>

The first evidence regarding the contribution of Wnt signalling came from experiments with the otic ectoderm of chicks.
* Data showed that specific marker genes, such as Pax2, were induced to a greater extend with FGF19 and Wnt8c present as compared to FGF19 alone <ref><pubmed>11110663</pubmed></ref>. Ladher ''et al''.(2000) hypothesised that FGF19 induced Wnt8c, and together they induced the otic gene markers.

Another possibility is the independent action of FGFs and Wnt signalling.
* Studies have shown that Wnt signalling onto Pax2+ cells results in differentiation of those cells into otic placode tissue. Pax2+ cells that were not exposed to Wnt signalling differentiate as epidermis <ref name="PMID16452098"><pubmed>16452098</pubmed></ref>.
* Wnt signalling also suppresses Foxi2, resulting in a Foxi2-negative area of particular size, which then allows for FGFs to induce otic genes <ref name="PMID16452098"/>. In this case, Wnt signalling determined the size of the otic placode, yet acted independently from FGF signalling.
* Phillips et al. (2004) studied the role of FGF and Wnt signalling; specifically looking at FGF3, FGF8 and Wnt8. Their data showed that Wnt8 is not absolutely necessary for otic induction, however it is required for timely initiation of the otic field. <ref><pubmed>14757644</pubmed></ref>

'''The neural domain'''
[[File:neural domain.jpg|thumb|200px|The expression of Sox2 and Sox3 during development of the ear]]
During the early stages of embryonic development, a neural competent domain is established. This domain will eventually give rise to neurons and hair cells. Various signalling pathways are required to initially create this domain and to maintain it later on. <ref name="PMID19247974"><pubmed>19247974</pubmed></ref>

* ''FGF and Sox''
FGF signalling and the Sox genes are essential for the establishment of the neural competent domain. An important aspect of Sox genes is that they have a state of self-renewal, as well as a state of neural commitment. <ref><pubmed>15863505</pubmed></ref>
As investigated by Rex et al. (1997) and Pevny and Placzek (2005), "SoxB1 genes (Sox1, Sox2, Sox3) have been linked directly to ectodermal cells that are competent to acquire neural fate, and the commitment of cells to a neural fate".<ref><pubmed>9215646</pubmed></ref> <ref><pubmed>15721738</pubmed></ref>

Before the otic placode becomes distinct, Sox3 is already expressed in a broad area around the location of the future otic placode. Later in it will only be found in the proneural region of the otic placode. Based on this, the review by Alsina et al. (2009) suggests that a neural fate acquisition occurs prior to otic placode formation.<ref name="PMID19247974"/> During the early stages of development of the otocyst, Sox2 and Sox3 are found in proliferating cells within the proneural region. Both are expressed when neurons are generated, however, Sox3 switches off and only Sox2 remains during further development of the ear. This suggests that the ongoing expression of Sox2 plays a role in sensory cell development, as explained in the review by Alsina et al (2009).<ref name="PMID19247974"/>

-We will look into this in further detail when describing the development of the elementary sensory unit of the ear-

* ''Notch signalling''
Notch signalling is required for several developmental processes, including the maintenance of the neural competent domain.

In the notch signalling pathway, notch is the receptor, with most of its ligands being transmembrane proteins. Signalling is therefore restricted to neighbouring cells. Research by Daudet and Lewis (2005) reveiled how notch signalling plays a role in inner ear development, including:

- Notch signalling mediates lateral inhibition and thereby controls the differentiation of hair cells and supporting cells - in particular in the vestibular regions <ref name="PMID15634704"><pubmed>15634704</pubmed></ref>

- An early phase of Notch activity promotes formation of prosensory patches <ref name="PMID15634704"/>

- Other signalling pathways are likely to cooperate with Notch to specify prosensory regions of the otocyst <ref name="PMID15634704"/>

====The Otocyst====
[[File:neural fate.jpg|thumb|200px|Recent model related to sensory fate.]]

'''Patterning of the otocyst'''

The otocyst, also known as the otic vesicle, is present once invagination of the otic placode has occurred. Regionalisation of the otocyst results in the topological organisation of the ear. The neural tube affects the patterning of the otocyst, and FGF, Wnt and Hh signalling pathways are also known to play a role.
FGF and Wnt rely on signals from the hindbrain. <ref><pubmed>17891710</pubmed></ref>

Prosensory patches emerge within the otocyst. These develop as a differentiate from the neural competent domain.<ref name="PMID21266409"><pubmed>21266409</pubmed></ref>

- haircells (sensory patch)

- neurons (neural competent domain)

As proposed in recent models by Neves ''et al.'' (2011): Jagged 1 functions through lateral induction to activate Notch signalling. Notch signalling then functions through lateral inhibition and regulates Sox2 expression. Sox2 specifies sensory fate within the prosensory domains. "This confines sensory competence to the prosensory patches, ensuring the development of sensory organs of the correct size and location." <ref name="PMID21266409"/>

'''Establishing polarity and formation of inner ear structures'''
[[File:z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.]]

The different axis of the inner ear are fixed at different points in time. This means different signals are involved to establish the polarity and allow for development.<ref><pubmed>9389659</pubmed></ref>
The dorsal-ventral polarity is very significant in the development of inner ear structures. The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle.

The neural tube plays a role in patterning of the placode and it has been shown similar signals from the neural tube are also needed to establish the dorso-ventricular axis of the inner ear.<ref><pubmed>16325169 </pubmed></ref>

* ''Shh signalling''
The notochord produces Shh, which helps in patterning the dorso-ventricular axis of the neural tube. <ref><pubmed>18621990</pubmed></ref> This signal diffuses further and also affects the developing otocyst, where a gradient of Shh receptors is located from the dorsal to ventral aspect. <ref><pubmed>12231626</pubmed></ref>
Dorso-ventricular patterning and development of inner ear structures – in particular ventral structures – is achieved by the graded response to Shh.

As reviewed by Grooves and Fekete (2012) “data suggests that Shh acts on the ventral otocyst directly to regulate cochlear development, and that dorsal development can be regulated by signals from tissues adjacent to the otocyst that require Shh signaling for their normal development.”<ref name="PMID22186725"><pubmed>22186725</pubmed></ref>

* ''Wnt signalling''
Shh signalling for the ventral aspect is complemented by signals for the dorsal aspect of the inner ear. Wnt signalling takes places in the otic placode, as described above. This is initially as a gradient from medial to lateral <ref><pubmed>20171206 </pubmed></ref>, which later in the otocyst will be a gradient from doral to ventral <ref><pubmed>16452098</pubmed></ref>

As further suggested in the review by Grooves and Fekete (2012) “Wnt and Shh signals regulate different inner ear genes in different ways, with opposing gradients of Shh and Wnt signaling regulating the spatial localization of transcription factors, ultimately leading to the differentiation of a correctly patterned inner ear.” <ref name="PMID22186725"/>

* ''Hedgehog signalling''
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR'''
|- bgcolor=#E7FEFF
|
* Development of the inner ear: This starts out with the induction of the otic placode and consists of 3 major stages
'''1.''' Pre-placodal domain: After gastrulation, a pre-placodal domain is present adjacent to the anterior neural plate. The various placodes will arise from this domain.

'''2.''' Pre-otic field: Local signals establish the identity of each placode, including the otic placode. FGF signals from both rhombomeres and the cranial paraxial mesoderm are important otic inducers.

'''3.''' Otic placode/epidermis fate decision: signalling occurs to determine precisely which cells become the otic placode and which cells aquire the epidermal fate. FGF and Wnt signalling is necessary in this step, which could possibly be dependent or independent of each other.

* Neural component: During the early stages of embryonic development, a neural competent domain is established as part of the otic placode. FGF, Sox and Notch signalling play a role in creating and maintaining this domain. Once invagination occurs and an otocyst has formed, signalling pathways allow for patterning of the otocyst and formation of prosensory patches. Hair cells develop from the sensory patches and neurons develop from the remaining neural competent domain.

* Establishing polarity and formation of inner ear structures: The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle. For this reason, it is important for normal development of the inner ear to establish polarity, such as the dorso-ventral axis. Various signals are involved, including Shh and Wnt signalling. Hedgehog signalling needs to be suppressed.
|}

==Abnormal Hearing==

===Genetic===

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFA500"
|'''Genetic abnormality'''||'''Description'''||'''Image'''
|- bgcolor="#FFEFD5"
|''Mutation of GJB2 gene'' ||
* Approximately 60% of congenital deafness in developed nations is caused by genetic factors.
* More than 50 loci have been found to be responsible for the genetic causes of non syndromic deafness (isolated hearing loss with no affects to other parts of the body) called NSD and accounts for more than 80% of genetic related congenital deafness. GJB2 gene which instructs the protein Connexin 26 to be formed, is the most common cause of NSD.
* Connexin 26 is found all over the body, with a great number on the skin and in the inner ear.
*Over 90 of the GJB2 gene mutations have been associated with NSD. <ref><pubmed> 10980526 </pubmed></ref>

||
[[File:Mutation_on_GJB2_gene.jpg|x250px]]

|- bgcolor="#FFCC99"
|''Autosomal dominant hearing loss'' ||
* Autosomal dominant hearing loss is transferred directly though the previous generations and can usually be detected when reviewing at a family tree.
* There is a 50% probability that the child will also have hearing loss, and subsequently increases if both parents have the dominant gene. Research has shown that the phenotype due to GJB2 varies due to the great range of the degree of deafness in the patients.
* This alludes to the fact that other environmental causes have also contributed to the patients hearing impairment <ref><pubmed> 10980526 </pubmed></ref>.
* M34T missense mutation has been found in families where there are both affected and non affected people thus indicating its contribution to autosomal deafness both dominant and recessive deafness.
* Similarly, studies have shown additional missense mutations R75W, D66H and G59A are also causes of DNFA however they have been connected to other clinical manifestations <ref><pubmed> 11216656 </pubmed></ref>.

||
[[File:Dominant_diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Autosomal recessive hearing loss'' ||
* Autosomal recessive deafness is an inheritance of both the mother and father’s recessive genes of connexin 26 mutation.
* There is a 25% chance that the child will have hearing loss. However normally as both parents have normal hearing, it is difficult to foresee if the child will inherit hearing loss.
* The most prevalent connexin 26 gene mutation in the majority of ethnic groups for DNFB is the 35delG.
* Mutations in the connexin 26 genes equate to half of the DNFB cases <ref><pubmed> 14979964 </pubmed></ref>.

||
[[File:Autosomal_Recessive_Inheritance_Diagram.jpg|x250px]]

|- bgcolor="#FFCC99"
|''X linked hearing loss'' ||
* X linked hearing loss is carried by the mother and passed down to both the male and female children.
* Generally only the male children are affected if they receive the affected X chromosome while the daughters will be the carrier of the gene.
* The hearing loss can be a combination of both conductive (damage to the outer or middle ear) and sensorineural hearing loss (malfunction of the cochlea and or the hearing nerve) <ref><pubmed> 1163535 </pubmed></ref>.

||
[[File:X_Linked_Recessive_Diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Mitochondrial hearing loss'' ||
* Mitochondrial hearing loss is passed down solely through the mother.
* It is caused by mutations in either MT-RNR1 or MT-TS1 leading to moderate to profound hearing loss.
* MT RNR1 is generally correlated to aminoglycoside ototoxicity and sensorineural hearing loss independent of aminoglycoside ototoxicity occurring usually in the 20’s.
*Aminoglycoside ototoxicity refers to the increased chance of hearing loss after consuming antibiotics and is irreversible.
* MT-TS1 is sensorineural hearing loss occurring during childhood and is generally considered nonsyndromic <ref><pubmed> 20301595 </pubmed></ref>.

|}

NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS

'''Genetic Syndromes'''

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFF000"
|'''Syndrome'''||'''Description'''||'''Image'''
|- bgcolor="#FFFDD0"
|''Usher Syndrome'' ||
* Most common cause of congenital deafness due to defects in the inner ear and also causes vision loss
* Separated into 3 subgroups: USH1, USH2 and USH3<ref><pubmed> 16434480 </pubmed></ref>.

## USH1 - profound deafness at birth
## USH2 - Moderate level of deafness at birth
## USH3 - Hearing normal at birth but will gradually worsen as the child ages
* Various genes are thought to cause the disorder most recent is WHRN gene <ref><pubmed> 16452831 </pubmed></ref>.

||
[[File:Basal_Cochlear_Outer_Hair_Cells.jpg|x250px]]
|- bgcolor="#FBEC5D"
|''Pendred Syndrome'' ||
* Autosomal recessive disorder which causes progressive sensorineural hearing loss, and can also affect the thyroid gland, accounting for more than 10% of severe hearing impairment.
* Patients usually have structural malformations of the inner ear, in some cases a missing cochlear.
* The syndrome is caused by a variety of gene mutations, SLC26A4 gene causing more than half of all of the Pendred Syndrome cases.
* There is no current treatment option, and is most important that it is screened for in childhood hearing loss in order to teach differing ways of communication <ref><pubmed> 18285825 </pubmed></ref>.

'''All of these defects are suggestive of a developmental arrest at 7 weeks of human embryonic development. In addition, it has been noted that patients with Mondini malformations usually have reduced numbers of hair cells and spiral ganglion cells (11); these latter microscopic defects are thought to lead to the deafness. '''

||
[[File:Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px]]
|- bgcolor="#FFFDD0"
|''Goldenhar Syndrome'' ||
* There are a varying amount of malformations usually regarding the ears, mouth and jaw such as microtia and preauricular appendages.
* There is limited knowledge as to how this syndrome occurs, and there are currently no treatments for the subsequent hearing loss. <ref><pubmed>10829494 </pubmed></ref>
* It is thought that environment could play a role with an increased level of children developing this syndrome during the Golf War <ref><pubmed> 9408975 </pubmed></ref>.

||
[[File:MRI_of_Goldenhar_Syndrome.jpg]]

|}

===Environmental===

'''Infections'''

{| cellpadding=5 style="border:1px solid #74C365"
|- bgcolor="#009F6B"
|'''Organism'''||'''Description'''||'''
|- bgcolor="#F0FFF0"
|''Toxoplasmosis'' ||
* Toxoplasma gondii is an intracellular protozoan and can infect humans through undercooked meat containing bradyzoites or by legumes infected by oocysts (greatly infectious).
* A study published in 1988 collected data from 23,000 pregnancies which found mothers with an IgG antibody to toxoplasmosis during pregnancy doubled the incidence of deafness for the child. This was identified along with other symptoms such as microcephaly and low IQ scoring. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis.
* Congenital toxoplasmosis also results in mental retardation and deafness along with blindness and usually multiple organs affected such as Chorioretinitis. Notably, the infection risk differs during the gestation time: “1% at less than 6 weeks, 4–6% at 6–16 weeks, 20–40% at 16–25 weeks and 60–80% at 36 weeks of gestation” (http://www.marmaramedicaljournal.org/pdf/pdf_MMJ_446.pdf)
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref><pubmed> 3041362 </pubmed></ref>.
* Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 10356003 </pubmed></ref>.
*There have been inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>. Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 11561963 </pubmed></ref>.
* Notably, although this was an uncontrolled trial, this prenatal treatment was proven to be of some benefit <ref><pubmed> 10356003 </pubmed></ref> <ref><pubmed> 12618153 </pubmed></ref> <ref><pubmed> 1929726 </pubmed></ref> <ref><pubmed> 11821335 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article was published in the Lancet providing clear evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody.
* Studies have subsequently shown that the fetal infection risk will differ throughout the duration of the pregnancy. During week 1 to 10, there is a 100% fetal transmission rate, leading to an 81% rate during the first trimester, due to the immaturity of the fetal defense mechanisms and solely relying on maternal immunoglobulin G. This decreases throughout the second and third trimester, however the infection rate goes back to 100% in the last month of pregnancy. The sudden decrease is thought to be due by the maternal antibodies along with fetal cell mediated immune responses along with the humoral responses.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium. (G Tondury, DW Smith Fetal rubella pathology). As the cells appear desquamated within the vessel lumens, it is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli, which in turn leads to an increase in infection and damage to the developing fetal organs.
* Fetal organ development may be compromised by the virus prompting apoptosis. Studies indicate that the caspid protein dependent mechanism of the Rubella virus leads to apoptosis. (Rubella Virus Capsid Protein Induces Apoptosis in Transfected RK13 Cells, Robert Duncan). Rubella infected cells which do not undergo apoptosis result in a reduced growth rate and a shorten life span due to a decreased mitotic activity.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation.
* As Rubella has long been a known congential disease, through the Rubella vaccine, this has almost completely eliminated the disease in western countries. Thus as this is an entirely preventable disease, future programs should of Rubella prevention should lead to Rubella being a disease of the past.

(Rubella, the lancet, DWG Brown AND KV Pugachev, TK Frey Rubella virus induces apoptosis in culture cells)

(Onset and severity of hearing loss due to congenital rubella infection)

|- bgcolor="#F0FFF0"
|''Cytomegalovirus'' ||
* Cytomegalovirus (CMV) is an enveloped herpes virus which is passed to the fetus via vertical transmission.
* As 95% of pregnant women are asymptomatic, it is incredibly hard to diagnose.
* The virus can be classified into acute and non acute infections. Acute maternal infection can be verified by low IgG avidity levels.
* There are 2 methods to determine if the fetus has contracted CMV. A cordocentesis can be conducted to obtain fetal blood for sampling however issues have been raised regarding its safety and notably accessibility. (Weiner C.P.: Cordocentesis. Obstet Gynecol Clin North Am 15. 283-301.1988).
* Amniocentesis can also diagnose the CMV via PCR and is considered the better diagnostic tool due to the quick and reliable results it gives. High DNA copy numbers for the CMV infection relates to a greater severity of the disease and hence could indicate the hearing impairment outcome.
* A recent study has noted the role of CMV causing sensorineural hearing loss and subsequently being a high risk factor for hearing impairment. The results showed that more than half of the children participating had CMV IgG antibodies, with 20% being found as CMV DNA positive which indicates that the child has an active infection. (Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology, Eva Karltorp).
* There is no current treatment protocol for CMV, however a non random sampling trial has suggested the treatment of hyperimmune globulin giving promising results in the study. (Nigro G., Adler S.P., La Torre R., et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353. 1350-1362.2005; ).
* Another study showed that treatment of the symptomatic cases of CMV infection with intravenous ganciclovir (or Valganciclovir orally) for 6 weeks has indicated improvement in the child’s hearing. (Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46S:S22-S6.)

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''||'''
|- bgcolor="#FFA6C9"
|''Alcohol consumption during pregnancy'' ||
* Fetal Alcohol syndrome is a variety of conditions which occur in the fetus if the mother consumes alcohol during pregnancy. There is no safe level of alcohol consummation during pregnancy.
*Fetal Alcochol Syndrome is associated to 4 hearing impairment disorders:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss
(Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review. Church MW, Kaltenbach JA Alcohol Clin Exp Res 1997 May;21(3):495-512.)
*It is also associated with a variety of other malformations (skeletal and visceral), growth retardation and nervous system defects. The developmental delay of the auditory system is thought to be due to decreased growth of neurons and myelin and subsequently the synapses.
* Sensorineural hearing loss is thought to be caused by a greater amount of apoptosis during the inner ear development and thus leading to decreased levels of auditory nerve fibres and sensory receptor cells. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
*

|}

===Structural malformations of the ear===

{| cellpadding=5 style="border:1px solid #880085"
|- bgcolor="#9457EB"
|'''Structural malformation'''||'''Description'''||'''Image'''
|- bgcolor="#FAF5FF"
|''Stenosis'' ||
* Internal auditory canal stenosis is classified as someone who has an internal auditory canal 2mm or less.
* It is considered a rare disease with only 2.5% of patients with congenital hearing loss being affected by stenosis .
* It is thought to be as secondary to vestibulocochlear nerve hypoplasia <ref><pubmed> 9892864 </pubmed></ref>.

||
[[File:Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px]]
|- bgcolor="#E0CEF2"
|''Enlarged vestibular aqueduct'' ||
* Approximately 7% of all sensorineural hearing loss patients had an enlarged vestibular aqueduct.
* The most recognised cause of an enlarged vestibular aqueduct is due to a mutation on chromosome 7 on the SLC26A4 gene <ref><pubmed> 16570074 </pubmed></ref>.
* There is no current treatment and thus is important to identify it when the patient is a child so that alternative communicative methods can be taught.

(Sensorineural hearing loss in Patients with large vestibular aqueduct, Okumura)

||
[[File:Enlarged_Vestibular_aqueduct.jpg|x250px]]
|- bgcolor="#FAF5FF"
|''Microtia''||
* Deformation of the outer ear which can be with or without the external ear canal.
*There are 4-5 grades of microtia which range from a small ear to deformed outer ear to no ear present at all.
* Treatment involves the complete reconstruction of the outer ear and occasionally the middle ear depending on the level of hearing loss associated with it <ref><pubmed> 10890145 </pubmed></ref>.

||
[[File:Microtia_boy_surgery.jpg|x320px]]

|}

---------

==Technologies to detect==

The importance of having a neonatal screening test for hearing within the early days of life are important for the rest of that individual’s life. Screening is used to identify the children most at risk of having a congenital hearing problem. The importance of having an early diagnosis and having a method of intervention is crucial for the development of speech and language and learning of the child later in life, as reviewed by Oudesluys-Murphy ‘’et al’’. 1996. <ref name="PMID8789756"><pubmed>8789756</pubmed></ref>
Screening tests allow for the detection of hearing loss within the few days of life. This could be due to a dysfuctional cochlea or various other problems as discussed in our abnormal hearing section. Within Australia there are a few simple test that allow newborns to be tested fast, accurately and reliable <ref name="PMID8789756"/>.

===Oto-acoustic testing===
[[File: infant hearing test.jpg|thumb|300px| Testing the hearing of an infant]]

The oto-acoustic test measures the integrity of the inner ear. This involves the cochlea and its physiological effects - the production of an otoacoustic emission in response to sound <ref name="PMID8220282"><pubmed>8220282</pubmed></ref>. It involves inserting a probe into the ear canal, which then produces clicks or tones that are normally picked up by the cochlea. The function and healthiness of the cochlea can be measured, as the different parts of the cochlea respond to different forms of stimuli in terms on pitch and frequency <ref name="PMID8220282"/>.

For this test, there are two methods used for screening the hearing in newborns.

• The production of a single click or tone called the Transient Evoked Otoacoustic Emission test (TEOAE) <ref name="PMID8220282"/>

• The production of two simultaneous tones named the Distortion Product Otoacoustic Emissions Test (DPOAE) <ref name="PMID8220282"/>

===Auditory Brainstem Response===

The Auditory Brainstem Response tests the neurological function of the auditory brainstem. It is more so used as a referral test, rather than a screening test, as generally hearing loss is already suspected <ref name="PMID11667937"><pubmed>11667937</pubmed></ref>. This test uses a click or a tone, which causes the production of impulses by the neurons from the auditory nerve, travelling along the auditory pathway. This is then measured and detected by external electrodes that are on the scalp and the earlobe of the newborn. <ref name="PMID11667937"/>

===Automated Brainstem Response===

This cheaper and quicker method uses an ear cup that is fitted over the infant’s ear <ref name="PMID11343042"><pubmed>11343042</pubmed></ref>. This then sends out a stimulus and a response is measured through a series of electrodes that are connected to the earlobes, scalp, shoulders and neck<ref name="PMID11343042"/>. The automated brainstem response uses a computer to visualise and calculate the results, and produce a result of either ‘pass/refer’. Data of the patient are cross-referenced with a collection of results regarded as normal responses<ref name="PMID11343042"/>.

===OtoSCOPE===

A new genetic testing method called OtoSCOPE discovered in 2010 has greatly increased the efficiency for testing nonsyndromic hearing loss and Usher syndrome. It provides a great diagnostic tool, as all the genes related to hearing loss can be sequenced simultaneously thereby decreasing cost and time. The patients can be informed relatively early for any genetic abnormalities therefore providing early prognosis and genetic counselling. <ref><pubmed>21078986</pubmed></ref>

==Technologies to overcome the problems==
Depending on the hearing loss, there are different types of technologies to overcome this. Types of hearing lost are conductive and sensori-neutral . One type is the conductive, caused by the damage or blockage of the outer or middle ear, the other is sensori-neutral, where the damage is to the auditory pathway or nerve. In some cases there is a combination of the two. And there are two current technologies that overcome this problem and they are the the hearing aid and the cochlea ear implant.

===Hearing aid===
Hearing Aids are a major advance in helping people hearing, they work by amplifying the sounds so they can be detected even by the damaged inner ear. This method of hearing relies on the healthiness or still relative functioning cochlea. The damage of the sensori-neural pathway is overcome by the amplication of sounds to compensate the loss of hearing cells or hair cells in the cochlea. This is proportionate to the amount of hair cells still functioning. This amplication of the sounds, helps the patient hear and listen and communicate with others. This however also amplifies background noise. They consists of the microphone, amplifier and a speaker. From the sound being received by the microphone, this converted by the microphone into electrical impulses and replays it to the amplifer. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref name="NIH">{{citation
|title= Hearing Aid Basics
|url=http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

===Cochlea Ear Implant===
[http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx Cochlea ear] implants help the hearing impaired to listen. This is through having a device to provide a sense of sound. The cochlea implants consists of a few major components in helping the patient hear. It consists of a microphone, which detects the environmental sounds, a small electronic processor that selects the sound produced from the microphone. There is also a transmitter and the stimulator. This converts the signal that comes off the electronic processor into electrical impulses, which leads up the final component which is the electrode array. This picks up the electrical impulses and delivers them to the correct region of the auditory nerve. These methods of hearing or sensing sound are used only in severer or profoundly hearing impaired who have a dysfunctioning cochlea. <ref><pubmed>PMID:6028666</pubmed></ref> [http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx]
<ref name="NIH">{{citation
|title= cochlea implant
|url=http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

<ref name='cochlea_NPR'>{{cite=book| first=Hendrinkus| last=Dulfhuis|coauthors=| title=''Cochlea Mechanics: Introduction to a time Domain Analysis of Cochlea''| date=10-2-2012| publisher Springer Science+ Business Media|url=http://books.google.com.au/books?id=1UpECoc_q3UC&pg=PA5&lpg=PA5&dq=Gabriele+Falloppio+ear&source=bl&ots=mc9sb_0UR1&sig=WqdWXmDrJWV-2rqlWF3ihzMnWLE&hl=en&sa=X&ei=ozFoUPL8BoiQiQf_qoDYDw&ved=0CEEQ6AEwAw#v=onepage&q=Gabriele%20Falloppio%20ear&f=false| work=cochlea implant| pages = | accessdate = 20012-10-01 | language = }}</ref>

==Current Research==

* ''' ''Hair cell differentiation'' '''

A recently published paper by Pan ''et al.'' (2012) investigated the various levels and durations of expression of a particular transcription factor, which is necessary for hair cell differentiation. The ''Atoh1'' transcription factor was tested for by using conditional knock-out mice - ''Atoh1-cre'' <ref name="PMID22279587"><pubmed>22279587</pubmed></ref>. They determined that reduced levels of ''Atoh1'' resulted in the progressive loss of hair cells from the organ of Corti shortly after birth <ref name="PMID22279587"/>. Similar data was obtained when the deletion of the ''Atoh1'' transcription factor was delayed. Slight differences were noted between inner and outer hair cells: the loss of inner hair cells was more significant than the loss of outer hair cells. This indicates that ''Atoh1'' may play a role in the differential development of inner and outer hair cells.
[[File: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears.]]
[[File: Atoh1 hair cell loss.png|none|thumb|200px|Conditional deletion of Atoh1 results in death of organ of Corti cells and patchy Myo7a-positive presumptive hair cells which are innervated by many nerve fibers.]]

* ''' ''Stem cell therapy'' '''

The discovery of stem cells has led to an entirely new era in research, and the potential to prevent and treat conditions such as hearing loss.
It has been discovered that stem cells are present in the inner ear. In non-mammalian vertebrates, these stem cells allow the inner ear sensory epithelium to recover and function again after being damaged. This is not the case when it comes to mammals. Cells capable of regeneration are found in the vestibular sensory epithelium and in the neonatal cochlea. <ref><pubmed>8456285</pubmed></ref> However, only very limited regeneration may take place after damage has been done to the inner ear. Research is ongoing in various laboratories worldwide, such as at the University of Sheffield, as to how stem cells can be used to regain the sense of hearing. Early September 2012 there was an incredible breakthrough, as scientists from the university used [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx human embryonic stem cells to restore hearing in a common form of deafness.] This proves human stem cells could be used to repair the damaged ear and will hopefully lead to various other stem-cell based therapies.

[[File: aquaporins.png|thumb|200px|Aquaporins]]

* ''' ''Middle ear homeostasis'' '''

A recent article by Morris ''et al.'' (2012) investigated the mechanisms responsible for the ion homeostasis in the middle ear and how this relates to disease. They used BALB/c mice for immunohistochemistry of particular ion homeostasis factors of the middle and inner ear <ref name="PMID22720014"><pubmed>22720014</pubmed></ref>. This was then used to compare transport and barrier mechanisms and identify what is present in the tympanic cavity. Next, the middle ears received transtympanic injections with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation <ref name="PMID22720014"/>. Data shows that cellular hypertrophy occurred and localization of ion channels, such as aquaporins, was preserved within the inflamed middle ear epithelium<ref name="PMID22720014"/>. Morris ''et al.'' suggested that these channels could be used as a therapeutic target.

* ''' ''Molecular mechanisms - ongoing project'' '''

The HEARing Cooperative Research Centre ([http://www.hearingcrc.org/ CRC]) is involved in many ongoing research projects. Professor Doug Hilton supervises one of the projects: Genomic & molecular therapeutic approaches to environmental and age-related hearing loss.

A major public health issue is presbycusis - age-related hearing loss. It is known that apoptosis of cells within the cochlea plays a role; however, the many other factors involved and their molecular mechanisms are not yet fully understood. This research project is looking at the genes, proteins and regulatory pathways involved in both hearing and hearing-loss. The aim is to use this knowledge to identify molecules that can be targeted to [http://www.hearingcrc.org/research/projects/r122 prevent and/or treat hearing loss.]

==Glossary==

*'''Cristae''': the sensory organ of rotation located in the semicircular canal of the inner ear

*'''Ectoderm''': the outermost layer of the three primary germ cell layers in the very early embryo

*'''Epidermis''': surface epithelium of the skin, superficial to the dermis

*'''Gastrulation''': The inward migration of cells

*'''Hindbrain''': The lower part of the brainstem, comprising the cerebellum, pons, and medulla oblongata

*'''Lateral inhibition''': process whereby one cell takes on a state and the adjacent cells takes on the opposite state

*'''Mesoderm''': the middle layer of the three primary germ cell layers in the very early embryo

*'''Neural plate''': a thickened plate of ectoderm along the dorsal midline of the early vertebrate embryo that gives rise to the neural tube and crests

*'''Neural tube''': A hollow structure formed after gastrulation, from which the brain and spinal cord form

*'''Open neural plate stage''': stage of the neural plate before closure into the neural tube

*'''Otic placode''': a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops

*'''Otocyst – otic vesicle''': The structure formed by invagination of the embryonic ectodermal tissue that develops into the inner ear

*'''Pre-placodal domain''': An ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

*'''Proneural region – neural competent domain''': a region of the otic placode involved in neurogenesis

*'''Prosensory region''': region containing a population of cells that can develop into hair cells or or supporting cells

*'''Rhombomere''': a segment of the developing rhombencephalon (hindbrain segment)

*'''Saccule''': one of two otolith organs. The smaller of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Somite''': A segmental mass of mesoderm in the vertebrate embryo, occurring in pairs along the notochord

*'''Utricle''': one of two otolith organs. The larger of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Vestibular region''': the region of the inner ear close to the cochlea. Here the semicircular canals converge

*'''Vestibulo-acoustic ganglion''': The cranial ganglion of cranial nerve 8

==External Links==

[http://news.yale.edu/2012/02/16/yale-study-how-mitochondrial-dna-defects-cause-inherited-deafness|Yale study: how mitochondrial DNA defects cause inherited deafness]

== References ==
<references/>

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

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012-09-30T11:48:14Z

Z3333431: /* History */

{{2012GroupDiscussion}}

This is a recent review on hearing. http://jcb.rupress.org/content/190/1/9.full JCB content allows reuse.

=Student evaluations=

I liked the tone of the introduction, it was light hearted and enjoyable to read, especially the image of the dog in the beginning which I thought was great. It also instructed the reader about the content of the page, thereby having a good balance between being engaging and informative.

The development section is extremely detailed, which is good in terms of showing a breadth of research and understanding however this needs to be offset with a greater deal of visual information. The subsections detailing the middle and outer ear are in need of some images showing the pharyngeal arches and their morphological changes from week to week. It would also be nice to see either some hand drawn images or computer drawn diagrams included somewhere in the page just for some variation. Towards the end of the page in the Abnormal hearing and the technological sections it tends to become very text heavy and need some image content. For example a photo of a cochlear implant would be useful.

There is some variation in the referencing style in Technology section with references appearing at the end of the section. It would be better to incorporate these references into the text as endnotes as they appear in the other sections of the project. Furthermore some of the tables are incomplete and require the addition of images. The image column in the structural malformations of the ear is empty. I’m not sure if there was a formatting problem or otherwise, though this need to be rectified.

Overall the page is very well written with an appropriate style aimed at students of the same level or higher. The glossary is extensive as is the reference list, showing an obvious depth of research.

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'''Please use this space to post your Group 6 student evaluation'''
Very clever start to the page. Introductory picture and statement draws reader in. Succinct but depth of information is really good. Somewhat overwhelming, but still very good. Break up in the information a little more.

The use of tables is really good and the coloured textbox was eye-catching and informative, similar to a textbook summary and great for wiki.

Distribution of abnormalities between environmental and genetic was also very good but further subheading for each syndrome would be better for quick access to desired information.

The development of the ear section is very well researched and informative but need pictures. I see that you havn’t gotten to really uploading lots of pictures yet but it’s really quite essential for you to do this esp. for this section as it’s the main focus. A few had drawn ones would be sufficient.

The extensive references are also impressinve.

Summary: break up sections more and more hand drawn images.

Good luck with the rest ☺

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This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well.

The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective.

More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.

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Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:34, 25 September 2012 (EST)

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"The humorous image at the beginning accompanied by the “CAN YOU HEAR ME” in the introduction was a very clever way of drawing the reader in and making your message loud and clear, with all pun intended. Great work! I like how you also clearly introduced what your page will discuss.

No issues with the history timeline – it is well set out and very clear and concise. The section of the Adult Anatomy is quite clear also, however you refer to histology in the title – perhaps include an image that shows the histology of a certain structure. In regards to the section on Development, it is very clear that a lot of work has gone into this. However, be aware that you must reference all your information to avoid being penalised or accused of plagiarism. Additionally, images would help your explanations – it is slightly word dense at the moment so perhaps arrange some of the content into dot points in order to engage your reader. The sections on the Otic Placode and Otocyst are great examples of webpage layout, with the dot points and a clear image which links to the content. I especially liked how a summary of the inner ear was included – this demonstrates an awareness of peer teaching and reiterates your key points. Excellent!

The section on abnormal hearing was a joy to read and was cleverly set out in tables – the information will be even more enhanced by the images I can see you have indicated you will add. I also liked how you divided the different congenital abnormalities into environmental and genetic. In order to enhance these sections, incorporate some dot points or a diagram showing how viruses/drugs can cross the placenta.

The “Technologies to Detect” would best be organised under subheadings – at present it is a little daunting to read in the paragraph-paragraph format which is a shame because the information is very interesting! Also, be aware of correct referencing formats which you can find on the tutorial page – your in text references should be numbers and the references should go at the end of the webpage. I liked the “Technologies to overcome the problems” – may I suggest including images or diagrams of these technologies?

It would be great to see more examples of Current Research. However, what you have presented thus far is great – you have clearly described the aims and findings of research.

Overall, good work – just make sure you are consistent with referencing and strike a balance between images and text."

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What drew me into reading this page, was the humerous image at the beginning together with the perfect introduction that encourages people to read on. The sub-headings, headings, figures and tables make it really simple for the reader to take in all the key points of the research area. I particularly like the inclusion of technologies to detect abnormalities. However, this great balance is not met in the development section where there is too much text and not enough images or diagrams to guide the thinking. I would suggest trying to simplify the information into key points by eliminating any information that would not necessarily contribute to a sound understanding of the topic. This could possibly be achieved further by having a separation or different sub-heading for the description of the development process and the description of the cellular structure.

What stands out the most about this page, is the amount of research you have put in to the genetics and molecular processes of development and abnormalities. Whilst it is very interesting and shows the amount of time you've put into having a clear understanding, at times it seems the naming of genes and their proteins do not contribute to a sound understanding but rather adds confusion. For example, your reference to FGF and Sox are important but you have further included the different types of FGF and Sox proteins without offering much of an explanation about what distinguishes them from eachother. Generalising in these cases (to just FGF not FGF1,2,3..) would not limit the extent to which a student may learn from your information but will avoid any confusion.

Another way you could further improve the page is with the inclusion of student-drawn images or learning aids to accompany the text. This way you can avoid the inclusion of unnecessary information on borrowed images, for example, the wild-type inner ear morphology image. The referencing system is consistent and well set-out on the page and the long list of references and interesting discoveries is impressive. Overall I would just encourage condensing the information into dot points that help simplify the reader’s understanding.

Good luck!

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Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

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Group Assessment Criteria:
# ''The key points relating to the topic that your group was allocated are clearly described.'' The introduction clearly outlines the key points of the project and the content is well described in the text.
# ''The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'' The choice of content and headings shows a good depth of research and understanding of the topic area. The ‘Summary of the inner ear’ table was a good idea and ties in all the information nicely.
# ''Content is correctly cited and referenced.'' There are large paragraphs of texts that have no references. The images provided display the copyright notices and explanations.
# ''The wiki has an element of teaching at a peer level using the student’s own innovative diagrams, tables or figures and/or using interesting examples or explanations.'' The introduction is well written and catches the readers interest and attention. Most of the normal development section is easy to understand, however the abnormalities section is difficult to understand due to the scientific jargon. Some hand-drawn images and tables would be beneficial in order to reduce the large paragraphs of text.
# ''Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'' The amount of information provided is evidence of the significant research that went into this project, and the sections such as ‘Technologies to overcome the problems’ shows research that goes ‘beyond the formal teaching activities’.
# ''Relates the topics and content of the Wiki entry to learning aims of embryology.'' The topics and content are well related to the learning aims of embryology
# ''The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.'' All the content is relevant to the key areas of the development of the eye and demonstrates an extensive amount of research into the topic.

Additional points:
* The amount of text is overwhelming. You should make better use of tables, figures and diagrams to breakup/replace the text.
* Adult anatomy and histology: no reference to histology. Would be beneficial to have a brief explanation of the functions of each structure.
* Overall impression: Very well researched topic and I'm sure the use of tables, pictures and diagrams will make it more appealing to read!

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The image of the dog at the top of the page, while amusing, is not helpful nor appropriate for the academic nature of this website. The rest of the page however, is quite good. The information is extensive, very extensive. What i particularly like is that you have included a large amount of information on the actual development of the sense. It is easy with this assignment to talk at length amount the gross anatomy/physiology of the sense, without really dealing with the embryology of it.

As with most of the other projects, there are some sections that would benefit from a diagram or image. I know this is hard, especially for a paragraph dedicated to "mutation of gjb2 gene", but the large bloc of text is really quite trying for the reader. I found myself losing interest quite quickly.

Reference list is well pull together with a large body of research giving weight to your summary/ideas. Another this of note is how well explained your images are. This provides valuable information in trying to understand some of the ideas presented.

This is some discontinuity between the sections regarding how your present and list your information. This is probably just a by product of teamwork that can be ironed out easily.

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The introductory image at the top of the page is very good but the "can you hear me' bit was overkill for me - maybe consider revising that. Also the small spelling mistake at the start of the introduction (should be senses not sense) is quite off-putting and should be fixed. Otherwise a good introduction.

The history timeline is very good and serves as another good introduction to the topic. Some external links are missing here though.

For development there is a lot of information in the outer ear section but not much in the middle and inner sections - it looks imbalanced and may be improved by adding to the other sections or perhaps splitting up the sections differently. Other than this the development section is very good with a lot of well researched information. The images are also good but don't forget to add the "student template". The inclusion of the summary box is a very good idea and is a good feature of the page.

The abnormal section is also very good and well researched. The subheadings are used effectively and the tables are a good addition. Adding images in the tables as well as the text will help to break up the text and promote interest.

The technology sections are an interesting addition however could be improved by referencing using the wiki system rather than standard in-text citations.

A good start has been made in the current research section however if possible add more current topics of research.

The glossary is very good and the references are extensive however don't forget to add to the external links.

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Firstly the use of humour in this page is brilliant! Makes for an interesting and engaging read. The use of photographs and figures are particularly useful to help understand the topic but don't forget that the student template notice needs to be added to each photograph/diagram that you include. The referencing is great and extensive, perhaps though it might be an idea to see what is going on with reference number 56. The general layout of the page is really attractive too with a good balance of images and text, tables and especially the colourful Summary box. The content seems to address the course aims and requirements.

The introductory paragraph is to the point, well written and engaging. Similarly the structure and content included in the historic section is detailed and easy to read due to the table layout. The section about the development of the inner is well written but is somewhat overwhelming to look at just because of the amount of text. Maybe this could be combated by separating it into a few more paragraphs. The inclusion of genetic information in this area is great. The information under the subheading "The Otic Placode" onwards is particularly well done.

I like how the section on abnormalities is set out. However one problem with the area is the NOTE just before the table of genetic syndromes, I don't understand its purpose. Similarly the link in Goldenhar Syndrome entry appears random in comparison to the remainder of the entries.
Perhaps some more images in the abnormality section would be beneficial in breaking up the text. The paragraph discussing Rubella has two sentences in brackets at the bottom. Not sure why they are there either. If possible make "Infections" and "Drugs" into subheadings. I assume that information is still forthcoming for the section on Isotretinoin.

"Technologies to detect" is a good entry but perhaps consider changing subheading title as it is a little vague and incomplete. Also with this section there are loose references which should be included in the reference list at the bottom of the page rather than in the middle of the text. The information on hearing technology is brief but to the point. Again with the section on current research it may be an idea to include subheadings rather than bullet points, just so it is more easily accessed from the contents box at the top of the page.
Hope this helped.

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The introduction gives a good overview of the project and serves its purpose well. In addition, the technology section is another thing that stands out in this page along with the glossary and extensive referencing. These sections don't need to be worked on, but rather concentrate on expanding the page and adding a few more subheadings including headings of "current treatment" and "infection".

Information is very easy to follow due to the right choice of subheadings, tables and graphs. A few more tables and images with labels would make the information even easier to understand. Sometimes the amount of information becomes overwhelming, therefore try to break up the amount of texts by adding diagrams in between. Student hand drawn diagrams would be an excellent tool to employ as they can go well with the information provided.

The division of information between inner/middle/outer ear makes the structure easy to follow. This is a very good idea and an example as to how to break up the rest of the information which is all crammed together.
The citation and referencing seems to be correct, however, there are a number of paragraphs without any references, this is something that needs to be looked into. However, the level referencing at the end is great.

Also, there does not seem to be enough links. A few external links will benefit the page and allow readers to interact a fraction more.
Overall the page is very informative, however, altering the outlay and including a few diagrams, labeled images and external links would make the information easier to apprehend.

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Overall this is a well written page and is thoroughly researched.
While your introduction is small it is to the point. It gives an overview of hearing, its importance and outlines what your page is going to discuss.

The adult anatomy and histology part is confusing, I assume the adjacent image is related to the section and that development is a separate section. If that is so maybe the ear image should be thumb nailed or made smaller so that development looks like its own part.

Some images for development would be a nice addition to the well-researched information. While the class understands what it means others searching this page will have no point of reference as to what pharyngeal arches are for example, this is only a minor problem though.

The format of your development section is slightly confusing. Maybe by adding a line under inner and outer ear it would define it as a section on the respective area of development. I do like the summary of inner ear development at the end.

Technologies to detect, could possibly be name detection technologies/techniques has in text citations, I don’t think that these are necessary for this type of assignment.
--[[User:Z3220343|Z3220343]] 21:34, 25 September 2012 (EST)

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Group 6-Hearing

-you had me at puppy

-good intro (a few typos) and history (I like your table)

-the start of adult anatomy and histology should have an opening sentence instead of just listing information. There is no histology?

-I'm guessing the heading for development is meant to be bigger instead of it appearing to be part of "adult anatomy and histology"? This section is very comprehensive!

-your "neural domain" drawing is a good way of explaining this concept

-the summary box is a great idea, but perhaps it should be entitled "Summary of inner ear development"

-I don't understand why this is present- "NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS". You have explained what non-syndromic hearing loss is in the 1 Mutation of GJB2 gene section, but as your note says, it might be good to have a brief section with these definitions

-your genetic and structural disease tables are nice but I feel that the formatting should be the same for all of the diseases, or you should explain why you've chosen to emphasise these abnormalities

-the PDF in the Toxoplasmosis section seems to have some good info, but should be formatted like the other references

-the references in the rubella, cytomegalovirus infection, drugs and technologies to detect sections need to be formatted properly. Some info in drugs section isn't referenced at all

-technologies to detect is not a very informative heading, you need to specify what you're detecting. The syntax in this section and "technologies to overcome the problems" is poor (including the headings)

-in text hyperlinks in current research section are good for making page more interactive

-you appear to have used a lot of great resources

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Hearing review:

This group successfully energies the audience with a funny picture, along with a great introduction and an interactive writing style from the first paragraph. This page needs to address the reoccurring text to image ratio, allowing the reader more explanation complementing the hard work of explaining concepts. The highlight of this text was the abnormal hearing section which I found to be very interesting along with sound presentation of ideas. The demise of this page is the lack of information in current research and being starved of visual stimuli.
Overall a good attempt to line up embryological teaching concepts, when these easily addressable points are responded to a commendable finish will be apparent.

--[[User:Z3330795|Z3330795]] 09:55, 26 September 2012 (EST)

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Introduction needs more details. It has no references, so you need to research more and write more details with references. It would be good if you add an image of the ear with its structural components labelled, and explain the function of the structures.
The history section is too short so far. It needs more details and more references. Also, it would be good if you add images to support it.

Adult Anatomy and Histology has a good image, but you need more text details and you need to explain the structures more properly. And although ‘histology’ is mentioned in the heading, there is no explanation of the histology of the ears in the section at all. You need to reference the explanations of the ear structures.

Development section has a lot of detailed information so far, but needs more references and more images to balance the text. There is too much text but not enough images. The images that are currently there needs more description in the image details.
Genetic syndromes has a column that is labelled ‘images’ but there are no images there. You need to add images there.
Abnormal hearing section is very detailed and well done so far. However there is too much writing and no images at all. You need to add more images to balance the text to make it easier to read.

You may need some more examples in “Technologies to overcome the problems” section and you need to add more reference to the information posted so far.

Current research section needs a lot more work. Please add more article summaries and images with description from the articles to support the text.

Glossary section is good so far, but perhaps add some more words.
The reference section is good so far and has correct formatting.

There are no external links listed as of yet. Please add some useful external links.

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Hearing

The introduction is concise and straight to the point. It gave an overview of the webpage and clearly indentified the purpose. The use of humor is welcoming though I think that image of the dog is over the top. Due to the great choice of subheadings, the development part is very easy to follow. More images to accompany the text would make it easier to understand would help break up some of the text. The current research section feels lacking. Referencing need to improve as some paragraphs have none.

=Hearing=

Normal and Abnormal

==Discussion Topics==

===Introduction===
Not what hearing is but what we are going to talk about

Image for hearing <pubmed>20624897</pubmed>
===History===

Research Contribution

==== Bartolomeo Eustachi 1514–1574 ====
Proposed that the tympanic membrane was connected to the nasopharynx was in the book ''De Auditus Organis'' in 1563. This was focusing on the the middle ear. His knowledge had allowed him to rediscover the tube found many years before and describe it correctly. This tube, the eustachian tube was named after him, by Antonio Maria Valsava and was shown in his book ''De aure humana tractatus''. <ref name="/PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 De aure humana tractatus.]

==== Antonio Maria Valsava 1666-1723 ====
The pioneer in the anatomy of the ear, published his first book ''De aure humana tractatus'' in 1704 this was the first to show and clearly describe the ear. He had been able to describe the anatomy and physiology of the ear by dissecting over thousands of corpses. He was able to separate the ear into its divisional compartments of inner, middle and outer ear.

http://books.google.com.au/books?id=_JDOVMDi8d4C&pg=PA843&lpg=PA843&dq=Gabriele+Falloppio+ear&source=bl&ots=BWTIaLrqRS&sig=BLfW2dTzfmYkZTOGljxCsdCWij4&hl=en&sa=X&ei=gC5oUIb6AoaViAfQx4HYDw&ved=0CDgQ6AEwBDgU#v=snippet&q=%20ear&f=false

===Adult Anatomy and Histology===

<pubmed> 15495168 </pubmed>

<pubmed> 16015653 </pubmed>

<pubmed> 9433684 </pubmed>

===Development===

<pubmed> 6650859 </pubmed>
====Outer Ear====

Historic paper

<pubmed> 17104502 </pubmed>

<pubmed> 22296782 </pubmed>

<pubmed> 12874121 </pubmed>

====Middle Ear====

<pubmed> 18803631 </pubmed>

<pubmed> 21196256 </pubmed>

<pubmed> 14973294 </pubmed>

<pubmed> 11237469 </pubmed>

<pubmed> 16600992 </pubmed>

====Inner Ear====

(can include balance organs as well)
cochlea and semi circular canals and the physiological function - how hearing works

Some papers to start with:

<pubmed>15319325</pubmed>

<pubmed>17891709</pubmed>

<pubmed>10887092</pubmed>

<pubmed>19247974</pubmed>

===Abnormal Hearing===

Just putting my articles in here so I can refer to them at a later date - will change the referencing when I have structured my points better

- DISCUSS CONDUCTIVE AND SNESORINEURAL HEARING LOSS
- ADD PICTURES OF GENETIC TRANSFER
- ADD PICTURE OF LOCATION OF GENE GJB2

Genetic defects:

1. [http://ghr.nlm.nih.gov/gene/GJB2| GJB2 Gene] (accounting for 50% of non syndromic hearing loss)

Environmental

1. Drugs:
Hearing, Speech, Language, and Vestibular Disorders in the Fetal Alcohol Syndrome: A Literature Review. Michael W. Church and James A. Kaltenbach, Alcoholism: Clinical and experimental review. Vol. 21, No. 3, May 1997 [http://www.ncbi.nlm.nih.gov/pubmed/9161611| PMID: 9161611]

2. Infections:
Congenital Rubella Deafness: A preventable disease. C. S Peckham, J. M Martin, W. C Marshall, J. A Dudgeon, The Lancet, February 3, 1979 [http://www.ncbi.nlm.nih.gov/pubmed/84910| PMID: 84910]

[http://www.ncbi.nlm.nih.gov/books/NBK1434/ |Deafness and Hereditary Hearing Loss Overview]

Etiological diagnosis in the hearing impaired newborn: Proposal of a flow chart. De Leenheer, E.M.R. ; Janssens, S. ; Padalko, E. ; Loose, D. ; Leroy, B.P. ; Dhooge, I.J. International Journal of Pediatric Otorhinolaryngology, 2011, Vol.75(1), pp.27-32

[http://sirius.library.unsw.edu.au:9003/sfx_local?frbrVersion=3&ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2012-08-26T10%3A07%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-sciversesciencedirect_elsevier&rft_val_fmt=info:ofi/fmt:kev:mtx:&rft.genre=article&rft.atitle=Congenital%20cytomegalovirus%20(CMV)%20infection%20as%20a%20cause%20of%20permanent%20bilateral%20hearing%20loss:%20A%20quantitative%20assessment&rft.jtitle=Journal%20of%20Clinical%20Virology&rft.btitle=&rft.aulast=Grosse&rft.auinit=&rft.auinit1=&rft.auinitm=&rft.ausuffix=&rft.au=Grosse%2C%20Scott%20D.&rft.aucorp=&rft.date=2008&rft.volume=41&rft.issue=2&rft.part=&rft.quarter=&rft.ssn=&rft.spage=57&rft.epage=62&rft.pages=57-62&rft.artnum=&rft.issn=1386-6532&rft.eissn=&rft.isbn=&rft.sici=&rft.coden=&rft_id=info:doi/10.1016/j.jcv.2007.09.004&rft.object_id=&svc_val_fmt=info:ofi/fmt:kev:mtx:sch_svc&svc.fulltext=yes&rft_dat=%3Csciversesciencedirect_elsevier%3ES1386-6532(07)00336-8%3C/sciversesciencedirect_elsevier%3E&rft.eisbn=&rft_id=info:oai/%3E| Congenital cytomegalovirus] (CMV) infection as a cause of permanent bilateral hearing loss: A quantitative assessment. Journal of clinical virology [1386-6532] Grosse, Scott yr:2008 vol:41 iss:2 pg:57 -62

Congenital Infections. JF Bale. Neurol Clin. 2002 Nov;20(4):1039-60, vii. [http://www.ncbi.nlm.nih.gov/pubmed/12616680| PMID: 12616680]

Related to both middle and inner ear (so we can link the technologies to this)

===Technologies to detect===
Any technologies (like pre-testing) that identify any problems with hearing development

===Technologies to overcome the problems===
(hearing aids, cochlear transplants, etc)

===Current Research===

===Glossary===

===References===

------------------------------

Allocated subheadings

J: adult anatomy, outer and middle ear development

M: Inner ear

P: History and Technologies

B: Abnormal Hearing

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==Our Thoughts - put new comment at the top please==

Hey all!

I just put student templates with almost all images, and they should be fine now. The only one that may need editing is the one on the development of the pinna. ALSO(!) do we need a student template if it is a student drawn image?? If any images are uploaded from now on, please just put all the information with it straight away, so we don't have to worry about that anymore :) Thanks guys! M. --[[User:Z3333865|Z3333865]] 16:55, 28 September 2012 (EST)
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http://www.sonoworld.com/fetus/page.aspx?id=205 picture of ear at 6 weeks

--[[User:Z3292017|Z3292017]] 11:44, 26 September 2012 (EST)

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Hey all! We are starting to get some really good and useful feedback :) Hope everyone is ready to get stuck into editing from tomorrow onwards, cause the project is DUE WED 03/10/2012 - WHICH IS NEXT WEEK!! Keep this in mind. From what I read so far, the aim will be the simplify/reduce our text and include more images. Referencing needs to be fixed as well for some parts of the project.. but all in all its quite good :) M. --[[User:Z3333865|Z3333865]] 09:03, 25 September 2012 (EST)
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Hey! To everyone who is working on the history, please add this to the table! I'm about to change it now so that there is simply one table with significant dates and explanations. And it would be good if we can quickly meet up after one of the lectures tomorrow :) anyone who can't make it, please let the others know. M --[[User:Z3333865|Z3333865]] 14:31, 17 September 2012 (EST)

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Hi P,
How are you going with your research? We really need to have it complete by this weeks lab so that we can spend the next couple of weeks adjusting the information. Thanks, B --[[User:Z3292017|Z3292017]] 12:08, 17 September 2012 (EST)

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Hey M,

Yeah summary sounds like a good idea and maybe wiht some bolded words etc? Ive created 2 tables where I will briefly summarise the remaining diseases such as structural and genetic syndromes as my section will be too long and more boring than what it already is if I keep going. Yes, I think by our next lab would be a good idea. B. --[[User:Z3292017|Z3292017]] 19:22, 15 September 2012 (EST)

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Hey B and others,

My section is almost finished. I mainly have to focus on the images. I was also thinking of putting a summary box in my section, because there is just so much text! About the due date.. I think it will be good for us all to have most of the research and text done by lab 8 (19/09/12). We can then focus on the layout and images and tables, etc. What do you think? M. --[[User:Z3333865|Z3333865]] 17:57, 15 September 2012 (EST)

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Hey guys,
I have been updating all of my abnormalities and along with the references, it will all be completed by Sunday night, exempt all the photos as that will be my final research. Thought I would update you all so we can get a finish timeframe in mind!
B. --[[User:Z3292017|Z3292017]] 15:08, 15 September 2012 (EST)
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Hi P,
In regards the technologies, you should take a look at my section, because the technologies should really be perhaps how abornal hearing can be detected in the womb (such as amniocentesis for Rubella) and also the different insstruments used for hearing and why they do and don't work on certain patients. and perhaps with the history go a bit more indept/ greater explanation. such as if the first hearing aid was developed, find a picture and say what they originiall used to create noise for the patient etc. Use bulletpoints if you don't want it to seem too full on Do you guys agree?
B. --[[User:Z3292017|Z3292017]] 15:02, 15 September 2012 (EST)
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Hey P.
The history section should contain major discoveries and the person(s) of interest. I started writing things down in a table. If anyone find info they should put that in and the original document/article should be referenced if possible (not a review). Hope this helps cause we really have to put all our info together soon. M. --[[User:Z3333865|Z3333865]] 12:40, 14 September 2012 (EST)
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Hey guys, for the history, im not 100% what I supposed to write about, i know its late and i'm an idiot for asking now, but am i supposed to write like the old research papers like what they used to think? like how they thought the ear formed like from the 1800's or whatever? and how technologies also helped proved it wrong or proved that they are right? P. --[[User:Z3333431|Z3333431]] 13:13, 12 September 2012 (EST)
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DW, I had a look at the editing basics and the references are working now! :) M. --[[User:Z3333865|Z3333865]] 10:20, 3 September 2012 (EST)

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Hey ppl!

I can't seem to link my references. '9' and '10' in my inner ear section step 2 should be the same number, but I can't seem to get it to work... can anyone help?

Thanks, M. --[[User:Z3333865|Z3333865]] 09:46, 3 September 2012 (EST)

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To all,
I find it very difficult to find images which have the correct copyright statement and are not already used on this embryology website.
So if anyone finds an image which we are allowed to use, please post it up and let the others know :)

And to B. That sounds good :) Speak to you tomorrow! M. --[[User:Z3333865|Z3333865]] 13:22, 27 August 2012 (EST)

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Hi!

In regards to my abnormalities (we can all discuss further this week), I will be focussing mainly on the gene GJB2 (which accounts for 50% of non syndromic hearing) and then for acquired hearing (organisms), I will focus mainly on what is known as "TORCH" organisms (i.e., toxoplasmosis, rubella, cytomegalic virus, and herpes) and go into details in them and then as M said before, just list the other in a table.

Thanks,
B. --[[User:Z3292017|Z3292017]] 17:45, 26 August 2012 (EST)

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Hey!

In regards to the hearing abnormalities, yes I would do the most common ones. It will be way too much otherwise!
Just name the other abnormalities for now - depending on how long your section is we will include them or leave out.
At the end of your section we can also put a table down with a summary of the common ones you explained in detail before :)

M. --[[User:Z3333865|Z3333865]] 13:07, 26 August 2012 (EST)

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Hey guys,

Sorry I haven't been communicating via the discussion page, I've been sick in bed with a virus for the past week and half! Anyway, as I am focussing on the hearing abnormalities, I just wanted to clarify some things with you all. Firstly, there are A LOT of genetic disorder which contribute to hearing loss so I was thinking I would group them and would write in depth into the most common ones and then a brief description or just name the others.
I'm currently compiling some research papers, so I will most likely get to writing some points on this page tomorrow.

Let me know if you have any suggestiosn etc and if I find any other articles in my research I will send them through!
--[[User:Z3292017|Z3292017]] 18:44, 25 August 2012 (EST)

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Hey all!

For this week, please find some good papers relating to your section - both primary and secondary - and start reading them.
It will take some time to get all the info together and to also make it look good with pictures etc.
So the sooner we start the easier it will be in the long-run!!

--[[User:Z3333865|Z3333865]] 21:00, 18 August 2012 (EST)

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Hey everyone!

I guess if we end up doing the sensory topic and focus on the ear we can come up with some headings that we might want to use in our project.

This is the [[Sensory_-_Hearing_and_Balance_Development| link to our lecture on the ear]]

I guess one way of doing this would be to divide it into inner, middle and outer ear and talk about the development of each. I guess we could include the progressive development over the weeks including cellular, molecular and morphological changes. We can also describe the developed ear, any genetic mutations or incorrect signal pathway that cause any defects. Then one part of it can be current research and any past research or noble prizes.

Cheers!

--[[User:Z3333794|Z3333794]] 11:31, 9 August 2012 (EST)

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Hey all!

So we have to decide between normal development or abnormal development.
Normal development can have headings as mentioned above, apart from the genetic mutations and defects.
When focussing on abnormal development of the ear we can look at those mutations and defects. We can also look at technology such as hearing aids and the cochlear implant.

Please put down your preference!
I really dont care.. but I think that if we have to discuss development it will be easiest to look at normal development.

--[[User:Z3333865|Z3333865]] 13:06, 14 August 2012 (EST)