The Johns Hopkins Medical Journal 27 (1916)

From Embryology
Revision as of 20:44, 16 February 2020 by Z8600021 (talk | contribs) (→‎CONTENTS)
Embryology - 6 Apr 2020    Facebook link Pinterest link Twitter link  Expand to Translate  
Google Translate - select your language from the list shown below (this will open a new external page)

العربية | català | 中文 | 中國傳統的 | français | Deutsche | עִברִית | हिंदी | bahasa Indonesia | italiano | 日本語 | 한국어 | မြန်မာ | Pilipino | Polskie | português | ਪੰਜਾਬੀ ਦੇ | Română | русский | Español | Swahili | Svensk | ไทย | Türkçe | اردو | ייִדיש | Tiếng Việt    These external translations are automated and may not be accurate. (More? About Translations)

Historic Disclaimer - information about historic embryology pages 
Mark Hill.jpg
Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

The Johns Hopkins Medical Journal - Volume 27 (1916)

https://archive.org/details/johnshopkinsmedi27john

The Johns Hopkins Medical Journal


VOLUME XXVII

BALTIMORE

THE JOHNS HOPKINS PRESS

1916


BULLETIN


OF


THE JOHNS HOPKINS HOSPITAL


Vol. XXVII.-No. 299.


BALTIMORE, JANUARY, 19 16.


CONTENTS

Gaucher's Disease. A Report of Two Cases in Infants. (Illustrated.) By J. H. Mason- Knox, Jr., Ph. D., M. D., H. Roswei.i, Wahl, M. D., and Harry C. Schmeisser, M. D., Ph. D. 1

Pleural Eosinophilia. With Report of a Case. (Illustrated.)

By Stanhope Bayne-Jones, M. D 12

A Colorimetrie Method for the Determination of the Hydrogen Ion Concentration of Biological Fluids, with Special Reference to the Adjustment of Bacteriological Culture Media. (Illustrated.) By S. H. Hurwitz, K. F. Meyer, and Z. Ostenberg .

Hodgkin's Disease of the Intestines. With Report of :i Case. (Illustrated.) By L. M. Wabfield, M. D., and H. T. Kristjanson', M. 1)


Notes and News


GAUCHER'S DISEASE.

A REPORT OF TWO CASES IN INFANTS.

By J. H. Mason Knox, Jr., Ph.D., M. D., H. Roswell Waul. M. D., and Harry C. Sc ihmeisser, M. D., Ph. D.

(From the Thomas Wilson Sanitarium, the Department of Pathology of the Western Reserve University Medical School, and the Departments of Pediatrics and Pathology of the Johns Hopkins University.)


The cases of Gaucher's disease reported in the following paper occurred in two children of the same parents that came under observation during a period of two years. The first child was admitted to the Thomas Wilson Sanitarium in the service of Dr. Knox. The disease ran a fatal course in a comparatively short time, the clinical and anatomical findings, the latter studied by Dr. Wahl, being prepared for publication in January, 1915. About one year before, the second child had been admitted to the Harriet Lane Home of the Johns Hopkins Hospital in the service of Dr. Howland. In this case also the clinical aspects were studied by Dr. Knox and an excised gland was examined by Dr. Wahl. The case likewise ran a rapidly fatal course and was studied anatomically by Dr. Schmeisser. It was decided to include the two cases in one report.

Historical. — Through the recent investigations, notably those of Bovaird, Brill, Mandelbaum, Libman, Reuben and others, the uncertainty surrounding the disease described by Gaucher in 1882 has been largely removed. It is now agreed that the term " Gaucher's disease " can be properly applied to only a small group of splenomegalies, namely, to those cases in which the organs show the presence of certain distinctive large cells. Of the total of 16 cases reported since 1882, L2 have been described in the last decade and three, exclusive of our cases, within two years. Unquestionably the condition is


more prevalent than has been suspected, and as the peculiar features of the disease become more generally known, the number of cases reported will probably increase rapidly.

The literature of the subject has been so thoroughly presented by Mandelbaum that a further review is unnecessary. It may be helpful, however, to present briefly in tabula] the instances of Gaucher's disease — proven to be such by microscopic examination — heretofore reported and to comment briefly upon the more important features. The cases ai i epted by Mandelbaum, together with two more recent one-, an summarized in the accompanying table (see pages I and 5), an analysis of which gives the following more important data :

Analysis of Table: Sex. — The disease appears to be more prevalent in the female. Of the 16 patients there were but three males.

Age.— It may manifest itself at any age. but the majority of cases reported have been in young adults. The oldesi MarchandV was a woman 44 years old; the youngest, STie mann's," was a child of 14 months. It is probable that the condition in the older patients bad existed befori

being recognized.

Symptoms. — The onset of the disease is insidious, th toms being vague and indefinite. A feeling of weigW accom panying i! I irgement of the abdomen was usuallj |



Eleven of the patients had some form of hemorrhage, usually epistaxis or bleeding from the gums or into the skin. Dull oal pain was complained of in 10 instances. (Edema of cases; in lour there was lever and in four a moderate degree of dyspnoea. Three of the patients suifered fron sweating, and in several there was more

or less In all there was gradual loss of weight.

Death ensued from exhaustion or from some intercurrent malady.

I he most constant physical sign was the enlargement of the abdomen, due primarily to the increase in hulk of the spleen and liver.

I he spleen is described as " filling the abdomen " in a number of instances. In Case 9 it reached a maximal size I cm. — and weighed 8100 gni. The relation of the spleen to the body weight, which is normally about 1 : 400, may in this condition be altered to 1 : 5 or 6. In each instance gan retained its normal outline aud was firm and resilient to palpation.

Liver. — Enlargement of the liver was noted in 14 cases. It was not so marked as was that of the spleen, and seemed to at a somewhat later period. The organ was firm and its was hot altered. Lymph Glands. — The superficial lyniph glands were moderately enlarged in 10 instances, and in three additional cases certain internal groups of lymph glands were enlarged. In two cas inds were not enlarged.

Color of the Skin. — Gaucher described his patient as having a skin of a peculiar leaden hue, which became more pronounced towards the end of the illness. A similar yellowish or brownish -t marked on the face and extremities, was noted in 11 cases. In two "slight jaundice" was mentioned, and in three cases no pigmentation was described.

ting. — Brill and Mandelbaum have described a " brownish -yellow wedge-shaped thickening of the conjunctiva " extending from the cornea to the inner and outer eanthus. They consider this of diagnostic significance. This alteration in the conjunctiva has not been noted in the majority of the cases thus far reported, but its importance for diagnosis must be determined later.

Blood.- — The blood presents the picture of a secondary i of varying severity, dependent upon the course of the disease. In a few cases the red cells and the haemoglobin are only slightly altered. The most striking feature of the blood picture is the reduction in the number of leucocytes. This appears to be a constant finding. The minimal white count reported was 500 to the cubic millimeter. The differential count is usually within normal limits, and abnormal cells have been found only rarely in the circulating blood.

Family History. — The incidence of the condition in other children of the same parents is to be particularly noted. In many of these additional cases Gaucher's disease was not proven by pathological examination, but presumptive evidence of the condition wa - .. a large spleen and other important

The family history is recorded in 12 of the above cases,


and in nine of these an enlarged spleen and symptoms strongly suggesting the disease were found in one or more brothers and sisters of the patient. This tendency to appear in several members of the same generation is apparently a suggestive feature of the malady, hi no instance was the disease transmitted from parent to offspring.

Cause of Death. — Gaucher's disease is essentially chronic and may last for years. Niemann's case and those we are about to describe — all in infants — suggest that the process is more intense in early life. Of the seven patients treated expectantly, two died from exhaustion after much emaciation, and five from intercurrent affections or from accident.

Splenectomy. — The spleen was removed in nine cases. Three of these patients died shortly after the operation. Six were reported living at various periods after the operation, one after 41 days, one after six weeks, three after five weeks, and one after 16 months. In most of these the sense of weight in the abdomen had been relieved, but there is no evidence that the further progress of the disease w-as arrested.

Syphilis and Tuberculosis. — An effort was made to determine whether syphilis or tuberculosis was concerned in the etiology of the condition. Of the 16 cases no evidence of syphilis was found at autopsy in two instances; in five others the Wassermann test was negative; in only one (Niemann") was it positive. In 13 of the 16 cases no tuberculosis was found on examination of the organs or of the excised spleen. Tuberculous lesions were present at autopsy in three instances. It can be confidently assumed that neither syphilis nor tuberculosis plays an etiological role in this disease.

Microscopical Findings. — In each instance the presence of peculiar, pale round or oval cells, having an average diameter of from 20 to 40 microns and one or several relatively small nuclei, is the characteristic feature of the disease. In many of the cells the protoplasm stains poorly, is finely granular and vacuolated. Their relative number varies greatly, depending apparently upon the severity of the process. In some instances they occupy almost the entire organ; or they may be found singly or in groups among the normal cells. The spleen, liver and lymph glands are most frequently involved, although the bone-marrow and, as in our cases, nearly all the tissues of the body may be affected.

Origin of the Cells.- — The origin of these cells has been much discussed and will be referred to in detail later on in the paper. The views thus far held are that they arise either from the reticulum or from cells lining the blood and lymph vessels.

Pathogenesis. — The cause of this remarkable condition is as yet unknown. It has no connection with a neoplastic growth, as Gaucher at first thought. No evidence of a bacterial or protozoan infection has been found. A number of writers have considered the disease dependent upon a chronic intoxication of an undetermined nature.

Case I. — S. G., a white female infant, 9 months of age, was admitted to the Thomas Wilson Sanitarium June 12, 1912.

Family History. — The father, a moderate user of alcohol, was 41 years of age and well. The mother was 38 years of age and


January. 1016.] well. Both parents were Russian Hebrews of small means. They had had 11 children, as follows:

1. A girl, 20 years, well.

2. A boy, died at S months, cause unknown.

3. A boy, 18 years, well.

4. A boy. died at 14 years of hip disease.

5. A girl. 14 years, well.

6. A girl, died at 1 year, " smothered in bed."

7. A boy. 11 years, well.

S. A girl, died at IS months of convulsions. 9. A boy, 6 years, well.

10. A girl, 4 years, well.

11. A girl, the patient.

Past History and Present Illness. — The patient's birth was spontaneous. She was breast-fed for one month and then given a cow's milk mixture. She never thrived. For a month or two she vomited frequently, but for three months the milk was well retained. She slept well; cut two teeth at six months and was never acutely sick. The gain in weight, however, was very slow. The stools were from two to four in 24 hours, yellow and formed.

Physical Examination. — On admission the patient weighed 11 pounds. She was considerably emaciated. The skin was pale, with a slight brownish pigmentation, more marked on the face and arms. The abdomen was prominent; the cervical and axillary glands were slightly enlarged. The lungs were clear. The heart was not enlarged. There was a soft systolic murmur heard at the apex. The upper border of the liver began at the 6th rib and extended 2% inches below the costal margin in the right nipple line. The surface of the liver was smooth and firm and the notch was readily palpable. The spleen was represented by a large mass extending 4% inches below the left costal margin to the level of the umbilicus. The surface was firm and a little rough; the notch was palpable. The kidneys were not felt. The reflexes at the knee were present.

The blood examination on admission was as follows: Leucocytes, 10,400; red cells, 5,200,000; haemoglobin, 90%. Differential count: Polymorphonuclears, 42%; large mononuclears, 5%; small mononuclears, 41%. Examination of the stools showed an excess of fatty acid crystals but no bile. During the first month after admission the child gradually lost in weight. On July 12, 1915, the blood condition was as follows: Red cells, 4,400,000; leucocytes, 25,400; haemoglobin, 60%. Differential count: Polymorphonuclears, 59<^ ; large mononuclears, 3.2%; small mononuclears, 36% : transitionals. 1% ; myelocytes, 1%. The Wassermann and Von Hrriuet tests were negative.

The patient continued to lose strength and weight. She was given a milk mixture successfully. There were from two to four fecal stools in 24 hours and no fever. There was a continuous loss of weight to 8% pounds and death resulted from exhaustion at the age of 11 months, two months after admission to the sanitarium. The day before death a marked change took place in the differential count of the leucocytes. Their total number was increased to 35,000. The differential count was: Small lymphocytes. 52 large lymphocytes, 9%; large mononuclears. 5% ; polynuclears, 3% : unclassified, 1%.

Autopsy (four hours after death).— The body is that of a very emaciated white female infant 61 cm. long. The external ear contains a dried hemorrhagic discharge. The abdomen is very prominent. The veins are distended, but there is no caput -Medusa?. The outlines of the lower edge of the liver and of the spleen are visible through the thin abdominal wall, the notches being easily recognized. The inguinal glands are considerably enlarged and are firm. The peritoneal cavity contains no excess of fluid. The liver extends 7 cm., the spleen 5.5 cm., below the costal margin. The heart weighs 25 gm., and shows no gross abnormalities. The lungs are voluminous, but everywhere contain air. In the lower right lobe the tissue feels denser and


tougher than elsewhere and the pleura is a little more prominent. On section this part of the lung tissue is subdivided into small lobules by dense bands of fibrous tissue.

The liver is considerably enlarged and weighs 415 gm. It has a pale, grayish-pink color. Its surface is smooth and glistening and the capsule is not thickened. The lobules appear through the capsule as minute, pink dots surrounded by a pale yellow periphery. On section the organ cuts with a slightly increased



Gauchee's Disease— Case I.— Diagram showing enlargement of liver and spleen. July 1, 1912.

resistance and shows a pale yellow or a slightly mottled grayishyellow, moist surface, from which a thick yellowish mucoid material can be easily scraped off. This material does not feel greasy, but resembles condensed milk in consistence. There is a slight patchy fibrosis. The gall-bladder is small and contracted, containing about 1 cc. of thin yellow bile. The bile passages are patent. The common bile-duct is partly surrounded by three firm lemon-yellow lymph nodes, from 3 to 8 mm. in diameter.


SUMM


Author and Reference.


Gaucher: These de Pal


Collier: Tr. Path. Soc. London, 1895, XLVI, 148.

Picou and Raymond: Arch, de med. exper. et d' anat. path., 1896, VIII,


Bovaird:

Am. -lour. Med. Se., 1900, n. B., CXX, 377.

Brill, Mandelbaum and M Libman: Proc.NewYork

Path. Soc. 1904,1V. 1 13; Am. Jour. Med. Se., 1905, n. g., CXXIX, 491.


Bchlagenhaufer: Virchowa Arch. {. path. Anat., 1907, CLXXXVII, 125.


V.. n Berzel: Wien. klin. Wchnschr., 1907, XX. 123.


Marchand :

Munchen. Med. Wchnschr.. 1907, I. IV. 1102; also Kesel: Beitr. z.path. Anat. u. z. allg. Path.,

1909, XLVI, 241.

Brill. Mandelbaum and Libman: Am. .Tour. Med. Sc., 1909, n. s., CXXXVIT, 849.

de Josselin de Jong u. van Heukelom : Beitr. z. path. Anat. u. z. allg. Path.,

1910, XLVIII.598.

Mandelbaum :

Jour. Exper. Med., 1912, \\ I. 7H7.


Wilson :

Surg., Gvnec. and Obst., 1913, XVI, 240.

Downes:

Med. Rec., 1913, LXXXIII, 697.


Xiemann : Jahrb. f. Kinderh., 1914, LXXVIX, 1-10.


Erdman and Moorhead: Am. Jour. Med. So., 1914, n. ?., CX1.VII, 213.

Herrman, Roth and Bernstein: Arch. Pediat., 1914, XXXI, 340.


17 mo.


7i


Chief Symptoms.


2 mo.


14

urn.


Never robust ;epistaxis. irregular menses, enlargement of abdomen. In last months, bleeding from gums, abdominal pain, oedema of feet, fever.

Never robust; enlargement of abdomen, epistaxis, emaciation, subnormal temperature.

Abdominal pain, from 4th year. menorrhagia, bleeding from viiiii>. oedema of ankles, fever, loss of weight, enlargement of abdomen.

Increasing enlargement of abdomen, shortness of breath.


51 X 25 cm. (bv palpation). Weight, 4700


Weight, 2070 gm.


'Filled abdomen."


Weight, 6250 gm.


Sweating, epistaxis, enlarged Weight, 5280 gm. Weight, 4800 gm. spleen, pain in splenic region ami in legs, petechial hemorrhages, dyspnoea.


Extends to umbilicus. Weight, 3500 gm.


Three f i nge rbreadths below costal margin.


Not enlarged.


Enlargement of abdomen, oedema 31 X 20 X 12 cm.

of feet, bleeding from gums, , Weight, 3510

epistaxis, increasing weakness, gm. pain over liver.


Epistaxis, during childhood. At Ml years, abdominal pain, vomiting, enlargement of abdomen. Later, chills and sweating.

Pain in abdomen at 24 years. At 35 years, great weakness, myomatous uterus, ovarian tumor. Later, increased weakness, cachexia, hemorrhages in skin.

At 21 years noticed abdominal tumor, sweating, hemorrhages of the skin, anemia, emaciation, epistaxis, bleeding from gums and bowel, dyspnoea.

Enlargement of abdomen, weakness, bleeding from gums, attacks of syncope, vomiting.

Enlargement of abdomen, slight abdominal pain, epistaxis, increasing languor.


Frequent digestive disturbance, anaemia, abdominal pain, redema.


Enlargement of abdomen, loss of appetite, headache, emaciation, dyspnoea.


Never thrived; indigestion, pallor, enlargement of abdomen, oedema of eyelids and feet, low irregular fever.

Healthy infant, large spleen noted at 14 months. From this time nervous indigestion.


Large spleen noted at 4 years, abdominal pain, epistaxis, hematemesis, bleeding from gums, asthenia.


32 X 16 X 12 cm. Weight, 3000


41 X 15 cm. Weight, 2720 gm.


45 X 25 X 13 cm. Weight, 8100 gm.


Reaches to symphysis pubis.


18 X 9-5 X 5 cm.

Weight, 490 gm.


Weight. 5280 gm.


35X13.5X6.5 cm. Weight, 1813 gm.


Extends below level of navel.


Extends to level of umbilicus.


27 X 13 X 10 cm. Weight, 1320 gm.


Weight, 3000 gm.


Extends a "handbreadth" below costal margin.


24 X 26 cm. Extends 3 fingerbreadths belowcostal margin.


35 X 30 X 12 cm. We ight, 3900


Extends 2 fingerbreadths below costal margin.


Extends 3 fingerbreadths belowcostal margin.


Extends 3 inches below costal margin.

Extends 1 inch below costal margin.


Extends to 1 cm. above ant. sup. spine.


Lymph glands


Enlarged slightlv.


Not palpable, mesenteric glands large.

Enlarged at hilus of spleen.


Enlarged sligbtlv.


Enlarged in thorax and abdo


Enlarg

iy


Enlarged.


Enlarged sli lv.


Not enlarged.


Much enlarged.


i;,


X"ot enlarged.


Enlarged slightlv.


Extends 2 finger- Inguinal glands breadths below enlarged, costal margin.


Extends 5 cm. below costal margin.


But little

larged.


R. B. C: 2,281,000

W. B. C: 3,600, in

last niontlis.


R. B. C: 1,300,000

After operation:

W. B. C: 20,000

Dif. count, normal.


Unknown.


One sister, enlarged spleen ; three other children died of tuberculosis.

Xo similar cases.


R. B.C.: 2,S80,000 ! One sister, enlarged

W. B. C: 4,000 spleen and liver.

Hb. : 60%


At 15 vears:

R. B" C: 5,000,000 W. B. C: normal.

Later: W. B. C: 4.000 Hb. : 45%

At 43 years:

R. B". C: 4,700,000

W. B. C: 1,300

Later: W. B. C: 800

Dif. count, normal.

Hb. : 65%

At 37 years :

R. B. C: 4,200,000 W.B.C.: 7,000

Dif. count, normal. Hb. : 92%

"Xo leucocytosis."


R. B. C: 3,500,000

W.B.C.: 3,600 too. 200

Dif. count, normal. Hb. : 35%

R. B. C: 4,700,000

VV. B. C: 3,800

Dif. count, normal. ffl>- : 65%


R. B. C: W. B. C:

Dif. count Hb.:


2,208,000 5,000 normal. 35%


R. B. C: W. B. C. : Hb.:


5,200,000 4,800

Sir,


R. B. C: 3,840,000 W. B. C: 1,400 to 900

Dif. count, normal. After operation:

W. B. C: 16,000


Blood said to be normal in R. B. C, W. B. C. and Hb.


R. B. C: 5,000,000+ W. B. C: 10,000

Dif. count, normal. Hb. : anm


Four out of six brothers and sisters had fame condition.


One sister has large spleen; five children of parents well.


Xo history of similar condition in family.


Brother of Case 5 ; four out of six brothers and sisters had the same condition.


Three sisters and one brother had large spleens; seven brothers and sisters well.

One sister has large spleen; one sister has large liver; two children are well.


Xo history of similar condition.


One brother died with large spleen; two brothers well.


One sister, next in age, had a large spleen: seven children well.


Expectant.


Expectant.


Splenectomy.


Splenectomy.


Expectant.


Expectant.


Splenectomy.


Expectant.


Expectant.


Splenectomy.


Splenectomy.


Splenectomy.


Splenectomy.


Expectant.


Splenectomy.


Died. Tuberculosis, pulmonary and intestinal.


Died. Bronchopneumonia ; no tuberculosis.


Living five months after operation.


Died three hours after operation.


Died. Exhaustion, pericarditis.


Died. Tuberculosis, pulmonary and glandular.


Living five months after operation.


Died. Exhaustion.


Died. Fracture of skull.


Living five months after operation.


Died one day after operation.


Died 12hours after operation.


Living 41 days after operation.


Died. Exhaustion.


Living after 16 months.


Splenectomy.


Living after sixweeks.


Histological Findings.


Spleen: Parenchyma replaced by large irregular cells with pale-staining cytoplasm in connective tissue spaces. Liver: Cirrhosis (?).

Spleen: Characteristic cells. Lymph glands: do.


Spleen: Characteristic cells. Lymph glands: do.


Spleen: Characteristic cells. Lymph glands: do.

Liver: Cirrhosis with do. Adrenal : A few do.

Spleen: Characteristic cells. Liver : do.

Lymph glands: do.


Spleen: Characteristic cells. Liver: do.

Lymph glands: do. Bone-marrow: do.


Spleen: Characteristic cells.


Spleen: Characteristic cells. Liver: do.

Lymph glands: do. Bone-marrow: do.


Spleen: Characteristic cells. Liver: do.

Lymph nodes: do. Bone-marrow: do.


Spleen: Characteristic cells.


Spleen: Characteristic cells. Liver: Cirrhosis and do. Lymph glands: do.

Bone-marrow: do.

Spleen: Characteristic cells.


Spleen: Characteristic cells; not so extensive transformation as in other cases.


Spleen: Characteristic cells

Liver: do.

Lymph glands: do.

Spleen: Characteristic cells.


Spleen: Characteristic cells.


C ii t ion unlike any

known form of splenic hypertrophy.


>«o note on bone-marrow, liver or adrenals.


No note on other tissues. Case similar to Case 1.


Xo note on bone-marrow.


Disease said to involve Iymphatieohematopoietie system, due to poisoning; possibly tuberculosis.

Constant abdominal pain after opera


tion, lame.


Liver still


Ascites noted.


More abdominal process than in Case 5. No tuberculosis.


Wassermann and von Pirquet. negative.


Wassermann negative. Xo tuberculosis.


Two other cases reported, thought by Marchand not to be Gaucher'8 disease.

Probably :i comparatively early ease. Wassermann negative. Wedge-shaped thickening of conjunctiva.

Wassermann positive. I > tensi ve changes, very similar to those in our cases.

nann negative. [No. 299


The spleen weighs S6 gm. and measures 13x5x4 cm. The surface has a mottled, patchy, grayish-pink color. The organ feels firm and its edges are rounded. The surface is smooth and glistening. The capsule is slightly thickened. On section the organ cuts easily and the splenic pulp is triable. The cut surface is rather moist and shows numerous red. slightly translucent areas l mm. in diameter, surrounded by a soft, faint reddishvellow peripheral zone that can be scraped out quite easily and 'resembles the material removed from the liver, although in the spleen it has a p.nker appearance. There is no marked increase in the fibrous tissue.

The pancreas shows no pathological changes. The kidney corlightly swollen and has a pale yellow color. The striations are poorlv defined. The adrenal glands are considerably enlarged, each weighing 5.5 gm. On section a considerable amount of a brick-red fluid escapes from the medulla. The latter is large and prominent and has a pale yellow color. The cortex appears normal, though its yellow color is quite marked. In the mucous membrane of the stomach, near the pylorus and projecting 3 mm. above the surface, is a firm nodule 0.5 cm. in diameter, from which a grav mucoid material can be expressed. The intestinal mucosa shows congestion and a few small ecchymoses. The Peyer's patches are swollen. The appendix is rather large, but otherwise normal. The solitary follicles of both the small and large intestine are enlarged and surrounded by a narrow zone of congestion. The pelvic organs show nothing abnormal. There is a general enlargement of all the lymph glands, though the epitrochlear and other superficial nodes, except the inguinals, were not felt. They present a uniform appearance, being more or less bright yellow in color. They are quite firm and cut with a slightly increased resistance. On section a moderate amount of pale yellow viscid material escapes from the central part of most of the glands. The largest glands are near the head of the pancreas, measuring 1.5 x 2 cm. The thymus has an unusually pale yellow color, but otherwise is normal in size and appearance.

MlCBOSCOPiCAl Fim.ings: Heart— Many of the nuclei of the heart muscle are surrounded by a clear zone. Vacuoles of varying size, usually very small, are numerous in the muscle fibers. In some areas, where the fibers are cut in cross-section, the vacuoles are so numerous that the tissue resembles a markedly Catty liver. These vacuoles stain neither with Sudan III nor with osmic acid.

Lungs. — Most of the lung tissue appears normal. The air sacs contain a few desquamated epithelial cells. There is, however, a peculiar swelling of the cells of the interstitial tissue which gives them a finely vacuolated appearance. As indicated in the macroscopical report, the pleura over the lower lobe is thickened, and broad bands of loose connective tissue pass in, dividing the lung tissue into regular, well-defined lobules. The interstitial tissue is very much thickened and infiltrated with lymphocytes, swollen cells, many of which have a vacuolated protoplasm, and young connective-tissue cells. The connective tissue about the bronchi and the vessels is markedly increased. Surrounding the muscularis of some of the small arterial twigs there are several concentric rows of markedly swollen, pale, vesicular or granular cells, similar to, if not identical with, the large pale cells of the spleen and lymph nodes. The lumina of these vessels are often completely obliterated. The air sacs contain many large, irregularly round, faintly pink-staining, granular or vacuolated cells with a small nucleus, rich in chromatin; these resemble somewhat the large pale cells of the liver and spleen. They also resemble closely the swollen, partly degenerated cells in the air vesicles.

Liver.— The capsule is not thickened. The lobulation is well marked in some areas and obscure in others. In the former there is a considerable increase in the fibrous tissue of the portal spaces with extension into the lobule. The intralobular architecture is


entirely obliterated, the normal arrangement of liver cells in ', columns, radiating from the central vein, being replaced by an j irregularly distorted conglomeration of large polygonal or irregularly round, granular cells of two types. The cytoplasm of the predominating type stains deeper and shows coarse protoplasmic granules and numerous small vacuoles. The cells of the other type frequently appear to be inserted between those of the first, and are distinguished by their very faintly staining, finely granular or vacuolated cytoplasm. They suggest swollen endothelial cells, whereas the darker-staining cells resemble swollen transformed liver cells. In both cases the nucleus is relatively small, stains rather deeply, and may contain one or two definite chromatin granules. Although in most of the cells the cytoplasm is granular, in some there are many vacuoles, which are usually small, though large ones occur. In other cells the cytoplasm may contain vacuoles of various sizes; it may present a streaked appearance or may be concentrated into a small area in an otherwise vacuolated cell. No normal hepatic cells are present. A few elongated or oval cells with a finely granular or vacuolated cytoplasm are embedded in the fibrous tissue of the portal spaces, especially where there is considerable fibrosis.

Spleen.— The most striking change in the spleen is the replacement of the lymphoid cells by large cells separated into clusters and columns by very prominent sinusoids. The lymphoid cells and splenic pulp cells are present only about the Malpighian bodies, which are also being infiltrated with these large pale cells. The latter tend to group first in the center of the corpuscle. A few lymphocytes are occasionally present in or about the sinusoids. The capsule and trabecule are slightly thickened and, strands of fibrous tissue extend into the parenchyma of the organ. \ The Malpighian bodies are diminished in number and show a striking tendency to be replaced by large cells— the process beginning in the center of the Malpighian body and progressing peripherally. These large, round, oval or polygonal-shaped cells usually have a faintly staining granular and vacuolated cytoplasm. The reticulum encloses clusters of these cells. Frequently strands of reticular fibrillas occur between the individual large cells. Some of the large, pale cells lie free in the reticular spaces. They may contain two, rarely three, nuclei. A few of the large, pale cells contain red cells or nuclear fragments. This phagocytosis is not frequent. The endothelial cells of the sinusoids are markedly swollen and mitotic figures may occasionally be seen. All transitional stages occur between the large, swollen endothelial cells and the very large pale, finely granular cells lying free or attached to the wall of the sinusoids. Blood pigment is present, especially in the large, pale cells about the Malpighian bodies.

Pancreas.— Many of the cells of the islets appear swollen and granular and small vacuoles are frequent in the cytoplasm. In the interlobular connective tissue there are a few small foci of large, rounded, vacuolated, endothelial cells; otherwise nc abnormal is noted.

Kidneys— The capsule is not thickened and the interstitial tis sue is not increased. The epithelial cells of the convoluted tubules are swollen; the cytoplasm is granular and often contains small vacuoles. The glomeruli are prominent. The cells in the capillary tuft tend to become swollen, and their cytoplasm is often distinctly vacuolated. Occasionally, two or more of these cells! may become so much enlarged and filled with vacuoles that they I appear identical with the large, pale cells of the spleen.

Adrenals.— In the cortex the cytoplasm is granular and is often } undergoing a vacuolar or cedematous change, especially in the outer zone. The medulla is very much enlarged and is the seat of a peculiar change which, in some areas under the low power, gives it the appearance of adipose tissue, owing to the replacement of the medullary cells by large, irregularly rounded, granular or vacuolated cells embedded in a coarse reticulum. On higher magnification these large cells have a granular or vacuolated foamy


les


January, 1916.] cytoplasm and a small nucleus; they seem to be identical with the large cells described in the spleen. In some areas the medulla has the appearance of a very wide-meshed, irregular reticulum, the spaces of which contain a granular or vacuolated cytoplasm more or less completely subdivided by cell outlines and containing deeply stained, scattered nuclei. The cells lie without the blood-vessels and sinuses, and usually fill the reticular spaces in which they occur. In some sections there are a few more or less compressed cords of medullary cells separated from the cortex by a larger or smaller zone of the large, pale, foamy cells.

Gast ro-intestinal Tract. — Vacuoles are frequent in the epithelial cells of the mucosa and in many of the stroma cells. The epithelium of the intestinal villi has, for the most part, desquamated: the tunica appears o?dematous and contains some polymorphonuclear leucocytes and lymphocytes. Large, pale, slightly foamy cells occur in the stroma between the glands. These are especially abundant between the glands of the appendix and resemble the large, pale cells of the spleen. In the caecum the serous surface is partly covered by a flat layer of lymphoid tissue, within which are many large, pale granular cells, identical with those of the spleen and lymph nodes. Beneath the serosa and between the different layers of the small intestine small foci of similar large, pale cells occur.

The thymus is distinctly lobulated. The lymphoid cells have disappeared except in the immediate vicinity of, and where they radiate from, Hassall's corpuscles. Numerous large, pale, granular or vacuolated cells, similar to those of the spleen, are embedded in a wide-meshed reticulum. They occur singly and in clusters. None of these cells are seen in the capillaries or lymph sinuses. The lymph glands present a variable appearance, but in all of them there has been a more or less extensive replacement of the lymphoid cells by the pale granular cells described in the spleen. In some sections there are comparatively few of these large cells, and they are most abundant in the medullary portion of the node. In other sections practically all of the lymphoid cells have disappeared, giving the appearance of an endothelial tumor, except that the normal architecture and framework of the gland is still intact. The peripheral and medullary sinuses are easily recognized, and are more or less filled with large, pale, rounded cells. All intermediate stages between these two may occur. In some of the glands there are irregular bands of young cellular connective tissue in which vacuoles occur. The large, pale cells appear to develop first in the medullary part of the gland. Some of these cells show phagocytosis of red blood cells and leucocytes. In the later etages the cells appear in the lymphoid foci and in the peripheral sinuses. In the late stages the lymph and blood sinuses are very prominent and the lining endothelial cells show all transitions to the large, pale, vacuolated cells occurring in the spleen. Mitosis is occasionally seen in these endothelial cells. In other portions these cells appear to be closely related to the reticulum. They are usually rounded or polygonal in shape and contain a considerable amount of granular protoplasm, which tends to be vacuolated or foamy, and a rather small nucleus rich in chromatin. The cells are arranged in alveoli bounded by reticulum or by blood-vessels or sinuses. The connective tissue is not markedly increased in any of the lymph nodes, though in the larger glands the large, pale cells are separated into distinct lobules by strands of fibrous tissue. There is no blood pigment present. The large, pale cells infiltrate all of the lymphoid foci of the alimentary tract, but the lymphoid cells always predominate. This is especially well marked in the flattened mass of lymphoid tissue on the serous coat of the caecum, in the solitary lymph follicles of the large and the small intestine, in the lymphoid tissue of the appendix and in minute lymph nodes near the intestine.

Special Microscopical Technique.— Examination of frozen sections of material fixed in formalin shows the presence of a homogeneous, slightly refractile substance in the large, pale granular


or vacuolated cells. It fills the vacuoles in the protoplasm noted in the paraffin and colloidin sections. It is not as readily removed by ether as by absolute alcohol. This substance in the large, pale cells reacts in a peculiar but distinctive way to the fat stains. With scarlet red the large cells show many minute, faint orangestaining droplets. In some cells more of the dye is taken up; in others a few of the droplets take a deep orange-red color. The same results were obtained with Soudan III. In both cases the fat control section stained a deep orange-red. With Nile-blue sulphate the large cells took a faint violet, pale blue, or pink color, which in chromated sections changed to a deep blue, while the fat in the control section stained bright red and the fatty acid stained purple or blue. With osmic acid the homogeneous substance in the large, pale cells stained either faintly gray or not at all. It was stained black with the Weigert-Pal myelin sheath stain and was doubly refractive in many of the cells. Some of the large cells took a dirty, reddish-brown color with scarlet red. In the liver, spleen and lymph nodes there were scattered large, pale cells more or less filled with droplets of neutral fat. These were especially abundant in the thymus. The large cells, embedded in the periportal fibrous tissue of the liver were mostly filled with droplets, staining red with scarlet red. The cortical cells of the adrenal gland were more or less filled with red-staining droplets, after treatment with scarlet red, standing out in sharp contrast with the non-staining or pale orange droplets filling the large, pale cells in the medulla. In the kidney most of the large, pale cells in the glomerular tufts contained red-staining droplets after treatment with scarlet red, but did not stain with osmic acid. A few scattered droplets of neutral fat were present in the epithelium of the convoluted tubules. The vacuoles noted in the heart muscle did not stain with any of the fat dyes. After treatment with Ciaccio's and also with Bell's stain for lipoids, some lipoid droplets were present in the large, pale cells. In most of the organs, especially in the liver, spleen and lymph glands, there were all transitions between cells that did not stain at all and those which contained deep orange-staining droplets after treatment with scarlet red. These varying reactions to the different methods for the demonstration of fats and lipoids in tissues suggest the presence of some fat-like substance, within the large, pale cells, that may be in the process of transformation into neutral fat and possibly represent an intermediate stage between the latter and a closely bound molecule of proteid and fat.

Case II. — On February 11, 1914, the mother of the former infant (Case I) brought to the out-patient department of the Harriet Lane Home another female infant, S. G., 5 months of age, and remarked that this baby had the same disease as her sister, who had died 20 months before. The similarity in appearance of the two infants was striking.

Past History and Present Illness. — The patient's birth was normal. She was exclusively breast-fed. She had always been thin and sickly, but presented no symptoms of any acute disorder. She was brought to the clinic because of her weak and emaciated condition.

Physical Examination. — The patient was much emaciated. She weighed 9 pounds. The temperature was 96.4° F. The skin had a grayish-yellow color. There was no general glandular enlarge ment. The right lung was clear. There was slight impairment and a few moist rales at the base of the left lung. The heart sounds were clear. The abdomen was full, measuring 14 inches in circumference. The superficial abdominal veins were dilated. The liver was enlarged and firm and extended 2% inches below the costal margin, from the sixth interspace. The spleen was enlarged, firm in consistence, and reached 2% inches below the costal margin, extending slightly below the level of the umbilicus. The cervical glands were palpable; the inguinal and axillary glands were slightly enlarged. The reflexes were normal, as were also the electrical reactions. Slight lateral nystagmus was noted. [Xo. 299


The patient returned occasionally to the clinic, but her condition remained unchanged. In May the blood condition was as follows: Red blood cells, 3,024,000; white blood cells, 11,240; haemoglobin. 65%. Differential count: Polymorphonuclear cells, 34%; lymphoc; transitionals, 3.5%; eosinophils, 1%: baso phils, i Pirquet and Wassermann tests were nega tive.

The patient was admitted to the Harriet Lane Home May 18, 1914, the condition being practically unchanged. On July 22. the temperature rose to 102° F., and continued irregularly elevated. In August a number of furuncles developed. In September a sharp rise in temperature was occasioned by an otitis media, secondary to a nasopharyngeal infection. The leucocytes varied from about 1S.O0O to 22.000, the differential count showing polymorphonuclear cells. 317 ; mononuclear cells. 67' , . On < Ictober 29. the patient was given a treatment with radium applied over the splenic area.

On October 21. some lymphatic glands from the neck and axilla were excised. Microscopic examination of the sections showed that a considerable number of areas of the gland were occupied by the large, round, oval endothelial-like cells, known to be characteristic of Gaucher's disease. This is the first time that a diagnosis of this condition has been confirmed during life, except by removal of the spleen.

On October 28, 1914, blood examination was as follows: Red blood corpuscles, 4,608,000; leucocytes, 6,480. Differential count: Polymorphonuclear leucocytes, 77%; mononuclear leucocytes, 21%; transitionals, 17c. The reduction in the number of leucocytes seemed to be directly due to the effect of the radium. There was. however, no marked change in the patient's condition. The temperature remained elevated. On November 1, a second treatment with radium was given. This was followed by a further fall in the leucocytes to 5560 per c. mm. Following this second radium application the patient became stuporous and toxic. Internal strabismus developed with nystagmus. The leucocytes were further reduced, on November 12, to 4980, and on December 2, to 2360. At this time the differential count showed: Polymorphonuclears, mall mononuclears, 397c; large mononuclears. 19%; transitionals, 1%: myelocytes, ?,,. The spleen seemed somewhat diminished in size, being felt 1% inches below the costal margin. There was no improvement, however, and the child gradually became weaker and took her food badly.

Examination of the eyes by Dr. Powers showed the following interesting condition: Both fundi were pale, the region of the disk in each eye was white with no distinct margin. In the region of each macula there was a bright red spot, slightly larger in the left than in the right eye.

The patient continued to lose strength and died from exhaustion on December 24, 1914.

AiTorsv. — The body is that of a greatly emaciated, white female infant. 61 cm. in length. The conjunctivae and buccal mucous membrane are pale. The ribs and other bony structures of the body are very prominent. The abdomen is greatly distended. The lower edge of the liver and spleen can readily be seen through the abdominal wall. The abdominal muscles are very thin and there is practically no subcutaneous fat.

The pleural and pericardial cavities are not implicated.

The thymus on section presents the same characteristic appearance as seen in the lymph glands (see below).

The heart weighs 25 gm. The myocardium is reddish-brown, mottled with wavy yellowish-gray streaks.

The Jungs are of a similar appearance. They are voluminous, contain air, have a delicate, smooth pleura and a pronounced lobulation. The lobules are separated by narrow, bluish-white, translucent lines, bordered on each side by a zone which is still more translucent. The center of the lobule forms the air-containing portion of the lung and is yellowish-pink.


The spleen is much enlarged. It weighs 100 gm. and measures ] 10 x 6 x 3.5 cm. Its capsule is delicate with a smooth and glisten- j ing surface. The consistence of the organ is increased and its I edges are round. The parenchyma is mottled; small grayish and bright red tir^as about 2 mm. in size alternate with larger, patchy,' yellowish-pink, frothy areas. On section the characteristic mottled appearance is more pronounced. The trabecular and the Malpighian bodies are inconspicuous. The frothy, yellowish, slightly sticky material encountered on sections of the liver occurs here also.

The stomach., duodenum and pancreas appear normal. The liver is greatly enlarged. It weighs 420 gm. and measures | 28 x 10 x 4.5 cm. It is of normal shape. The capsule is delicate and ! its surface is smooth and glistening. Through it a uniform yellowish-pink, opaque parenchyma is visible. The lobules can bei| made out as tiny pink spots surrounded by a yellow periphery.! On sectioning, the knife adheres slightly and a frothy, yellowish, slightly sticky material can be scraped off. The parenchyma is putty-like in appearance and consistence. The cut surface is similar in appearance to the external surface. The gall-bladder con- i tains a small amount of apparently normal bile. The bile-ducts j present nothing abnormal.

The adrenals are enlarged. They weigh 8 gm. and measure 4 x 3.5 x 1 cm. Their appearance externally presents nothing of , interest. On section the medulla is more yellow than usual.

Kidneys. — The cortex of the kidneys is slightly swollen and has a yellowish tint. The glomeruli and stria? are in places indistinct. I The pelvic organs appear to be normal.

Intestines.— The Peyer's patches of the small intestine, espe- , cially near the ileo-caecal valve, are enlarged. The lymph follicles are very translucent. Just near the ileo-caecal valve the mucous membrane of the caecum is congested. The rest of the caecum ancl the large intestine present large, translucent, solitary follicles. ! Lymph Glands.— All the lymph glands are similarly involved. They are enlarged, discrete and slightly firm. Externally and on section they have a uniform, frothy, yellowish-pink color. The glands about the pancreas and hilus of the liver are most involved. The posterior cervicals on the right side are somewhat different from the glands of other regions. They are enlarged, more juicy, and both externally and on section they have a more reddish-pink color.

The aorta is normal in appearance. The bone-marrow is hyperplastic and of a yellow color. Brain, Spinal Cord, etc. — In the pia-arachnoid of the frontal lobe is a small amount of translucent, gelatinous material; otherwise the brain and spinal cord show nothing abnormal.

The following additional tissues were removed for microscopical examination — in gross they presented nothing abnormal: the thyl roid, submaxillary, salivary glands, hypophysis, various cranial and peripheral nerves, skin, striated muscle, various arteries and;| veins.

Microscopical Findings— The microscopical findings in this case closely resemble those of Case I; a detailed description will therefore be omitted, and emphasis placed upon additional findings.

Lungs.— The lung tissue throughout presents a picture similari to that described in the right lower lobe of the first case. Many of the bronchi, arteries and veins contain a few large cells, identical] in appearance with those found in the air spaces.

Spleen.— The characteristic large cell in this case is also found j in the lumina of the arteries.

Pancreas.— Both the acinar and island cells appear slightljl swollen and granular. They frequently contain vacuoles of vary! ing size and shape.

Liver. — The cells of the first type in places show an imperfec trabecular formation and are undoubtedly to be considered at altered parenchymatous cells. Cells of the second type are alM found in the intima and in the lumina of the portal vessels.


NUARY, 1916.] Wren als— The medulla shows the same changes as in the first e It is rather difficult to determine exactly where the medulla ps and the cortex begins. This makes the medulla look unlally wide. In .the adventitia of a large artery of the capsule >re is a mass of the characteristic large cells. In other parts of \ capsule masses of what appear to be young cells of the same je occur. They are smaller and have a darker pink cytoplasm, ,ich is more granular and does not contain so many small, clear ) P lets. Many of these cells contain red blood cells. Cells repreiting all stages from this apparently young cell, which closely embles the polyblast of connective tissue, to the typical large 1 are seen in these masses of cells and also scattered in the shes of the capsule.

v _The characteristic large cell is frequently seen in the imerular tufts, between the tubules and at times in the capilies.

3astr(hintestmal Tract.— The parietal and cuboidal cells of the stric tubules contain small vacuoles. A few of the characteris large cells are seen scattered in the lower part of the mucous mbrane. The tubular epithelium of the colon contains some all vacuoles, which are to be differentiated from those of the ge goblet cells.

Uhymus. — Most of the lymphoid cells, of both the cortex and the dulla, have been replaced by more or less closely grouped large Is similar to those in the first case. Only a few imperfect lymph licles remain, and a sharp differentiation into cortex and mella cannot be made.

Lymph Glands.— Glands taken from different regions of the ly show an extensive replacement of the lymphocytes by a large 1, identical in appearance to that in the thymus. These cells ? chiefly located in the medulla. In some glands the " Keimltra " are very prominent and mitotic figures are frequent iong the large lymphocytes within them. They also contain ittered large cells which closely resemble the characteristic ge cell of the medulla, except that they contain nuclear fragrcts and red blood cells. These phagocytes are limited almost tirely to the " Keimcentra." There are no well-defined transits between the proliferating large lymphocytes and the large, le cells. Some of the large, pale cells are more or less filled with tall, greenish-yellow pigment granules, especially in those areas iere there is considerable congestion and hemorrhage. There

some patchy increase in young connective tissue. The enthelial cells of the vessels and sinuses are swollen, but there is

evidence of proliferation. The glands of the peritoneal cavity e more involved than the superficial glands. Bone-marrow. — The fat is entirely absent and a large cell iden:al in appearance with the one in the spleen is present in large mbers.

Thyroid. — The acinar epithelial cells are swollen and project to the lumina as round or oval cells with a pale cytoplasm filled th droplets.

Submaxillary Glands. — The epithelium of the ducts and acini itains vacuoles.

Brain.— Scattered through the pia and the brain substance of th the cerebrum and the cerebellum are large cells, identical in pearance with the characteristic large cell of the spleen of the st case. These cells are most common in the neighborhood of e Purkinje cells. The greater part of the cytoplasm of the Puruje cells is filled with small droplets, only a small zone of noril cytoplasm remaining about the nucleus. The cytoplasm of ese cells resemble closely that of the characteristic cell menmed above. The hypophysis shows no lesions. SpinaZ Cord.— The anterior horn nerve cells have their cytoplasm

ed with clear droplets. In the spinal root ganglia the bipolar Us have a pale nucleus and their cytoplasm is filled with small,

ar droplets.


Nerves. — Nerves of various size and from various parts of the body show a vacuolization of their medullary sheaths.

The skitt, striated muscle, arteries and veins of all sizes, and tonsils show no lesions.

Discussion. — The origin of the characteristic large pale cells is not very clear. In structure, position and staining reactions they are identical with those described in the small group of cases of primary splenomegaly first reported by Gaucher, who at first considered them to be epitheliomatous cells; but at present this neoplastic theory has very little support. Some authors hold that they are endothelial cells, others that they are derived from the cells of the reticulum, and still cithers believe that they come from both. Recently, one author, Mandelbaum, has advanced the theory that they are derived from large lymphocytes.

In the present cases there is no evidence that the large cells are derived from any one particular tissue cell. On the other hand, there is good reason to believe that several different tissues may produce the same large pale cell. In some places there is strong evidence that they are derived from the endothelial cells of the lymph sinuses (Figs. 8, 10, 11). On the other hand, there are just as good reasons for believing that they arise from the cells of the reticulum (Figs. 2, 3, 4). In many areas the endothelium shows no change, while the reticular spaces are filled with large pale cells, many of which are closely related to the reticular fibers. This is particularly true of the spleen, where there is generally little change in the sinusoids, in marked contrast to the presence of the columns and clusters of large pale cells outside the sinuses. In some places small vacuoles were present in the cytoplasm of the large lymphocytes, and it is possible that some may develop into the large, pale granular cells; but no such transition was seen. In the liver the large, pale granular or vacuolated cells are most probably transformed hepatic cells. In certain places they are arranged in radiating columns. In some sections a crescentshaped mass of finely granular, deep eosin-staining cytoplasm could be seen at one side of a large cell, suggesting a hepatic cell in which a small part of the normal cytoplasm had persisted, while the greater part had been changed by an infiltration of some homogeneous substance and the nucleus had become smaller. No normal hepatic cells were seen and. in this respect, the liver is identical with that in Niemann's case. Similarly, the young connective-tissue cells and fibroblasts may take up this lipoid substance and become transformed into some of these large pale cells, thus accounting for the appearance of the latter about small arterioles (Fig. 18), and of those embedded in the periportal fibrous tissue of the liver. The large cells in the glomeruli of the kidney may come either from endothelial cells or from reticular cells. At no place is there evidence of any neoplastic nature in them. A few mitotic figures were seen in some of the endothelial cells, but only in those attached to the vessel wall. The large cells were not seen free in the large vessels. It is primarily the thelial cells lining the small lymph sinuses and the cells of the reticulum that become transformed into these


LO I Xo. 299i


these (in our cases) the reticular o the lymphadenoid tissue seem the most susceptible. The disappearance of the substance within the large pale

•i treatment with absolute alcohol or ether, and its atypical Pat-like reactions to the microchemical tests for fats and lip very little doubt but that the large rolls owe

their size to the accumulation, whether it be degenerative or infiltrative, of a lipoid substance, the exai I nature of which is unknown. This substance does n< >t behave like fat; yet its

as i" neutral la i -lain- show that it is closely related

ats. It resembles myelin. Apparently, it represents a

lipoid substance arising from a perverted metabolism. The

and mode of formation of this lipoid substance are

obscure, bu1 il is probablj closelj related to lecithin. Whether

'initiation in the large pale cells and in the parenchymal cells is due to a degenerative or to an infiltrative process cannot be determined with our present knowledge of the condition. The peculiar bilateral change in the medulla of the adrenal glands may play a very important role in this metabolic disturbance, resulting in the accumulation of the lipoid substance in all of the tissues, liver, heart, kidney, pancreas and connective tissue, apparently wherever fatty degeneration and deposits occur. In fact, there is considerable fatty degeneration cither superimposed on this "lipoid metamorphosis " or representing an end-product of it. It may also be, as Schultze first suggested, that the spleen, which is said to play a not unimportant part in fat metabolism in some abnormal conditions, is largely responsible in these cases.

The names applied to this disease are innumerable and misleading, because they attempt to be descriptive terms. They fail to describe the new cases and the constant variations which

ing added each year, and which should all be included in a term which would connote the causal factor. As this, however, is unknown at the present time, considerable confusion would be avoided if all cases were termed simply "Gaucher"* disease." until more definite information concerning the nature of the process is obtained. As the process in this disease is a very general one and not specific spleen, the term "splenomegaly" is a misnomer. As more cases are described, a greater or less number of organs seem to be involved. At first it was thought that only the spleen and I- mph glands were involved, but the liver was then added, and, more recently, the thymus and the bone-marrow. In our cases the medulla of the adrenal glands must also be

to this list, and it is to be noted that similar but less promh - were found in other organs and in the

central nervous system. It is also very probable that the case described by Schultze, in which there was implication of the spleen alone, associated with a lipoidaemia, represents an

stage in the same process, inasmuch as the morphology,

Q ami microchemical reaction of the cells were similar. Schultze showed that the sections of the spleen of his case reacted to the microchemical tests for fats and lipoids just as did the sections of the generally accepted cases of Gaucher's disease described by Eisel and by Schlagenha titer; and the same reactions were obtained in our case. Apparently, any


disease in which the spleen, together with any other oro-an. shows numerous large, pale granular or finely vacuolated cells. giving the characteristic microchemical reactions for lipoids and showing a tendency to be widely and diffusely distributed belongs to this group, and any attempt to limit the condition to any single organ or any single set of organs is largely arbitrary.

Accordingly, it would appear that Gaucher's disease is nfi primarily a disease of the spleen or of any other organ or set of organs, but is a generalized process due to a disturbance in fat metabolism, manifesting itself by lipoid metamorphosis, that is, by the more or less diffuse accumulation of lipoid material in many cells with the formation of characteristic large p»> cells. This process is most prominent in the hematopoietft system, especially in the spleen and lymph nodes, organs that are said to play a not unimportant role in abnormal fat metabolism.

Summary. — It is quite evident, that the characteristic lesion in these two cases is the widely diffused accumulation and proliferation of the large, pale granular or finely vacuolated cells, most prominent in the lymphadenoid tissues, but apparently involving more or less extensively the reticular cells and the lymph-vascular endothelial cells, the process being generally associated with localized accumulations such as have been described in the medulla of both adrenal glands. The process was equally marked in the lymph nodes as in the spleen and probably had begun simultaneously in both locations, other sw ceptible tissues being subsequently implicated. The large pasj cell was also found in bronchi, arteries, veins, capillaries, gl<§ merular tufts, scattered between renal tubules, in the mucous membrane of the stomach, in the capsules of various organs, in the pia, brain and in large numbers in the bone-marrow. The occurrence of vacuoles in the parenchymal cells of most of the viscera — including the heart, pancreas, kidneys — thyroid, submaxillary salivary glands, in the Purkinje cells of the brain, in the nerve cells of the anterior horn of the spinal cord, in the bipolar cells of the posterior root ganglion of the spinal coxd, taken in conjunction with the negative results after the use of fat stains, indicates either a vacuolar degeneration or an accumulation of lipoid material in those cells as in the large pale cells, and suggests the presence of a very general pathological process, involving especially the lymphatic system. The phagocytosis was more marked and extensive in the second case than in the first. There was also more fibrosis, a greater proliferation of lymphocytes and more blood pigment than in the first ease.

Conclusion. — The characteristic large, pale granular 0] finely vacuolated cell with its lipoid contents, the predomj nance of this cell in all of the organs of the hematopoietic system, the familial character of the two cases, the eliniol history, the physical and pathological findings, leave no doi» but that they belong in the group of cases first described by Gaucher. It is true that our cases showed a unique implication of the medulla of the adrenal glands, that the Peyer's patches and the thymus were equally involved and that there was I much more general and diffuse distribution of the character


THE JOHNS HOPKINS HOSPITAL BULLETIN, JANUARY, 1916.




.W^ggS?


«VI^S


g


Fin. 1.




Fig. 6.


I JOHNS HOPKINS HOSPITAL BULLETIN. JANUARY, 1916.



4



Uk&J&PTtkgJfr >• ,1-." >i,'


^^^^f^,-,; :> ^;



1





istic large cells ; but this may be a manifestation of one and the same process, which in infancy is apt to be more rapid and widespread, as has been suggested by Niemann (see table).

Final Summary. — In this report we have presented the cases of two infants, sisters, who did not thrive from birth and died, one at 11 months, the other at 15 months of age, from gradually increasing weakness. The most striking clinical feature was the great enlargement of the spleen and liver. The blood picture was that of a moderate anaemia. The leucocytes were rarely increased, and for the most part were markedly reduced in number. The skin in both cases had a peculiar yellowish-brown hue, more marked on the face and exposed surfaces. In one case the diagnosis was confirmed during life by the examination of an excised lymph gland. Microscopically, in both cases nearly all the organs were found to contain large, pale, granular or finely vacuolated cells, in which there was a peculiar refractive substance having the chemical and staining properties of lipoid material. These cells are apparently identical with those described by Gaucher, and later by a number of observers, in the condition called " Gaucher's disease." Our own cases and that of Xiemann are the only ones in which the disease has been reported in infancy. The observation of "cherry-red spots in the maculae of Case II, in view of the presence of similar cells in the nervous tissues of cases of amaurotic family idiocy (Figs. 21, 22), lends additional interest and suggests the possibility that the essential degeneration in the latter condition may be of a similar character.

DESCRIPTION OF PLATES.

Fig. 1. — Spleen (X65). Iron hematoxylin stain. Shows the relative disappearance of the lymphoid cells in the pulp and the presence of many pale granular or vacuolated cells between the sinusoids. Note the similar large, pale cells within the Malphigian bodies, also the prominence of the endothelial cells of the sinusoids.

Fig. 2.— Spleen (X 70). Iron hematoxylin stain. Shows the distended sinusoids separated by columns and nests of large, pale, granular cells. This represents a typical section of the splenic pulp.

Fig. 3.— Spleen (X 65). Bielschowsky silver method for demonstration of the reticulum. Shows the general architecture of the spleen with the well-marked sinusoids, the intervening large, pale cells and their intimate relation to the reticulum.

Fig. 4.— Spleen (X480). Bielschowsky stain. Shows the character of the large, pale cells and their intimate relation to the reticular fibers.

Fig. 5.— Lymph Gland from Case I (X70). Hematoxylin and eosin stain. Shows columns and nests of large, pale cells imbedded in the lymphadenoid tissue. Compare with Fig. 9.

Fig. 6.— Lymph Gland (X70). Hematoxylin and eosin stain. Shows in one portion the large cells just appearing; in another the complete replacement of lymphoid elements by the same.

Fig. 7.— Lymph Gland (X 65). Iron hematoxylin stain. Shows the complete replacement of the lymphoid cells by the large, pale, finely vacuolated cells which are enclosed in the reticular spaces.'

Fig. 8.— Lymph Gland (X 70). Iron hematoxylin stain. Shows the large, pale cells apparently arising from the endothelial cells lining the sinuses.

Fig. 9.— Lymph Gland from Case II (X 65). Hematoxylin and eosin stain. Shows the presence of the large vacuolated cells in


clusters and isolated in the lymphadenoid tissue. Note the presence of these cells in the germinal follicles, some showing phagocytosis.

Fig. 10.— Lymph Gland (X 4S0). Iron hematoxylin and eosin stain. Shows the character and location of the large, pale cells. Some of these cells are still attached to the wall of the sinus.

Fig. 11.— Lymph Gland (X480). Iron hematoxylin and Van Gieson's stain. Shows the ragged, irregular outline of some of the large cells, the extension of their protoplasmic processes into the reticulum and the apparent origin of some of the. cells from the reticulum.

Fig. 12 — Liver (X70). Iron hematoxylin stain. Shows the fibrosis, the distortion of the intralobular architecture, and the absence of normal hepatic cells.

Fig. 13.— Liver (X260). Iron hematoxylin stain. Shows the character of the parenchymal cells. Note the pale and the finely vacuolated darker types, also the absence of normal liver cells.

Fig. 14. — Thymus (x 80). Iron hematoxylin stain. Shows three Hassall's corpuscles, each surrounded by a zone of lymphocytes and columns and nests of large, pale, granular cells.

Fig. la.— Lymph Follicle in Intestinal Submucosa (X90). Hematoxylin and eosin stain. Shows the presence of the large, finely vacuolated cells to one side of the lymphoid mass.

Fig. 16.— Kidney (X370). Iron hematoxylin stain. Shows a glomerulus. Note the characteristic large, pale, granular cells in the capillary tuft.

Fig. 17. — Adrenal (XSO). Iron hematoxylin stain. Shows the inner portion of the cortex and part of the medulla. Note the large masses of pale, granular cells inclosed in the reticular spaces of the medulla, the smaller, more scattered foci and the numerous red blood cells (stained black).

Fig. IS. — Wall of a Small Blood-vessel in the Lung (X340). Hematoxylin and eosin stain. Shows a zone of characteristic large, pale, granular cells surrounding the wall of the vessel.

Fig. 19. — Brain (X 160). Iron hematoxylin and eosin stain. Shows the cortex of the cerebrum with the characteristic large, pale, granular cells. Note the apparent origin of these cells from the vessel endothelium.

Fig. 20. — Brain (X450). Iron hematoxylin and eosin stain. Shows the cortex of the cerebrum with the characteristic large, pale, granular cells.

Fig. 21. — Brain of Amaurotic Family Idiocy (X 160). Hematoxylin and eosin stain. Shows the cortex of the cerebrum with large, pale, granular cells. Note the close resemblance of these to the cells in Fig. 19.

Fig. 22. — Brain of Amaurotic Family Idiocy (X 450). Hematoxylin and eosin stain. Shows a portion of the cortex of the cerebrum with the large, pale, granular cells. Note their close resemblance to the cells in Fig. 20.

BIBLIOGRAPHY OF FATS AND LIPOIDS.

1. Aschoff, L.: Zur Morphologie der lipoiden Substanzen. Beitr. z. path. Anat. u. z. allg. Path., 1910. XLVII, 1-50.

2. Bell, E. T.: The Staining of Fats in Epithelium and Muscle Fibers. Anat. Rec, 1910, IV, 199-212.

3. Bell, E. T.: Ciaccio's Method for the Demonstration of Lipoids. Jour. Med. Research, 1911, n. s„ XIX, 539 546.

4. Bonnamour, S.: Recherches histologiques sur la secretion des capsules surrenales. Note prgliminaire. Conipt. rend. Ass. d'anat., 1902, IV, 54-57.

5. Bullard, H. H.: The .Microscopical Demonstration of Fats in Tissue Sections. Jour. Med. Research, 1912-13, XXII, 56-66.

6. Ciaccio, C: Leber das Vorkommen von Lecithin in den zellularen Entziindungsprodukten und uber besondere lipoidbildende Zellen (Lecithinzellen). CentralW. f. allg. Path. u. path. Anat., 1909, XX, 385-390.


12 [Xo. 399


7. Ciaccio, C: Beitrag zuiu Studium der Zell-Lipoide in normalen

und pathologischen Verhaltnissen und einer besonderen Entartung

von lipoiden Typus (lecithinische Entartung). Ibid., S. 769-771.

S. Dietrich, A.: Zur Differenzialdiagnose der Fettsubstanzen.

Verhandl. d. deutsch. path. Gessellsch., 1910, XIV, 263-268.

9. Kaiserling, C. : Nachweis, Vorkomruen und Bedeutung der Zell-Lipoide. Berl. klin. Wchnschr., 1910, XLVII, 2156-2161.

10. Kasarinoff: Vergleichende Untersuchungen sur Histologie der Lipoide. Beitr. z. path. Anat. u. z. allg. Path., 1910, XLIX. 490-500.

11. Klotz, O. : Studies upon Calcareous Degeneration. Jour. Exper. Med., 1906, VIII, 322-336.

12. Idem: On the Large White or Soapy Kidney. Jour. lied. Research, 1909, XV, 27-44.


13. Polosow, A. A.: Zur Morphologie der Lipoidsubstanzen. Centralbl. f. allg. Path. u. path. Anat, 1910, XXI, 1014.

14. Schultze, W. H.: L"eber grosszellige Hyperplasie der Milz bei Lipoidaemie (Lipoidzellenhyperplasie). Verhandl. d. deutsch. path. Gessellsch., 1912, XV, 47-50.

15. Smith, J. L., and Mair, W.: An Investigation of the Principles Underlying Weigert's Method of Staining Medullated Nerve. Jour. Path, and Bacterid., 1909, XIII, 14-27.

16. Idem: Further Observations on the Bichromate Haematoxylin Method of Staining Lipoids. Jour. Path, and Bacteriol., 1911, XV, 179-181.

17. Smith, J. L.: The Staining of the Fat by Nile-blue Sulphate. Ibid., pp. 53-55.


PLEURAL EOSINOPHILS. WITH REPORT OF A CASE.

By Staxhope Batxe-Joxes. M. D. (From the Medical Clinic of The Johns Hopkins Hospital. Baltimore. Md.)


INCIDENCE. Eosinophile pleural effusions have been recorded in 68 cases. Sixty-three of these have been assembled and analyzed by E. Schwarz 1 in his recent monograph on the general subject of eosinophilia. In addition to these, cases have been reported by Baur, 2 Kipp, 3 and Mosny and Portoealis. 4 These instances of the presence of eosinophile cells in pleural effusions are few indeed in comparison with the great number of effusions which have been examined during the 15 years that have passed since "Widal and Bavaut " called attention to the clinical significance of pleural cytology. This figure, however, cannot be taken to indicate the actual incidence of pleural eosinophilia. It may be assumed with certainty that many


pleural fluids have not been examined microscopically, and that relatively few of them have been stained with polychrome dyes, proper for the demonstration of eosinophiles. The case to be reported almost escaped recognition because of a temporary failure to apply an eosin-containing stain, and it serves as a text for calling attention to the knowledge which will be gained by the use of polychrome stains in the routine study of pleural effusions. Pleural eosinophilia, nevertheless, is a comparatively rare condition. Its incidence, as determined by investigators applying constant methods to cases in series, is about 1 to 5 per cent of all cases of pleural effusion.

Pleural eosinophilia following lobar pneumonia, as in the instance which i- the subject of this communication, has been


TABLE I. Summaby of Cases of Postpneumonic Plepbal Eosinophilia.




Author.


Etiology.


Day of puncture.


Red blood cor.


Eosinophiles.


Poly-neutro.


Lymphocytes.


'- Endothelial.


Remarks.


Barjon & Cade. 6


Postpneum. 21,26


Numerous.


40 . 46


22,11


1« 16,o


15,10


Animal inoculation negative.


Sandomirskv. 7


24.27



20.13


69,24


9.54




Widal ^ FaureBeaulieu.'



3,5.9,10 19,22,20 31,34,56,69


5! .2700

730,1060


65,24

^.5,76


10,8,1,1.9

. ."> . 1 . •"• 2,5.7


3.0,0.4 1,1.8,1

2.71


23. 31. IS, Hi

21.12.7

7,17,18


Some mast-cells. Enormous toxicity. Eosinophiles in blood, 3' ! to 16% to 0.17c.


Malloi?el. 9 Obs. XLV.

Obs. XLVI. Obs. XLVII.


»


9,15,18

1,8 8,11,22


Present. Fluid at first


A few at first, then many, then none.

None at first,


Manv.


Scanty.

Abundant.

Few.




Obs. XLVII I.


tl


1 month.


purulent ; then hemorrhagic. Many.


then many. Many.


None.


Many.



Not tuberculous.


Mosny, Duninnt. i Saint-Giroi


6,7.9

11,13,16

18.21,23

2.".. 27



0.3.4 2S.20.51 35, 81 78.5,86


73. SO. 15 50.14.7.111 11.1,3.1.5 0.5.0.5


1.5,0.27,15

12.ii.27

I.e. li.:, ii.ii


26,70,56 39,30,14.7 6.5.10.S


Fluid ill purulent.

(2) Sero -purulent.

Sterile, with ll r '< mastcells.

Blood, 2. "'-11 - BE ophiles.


January, 1916.] L3


recorded in eight cases. Of the 68 cases mentioned in the preceding paragraph, eight were of metapneumonic occurrence, giving approximately 12 per cent as the special incidence of postpneumonic pleural eosinophilia among all eosinophile pleural effusions. The findings in these cases are shown in Table I.

REPORT OF CASE.

J. A. N., white, male, aged 30 (Gen. No. 101461, Medical Xo. 33908), was admitted to The Johns Hopkins Hospital on March 20, 1915, to the medical service of Dr. T. C. Janeway.

The patient was a sailor whose health had always been robust. Since the age of 16, he had lived on ship-board, sailing frequently in the tropics. He had never suffered from any severe acute illness and had not acquired any tropical disease. Gonorrhoea eight years previously and periodic excesses in drinking alcohol were the only other significant facts in his past history.

He complained of " pain all over, sick stomach, and spitting blood." The history of the illness which caused him to come to the hospital was a typical account of the onset of a lobar pneumonia. When he entered, on the fourth day of his illness, he had consolidation of the entire right lung. His temperature was 105° P.; respirations 40 per minute. The results of the special examinations were as follows:

Blood: (March 20th) R. B. C. 5,032,000. Hb. 85 per cent. W. B. C. 11,000. The differential count, with Wilson's stain, showed polymorphonuclear neutrophiles 93 per cent; mononuclears 7 per cent. No eosinophiles were seen in counting 250 cells. The blood culture was negative, but a culture from material obtained by puncture of the lower lobe of the right lung yielded a pneumococcus of Group II. A similar pneumococcus was grown in pure culture from the sputum. The Wassermann test was negative. Chlorides were absent from the urine. No tubercle bacilli were found in the sputum. The feces were examined frequently for ova and parasites, but none were found.

The temperature remained between 103° and 105° F. until March 23d, the seventh day of the disease, after which it gradually declined. For the next seven days, however, the temperature remained between 99° and 100° F., with the pulse proportionately accelerated, while the respirations were from 20 to 25 per minute. During this time, the signs of resolution began to supersede those of consolidation. The leucocyte count, which had been 25,000 became 14,000 on March 27th. No eosinophiles had been seen in the differential counts up to this time. The percussion note remained dull at the right base; and as empyema was suspected, the pleural cavity was aspirated on March 29th.

Thoracentesis I. — Five hundred cubic centimeters of a cloudy, amber fluid were withdrawn. This fluid clotted readily and had a specific gravity of 1015; it contained 40 grams of protein and 2.5 grams of chlorides per liter. Cell count: White cells, 580 per cu. mm.; red corpuscles, 2000 per cu. mm. Sediment of this fluid stained with methylene blue showed that the predominant cell was the " small mononuclear." No bacteria were seen. Cultures of this fluid remained sterile, and a guinea-pig inoculated with a considerable amount of the sediment was not affected.

Within a week after the aspiration of the fluid, the patient's temperature became normal, and remained so. The signs of consolidation gradually disappeared over most of the right lung, except over a small area in the interscapular region, while the dullness at the right base persisted. A second aspiration of the right pleura was performed on April 5th.

Thoracentesis II. — Twenty cubic centimeters of turbid yellow fluid were obtained. This fluid clotted quickly. The white cells numbered 600 per cu. mm., showing a predominance of eosinophiles when stained with Wilson's stain. The differential count showed


a significant contrast with that of the blood, the leucocytes of which numbered 11,200 on the day of the aspiration.

Type of cell. Percentage in Percentage

pleural fluid. in blood.

Polymorphonuclear neutrophil 6 72

Polymorphonuclear basophile o 5.6

Eosinophile

Polymorphonuclear 44 12

Mononuclear 1 q

Small Mononuclear 30 96

Large mononuclear 16 72

Transitional 9 44

Endothelial cells 1 q

Total s 100 100.00

Cultures and inoculations with this fluid were negative.

It became evident that the pleura was thickened over the right base, with little or no fluid remaining in the chest-cavity. A radiograph (Plate No. 29060), taken on April 16th, showed: " Mediastinitis. Extensive infiltration of both lungs. Patchy consolidation of the upper lobe of the right lung, with thickened pleura over this lung." It was the opinion of Dr. Baetjer that these changes were largely postpneumonic, and could not be called tubercular. Tuberculin tests (Calmette) were negative.

On April 10th, the right pleura was again tapped. At this time the blood showed W. B. C. 7500, with 15 per cent of eosinophiles.

Thoracentesis III. — Fifteen cubic centimeters of yellow turbid fluid, which clotted almost immediately. A sp. gr. determination and cell count were not made. The hydrogen-ion concentration of this fluid was lO-'.s (Dr. Levy) — practically a neutral reaction. Differential count. Wilson's stain. 300 cells counted.

Type of cell. Per cent.

Polymorphonuclear neutrophile 5.6

Polymorphonuclear basophile 0.3

Eosinophile

Polymorphonuclear 46.0

Mononuclear 1.0

Small mononuclear — granular 2.3

non-granular 39.0

Large mononuclear 1.6

Endothelial cells 1

Unclassified (degenerated cells) 3.2

100.0 With Ehrlich's stain the differential count was: P. M. N. 1 5 per cent. P. M. E. 40 per cent. S. M. 40 per cent. L. M. 5 per cent.

Special Studies of the Cells of tiie Pleural Fluid.

When treated with ammonium sulphide for the " iron-reaction " in the granules of the white cells, according to the method of Barker, 11 smears showed that nearly all the coarsely granular cells exhibited dark brown to black granules. Forty per cent of the white cells gave this reaction — a percentage about equal to that of the eosinophiles present in the fluid.

Oxydase reaction: Smears treated with £-naphthol and dimethylparaphenylendiamin, and counter-stained with aqueous saffranin, showed the violet-black granular oxydase reaction in 59 per cent of the white cells. Obviously, this included some of the mononuclear cells other than the mononuclear eosinophiles.

The patient improved steadily, the pulmonary signs gradually clearing. He was discharged on April 20, 1915.


M [No. 299


On May 17th, he was seen when he landed from a cruise during which he had served as stoker on a steamship. He looked well and had gained weight. There was slight dullness at the right base, hut no signs of pleural effusion. His leucocytes were 7900 per cu. mm., with only 1.5 per cent of eosinophiles, and a practically normal differential count. No mononuclear eosinophile cells were present in the blood at this or any other time.


DISCUSSION' OF CASE.

This case presented two metapneumonic phenomena, namely: a pleural effusion and eosinophilia of the pleural fluid, together with blood-eosinophilia. The details of these conditions have been described with the report of the case; a ion of their significance will be taken up in the succeeding paragraphs.

Small serofibrinous pleural effusions are common in pneumonia. Such effusions have been found in 65 per cent of a series of i ases studied by puncturing the pleura." Significant metapneumonic effusions, large enough to give physical signs (400 cc), occur in 5 per cent of the cases." In this case, the exudate was straw-colored, with sp. gr. 1015, albumin 40 grams per liter, 600 white cells and 1000-2000 red cells per cu. mm. It clotted quickly. Its reaction was neutral, with an H-ion concentration of 10~ 7 - 5 , which eliminates any chemical abnormality which may affect the staining reaction of the cells of the exudate. The fluid was non-toxic when injected into guinea-pigs, was sterile when cultured, and did not produce tuberculosis in the animals into which it was injected. Corroborative of the non-tuberculous nature of the exudate, was the fact that at the time of the removal of the fluid, the patient gave no reaction to the 1 per cent and 5 per cent tuberculin conjunctival tests. The cytology of these exudates is variable: usually the polymorphonuclear leucocyte is predominant; rarely, as in this case, the eosinophile is the chief cell.

Eosinophiles in the blood in lobar pneumonia are usually rare before the crisis, begin to appear shortly before or after the crisis, and rise to normal or increased numbers after the crisis. The noted cases of postcritical eosinophilia in pneumonia seem to indicate that the condition is partially independent of the local process and the fever, but that it is in some way associated with the reaction by which the organism regains health. It seems likely that some substance which stimulates the production of eosinophiles is produced in the 1 tissues. The eosinophiles in the blood in all these cases have been of the usual polymorphonuclear type of a-cell.

Pleural eosinophilia after pneumonia, which has been observed eight times, has always been associated with blood eosinophilia. but differs both in degree and in exact morphological type of the eosinophile cell which appears in the blood. The local eosinophilia may amount to from 40 to 80 per cent of the cells of the pleural exudate, while the blood-eosinophilia is generally of a lower degree, in this case 47 per cent for the former as compared with 15 per cent for the latter. In the absence of any other reason for eosinophilia, the hemic and pleural eosinophilia must be attributed to a common cause


associated with the specific disease — an eosmotactic substance, the nature of which will be considered later.

The eosinophiles in the pleural exudate were very different from those present in the blood. In addition to the usual multilobed eosinophile, this fluid contained mononuclear eosinophiles, whose characteristics are shown in the accompanying illustration (Fig. 1 (1)). These mononuclear eosinophiles varied in diameter from 11 to 15/x; the nucleus was round, filling about one-half of the cell ; it w T as dense, but not so dense as the nucleus of the lymphocyte, and contained masses of chromatin of varying size and shape. The cytoplasm was faintly basophilic and contained large refractile granules, which stained intensely red with eosin, gave the oxydase reaction, and showed a brow-n reduction of ammonium sulphide, when tested for the " iron-reaction," characteristic of eosinophiles. These cells looked like the typical eosinophilic myelocyte.

Two main theories of the origin and nature of these cells have been proposed. Ehrlich " and his followers, applying their theory of the myelogenous origin of eosinophiles, regard these cells as emigrated blood-eosinophiles, which have assumed a mononuclear form in the process of karyorrhexis. Dominici " and Widal I6 have held the opinion that these eosinophiles arise locally in the diseased structure by myeloid metaplasia of lymphoid tissue. The occurrence of mononuclear eosinophiles in nasal polyps and numerous other pathological and experimental eosinophilic lesions, is strong evidence in favor of the supposition that they have a local origin. Sclnvarz 1 sums up the controversy by saying that while the bone-marrow usually plays the chief role in the increase of the eosinophilies, the fixed mesenchymal cells may also give rise to them. In the embryo, hematopoietic mesenchyme is widely distributed. In the adult the bone-marrow becomes the chief seat of blood formation, but throughout the body myeloid rests remain in a state of latent function. This tissue, present in the spleen, lymph-nodes, intestines, and in the adventitia of blood-vessels, resumes its function when acted upon by the proper stimulus, e. g. an eosinotactic substance, and produces any or all of the myeloid cells.

Among the mononuclear cells of this fluid were a number of granular cells which could not be classed with either the ordinary lymphocyte or myelocyte. These cells gave typical oxydase reactions, and had characteristics suggesting a myeloid origin, similar to that proposed for the eosinophiles. The other elements of the mononuclear group (called by Kipp* and Pappenbeim " Group L"), were typical lymphocytes and endothelial cells.

Occasionally, small basophilic cells with "budding nuclei"' were found. These were difficult to distinguish from normoblasts (Dr. W. Baetjer) when the origin of the specimen was not known. Such a cell is shown in Fig. 1 (8).

Basophilic leucocytes formed 0.3 per cent of the cells (Fig. 1 (?)). In 1913. Mosny and Portocalis * found such basophils in a pleural effusion and described their discovery as "un element nouveau." They are probably mast-cells from the pleura, and have no special significance.


THE JOHNS HOPKINS HOSPITAL BULLETIN, JANUARY, 1916.





9


« 


null


Micrometer Scale



S."B-3


Fh;. 1. — Cells of Pleural Fluid, Drawn to Scale with Camera Lueida. Wilson's Stain.

1. Eosinophils — mononuclear.

2. Eosinophils — polymorphonuclear.

3. Mononuclears — lymphocytes.

4. Mononuclears — with polychrome granules.

5. Mononuclears — endothelial cells.

6. Polymorphonuclear neutrophile.

7. Polymorphonuclear basophiles.

8. Mononuclear cell with budding nucleus.

9. Degenerated cell.


January, 1916.]


JOHNS HOPKINS HOSPITAL BULLETIN


15


Polymorphonuclear eosinophiles formed 5.G per cent of the cells of this exudate. They are without significance here, except as an indication of the absence of any very acute inflammation at the time of the aspiration of the pleura.

Occasionally, bizarre elements were found, large vacuolated cells containing polychromatophilic granules and masses of chromatin, which took a deep stain. There were evidently degenerated cells, showing a striking contrast to the freshlooking mononuclear eosinophiles (Fig. 1 (9)).


The etiology of pleural eosinophilia has never been elucidated. The most positive inference deducible from the reports of the condition is that the substance determining the presence of eosinophile cells in effusions is a property of the exudate itself, and is independent of the bacterial, mechanical, or other cause of the effusion. Pleural eosinophilia has been found in pleurisy due to the following causes : ' trauma, tuberculosis, sepsis, typhoid fever, syphilis, pleuropericarditis, pneumonia, polyarthritis, nephritis, pulmonary gangrene, hemorrhagic infarct of the lung, endothelioma, septic endocarditis, gonoeoccal sepsis, myocarditis, cardiac insufficiency, puerperal sepsis, neoplasm, influenza.

From this list of heterogeneous diseases involving the pleura which have been associated with eosinophilic exudates, no etiological conclusions can be drawn. The list, however, serves to show that the eosinotaetic substance is independent of the local cause of the pleural effusion. Weidenreich " and others have considered that the erythrocytic content of the exudate determined the degree of the eosinophilia. In conclusive opposition to this may be taken the investigations by which it has been shown that eosinophilic granules have little in common with hemoglobin. Staiibli " has demonstrated that cells which actually ingest red corpuscles do not form eosinophile granules. If, however, Weidenreich's hypothesis had not been disproved, the fact that one-third of the exudates reported contained a minimal number of red blood-corpuscles would indicate the inadequacy of his explanation. In a similar manner, attempts to relate the eosinophilia to the presence of other cells in the exudate have been unsuccessful. The eytological formula; of the exudates are too inconstant to serve as a basis for etiological deductions. The sterility of the exudate or its bacterial content has no influence upon the presence or absence of eosinophilia. As a rule, bacteria or their products tend, on the contrary, to exert an anti-eosinophilic action. Widal and Eavaut 5 have shown that most of the eosinophilic exudates are sterile, but that some of them exhibit an unusual degree of toxicity for laboratory animals. The experiments on which these conclusions are based are negligible as regards their bearing on the question of toxicity, but they point in the direction in which is to be sought the substance which stimulates the production of this type of eosinophilia. Since all other factors have been eliminated, the chemical prope] the exudate appear as the important element in the rea Schwarz ' has advanced the hypothesis that protein split products in the exudate form the eosinotaetic substance which


produces the local or pleural eosinophilia (histoeosinophilia)

together with its associated bl l-eosinophilia (hemi

philia). In an exudate undergoing resorpti r, at least,

becoming altered by the action of immune ferments, split products of proteins are formed, and these substances are demonstrable in the exudates as proteoses and peptones. The experimental work on anaphylactic eosinophilia and eosinophilia in helminthiasis has shown that the split products of proteins are capable of producing both local and general eosini >philia. As ferment action in any exudate, regardless of the immediate cause of the effusion, produces these eosinotaetic bodies, this hypothesis is the only one broad enough to include all the known factors in the occurrence of pleural eosinophilia. The hypothesis, however, is only partially established by experiment, but it seems especially worthy of i correlates a known mild process with a known biological healing-reaction, and as it explains how pleural eosinophilia may occur in many different forms of pleurisy.

DIAGNOSTIC SIGNIFICANCE.

The eosinophilia of pleural effusions occurs in so many

diverse conditions that it cannot be correlated with any special

morbid process. The small number of tuberculous pleurisies

in the cases of pleural eosinophilia has been pointed out by

several authors. For instance, Widal and Pavaut 5 found f

instance of eosinophilia in fifty tuberculous effusions. Aside from the suggestion afforded by this, that a pleural effusion containing eosinophiles is usually not tuberculous, no nostic significance can be attached to the presence of an eosinophile exudate.

PROGNOSTIC SIGNIFICANCE.

Eosinophile pleural effusions are generally transient and benign. The fatal ending in the lethal cases has been determined by such complications as septic endocarditis, rather than by the pleural or pulmonary disease. On the hypothesis that the eosinophilia is conditioned by the absorption of protein split products from an autolizing exudate, the mildness of eosinophile effusions is comprehensible. The rinding, therefore, permits the making of a favorable prognosis.


This communication presents the account of a case of postpneumonic pleural effusion which contained 45 per cent of eosinophiles. The report of eight similar cases gathered Erom the literature are summarized.

Many of the eosinophile cells of this exudate were of the mononuclear type. The patient's blood exhibited a slight eosinophilia, but did not contain any mo) uclear eosinophiles. The morphology of these pleural eosinophiles 3U strongly that they have a local origin outside of the bonemarrow.

A review ol I factors in pleural eosin ophilia seems favorable to the hypotl 3 hwarz:' that

protein split products in an exudate und< orption


16 [No. 299


may constitute the eosinotactic substance that produces both the general eosinophilia and the local eosinophilia.

Eosinophilic exudates have no diagnostic significance, but are of good prognostic import.

REFERENCES.

1. Schwarz, E.: Ergeb. d. allg. Path. u. path. Anat, 1914. XVII. 138-790.

2. Baur, Levy et Petzetakis: Arch, de med. exper. et d'anat. path., 1913, XXV, 581-594.

3. Kipp, R.: Folia hajmat, 1914, XVII, 43-64.

4. Mosny et Portocalis: Jour, de physiol. et de path, gen., 1913, XV, 120-129.

5. Widal et Ravaut: Compt. rend. Soc. de biol., 1900, L, 648, 651, 653.

6. Barjon et Cade: Arch, gen de med., 1903, CXCII, 1859.


7. Sandomirsky, K. : De revolution de la formule cytologique dans les pleuresies, These de Geneve, 1905.

8. Widal et Faure-Beaulieu: Arch. gen. de med., 1906, CXCVII, 1S49.

9. Malloizel, L. : Recherehes anatomo-cliniques sur les reactions pleurocorticales, These de Paris, 1907.

10. Mosny, Dumont et Saint-Girons: Arch, de med. exper. et d'anat. path., 1912, XXIV, 489.

11. Barker, L. F.: Bull. Johns Hopkins Hosp., 1894, IV, 93, 121.

12. Norris, G. W. : Osier and McCrae, " Modern Medicine," 1914, I, 248.

13. Lord, F. T.: Ibid., 1914, II, 1012.

14. Ehrlich, P.: Folia ha?mat, 1904, I, 704-70S.

15. Dominici, H.: Folia hannat., 1909, VII, 97-106.

16. Widal et Faure-Beaulieu: Jour, de physiol. et de path, gen., 1907, IX, 1014.

17. Weidenreich: Folia hsemat, 1905, II, 163.

18. Staiibli, C: Samml. klin. Vortr., 1909, DXLIII, 43.


A COLORIMETRIC METHOD FOR THE DETERMINATION OF THE

HYDROGEN ION CONCENTRATION OF BIOLOGICAL FLUIDS,

WITH SPECIAL REFERENCE TO THE ADJUSTMENT

OF BACTERIOLOGICAL CULTURE MEDIA.

By S. H. Hurwitz, K. F. Meyer, and Z. Ostenberg.

m The George Williams Hooper Foundation for Medical Research, University of California Medical School,

San Francisco, Cat.)


Introduction.

The continuation within the organism of certain physiological processes depends in great measure upon the character and the constancy of the reaction of the body fluids. Changes in either will be attended by serious consequences to the cells and enzymes which find the body fluids, and more especially the blood, their natural medium. The biological importance of the constancy of the reaction of the blood has been especially emphasized by the recent studies of Henderson ( 1 ) . These have shown that there exists within the organism a regulatory mechanism whereby the normal reaction of the blood is permanently maintained.

Equally important is the reaction of the medium for the successful perpetuation of life outside of the organism. This is well illustrated by the well-known and intimate association between the acidity or alkalinity of solutions containing active enzymes and the rate of their activity, and also by the influence which the reaction of a bacteriological culture medium exerts upon the biological characters and the viability of bacteria. It is not unlikely, too, that the success or failure attending the cultivation of groups of cells or tissues in vitro depends, in no small measure, upon the reaction of the plasma ; indeed, the frequent transfer of such tissues from media containing the products of their metabolism to fresh plasma prolongs their life. The proper adjustment of the reaction of a biological fluid is, therefore, of the greatest importance for the favorable progress of many physiological processes.

As will be shown later, an exact knowledge of the reaction of a medium can be gained only from a determination of its hy


drogen ion concentration. It is the purpose of this paper to present a simple colorimetric method which makes it possible I to determine with considerable accuracy and rapidity the hy-| drogen ion concentration of biological culture fluids, and to show how such media can be adjusted to any optimal concentration of ionized hydrogen.

The Eeactiox of a Solution.

Eecent progress in our knowledge of the physico-chemical properties of solutions has changed considerably our conception of the reaction of a solution. The importance attributed to indicators in ascertaining the reaction of a medium, and to their value in the readjustment of such a medium to the proper reaction by titration, is gradually dwindling before the extensive knowledge gained by modern physico-chemical studies. Indicators, as we now know, do not necessarily change color at the neutral point, but rather at a definite equilibrium of hydrogen and hydroxvl ions which is peculiar to each indicator, this point of change being dependent upon the chemical constitution of the indicator. It follows, therefore, that the determination of the reaction of a medium by titrating to a convenient end-point is without real significance.

According to the theory of solutions, the acidity in water is explained by the occurrence of hydrogen ions, formed from dissolved electrolytes, in excess of hydroxyl ions; neutrality is, therefore, the condition when, as in pure water, the two concentrations are equal. Because it is easier and more accurate to determine the hydrogen rather than the hydroxy]


January, 1916.]


JOHNS HOPKIXS HOSPITAL BULLETIN.


1:


ion concentration of a solution, it has become the established usage to express its reaction in terms of hydrogen ions.

Present Methods of Adjusting the Reaction of Culture Media.

In most bacteriological laboratories of this country adjustment in the reaction of culture media by titration has largely replaced all other methods. In a very recent paper Clark (2) has critically reviewed the method of " titratable acidity," and has set forth in a comprehensive way the reasons why the titrimetric method in its present form is inaccurate.

The inadequacy of the method of titration is attributable chiefly to the physico-chemical properties of the available indicators. The indicator most commonly employed for the titration of media is phenolphthalein which, like most indicators possesses no true end-point, since its zone of color change is broad, lying between the hydrogen ion concentration of pH = 8.00 and pH = 10.00. 1 If the tint of phenolphthalein at pH = 8.50 is taken as a standard end point it is possible to show that media corrected from this point to definite degrees on the Fuller scale have different hydrogen ion concentrations.

This discrepancy can be demonstrated quite readily, if one chooses at random various samples of laboratory media and compares the titratable acidity with the actual hydrogen ion

TABLE I.

A Compabison Between the Degbees in Reaction (Ftjlleb Scale)

akd the Hydeogex Ion Concentration of Vabious Media.


No.


Medium.


Degrees in Fuller Scale.


Hydrogen Ion Concentration. Value for pH.


1


Plain broth


+0.8


7.3


2


Plain broth


+0.4


7.8


3


Plain broth


+0.5


7 .-'"


4


Plain broth


Neutral


8.4


5


Plain broth


+1.0


7 .7


6


Veal-infusion


+1.0


7.1


7


Veal-infusion


+0.5


8.1


S


Veal-infusion


+0.9


7.6


9


Sugar-free broth


+0.9


7.58


10


Plain broth


+0.8


6.9


11


Liebig's broth


+0.5


7.9


12


Extract


+ 1.0


7.2


13


Ox-heart broth


+1-1


6.9


14


Liebig's broth


+0.8


6.9


15


Plain brotli


+0.8


7.1


16


Chicken broth


+1.1


7.2


17


' Hycerine broth


+ 1.0


7 . 45


IS


Liebig's broth


+0.8


7.0


19


Plain broth


+ 1.0


6.6


20


Liebig's broth


+0.8


7.0


concentration as measured colorimetrically. Table I illustrates the results of such a comparative study of twenty different batches of media. Similar observations were made by Clark who compared the titration curves obtained in the usual way with the determinations made by the use of the hydrogen electrode.


Unfortunately the use of the hydrogen electrode which gives the most accurate knowledge of the reaction of a medium in terms of the concentration of hydrogen ions is not for practical use. Besides being time-consuming : the gas chain electrometrie method necessitates special training in physicochemical technique.

Heretofore the colorimetric method has not given promise, because of the lack of a suitable indicator, and because of the presence of coloring matter in the fluids to be tested. We believe, however, that both of these difficulties have been overcome in the procedure to be described.

Principles of the Colorimetric Method.

Already brief mention has been made of the principle which underlies the use of indicators in the titrimetric method. It was pointed out that the change in color of an indicator during an ordinary titration means that the hydrogen ion con tion of the solution has attained a certain degree cha istic for that indicator. Different indicators show color changes at varying degrees of hydrogen ion concern For example, the color of phenolphthalein changes from colorless to red between the values pH = S.00 and pH= 10.00 (lxl0" s and lXlO" 10 ); whereas methyl orange passes from its full acid color over into its alkaline color as the hydrogen ion concentration falls from pH = 3.0 to pH = 4.7 ( 1 X 10" 3 and 4 x 10~ 5 ) . At intermediate points various shades of color are obtained, a certain color indicating a definite hydrogen ion concentration.

Through the investigations of Friedenthal (3) and Salm ( 4 ) and of Sorensen (5), we now know the range of color change of a large number of indicators. From the large group studied several have been chosen for practical use. which, because of the extent of their range of color and because of the only slight interference of proteins in the test solutions, are of particular value for studies on hydrogen ion concentration.

In carrying out the colorimetric method it is necessary to have a series of standard solutions of known hydrogen ion concentration, and an indicator exhibiting a wide range of easily distinguishable color changes at hydrogen ion concentrations approximating those of the solutions to be i he pro cedure of making the readings is then quitnecessary only to add an equal amount of indicator both to the standard solutions, and to the test solution, and to determine which of the colors in the standard series most closely matches that of the solution tested.

Standard Solutions and Method of Notation.

The standard sol: in the method to be de were those recommended by Levy, Powntree and Marriott (6) for the determination of the i D concentration of

the blood. These consist of standard phosphate mixtures pre


1 The significance of the expression pH =p to designate the hydrogen ion concentration will be explained in a subsequent paragraph.


2 McClendon (Am. Jour. Physiol., 1915, XXXVIII, 180, 186) has described a new hydrogen electrode and a direct reading potentiometer, the use of which reduced the time necessary for a determination from forty to about two or three minutes.


is [No. 299


pared according to the directions given by Sorensen (7) . Since phenolsulphonephthalein shows definite variations in quality of color with small differences m hydrogen ion concentration between pH = 6.4 and pH = 8.4. it was chosen by these workers as the most suitable indicator. Experience in the use of these standard solutions containing phenolsulphonephthalein has further emphasized its value as an indicator for this work, not only because of the great breadth of its color range on either side of the neutral point, but also because of the ease with which the various gradations of color can be differentiated, even in the presence of the pigments which occur in most biological fluids. Furthermore, as Sorensen (8) points out. the fact that the phthalein group of indicators is more suitable for use in the presence of proteins or their splitproducts makes them especially valuable in studying the reaction of biological fluids by the colorimetric method.

In recording hydrogen ion concentration it is most convenient to use logarithmic notation as employed by Sorensen (9) rather than to record the actual concentrations because the significant variation is in the logarithm of the numbers which represent the quantity of hydrogen ions. For instance, N/10 hydrochloric acid is 0.001 X with respect to its hydrogen ions, and the hydrogen ion concentration is expressed conveniently as 9.1 X 10"- or simply 10' 104 , the index, — 1.04, being the logarithm of 0.091. The method of notation is still more simplified by dropping the 10 and minus sign and designating the hydrogen ion concentration by the expression pH = 1.04. where pH is the hydrogen ion exponent.


Equivalents of the Logarithmic Valves pH = 6.4 to pH: in Actual Concentrations of Ionized Hydrogen.


logarithm


Actual Hydrogen Ion Concentration


Logarithm


Actual Hydrogen Ion Concentration


pH.


H.


I'M.


H.


6.4


4.0 X10-'


7..". :


0.32 X lO

6.6


•2.:. XlO-7


7j;


li. 2o xio-

6.8


1.6 XlO- 7


7.7


0.2 X10-'


7.0


i.n xio-j


7.8


0.16 X10-'


7.1


0.8 xlO" 7


8.0


0.1 xio- 7


7 .

0.63 X IO

S.2


0.063 X 10-'


7.3


CS X10-

8.4


0.04 X 10- 7


7.4


0.4 X10-




3 The hydrogen ion concentration of the blood averages about 0.3 X 10 7 or pH = 7.5.

In Table II is given the equivalent of the logarithmic notation in actual concentrations of hydrogen ions. Only such equivalents are given which fall within the range of color change for phenolsulphonephthalein.

Method.

1. Method Used in Comparing Colored Fluids. — One of the greatest obstacles met with in the application of colorimetry to the determination of the ionization of biological fluids is the turbidity and the pigment present in the majority of such fluids. It is obvious that the addition of an indicator to a solution which is already colored gives rise to a tint which can


not be matched against a standard color scale made up with distilled water. This difficulty has been overcome by various workers in different ways : Sorensen (10), for instance, recommends the addition to the standard solutions of several drops of a solution of some neutral dyesfuff so as to compensate for the color of the fluid under investigation. Similarly, turbid solutions can be compared by adding to the standard solutions varying amounts of a freshly prepared suspension of barium sulphate. Such procedures, as must be quite apparent, render the method more complicated and less accurate.

Eealizing that this difficulty had to be overcome before the method could be made applicable, we tried various means of freeing such solutions of their color — dialysis, adsorption, and ultra-filtration. The method of dialysis, recommended by Levy. Rowntree and Marriott (11) for determining changes in the hydrogen ion concentration of the blood was first tried. This procedure, although invaluable for blood determinations, cannot be made applicable to studies on the hydrogen ion concentration of biological fluids. As we know, these fluids contain substances, chiefly the phosphates, carbonates, and colloids, which tend to preserve the original hydrogen ion concentration of the solutions. The value of these so-called " buffers " must be determined, if such fluids are to be adjusted to any desired ionization. In tests upon the dialysate, however, the influence of these " regulators " is not fully ascertained. The use of filtration through collodion membranes, although more accurate, is more difficult and equally objectionable for the reasons just given.

The removal of coloring matter by adsorbents like charcoal and Kieselguhr was early discarded, because both of these substances contain free alkali which changes the hydrogen ion concentration.

In order to obviate all of these difficulties, we have constructed a simple device* (Fig. 1), whereby the medium tested serves as a background for the standard test color to which it imparts its own characteristic quality of color, thus making the color of the fluid to be tested directly comparable with the standard test solutions. This apparatus 5 consists of the parts pictured (Fig. 1) : A block of wood about three inches long, two inches wide and one and a half inches thick serves for the construction of the comparator. Into this block four holes, A, B, C, D, are bored vertically; these are arranged in two pairs, one beside the other. Slots £ and S' are then cut through the holes. If test tubes of the proper thickness are now inserted into holes A, B, C, and D, and the apparatus is held against a white background, the light in passing through each slot must pass through the two pairs of tubes.


1 After constructing our instrument we found that Walpole (Jour, of Biol. Chem., 1910-1911, V. 207) has made use of the same principle for reading colored fluids. Instead of having the four test tubes arranged parallel to one another, he has placed them end on in pairs.

2 Inasmuch as the test consists merely in comparing the qualities of colors and not their intensities, as is done in ordinary colorimetry, it was thought advisable to use the term comparator rather than colorimeter for the apparatus.


The tube in .1 is the standard comparison tube of known hydrogen ion concentration. Into the hole /.' is placed the tube containing the fluid to be tested plus the correct amount of indicator. To compensate for the color of the test fluid a sample of this without indicator is placed into C which is just behind the standard test color. Into I) is placed a tube containing distilled water; this tube is used merely to make the field of view of both slots of the system similar.



Fig. 1. — Diagram of Comparator. Into the holes A, B, C, D, are placed the four test tubes: A receives the standard comparison tube; B receives a tube containing the medium plus indicator; into C is placed the test solution to compensate for the natural color of the medium, and into D a test tube containing water. S and S' are the slots through which the colors are matched. M and M' are metal bands designed to equalize the portions of color fields exposed to view.

The titrations are most conveniently carried out in a specially constructed tube shown in Fig. 2. The acid or alkali used for




iiT\°-' 2 ~ Dia g ram °i Titration Tube. Test solution and acid or alkali are mixed in part A; comparisons of the color of the solution are made in part B, which is inserted into hole B of the comparator. Tube B is offset from part A, in order that part A will not crowd the other tubes in the comparator.

the titrations is run into the larger tube and thoroughly mixed with the test fluid. For making the comparisons, the fluid is run into the side tube, which is of the same internal diameter


and thickness a, tubes A, C, and D; this tube is inserted into the hole B of the comparator.

. In making a rending that standard tube is chosen which at first glance appears most nearly like the color of the fluid tested. Then comparisons are made with the standard just above or below in the scale, until the closest approximation is obtained. In this way it is possible to read quite accurately between any two parts on the standard scale. It has been our experience that this method of making readings is applicable to most of the biological fluids possessing any great transparency and whose natural color is not too intense. For determinations upon yellow and straw-colored fluids it is especially useful, since phenolsulphonephthalein, in the presence of an alkali, imparts to them a brownish red tint, which can be readily matched by blending the natural color of the medium with that of the appropriate standard solution, as is done in the comparator.

2. Preparation of the Reagents.— In addition to the indicator N/20 acid and alkali are needed for standardization and N/1 acid and alkali for adjusting the medium to the desired concentration of ionized hydrogen.

The same strength of indicator is used in the titrations as was added originally to the standard test solutions. This is an aqueous 0.01 per cent solution of phenolsulphonephthalein made up as follows : A measured volume of indicator is obtained from a standardized solution' (1 cc = 6 milligrams) is added to the required amount of distilled water. Oi this a measured volume is taken and boiled for several minutes to expel the carbon dioxide. The solution is then made up to the original volume, so as not to alter the concentration of the indicator.

In order to keep the concentration of indicator during titration the same as its concentration in the standard comparison tubes (0.3 cc. to 3 cc. or 1 to 11), the solutions of N/20 acid and alkali used for titration are so made up that one-eleventh of their volume consists of the indicator solution. For instance, two liters of such a solution ' are prepared according to the following formula :

Acid or alkali X/10 1000 cc.

Indicator, 0.01 per cent 182 cc.

Distilled water to make 2000 cc.

These solutions containing the indicator arc used, however, only if the method is carried out according to procedure B, described below.

The normal solutions of acid or alkali are measured, sterilized and again made up to the original volume. Adjustments

'This is the well-known standardized solution of phenolsulphonephthalein prepared by Hynson, Westcott & Company, of Baltimore. Md., for testing kidney function.

7 This solution must be protected from light, moisture, and carbon dioxide. If the vessel containing it is covered with a box and the glass tubing leading from it to the graduated pipette is surrounded with an opaque paper, the solution can be kept for a long time without fading of the indicator. The solution is protected from moisture and carbon dioxide by inserting Into one opening of the stopper a tube containing potassium hydroxide and calcium chloride.



in the reaction of bacteriological culture media are to be made after sterilization with sterile acid or alkali for reasons which will be discussed later. For the adjustment of other culture fluids, however, no such precautions are necessary.

3. Preliminary Test. — The medium is tested first to ascertain what its ionization is before adjustment. This preliminarv test can be carried out quickly : To 3 cc. of fluid is added 0.3 cc. of a 0.01 per cent solution of the indicator, the fluid being read directly in the comparator. In most instances the culture fluid has been roughly adjusted by the usual methods so that its reaction falls within the limits of the scale (pH = 6.-± to pH = 8.4). If the medium has not received a preliminary adjustment of reaction, it may be too acid or too alkaline to be read directly. In that event titrations are carried out in the manner to be described. From such titration^ is determined the amount of acid or alkali needed to bring a liter of the medium tested from its present reaction to a desired optimal ionization.

4. Method of Titration — Proc dure A. — It may be well, before describing the manner of carrying out the titration which was finally adopted because of its greater simplicity, to present the method as it was first tried. In procedure A the several steps in the titration, instead of being combined as in procedure B to be described below, are carried out separately.

To each of ten test tubes s of the same internal diameter and thickness as those containing the standard solutions are added 5 cc. of the medium tested. From a one cubic centimeter pipette graduated into hundredths is added N/20 acid or alkali, 0.1 cc. to the first tube, 0.2 cc. to the second and so on up to 1 cc. to the tenth tube. An amount of the indicator solution corresponding to one tenth of the whole volume is now added to each tube. The amounts of the acid or alkali and of the indicator solution added to each tube in this procedure are given in Table III. This gives a series of tubes containing

TABLE III.

Amounts of N/20 Acid or Alkali and Amounts of Indicator

Solution Required for Each of 20 Tubes Tftrated

According to Procedure A.


No. of Tube.


N/20 acid or alkali

in cc. Amount of indicator

in cc.


ii. 1 ii.2 0.3 n.4 II. .3 0.310.32 0.33 0.34 0.35


X li'i acid or alkali

in cc. Amount of indicator

in cc.


10


0.6

0.30


ii.7 n B ii. 'J 1.0 0.37 |> 38,0 !! 10


15 1C ! 17 18 la 20


1.1 1.2 1.3 1.4 0.410.42 0.43 0.44


1.7. l.C 1.7 1.8 1.9 2.0 0.450.46 0.47 0.48,0.49,0.50


8 The titration of ten such tubes will ordinarily suffice if the medium has been roughly adjusted to begin with. In Table III are given the amounts of alkali and indicator to be added to 20 tubes should it be necessary to carry the titrations above the tenth tube.


the medium in a graded scale of hydrogen ion concentration and comparable in quality and intensity of color with the standard comparison tubes.

From among the ten tubes is chosen the one whose color most closely approximates that of the standard solution to which it is compared. The desired ionization may lie at a ' certain point between any two of the tubes of the series, in which case it is necessary to interpolate. If, for instance, tube No. 1 corresponds to the value pH = 7.3 and tube No. 2 to pH = 7.G, and the hydrogen ion concentration desired in pH = 7.5, the correct amount of N/1 acid or alkali to be added will lie on the curve two-thirds of the distance between that » required to obtain the ionization 7.3 and that needed to give the i value pH=7.6.

5. Procedure B. — For practical use it has been found advisable to combine some of the steps in the titration so as to increase the rapidity of the method without affecting its accuracy. Instead of adding the alkali and the indicator separately to each tube, the two solutions have been combined in the planner already stated in the paragraphs on the preparation of the reagents. This solution is kept in a vessel shielded from the light and the apparatus is so arranged that the solution can be delivered directly into a graduated one-cubic-centimeter pipette, provided with a ground glass stopcock on the principle of a burette. With such an arrangement, the titration can be carried out quickly and the amounts of acid or alkali used are read directly on the pipette.

The method is further simplified because the titrations can be carried out with 3 cc. instead of 30 cc. of the medium, as in procedure A. Furthermore, greater accuracy is attained, since the readings in hundredths of a cubic centimeter can navt be made directly on the pipette. This does away with the necessity of interpolation for amounts between tenths of a cubic centimeter — a process which is subject to inaccuracies. Readings on the pipette in terms of the N/20 solutions used for titration can be converted directly into N/1 acid or alkali per liter by reference to Chart I, which will be described below.

The method of making the comparisons is identical for both procedures. A and B.

6. Method of Adjusting the Media. — The manner of adjusting the medium to the desired hydrogen ion concentration may be made clear by a specific example. The medium which has been roughly standardized to +0.5 or +1.0 (Fuller scale) is sterilized in amounts, the volumes of which have been previously measured. This may be done in ordinary flasks, which have been graduated before use to a definite volume, so that any fluid lost by evaporation during sterilization may be made up by the addition of sterile distilled water. If it is desired, for example, to adjust such a medium to the hydrogen ion concentration of the blood, which corresponds to about pH=7.5 on the scale, a 3 cc. sample is titrated, as already explained, until a color is obtained which matches 7.5 on the scale. Now the amount of N/20 alkali used is read directly on the graduated pipette. Should this reading be 0.46 cc, for instance, its equivalent in terms of N/1 alkali per liter would


January. 1916.] -.'I


be 9 cc. This conversion of N/20 into X, 1 alkali can be made directly from Chart I, on which the X/20 solution is plotted as abscissa? and the X/l solution as ordinates. If now 9 ce. of N/1 alkali be added to a liter of the medium, the desired hydrogen ion concentration will be obtained. Should the medium be alkaline to start with, it is. of course, nei to titrate with N/20 acid and to adjust the medium with an equivalent amount of normal acid. For this correction the lower curve of Chart I is used.


Chart I. — Curves indicating the actual amounts of N/1 acid or alkali necessary to adjust one liter of medium to the desired hydrogen ion concentration, as indicated by the amount of N/20 acid or alkali used.

Although the titrations are made with N ; 20 acid or alkali solutions in order to insure greater accuracy in measurement, it is desirable for practical purposes to make the adju with normal arid or alkali so as not to dilute the media too much. The conversion of the amounts of N 20 solution used into the corresponding amounts of N/1 solution required per liter is accomplished most readily and accurately by plotting


a curve. Such a curve must take into account three factors : the alteration in volume due to the addition of concentrated rather than dilute alkali or acid; the differences in the dilution of the " buffers " of the medium, in the one instance by \ 20 solution, and in the other by N/1 solution; and lastly, the degree of correspondence between the N/20 solution used for the titration and the N/1 solution used for adjusting the medium.

Only the first of these conditions can be satisfied by a curve plotted from theoretical calculations. In fact the use of such a curve has convinced us of its inaccuracy. In order to correct for all three of the variables, it was found necessary to plot a curve from data obtained by the titration of an average laboratory medium. This is done in the following mauner: To five 25 ce. samples from each of two media, one originally acid and the other alkaline in reaction, was added N/1 alkali and acid in the amounts of 0.1 ce. to the first sample, 0.2 cc. to the second and so on up to the last. From each of these samples 3 cc. were then withdrawn and to each was added 0.3 cc. of the indicator. A 3 cc. sample of the same medium was now titrated with N/20 alkali or acid, after the addition of 0.3 cc. of the indicator solution, until its color matched successively the color of each of the five tubes. The amounts of X 20 solution required were plotted as abscissa? and the corresponding amounts of N/1 solution as ordinates.

The upper and lower curves of Chart I express the relation existing between the number of cubic centimeters of N/1 alkali or acid per liter of medium and the number of cubic centimeters of X 20 alkali or acid per 3 cc. of medium necessary to bring about the same hydrogen ion concentration. In this way account is taken also of the effect upon ionization of the " buffers," by the dilution of the medium in the one instance by N/20 solution and in the other by N/1 solution. Such curves plotted for an average medium ' will be found true for almost all similar media.

It is recommended that each worker using this proi plot such reference curves. This will add greatly to the accuracy of the method, since, besides correcting for volume and dilution of "buffers," these curves correct also for any error which may arise from lack of correspond the N/20 solutions used for titration and the X 1 solutions used for adjusting the media.

In order that the application of this method may yield satisfactory results in the adjustment of bacteriological culture media, it is essential, in the first pi; lie medium be

roughly adjusted in the beginning, and secondly, that the correction in reaction be made with a sterile acid or alkali. Such a rough correction conducted in the usual manner serves a two-fold purpose : ( 1 ) it brings the

of the standard scale, thus making a direct reading in terms of hydrogen ion concentration possible; and (2) it tates the addition of smaller quantities of acid or alkali for the


•Most of the media tested in this laboratory were prepared by extracting meat for 1S-24 hours in the cold and then adding to this extract one per cent peptone, either Witte or Chapoteaut.


[No. 299


final adjustment of the sterile medium. This obviates the dilution of the active ingredients and the possibility of precipitate formation, which may result from the addition of too large quantities of acid or alkali. 10

The fallacy of correcting by the titrimetric method the reaction of a medium before sterilization applies all the more to the procedure under consideration. It is now well known that media show not only an increase in titratal.de acidity after sterilization (12). but, as would be anticipated, sterilization - the equilibrium of hydrogen and hydroxyl ions (13). This change may or may not be accompanied by precipitation. It follows, that adjustments in the hydrogen ion concentration made before sterilization do not hold for media after they have been sterilized. This is all the more true of the finer adjustments in the ionization which are obtainable by the procedure outlined. It has, therefore, become the custom of some workers (14) to correct their media by adding a sterile acid or alkali to the sterilized medium.

The matter is much simplified, however, where the question of sterilization does not enter, as in the case of other culture fluids, fir instance, those containing active enzymes. The latter can be readily adjusted to any optimal ionization directly, if their range of activity' lies within the concentration of hydrogen ions represented by the standard solutions used.

Results of the Method.

In order to determine the accuracy and the usefulness of the method, titrations were carried out on various samples of media — bouillon, agar, and gelatin, chosen at random from the different batches in the laboratory. Most of these had been adjusted previously according to the Fuller scale, so that their reaction fell within the limits of the colorimetric scale. In practice such media are usually found acid, necessitating. therefore, an addition of alkali to adjust them to the desired reaction. In order to test out the applicability of the method to the adjustment of media found to be too alkaline, titrations were also carried out with N/20 acid instead of alkali upon samples which had been previously made alkaline.

After determining the amount of N/1 alkali or acid needed to bring the test medium to the desired hydrogen ion i tration, this amount was added to a 25 cc. sample and a determination again made of the adjusted medium.

Forty-nine determinations were made upon twenty-three different samples of media. The results of the titrations are recorded in Tables IV and V. In Table IV are listed the various media just as they were prepared for use in the laboratory, while in Table V are recorded the results of titrations of media made alkaline for experimental purposes.

It will be seen that, for the most part, the correspondence between the hydrogen ion concentration desired and that obtained bv the addition of the correct amount of alkali or acid


10 As Clark (p. 127) points out, proteins exist in solution only within certain narrow limits of hydrogen ion concentration, and the precipitation of these and other substances of a complex medium occurs as the hydrogen ion concentration is changed.


is very close. Such accuracy in titration is readily obtained after sufficient familiarity with the technique and the standard color scale.

In several instances determinations of the hydrogen ion concentration of solid media were made. Media containing agar or gelatin were first rendered fluid by bringing them to the proper temperature. To the fluid solution was then added the indicator. The medium was inverted in the test tube several times to distribute the color evenly, and allowed to solidify. 11 Determinations of the hydrogen ion concentration of the solidified medium could then be made directly in the comparator. Most of the samples tested in this manner were sufficiently transparent to make a color comparison extremely accurate. In a few cases samples of agar were adjusted with the calculated amount of acid or alkali and determinations of the adjusted samples of the solidified media were made, as in the case of fluid media. These tests convinced us of the usefulness of the method for the determination of the hydrogen ion concentration of solid media.

Usefulness and Applicability of the Method.

In discussing the practice of adjusting media by the method of titration in general use, attention was called to the variations in hydrogen ion concentration possessed by media adjusted to the same point on the Fuller scale. In spite of these variations in reaction, however, most bacteria have been successfully cultivated. Clark's experience has been that B. colt and certain streptococci will grow in media with hydrogen ion concentration values varying from pH = 5.5 to pH = 9.0. This fact is now readily explained by the presence in such media of " regulators " or " buffers." These, as already explained, prevent rapid changes in hydrogen ion concentration, which may be produced by the metabolic products of bacterial growth. This explains the value of an infusion rich in " buffers " (principally the phosphates, carbonates, and amphoteric proteins) whose ionization is little altered by a considerable variation in titratable acidity.

Chart II illustrates graphically the difference in the " buffer effect" of several such media, as measured by the amount of N/20 acid or alkali needed to bring each from one concentration to another given concentration of hydrogen ions. It will be observed that the media rich in " buffers " show flatter curves than those that are poor in "buffers," for the reason that a transition from one point on the scale to another requires more acid or alkali. Similar curves obtained by the use of the hydrogen electrode have been plotted by Clark (15). It is more simple, however, to obtain such curves by using the colorimetric method. Their value rests in the important information they give concerning the "buffer" content of a medium upon which depends, in large measure, its usefulness for the growth of bacteria.




11 Readings should be made on the solidified medium at a constant room temperature, since the hydrpgen ion concentration changes with the temperature.


January, 1916.] 23


TABLE IV. Titration of Acid Media Showing Value of pH Desired and That Obtained by Adding Correct Volume of N/1 Alkali to a 25 cc.

Sample of Medium.


Aug. 7 Aug. 12


Veal-infusion.

Plain broth. Liebig's broth.


Aug. 16 Plain broth.


Aug. 11

Aug. 11

Aug. 16 Aug. 17 Aug. 17

Aug. 17

Aug. 17 Aug. 26


Extract. Ox-heart broth.


Ox-heart broth — no peptone.

Chicken broth.

Plain agar.

Sugar-free broth.

Plain broth.


Glycerine broth.


Liebig's broth.


14 Aug. 30 Ox-heart broth.


15 Aug. 30 Ox-heart broth

plus 10% bile.


+ 1.0

+0.8 +0.8

+0.S + 1.0

+1.1


+1.1

+ 1.0


+ 1.0


+0.9

+ 1.0


+ 1.0


Below 6.4


6.9 6.9


6.9 6.9


Below

6.4


7.1 7.2


7.45

Below 6.4

Below 0.4

6.9

7.0

6.9


7.6 7.6


7.0 8.2


t .0

7.9


N/l alkali

added per 25 ec.


0.46

0.17

0.195 0.20

0.13

0.195

0.285

0.08 0.21

0.25 0.30 . 35

0.30 0.43

0.4*

0.20

. 1 85 0.26

0.195 0.275 0.375

0.08 0.15

0.285 0.35

0.435 0.37

0.17

0.285

0.30 0.25

0.21


0.225


7 . 45



0.073


7.55



0.087

0.095


I '-•


Medium poor in "buffers" as shown by titration curve.


0.06

0.0S8

0.13


7.6

7.9 S.15



0.04 0.096


7 . 55 7.9


Plotted as Curve V, Chart 11 ;

medium poor in "buffers."


0.114

0.14

0.164


7.4 7 . 55 7.75


Plotted as Curve VII, Chart II.


0.17 0.21


7.15

7.3


Plotted as Curve VI, Chart II.


. 23


7.65



0.12


7.9



08 i 0.12


7.45 7 . 55



0.09 0.13 0.18


7.3 7.65

7.9


0.04 0.07


7.9



0.13 0.17 0.21

0.19


7.05 7 . 35

7.5



0.08


7 . 25



0.13


7.8



0.15 0.12


7 . 55 7 . 35



0.1


7.65



Recorded readings by Fuller method were made before sterilization. TABLE V. Titration of Alkaline Media Showing Value of pH Desired axd That Obtained by Adding the Correct Volume of N/l Acid to a

25 cc. Sample of Medium.


No. of

Exp.


Date.


Medium.


Titration by Fuller Scale.


Preliminary Test.


Standard desired.


N/20 acid in cc.


N/l acid

added per 25 cc.


Value of pH obtained.


Remarks.


1


Aug. 18


Plain broth.



8.3


7.9

7.4


0.33 0.49


ii 12 .1 16


7.9

7 . 15


Plotted as ( lurve I. on 1 lhai t II.


2


Aug. 19


Sugar-free broth.



8.3


7.8

7.4

7.::


0.21 0.33

0.44


0.08

0.115

0.15


7.85

7 1 , 7.:!


Plotted a> ( lurve II, oi 11.


3


Aug. 20


Liebig's broth.



7.7


7.2


0.10


0.04


7.2


Plottedas Curve III, Chartll.


4


Aug. 20


Liebig's broth — no peptone.



8.4


7.6 7.3


0.44 0.64 0.82


0.15 1 1 . 20 0.24


7.'.i 7.6 7.3



5


Aug. 21


Ox-heart broth — no peptone.



_


7.1


0.33

0.52


0.12 0.17


7 5 7.1


Plotted as Curve \ . 1 harl [I.


6


Aug. 24


Ox-heart glucose broth.



7.1,


7.1


0.10


0.04


7.1



7


Aug. 26


Liebig's broth.



8.35


7.9


0.21 0.44 0.56


0.08 0.15

ii. 18


7.9 7 . 55

7.2:.



8


Aug. 30


Ox-heart broth plus 10% bile.



8.3


7.9 7.3


0.33

0.56


0.12 0.18


7 . 85



24 [No. 299


The real usefulness of the colorimetric method, however. must be sought in its greater accuracy and in its wide scope of applicability. It will be found of great value in the adjustment of the hydrogen ion concentration of media for organisms

D fJ ^ 4 i o  ; pertr °P hie de la Slande'pituitaire consecutive a la cas • T hi rCh,VeS itali «ines <3e biologie. 1905, XLIII 405

Or M nil e ,K J \ a r d Gr °* Z - S: la> Einfluss der Oration *uf den SschreZn Wlen klin - ^1-schr., 1907. (b)I. Mltteilung:

Snir^^:^^ 1 ' 111111011611 ^ 616 " 8 - ArCh " f ' E ^wic k lung S schr!T9 d o , rs J 277 rnterSUChUngen a " Sk ° PZen - Wien k,i " scMeenTJ*" EinflUSS d6r tanersekretorlschen Anteile der Ge1910 S 459 a dje aUSS6re Erscheinun S de * Menschen


observed by various investigators, this having been possible '"" ' *e comparative ease with which experimental deficiency „l the hypophysis can be produced. It was first pointed out by Crowe, Cnshing and Homans" that there is a definite retarding influence exerted upon the sex glands bv experimental removal of the hypophysis. In an adult do/ two years ot age. a partial though extensive removal of the hypophysis was earned out. The ammal seemed to become sexually impotent and a marked adiposity developed. It was sacrificed 104 days after the operation, and at autopsy there was found to be marked atrophy of the testes, with complete degeneration of spermatogenous cells and an absence of spermatozoa.

In 1912 Aschner" published his results of a thorough and comprehensive study of experimental hypopituitarism, showing that there is in this condition, beyond a question of doubt marked retardation of sexual development. In brief, there is a failure of development of the test,.-: in gross and in its histological structure. Spermatogenesis appears very late and then is only imperfectly developed, or fails to appear at all There is a conspicuous absence of spermatozoa. This retarded development is also observed in the penis, prostate and vas deferens. The sexual activity of such animals is reduced to a minimum. The conditions in the female are exactly analogous. In a series of similar experiments vet unpublished,' I have confirmed these results, although my explanation is not in full accord with Aschner's, who attributes many of his results to operative injury „f the tuber cinereum and its neighborhood during the removal of the gland. It is my opinion that the pituitary body can he removed without injury to these structures and that the failure of sexual development is due primarily to pituitary insufficiency.

Following upon these studies ,,f hypopituitarism, attempts were made to brine- about, in various ways, conditions of pituitary hyper-function, with the idea of reproducing some of the symptoms of acromegaly. In most instances these efforts failed to produce constant and positive results, at leas! in so far as the genital system was concerned. V,,n Cyon studied effect of mechanical and electrical stimulation of the hypoP h y sis > with especial reference to the circulation, bul made no mention of the influence upon the sex glands."

The production of hyperpituitarism l.\ the transplantation of the pituitary body has also pro ed ti bi mm. Qushmg an, I Homans i , rs t to show that i

totally hypophysectomized animals could be by

transplantation of th< ti; physis. I, thi partially hypophysectomized animals the development of the chai cachexia could thus be retarded.

dairmont and E I ried to produce experiim

into

the spleen, but without " Loc. cit., p. 156.

"Aschner, B.: Ueber die Funktlon der Hypophyse \roh f d ges. Physiol., i'.\l.\

13 Cyon, V. v.: Zur Physiologic der Hypophvse. Arch. f. d ges Physiol., 1901, LXXXVII, 565-593.

"Clairmont. R, and Ehrlich, H.: Qeber Transplantation der Hypophyse in die \niz von Versuchstieren. Arch f klin Chir 1909, I. XXXIX, 596.


32 [Xo. 300


Schafer, 15 employing dogs, cats, apes and rats, transplanted the hypophysis snbcortically, and also into the subcutaneous

tissues, muscle, peritoneal cavity and kidneys, without permanent growth and healing of the graft. There was a transient polyuria, but no effect upon growth or metabolism could be demonstrated. From these and many other results the conclusion may be drawn that efforts to produce experimental hyperpituitarism by transplantation of the hypoph; uniformly unsuccessful.

Without entering into a discussion of the physiological properties of pituitary extracts, it may he of service to mention briefly some "f the effects of the administration of pituitary extract, with especial reference to it> effect upon the genitourinary system.

Dale" was the first to describe the direct stimulating action of pituitrin on the uterine musculature. Blair-Bell" in addition described its stimulating action upon the musculature of the bladder.

Frankl-Hochwart and Frohlich " experimented further with hypophysin, a pure extract of the posterior lobe, and confirmed and elaborated the findings of Hale and Blair-Bell. Herzberg " used intramuscular injections of a similar product,

"hypophysin," in cases of pregnancy, with apparently g 1

success in causing mure powerful contractions of the uterus during parturition.

Magnus and Schafer ( 1901 )"" and later Schafer and Herring (1906) showed that extracts of the posterior lobe have the characteristic power of producing kidney dilatation and diuresis, especially when injected intravenously. The galactagogue action of posterior-lobe secretion, as described bj Ott

and Scott" and as further investigated by Mackenzie," I

only be mentioned, a? hearing out the relationship of the pituitary body to milk secretion during and after pregnancy.


15 Schafer, E. A.: Die Funktionen des Gehirnanhanges (Hypophysis cerebri). Berner Universitatschriften, 1911, Theil 3.

18 Dale. H. H. : On some physiological actions of ergot. Jour. Physiol., 1906, XXXIV, 163-206.

The action of extracts of the pituitary body. Bio-chem. Jour., 1909, IV, 427-447.

,; Blair-Bell, W.: The pituitary body and the therapeutic value of the infundibular extract in shock, uterine atony and intestinal paresis. Brit. Med. Jour., 1909, December: also, Liverpool Med.Chir. Jour., 1910, January.

"Frankl-Hochwart, L. v., and Frohlich, A.: Zur Kenntnis der Wirkung des Hypophysins auf das sympathische und autonome Nervensystem. Arch. f. exper. Pathol, u. Pharmakol., 1910, LXIII, 347.

" Herzberg, S. : Klinische Versuche mit den isolierlen wirksamen Substanzen der Hypophyse. Deutsche med. Wchnschr., 1914, XXXIX, 1-207.

"Magnus, R., and Schafer, E. A.: The action of pituitary extracts upon the kidney. Proc. Physiol. Soc, London, 1901, XXVII, 3.

"Ott, I., and Scott, J. C: The action of infundibulin upon the mammary secretion. Proc. Soc. Exper. Biol, and Med., 1911, VIII, 48.

-" Mackenzie, K. : An experimental investigation of the mechanism of milk secretion, with special reference to the action of animal extracts. Quart. Jour. Exper. Physiol., 1911, p. 305.


Borchardt (1908) a was the first to demonstrate that glycosuria could lie produced in rabbits by the injection of pituitary extracts.

.Many studies have been made on the effect of feeding and the injection of pituitary extracts obtained from different divisions of the gland. These studies have been directed chiefly toward the effect upon growth of the organism. The results have been strikingly contradictory. Thus, Crowe, dishing and Etonians " 4 found that repeated subcutaneous injections of sterile extracts or emulsions of the whole gland, or of the posterior lobe alone, given subcutaneously, were apt to lead to emaciation. Caselli noted no effect on growth after longcontinued injections of a whole-gland glycerin extract. Franchini (lfllOr 5 studied the effect of extracts of bovine and equine hypophysis) and particularly of extract of the posterior lobe. His conclusion- are concerned chierly with the influence upon metabolism, no mention being made of the effect upon growth or upon the genital system.

Likewise attempts have been made to simulate conditions of hyperpituitarism by feeding the fresh gland or glandular extract over long periods of time. These experiments are similarly concerned mainly with the question of growth. Caselli " believes that growth is retarded by the feeding of pituitary gland.

Sandri's" experiments in feeding young mice with bovine anterior lobe were quite negative. The feeding of posterior lobe arrested development — an effect attributed to the toxicity of the active principle.

In Schafer's* experiments with the feeding of pituitary substance (anterior lobe) to young rats there seemed to he a definite increase in the growth of those receiving the glandular extract: there was certainly no retardation of growth. More recentlv Aldrich." and similarly Lewis and Miller. 2 ™ have reported negative results after feeding hypophysis to young rats.

Wulzen ( 1914 |" reports retardation in the growth of young fowls by the addition to the diet of fresh, unmodified anterior lobe of the ox pituitary.


= Borchardt, L.: Die Hypophysenglykosurie und ihre Beziehung zum Diabetes bei der Akromegalie. Ztschr. f. klin. Med., 1908, LXVI, 332-348.

Lor. , it., p. 127. ,

"Franchini, I.: Die Funktion der Hypophyse und die Wirkungen der Injection ihres Extraktes bei Thieren. Berl. klin. Wchnschr., 1910.

M Caselli, A.: Revista sperimentale di freniatria. Reggio-Emilia, 1900, XXVI, 176, 486.

21 Sandri, O. : Archives italiennes de biologie, 1909, LI, 337.

28 Schafer, E. A.: The functions of the pituitary body. Proc. Roy. Soc, 1909, LXXXI, 453.

29 Aldrich, T. B.: On feeding white rats the posterior and the anterior parts of the pituitary gland. Amer. Jour. Physiol., 1912, XXXI, No. 2, 94.

" Lewis, D. D., and Miller, J. L.: The relation of the hypophysis to growth, and the effects of feeding anterior and posterior lobe. Arch. Int. Med., 1913, XII, 137-144. =" Wulzen, Rosaline: The anterior lobe of the pituitary body in its relation to the early growth period of birds. Amer. Jour. Physiol., 1914, XXXIV, 127-139.


l-'i beb \i;v. 1916.]


Behrenroth is the only author who makes special mention of an accompanying effect upon another of the ductless glands, produced by either the feeding or by the injection of pituitary extracts. His is the only work, furthermore, which deals with the effect of pituitary extract upon the genital system. 31 He carried out the hypodermic administration of pituitary extract mainly for the purpose of observing its action upon the kidney. blood-pressure and metabolism. In giving the results of his investigations on the blood-pressure changes produ pituitrin, he makes a brief statement in regard to the genital development of rats which had received hypodermicallj doses of pituitrin." He does not state the time during which the injections were continued, nor the derivation of the pituitrin, though it may he assumed that the extract was probably of the infundibular portion of the gland. If the injections were frequently repeated, a state of cachexia was produced, followed usually by the death of the animal. If they were given at intervals so chosen that no general disturbance- were produced, the animals were usually stronger and more active than the controls of equal age. An increased growth of the skeleton was not obtained, but there was found to be a premature and extensive development of the sexual apparatus, particularly of the testes, and the animals proved to be sexually overactive. At autopsy the teste- in the gross were large and hyperaemic, while microscopically they showed simply an early extensive spermatogenesis. No changes were observed in the other organs.

He observed no effect upon grown rats following administration of pituitary extract either in large doses or in often repeated small doses. In a litter of young dogs a premature sexual ripening was not obtained. Behrenroth is at a loss to explain the variability in these results. A possible explanation may be a difference in the activity of the extracts, or a failure in some cases to administer the correct amount necessary to produce a stimulating effect. Only slight changes were observed in the female animals. His series is a small one. the microscopical report is very limited, and in the original work no drawings or diagrams are given. We shall have occasion to return to these results.

From this brief review of the literature it can readily that both experimentally ami clinically there is a direct interrelationship between disturbances in the genito-urinary sphere and affections of the pituitary body. The normal hypophysis Beems without doubt to exert a stimulating influence on the development and activity of the genital organs, h activity of the gland is followed by premature development and overactivity of the genital organs: its deficient fu results in genital underdevelopment and the non-appearance ™ Bex characteristics. Previous suggestions on the p other investigators, and almost certainly our own n ate that it is the anterior lobe of the hyp, erts this specific influence upon the sex glands.

"Behrenroth, Erich: Ueber die Einwirkung des Hirnanhangsextraktes auf den Blutdruk des Menschen nebst Bemerkungen uber einige Injektionsversuehe am wachsenden Tier. Deutsch. Arch. f. Klin. Med., CXIII, 393-395.


The idea is an old one that a deficiency in the secretion of any one of the ductless glands can in large measure I come by administration of the extract of the gland in question. The administration of glandular extract by mouth, hypodermically. intravenoush and intraperitoneally, has been carried out both clinically and experimentally, and undoubtedly in many instances much benefit is obtained; for example, in experimental hypopituitarism in the dog. prolongation of life and a more nearly normal development have followi administration of pituitary extract, and similarly in i conditions beneficial results have been obtained. Empirical feeding and other forms of glandular administration have also been practised in condition- of thyroid and ovarian deficiency, but with result- uever quite under the control of the observer and not capable of close analysis and test. Thus, so far as 1 am aware, no histological evidence has ever been given of any effect upon either of these glands or upon any other of the ductless glands, produced by administration of gland extracts, and consequently we have only subjective symptom- and more or less indefinite and uncertain objective signs and manifestations to indicate the result of our therapy. Reference should be made here to the splendid work of (uidernatsch r,! and to the very definite re-ults he has obtained by feeding thyroid and thymus extract to young tadpoles. In his experiments thyroid extract had the effect of producing very early and rapid development of the young tadpole into a miniature frog, whereas thymus extract had no such stimulating action upon differentiation, hut on the contrary produced overgrowth of the young tadpole into a giant tadpole. No reference imade to the effect upon the individual ductless glands.

This research is based on the conception that if hypopituitarism results in retardation or cessation of body am] reproductive development, then one may expect increased growth and increased rapidity of sexual development from the administration of pituitary extract. Interest was aroused in the possibility of producing over-development and activity in the sex glands by the feeding of pituitary extract during the course of some experimental work done in the Ilunterian Laboratory six years ago. Preliminary studies were carried out on the effect of anterior-lobe feeding upon growth and development. Two young female dogs ,,f the same litter were taken: to one of these, dried extract of anterior lobe was in daily doses of 0.5 gm. The second female was used as a control. At the end of about . months of this feeding the animals were sacrificed, and in the routine examimr the ductless glands it was found that the ovary of the animal receiving the anterior lobe extra I corpora

lutea and corpora albicanl ia, ; .' hi reas in i animal

tin' ovary contained simply the unripe Graafian follicles not yet mature enough fo occurrence of ovulation. Here

was a hint which -;*<- encouragement for more thorough of tin- subject, which was begun threi


32 Gudernatsch, J. F. : I. Feeding experiments on tadpoles. Arch. f. Entwcklngsmechn. d. Organ., 1912, XXXV. 457. II A further contribution to the knowledge of organs with internal secretion. Am. Jour. Anat., 1914, XV, 431.




U [No. 300


ago. li i- the purpose of this.reporl to give the results of pituitary Eeeding in young rats, with especial n the early ient and the histological changes pro*

in the sex apparatus and to its influence on breeding

parturition. In this report the facts in regard to tl (feel

upon growth will be considered only in a general way.

Methods or Study. Young rats were used in these experiments, in the firs! place, because they are hardy animals and their active sexual life and development, as well as their breeding habits, can he readily observed oven under the somewhat abnormal environments of laboratory experimentation: and. in the second place, because it was thus possible to obtain young animals of pure breed and known pedigree and to avoid in this way < the possibility of variations in body growth as well as in genital development in different members of the same litter — a possibility which might arise in case the animals were of mixed parentage. In our experiments the members of the different litters when weaned varied in weight, size and general appearances only to a negligible degree, the variation in weight in many instances being merely a fraction id' a gram. Where there was an appreciable difference, the odds were usually taken by the experimenter in choosing the animals to be fed and those to be used as controls. The animals were used as soon as weaned, their ages at the tune varying between d I weeks." They were placed in wire cages, of double size for pairs, with an abundant supply of fresh water. The food consisted of cracked grain (com. barley and seed) and white bread soaked in rich milk, given in definite amounts daily to each rat. The amount id' grain was so calculated that there was always some remaining m the cage on the day alter feeding. At the beginning of the experiments only cracked grain was given, hut as it was apparent that the animals were not developing or increasing in weight satisfactorily, the bread-and-milk diet was added, with a consequi m rapid growth. Dried powdered extract of bovine anterior and posterior lobe, separately and in combination, was used. In

each experiment controls were taken from the sa litter and

were kept under precisely similar conditions without glandular administration or with control-feeding of ovarian or corpus luteum extract." At first 0.1 gm. and later .05 gm. of the powdered extract (anterior, posterior and combined lobes) was given daily in a pill of bread and milk. The extract was given in pill form in order to insure each animal's receivii a the quota desired. Thus when two animals occupied the same cage the experimenter could be sure that each received I amount. The animals ate the pills greedily, and thus no difficulty was experienced in administering the extract. In


It is a pleasure to express here my gratitude to Dr. W. E. Castle of the Bussey Institution, Harvard University, Boston, tor his kindness in furnishing the experimental animals used in this work and for his helpful suggestions in regard to their care and feeding. 4 I wish to express here my appreciation of the kindness of Mr. Charles M. Bell, of the Armour Laboratories in Chicago, in furnishing the pituitary extract used in these experiments.


several instances ovarian or corpus luteum extract in equal amounts was given to the control animal, to offset the effect. if any. of the feeding of the pituitary extract itself. However, as the material is fed in such small amounts this objection is practically negligible.

At the beginning of the experiment, for a period of about 12 days. 0.1 gm. of the extract was given. Tinder this dosage, however, the animals did not gain satisfactorily in weight; there was loss of appetite and a tendency to diarrhoea, due undoubtedly to overdosage, and consequently the amount was decreased to .05 gm.. or half the original close. The feeding was continued over different lengths of time, varying from 12 days to 6 or 8 months. During this period frequent observations were made on the growth and weight of the animals and upon the development of the genitals ami nipples. At the end of the experiments the ductless glands were preserved in fixatives and embedded in paraftine. Sections were cut. 5p in thickness, stained usually in hematoxylin and eosin. and compared. The technical procedure was kept absolutely the same for the fed animals and the controls. Some of tin i arlier experiments were interrupted because of a peculiar snuffles and bronchopneumonia which developed among the rat-, causing their almost immediate death. In no case was an animal which had shown any previous signs of decline or disease included in the final results. In a few instances pairs of rats of the same litter were selected, one pair being fed anteriorlobe extract, the other being used as a control: observations were then made on breeding, time of parturition and the size and weight of the litters. In these few cases interesting comparisons can he made on the effects of feeding anterior- and posterior-lobe extracts. In other words the conditions of experimentation were made as nearly as possible the same for all the animals under observation. 3

Experimental Iiesclts. In reporting the experimental findings it i^thougbt besl b give a condensed account of each protocol in tabular form instead of the complete protocol of cadi case. Many id' the findings, especiallj those relative to weight and growth and to tin histological changes in the ductless glands other than the sex glands will he reserved for a later report. First, it may be of interest to record sonic of the more acute experiments — those intended to show the effect of whole-gland feeding (anterior and posterior lobes, including the intermediary portion) over a brief period of time. For this purpose the record of twd female rats of Litter IV will be given.

The Effect of Feeding Pituitary Extract (Whole Gland) Over a Brief Period to a Young Female Rat. Litter IV.— Litter of black rats, 3 males and 2 females. Born Feb. 10, 1913; weaned at the age of 4 weeks. Glandular feeding (whole gland, consisting of equal parts by weight of the dried powdered extract of the anterior and posterior lobes) begun to


35 In so far as I am aware, these are the first observations to be made on histological changes produced in any of the ductless glands by the oral administration of pituitary extract.


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.


PLATE VII.



Fig. 1.— Female I (pituitary fed)



-££&&*>


Fig. 2. — Female II (control), x 26.

and'fne^eSinnin^nff, 11 * ^ ° De PlaDe th< l 0Vary ' the fimbriated end of the tube ," u e ne s inning of the uterine cornu ot two voung rats 2V- mn« oirt r.r th* same litter, to the first of which (Fig. 1. Female I pituftary ext?ac™°whole rtLd f «as given over a period of 42 days, from the time when the animal wa 4 daV s old the second, the control (Fig. 2, Female II), received no gUnduTar feeding Both animals were sacrificed when they were 72 days, or 2% mo old rnnnrp

Z ff ', the P TT Ce , 0t C ° rp0ra 1Utea <a «>• the s"»"it, "of 'unripe follicles («./.), the marked endometrial hyperplasia in the uterine cornu (« the

proliferation of the fimbriated end of the tube (/. e .), and "the increased 'vase,

ioincies (H, /.) , the absence of corpora lutea, the smaller degree of hnnchin^ of the fimbriated end of the tube (/. and the simple thin mucous membranf

^m^meTriur 111 '"'- 1 " • =P"mordial follicle. BV^SSESSZ


February, 1916.]


Female I, March 12, when the animal was 30 days old. Female II used as control. At first 0.1 gm. was given daily; but as this dose was found to be too large (the animal failed to gain in weight, and there was loss of appetite and a tendency to diarrhcea), after 10 days it was reduced to .05 gm., and this amount was given for the following 32 days, the feeding thus lasting altogether for 42 days. At the beginning of the experiment, Female I weighed 27.6 gms., 3.4 gms. more than the control. At the end of the observation the weight of Female I was 93.5 gms., as compared with 81.9 gms., the weight of the control — a rather remarkable gain in so short a time. Both animals were autopsied on April 22 at the age of 72 days, or 2% months. Besides the definite gain in weight, the nipples were larger and more conspicuous in Female I, the animal receiving the whole-gland feeding (c/. protocol).


TABLE I.


CONDENSED PROTOCOL. LITTER IV.


Date.


Female I Whole-gland feeding for 42 ilays.


Mar. 11. Weight, U7.0 gms.

Mar. 18. Weight! 31.2 gms.

Mar. 31. Pectoral nipples fairly large.

Mar. 31. Weight, 60 3 gms.


Female II. Control. Xo gland administrate


Weight, 2 1 _ Weight, 25.8 gms. Nipples fairly prominent. Weight, 50.0 gms.


Apr. 13


Weight, 77.0 gms. W.-ight, 72.2 gms.

Large, conspicuous nipples. Ani- Nipples small. Hair fairly thick.

mal large, active, inclined to

be vicious.


I utopsy. Weight. 93.5 gms. Generally larger animal a- compared with control.

Uterus and cornua definitely

larger than in control : both of the latter thicker and have an cedematous swollen appearance as compared with control, slightly smaller than in Female II. Two or three yellowish granules seen — probably corpora lutea.


I II to/ls II

Weight, 81.9 gms.

Fur smoother and more delicate than that of Female I i fed animal >.

i arnaa and <y\ nries definitely smaller than in Female I. Ovaries contain two or three small, yellowish grannies resembling in appearance those in ovaries of Female I. and in addition several glistening bodies, possibly Graafian follicles.


acerning the other ductless gland


By comparison of the condensed tabulated protocol of the fed animal with that of the control, the following points become apparent. The animal fed with pituitary whole-gland extract (Female I) developed more rapidly than the control,

'ii by the final weight. The nipples were no1 larger than those of the control, and the hair possibly coarser. Furthermore, at autopsy the body of the uterus, the cornua and ovaries were found to be definitely larger and more vascular and cedematous than those of the control, and the ovaries of the fed animal contained what appeared ii and on examination proved to be. corpora lutea. win conspicuously absent in the ovaries of the control animal.

Microscopic— Both ovaries, the cornua and the body of the uterus in each case were fixed in Carnoy's solutii were made at different levels in the cornua. Comparis these sections from corresponding levels showed the same differences between Female I and Female II as those illustrated m Fi gs . 3 anf i 4 _ Serial seetiong

at short intervals through the entire ovaries in order t nm>mo- possible Graafian follicles or corpora lutea at d j?™ 8, F " r purposes of comparison the ovary was that a section through its center included the fimbria trenuty, the tube and the beginning of the cornu | 1 and 2).


A »f the low-power drawings of the ov:

I (whole-g Female II (co ows the following

at the early age of 2f month- £ the pituitary-fed

animals (Fig. 1 | -bows the presence of corpora lutea which are conspicuously absent in the ovary of Female II. In fact, in the latter we find numerous primordial follicles (p. f.) and a number of young unripe Graafian follicles (u. /.). There are very few primordial follicles in the ovary of Female I (Fig. 1, p. f. ) ; it shows increased vascularity in the medulla and hilus; the fimbriated end (Fig. 1. f. e.) of the tub more extensively divided; the folds of mucous membrane are very mu.h higher, and with the high power magnification one sees that the lining columnar cells are considerably taller and more uniformly ciliated. Furthermore, the uterine cornu (m. c), the end of which is represented in Figs. 1 and 2, shows a marked hypertrophy and hyperplasia of the mucous membrane lining (endometrium, end.) and an increased thicl of the muscular coats (myometrium, my.), together with an increased vascularity, the latter being particularly noticeable in the high-power study. All these findings are characteristic of the sexually mature female genital system.

Figs. 3 and 4 illustrate the difference between the uterine cornu of the pituitary-fed animal. Female I. ami that of the control, Female II. These sections were taken from the midpoints of the cornua, but similar differences were observed at other corresponding points. In Fig. 3, as compared with Fig. 4. the striking differences are: The marked hypertrophy and hyperplasia of the mucous membrane (endometrium, end.), with the formation of uterine glands ( u. g.) — a condition resembling the change occurring in pregnancy; the increased thickness of the muscle coats (myometrium, my. I : and the increased vascularity. (Note the simple structure of the uterine cornua in the control animal, i

A comparison of Figs. 5 and 6 shows these differences to an even greater extent. The sections, here taken at the junction points of the uterine cornua, indicate that an even more marl. us taken place in the body of the uterus of the

pituitary-fed animal than is represented in the cornua (Fig. 3). The lining cells of the uterine mucosa are taller and richer in protoplasm, and are supplied more uniformly with cilia, in the fed animal than in the control.

In view of the marked changes produced by the feed pituitarj extract to the young female rat. we are warranted in saying that the extract caused early and ovulation,

marked growth and indications of activity on the part of the fimbriated end of the tube, and a marked hypertrophy and hyperplasia of the uterine mucosa. Tie were en tirely absent in the' control animal. When we consider that they appeared at the early age of ij months, whereas normally they should occur between the ages of 3 and 1 months — and even then less extensively — we have undoubted proof of the extremely selective and aim action of pituitary

nital system.


36 [Xo. 300


On the Comparative Effects of the Feeding of Pituitary

Whole-Gland, Posterior-Lobe, and Ovarian (Corpus

Ltjtetjm) Extract. Comparison of Conditions in a

rol Receiving No Glandular Extract.

Four male rats from Litter II were used in this experiment.

In the litter, born February ti. 1913, there were 5 young.

3 pairs and one single male. The animals were of the same

breed, narrow selection series, and of the tame variety of gray

rai (Mus Norvegicus). The young rats were weaned on

March 5. when 27 days, practically 4 weeks, old. and were

TABLE II —CONDENSED TABULATED PROTOCOLS OF MALES OF LITTER II, TO SHOW THE COMPARATIVE EFFECTS OF

FEEDING PITUITARY WHOLE-GLAND AND POSTERIOR-LOBE, AND OVARIAN EXTRACTS.

FEEDING BEGUN WHEN ANIMALS WERE FOUR WEEKS OLD.


until April 12, when the animal was sacrificed. The feeding was continued altogether for 36 days. Age at autopsy, 65 days.

A final comparison of the four male rats unfortunately cannot lie made, as the period of feeding and the ages of the animals at autopsy were not the same in each case. However, comparative observations were constantly made at different periods during the feeding and are- of considerable interest. They are summarized in the following protocols:

Male, Pair I (whole-gland feeding). — The testes remain descended at an earlier period than in the control (male, Pair III, ef. March 12). The weight of the right testis at autopsy, at the


Male. Fair 1. Whole-gland feeding, 16 days.

Age at autopsy. 44 days


Male, Pair II. Ovarian feeding. ".4 days autopsy. 65 days


Mar. Mar.


Weight, 30.4 gms


tes descended. prominent.


tal


External genii Testes descended, of good size: can be readily slipped back into abdomen.


Has lost some weight, due to too Testes at times in "Women; can

large a dose of extract. In good readily be expressed downwards, condition. Good coat of fur of delicate texture. Found dead in cage this a. m. No Large testes and scrotum. Animal apparent cause. Seemed well on looks vigorous previous dav. Possibly too large slight en


.4 ii topsy.

Congestion of lungs.

Testes quite large, on gross examination, for rat of this age.

Weight of right testis. 0.260 gm.

Nothing of special note revealed by autopsy on gross examination.


Apr. 6.


Apr. 12.


Male, Pair III. Control. Age at autopsy. 59 days.


Single Male.

Posterior-loU' tending. 36 days.

Age at autopsy. 65 days.


Weight. 29.4 gms


Weight. 30.5 gms. s on all Testes descended


Testes descend when rat

fours. When rat is picked up. at all times, testes enter abdomen. i penis i ef fa


Remain outside External genitalia size.

generous size.


Testes not descended at all times. Testes and scrotum large by coinNot a vigorous animal. parison with control male. Slight enteritis.


Testes not as large as in single male Rat large and vigorous. Testes and (posterior-lobe feeding), nor quite scrotum large and of greater size so large as in ovarian-fed animal. than those of control. A fairly No tremor of limbs. marked tremor of legs and body.

Weight •")4.3 gms. Weight, 81.2 gms.

Pound dead in cage this a. ni. Ex- Testes slightly larger than in

ternally nothing unusual. Scro- ovarian-fed animal i male. Pair

turn arid penis small. II ).

Weight of right testis, epididymis

and vas. 0.260 gm. Weight of left testis, epididymis and as, 0.270 gm.


Weight. 89.7 gms.

Well grown, fat. lively and in good condition.

Sacrificed. Weight of right testis. epididymis and vas. 0.870 gm.

Weight of left testis with epididymis. 0.860 gm.

Weight of both seminal vesicles, 0.340 gm. Seminal vesicles large and Tortuous.

Testes slightly larger and harder

Ilian those" Of posterior b.be-fed

male. Fur heavier and slightly

coarser.


Weight, 83.7 gms.

In very good condition ; well grown. not especially adipose.

. /. Weight of right testis, epididymis and vas. 0.740 gm.

Weight of left testis, epididymis and \as. (1.730 gm.

St minal vesicles. 0.330 gm.

Testes smaller on palpation and inspection than in ovarian-fed rat i male. Pair III.


separated into three pairs and one single male, each pair and the single male being placed in different rages.

Male, Pair I. received whole gland extract (anterior and posterior lobes, 0.05 gm. of each) for 16 days, from March 6 to .March 22. The feeding was continued altogether for 16 days. Age at autopsy, 44 days

Hale. Pair II. received 0.1 gm. ovarian extract (corpus luteum, Parke, Davis & Co.) for 14 days, beginning March 9; then 0.05 gm. daily for the following 29 days, until April 12. The feeding was continued altogether for 43 days. Age at autopsy, 65 days.

.1/ a iY, Puii III. used as a control. Died suddenly April 6. Age at autopsy, 59 days.

Single male received 0.1 gm. posterior-lobe extract for 15 days, beginning March 7; then 0.05 gm. for the following 21 days, or


age of 44 days, is the same as the weight of the right testis of the control animal (0.260 gm.) at the age of 59 days. One tenth of a gram daily, both of whole-gland and of posterior-lobe extract, proved to be too large a dosage <c/. March 22).

Male. Pair II (ovarian feeding l. —There is no difference in the period of permanent descent of the testes as compared with that in the control animal i </. March 12). There is a tendency toward the deposition of fat and a marked increase in weight— as shown at autopsy, an increase of 6 gms. over the animal fed with posteriorlobe extract (c/. April 12). The fur of the animal fed with ovarian extract is heavier and slightly coarser than that of the animal fed with posterior lobe (ef. April 12). The testes are slightly heavier (0.1 gm), but this may be due rather to an mhibitive effect of the posterior-lobe extract than to a stimulating effect of the ovarian extract (c/. April 12).


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.


PLATE VIII.



-Female I (pituitary fed). X 31.


Female II (control). X 31.


Figs 3 and 4 represent transverse sections through the middle of the right uterine cornua of the same young rats whose ovaries are represented in Figs. 1 and 2.

Fig. 3. Section from the uterine cornu of the female to which pituitary extract (whole gland) was given over a period of 42 davs from the time when the animal was 30 days old '

no F gfand e^act POnding SeCU ° n fr ° m U,e C ° ntro1 femaIe who received Note in the endometrium [end.) the marked hypertrophy and

SSSSM tte Uterine mUC ° Sa WUh aCUve g,and formation,,. ," suggesting the pregnancy reaction, the very cellular character of

%££&"££? mCreaS6d thiCkneSS ° f the —mature of Z



Fig. 6.— Female II (control


). X 32.


, fTif ; ♦ represent transverse sections through the junction points

ot the uterine cornua (cervix uteri) of the same rats, whose ovaries and cornua are represented in Figs. 1, 2, 3 and 4.

Fig. 5. Section from the cervix of the uterus of Female I, to which pituitary extract (whole gland) was given over a period of 42 davs from the time the animal was 30 days old.

Fig. 6. Section taken from the control animal at a point corresponding to that represented in Fig. 5.

The histological differences in Figs. 5 and 6, are similar to hut even more marked, than those represented in Figs. 4 and 5.





Fig. 5.— Female I (pituitary fed). X 32.


February, 1916.] 37


Male, Pair III (control animal without glandular administration) The tendency for the testes to return to the abdomen persisted longest in this animal (cf. March 22). On gross palpation they are smaller than the testes of any of the other animals (cf. March 22). The weight of the right testis of the control is the same as that of the animal fed with whole-gland extract, though the former animal was two weeks older than the latter.

Single Male (posterior-lobe feeding).— The testes permanently descended at an earlier period than those of the control (cf. March 18). On palpation "they were larger. At autopsy the animal weighed less than the ovarian-fed animal (cf. April 12), and the weight of the testes was also less.

Briefly summarized, the mam differences that may be observed from the protocols are as follows :

Posterior-lobe feeding, as compared with the feeding of ovarian extract, does not produce a stimulating effect on the growth of the body or testes. Whole-gland feeding increases the growth of the testes as compared with those of a control animal. Ovarian extract has a tendency to cause the deposi


Comparison of Animals Receiving Whole-Gland Feeding

and Ovarian Feeding with a Control Receiving

No Glandular Extract.

Three female rats from Litter II, the mates of the three paired males of the preceding table, were used for this experiment. Two of the animals died suddenly of snuffles; the third was sacrificed. They were of the same age at the time of autopsy, which was carried out immediately. The two animals dying of snuffles had been in good condition up to within a day or two of death. The third animal was entirely well.

Female. Pair I. received 0.1 gm. pituitary whole-gland extract (anterior and posterior lobe in equal parts) for 16 days, then 0.05 gm. for the following 8 days. Total period of feeding, 24 days. Age at autopsy, 53 days.

Female. Pair II. received 0.1 gm. of ovarian (corpus luteum) extract for 13 days, then 0.05 gm. for the following 10 days. Total period of feeding, 23 days. Age at autopsy, 53 days.

Female. Pair III, used as control, with no glandular administration. Age at autopsy, 53 days.


TABLE II CONTINUED.— A COMPARISON OP THE HISTOLOGICAL APPEARANCE OP THE TESTES OP POUR MALE RATS OF LITTER II, THREE OF WHICH RECEIVED RESPECTIVELY WHOLE-GLAND, OVARIAN AND POSTERIORLOBE FEEDING, THE FOURTH BEING USED AS A CONTROL.


Male of Pair I.

Whole gland feeding. 16 day:

Age at autopsy. 44 days.


Testis: So spermatozoa present. Karyokinesis quite active, but only in its early stages. Development has reached the stage of the spermatocytes of the first order, spermatids present. Majority of the tubules lined with 2 or 3 rows of cells, in places with 4 rows.


Interstitial cells few.


Male of Pair II. Ovarian feeding. 34 days Age at autopsy. 65 days.


Male of Pair III. Control. Age at autopsy, of! days.


Testis: Spermatozoa present in fairly Testis: A T o spermatozoa present. Karyo


good numbers, though not as numerous as one would expect from the degree and extent of karyokinesis present. The majority ' of the tubules are at the spermatid stage and contain a great amount of secretion.


kinesis quite well advanced, but only to the spermatocyte stage and hardly as far as in the case of the male ol Pair I (whole-gland feeding), al though the latter is 15 days younger Tubules contain a small amount ol secretion.


Interstitial cells fairly numerous and interstitial cells few. No speciallj present in larger numbers than in noticeable difference from male of testis of the male of Pair I. Pair I.

Epididymis lined with a lower type of Epididymis not examined.

columnar cells, not so regularly!

ciliated. Lumina of the tubules

somewhat wider and containing some

few spermatozoa and here and there,

a few free cells. A good deal of vacuolation in the

tubular cells and between them, possibly due to the disappearance of fat

or lipoidal substance.


Single Male. Posterior-lobe feeding. 36 dn Age at autopsy. 65 days.


Testis: Spermatozoa just beginning to become conspicuous in certain of the tubules. These latter are mostly in the spermatid stage at least. Karyokinesis quite active, though possibly somewhat less far advanced than in the male of Pair II (ovarian feeding). The cells are more protoplasmic.

Interstitial cells fairly abundant and large. Connective tissue fairly perceptible.

Epididymis: Cells stain well, have abundant protoplasm, of medium height, ciliated. Some secretion and a few free cells in lumina. No spermatozoa seen. Very little, secretion in the tubules.


tion of fat and a coarser growth of hair. The histological appearance of the testes of these four rats, illustrating the effect of different gland feeding, is indicated in the accompanying table.

From this table, as far as comparison can be made, after allowing for the differences in the ages of the animals, the following facts may be deduced. The feeding of whole gland to the male of Pair I caused an appearance of development of the testes as far advanced as in the control animal, although the latter was 15 days older. No especial effect upon the interstitial cells was noted.

There was little difference in the effect of ovarian and posterior-lobe feeding on the male of Pair II and the single male respectively. Neither extract seemed definitely to stimulate testicular development, but on the contrary appeared to retard it. This effect was possibly more definite in the ovarian-fed animal. Not only over the whole body, but also in the testis of the ovarian-fed animal there was a tendency toward the deposition of fat.


From a consideration of Table III it will be seen that whereas, at the beginning of the experiment, the rat which received whole-gland feeding was the lightest in weight, at the end, after 34 days of feeding, it weighed more than either of the others. Next in weight at the end of the experiment was the ovarian-fed animal. There is an indication here of the stimulating influence on growth of whole-gland extract. There is also seen to be a tendency toward the production of slight diarrhoea, muscular tremors, nervous manifestations and weakness of the hind legs by the feeding of too large a dose of the whole-gland extract; and it was for this reason that the dose of pituitary extract was decreased, as in other experiments to be reported later. None of these symptoms, except tremor, were apparent in the ovarian-fed animal, and they were not observed in the control.

The effect of glandular feeding was apparent even in the nipples. Tli' ost conspicuous in the rat receiving

whole-gland extract, and were very small and inconspicuous in the control. This increase in development of the nipples is a


[No. 300


m _ CONDENSED TABULATED PROTOCOLS OF THE THREE FEMALES OF LITTER II, FED ON (1) WHOLE-GLAND AND (2) OVARIAN EXTRACT, AS COMPARED WITH ONE ANOTHER AND WITH (3) A CONTROL WITHOUT ANY GLANDULAR ADMINISTRATION.


Mar. 5.


\V. i-hr. 2S.2 gms.


Mar 12.


Externa] genitalia


Mar. 23.


In good condition vigori us animal tinguishflble.


Mar. 30.


Died suddenly. \


Female. I'air I. Whole-gland feeding 24 da Age at autopsj . .">_' 'in


nail and white


Slight diarrho-a. Not a fairly easily dis


Very remarkable fine tremor practically till the muscles. Heart-beat strung, respirations and pulse rapid. Weak ness of hind legs. Weight. 57.5 gms.

Autopsy.

Immediate autopsy.

urtni.s fairly large, with apparently a definite mass of Graafian Collides, translucent in appearance.

Ovaries, tubes and uterus preserved in Carnoy s solution.

No enteritis present.


Female, Pair II. Ovarian feeding, 23 days. Age at autopsy, 53 days.


Weight, 28.7 No difference i


Female, Tair III. Control.

No glandular administration.

Age at autopsy. 53 days.


appearance of external genitalia.


Weight. 56


ti gms.


Nipples ii-i


readily visible, and slightly smaller


than in


the female of Pair I. Tremor in


feet and


Huly also well marked.


Found dead in cage this a. m. Appeared to be will mi previous day. No external features of special note.

Ovaries, tubes "iitl uterus preserved. Nothing striking on gross examination. Graafian follicles less conspicuous than in the female of Pair I. Ovary and uterus of fair size ; larger than in control and possibly slightlylarger than in animal fed with whole gland.


Weight, 30.1 gms.

No difference in external genitalia.

Nipples just visible. No diarrhoea. Smaller than either the female of Tail- I or the female of Pair II.

Weight. 54.2 gms.

Nipples fairly easily seen. Absolutely no tremor apparent or felt in muscles of body generally.


Killed by mate.

Ovaries, tubes and eornua of uterus noticeably smaller than in the females of Pairs I and II.


rather remarkable effect of pituitary feeding over so short a period.

Examination of the ovaries, tubes and uteri in the gross showed that they were farther developed in Females I and II, the animals fed with glandular extract, as evidenced by the definite mass of Graafian follicles in the ovaries and by the larger size of the uteri of these two animals. There is no doubt that here both whole-gland and ovarian feeding had a stimulating effect upon ovarian and uterine development. The ovarian extract was equally as stimulating in this respect as the wholegland extract — a fact due in all likelihood to the small amount of anterior lobe contained in the dosage of whole gland that was administered, for it would seem that it is the anterior lobe which is responsible for the stimulating action. The posteriorlobe element seems without doubt to have rather an inhibitive action in this regard. Further evidence in support of this \ ifw will be given later.

We come now to a comparison of the histological findings in the ovaries, tubes and uteri of the three female rats (c/. Table IV).

By comparing the histological appearance of the ovary and tube in each animal, as given in the above table, it is apparent that tlie whole-gland extract and the ovarian extract have exerted a stimulating effecl upon the development of these organs. In evidence of this we find a strikingly greater number of well-developed Graafian follicles and a small number of primordial follicles in the ease of the animals fed with wholegland and witli ovarian extract, as compared with the control. 'l'le -mall number of primordial follicles present in the Eormi i would indicate that a great many have undergone development and are approaching maturity, whereas in the control most of them are still dormant. Corresponding to the greater o

pment, as indicated by the developing follicles, there is an accompanying moderate increase in the amount of interstitial tissue. The reaction is not confined to the ovary, for in


TABLE IV.— HISTOLOGICAL COMPARISON.


Female, Tair I.

Whole-gland feeding. 24

days. Age at autopsy.

52 days.


Ovaries: Fairly large, and in each a definite mass of Graafian follicles seen in gross : translucent in appearance. Microscopic examination shows a moderate number of developing follicles and a few unripe primordial follicles. Xo corpora lutea.

Interstitial tissue fairlv rich.


irnbriated ends of tubes lined with compact, tall, ciliated columnar cells.


Female. Pair II. Ovarian feeding. days. Age at topsy, 53 days.


varies: A large number of well-developed Graafian follicles, a considerable number beginning to develop, and a few primordial

follicles.


Interstitial tis


Imbriw of tubes lined with tall, folded columnar epithelium, which is fairly uniformly ciliated.


Female. Pair 111. Control. Xo glandular administration. Age at autopsy, 53 days.


Ovaries>: A modi-rate number of Graafian follicles not far developed. A large number of primordial follicles with no sign of development in marked contrast with Female I ( wholegland feeding! and Female II (ovarian feeding!.

Interstitial tissut less in amount than in ovary of Female I and ovarv of Female II.

Fimbria- lined with cells not especially large or active in appearance, in contrast with conditions in the two other animals. Considerable folding of mucous membrane : cells mostly ciliated.


the case of the two animals that received glandular extract there is a greater branching of the fimbriated ends of the tubes, a taller epithelial lining and a more complete ciliated lining of the cells. These are evidences of activity on the part of the tubes. In this respect ovarian extract seems to be equally as stimulating as whole-eland extract.

The Effect of Axtekiok-Lobe Feeding on the Young Male Eat. Two male rats of Litter III, of pure breed, were taken for this comparison, one being fed anterior-lobe extract and the other being used as a control without glandular administration. In this litter there were five young, two pairs and one single male. Fair 1 were given posterior-lobe extract. Pair 11 were used as controls, and the single male received anterior-lobe extract.


February, 1916.] 39


The protocol of the animal fed with posterior lobe will not be led here, and for purposes of comparison we shall give briefly the protocols of only two of the animal- ns< d in this experiment, to show the stimulating effect of anterior-lobe feeding upon testicular development, when these animals are compared with a control without glandular administration.

Male, Pair II. used as a control without glandular administration. Died, April 24. Age at autopsy, 71 days.

Single Male I, received daily 0.1 gm. of anterior-lobe extract (Armour & Co.), beginning March 9, at the age of 25 days, and continued for 14 days. Fearing that the dose of glandular extract was too large, 0.05 gm. of the extract was given for the following 71 days. The animal was sacrificed June 15. Total period of feeding, 85 days. Age at autopsy, 123 days.

During the course of the experiment the right testis was removed Burgically from each animal. This was done on April IS. when the animals were 65 days old. The purpose of the procedure was to obtain a comparative observation on the testes of the two animals at a definite time during the course of the experiment, and by preserving the animals' lives to make another observation on the remaining testes after a considerably longer period of feeding had elapsed. The testes thus removed were weighed and examined with results to be given.

TABLE V.— CONDENSED TABULATED PROTOCOLS OF ANIMALS AFTER ANTERIOR-LOBE FEEDING OF SINGLE MALE I, AS COMPARED WITH THE CONTROL MALE OF PAIR II.

(Protocols given up to the time of removal of the right testis in each animal, at the age of 65 days.)


Date Single Male I. Male of rair II fontrni

atC - Anterior-lobe feeding for 40 days. No glandular administration.


Mar. 8. Weight, 23.6 gms.


Weight, 23.4 gms.


Mar. 12. Weight, 25.9 gms. Weight, 22 3 gms

Testes not descended. Animal Testes not descended has been gaining slightly in weight.


Mar 18. Testes just descended.,


Testes not descended.


Mar. 23. Weight. 38.6 gms. Weight. 35 gms

1 es t e s completely descended. Testes not completely descended Rat very vigorous. Genitalia Genitalia smaller' than those larger than those of control. of Male I


Mar. xo. Weight, 61.8 gms.


Weight. 46 gms.


6 ' r'n'f, h V- S2 / ms : Weight. 70.1 gms.

those % d<,hI ; Ue , ly larser tban External genitalia definitely those of control. smaller than those of Male i.

1: nL'f 8 ?. 1 ' S3 5 gms - Weight S0.2 gms

trol g '\i ln Sraeral than con- Genitalia smaller than those of

larger ami V' 1S '"'"" S ' , T ?? tes MaIe L Fur soft and .1

-' r and firmer on palpation, lur thicker and harsher.

1S i' n-4 ",!?'• 65 d . a ^ Age of animal. 65 days.

control mS! r s " TOUS thnn Lightly anaesthetized with ether surgically e **** removed aD d right testis similarly re


> W> -MiCBOSCOMC^Exam ixatiox OF THE TEST ES REMOVED.

^U^ter ^?^"/' °- 9 ?. ** I Wei S ht of "ght testis, 0.570 gm. Te « larc^ranrf fi?J? """"'"J ' after fixa ° ion in formalin'

, ,n, lm " rtnlmeroI >PalPa-!7V s / ( -* smaller, less vascular and that of conJr'ol rascnIar than less firm than that of Male I.

'"gin^n:""' '",'"'- Bh ° w be-lspermatogenie tubules mostly ire ulJ 1 '" ";) "'-enesis and lined with one or two rows of layers dinJiiS manv c ""- '" :! - 'spermatogonia. karyokin"' 1 '"'" 2 Vf " ry actiVH spermatozoa; no spei a", in! h "i Spermatozoa are Vascularity ess.

tl hnl>? V maD - V 0f tn "

monies. Numerous spermatids. Interstitial cells in fair nu

No gi ... d iffi dci in number from those in testis /:;,,./,,/„,„,. t„, , , terior-lobe-fed animal.

lini "in U, ' s '"ger and Epidia Tubules smaller

1 n rl ™ h,mnar cells taller than in Male I : they do not e „/ Protoplasmic. contain free cells or spermacontam spermatozoa. tozoa.


Tubule


The results obtained from the feeding of anterior-lobe extract to Single Male I. beginning when the animal was 25 days old and continuing over a period of 40 days, compared with conditions in the control male of Pair II. ma) be summarized as follows. At the beginning of the experiment the animals were of practically the same weight. Anterior-lobe feeding had a definitely stimulating effed upon the growth of the fed animal, apparent not only in the rapid gain in weight but also in the increase in growth and in its more vigorous appearance. There was also an earlier descent of the tesl for the fur to become harsher and thicker than that of the control. In the gross, furthermore, the gland appeared larger and more vascular than the testis of the control. The gross difference m size of the testes these two animals is well represented by the photographs (Fig. IK), which show the actual dimensions. The body of the testis of the animal receiving anterior-lobe extract measures 3 mm. longer than the control. Its weight not only absolutely, but also in proportion to the body-weight, was very nearly twice as great as in the control, namely, 0.980 gm. as compared with 0.5T0 gm. Histologically, it has the appearance of maturity i Fig. 7 ) at the age of 65 days, or 2}, months, after 40 days of anterior-lobe feeding. The control at this period ( Fig. 8) shows a relatively very much underdeveloped and immature testis. It thus becomes evident that the administration of anterior-lobe extract shortened the period of complete sexual development by one month, or about one-third — a very considerable proportion of the brief period of sexual development in the rat. The remarkable maturity ( Fig. J | of the testis of the animal receiving anterior-lobe feeding at or before the age of 65 .lays — well before the normal time — is evidenced histologically by a very active karyokinesis : the tubules are lined with the typical cellrows (spermatogonia, spermatids, spermatocytes, spermatozoa I in regular order, and spermatozoa are abundantly present. In fact the testis gives evidence of being more active than the testis of a normal adult rat of from three to four months of age. The testis of the control I Fig. 8) is still immature ; I is practically no karyokinesis and no spern the

tubules being lined merely with one or two rows of undifferentiated cells. The interstitial cells do no! seem to increase in number proportionately to the increase in spermatogenic cells and spermatozoa.

A Comparison of the Relative Stimulating Ej Posterior- and Anterior-Lobe (Pitditari i : Upon General axd Testicular Development.

With the positive demonstration, as shown in the prei table, of the definite stimulating action of ie extract

upon the development in the comparative

at two male rats i < Litter III were used — the male of Pair I and the sii I

male, to whom antei fifered

from a complication (intestinal o


I" [No. 300


eal removal of the right testis in another study, and for this to be sacrificed at the age of 3i months, after 2i months of anterior-lobe administration. The male of Pair 1 continued to receive posterior-lobe extract over a period of 7$ months, until lie was sacrificed at the age of Si months. An interesting comparison of the results in the two animals was then made, as shown in the accompanying table. The growth of the animal fed with anterior lobe, not only in general but also as regarded the sex glands, was considerably in excess ol that of the male of Pair I. to which posterior-lobe extract was administered; and in spite of the great difference in the ages of the animals at autopsy (3i months as compared with Si months), the development of the sex -lands was farther advanced in the animal aged 3£ months, after anterior-lobe feeding, than in the animal receiving posterior lobe, at the age of Si months. This would appear to be rather striking evidence that posterior-lobe extract docs not bring about a stimulus to development of the sex glands in any way comparable to that exerted by anterior-lobe extract.

Male, Pair I. — Posterior-lobe extract, 0.1 gm. daily for 14 days, beginning March 9, when the animal was 25 days old; then 0.05 gm. daily for 7 months, or until the animal was sacrificed, October 25, at the age of 8 months and 16 days.

Single Male. — Anterior-lobe extract, 0.1 gm. daily for 14 days, beginning March 9, when the animal was 25 days old; then 0.05 gm. for 2 months, or until sacrificed June 1, at the age of 3 months and 16 days.

TABLE VI.— A COMPARISON IN TWO MALE RATS OF THE INFLUENCE OF POSTERIOR-LOBE FEEDING OVER A LONG PERIOD (7% MONTHS) AND ANTERIOR-LOBE FEEDING OVER A SHORT PERIOD (2% MONTHS). LITTER III.


Date.


Male. Fair I.

Posterior-lobe feeding 7%

months.

Age at autopsy, 8% months.


Single Male.

Anterior-lobe feeding 2%

months.

Age at autopsy, 3 *A months.


Weight, 23.7 gms.

Feeding of posterior-lobe extract begun, at first in 0.1 gm. doses for 14 days, then in 0.05 gm. doses for IV2 months, or until the animal was sacrificed.


Weight, 23.6 gms.

Feeding of anterior-lobe extract begun, at first in 0.1 gm. doses for 14 days, then in 0.05 gm. doses for 2 months, or until the animal was sacrificed.


Mav 17. Weight. 124.5 gms. Weight. 146.9 gms.

Rat not as large and vigorous as Rat has grown more rapidlj


anterior-lobe-fed animal. Fur thinner and more delicate. External genitalia smaller.


gained in weight faster than male. Pair I, i received posterior-lobe ex Fur is harsher and thicker Animal is more vigorous ii general. Externa! genitali;i both on inspection and oi palpation, are definitely largi than those of animal posterior lobe.


ch


hich ract.


fed


1. Animal growing. Testes moder-jAw/mnt saiiificed because of comately large. plication following surgical

Tendency to diarrhoea from be- removal of right testis. Age ginning of posterior-lobe feed- 3". months. ing. Right Testis: Weight. 1.720

gms. Large and normal in appearance. \Seminal vesicles large, filled, and

tense. Feces formed at all times.

Animal sacrificed. Age S%\ months.

Weight of right testis and epididymis. 2.28 gms.

Weight of left testis and epididymis, 2.240 gms.

Weight of seminal vesicles and vasa, 2.420 gms.

Testis large and of normal appearance. Fair amount of secretion in seminal vesicles.


Histological Comparison of Testis of Male, Pair I, at the Age of &y 2 Months and afteb 7% Months of Posterior-Lobe Feeding, with Testis of Single Male at the Age of 3% Months and after 2% Months of Anterior-Lobe Feeding.


Left Testis: Weight, 2.240 gms. Left Testis: Weight, 1.720 gms.

Spermatogenesis observed but Spermatogenesis active and more normal-appearing. The tubules are lined with a greater number of cell layers in regular order. Spermatozoa appear more mature. The striking effect of anterior-lobe feeding is seen in this animal at the age of 3% months as compared with the posterior-lobefed animal at the age of 8% months. The lumina here Epididymis: Lumina appear


than in testis of anterior-lobe fed animal, in that the lining cell layers are fewer and the lumina contain many immature, elongated spermatozoa and relatively few mature ones, although the animal was 8% months old.

Epididyn


are somewhat larger than in the epididymis of the single male. The lining columnar cells are not as tall. There are many spermatozoa in the tubules, "and few other cells.


.mailer, due to the taller columnar lining cells. They contain many spermatozoa and many large karyokinetic cells, indicating a rapid casting off of cells following active cell division in the spermatogenic epithelium, few and Interstitial cells in places appear dense and larger than those in the testis of male. Pair I.

Vascularity is less than in single Vascularity increased.

maie (anterior-lobe feeding). \ ...

Prostatic Gland: The acini are [Prostatic Gland: The acini are larger and fewer in number ; ;


there is very little infolding of the epithelium, which is composed of low cubical cells. The lumina of the acini are J distended with a homogeneous pink-staining secretion. Veryfew voting newly formed acini (cf. Fig. 8i.


...nailer, more numerous, with considerable infolding of the epithelium, which is composed of low columnar cells. It has the appearance of active hyperplasia. Many of the smaller acini show much infolding of the. epithelium and contain very little secretion (c-f. Fig. 01."


Seminal Vesicle: Smaller, less Seminal Vesicle: Larger, markdistended ; epithelial lining edly distended with secretion : lower and less branching into I epithelium slightly taller and the lumen. : shows much infolding.

Vas Deferens: Smaller, not dis-iFos Deferens: Larger, distended tended with secretion : c n- with secretion containing preat tains no spermatozoa. Epithe- numbers of spermatozoa.^ Kpr lium less tall and less ciliated. thellum tall, more Muscle coat less bulky. Muscle coat thicker.


ciliated


A comparison of the results of anterior- and posterior-lobe feeding given in Table VI shows, in brief, that anterior-lobe feeding over a period of 2i months has produced not only a greater bodily growth and development, but also a more rapid genital development than has followed posterior-lobe feeding for Ii months. Indeed it would seem, as heretofore stated, that posterior-lobe feeding has had a distinctly retarding influence upon the development of the sex glands, for otherwise it would be difficult to understand the incomplete development of the testis of the male of Pair I, at the age of Si months, as compared with the testis of the single male at the age of 3| months. In other words, anterior-lobe feeding for 2£ months has caused a more active and advanced spermatogenesis at the age of 3i months than is observed in the testis of the animal aged 8£ months, after U months of posterior-lobe feeding. This effect of anterior-lobe feeding corresponds with the results in a previous experiment (Table V).

Posterior-lobe feeding also tends to produce intestinal peristalsis, as indicated by the persistence of an occasional slight diarrhoea.

Anterior-lobe extract does not seem to cause any marked change in the number of interstitial cells. In the epididj mis, however, the tubules are lined with taller and larger cells, and there are more spermatozoa and free cells in the lumina. The vascularity of the testis and epididymis is also increased.

Thus it would appear that no matter what may be the age. even after maturity, of the animal receiving posterior-lobe


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.



feeding).


Fig. S— Male, Pair II (control).


Figs. 7 and 8. Sections of right testes of two young rats of the same litter, removed when the animals were 65 days or 2% months old. Testes in gross shown in Fig. 7A.

Fig. 7. Typical appearance in section of the right testis of Single Male I, to which anterior-lobe extract was given over a period of 40 days from the time when the animal was 25 days old.

Fig. S. Typical appearance in section of the right testis of Male, Pair II, control, receiving no gland extract.

Note in Fig. 7 the very active mature development of spermatogenesis with the production of numerous spermatozoa.

Note in Fig. 8 the immature development of the spermatogenic tubules with very little cell division and without spermatozoa. Tubules lined simply with one or two rows of primitive spermatogenic cells.


7|S




OJ9I 8l2


8)5


Fig. 7A. — Photographs (actual size) of the right testes of Single Male I (anterior-lobe feeding for 40 days) and Male, Pair II, control (without gland feeding). The testis represented in the lower photograph, and taken from the animal receiving the anterior-lobe extract, weighed 0.9S0 gm. as compari d with 0.570 gm. the weight of the testis of the control represented in the upper photograph.



71/ 9 -~ Male . Pair I (posterior-lobe feeding '/> months). Age of animal at autopsy, ^ ' months, x 55.



Fig. 10. — Single Male (anterior-lobe feeding l' 1 .. months) Vge of animal at autopsy, 3%

months.


Fig. 9. Representative section from the prostatic ;dand of a rat 8% months old. after feeding of pituitarj posterior-lobe extract for 7% months

1'ig. 10 Similar representative section from a rat ::' L . months old of tin- sain.' Litter III. alter on]

months ot feeding of pituitary anterior-lobe extract, evtr t the .h- VDer P lastic appearance of the prostatii nd I Fig. 1m in the animal who had received anterior-lobe

irac't. notwithstanding the fact that this ai ir younger than the male whose prostatic gland is repre

"!, i ••'" g ' fl an indication of the marked stimulating action of the anterior-lobe extract and the possibb inhibiting action of posterior-lobe extract.


February, 1916.] 41


extract, the testis never reaches the stage of development and activity observed in the testis of an animal receiving anteriorlobe feeding.

In a previous experiment (page 39, Table V) and in Pigs. ". and 8 evidences are given for believing that anterior-lobe feeding has a marked stimulating action upon the development of the testis. The prostatic gland, seminal vesicle and vas deferens were not examined in this case. This stimulating action of the anterior-lobe extract was undoubtedly exerted upon the latter organs also, for in the experiment just quoted we find evidences of increased and active development on the part of the prostatic gland, seminal vesicle and vas deferens as well as the testis, as a result of a brief period (2| months ) of anterior-lobe administration, as compared with posterior-lobe administration over a period of 7| months. To illustrate this point, representative sections from the prostatic glands of the two males under consideration were drawn, and are shown in Figs. 9 and 10. The differences are striking, and the figures with their legends are self-explanatory.

In Table VI it is stated that the testis of the male of Pair I, the animal receiving the posterior-lobe extract, shows a very inactive spermatogenesis in comparison with the testis of the single male fed with the anterior-lobe powder. As a result, as would be expected, there are very few mature spermatozoa in the former, whereas in the latter spermatozoa are very abundant. As an index of the active spermatogenesis produced by anterior-lobe feeding we have, in addition to the appearance of the testes themselves, the presence of great numbers of spermatozoa in the secretion distending the vas deferens in the former (Figs. 12 and 12A), while in the case of the animal receiving posterior-lobe powder the vas contains no spermatozoa, and no secretion, and the walls are collapsed (Fig. 11). These differences in spermatogenic activity are all the more striking when one realizes that the animal receiving the anterior-lobe feeding (Fig. 12) was only 3^ months old, while the animal receiving posterior-lobe feeding was 8i month- old when the autopsy was performed.

The Effect of Prolonged Feeding of Pituitary ( Anterior Lobe) Extract Upon Breeding and Pregnancy and Upon the Final Development and Histological Appearance of the Sex Glands. In view of the definite stimulating influence of anterior-lobe feeding upon the development of the genital system in both male and female, resulting in the early maturity of testes and varies, it was thought of interest to observe the e anterior-lobe feeding on one pair of rats, using as controls a second pair of the same litter without glandular administration, m order to determine whether, with the earlv histological maturity, the sexual instincts were also prematurely developed, and also whether the animals were fertile at the earh a winch the testes and ovaries were known to be mature animals were observed for a sufficient length of time to enable as to draw some fairly definite conclusions. Thev wer m adjoining cages under precisely similar circumstances and under conditions as nearly quiet and undisturbed as pi


At the beginning of the observation both the male and the female of the control pair ^vro a trifle larger and heavier thai, the pair selected for the feeding of anterior lobe, and thus the odds of the experiment were placed in favor of the control animals.

Two pairs of rats of Litter I, born January 31, 1913, were used in this observation. On March 5 the weights were as follows: Male. Pair I. 32.1 gms. ; male, Pair II, 33.3 grns.; female, Pair I, 27.6 gms.: female. Pair II, 20.; gms. The lighter pair, as stated, were selected for the glandular feeding, the heavier, Pair II. being used for control. The feeding of anterior-lobe extract was begun on March 6, in daily dose's of 0.1 gin., and was continued in this dosage for in days, after which time 0.05 gm. was given daily until November 22, when the animals were sacrificed. The feeding was thus begun when the animals were 34 days old and was continued for approximately 8| months.

Pair I. Male and Female.— Anterior lobe extract for a period of 8 months, beginning when the animals were 34 days old. Both were sacrificed when approximately 10 months old (accurately, 9 months and 22 days).

Pair II, Male and Female.— Used as controls. The autopsy on the male was done at the age of 10 months, and on the female at the age of 7 months and 6 days.

The condensed protocols are given in tabulated form in Table VII, to show the general effect of continued anteriorlobe feeding upon growth, weight and development, and upon the time of breeding, the rapidity of successive pregnancies and the size of the litters. In Table VIII are given the histological findings at the age of 10 months in the ovaries and testes of the pair receiving anterior-lobe feeding, as compared with the findings in the sex glands of the control pair — in the male at the age of 10 months and in the female at the age of 7 months and 6 days, at which age this animal, although adult and mature, died suddenly.

In summarizing the comparative observations on the male of Pair I (anterior-lobe feeding) and the control male of Pair II, it is seen that — in spite of the fact that at the beginning of the experiment, when the rats were weaned, the male of Pair I weighed less than the control male of Pair II (32.1 gms. as compared with 33.3 gms.) — nevertheless, the male of Pair I. receiving anterior-lobe extract, very soon overtook the control male in weight (cf. under March 30). This difference in weight gradually increased during the succeeding 1 months, until at the end of the experiment, when the animals were sac ificed, the weight of the animal receiving anterior-lobe feeding was 256.8 inns., or 26.4 gms. in excess of the weight of the control (cf. November 22 and 30). With this marked

ncrease in weight there was a more active development of the external genitalia, and an earlier complete di scenl of the testes, which even on gross inspection and palpation urn- defii larger than thosi of the control male. There was also an increased weight of the teste- both absolutely and propi aterj to tin body weight. Thus, for example, using the right testis of eai h annual for comparison, the weight of the testis in the case of the male receiving ai r was

0.73 gm. per 100 gms. of body weight, as compared with 0.59


TABLE


,XDFXSED TABULATED PROTOCOLS OF TWO PAIRS OF RATS OF LITTER I. TO SHOW THE CONDITIONS AFTES ^ROLO?GED FEEDING OF ANTERIOR-LOBE EXTRACT TO PAIR I, AS COMPARED WITH THOSE AFTER PROLONUE ^ r0NTR0L PAIR n RECEIVING NO GLANDULAR EXTRACT.

(With special reference to weight, growth, development, breeding, pregna ncies, and the size of the litters.)


Pair I. Anteriorlobe feeding for 8% months, begun Mar ...


Male.

Age at autopsy. 1" months.


Female.

Age at autopsy. 10 mouths.


Weight, 32.1 gms.

Weight, 38 7 gms.

Testes descended at all times.


Weight. 27 6 gms.


Weight, 29 9 gms

Smaller than mate.


Mar 23. Mar. SO

Apr 6.

Apr. 20. May IT.

June 1.


Weight, 4l.i» gms. ,. ,

nded. Hair delicate. ,1 active and playful.

Weight. 58.9 gms.

Internal genitalia quite large. slight tendency to diarrhcsa.


W.ight. 20.7 gms. Animal in good condition.


Weight. 43.5 gms. Nipples barely perceptible tendency to diarrhoea.


Slight


Pair II. Control. No glandular administration.


Male. Age at autopsy. 10 months.


Female. Age at autopsy. 7 months. 1 week.


Weight. 33.3 gms.


Weight, 20.7 gms.


Weight. 37 9 gin- Weight. 32.2 gms.

Testes at li - descended, at other Nothing of special note.

times disappear into abdomen. Vigorous-looking animal.

Weight. 43.3 gms. Weight. 32.4 gms.

Testes fairly large, and descended at all times.

Weight. 61.8 gms

External genitalia about as in male

of Pair I. No tendenej to loose

bowel movements.


Weight. 40.3 gms. Nipples as in fema


ippl.s as in female, of Pau *. looseness of bowel movements.


„- ., eon m Weight. 51.9 gms.

AY.i'nTl h.^et-niken control male NMppl.p ,,..;..; dl.tlnctly in weight.


isible and


W. iight. 90 . gms

Rat mon I ig - I

External genitalia ... of control.

Weight, ins.--' gms.

Weight. 141 gms

\nimal larger in general than control. Testes .1. tinit. 1> larger.

Weight. 167.4 ems

larger than those c,t control


Weight. 69.9 gms. control. Hair thicker and harsher than tnat

er than of control.


Weight. 66.1 gms. External genitalia about as of Tair I.

Weight. 84. 8 gms Animal not as vigoi Pair I.


June 4.

June 6.

June 22.

July 27.

Aug. 30

Sept. 1 Sepl -i


Weight, 70.2 gms.

Wi ight, 113.1 gms.

Nipples more prominent, abdomen fuller than iii control.

Weight. 146.4 gms. .

„„,,,( incununt. Has gained 21 gms. in weight in one week. As

f al as male of this pair.

Nipples large. Vagina larger than that of control


Weight, B9 gms.

Weight. 122.0 gms.

Genitalia smaller than those of male Nipples very small : just visible. of' Pair I.


Pregnancy I.

wis horn whin the parents were 124 days, or 4.1 months, old. Male replaced in cage with female. ™Vam-irs well and active.

Eiffi ^l&y larger than S» ^fe «'• ** ^tEfof^&r^ tnose^'co^ofxemar

coarser.


Weight. 2.1 gms. male Nipples prominent, though possibly less so than in female of Pair I.

Weight. 62.6 gms. male of Hair softer, thinner and more dt licate than that of female of Pair I.

Weight. 68.6 gms.

Weight. 95.3 gms.


Weight. 130.2 gms.

Testes noticeably s

of male of Pair


Weight. 122.1 gms. than those Smaller than female of Tair I. Nipples very much smaller ; just visible. Fur softer. Vagina smaller.


No signs of pregnancy.


Weight. 150 gms.


Weight, 130.6 gms.


\v,u»ht 108 q ems Weight. 140.6 gms.

M n vi--orous g than control. Testes Nipples still definite!., .1, , ably larger. those of control tenia!


larger than


- - " ms ' ^ »u » ™«i„ Nipples' becoming slightly larger.

genitalia smaller than those of male " e definitely smaller than

of Pair I. Hair softer and finer. thLe=f female of Pair 1.

„- v.. ict - .„„. Weight, 143.8 gms.

Weight, lfal.i gms. Nipples still verv small — much

Rat smaller than male ot Tair I. - N 6 m ' all ,„. { han tnc ; se o£ female „f Testes smaller.


Weight.


ms Weight. 184.6. gms

Animal pregnant the second time Abdomen bulging in flanks.

Pregnant y I /.

Female of this pair gave birth on this date to a second litter of three The voung are normal and healthy-looking. Mother in good condition Young ar? designated hereafter as Eat A. Rat B, and Rat C.


Sept 6. Weight. 235.5 gms.


Weight, 153.9 gms.


Weight. 189.7 gms.


Weight, 191.4 gms.


Sept. 28. Oct. 5.


Wright. 172.3


Weight, loo.l gms. .

\nimal found dead in cage 1'H.tJ' date Had recently lost weight. Seemed in good condition on previous day.

Autopsy.

Autopsy done on same day. Very little subcutaneous fat. Some tat in omentum and mesentery.

Combined weight of both crane145 gm. Small, reddish,

luemorrhagic-looking nodules, resembling corpora lutea, in each ovary Corona of uterus have an eedematous appearance. Death due to pneumonia.


Weight. 236.6 gms. Weight. 16". 4 gms.

of the second litter. Rat A, Rat B, and Rat C, were weaned on' tins date The feeding of anterior-lobe extract was begun to Rat \ and Rat C, which were paired. Rat B was given ovarian extract. I or further protocols of these animals see table following.!

Wright. 180 6 gms.


12. Weight. 254.0


Autopsy.

noticeably larger than those c introl male, and more vascular. Tubules plainly visible in the gross. Wright of right testis. 1.89 gms. Weight of left testis, 1.00 gms. Wright of seminal vesicles, prostate and bladder. 3.06 gms.


Nov. 22. Weight. 182.6 gms. Animal sacrificed.

Autopsy.

Wright of ovaries, uterus and upper vagina, "780 gms.


Weight, 207


Weight. 222.6


Weight. 230 Animal sacrificed.

Autopsy. Testes not esp

vascular. Weight of right testis. 1370 gms Wright o, I " gms.

Weight of seminal vesicles, prostate

and bladder. 2.830 gms. . Moderate amount of tat In retroperitoneal tissues; very little in omentum. Hair not particularly coarse


large


THE JOHNS HOPKINS HOSPITAL BULLETIN. FEBRUARY, 1916.



Fig. 11.



Fig. 12.




Fig. 12A.


Fig. 11. — Vas deferens cf Male, Pair I (posterior-lobe feeding for l l fe months). X 41.

Fig. 12. — Vas deferens of Single Male I (anterior-lobe feedingfor 2% months). X 41.

Fig. 12A. — High power drawing of area (a) in Fig. 12, showing numerous spermatozoa in the lumen of the vas which is lined with tall ciliated columnar cells. X 170.

Note in Fig. 12 the vas deferens distended with secretion containing large numbers of spermatozoa, as compared with the vas in Fig. 11 from which secretion and spermatozoa are ah at



C0T\Vs>©^>



riiiiiiimnimiiiliiii




Fig. 13. — Left testes, seminal vesicles and prostatic glands of two males of the same litter (cf. Tables XI, XII and XIII), to one of which corpus-luteum extract was fed over a period of 6 months, the other being used as the control. Xote the smaller size of the sex glands in the ovarian-fed male, to the left in the figure. The weight of testis of the ovarian-fed animal was 1.93 gnis., as compared with 2.30 gms. in the control; seminal vesicles and prostatic gland, 1.7 gms., as compared with l.S gms. in the control.

Xote difference in the size of the seminal vesicles (s. v.) and the prostatic lobes i p. I.) in the two cases.


Fkbruabt, 1916.] i:;


gm. per 100 gnis. of body weight of the control male. The fur of the fed animal was also coarser and thicker.

In the case of the female rats similarly observed, th are practically analogous. The weight of the female of Pair I was less at the beginning of the experiment than that of the control, being 27. 6 gms., as compared with 29. 1 ; gms. Very soon, however, the female of Pair I. receiving ante extract, overtook the control female in weight, on April (j weighing 69.9 gms., as compared with 62.6 gms. This overweight increased and was maintained during the succeeding five months, except immediately following the pregnancies : and on October 12. when the animal had recovered from her pregnancy, she weighed 180.6 gms.. as compared with 155.1 gms., the best weight of the control female, on September 6. "With this increase in the weight of the female receiving anterior lobe there was also a more rapid development gener


normal and healthy, did not breed ai ail. Granting naturally

that a single ohservati f this kind is m no way c

it w,,nld nevertheless seem to indicate that, although

the somewhat unfavorable It ratory conditions the control

animals failed to breed at all. the feeding of anterior-lol \ tract to Pair 1 acted as a stimulant to breeding and of!

possible inhibiting influences of the laboratory envir int.

1,1 regard to the size of the litters no , I, Unit,, comments can be made. After the Brsi pn -nancy there were six young, a fairb large litter. The second litter, however, was a small one, i onsisting of only three young.

In addition to noting the effect of prolonged feeding of anterior-lobe extract upon growth, development and breeding in tin- experiment, it was also possible to observe whether the early signs of activity of the sex glands were still visible after 8| months of glandular feeding; whether the normal control


TABLE VIII.— SHOWING THE LATE EFFECT UPON THE WEIGHT AND HISTOLOGICAL APPEARANCE OF THE SEX GLANDS IN A PAIR OF RATS AFTER PROLONGED FEEDING OF PITUITARY ANTERIOR-LOBE EXTRACT AS COMPARED WITH THE CONDITIONS IN ANOTHER PAIR RECEIVING NO GLANDULAR EXTRACT.

LITTER I.


Pair I, Male.

Anterior-lobe feeding 8% mouths.

Weight. 256. 8 gms.


Weight of left testis, 1.90 gms.

Weigh) of right testis, 1.89 gms.

Spermatogenesis active. Tubules contain a fair number of spermatozoa and are lined with several rows of cells in typical order.

Epididymis contains a great many -i > rmatozoa. The lining cells cont: in a large amount of lipoidal substance : there is variolation about the nuclei ; the cells are more ciliated

Interstitial cells present in fair number : more numerous than in the control male.

Testis larger and more vascular on gross inspection than that of the male of Pair II.

Seminal Vesicles and Prostate: Weight, 3.06 gms. No special difference from male of Pair II. except as to size and the larger number of spermatozoa.


Pair II. Male. Control.

Xo glandular administration.

Weight, -y.WA gms.


Pair I, Female.

Anterior-lobe feeding SV. months.

Weight, 182.6 gms.


Weight of left testis. 1.46 gms

Weight of right testis, 1.370 gms.

Spermatogenesis less active than in male of Pair I. Tubules contain fewer spermatozoa and are lined with fewer cell layers.

Epididymis contains few spermatozoa — much less numerous than in the male of Pair I. I.umina of tubules smalli r less tall, contain less lipoidal substance and show less variolation about the nuclei.

Interstitial cells are very few in number: they appear ilflinit.lv fewer than in the male of Pair I.

Testis smaller and less vascular on gross inspection than that of the male of Pair I.

Seminal Vesid, - »»,( Prostate: Weight. 2.830 gms. Definitely smaller than in the male of Pair I ; contain few free cells and spermatozoa.


Weight of ovaries, uterus and upper vagina. 0.780 gms.

Ovary larger than that of the female of Pair II. and contains very few primordial, several medium-developed and a few large follicles. There are several vacuolated cellular corpora lutea. with beginning formation of corpora fibrosa.

Interstitial tissue rich in cells.

Vascularity, as seen at hilus, greater than in the female of Pair II.

Fimbriated end of tube much branched, and lined with tall, ciliated columnar cells.

Fallopian tuhc lined with tall cells, partly ciliated : mucous membrane much folded ; muscle coat thick.

Oornu of uterus lined with thick, much folded mucous membrane containing a few glands : lumen smaller than in female of Pair II ; vascularity greater. Muscle coat well developed.


Pair II Female. Control.

No glandular adminisrtatioi

Weight, 172.3 gms.


Weight of ovaries I alone i. 0.145 urns.

Ovary smaller I ban in the female of Pair I. and contains more primitive follicles, more developing and more mature follicles. Corpora lutea fewer in number. larger and less fibrous and organized — i. e., younger Corpora ha?morrhagica seen' in the gross specimen.

Interstitial tissue abundant and cellu lar.

Vascularity, as seen at hilus. less than in the female of Pair I.

Fimbriated end of tube branched, less active-looking.

Fallopian tube smaller; lining cells less tall ; lumen larger ; less folded mucous membrane. muscle coat thicker.

Horn u of uterus lined with thinner, less folded, less vascular mucous membrane, containing no glands. Muscle coat less well developed.


ally; the nipples became larger and the hair coarser and thicker.

In regard to breeding, pregnancy and parturition, it is interesting to note that Pair I, receiving anterior-lobe extract. bred at the early age of 3i months and that the female gave birth to a litter of six young when she was i month- and old i cf. June 1 )— a fact which demonstrates that the instincts arly awakened and that the female can be impregnated at this comparatively early age as a result of the premature hisio il maturity of the testis and ovary produced by i ! ing of anterior-lobe extract. This latter effect was also shown in an earlier experiment (Tables V. VI and VII).

There was nothing abnormal noticed about eithei : Che second pregnancy and delivery of three young o after an interval of three months— which ma

rapidly succeeding pregnancy under the somewhat mal breeding conditions of a laboratory. ! then two pregnancies in the pair reci ing by the time the animals were ; months period the control pair, although thev appea


animals in due time reached the stage of development acquired much earlier by the fed animals, and whether the early over-" development of the sex glands of the fed animals, as compared with the controls, was maintained throughout the subsequent adult life of the animals.

Table VIII gives the weights of and histological findings in the sex glands of the male and female nits of Pair I. Litter 1. fed with anterior-lobe extract for 8$ months, as compared with the sex glands of the control male ami female of Pair II. The control female, though younger ai the time of autopsy than the female receiving anterior loin-, was nevertheless mature i

for i!i> purposi o1 comparison as a normal adult control rat.

Tie- results in i hi - of the two male- will be summarized first. Both animals were approximately LO months old when they were sacrificed — fully matured adult rats. It will that the Is of the animal receiving anterior-lobe

extract over a per ! 8 : , months still continued to show a

greater and mi hosi of the

This is indicated by the following findings :


4-1 [No. 300


testis is greater, both absolutely and in relation to the bodyweight : spermatogenesis is more active; the epididymis contains many more spermatozoa and is made up of tubules with larger lumina and taller lining cells, containing more lipoidal substance; the interstitial cells of the testis are more numerous : the seminal vesicles and prostatic gland are larger and heavier; the vas deferens is larger and more distended, and contains many more spermatozoa; and the vascularity of the testis is greater in general. These results are at variance with those of Behrenroth. who states that in a short, time the control animal reaches the stage of development of the fed animal. thus suggesting that the effect of pituitary administration (in his experiments by subcutaneous injections) lasts only for a time in the early life of the animal, and that there arc no permanent or late changes.

In comparing the results in the females we find that the differences observed in the weight and appearance of the sexglands are comparable to those in the sex glands of the males. The control female of Pair II died of acute pneumonia at the age of 7 months and 1 week, but this discrepancy in age, though unfortunate for a precise comparison, nevertheless does not alter the value of the observation, for after the age of 7 months a difference of 2 months in age would make practically no appreciable alteration in the histological appearances of the ovaries and uteri. Furthermore, the differences observed in these two animals are far in excess of any change that could be attributed to the difference in their ages. Thus we find that the ovary of the fed animal is larger in the gross than that of the control. (A record of the weight of the ovaries alone was unfortunately lost.) Also the ovary of this animal contains a number of corpora lutea with beginning formation of corpora fibrosa, several large and medium-sized Graafian, and a few primordial, follicles. The ovary of the control contains a greater number of primordial follicles, more developing and mature Graafian follicles and few corpora lutea, which in this animal are younger, less fibrous and less organized. In the gross specimen corpora hemorrhagica were also observed. These findings would seem to indicate that the ovary of the female receiving anterior-lobe feeding is an older, a more senile ovary, so to speak, which has run its course and has undergone a far more extensive ovulation, as indicated by the few primordial follicles and the presence of corpora fibrosa. Furthermore, the ovary of the fed animal shows a rich amount of interstitial tissue and a greater vascularity than that of the control ; the Fallopian tube has a more highly branched fimbriated extremity, the lining cells of the tube are taller and more uniformly ciliated, and the muscle coat is thicker; the uterus is lined with a thicker endometrium, which is more vascular and more folded, contains glands which are absent in the control and has a heavier musculature.

We have. then, evidence that pituitary anterior-lobe extract exerts its stimulating influence upon both the male and the female sex glands, not only in early life but also well into the adult period, and that this influence is not specific for any single part, but affects the whole of the sexual system.


The Influence of Anterior-Lobe Feeding Carried

Through the Parents Into the Second

Generation.

We have seen that the feeding of anterior-lobe extract to young rats causes an early maturity of the testes and ovaries, and we might therefore expect early breeding and pregnancies with possibly larger litters, since ovulation is markedly stimulated. It also seems reasonable to suppose that the younger the animal at the beginning of the glandular administration, and the longer the feeding is continued, the more marked will be the stimulating action exerted. The possibility was thus suggested of subjecting an animal to anterior-lobe stimulation during intra-uterine life and during the period of lactation by administering the extract to the mother, and at the end of the period of lactation by giving the glandular extract by mouth as in the case of the parents. A single experiment, which yielded several suggestive findings, may lie here reported.

To the parent pair of Litter I (cf. Table VII) anterior-lobe extract had been given from the time when the animals were 34 days old. and was continued during the two pregnancies — in fact until the animals were sacrificed. As a result of the second pregnancy a litter of three rats was born; these are designated as Eat A (female). Rat B (male) and Rat C (male). The young having been weaned at the age of 31 days, a daily dose of 0.05 gm. of anterior lobe in pill form was given to Rat A and Rat C, which were paired. To the remaining male, Rat B. ovarian extract (corpus luteum) was given daily in the same dosage. In this way Rat A and Rat C were subjected throughout their intra-uterine as well as extra-uterine life to anterior-lobe stimulation. It was believed that in this way an even greater body growth and an earlier and more active sexual development could be produced than in the experiments heretofore reported. In the case of Rat B, the remaining male, ovarian extract, for the sake of comparison, was substituted for the anterior-lobe feeding.

Although the facts as brought out in this single observation are in no way conclusive, they are nevertheless very suggestive and for this reason are given here. The more rapid growth and increase in weight of the rat of the second generation is well illustrated in Rat C as compared with his male parent. At corresponding ages it is found that Rat C was considerably heavier than his male parent. Thus, soon after weaning, when 34 days old, the parent male weighed 32.1 gms., whereas Rat C, when only 31 days old, weighed 51.7 gms. Again, at the age of 80 days the parent male weighed 108.2 gms., as compared with 126.6 gms.. the weight of the young Rat C at the same age. In the ease of the females the difference in wei^H at the age of 80 days is even more striking, the parent female weighing 79.2 gms. as compared with 117.1 gms.. the weight of the female offspring.

In regard to the time of breeding and the first pregnancy we find that Rat A and Rat C of the second generation bred at the age of 74 days, as compared with 104 days, or 3i months, in the ease of the parent pair. In the ease of the parent pair the first litter was horn after 125 days, or 4^ months, as compared with 95 days, or :U months for the young pair. Thus


February. 1916.] 45


we see that breeding and pregnancy occurred one month earlier in the pair of the second generation — a period more than onethird of the normal time of adolescence of the rat — coi ably earlier than the average normal breeding-time. We see. too that the litter born to the pair of the second generation numbers eight as compared with six in the litter of the parent pair. The average weight of the young, however, is greater in the litter of the parents, the average being 3.9 gms. as compared with 3.56 gms.. the average weight of the young in the litter of the second generation. So far, then, as the results of


A comparison may also be mad.' between the two males, Hat C and Rat B, the former receiving anterior-lobe stimulation throughout, and this effect in the latter being interrupted by the substitution of ovarian feeding when the animal was weaned. The feeding of anterior-lobe and ovarian extracts was continued during the succeeding (5 months. Both animals were sacrificed on March 30, 1914. at the age of 7 months. At the beginning of the experiment the slight advantage m growth and development was in favor of Bat B. which received the ovarian extract (cf. difference in weight September 22).


TABLE IX.— CONDENSED TABULATED PROTOCOLS SHOWING THE EFFECT OF ANTERIOR-LOBE FEEDING IN PARENT

PAIR CARRIED THROUGH THE YOUNG OF THE SECOND GENERATION.

LITTER I, PAIR I (PARENTS). ANTERIOR-LOBE FEEDING.


A litter of three rats born Sept. 4. Rat A ( female I, Rat B imalei. Rat C (male). Rat A paired icitlt Rat C.


Date.


Sept. 22.

Sept. 26.

Sept. 28.

Oct- 5.


Oct. 19.

Oct. 26.

Nov. 22.

Dec. 1.


Rat A (female). Anterior-lobe feeding, begun Oct. 5.


Weight, 23.8 gms.

Weight, 26.2 gms.

Weight, 34.2 gms.

Weight. 47.8 gms.

Weaned on this date and paired with Rat C

(male!. Anterior-h>be feeding begun. Vaginal

septum not yet perforated.

Weight. 57.2 gms.

Vaginal septum not yet ruptured.


Rat C (male I. Anterior-lobe feeding, begun Oct.


Weight, 67.4 gms.

Vaginal septum unruptured.


Weight. 92.8 gms. Hymen ruptured. Free


Weight. 117.1 gms. Nipples still quite small.


ntrance into vagina.


Weight, 26.8 gms. Weight. 29.3 gms. Weight. 39.1 gms.

Weight, 51.7 gms.

Weaned and paired with Rat A (female). Anterior-lube feeding begun. Testes descended and fairly large.

Weight. 63.4 gms.

Animal smaller than Rat B (ovarian fed).

T.sti's large — possibly slightly larger than

testes of Rat B.

Weight 7.".. 9 gms.

Testis pussililv slightly larger than those of Rat B.

Weight. 195 gms.


Weight, 126.6 gms.

Animal smaller than Rat B (ovarian-fed).


Weight. 136.8 gms. Weight. 136.3 gms.

Definitely pregnant. Rapid gain in weight. Ab- Although animal is smaller generally than Rat


domen full : blood-stained secretion in vagina. Nipples rapidly increasing in size. (Pregnancy in less than three months.)


the testes are as large, if not larger, than those of the ovarian-fed animal. Rat removed from female to-day.


Rat A, weight, li',n.r, gms .

Gave birth to-day to a litter of eight young. Three died soon after birth, and one was killed

by the parent rat. One of the dead young still in its membranes with cord and placenta

attached. The dead young present no abnormalities, but are smaller than the four living.

Mother neglected the young, as in the case of the first pregnancy of the parents. Litter I,

Pair I. Fair amount of bleeding during parturition. Average weight of three of the dead young, 3.56 gms. Weight of mother after birth of litter. 125.1 gms.

Dec. 19. March 30. 1914.

Weight 122 gms. Animal kept until March 30. 1914. when it was

Animal anesthetized on this date for X-rav sacrificed and autopsied.

photograph, and died under the anaesthetic.

thus preventing further comparison. Autopsy.

The animal was still remarkably small, consider- vv.-i^ht 181 gms Weight 161 6 <

Va"uw aVdTtrLf^usnluy small though quite E^^' ^ nitalia lar eer on palpation than those External genitalia smaller on palp

• T a w^oui,e r i'.;'; :l . ,,IV nn r , 0m P re .S nanc y- , Weight of right testis. 1.95 gms. Weight of right testis. 1.620 gms.

rhaglca and lutla. contaln corpora ha-mor- Wpis ,„ , lf ,„ ft testis, 2.050 gms. at of left testis. 1.500 gms.


Rat B (male). Ovarian feeding, begun Oct. 5.


Weight. 27.9 gms.

Weight, 30.5 gms.

Weight. 43.9 gms.

Weight. 57.4 gms. Weaned on this date. Ovarian feeding begun, for e C (anterior-lobe feeding).

Weight, 78.1 gms.

Larger generally than Rat C. receiving lobe.

Weight, 89.6 gms.


Weight. 123.5 gms.


Weight, 165 gms. Testes quite large.

Weight, 173 gms.

Animal has grown larger and has become fat

more rapidly than male Rat C (anterior-lobe).

Fur seems heavier and coarser. i Similar

facts observed in the ease of ovarian-fed male

of Litter I — cf. Table XI. i


March 30, 1914. Animal kept until March 30. when it ficed and autopsied.

Autopxu.


ind


Very little fat in general.


ras, Weight of seminal vesicles, prostate and vas. 0.760 gm. Very little fat in general.




this experiment go, they suggest that the feeding of pituitary anterior lobe to parent rats exerts an influence upon the offspnng in intra-uterine life and .luring lactation, and that. when carried further in the life of the animal, it has a markedly stimulating effect upon growth, weight and di elopi m at, and causes an earlier breeding and an increased number of offspring. The results are sufficiently suggestive to encourage I i<-*her experiments along this line. Whether one could eventually produce a strain of larger rats with a more active sexual life, ant, on the other hand, whether the result would overstimulation and eventual deterioration of the strain, remain interesting questions deserving further study.


There was an early increase in the weight of tl varian-fed

male over the weight of the male receiving anterior lobe, although at the end of the experiment tin -ult was

very marked. Later on in the progress of the feeding, the external genitalia of the animal receiving anterior lob larger on gross inspection and palpation than those of the ovarian-fed animal. Furthermore, at autopsy there was found to be a very definite difference in the weight, both absolutely and in relation to body-weight, and weight of the testes, seminal vesicles, prostatic gland- and ?as deferens, in favor of the animal receiving anterior lobe (cf. under March 30). The total weight of the entire genital system in Kat C (an


46 [Xo. 300


terior-lobe feeding) is 5.50 gins, as compared with 3.88 gms., the weight in Rat B (ovarian feeding). Calculating upon a

rropor,tionate to body-weight we find that the wei{ the genital system of the rat receiving anterior lobe is 3.03S gms. per 100 gms. of body-weight, as compared with 2.40 gms. per 100 gms. of body-weight in the ovarian-fed male. Hen- we ave a definite example of the continued stimulating action of prolonged anterior-lobe administration upon the mi. nt of the genital system. In Table X a comparison is made of the histological appearand es of the sex -lands of these two males.

TABLE X— SHOWING THE COMPARATIVE HISTOLOGICAL

APPEARANCE OF THE TESTIS IN RAT C AND RAT B.

(Continued from Table IX.)


Rat C (male). Anterior-lobe feeding

I begun when the animal was 31 flays old and continued for approximately 6 months).


Rat B (malei. ovarian feeding i begun when the animal was :;i flays old and continued for approximately months).


RiijJit Testis: - '< very

active. Large numbers of spermatozoa are seen in tile tubules, which contain a considerable amount of secretion and many free .'-lis.


Interstitial cells are present in moderate numbers.

Epididymis: The tubules are rather largf. m iderately distended with secretion containing largt numbers of spermatozoa. They are lined with a low columnar epithelium composed of cells having a kind of ciliated U,rder.

I'n.statir ijbnid nwl s< minal Vesicle: More proliferation of the epithelium evident in the indentations and infolding of the lining cells. More secretion in the lumina. Spermatozoa are present in considerable numbers in the seminal vesicle.

Vas Deferens: The lining cells have a .baser protoplasm and are more abundantly supplied with cilia. Muscle coat somewhat heavier.


RigM Tcxti*: Sinyniatogenrsis much -. active. There are fewer free tills and a strikingly smaller number of spermatozoa in the tubules, which are lined with spermatogenic cells in fewer num- mid in less compact arrange ment Interstitiai cells are less numerous and smaller.

Epididymis: Tubules smaller an 1 less distended w-itb a secretion that contains relatively few •]•• I matozoa. The lining cells are of a low columnar type and have a scant, imperfect, ciliated border.

/ ostatu Gland </.../ Si mina! Vesii I' More simple and regular in the structure of the acini and tubuli There is less infolding ami I ing of the epithelial lining- Less

i retion in the tubules. Spermatozoa are present in large numbers in the seminal vesicle. Vas Deferens: The lining cells are more vacuolated and less abundantly ciliated.


The results as given in Table X show that the prolonged administration of pituitary anterior-lobe extract, at first to the parents and then to their young, had a markedly stimulating effect upon the sex glands of Rat C. as compared with Rat B, in whose case ovarian extract was given over a period of 6 months instead of the anterior-lobe powder. Both animals were adult: nevertheless Rat C (anterior-lobe feeding i showed a sexual development considerably in excess of that of Rat B (ovarian feeding). Thus we find that spermatogenesis is mm h active; the interstitial cells are more numerous: the tubules of the epididymis are larger and are filled with tion that contains many more spermatozoa; the prostata is more hyperplastic in appearance : and the vas deferens is

. and its lining cells are more protoplasmic and i These, in short, are definite evidences of increased sexual development apparent even in adult life as a result of prolonged administration of anterior-lobe extract, as compared with the effect of ovarian extract. The appearance of the sex glands after ovarian administration is indicative, furthermon

effect of the extract upon the development of the male sex glands.


The Effect of Prolonged Ovabian (Corpus Luteum) Feeding ox the Male Rat.

At the same time that observations were being made on the effect of anterior-lobe (pituitary) extract, similar experiments were being conducted to test the effect of ovarian (corpus luteum) feeding upon another rat of the same litter. The latter were carried out in order to observe the results of feeding another glandular mieleo-proteid substance per se, without regard to any specific action upon general bodily development or upon genital development, and incidentally to determine whether any retarding or inhibiting influence was exerted upon the development in general or sexually. The latter effect. if obtained, would seem to indicate that the ovarian extract exerts a counteracting or neutralizing influence upon the need for the secretion of the testis, ami thus interferes with its development.

Two male rats were used in this observation, as any slight histological differences in the testes would be readily recognized. The con. lens. .1 tabulated protocols in the following table show the effect of ovarian feeding on Male II of Litter 1 a- compared with Male III of the same litter, which, was used as tie- control without glandular administration. (The administration at the same time of anterior-lobe extract to the male of Pair I. Litter I (Tables Y1I and VIII), in another observation, makes it possible to compare the effects of anterior-lobe and ovarian feeding.)

Ovarian feeding was begun to Male II on March 8, 1913, when the animal was 5 weeks (accurately. 36 days ) old. and was continued for 42 days, or until April 19 {cf. Table XI). when the right testis was removed surgically without sacrificing the animal. The right testis of the control had been similarlyremoved on April 19. Both glands were at once weighed and fixed in formalin and later sectioned for histological comparison. The feeding of ovarian extract was then continued to Male II until, August 30, making a total period of feeding of 5 months and 3 weeks. On this date both animals were sacrificed and the remaining left testis was removed from each, preserved and studied comparatively. Thus we were able to make two comparative observations on the testes, one early in the period of feeding and the other at the age of 7 months. The dosage of the ovarian extract, by weight, was the same as the dosage of anterior-lobe extract to the male of Pair I. namely, 0.1 gm. daily for -2 weeks and then 0.05 gm. until the end of the experiment.

In comparing the summarized protocols, it is seen that the proton- r of corpus-luteum extract over a period of

6 months had the following effect :.

Whereas, at the beginning of the observation, the control animal was considerably the heavier (5.5 gms.). nevei the ovarian-fed male soon overtook the control in weight {cf. under April 13) and at the end of the experiment weighed 15.G gms. more than the control {cf. August 10). owing in Large part, undoubtedly, to an early and greater deposit of fat subcutaneous! a troperitoneaUy. This is in keeping with

results obtained pr riously (Tables II and IX).


February, 1016.]

In spite of the greater body-weight of th d male,

the testis is -mailer in gross and the weight of the gland ,„,, onlj absolutely but in proportion to the bod; Thus, on April 20 the weight of the right testis of the ovarian1( ,,l ma]l . per 100 gms. of body-weight, was 0.945 gm., as compared with 1.11 gms., the weight of the i of the

TABLE XI— PROTOCOLS OF TWO MALE RATS OF LITTER I ONE OF WHICH (MALE II) RECEIVED OVARIAN (CORPUS LTJTEUM) EXTRACT OVER A PERIOD OF FIVE MONTHS AND THREE WEEKS, THE OTHER, (MALE III) BEING USED AS THE CONTROL. LITTER .1. Male 1L . m , M;l1 " " Control.

Ovarian (corpus luteum) leeaint, jj R i a nclul:ir administration,

for •" months and weeKs. Al , ( , , lt au topsy. 7 months. Age at autopsy, c montns.


Weight 28 5 gms. Weight, 34.0 gms.

We - ' 56 5 gms. \\ iuh.. r.T r. gms. .

Rat eaining rapidly in weight. Growing rapidly. No apparent ^„.ft„ c „nri seroOim nuite large. difference in external genitalia frurn those of Male II.


Mar." - Testes and scrotum quite large.


War "50 \ large rat External genitalia Testes and scrotum larger than in relation to body size not those of the ovari very large.


those of the ovarian-: i Male in.


\nr 13 W.ight. 103.1 gms. Weight, 100.5 gms.

His overtaken the control in Genitalia slightly larger than weight. External genitalia thos,- of ovarian-fed male. Fur haw- not developed in propor- somewhat coarser. tion to the general growth of the body.


Apr.


20 Weight. 104.8 gms. Weight. 9'J. 3 gms.

' Right testis removed (Apr. 19) Right testis removed (April 18) and placed in formalin, for and placed in formalin for subcomparison, at this early sequent histological comparistage, with the testis of the] son. eoi 1 male. .

Weight of right testis. 0.990 gm. Weight of right testis. 1.140 gms. Appears -mailer and feels less Larger and feels firmer than firm than the testis of control male.

Tunica albuginefl is slightly more vascular.

Fur is less coarse.

May 17 Weight. 177.1 gms. Weight. 146.3 gms.

A larger, more vigorous rat than Animal smaller, less fat-looking


that of Male II (ovarian-fedi. On cross-section tin' tubular structure of the testis appears coarser.


control. Has considerably overtaken the control animal in weight, apparently owing to a greater deposition of fat.


June 1 .Weight, L'30.9 gms.

to Animal has been gaining rapidly July 27. in weight. Testis smaller than that of control.

Autopsy. Aug. 10. Weight, 229.3 gms.

Mei, subcutaneous and retroperitoneal fat than in control.

Weight of left testis, 1.930 gms. Smaller on gross inspection and by weight, although in general this animal is considerably- heavier than the c mtrol.

Weight of left testis after fixation and clearing in oil. 1.460 gms.

Weight of seminal vesicles, prostaiie gland and bladder. 1.770 gms. i after fixation and clear ingi.


than Male II. The testes both the control and Male II I ovarian-fed) are smaller than those of the anterior-lobe-fed male of Pair I of the same litter (cf. Table VII).

Weight. 198.0 gms. Gaining in weight less rapidly than the ovarian fed male.


i utopsy. Weight. 203.7 gms. Less fat generally than Male II.

Weight of left testis. 2.30 gms. Larger on gross inspection and by w.ight than testis of Male II. though this animal is considerably smaller than Male II. receiving ovarian extract.

Weight of left testis after fixation and clearing in oil, 1 f90 gms.

Weight of seminal vesicles, prostatic gland and bladder. 1.830 gms. (after fixation and clearing).


control; and on August 10 the weight of the lefl I ovarian-fed animal was 0.610 gm. as compared wit] 0.81

ight of the lefl testis of the control. Although limed weight of the seminal bladdei is only slightly greater in the control animal i I nevertheless, when considered in relation to the bo

rence per 100 gms. of body-weight is Ear more There seems to have been a definitelj ad pose i whole body of the male produced by the fee


luteum extract. Tins corresponds with results previously

recorded (Tables II and IX i. The condition may be c pa red to a sort of eunuchoid state, and it is probable, furthermore, that the internal as well as the external secretions of the testis have been inhibited, or that the demand for the production of thi - '••• the testis has bei □ neutralized by the feeding of the ovarian extract. This would explain the greater body-weighl and the diminished size and development of the sex glai

It is interesting also to note that the growth of the external genitalia both of the ovarian-fed animal and of the control was less rapid than in the male of Pair I of the same litter, which received anterior-lobe extract in connection with a net In r experiment (cf. Table VII).

The gross testicular structure is coarser, and the tubules, even to the naked eve. are larger in the control than in the ovarian-fed animal. The fur of the ovarian-fed animal is softer and more delicate.

It is apparent, then, from the above facts, that the feeding of corpus-luteum extract to the male rat produces an ini body-weight, due to the general deposition of fat, and that it has a definitely retarding influence upon the growth and development of the genital system. This is especially evident when we compare the results obtained from the feeding of anterior-lobe (pituitary) extract under the same conditions.

The succeeding two tables uive the histological findings in the testis, epididymis, .seminal vesicles and prostatic glands of the ovarian-fed male and the control. In the first of these tables (Table XII) the right testes of the two animals, which were removed surgically after 42 days of ovarian feeding to Male II. are compared. In Table XIII the. findings in the remaining left testis of each rat at autopsy at the age of 7 months are given. Thus, we have, then, the results obtained

by f ling corpus-luteum extract over a short period of I".'

days and after a long period of 5 months and 3 weeks.

TABLE XII.— COMPARATIVE HISTOLOGICAL FINDINGS IN THE RIGHT TESTIS OP MALE II, LITTER I, (OVARIAN FEEDING FOR FORTY-TWO DAYS) AND IN THE RIGHT TESTIS OF MALE III, LITTER I (CONTROL, RECEIVING NO GLANDULAR EXTRACT).

I. TITER I.


Male II. ovarian feeding for 42 days, begun when animal was ."> weeks old. Right testis removed at the age of 2 '.. months.


Weight of right testis. 0.990 gm.

.s;,, , iimIi.i, ,,, .-is fairly well advanced. Active karyokinesis. Tubules in large pari contain spermatids and spei I in smaller number than in Many tubules show all karvokinesis and only one i

cell rows ; 501 1 thesi

have an atrophic apP 1 I.uinina less full and fewer sperm., i

Interstitial cells few ; here and there a fuiri / pidid aller I ban In

Fewi i

ated cells

they '

Lining

plasm less abund

the pi otop (fat?).


Male III. Control. No glandular administration. Right testis removed at the age of -'months.


of right testis, 1.14n gms - - definitely farther advanced, practically complete. All tubules contain spermatozoa and show active karyokinesis Lumlna of the tubules mostly

contain a considerable I "tit

of seen tion, spermatozoa and


free


ells


Interstitial cells more numerous.

lid : r than in Male

II. Epididymis larger. much more i, i

Ids, In the tu fairly tall, more ciliated and richer In profr plasm. No < •

out the


48 [ No. 300


TABLE XIII.— COMPARATIVE HISTOLOGICAL FINDINGS IN THE REMAINING LEFT TESTIS OF MALE II, LITTER I, (OVARIAN FEEDING FOR FIVE MONTHS. AND THREE WEEKS) AND IN THE LEFT TESTIS OF MALE III, LITTER I (CONTROL, WITHOUT GLANDULAR ADMINISTRATION).

LITTEK 1.


Male II. Ovarian (corpus luteum) feeding for 5 months and 3 weeks, beginning when animal was 5 weeks old.

Left testis nt autopsy 'it thi <"» of : months.

Weight of left testis. 1.930 gms.

Sj<( rmatogenesis moderately active. The tubules contain relatively few spermat. zoa. The spermatogone cells are less closely packed and in manv places are arranged in fewer cell ' rows. The lumina of the tubules on the whole are not filled with free cells and secretion.

Interstitial nils are few in number and with a scant amount of protoplasm, which gives them an atrophic appearance.

Epididymis: Lumina of the tubules are large, and in many instances contain little, or no secretion. The lining cells are of the low columnar type and without a ciliated border. In some tubules spermatozoa are present in moderate numbers, in others they are absent altogether. There are very few free cells in the tubules.

Seminal Vesicle: Made up of large simple tubules, lined with low columnar epithelium. There is verv little secretion in the tubules, in which mi spermatozoa are seen.


Prostate Gland: Simple acini with a small amount of secretion and no spermatozoa.


Left testis at autopsy ai tin agi of ~ months

Weight of left testis. 2.30 gms.

spermatogenesis very active. All the tubules contain a great many spermatozoa and intermediate cells. The tubules are lined with many rows of cells in compact arrange ment, and most of them are filled with spermatozoa, free cells and secretion.

Interstitial cells are definitely more numerous and larger and occur in larger groups than in Male II

Epididymis: The tubules are very nearlv of the same size as in Male II. but are filled and distended with secretion containing enormous numbers of spermatozoa. There, are no tubules without great numbers of spermatozoa. The cells lining the tubules are larger than in Male II, and nonciliated. Very few free cells are seen in the tubules.

Seminal vesicle consists of large tubules with wide lumina. as a result of being filled with secretion. The lining epithelium is, in consequence, thinner and lower. There is more infolding and irregularity of the walls, indicating proliferation of the lining cells.

Prostate aland shows evidences of proliferation : also lymphoid cell accumulation. No spermatozoa seen.


Prom the two foregoing tables it is seen that the feeding of corpus-luteuni extract over a brief period of 42 days and over a longer period of 5 months and 3 weeks had the following effect upon the male sexual system :

The gross size and weight of the testis, both absolutely and in proportion to the body development, is less than in the control. Spermatogenesis is not so active, and as a consequence spermatozoa are less numerous. The interstitial cells of the

• stis are fewer in number and have a scantier protoplasm and a more atrophic appearance. The epididymis is smaller, it looks less active and contains less secretion and fewer spermatozoa and free cells in the lumina of the tubules. The cells lining the latter are of a lower columnar type and are not as abundantly supplied with ciliated borders. Moreover, at autopsy the seminal vesicles and prostatic gland of the ovarianfrd male appear smaller, less active and contain less secretion than those of the control (Fig. 13).

From these facts we see that the retarding influence of ovarian extract upon the male sexual development is exerted throughout the life of the animal, and not only upon the testes hut also upon the entire genital system.

Discussion of Results. It is the anterior-lobe element in the secretion of the pituitary gland that is to be looked upon as supplying the principle responsible for the stimulating and activating influence upon sexual development and function. This explains why. in the


disease acromegaly — now generally believed to be due to an over-function of the anterior lobe of the pituitary gland consequent upon adenomatous hyperplasia — we find in the earlv stage an exaggerated sexual activity and libido, and in the late stage, that corresponds with pituitary involution and inactivity, a disappearance of the sexual function. The sex glands in this late stage show, histologically, atrophy and various forms of degenerations. Additional light is thrown on those experimental and clinical conditions of underdevelopment and genital inactivity and hypoplasia occurring in conditions of experimental removal of the anterior lobe of the pituitary, and in clinical conditions of under-function consequent upon disease of the pituitary itself, or of its neighborhood, compromising the function of the gland.

The belief, furthermore, that a deficiency of posterior-lobe (and pars-intermedia) secretion is responsible for the genital hypoplasia seen in many clinical and experimental disorders of pituitary function, as suggested by Biedl. 36 seems untenable, in view of the results obtained by the feeding of posterior-lobe extract to rats. The latter extract certainly does not stimulate, but would seem even to retard, sexual development; consequently its loss should not be associated with genital hypoplasia. By " posterior-lobe "' extract, as used in these experiments, we mean as well the extract of the pars intermedia, that anatomical division of the pituitary gland which closely invests the posterior or nervous lobe proper and which would naturally go with the latter when the gland is divided into its two main divisions of anterior and posterior lobes. Extracts made from the posterior lobe would thus ordinarily contain pars intermedia substance. Furthermore, it seems to have been shown beyond doubt that the secretion from the pars intermedia travels through the meshes of the posterior lobe and therefore would lie contained in the latter. (Herring," Cushing and Goetsch, 3 ' Cow. 39 )

It seems probable that in conditions interfering with the normal function of the pituitary gland, both the anterior and posterior lobes are involved, and that we therefore see in the corresponding clinical states symptoms due to disturbances in both lobes. We know that a deficiency in posterior-lobe secretion is followed by a tendency to the deposition of fat and to changes in metabolism such as an increased tolerance for carbohydrates.'" and that these changes can be favorably influenced by the administration of posterior-lobe extract. The genital disturbances which are associated with these changes in clinical states should therefore be benefited by the administration of anterior-lobe extract. The carbohydrate tolerance,


"Biedl, A.: Innere Sekretion, 1913, 2te Aufl., Theil II, 187.

»' Herring, P. T. : The histological appearances of the mammalian pituitary body. Quart. Journ. Exper. Physiol., 1908, I, 121-159.

M Cushing, H., and Goetsch, E.: Concerning the secretion of the infundibular lobe of the pituitary body and its presence in the cerebrospinal fluid. Am. Journ. Physiol., 1910, XXVII, 60-86.

»Cow, D.: On pituitary secretion. The Journ. of Physiol., 191a, XLIX, No. 5, 375-376.

"Goetsch, E., Cushing, H., and Jacobson, C: Carbohydrate tolerance and the posterior lobe of the hypophysis cerebri. Bull. Johns Hopkins Hosp., 1911, XXII, 165-190.


February, 1916.] 19


which, as was stated in the paper just quoted, could be used as an index to posterior-lobe deficiency, might also serve a similar purpose in determining the degree of anterior-lobe deficiency. and thus be a guide to the dosage to be used in our gland therapy. From this it becomes evident that the best results should be obtained by giving pituitary whole-gland extract in these clinical cases of under-function of the hypophysis.

As a result of the farts learned from the feeding of pituitaryextract to rats, we should feel encouraged in our efforts to benefit states of ductless-gland under-function. particularly of the hypophysis, by the oral or possibly the hypodermic administration of gland extracts. Considerable success has already been obtained from such therapy. Thus, for example, a number of cases of pituitary disease, showing, among other symptoms, the characteristic sexual disturbances (amenorrhoea, and loss of libido and potentia si vualis), have been n by Cashing* in which, after administration of pituitary extracts by mouth, there has been a return in part or entirely of menstruation and of libido and potentia sexualis. In the -am place, supplementary feeding after surgical procedures on the pituitary gland is recommended. Since many of the clinical conditions showing genital aplasia, adiposity and underdevelopment combine symptoms referable to certain of the ductless glands other than the pituitary, the extract of the latter should be given to help bring about normal sexual development and activity, and with it might be given extracts of other ductless glands which would seem certainly to be involved.

And lastly, it seems likely that when we have learned the effect of administration of the different glandular extracts, such as the inhibiting effect of ovarian feeding upon the male sexual development, we could treat conditions of over-activity of one of the ductless glands with extracts of another of the endocrine series possessing an opposing or inhibiting action.

Conclusions.

I. The dried powdered pituitary extract derived from both the anterior and posterior lobes of the gland, when fed to young rats in excessive doses (0.1 gm. daily), causes failure to gain in weight, loss of appetite, increased peristalsis, a mild enteritis, and certain nervous manifestations, such as muscular tremors and weakness of the hind limbs. The latter -vmptoms are undoubtedly due to the posterior-lobe element in the wholegland extract, for they are similarly produced by using posterior-lobe, but not by using anterior-lobe extract. Even when whole gland is fed over a short period of time, from 25 to 40 days, it causes a more rapid growth and development and gain in weight, larger nipples in the female, and a i drier, harsher growth of hair than are seen in either control animals or after similar administration of ovarian (corpus luteum) extract in equivalent dosage.

The Influence I'pon the Fem< ands. -Id compari son with the development in control animals, the ovaries, tubes. and cornua of the uterus of animals fed with whole-gland


" Cushing, H. : The pituitary body and its disorders, Philadelphia. 1912, p. 318.


extract are larger, more vascular and (edematous in appearance, indicating increased development and activity. Even at the early age of 2% months, from one to two months before normal sexual maturity, the ovary is matured, and shows ovulation and Graafian-follicle formation, relatively few primordial follicle- and some increase in the amount of interstitial tissue. This rather striking appearance in so young an animal gives one the impression that an early ovarian maturity has been produced by the feeding of the pituitary extract. The fimbriated end of the tube is more branched and the lining columnar cells are more ciliated, an indication of greater activity. There is marked hyperplasia of the uterine mucosa. the lining cells of which are more uniformly ciliated and active, and there is abundant gland formation in the endometrium. The appearance presented by the latter strikingly resembles in microscopic appearance the hyperplastic endometrium of early pregnancy. There is a generally increased vascularity produced in the whole sexual system. The overdevelopment is apparent even in the muscle coat of the uterus, which is considerably thickened and is also more vascular. A somewhat similar change is produced by the feeding of corpus luteum to the female (see below. IV I.

The Influi m • I pon the Male Sex Glands. — The testes show a considerably earlier growth and development ; they are completely and permanently descended at an earlier age. and their gross weight is greater than in the control animal. This is evidenced by the extremely active spermatogenesis, with formation of spermatozoa, and by a moderate increase in the amount of interstitial tissue, at a time when the control animal is sexually still very immature. All these developmental, structural and functional changes in the sex glands of both the male and the female, produced by the feeding of pituitary extract, show an extremely selective and almost specific action of the latter upon the genital system.

II. The feeding of pituitary anterior-lobe extract causes increased weight and greater and more vigorous body-growth and development over the control. There is similarly an earlier and more active genital development. The fur is harsher and thicker. Loss of weight, enteritis, and nervous manifestations are not observed as in the beginning of wholegland feeding (see above, I). As compared with the control, the animal fed with anterior lobe for only 40 days shows an earlier descent of the testes, which are also larger, more vascular and heavier, not only absolutely, hut in proportion to the body-weight. The testis is mature at least as early as 2\ months, after 40 days of anterior-lobe feeding. The period of complete sexual development is shortened by at leasl one month, or about one-third of its normal time. Histologically, the testis at tin- .i_ ; it shows an abnormally early

and active karyokinesis, more active in fact than is seen in the b stis of a normal rat at the age of from 3 to 4 month-. Th( testis of the control at this same age i> quite immature. The interstitial .ell- do not seem to increase in number proportionately to the increase in spermatogenic cells and spermatozoa. The epididymis contains more spermatozoa ami has a more active-looking structure. The prostatic gland, seminal


50 [No. 300


. and vas deferens show a correspondingly oarlv and

elopnient and activity. These changes produced

by the feeding of anterior lobe indicate that the latter supplies

the active principle in the whole gland responsible for the

bove, following the feeding of whole-gland

extract.

After prolonged feeding of anterior-lobe extract, over a period of 8 or 9 months, the sexual instincts are early awakened. along with the early maturity of the sex glands. As a result el' this, a pair of rats, after anterior-lobe feeding over a number of months, bred earlier and oftener, the female of this pair having two pregnancies in 7 months, as compared with none in the female of the control pair. The effect of anterior-lobe feeding lasts throughout the adult life of the animal. The control rat never reaches the degree of development and activity shown by the animal receiving the anterior-lobe extract. For even at the age of 10 months, after 8^ months of anterior-lobe feeding, the latter still shows a greater, more active and mature sexual development than the control.

The feeding of pituitary anterior lobe to parent rats exerts its stimulating influence upon the offspring in intra-uterine life and during lactation, and. when the experiment is carried further, and the feeding to the young is continued after weaning, it has an even greater stimulating effect upon growth, weight and development, and causes earlier and more frequent breeding, and an increased number of offspring in the litters. The stimulating effect upon the: sex glands is greater, the longer the influence of anterior-lobe administration i> exerted.

III. The extract of pituitary posterior tohe, even after prolonged administration, does not stimulate growth in general. nor the development of the sex glands, as does anterior lobe even after a very short period. Thus, for example, there is a much less marked development of the sex glands after administration of posterior lobe for 7i months than after anterior-lobe administration for 2i months. The posteriorlobe element in the whole-gland extract has an undoubted retarding influence upon the development of the sex glands. an effect very similar to that of ovarian extract upon the testes. This is shown by the relatively incomplete development of the


testes, for example, after S] months of posterior-lobe feeding. If given in too large a dose, the extract causes in the rats loss of weight, a mild enteritis and increased intestinal peristalsis.

I V. Ovarian extract (corpus luteum ). when fed to the male, especially, causi s a tendency toward the deposition of fat, not only in the body generally, but in the testes and other glands as well, with a resultant marked increase in weight. The fur is heavier and coarser than in the animal fed with the posteriorlobe extract. It does not cause an early descent of the testes. The latter are slightly hea\ ier than those of the posterior-lobefed animal. This may be due. however, to an inhibiting effect exerted by the posterior-lobe extract rather than to any stimulating effect of tin' ovarian extract. The tendency to retardation of testicular development i> possibly more definite after ovarian feeding than after posterior-lobe feeding. Corpus luteum. when fed to the female rat. is equally as stimulating as whole pituitary gland (active because of the anterior-lobe element which it contains), but not so stimulating as the equivalent weights of anterior lobe.

Following ovarian feeding there is. as compared with conditions in the control, increased development and activity of the female sex glands, increased follicle formation, a moderate increase in interstitial tissue and increased branching of the fimbriated extremity of the tube. Prolonged ovarian feeding. e. g., for 5 to ti months, to the male rat. as compared with the control, has the following effect : The gross size and weight of the testes, both absolutely and in proportion to the body development, is less, and histologically the sex gland- of the male show a retarded development and evidences of diminished activity. The definitely retarding influence of ovarian extract upon the male sexual development is exerted throughout the life of the animal.

Brieflv then, we can say that pituitary extract (anterior lobe), wdien fed to young rats, has a stimulating effect upon the growth of the animal and upon its sexual development and activity. Posterior-lobe extract, when thus given, lias a retarding influence. Ovarian extract (corpus luteum ) has a stimulating influence upon the female, and a retarding influence upon the male, sexual development.


A CASE OF PSEUDO-HERMAPHRODISM, WITH REMARKS ON ABNORMAL FUNCTION OF THE ENDOCRINE GLANDS. 1

By Wm. C. Quinby, M. D. (From the James B. Brady Urological Institute, Johns Hopkins Hospital)


Bobert S. was admitted to the Brady Clinic of The Johns Hopkins Hospital on June 8. 1915, for hypospadias and undescended testicles. He was 10 years old in July. 1915.

The family history relates that one brother died at birth. and one at 7 months of age. One younger sister is living and is normal. Both parents are well : they are first cousins. The


1 1 take pleasure in extending my thanks to Dr. Hugh H. Young for permission to operate on this patient and to report the case.


father has a slight hypospadias with the meatus about half an inch below the apex of the glans.

Until two year- of age the patient suffered from " marasmus," but otherwise has been entirely well and strong, and has had none of the exanthemata. His mentality is considered good, and he is now in the third grade, although attendance at school began only two years ago. His habits and activities are those of a normal boy; he spurns girlish pursuits, and much prefers such games as foot-ball. The pubic and axillary


February, 1916.] 51


hair has been present for four years. The voice lias always been " coarse" and the hands and feet " stubby." Since birth

the urethra has opened at the base of the penis and t!

havi not descended. There is an entire absei dstory

of abdominal pain or crises suggestive of retained mens

there has never been any bleeding from the penis. Libido has

not appeared as yet.

Physical examination finds the general bodily condition and color excellent. The musculature is well developed. The head is rather large, with prominent frontal regions, and the shoulders though broad, are markedly stooping. The forehead is of moderate height; the face is broad; the lips are thick; the nose is flat. The hair, dark brown in color, is rathi and is lacking over each lateral frontal region. The eyebrows are more sparse in their outer portions than toward the root of the nose. The eyes. ears, and mouth are normal. The ears show n<> stigmata and the upper central incisors are no broader than the other incisor teeth. The palate is moderately high. There is a considerable amount of fine hair on the upper lip; the axillary and pubic hair is abundant, the latter showing the female type of distribution. The hands are broad and short, the finger-nails have been bitten. The skin over the body is somewhat harsh. There are no abnormal deposits of fat. On examination, the heart, lungs; and abdomen are entirely normal. The breasts are undeveloped and of the male type. Very careful palpation shows no sign of any abnormal abdominal mass. There is no unnatural pigmentation of the skin. The growth of hair below the knee on each leg is in marked

On examination of the genitalia, the phallus is found to be represented by an organ 5 cm. long, curved markedly toward its ventral surface. There is a well-developed prepuce drawn into folds on the dorsum, but nut uniting completely in the mid-line on the ventral side. This covers the elans, which iwell developed except for the meatus, which is replaced by a ventral groove. At the base of this structure, between it and the slightly prominent mons, the skin rises in a fold, and encircling the phallus, extends downward on either side to form the bifid scrotum or labia majora. No testes or spermatic cords are to be felt anywhere. When the glans is drawn upward, the opening of the urethra is seen at a point corresponding to the peno-scrotal junction. From this to the ti] glans the middle line shows a longitudinal gutto r covered by striae of mucosa. The perineum from meatus to ami- is smooth and without trace of depression. There is nothi s labia minora. An abundance of hair is present, and the skin of the perineal region and adjacent thighs is harsh and

Then is a definite lack of equilibrium on the pari superficial vaso-niotor system. The hand- are cold, clammy, and often of dusky hue: the skin of hows mottling

on cooling, and the patient blushes very readily. All I relieves are lively, but there is no cremasteric reflex.

Rectal examination shows an apparent absi l

late, although in the region above this area there is felt a small mass which is about 2 cm. long and 1 cm. broad, nol and only slightly movable.


Radiog the head, chest, abdomen, pelvis and hands

are entirely normal. The urine is normal, and the n s of 150 gra ixtrose caused no glycosuria. The phenol sulphonephthalein output was 00 per cent during the first hour. The Wassermann test was negative.

I'd l-pn -- - -lie. 115; diastolic, 90.

Blood count: Red blood cell-. 5,128,000; white hi I cells,

7,780.

Differential count :

Polymorphonuclears 7.", . :.

Small mononuclears 12

Large mononuclears 4 .".

Transitional 4 . CK,

Eosinophils 4 e

Blasts none


100. ck;

Pharmacodynamic tests: Following the injection of five minims of adrenalin 1 : 1000. the systolic blood-pressure rose from 115 to 135 in the following 15 minutes, again reaching normal in 25 minutes. There were a few extra systoles during this time, hut no tremor, no change in the pupils, and no subjective signs. The pulse count reached 165. 10 minuteafter the injection. The injection of seven minims showed nothing further.

The eyegrounds ami the perimetric fields were normal. Hearing was normal.

Measurements:

Weight 34 . kilos.

Height, standing 146.0 cm.

Height, sitting 80.0 cm.

Span of arms 144.0 cm.

Girth of chest, at rest 73.5 cm.

Girth of chest, on inspiration 77.0 cm.

Girth of chest, on expiration 70.0 cm.

Length of head 18.3 cm.

Width of head 15.0 cm.

Height of face 10.5 cm.

Width of face 12.5 cm.

Height of palate to incisor teeth 4.5 cm.

Circumference of neck below thyroid cartilage 31.5 cm.

Circumference of abdomen at umbilicus 67.0 cm.

Distance between anterior superior spines 21.0 cm.

Distance between iliac crests 22

Distance between femoral tuberosities 26 . 5 cm.

Distance between top of symphysis and top of sacrum . . 17.0 cm.

Distance between top of symphysis and umbilicus 13.0 cm.

Distance between umbilicus and sternal notch 35.0 cm.

Distance between acromion processes 33.0 cm.

Distance between anterior superior spine and bottom of

patella (left) 42.0 cm.

Distance between anterior superior spine and bottom of

patella ( right I 41.5 cm.

Distance between anterior superior spine and internal

malleolus I left ) 73.0 cm.

Distance between anterior superior spine and internal

malleolus (right) 71.9 cm.

Length of feet (each ) 28.0 cm.

Circumference of thigh (each) 42.0 cm.

Circumference of knee l left) 29.0 cm.

Circumference of knee (right) 30.0 cm.

Circumference of calf (each) 28.0 cm. [No. 300


Distance between acromion and olecranon (left) 30.0 cm.

Distance between acromion and olecranon (right) .... 31.0 cm.

Distance between olecranon and ulnar styloid (each) . . 20.0 cm.

Circumference of biceps (left) 21.0 cm.

Circumference of biceps (right) 22.5 cm.

Circumference of forearm (left) 20.0 cm.

Circumference of forearm (right) 21.0 cm.

Circumference of wrist (each) 14.0 cm.

Circumference of hand (left) . . 18.0 cm.

Circumference of hand (right) 19.0 cm.

It will be of interest to compare some of these measurements with the averages obtained by Porter in his examination of over 34,000 school children. 2 We can thus roughly determine the age and sex which our patient most nearly approximates.

Weight most nearly corresponds to Porter's Boy of 13.

Height standing most nearly corresponds to Porter's. . .Girl of 13.

Height sitting most nearly corresponds to Porter's Boy of 15.

Span of arms most nearly corresponds to Porter's Boy of 13.

Girth of chest most .nearly corresponds to Porter's Boy of 14.

Length of head most nearly corresponds to Porter's. . . .Boy of 13.

Width of head most nearly corresponds to Porter's Boy of 16.

Height of face most nearly corresponds to Porter's Boy of 15.

Width of face most nearly corresponds to Porter's Boy of 13.

Although this is a rough comparison, it is interesting in showing that most of the measurements fall nearest to those of boys of from three to six years older than our patient.

An operation was performed on June 14, 1915, to better the hvpospadic condition and to search for the supposed testicles and bring them down. No trace of the spermatic cord could be found in the inguinal canal. On entering the abdomen I discovered an infantile uterus with tubes and ovaries of normal appearance. An ovary, with an adjoining portion of its tube, was excised for histological examination.

Histological Report.

The specimen consists of an ovary 2.5x1.3x1.7 cm., together with about 5 cm. of tube, bearing normal fimbria?. Eunning from one side of the ovary is a layer of very thin tissue, apparently a bit of the broad ligament, containing on one surface a small, very flabby mass in the position of the parovarium. The surface of the ovary is smooth, and on section it is seen to contain numerous areas varying in size. presumably follicles. The larger of these contain bloody fluid, the smaller watery fluid.

Microscopic Examination. — Sections of the ovary show a typically normal structure. Graafian follicles contain ova in various stages of development. No corpora lutea are seen, although there is in one area a splendidly preserved corpus fibrosum. A careful search failed to show any abnormal elements.

The Fallopian tube shows the usual papillary-like foldings of mucosa with normal epithelium.

The parovarium shows numerous tubules, thin-walled, ami having a single layer of epithelium.


2 W. T. Porter: The Growth of St. Louis Children. Trans. St. Louis Acad. Sci., 1S95, VI, 263.


DlSCUSSIOX.

It is evident from the foregoing that we are dealing here with a case of atypical sexe-ensemble, more commonly, though less correctly, called pseudo-hermaphrodism. The sex of an individual must always be determined by the nature of the gonad, regardless of the presence of abnormalities either of other parts of the genital system or of the secondary sexual manifestations of the body as a whole. Consequently, this patient is of the female sex ; and this in spite of so many secondary characteristics of the opposite, male, sex.

In the sphere of the internal genitalia the development has followed a normal course ; uterus, tubes, and ovaries are present, and are normal so far as examined. The external genitalia, however, show many deviations from the normal female type. The urethra opens in its usual position, but the clitoris is much overdeveloped, closely resembling a penis of the hvpospadic sort, and there is no external trace of vagina. It is to be presumed, on morphological grounds, that a rudimentary vagina exists, but attempts to examine the posterior urethra with an endoscope were without conclusive result because of the small size of the structures.

The patient, therefore, belongs to the class of female pseudohermaphrodites of the externa] type. But though the external genitalia are atypical, it is in the domain of the secondary sex characteristics that the most marked deviations are found. The voice, the hair on the face, the general bodily habitus, and the mental processes are all of the heterologous male type. Indeed, on adding the precocious hair development to the above appearances, this individual seems to possess a degree of maleness considerably greater than that usual in normal children at 10 years of age. The comparison with the normal averages of Porter given above bear out this impression. Only the distribution of the pubic hair, and the configuration of the thighs remain of the female type. In this respect the case is unusual, for though over two thousand case reports of pseudo-hermaphrodites are to be found in the literature, 3 those bearing the male gonad are about ten times as common as those bearing the female; and in these latter only a few reports describe such complete presence of the heterologous secondary manifestations of sex.

Relations between the Endocrine Glands and Sex Aberrations. — There has been of late years a rapidly increasing amount of evidence, both experimental and clinical, tending to show that the proper development of those attributes which constitute the. sexe-ensemble is dependent on normal activity of the endocrine system. Though it is to be doubted that internal secretory processes play any role in the primary determination of the sex of the gonad itself, it is certain that such processes are responsible for the normal progress of events from a very early age. The present teaching is well stated by Barker * when he says : " We are simultaneously, in


3 Neugebauer: Hermaphroditismus beim Menschen. Leipzig, 1908; also, Jahrb. f. sexuelle Zwlschenstufen. Bd. V.

Barker, L. P. : On abnormalities of the endocrine functions of the gonads of the male. Am. Jour. Med. Sci., 1915, CXLIX, 1.


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.



Figs. 1 and 2. — Front and side views of head Xote the shape ot the calvarium; the fiat nose and thick lips: the hair distribution in eyebrows and on upper lip.



Fig. 3. — Front view of body. Not< the male shoulders; the broad, short hands; the pubic hair with horizontal upper edge; the rather feminine rotundity of thigh, and the hypertrichosis of legs.



Fu;. 4. — Front view of trunk. Note the typical male breast and shoulders.


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.



Fig. 5. — Lateral view, with the patient standing, to show the general poise and round shoulders.


Fig. 6.— Right hand: to show the severely bitten finger nails and the configuration — the main in large of Marie.



Fig. 7. — The external genitalia. Note t lus with prepuce, and labia majora simulating a bifid scrotum; also the extensive growth of hair and the coarse skin.


Fig. S. — The external genitalia with the labia separated and the phallus raised. The median furrow of mucosa is seen, bearing the urethral opening, represented by a dark spot half-way between the examining fingers and thumbs. Note the entire absence of vagina.


THE JOHNS HOPKINS HOSPITAL BULLETIN, FEBRUARY, 1916.


PLATE XIII.



Fig. 9. — Low-power magnification of ovary, to show follicles.



Fig. 10. — Low-power magnification of tube in cross-section.



Fig. 12. Fig. 13.

Figs. 12 and 13. — Graafian follicle? containing ova in various stages of development.



Fin. 11. — Low-power magnification of parovarium showing l he characti epithelium-lined tubules



Fig. 14 A corpus liiircjsutn showing healing after rupture of a follich


February, 1916.] 53


a sense, the beneficiaries and the victims of the chemical correlations of our endocrine organs."

Space will not permit a detailed consideration of the probable, physiological action of each of the hormone-producing organs. We must, however, consider at some length the relation of the adrenal cortex to sex. for abundant and convincing evidence of its importance in this regard is at hand.

It will be recalled that the adrenal cortex i- devel >ed from the Wolffian ridge — that is. from the same rudimentary tissue as is the sex-gland — whereas the medulla is of neuroectodermal origin, as are also the sympathetic ganglia. During intrauterine life the gland is about equal in size to the kidney. This is due to an enlargement of the inner portion of the cortex — the so-called fetal cortex — which begins to degenerate at or soon after birth. The medullary portion of the gland produces adrenalin ; the cortical area is considered to lie the source of a hormone that influences growth, nutrition, and especially the reproductive organs. 5 Clinical and pathological evidence demonstrates the remarkable effect that lesions of the adrenal cortex exert on the various factors constituting sex. Pathologically such lesions may consist of simple hyperplasia, or there may be found hypernephromata. During pregnancy in human beings,, and in some animals during heat, hyperplasia seems to be a normal process. Much light has been shed on this whole subject by the admirable communication of Bulloch and Sequeira ; ° of Pibiger;' of Apert : s of Launois, Pinard, and Gallais : ' and of Glynn : "'and most recently by the exhaustive review of the literature in the article of Hofstatter."

The clinical manifestations of disturbed function of the adrenal cortex vary according to the age at which the disturbance arises. Apert makes five groups: (1) Case- in


"Vincent, S.: Ergebnisse d. Physiol., 1910, X, 581.

"Bulloch and Sequeira: On the relation of the suprarenal capsules to the sexual organs. Trans. Path. Soc. Lond., 1905, LVI, 189.

7 Fibiger: Beitrage zur Kenntnis des weiblichen Scheinzwittertume. Virchows Arch., 1905, Bd. 181., H. 1.

"Apert: Dystrophies en relation avec les lesions des capsules surrenales; Hirsutism et progeria. Bull. Soc. de pediatr. de Paris, 1910, December.

"Launois, Pinard, and Gallais: Syndrome adiposo-genital avec hypertrichose, trouble nerveux et menteux d'origine surrenale. Gaz. des hop., 1911, No. 43.

"'Glynn: The adrenal cortex, its rests and tumors; its relation to other ductless glands, and especially to sex. Quart. Journ Med., 1911-12., V, 157-192.

"Hofstatter: Unser Wissen uber die sekundaren Gesehlechtscharaktere. Centrbl. f. d. Grenzgebiete d. Med. und Chir., 1913, XVI, 37-420.


which the disturbance occurs in embryonal life, and is associated with a greater or less degree of hennaphrodism.

i-.'i Cases with Donna! sex organs, but with to., early and profuse development of bodily hair (hypertrichosis). (3) Precocious puberty. Overdevelopment of hair and fat. hut without trace of hermaphrodism. i4) After puberty. The menses disappear : the bodily fat increases as '1."- the hirsuties. i 5 ) Later eases -bowing loss of hair, and overgrowth of fat at the time of the menopause.

Glynn's article deals with the relation of adrenal ci tumors to sex. He rinds that adrenal cortical hypernephromata lie accompanied by sex abnormalities in children almost invariably. They are usually so accompanied when occurring in adult women before the menopause: whereas after the menopause, and in adult males, they are never so accompanied. In pseudo-hermaphrodite*, adrenal rests (or bilateral hyperplasia) are much more common in the individuals that bear the female gonad. Tumors occurring in males alter birth may cause marked bodily overdevelopment : so that a child sufrerinu; from this condition may have the appearance of an " infant Hercules." This condition may also lie associated with true sexual precocity.

The sexual changes seen in acromegaly, and after experimental interference with the pituitary body, 12 furnish evidence that this eland also exerts an action over some of the sexual characteristics. It may therefore be supposed that there existsome interrelation between the pituitary body and the adrenal cortex, though at present the evidence of such is largely speculative.

In view of the fact that such cases of endocrinopathy as the one here reported are almost surely due to an adrenal lesion, careful search was made for clinical evidence bearing on tinspecial point. None could be found, however. The pharmacodynamic tests were aegative, and no palpable t amor could be made out. Likewise, careful examination of stereoscopic radiographs of the skull showed a perfectly normal sella Turcica.

Conclusion.

A case of female pseudo-hermaphrodism of the external type is reported, showing unusual accentuation of the secondary -ex characteristics of the male. Judging from the literature, such cases represent an endocrinopathy of the adrenal cortex, surelj ; possibly al-o of the pituitary bod} .


"Crowe, Cushing and Homans: Experimental Hypophysectomy. Johns Hopkins Hosp. Bull., 1910 XXI. May.


JOHNS HOPKINS HOSPITAL BULLETIN.

The Hospital Bulletin contains details of hospital and dispensary practice ; abstracts of papers read and other proceedings of the Medical Society of the Hospital, reports of lectures, and other matters of general interest in connection with the work of the Hospital. It is issued monthly. Volume XXVJI is now in progress. The subscription price is $2.00 per year.

(Foreign postage, 50 cents.) Price of cloth-bound volumes, $2.50 each.

A complete index to Vols. I-XVI of the Bulletin has been issued. Price 50 cents, bound in cloth.


54 [Xo. 300


TITLES OF PAPERS APPEARING DURING THE YEAR, ELSEWHERE THAN IN THE BULLETIN. BY PRESENT AND FORMER MEMBERS OF THE HOSPITAL OR MEDICAL SCHOOL STAFF.


Abel, J. J.

Experimental and chemical studies of the blood with an appeal for more extended chemical training [or the biological and medical m1915, xlii. 135, 165.

Abel: J. J.. Turner, B. B„ Marshall, E. K., Jr., and Lam-son, P. D. i hi sis -Tr. Ass. Am. Phys., 1915, xxx.

Atchley, D. \V.

Nuclear digestion and uric arid excretion in a case of total occlusion of the pancreatic duct.- -Arch. Int. Med., 1915, xv. 054.

AUER, J.

The fun' tin nal effect of experimental intraspinal injections of sera with and without preservatives. — ./. Exper. .!/.. 1915, xxi. 4::.

At tit. J., and Meltzer, S. J.

Magnesium treatment of tetanus. — Tr. Asg. Am. Phys., 1915, xxx.

Baetjer, F. H., and Friedenwald, J.

Value of the X-ray in the diagnosis of gastrointestinal disturbances. — V. ) •< k M J [etc.], 1915, cii. 929.

Baetjeb, W. A., Barker, L. F., and Miller, S. R.

i . clinical diagnosis of acute leukaemic states. — Tr. Ass. Am. Phys., 1915. xxx.

Baetjer, W. A., Rowntree, L. G., and Marshall, E. K., Jr.

Further stiuli.-s of renal function in renal, cardiorenal and cardiac diseases. — Arch. Int. Med.. 1915, xv. 543.

Baetjeb, W. A., Ruhrah, J., and Ireland, R. A.

A case of lymphatic leukemia with apparent cure. — /. .1/". M. Ass., 1915, lxv, 948.

Barker, L. F.

<>n abnormalities of the endocrine functions of the gonads in the male.

Im. •/. U. Sc, 1915, cxlix. 1. The changing aspects of medicine i twenty-five years ago and now). — ./ I/. ,1. .U*. Gtuaiin, 1015-16, v. 49.

Introduction to diseases of the nervous system. — In Mod. Med., 2. ed. (Osier & McCrae), Phila. & N. i*., 1915, v. IT.

Barker, L. P., Baetjer, W. A., and Miller, S. R.

The clinical diagnosis of acute leukemic states. — Tr. Ass. Im Phys., 1915, xxx.

Beall, K. H.

'i'ht* epidemiology of pellagra. — Texas Statt •/. If.. 1915, xi. 268. Pellagra in Texas.— Tr. Southern Med. Ass., 1015. ix.

Berniieim. B. M.

Blood-vessel clamps . f practical utility. — Ann. Surg., 1915, Ixi ' 6

The newer blood-vessel operations— who should do them.- /.

If. /.. 1915, xxii. 9.

A simple instrument for the indirect transfusion of blood. — ./. Am. M.

Ass., 1915, Ixv, 1278.

Retaining clamp for a two-piece transfusion tube. — •/. Am. M. Sis.,

1915, lxiv. 1580.

Iiiemnlvsis following transfusion of blood: a study.- Lancet-Clinic,

1915, cxiii. 259.

Treatened and real gangrene of the extremities as s.-enl.y t lie modern

surgeon. Its causes and treatment. — South. If. ./.. 1915, viii. 512.

Berry, J. Mi \V

Recording the anatomical and physiological condition of feet by a

special system of measurements, and its results. — .li". / Oi thop

r I." lti.'xiii. 293.

A portable viewing box. — Am. J. Roentgenol.. 1914-15. ii. 137.

Bloodgood, J. C.

Stomach carcinoma. Its medical aspects. — ./. .Im. M. Ass., 1915, lxiv,

./.. 1915, hiii. 1:32. What every dentist should know about surgical lesions of and in the region of "the upper and lower jaw. With especial reference to the early recognition of the precancerous lesions. — ./. A T al 1915, ii. 1.

The Tobvhanna I'amp. — Mil. Surgeon, 1915, xxxvii. 117. First aid conference.— Old Dominion ! M. d x, 1915, xxi. 183. Results of the recent propaganda of caDcer control. — Penn. M. •/.. 1915, xviii, 808.

The cancer problem. — South. M. •/.. 1915, viii. 557.

What the civil surgeon can do for military surgery in times , •' peace. — South. I/. ./.. 1915, viii. 950.

What everyone should know about cancer. Pamphlets on cancer issued by the Council on Health and Public Instruction Of the Am. . 1015 : also /'mo. Health, Mich.. 1915, iii. 586.

The condition of patients after partial or complete resection of the colon. — Tr. Ass. Am. Phils., 1015. xxx.

Bloomfield, A. L.

The bacterial flora of lymphatic glands. — Arch. Int. Med., 1915, xvi. 197.

Bliwier, G.

Thrombosis, embolism, and phlebitis. — In Mod. Med. 2. ed. (0 S

McCrae), Phila. & N. Y.. 1915, iv. 526.

Boggs, T. R., and Pincoffs, M. C.

Unusual type of pulmonary mycosis. — Tr. As


Boyd, M. L.

Syphilis. — ,/. M. Ass. Georgia, 1915. iv. 338.

Papilloma of bladder. Report of two cases. — J. J/. Ass. Georgia.

Gonorrbceal ureteropyelitis : report of two cases treated by injections of antimeningitic serum. — Surg. Gyncc. £ Oost., 1915, xxi, 506.

Bridgman, E. W.

The value of the electrocardiogram in_the diagnosis of cardiac hyper -Beart, 1915, vi. 41.


-J. Am. .1/. Ass., 1015. lxiv. 391.


Brooks, B., and Allison, N.

Ankylosis : an experimental study

Brooks, B., and Murphy, F. T.

Intestinal obstruction : an experimental study of the causes of svmptoms and death. — Arch. Int. Med., 1015. xv. 392.

Brotherhood, J. S.

A simple colorimeter Eo kidney function. — ./. A m

Brown, L.

The significance of tubercle bacilli in the urine. Diagnostic tlies.-s in pulmonarv tuberculosis. — lxiv. 1977.

ainst tuberculosis. — T~i


is., 1015. s., 1915, -Month.,


Preliminary report. — •/. .1'


Phys., 1915, xxx.


Brown, L., Heise, F. H.. and Petroff, S. A.

I'eber das Vorkommen von Tuherkelbazlllen im Blute von Patienten mit Lungentuberkulose. — Ztschr. /. Tuoerk., 1915, xxiv. 97.

Bbown, T. R.

The duodenum in health and disease. — Internal. Clin.. 1915, iv. il. Intestinal stasis: the medical aspect. — Penn. M. J., 1914-15. xviii. Tn4. The normal amount of diastase in the urine and f.-eces, and its variations in diseases of the pancreas. — Tr. Ass. Am. Phys., 1915. xxx.

Brown, T. R., and Gaither, E. H.

Some observations on diagnosis of cancer of stomach. — Maryland M. J., 1015. lviii. 167.

Bunting, C. H., and Rand, P. K.

The effect of phosphorus poisoning upon the peroxidase reaction of the rabbit's liver. — J. M. Research, 1915, u. s.. xxvii, 283.

Bunting, C. H., and Yates, J. L.

The rational treatment of Hodgkin's disease. — J. Am. M. Ass. 1915,

lxiv. 1953

Hodgkin's disease and allied affections. — Wisconsin M. J., 1915. xiv. 04.

Btrnam, C. F., and Kelly, H. A.

Radium in the treatment of carcinomas of the cervix uteri and vagina — •/. Am. K. Ass., 1915. Ixv. 1874.

Burns, J. E.

Thorium — a new agent for pyelography. .1/. ASS., 1015. lxiv. 2126.

Camac, C. N. B.

Individualism or Institutionalism. Hemophilia. — Ret'. Haudb. Med. Si

Campbell, C. M.

The role of the psychiatric dispensary: a review of the first years work of the dispensarv of the Phipps Psychiatric Clinic— Am. /. Insan.. 1014-15. Ixxi. 439. Fundamental causes of dependency. — Proc. N. Jersey Oonf. Vhanttes

and Carer, tious. 1015. xiv. 45. ...

The roots of in. ntal disorder in childhood. — Sfofc ffosp. Bull., I tica, 1915, viii. s

Carter, E. F., and Pearce, R. G.

The influence of the vagus nerve on the gaseous metabollsn kidney. — Am. J. Physiol., 1915, xxxviii, 350.

Caulk, J. R. .. .„.

Diverticula of the bladder.— Interstate M. J-. 1915. ™«- 4 '* .

Surgery of the seminal vesicles and their ducts.— Surg., Qynec. d »"•-'

Exp'e'rimentarstudy of the effect of ureteral ligation 'with particular reference to its occlusion during pelvic operation— TV. Am. Ass. tffflnw Drin. Surg., 1915, x. Caulk, J. R, and Greditzer, H. G. .

Occluded renal tuberculosis.— Tr. Am. Urol. Ass.. 1915, ix. 4

A case of complete duplication of the renal pelvis and ureter.— Calif. Stati J. M.. 1015. xiii. 34. ,„,_ . ,,..,.

The mechanism of urination.— J. -4m. M. Ass., 191o, ixv. im


of the


Chestnut, J. H. Purpura, with


eport of cases.— J. Arkansas M. Soc, 1915,


February, 1916.] 55


Churchman, J. W.

Double internal jugular vein. High bifurcation of common carotid arterv. — Ann-. Surg., 1915. lxi. 235.

The treatment of ioint infections by lavage and direct medication. — inn Sunt. 1915, l'xii. 409.

Motor aphasia : with fracture of the base of the skull. — J. Am. M. A*.*.. L915 lxiv 1233.

Irrigating nozzle for cystoscopy, modification of the Young urethroscope, holder for figuration wires. — J. Am. .1/. Ass., 1915, lxv. 1027.

Cl.AKK, A. H.

A study of the diagnostic and prognostii

sure observations in cardiac disease. — Arch. Int. Med., 1915.

Clark, E. R.

An anomaly of the thoracic duct, with a bearing on the embryology of the lymphatic system. Wash.. 1915. — Carnegie Inst.. Wash.. Publ. No.

Studies on the growth of blood-vessels, by observation of i poles and by experiments on chick embryos. — Anat. lit,., r.n

Clark, J. G.

The surgical aspects of fecal stasis.— Penn If. /., 1914-15, xviii. 711. What do the newer methods of treatment offer the patient with malignant disease of the uterus. — A". York M. J. [etc.], 1915. cii, 485.

Clark, M., Marshall, E. K„ and Rowntbee, L. G.

Mushroom poisoning. Some observations in a case due to Amanita phalloides. — /. lm. It. Ass., 1915, lxiv. 1230.

Clakk, T. YV.

Can pneumonia in children be aborted? A preliminary report. — \ York State J. M., 1915, xv. 445.

Cole, R. I.

Pneumoccoccus infection and immunitv. — ,Y. York M. J. [etc.], 1915. ,-i. 1. 59; also Brit. /. Child. Dis., 1915, xii. 80.

The treatment of acute lobar pneumonia l>v specific methods.— TV. Ass. Am. Phys., 1915, xxx.

Colston, J. A. C, and Waters, C. A.

A report of. three cases of fibroselerosis of the penis treated by Rontgenization. without improvement. — Surg. Gynec. it Ob 1915

XX, 41.

CORNEK, G. W.

The corpus luteum of pregnancy, as it is in swine. Wash., 101.". — Carnegie Inst.. Wash., Publ. Xo. 222.

Crowe, S. J., and Wislocki, G. B.

Experimentelle Untersuchungen an Nebennieren mit besonderer Beriicksichtigung der Funktion des interrenalen Teiles. Beiti klin. Chir., l'.H.".. xcv. 8.

Cn.i.EN, T. S.

Unusual cases illustrating points in diagnosis and treatment. I. A calcined lymph-gland producing symptoms somewhat suggestive ,,f gallstones. II. An old and infected abdominal preirnanev with extension of the lon_- bones into the bladder and into the bowel! Ill, A further case of adenomyoma of the rectovaginal septum. IY. Operatii a for the radical cure of an umbilical hernia in a patient weighing 464 pounds. Y. Removal of a large tuberculous cyst of tie- mesentery

of the jejunum, together with the -responding segment of bowel :

recovers : later death, apparently from tuberculous meningitis

Surg., Gynec. d Obst., 1915, xx. 260, 261, 263. 265, 266.

Relation of obstetrics, gynecology and abdominal surgery to the

public welfare.— TV. Am. u. Ass., 1915, Ixvi ; Sect Obst

Abd. Surg., 13.

old infected abdominal pregnancy with extrusion of the long i

tlic fetus into the bladder and bowel. — Internat. J. Surg., 1915 xxviii.

2ii : also Surg., Gynec & Obst.. 1915, xx. 261.

CUSHING, H.

Concerning the results of operations for brain tumor.— J 1../ 1/

Ass., 1915, lxiv. 189.

Hydrocephalus. — In Mod. If erf.. 2. ed. I Osier & McCraei. Phila. & N. Y..

Tumors of the brain and meninges.- In Ifod. !/«/., 2 ed < osier & McCrae), Phila & N. Y.. 1915, v, 308

A centripetal versus centrifugal hospital service. — hi: Peti Bngham Hosp., Founder's Day, Bost., 1915, 22.

Cushing, H., and Goetsch, E.

Hibernation and the pituitary body. — /. Exper. J/., 191.". xxii, 25. Cushing, H., and Walker, C. B.

Distortions of the visual fields in cases of brain tumor. (Fourth

paper, i Chiasmal lesions, with especial reference to bitemporal

hemianopsia — [train, 1914-15. xxxvii. 341.

Cushing, H., and Weed, L. H.

Studies on cerebro-splnal fluid. VIII. The effect of pituitary extract opon its secretion ichoroidorrhoeah — Am. J. Physiol., 1914-15, xxxvi.

Dandy, W. E.

Zur Kenntnis der gutartigen Appendix-tumoren, spezieli des Myxoma. —Bcitr. c. klin. flu,:. 1915. xcv. 1.

Extirpation of the pineal body.— ./. Eiper. J/.. 1915, xxii. 237. Davis, D.

A simple apparatus for microscopic and macroscopic photography. — Anat. Rec, 1915, ix. 29.

Davis, J. S.

The use of skin grafts in the ambulatory I

of o0 cases /. Am. M. Ass., 1915, lxiv, . Clin. J 191

The celluloid tube in finger injuries: its use in adding length

™" 1 ' 1 phalanx after traumatic I"-- .

l»lo, lxiv. 1647.

The use of small deep skin grafts. — Clin. J.. 191.". xliv. 321.


Davis, J. S., and Hinnicutt, J. A.

The osteogenic power of periosteum : with a note on bone transplantation. An experimental study. — Ann. Surg., 1915. lxi. 672.

Dick, G. R., and Dick, G. F.

The bacteriologic examination of the urine in a case of eclampsia. — J. Am. M I 88 I'M.",, lxiv. 14."..

The bacteriology of the urine in non-suppurative nephritis. Its etiologic and therapeutic significance. — J. Am. M. Iss., 1915. lxv. 6.

Dickson, E. C.

Oidiomycosis in California, with especial reference to coci li granuloma ; including nine new cases of coccidioidal granuloma and one of systemic blastomycosis. — Arch. Int. Med., 1915. xvi, 1028. Botulism, an experimental study. A preliminary report.- •/. Am. M. Iss . 1915. 1m 192

Sarcoma occurring in a guinea-pig. — Proi /.v./ ,i Ifed

1915. xiii. 26.

Duffy, R. N.

The diagnosis of ruptured gastric ulcer and carcinoma of the body of the uterus. — Intermit. .1 . Surg., 1915. xxviii.

The appendicular liver. \. York M. •/. [etc.]. 1915, cii, 398; Detroit 11. !.. 1915. XV, 402.

Dunton, W. R.

Occupation therapy : a manual for nurses. Phila.. 1915.

Elting, A. W.

Abscess of the spleen. — Ann.


-W. B. Saunders Co..


Surg., 1915. lxii. 1S2.


Emerson, C. P.

Achondroplasia. Hypertrophic pulmonary osteoarthropathy. Paget's

disease-. Osteogenesis imperfecta, osteopsathyrosis. l.o,iiti,i.

Microcephalus. Facial hemiatrophy. — In Mod. tied., 2. ed. (Osier .\

McCrae), Phila. & N. Y.. 1915. v. 955.

Mental reactions in organic diseases. — Indianapolis U. I 1915, xviii.

97. 143

Indiana University School of Medicine. — ./. Indiana M. Ass., 1915.


iii. :;'.i Medical college training. — IRi.


.]/. J.. 1915. xxviii. 342.


Emmons, A. B.

The resources for giving prenatal care. — Am. .1 Obstet., 1915, Ixxi 385. Care of prospective mothers. — Huston J/. c £ S. •/.. 1915. clxxii. 618.

Erlanger, J.

An analysis of Dr. Kilgore's paper: "The large personal factor in

hi I pressure determinations by the oscillatory method." — Arch. Int.

Med., 1915. xvi, '.'17

Essn K, C. R.

Transited cavities in the cornus striatum of the human embryo. Wash.. 1915 —Carnegie Inst.. Wash.. Publ. No. 222.

ESTES, W 1.

Review of fractures to date I -. ./. Surg., 1915. xxix. 138

Dia "it -is and treatment of carcinoma of the breast — Med. Summary,

1915. xxxvii. 132.

Industrial injuries: treatment. — I. Social. J/.. 1915. xvi.

Medical supervision of students. — /. Smiut. M., 1915. xvi.

Diagnosis of i.e.! Lehigh Valley 1/. Ass., 1915. xli.

Evans, F. A.

An oxydase reaction on blood smears. A valuable test in the [di

tion of white 1.1 1 (ells of uncertain origin. — Ire//. Int. \l,<!., 1915.

xvi. 1067.

Eystek, J. A. E., and Evans, J. S.

Sino-auricular heart bl ck. with report of a case in man.- -Arch. Int. med., 1915, xvi. 832.

Eyster, J. A. E., and Meek, W. J.

The effect of adrenalin on the heart rate. 1915. x\\\ in 62

Finney, J. M. T.

The diagnosis :iiul choice of operation in certain affections of the stomach and duodenum. — ./. Tenn. J/ . Is*., 1915-16, rill, 161.

Finney. J. M. T., and Friedenwald, J

Our experiences with gastroenterostomy : in . hi red with a similar number lm. /. 1/ >. , 1915, el. 469.

Fisher, A. 0., and Carman, R. D.

Multiple congenita) osteochondromata. — An

Flexner, S.

The mode of infection an. I etlolog] of epidemic poliomyelitis, lm. ./ Dis Child., 1915, iv 353; also Lrcfc. Pediat., 1915. xxxii. .•'.'7 Present status of specific ipidemic mening

I m //, os . r.n:., xxx

Flexner, S.. and A muss. H. L.

Diffusion and survival of the pollomyelitic virus. — ./. Exper. M.. 1915,

xxi. 5iei

The rapid product ion of antidysenterli serum.- ' /

xxi. 515.

Flexner, S., Nogi i hi. M . and Amoss, H. L.

Concerning survival and virulence of the microorganism cull from pollomyi .!. Exper. 11.. 1915. xxi, 91.

FOBD, W. W.

The present status and the future of hygiene and public health in America.— Science, 1915. n. s., xiii. 1: also Tr. Ass. V. Phys.,


.;. Physiol Ball


a study of . no hundred pyloroplasty.


3urg., 1915. lxi. 112


' [Xo. 300


Fowler, H. A. .. .

Remarks on the clinical types of prostatic obstruction and tbu 1 management. — Tr. Am. [rot. Ass., 1915, lx, _oi.

FUTCHEB, T. B.

Aleuksemic lymphadenosis.


-Tr. Ass. Am. Pfctf*., 1915, xxx.


GATCH, W. D.

The proper depth rf anesthesia.— A m. J. Burg.. 101... xxix. ..*. Precancerous lesions. — /. Indiana II. iss., Wlo. vni. A-h.


Geeaghty, J. T.

i onsid. -ration of renal functional tests


Oils M. I . 1915,


Fun:ti nil tests in renal surgor . — / ." ?-..::;: 1:1 xiii 1 Figuration in the treatment of Madder tumors. — Surg., trynec. a Oost., 1915, xxi. 150

Geeaghty, J. T„ and Hinman, F.

Ureteral calculi: special means of diagnosis and newer methods intravesical treatment. — Surg., Gynec. A Obst., lOlo. xx. ol5.

Geeaghty, J. T., Rowntree, L. G, and Keith, N. M.

\ method for the determination of plasma and blood volume. — Arch. Int. Med., 1915, xvi. 547; also Tr. Ass. Am. Phys., 191o. xxx.

GlBBES, J. H. . ~

The pharmacology of scopolamin. — ./. South Car. M. Ass., 191o. xi, i ' On the indirect transfusion of blood. — Smith. M. J.. 1915, Tin, 4».

GlFFIN, H Z.

Clinical notes .in splenectomy. — A mi. s.ira.. mi... Ixii. lbb. Splenectomy for splenic anaemia in childhood and tor the spienic ana?mia of 'infancy. — Am. Surg., 1915, lxii. 879

Giffin, H. Z., and Sheldon, W. D.

Clinical and radiologic findings in pulmonary tuberculosis : the value of a co-operative diagnosis. — Journal-Lancet, 1915, xxxv. 213.

Gilchrist, T. C.

Cancer of the skin. — Mainland II. nightly, 1915, xlvii. 180.

Gilchrist, T. C, and Ketron, L. W.

Two cases <f multiple pigmented hemorrhagic sarcoma, with special methods of treatment. — Tr. Am. Dermal. Asa.. 1915. xxxix.

GODDARD, C. H.

Changes in the P wave of the human electrocardiogram. Med.. 1015. xvi. 633.

Goetsch, E., and Cttshxng, H.

Hibernation and the pituitary body.


1915, Iviii. 157: also .1/..). Fort


Int.


-J. Exper. If., 191c


Goldbach, L. J.

Squamous cell carcinoma of the larynx: report of a case. — A. York 1/. ./. [etc.], 1M5. cii. 513.

Grey, E. G.

Studies on the localization of cerebellar tumors. III. Posterior newgrowths without nystagmus. — ./. Am. II. .Is*.. 1915, lxv. 1341. Studies on the localization of cerebellar tumors. I. The significance of staggering gait, limb ataxia, the Romberg test, and adiadochokinesis. — ./. 2/erv. A Ment. Dis., 1915. xlii. 670.

Fibrin as a haemostatic in cerebral surgery. — Surij., Gynec. d Oost., 1915. xxi. 452.

HALSTED, W. S.

A diagnostic sign of gelatin. .us carcinoma of the breast. — •/. Am. M. Ass., 1915. lxiv. 1653. Halsted, W. S., and Reid, M.

\s to the cause of the dilatation of the subclavian artery in certain

cases of cervical rib. Experimental study. — Proc. Soc. Exper. Biol. A

Med., 1915, xiii. 1. HAMMAN, L.

Clinical aspects of carbohydrate metabolism. — Kentucky II. !.. 1915,

xiii 7s

The dispensary in a tuberculosis campaign. — 1 irginia it. Semi-Month.,

1915, xx. 372.

HANES, F. M

The luetin reaction in the diagnosis . f tertiary and latent syphilis. — Am. J. M. Sc, 1915, cl. 703.

The biologic classification of pneumococci and the serum treatment of lobar pneumonia. — Old Dominion .1. M. A .S.. 1915. xx. 134. Bilateral brain lesion : tumor on b-ft. hemorrhagic cyst on right.— OH Dominion ./. M. A 8., 1915. xxi. 151. Hastings, T. W.

Pathogenicity of street dust. Report by the Public Health Committee of the New York Academy of Medicine. — Med. Her., 1915, Ixxxn iii

Henderson, D. K.

Typhoid fever with permanent memory defect. lxxi. 685. Henxington, C. W.

The thymus question. — Buffalo M. •/.. 1915, lxx. 611.

Higgins, W. H.

Luetic arthropathies. — Am. J. M. 8c., 1915, cl. 733.

Hinman, F.

The diagnosis of ureteral calculi and a description of a techni.

of the wax-tipped catheter in the male. — Cat. state J. M., mi., xiii.

A "practical method of applying the wax-tipped catheter in the diagnosis of ureteral stone in the male. — J. Am. M. Ass., mi... lxiv.

Urinary antisepsis: a clinical and bacteriologic study. — •/. Am. M. Ass., 1915, lxv. 1769.


. J. Insan.. 1914-15,


Hinman, F., and Geeaghty, J. T.

Ureteral calculi : special means of diagnosis and newer methods of intravesical treatment. — Sinn.. Gynec. .1 Oost., 1915. xx. 515.

Hirschfelper, A. D.

Gehirnlipoid als Haemostaticum. — Hrrl. klin. Wchnschr.. 1915, lii. Pathologic physiology of lead colic: its relation to experimental

therapeutics.— J Am. M. Ass.. 1915, lxv. 516.

Brain lipoid as a haemostatic. — Laneet. 1015. ii. 542.

The clinical use of digitalis. — St. Paul .1/. ./.. 1015. xvii. 25...

Effect of digitalis in experimental auricular fibrillation. [Abstr.]

I. Pharmacol, and Exper. Tin rap.. 1915, vi, 597.

Hibschfeldeb, A. D., Abnson, J. M., Houde, R., Mebkebt, G. M., and Shapiro, M. J.

Effect of bad salts :l nd of the nitrites upon the movements of the intestines. — Proc. Soc. Exper. Biol, d Med.. 1914-15, xii. 215.

Hieschfelder, A. D., Hullsiek, H., David, S., Dunn, J., Cowin, C. and Smith, L. W.

Effects of drugs upon the vessels of the pia mater and retina. [Abstr.] J. Pharmacol and Exper. Therap., 1915, vi. 597.

Hirschfeldeb, A. D., and Schuxtz, F. H.

Clinical and experimental studies in chemotherapy with ethylhydroeiipr.-in in measles, scarlet fever and other infections. — Proc. .Soc. Exper. Biol. A Med.. 1914-15, xii. 208.

Hitzrot, J. M.

The surgical treatment of aneurvsm. — In Operative Therapeusis i Johnson.. N. Y.. 1915, i. 363. . m The tr.-atm.-nt of wounds and their diseases. — In Operative Therapeusis i Johnson I. N. Y.. 1015. i. 681. . The operative treatment of fractures. — In Opt ratin 7 7i< «/" ""* ' Johnson i. N. Y.. 1015. ii. 223.

Early manifestations of mental disorders. — State Hasp. Bull.. Utica. 1915, viii. 12.

Hookeb, D. R., and Morison, R. A.

The vascular tone and the distribution of the blood in surgical shock. — Am. J. Physiol., 1915. xxxvii, 86.

Hopkins, J. G, and Zinsser, H.

\ntil«.dv formation against Treponema pallidum agglutination. — J. Exper. M.. 1915, xxi. 576.

Hopkins, J. G, Zinsseb, H., and Gilbebt, G.

Notes on the cultivation of Treponema pallidum. — J. Exper. J/.. 101... xxi. 213.

HowLANii, J., and Marriott, W. McK.

Observations upon the so-called food intoxicati-ui of infants with especial reference to the alveolar air. — Proc. .Soc. Exper. Biol. A Mea..

a' study of the acidosis occurring in the nutritional diseases of infancy. —Tr. Ass. Am. Phys., 1915. xxx.


eport of cases. — Boston M. A


Hunner, G. L.

A rare tvpe of bladder ulcer in women : 8. J.. 1915, clxxii. 660.

Report of committee on a history of "The Institutional Care of the Insane in the United States and Canada. —Am. ./. Insan., 191o-lo.

Ought training schools for nurses to be endowed? [Editorial.] Johns

SK^S^-^STSTttefetaSHS&i Hospltal.-Vo*™ Hopkins W.

Fonv-five^ea'rs ago'anT'nJw: An address before the training school for nurses at the Sheppard and Enoch Pratt Hospital. May 10. 191o.— {ddres?-u l "ihVo|.en!nr!!f\b..I.'.bn ilubnVr'Psychopathic building at the SpHnLfi'bl state Hospital. June 0. 1915.— ifan/tond Psychiat. Th^ treatment of mental cases in general hospitals.— Hod. Hasp..

Th^generat'government of state hospitals.— Mod. Has,,.. 1015 iv 244 Organization and administration of hospitals for the insane. (Edi The a ca'r7oi°cas^"!f 'mcntlll'n^ase in general hosp.tals.-Hod. Hasp..


Hirwitz, S. H., and Carr, G. L.

„„ ,he mono.-.steitic form of Pagefs disease of bone.— Am. J. Roentgenol., 1915. ii. .55.

Hi-rwitz, S. H., and Drinker, C. K.

The factors of coagulation in primary pernicious anemia.— Arch, int.

S3'H;£;i,r^

J. Exper. M.. 1915. xxi. 401. Hi-rwitz S H Mfyer, K. F., and Ostenberg, Z. H ' "oTa'colorimet^fc thod of adjusting bacteiiologicalcuUure media to

anv optimum hydrogen ion concentration.— Pi oc. so,. Exper.

Med.. 1915, xiii. 24.

A few 'not'.-s on the treatment of ahteposed uteri.— Boston M- A s. t. Umita C tinnhi S the radical operation for cervical cancer of the uterus.Boston M. d 8. / . 1915. clxxiii, Si.


February . 5.


lXGRAHAM, C. B.

"Twilight sleep." — Colorado lied., 1915, xii. 13.

Observations upon the use of pituitary extract in obstetrics. — Colorado

Med., 1915, xii, 190.

JiXEWAV, T. C.

Dr. Francis Delafield. In memoriam. — Med. Bee, 1915. lxxxImportant contributions to clinical medicine during the past thirtv vears from the study of human blood pressure. — Tr. Ass. Am. Phils' i, xxx.

Jones, W., and Richards, A. E.

Simpler nucleotides from yeast nucleic acid. — /. Biol. Chem., 101 r. . xx. 25.

Keith, X. M., and Sxowdex, R. R.

Functional changes in experimental hydronephrosis. — Arch. Int. Med 1915, x\ _


Keith, X. M., and Peikce, G.

The excretion of sugars by the kidney. — Pn 1915, xi.i 210.


Sor. Bxper. Biol. ,{ Med.,


Keith, X. M., Rowxtree, L. G.. and Gebaghy, J. T.

A method for the determination of plasma and blood volume. — lrcft Int. Med., 1915, xvi. 547 : also Tr. Ass. Phys.. 1915, xxx.

Keith, X. M., Rowxtbee, L. G., and Mtllee, J. R.

Plasma and blood volume in pregnancy. — ./. Am. M. Ass., 1915, lxv. 770 Kelly, H. A.

Treatment of cancer by radium. — Maryland M. J.. 1915. Iviii 161. nsion of the kidney. Troy. N. Y.. 1915. — The So

21 pp.. 4°. — In sti xxix.

The radium treatment of fibroid tumors. — Surg., G-ynec. <£- Obst., 1915


xx, 271. History of retro 1915, xx, 598.


the uterus.— S . . G


uteri and vagina


J. Insan., 1914-15, lxxi.


Kelly, H. A., and Buexam, C. F.

Radium in the treatment of carcinomas of the — J. Am. Ass., 1915, lxv. 1S74.

Kejipf, E. J.

The behavior chart in mental diseases. 761.

The integrative functions of the nervous svstem applied to some

reactions in human behavior and their attending psvehic functions

hoanalyt. Rev., 1915, ii. 152. Some studies in the psychopathology of acute dissociation of the personality. — Psycho anal yt. Rev., 1915, ii

Kexyox, J. H.


Ketrox, L. W., and Gilchrist, T. C.

Two cases of multiple pigmented hemorrhagic sarcoma witii methods of treatment. — Tr. Am. Dermal. Ass., 1915. xxxix.

Kline, B. S„ and Meltzee, S. J.

The effect of previous intravenous injection of pneumococci upon experimental lobar pneumonia produced by the method of Intrabronchial insufflation.— Proc. 8oc. Bxper. Biol & Med.. 1915. xii. 185.

Klixe, B. S., and Winteenttz, M. C.

Studies upon experimental pneumonia in rabbits. VII. The production

of lobar pneumonia. — ./. Bxper. M. 1615 xxi 3n4

Studies upon experimental pneumonia in rabbits.' VIII Intra vitani

staining m experimental pneumonia, and the circulation in the

pneumonic lung.— J. Bxper. M.. 1915. xxi, 311

studies upon experimental pneumonia in rabbits. IX. The part of the

leucocyte in the immunity reaction.—/. Erper. M., 1915, xxi 320. Kxox, J. H. AI., Jr.

Report of a rase of myelogenous leukemia in an infant nine months old. — Area, itrh'it.. 191o. xxxi; 31

Pyelitis in infancy.— Johns Hopkins y. Alumnae Mag. 1915 xiv '53 1915, C xxvii', l I l4 S . t ' tUtlODaI infaDtS outside of in s«tntions.— Pediatrics,

Lamsox, P. D., Abel, J. J., Tuexeb, B. B., and Maeshaix E K Jb

On plasmapheresis.— Tr. Ass. lm. Pays., 1915, xxx.

Laxdois, F., and Bdbckhabdt, H.

M r teh U 1frd TT^!. r „. d i, e B ^^2? g V& flaIerter Golenke im K; Munch. Med. nchnsehr., 191o, Ixii. 723.

Laxdois, F., and Retd, M.

Da Lf,r^~ n l^V^ Se Vr% n - ;nhaWs g ^antho-Sarkom der Extremitaten. — Beiii. .. khn. Chir., lOlo, xcv, 56.

Levy, R. L., Rowxtree, L. G., and Mabbiott, vY M

c^ntS??L m ,? t ?h d /, "' determining variations in the hydrogen-ion con*m PjJ£?., 1915 ^ a -~ Arelt - '"' Ued > 1915 ' XTi 3 8 9 ; ils " Tr. A * s LlSSEE, H.

The hl tre S -umen^ a J? aUd ' S n^e* 86 -— A ™> h - '"* led., 1915, xvi. 509.

'•atment of congenital syphilis.— c<;/. State /. M., 1915, xiii.

LOEVEXIIABT, A. S.

Certain aspects of biological oxidation.— Arch, Int. Med., 1915, rv,

Loetexhabt, A. S., Dallixg, H. C, and Kolls, A. C.

intionoVlh i^tween the erythrocytes and hemoglobin to the oxygen Sf 1 ™ <. th . respired air.— Am. J. Physiol.. 1915, xxxvi. 356. rem,!™.™; b „ a n' sm adapting the oxygen capacity of the blood to the requirements of the tissues.— Am. j. Physiol.. 1915, xxxix. 77.


Physiol., 1915, xxxix.


Loeyexhabt, A. S., and Kolls, A. C.

A respiratory chamber for small animals. 67.

L.UETSCHEB, J. A.

A bacteriological and clinical study of the. non-tuberculous infections of the respiratory tract, with special reference to sputum cultures as a means of diagnosis. — Arch. Int. Med., 1915, xri Lyman, D. R.

The tuberculosis work in Connecticut, its development in the last decade, and its future needs.— Boston If. & 8. !.. 1915, clxxii. 657. The problem of the discharged sanatorium patient.— St. Paul M. .;..

The work of the Connecticut State T Commission, its

development and present outlook.— Proc. < loir, xiii

TubeTc"lofi< "gi^'xi"'^')- records — Tr - - v "'- 4*s. Study <t prevent. Visiting nurses in the tight against tuberculosis Month., 1915. xx. 376.


-Virginia M. Semi


Lynch; F. W.

Nitrous oxide analgesia in obstetrics versus scopolamine morphine

seminarcosis. — Chicago M. !; ,,,.],,. loir,, xxxvi

Nitrous oxide gas analgesia in obstetrics. — J. Am. It. Ass., 1915. lxiv.

Eutocia by means of nitrous oxide gas analgesia; a safe substitute for the Freiburg method ..,, Am. M. Ass.. 1915. lxiv. 11S7; also Illinois M. J., 191a, xxvn. 2; i i

Lyon, I. P.

Diseases of the spleen.— In Mod. Med. 2. ed. (Osier & McCraei. Phila. & N. 1.. lOlo. iv. 9."4.

MacCallcm, W. G.

The parathyroid gland. A brief digest of the literature of 1912-1913 Am. Med., loir... n. s.. ix. 244.

A case of multiple myeloma. — Proc. N. Torts Path. Boc. 1915 n s xv 25.

Aortic aneurysm perforating superior vena cava. — Pror. Y York Path . 1915. n. s.. x\ . 27.

McClube, W. B., and Saueb, L. W.

The influence of clothing on the surface temperature of infantJ. Dis. Child.. 1915, x. 42".

McCbae, T.

Saving the th.—Canad. M. Ass. J.. 1915. v, 60.

1915, lxv. 135 Arthritis deformans. — In Mod. Med. 2. ed. (Osier & MeCrae), Phila. &


N. Y.. 1915


895


Mi Cbae, T., and Coplix. W. M. L.

Colloid carcinoma of the peritoneum. — Tr. Ass. Am. Phys., 1915. xxx. Macht, D. I.

The history of opium and some of its preparations and alkaloids. — •/. Am. .If. Ass.. 1915. lxiv. 477.

in of the opium alkaloids individually and in combination with each other on the coronary artery and the coronary circulation — .7 Am

-., 1915, lxiv. 1489. Demonstration by the use of arterial rings of the inhibitory action rtain drugs on onstriction produced by epinepbrin —

J. Pha -,oi '

The history of opium 8., 1915, lxxix. 350.

Lber dem Begriff von "Bittachon" in der Hebraischer Literatur. — Jeschurum, 1915.

Mall, F. P.

On the fate of the human embryo in tubal pregnancy. Wash. 1915. — Carnegie Inst., Wash.. Publ. No. 221.

opment of the heart. — Ref. Bamlb. Med Be, :;. ed., 1915, v. 58

The cause of tubal pregnancy and the fate of the enclosed ovum. — •-<'., 1015, xxi I

Marriott, W. M., and Howlaxd, J.

Observations upon the so-called food intoxication of infants with especial reference to the alveolar air. — /'roe. Soc. Erper. Biol. «f I/erf 1914-15, xii. 51.

A study of the acidosis occurring in the nutritional diseases of infancy. — Tr. Ass. Am. Phys., 1915, xxx.

Marriott, W. M.. Levy, R. L., and Rowxtree, L. G.

A simple method for determining variations in the hvdrogen?ion concentration of the blood. — Arch. Int. Med., 1915, xvi. ::S9 : also Tr. I ... Am. Phys., 1915, xxx.

Marshall, E. K., Je.

The therapeutic value of organic phosphorus compounds. — ./. 1m M Ass., 1915, Ixj

The toxicity of certain hirudin preparations. — ./. Pharmarol. d 1 Therap., 1915, vii, 157.

M u:shall, E. K., Je., Abel, J. J., Tcbxeb, B. B., and Lamsox, P. D. On plasma] ii; Iss. Am. Phys., 1915, xxx.

Marshall, E. K., Jr., and Rowntbee, L. G.

Studies in liver and kidney function in experimental phosphorus and chloroform poisonim:. — ./. Exper. If., 1915, xxii, 333.

ii, E. K., Je.. Rowxtree, L. G., and Baetjer, W. A. Furth renal function in renal, cardiorenal and cardiac

Marshall, E. K., Jr., Rowxtree. L. G., and Clark, M.

Mushro to Amanita

phallo If. .1 ..... 1915, lxiv. i !

Marshall, E. K.. Jb., Ti bni b, B. B., and Lamsox, P. D.

Observations on plasmapheresis. Second paper. — /. Pharmacol. / Bwper. Therap., 1915, vii, 129


[No. 300


Mabshaxl. H. W. . ,,, r

The importance of vascular conditions in orthopedic cases.— Am. J.

LrteTesul'"s S 'oi 1 surgicaiSrVi : t ments for flexed scapula-, with a discussion of tie subject. — Boston it. ><- B. J.. 1915, clxxn. 812. <11 _

Foot strain and other common foot defects.— Boston 31. d 8. J., 1 10. clxxiii, 979.

Marshall, H. W., and Bbackeit. E. G.

Late results of operations upon hip joints for hypertrophic arthritis.— Boston If. d S. J-, 1915, clxx

Marshall, H. W., and Osgood, R. B.

Late results of operations for correction of foot deformities resulting from poliomyelitis.— Boston 11. d S. J., 1915. clxxm. 375.

Objective psychology or psychobiology with subordination of the medically useless contrast of mental and physical.— J. Am. 11. ass., The^'u'sUflraUon of psychobiology as a topic of the medical curriculum. ^Zzm S B zC'com^\ff!v the protection of its mental life— Survey, 1915. xxxiv, 55,.

Mllleb, S. R. _. , „,,

Parenchymatous syphilis: its diagnosis and treatment.— Marylana

^fspfial^idin^ypnil^-lv. For* State J. U., 1915, xv, 376

The importance of cerebrospinal fluid examinations in syphilis of the central nervous system. — South. 11. ./.. 1915, vni. 940. Milleb, S. R., Babkeb, L. F., and Baetjeb, W. A.

The clinical diagnosis of acute leukemic states. — Tr. Ass. Am. Phys., 1915, xxx.

Mi.not, G. R. , „, . ,

The effect of chloroform on the factors of coagulation. — Am. J. 1 hyswi., 1915, xxxix, 131.

Minot, G. R., and Denny, G. R.

Origin of antithrombin. — Am. J. Physiol, 1915, xxxvm, 233.


J. 11. 8c, 1915,


Mi.not, G. R., and Rackemasn, F. M.

Respiratory signs and symptoms in trichinosis.cL 571.

Mobbis, R. S. .

The occurrence of nuclear particles in the erythrocytes following splenectomy. — Arch. Int. lied.. 1915. xv. 514.

On the probable toxic effects of prolonged administration of parathyroid gland. — J. Lab. £ Clin, lied., 1915, i, 26.

Progress in Obstetrics.— Cal. State J. If., 1915. xiii, 21. Creatin and creatinin excretion during the puerperium and their relation to the involution of the uterus. — J. Ant. II. Ass., 191o, lxv. lbli. Bilateral congenital caput obstipum. — Surg., Gynec. d Obst., 191o. xx, 74.

MOSENTHAL, Hi 0.

Renal function as measured by the elimination of fluids, salt and nitrogen, and the specific gravity of the urine. — Arch. Int. Med., 191o,

The treatment of diabetes mellitus in dispensaries. — lied. Rec, 1915, lxxxvii, 589. . , . . ... „

The interpretation of a positive nitrogen balance in nephritis. — Proc. Sot: Eiper. Biol, d lied., 1915, xiii, 9.

Nixon, P. I.

Chaparro Amargosa in the treatment of amoebic dysentery. — Am. J. Trop. Dis.. 1914-15. li. 572. .. __

Non-bacterial urethritis. — lied. Rec, 191o. lxxxvii, 60i.

Opie, E. I., and Alford, L. B.

The influence of diet upon necrosis caused by hepatic and renal poisons. Part I. Diet and the hepatic lesions of chloroform, phosphorus, or alcohol. — J. Eiper. II., 1915. xxi, 1.

The influence of diet upon necrosis caused by hepatic and renal poisons. Part II. Diet and the nephritis caused by potassium chromate. uranium nitrate, or chloroform. — J. Eiper. II., 1915, xxi. 21.

Osleb, Sib W.

Remarks on cerebrospinal fever in camps and barracks. — Brit. 11. J.,

1915 1 189.

Medical notes on England at war. — Dominion If. Month., 1915, xliv, 41,

Remarks on the diagnosis of polycystic kidney. — Internat. Clin., 1915,

The coming of age of internal medicine in America. — Internat. Clin.,

1915 °5 s. iv, 1.

Medical notes on England at war. — J. Am. .If. Ass., 1915, lxiv. 1512.

Remarks on arterio-venous aneurysm. — Lancet, 1915, i. 949.

Note on acute infectious jaundice. — Lancet, 1915, ii. 605.

An address on science of war. Delivered at the University i ; 1. eds

Medical School on October 1, 1915. — Lancet, 1915. ii. 195.

Acute endocarditis. — In lfod. lfed. 2. ed. (Osier & McCraei rhila. &

N. Y. 1915. .

Diseases of the arteries. — In Ifod. lfed. 2. ed. (Osier & McCraei. rhila.

i N. T„ 1915. iv, 44n.

Aneurism.— In lfod. Med. 2. ed. (Osier & McCrae), Phila. & N. Y.. 1915,

iv 47i\

Raynaud's disease. — In lfod. lfed. 2. ed. (Osier & McCrae). PhiJa. &

N. T., 1915, iv. 975.

Angioneurotic oedema : Quincke's disease.- -In '-'. ed. usler

& McCraei. Phila. & N. Y.. 1915. iv. 99S.

Diffuse scleroderma. Ervthromelalgia. — In lfod. lfed. 2. ed. (Osier &

McCrae), Phila. & N. Y.. 1915. iv. 1014.

Osleb, Sk TV., and Gibson, A. G.

Diseases of the valves of the heart. — In lfod. lfed. 2. ed 1 Osier & McCrae), Phila. & N. Y.. 1915. iv. 212.


Paefitt, C. D., and Cbombie, D. W.

Artificial pneumothorax in the treatment of phthisis. — Canad. M. Ass. /-. 1915, v. 277. 373, 489.

Peaeody, F. W.

Clinical studies on the respiration. I. The effect of carbon dioxid

in the inspired air on patients with cardiac disease. — Arch. Int. Med.,

1915. xvi. 846.

Clinical studies on the respiration. II. The acidosis of chronic

nephritis. — Arch. Int. Med., 1915, xvi. 955.

Observations on dvspncea in cardiac disease. — Tr. Ass. Am. Phys.,

1915, xxx.

Peabce, L.

A comparison of adult and infant types of gonococci. — J. Eiper. M., 1915. xxi. 289

Peabce, L., and Beoyyx, W. H.

Chemopathological studies with compounds of arsenic. I. Types of the arsenic kidney. — •/. Eiper. If.. 1915. xxii. 517.

Chemopathological studies with compounds of arsenic. II. Histological ehanzes in arsenic kidneys. — J. Eiper. If., 1915. xxii, 525. Chemopathological studies with compounds of arsenic. III. On the pathological action of arsenicals on the adrenals. — J. Eiper. If., 191o. xxii, 535.

Peibce, G., and Keith, X. M.

The excretion of sugars bv the kidney. — Proc. 80c. Exper. Biol, d Med., 1915. xii, 210.

Pels, I. R.

The sugar content of the blood in certain diseases __of the skin. A preliminary report. — J. Am. Med. Ass., 1915. lxv, 2077.

Penbose, C. A.

A review of the theories and facts underlying the treatment of diseases bv soured milk cultures. — Maryland M. J., 1915, lviii, 53. •'Self manufacture." — Maryland If. J., 1915, lviii. 209. Splenectomy in pernicious anemia. — South. M. J., 1915, vlii, 81 9. The three p'hases of life. — Am. J. Nursing, 1914-15, xv, 1102.

Plaggemeyeb, H. W.

The mechanism of urinary obstruction in relation to variations in renal function. — J. Michigan State M. Soc, 1915, xiv, 391.

Plass, E. D. ..,.,.,

The significance of the non-coagulable nitrogen coefficient of the blood serum in pregnancy and the toxemias of pregnancy. — Am. J. Obst., 1915, lxxi, 608.

Pbatt, J. H.

Purpura and hemophilia. — In lfod. lfed. 2. ed. (Osier & McCrae), Phila.

Studies 'on uri'c acid metabolism in gout. — Tr. Ass. Am. Phys., 1915. xxx.

QciNBY, W. C. „ . .

The management of pneumothorax occurring as a complication 01 nephrectomy. — •/. Am. II. Ass., 1915, lxv, 2154.

Quinby, W. C, and Frrz, R.

Observations on renal function .„ nephritis. — Arch. Int. Med., 1915, xv, 303.

RAN'D, C. W. ., .

Hysterical joint neuroses; with especial reference to the hip ; and report of a case simulating fracture of the neck of the femur.— Surg., Gynec. d Obst., 1915, xxi, 489.

The endoscopic treatment of nocturnal pollutions. — J. Am. M. Ass.,

Prostafisme 48 sans prostate : a study of median bar formation as a cause of urinary obstruction.— X. York if. J. (etc.), 1915, en. 11-d. 1177.

Randolph, R. L- m n ... _.„ 1Q1 r,

Melanosis f the conjunctiva ; report of a case.— Ophth. Kec, lsio. xxiv, 20.

REEO, M.

-in doppelseitiges myeloides Chlorom der Mamma.— Beitr. z. Mm. 1915, xcv. 47.

Reid, M., and Halsted, W. S. „„,.,„!,,

is to the cause of the dilatation of the subclavian artery in certain cases of cervical rib. Experimental study.— Proc. Soc. Eiper. Btoi. a 1915, xiii, 1.

R %as I p" d en^ri D e r I i S ese F nze.lenha,tige Xantho-Sarkom der Extremitiiten. — Beitr. e. klin. Chir., 1915, xcv, 56.


acute experimental unilateral


Rem sen, C. M.

Surgical measures in appoplexy ; 1915, lxv, 16°


eport of a case. — J. Am. M. Ass., Orcrkthe treatment of closed fractures of the patella.-Soutt If- J I^lexf • 'suggestions ^ mo« ^lonal^meHjod. of ^de. ling with

"""ita&ta test in Parasyphllta^^^a^W^^^ 15 ^^

The mental symptoms in disseminated sclerosis. Psychiat., 1915, xiii, 361.


February, 1916.] Rous, P., and Turner, J. R.

A rapid and simple, method of testing donors for transfusion. —

./. Am. M. Asa., 1915. Ixiv. 1980.

The resistance to mechanical injury of the erythrocytes of different

species. — Proc. Soe. Exper. Biol. .1 Wed., 1915, xii. 106.

The protection of fragile erythrocytes agajnst mechanical injury. —

Proc. Soe. Exper. Biol. & I/,,/.. 1915. xii. li)7.

i Hi the preservation in vitro of living erythrocytes.- Proc. Soi

Biol. <( Med., 1915, xii. 122: also Tr. Aaa. lm. Phya., 1915, xxx.

Rowntree, L. G., Clark, M., and Marshall, E. K., Jr.

Mushroom poisoning. Some observations in a case due to Amanita phalloides. — /. Am. M. Asa., 1915. Ixiv. 1230

Rowntree, L. G., Keith, N. M., and Geraghty, J. T.

A method for the determination of plasma and M 1 volume. — Arrh.

Int. Med., 1915, xvi, 547: also Tr. Aaa Am. Phya.. 1915, xxv

Rowntree, L. G., Levy, R. L., and Marriott, W. M. •

A simple method for determining variations in the hydrogen-ion concentration of the Mood.— Arrh. Int. Med., 1915. xvi. 380: also Tr. las. lm. Phya., 1915, xxx.

Rowntree, L. G., and Marshall, E. K., Jr.

Studies in liver and kidney function in experimental phosphorus and chloroform poisoning. — I. Exper. .1/.. 1915, xxii. 333.

Rowntree, L. G., Marshall, E. K., Jr., and Baetjer, W. A.

Further studies of renal function in renal, cardiorenal and cardiac diseases. — Arch. Int. Med., 1915, xv. 54::.

Rowntree, L. G., Miller, J. R., and Keith, N. M.

Plasma and Mood volume in pregnancy. — /. Am. II. Ass., 1915, Ixv, 779.

Rushmore, S.

Progress in gynecology. — Boston J/, it 8. •'.. 1915, clxxiii. 166.

Sabin, F. R.

On the origin of the duct of Cuvier and the cardinal veins. — Anat. Record, 1915, ix. 115.

On the fate of the posterior cardinal veins and their relation to the development of the vena cava and azvgos in the. emhrvo pig. Wash.. 1915. — Carnegie Inst.. Publ. No. 223.

St HMEISSER, H. C.

Leukaemia of the fowl : spontaneous and experimental. Balto.. 1915. — The Johns Hopkins Press, 34 pp.. 4°.

Sellards, A. W., Strong, R. P., and Tyzzer, E. E.

Oroya fever Second report.— J. .4m. .1/. Ass.. 1015. Ixiv. 806. Differential diagnosis of verruga peruviana. Fifth report. — .7. Trap. 1/ [etc], I.ond.. 1915, xviii. 122.

Sellards, A. W., Strong, R. P., Tyzzer, E. E., Brues, C. T., and Gastiaburu, G. C

Report of the first expedition to South America in 1913 from the Harvard School of Tropical Medicine. — Harvard University Press. Cambridge, Mass.. 1915.

Selling, L.

The cerebrospinal fluid as an aid to the diagnosis of obscure cases of syphilis of the central nervous system. — Northwest M.. 1913. vii. 1.

Shallenberger, W. P.

Twilight sleep. — Atlanta Jour. Rec. Metl., 1915-16, lxii. 107.

Shakpe, W.

The operation of cranial decompression. — Am. ./. J/. 8c, 1915. cxlix.


563.


-In Operative Therapeus


Sharpe, W., and Farrell, B. P.

A new operative treatment for selected cases of cerebral spastic paralysis. — J. Am. J7. Ass., 1915. Ixiv. 482.

SlIII'I'KN, L. P.

The significance of Bacillus 1915, Ixiv. 1289.


oil in pasteurized milk. — J. Am. J/. .!<


Simon, C. E., and Jcdd, C. C. W.

Acute lymphatic leukemia ; on the occurrence of the Corynebacteriun lymphomatosis granulomatoses. — J. Am. M. Asa., 1915, Ixiv. 1630. The vacuum tube of Keidel. as applied to blood-culture work. — J. Am M. Ass.. 1915, Ixiv, S22.

Sisson, W. R., and Thompson, C. B.


Sisson, W. R., and Walker, I. C.

Experimental pneumonia (Friedlander type). — J. Exper. 1/.. 1915, xxii.

Sladen, F. J.

Indications found in the mouth, of value in the diagnosis of general conditions. — Proe. Soe. Oral II mi. <t Periodontology, CO 5. i.

Sladen, F. J., and Winternitz, M. C.

Venous thrombosis during myocardial insufficiency. Halto.. 1915. — The Johns Hopkins Presa., 4ii pp, 4 .

Slemons, J. M.

Placental bacteremia.— J. Am. .17. Aaa., 1915, Ixv. 1265.

Oystocia due to a funnel pelvis.— Col. State J. If., 1915, xiii. 91. Sloan, M. F.

Tuberculous women as nurses of the tuberculous. — Am. J. Nursing,

The great need of hospital facilities for negi s with tuberculosis. —

I Outdoor Life, 1915, xii. 128.


norrhea and sterility


Sloccm, R. B.

Ovaritis in typhoid fever, with consequent i

South. U. /.. 1915, wii. 706.

Smith, J. T., Jr.

Scopolamin amnesia in labor Cleveland If. ./.. 1915, xiv. 4::. Smith, W. H.

Relation of the hospital to the. community- ./, \ „, 1/. Aaa., 1915,

Snowden, R. R., and Keith, N. M.


-Arch. Int. ilea..


Snyder, C. D.


spiratory waves in sphymoman eier record

.'. Physiol., 1915, xxxvi. 430. Stearns, T., Wilson, D. W., and Janney, J. H., Jr.

The excretion of acids and ammonia after parathyroidectomy.— J. 1


Chem.. 191;

The effect

Chem.. 1915, xxi. 169


xxiii. 123.

d administration on parathyroid tetany.-./. Biol.


Stearns, T., Wilson, D. W., and Thurlow, M. DeG.


equilibria in the blood after parathyroidectomy

CM... xxiii. Nfl.


Steiner, W. R.


Myositis-Myotonia congenita: Th sen's disease. — In Mud. 1/ e,l . 2. ed

(Osier* McCrae), Phila. i.- N. v.. cur,, v, 871,

Historical address. The evolution of medicine in Connecticut, with the foundation ,,t the lale Medical School as its notable achievement. .N.-w Haven. 1915. — lule f niversity Press, 39 pp., 8°.

Stiles, C. W.

Recent studies on school children, with special reference to hook

worm disease and sanitation. — \. )„,-,;- 1/. ./. (etc |. cur,, cii. '.mm;

Difficulties in obtaining ages: popular ignorance and carelessness

regarding ones birthday and age. — Pub. Health lien.. Wash., 1915

xxx. 310.

Sanitary progress. County of New Hanover and City of Wilmington

N. C.—Pub. Health Rep., Wash., 1915. xxx. 685.

Zooparasite intestinal infections: an analysis of infections found

among ll's, school children iTTC white, 511 negr f t|„. citv of \

Pill. Health Rep., Wash.. 1915, xxx. 1991.

Stiles, C. W., Lumsden, L. L., and Freeman, A. W.

Safi' disposal of human excreta at unsewered homes — Pnh Health Bull 1915, No. 68.

Stone, H. B.

a treatment for pruritus ani. — Maryland U. ./.. 1915, lviii. 202. Strong, R. P.

Conquering the typhus plague. — .lm. Reel Cross Mag., 1915, x. -jt;7.

Recent investigations in relation to infectious diseases in South

America. — Am. J. Trop. Dis. [etc.]. 1914-15. ii. 465

World sanitation and the Panama Canal. — Tale Rev., 1915, Iv, 352.

Strong, R. P., and Tyzzer, E. E.

Experiments relating to the virus of report. — .7. Am. M. Ass.. 1915, Ixiv. 1124. Pathology of Oroya fever. Third report.— .7. .1


tic,.-,


ruga peruviana. Fourth .If. Ass., 1915, Ixiv. Sixth report.— A in. J. Trail. Dis.


Strong, R. P., Tyzzer, E. E., and Sellards, A. W.

Oroya fever. Second report. — ./. Am, M. Ass.. 1915, Ixiv, 806. Differential diagnosis of verruga peruviana. Fifth report. — ./. rroo 1/ [etc.]. Lond.. 1915. xviii. 122

Strong, R. P., Tyzzer, E. E., Brues, C. T., Sellards, A. W., and Gastiaiurc, G. C.

Report of the first expedition to South America in 1913 from the Harvard School of Tropical Medicine. — Harrartl I'nirersitu Press Cambridge. Mass.. 1915.

Strocse, S., Steix, I. F., and Wiseley, A.

The quantitative determination of blood sugar, using small amounts of blood. — Tr. Chicago Path. Soe, 1914-15, ix. 231.

Thayer, W. S.

Reflections on modern methods of treatment by sera and vaccines. — J. Florida 17. Is*.. 1915. ii. fit : also ./. South Cat . I/. Iss.. 1915, Xi. 240. Stokes-Adams syndrome with a remarkable delay in the A-Y conduction time. — Tr. las. lm. Phya., 1915, xxx.

Thomas, H. M.

Diseases of the cerebral blood-vessels. — In Mod. Med. 1 Osier & McCrae), Phila. ^ N. Y.. 1915, V, 387.

Thompson, C. B., and Sisson, W. R.

Friedliinder bacillus pneumonia : with report of cases. — Am. ./. 1/ 8c, 1915, el. 713.

Tinker, M. B.

What stomach symptoms justify surgical Intervention? — N. York if. /., [etc.], 1915, ci, 1083; also \ Tori Stati J. If., 1915, xv. 460.

Toi i.min, H.

The Influence on mortality ol a family history of tuberculosis, win be published by Peiin. Mutual Life Insurance Co., Phila.

Vai.k, A. deT.

Pellagra as a post-operative manifestation, with reporl ol

South, 1/ / .. 1915 • iii. 686

Post .operative intestinal I, -miction, will, Tr. \ Carolina

State Mr, 1 Sot . 1915, lxii.


60 | No. 300


VandebHoof, D.

The causes of indigestion — A study of one thousand eases. — South M. J., 1915, viil, 612.

Van Norman-, K. H.

Johns Hopkins Hospital, Baltimore, Md. Routine technic for handling specimens. A number of well administered h ispitals tell how they gather, protect and analyze urine and operating room tissue? : what is done with the records. A symposium.— !/"/. Hasp., 191o, v, .i4s.

Waldbon, C. W.

The present status of adenoid and tonsil operations.— Dental ' osmi J, 1915, lvii. 651. , f

Rcentgenologv of the accessory nasal sinuses with special reference to sinusitis in children. — Interstate il. J., 1915. xxii. 1031.

Waldbon, C. W., and Waters, C. A.

Rcentgenologv of the accessory nasal sinuses describing a modification of the occipitofrontal position. — Am. J. Roentgenol., 1915, ii. 633.

Warfield, L. M.

The normal differential leukocyte count. A proposed classification of

the white blood cells.—,/. Am. it. Ass.. 1015. Ixiv. 1296.

Hospital equipment. — Hod. Hosp.. 1915. v. 113.

Diastolic pressure: its determination and importance. — «. 1 oik it. J.

[etc.], 1915. cii. 5nv

I'iagnosis of incipient pulmonary tuberculosis. — II isronsm 31. ./..

1914-15. xiii. 192. m ,_

The intrameningenl treatment of syphilis of the nervous system. —

Iffeconnfi M. ./.. 1914-15, xiii. 436.

Waters, C. A.

A modification of the occipitofrontal position in roentgenography, of the accessor; nasal sinuses. — Arch. Recntg. Rag., 1915-161 xx. 15. Rcentgen'ization of the thymus gland in Graves' disease. — •/. Am. il. 1st., 1915, lxiv. 1392.

Waters, C. A., and Colston, J. A. C.

A report of three cases of fibrosclerosis of the penis treated by Rcintgenization with ut improvement. — Sunj., Ounce, d Obst., 1915, xx. 41.

Waters, C. A., and Waldbon, C. W.

Rcentgenologv of the accessory nasal sinuses describing a modification of the occipitofrontal position. — Am. J. Roentgenol., 1915. ii. 633.

Watt, C. H.

Intratracheal ether anesthesia in the surgery of the brain and spinal cord.— J. Am. M. Asa . 1915, lxv. S69.

Weed, L. H., and Cushixg, H.

Studies on cerebro-spinal fluid. VIII. The effect of pituitary extract upon its secretion (choroidorrhcea i. — .b». ./. Physiol., 1914-15. xxxvi.

Whipple, G. H.

Intestinal obstruction: a proteose intoxication. — J. Am. !/. Ass., 1915, lxv, 476.

Whipple, G. H., and Hooper, C. W.

Icterus. A rapid change of hemoglobin to bile pigment in the pleural and peritoneal cavities. — I'roc. Hoc. Exper. Biol ( Med., 1915, xiii. 22.

Whipple, G. H., and Speed, J. S.

Liver function as influenced by anesthetics and narcotics. — J. £'j/» " 1915, xxi. 203.

WHITHAM, L. B.

The relation of the ophthalmic department to the general hospital. — Mod. Hosp., 1915. iv. 304.

Wight, 0. B.

Volvulus of the ileum. — Northwest M.. 1915. vii, 142.


Williams, J. W.

The effect of pubiotomy upon the course of subsequent labors. — Am. J.

Obst., 1915. lxxii, 1.

The limitations and possibilities of prenatal care. Based on the stn.lv

of 705 fetal deaths occurring in It). 000 consecutive admissions to the

obstetrical department of the Johns II. pkins Hospital. — J. Am. M. Ass.,

1915, lxiv. 95.

Premature separation of the normally implanted placenta. — Surg.,

Qynec. .1 Obst., 1915, xxi. 541.

WlLLOCK, J. S.

Autoserum .therapy in the treatu — J. Am. If. Ass.. 1915. lxv. 14.


it of psoriasis and other skin diseases.


Wilson-, D. W., Jaxney, J. H., Jr., and Steabns, T.

The effect of acid administration on parathyroid tetany. — J. Biol Chem., 1915. xxi. 169.

The excretion of acids and ammonia after parathyroidectomy. — J. Biol. Chem., 1915, xxiii, 123.

Wilson-, D. W., Thurlow, M. DeG., and Steabns, T.

The acid-base equilibria in the blood after parathyroidectomy. — J. Biol Chem., 1915, xxiii. 89.

Winternitz, M. C, and Kline, B. S.

Studies upon experimental pneumonia in rabbits, of lobar pneumonia. — J. Exper. it.. 1915, xxi. 304. Studies upon experimental pneumonia in rabbits. VIII. Intra vitam staining in experimental pneumonia, and the circulation in the pneumonic lung. — J. Eiper. M.. 1915, xxi. 311.

Studies upon experimental pneumonia in rabbits. IX. The part of the leucocyte in the immunity reaction. — J. Exper. M., 1915, xxi. 320.

Winternitz, M. C, and Sladex, F. J. Venous thrombosis during myocardial


VII. The production


nsutfiei.ney. Balto.. 1915. — The


Johns Hopkins Press, 40 pp.,

WOLFSOHX, J. M.

Amaurotic idiocy. General and historical considerations, with report of a case: pathological report by Jean R. Oliver. — Arch. Int. Med., 1915. xvi. 257. An improved lumbar puncture needle. — ./. Am. H. Ass., 1915, lxv, 2164.

WOOLLEY, P. G.

Die Faktoren. welcho. die Gefiisserweiterung und Verzogerung des

Blutstromes bci Entziindungeu veranlassen. — Centralbl. f. alia. Path.

u. path. Anat.. 1915, xxvi. 217.

The lesions in experimental infection with Bacterium tularense. — .1.

Infect. His.. 1915, xvii, 510.

Intestinal stasis and intestinal intoxications : a critical review. — J. Lab.

.1 Clin, ilrd. 1915 i. 45.

Indigestion. (Editorial.) — J. Lab. .( Clin. il.. 1915. i. 142.

Alkali salt therapy in anuria. .Editorial.) — 7. Lao £ Clin. it.. 1915.

i. 144.

Angina pectoris, i Editorial. ) — J. Lab. c( Clin. H.. 1915. i. 153.

Growth and overgrowth. — V. York il. J. [etc.J. 1915, ci, 656.

Woolley, P. G., DeMar, A., and Clark, D.

Further experiments on the effects of long continued intraperitoneal injections of proteins. — J. Exper. 1/.. 1915, xxii. 114.

Yates, J. L.

The hospital's duty to medical science for the furtherance of human welfare — by research, production of papers, library and museum. — 1/.,./ Hosp., 1915, v. 110.

Yates, J. L., and Bunting, C. H.

The rational treatment of Hodgkin':

lxiv. 1953.

Hodgkin's disease and allied affections. — Wisconsin M. •/., 1915. xiv. 94.

Young, H. H.

The renaissance of urology. — Read at the Southern iled. As


il. Ass., lbl"


1915, ix.


PROCEEDINGS OF SOCIETIES.

Vol. XXVII.^No. 30 1.

BALTIMORE, MARCH, 1916.


CONTENTS

A Discussion of Acidosis. With Special Reference to That William Tully, of Connecticut, 1785-1859. (Illustrated.)

Occurring in Diseases of Children. By Kate Campbell Mead, M. D 7!)

By John Howland, M. D., and W. McKlM Marriott. d ,. , „ . ..

J Proceedings of Societies.

The Johns Hopkins Hospital Medical Society. 85

_. TT , . . . . _ . ~ ~ , , „, ,, Exhibition of a Case of Benzine Poisoning [R. L. Haden 1 ;

The Lse of Suction in the Post-Operative Treatment ot Bladder ~° L \

.. . , — The Interpretation of a Positive Nitrogen Balance in

Cases. (Illustrated.) .., , . . _. „ ,

_ T „ _ „ _ .„ >*epl)ritis [Herman O. Mosentiial] ; — On the Treatment

By John \\ . Churchman, M. D 69 v rut-..- *u \ r- * *

ol Hay Fever by \ accination with Aqueous Extracts of

tu t> i *• cc- „- * n„ •« „* u i n ti Certain Plant Pollens [G. H. A. ClowesI ; — As to the

The Relation of Angiogenesis to Ossification. Based t pon the L "

Study of Five Cases of Calcification and Ossification of the Cause of Ane » lis "' oi the Subclavian Artery in Cases of

Ovary. (Illustrated.) Cervical Rib [W. S. Halsted and M. R. Reid.]

By Eli Moschcowitz, A. B., M. D 71 The Johns Hopkins Hospital Historical Club 88

Leonardo da Vinci's Anatomy [Arnold C. Keeps.] The Pressure of Bile Secretion During Chronic Obstruction of

the Common Bile-Duct. Xotes on New Books 89

Bv W. T. Mitchell, Jr. and R. E. Stifel 7S Books Received 92


A DISCUSSION OF ACIDOSIS.WITH SPECIAL REFERENCE TO THAT OCCURRING IX DISEASES OF CHILDREN.

By John IIuwlwu. M. D., and W. McKim Marriott, M'. D.


(From the Harriet Lane Borne and the Department The- term acidosis is one that, at the present time, i- very generally and very loosely employed in clinical medicine. It is used, for the most part, to indicate that acetone bodies have been found in the urine by qualitative tests. In descriptions of most of the recorded cases, however, those symptoms that we may look upon as important for the diagnosis of acidosis are not to be found. It is assumed that the acetone bodies are very abnormal and that their presence signifies an unusual complication in the course of disease. Whereas, we may. in many instances, liken the mere presence of acetonuria to fever : for it occurs in most of the infectious diseases of Children with much the regularity that fever does. We do not look upon moderate fever associated with infectious processes as unusual or dangerous, nor should we look upon the acetone bodies in the urine as

unusual or dangerous. Eyperpyrexia may. hou lop

and in itself be dangerous or fatal. So, too, a production the acetone bodies may in itself determine a fatal outcome.




THE USE OF SUCTION IN THE POST-OPERATIVE TREATMENT OF BLADDER CASES.

Bv John- W. Churchman, M. 1>.


Professor of Surgery, Yale University

My interest in this subject was aroused by a case of extensive carcinoma of the bladder, which could be treated only by fulguration, through a supra-pubic wound. In this patient it was necessary, at the same operation at which the cancer of


able, I attempted to carry oil' the irrigating fluid by means of continuous suction. The apparatus was arranged a- shown in Fig. 1. The sterile water used for the irrigation reached the bladder through a permanent urethral catheter (a) which was



the bladder was treated, to do a supra-pubic prostatectomy. In order to rid the bladder of the urinary salts which were deposited on its wall, and to hurry the healing of the suprapubic wound, it seemed advisable to keep up continuous bladder irrigation ; and to keep the patient dry and coi


connected with a reservoir (b) provided with a drip apparatus (c). Into the supra pubic wound a large caliber tube ( d ) vras introduced, not deeply enough to enter the bladder itself. This tube was fastened to the abdominal binder and connected with a rotary electric suction pump <




THE RELATION OF ANGIOGENESIS TO OSSIFICATION. BASED UPON THE STUDY OF FIVE CASES OF CALCIFICATION AND OSSIFICATION OF THE OVARY.

By Eli Mo-cm owitz, A. B., M.D., Pathologist to the Beth Israel Hospital, New York I (From the Patho!<> atory of Beth Israel Hospital.)


The incidence within a short time of five cases of such a rarelesion as calcification and ossification of the ovary, seemed at first a fit opportunity to study the lesion from a morphological viewpoint. A closer study of the specimens, howe so many apparently novel data relating to the finer formation of bone, that inevitably the morphological becomes subsidiary to the histogenetic interest.

CASE REPORTS.

Case 1. (B. I. H. 2891.) — Ovary removed for " chronic ovaritis." Situated beneath the capsule of the ovary is a corpus luteum that is entering the terminal phase of its evolution. It is still possible; to differentiate the outer or lutein cell zone from the central core


of fibrin, although both have undergone nearly complete hyaline degeneration. The outer zone contains a small number of degenerated lutein cells and radiating strands of connective tissue arising from the stroma of the ovary. The fibrinous core is acellular.

Scattered in the outer zone are a large number of focal deposits of lime (Fig. 1). These deposits are small, discrete, roughly spherical and imbedded in a cavity formed by the surrounding hyaline tissue. The core of hyalinized fibrin is free from such deposits.

The remainder of the ovary shows the changes common in the adult ovary.

An almost healed corpus luteum within an otherwise normal adult ovary: in the outer or lutein-celled zone are scattered di its of lime. [No. 301


(B. I. H. 3529.)— S. F., aged 60, was admitted to the hospital October 19, 1912, suffering from chronic nephritis. The patient had been married 30 years, and had had six pregnancies, of which two had ended in abortions. She began to menstruate at IS vears: menopause at 40.

The main svmptoms on admission were vertigo, headache, fever and sweating, marked edema of the legs, increasing weakness cough and expectoration and loss of weight. The urine showed much albumin and many casts. Blood pressure, 200. The patient died in uremia. Nov. 7. 1912.

A u tops i, -Anatomical diagnosis: healed tuberculosis of the lungs- emphysema and congestion of both bases: brown atrophy of the heart muscle with hypertrophy of the left ventricle: chrome congestion of the liver and spleen; chronic interstitial nephritis, " osteoma " of the ovary.

Both ovaries are small and shrunken. In the right ovary, just beneath the capsule, is a mass of ivory hardness, measuring 5 x 3 x 2 mm. The mass is egg-shaped: its surface is convoluted and densely adherent to the surrounding tissue. The mass is surrounded by a narrow zone of dense white tissue resembling in structure and conformation a corpus albicans.

Uicrosa vmination.— (Pig. 2). The mass consists of a

homogeneous mass of lime embedded within a corpus albicans. The edge is wavy, and sharply circumscribed from the surrounding thin capsule of hyaline connective tissue. With the high power the fine fibrillar structure of the hyaline matrix can be distinguished in the calcareous area. Within the calcareous mass are clefts which are manifestly artefacts, due in all probability to the method of preparation.

mary.—A homogeneous nodule of lime deposited in a corpus albicans of an atrophic ovary. The lime mass contains no bone or cellular elements whatever.

Case 3. (B. I. H. 2887.)— R. H., aged 40, married 12 years, no children. Menstruation began at 14, regular every four weeks, and of eight days' duration. For the past few months she has been complaining of severe pain in the lower left abdomen. Pre-operative diagnosis: fibromyomata. Operation by Dr. L. J. Ladinski. Supravaginal pan-hysterectomy.

Gross Description. — Uterus: large fibroid in fundus. Fallopian tubes; both tubes adherent to each other by dense adhesions subtending the posterior aspect of the uterus. The left tube is greatly thickened, straight and spindle-shaped. The lumen is completely . obliterated and filled with a fine, white, honeycombed mucosa, which exudes a small quantity of seropurulent fluid. The muscu- lar coat is thickened. At its thickest point, the middle of the tube, it has a thickness of 1.5 cm. The right Fallopian tube is distorted and varies in thickness. At the isthmical junction is a nodule, the size of a bean, typical of so-called " salpingitis nodosa." From this point the tube suddenly becomes narrow for a distance of 3 cm., averaging in diameter a goose-quill, whence it gradually increases in size until at the fimbriated end it is 2 cm. in diameter. The fimbriated end is closed. Section of the tube through the isthmical nodule reveals the typical microscopic appearance of " salpingitis nodosa." In the narrow portion the lumen is very small; there are no villi, and the muscular coats are slightly thickened; at the outer end, the lumen is fairly large, convoluted, and lined with a smooth glistening white membrane. Midway between the lumen and the peritoneal coat, is a thin layer of bone which is continuous around the circumference. This layer is about 2 mm. thick, and its contour conforms to the wavy outline of the tube lumen. The left ovary is greatly enlarged, edematous, and contains numerous fresh and old corpora lutea.

The right ovary is very small, measuring 2.5 x 1.5 x 1 cm., and is deeply scarred. On section a hard dense calcareous mass, 8x5x4 mm., is found just beneath the capsule. This nodule is situated


within the center of a corpus albicans, being surrounded by a narrow wavy capsule of dense white hyaline tissue. The mass was shelled out with difficulty and was found to be egg-shaped, convoluted like a brain, with shallow sulci. The remaining portion of the ovary shows dense cirrhosis and a large number of corpora albicantia.

Microscopical Examination— The masses in the uterus reveal a typical fibromyoma with hyaline degeneration.

The description of the microscopic structure of the tube is irrelevant for our purpose and will be reserved for later publication. Calcareous Mass in the Right Ovary.— The lime is deposited within a corpus albicans, the fine fibrillar structure of which can be seen with the high power shimmering through the lime-eontaining area. The circumference is very wavy and finely spiculated (Fig. 3). Here and there, manifestly corresponding to the sulci observed grossly, are many bay-like excavations penetrating for short distances into the concretion.' These excavations are irregular in shape, vary in size, and with the low power of the microscope appear empty. The surrounding hyaline fibrous tissue, which along the greatest part of the circumference is in close apposition to the lime-containing area, becomes attenuated ov*er these excavations and is gradually lost at the roof of the excavation (Fig. 4). With the high power, however, these excavations contain distinct tissues. In all these escalations without exception, ice find abundant red blood cells, a fine fibrillar network of connective tissue and a fen: distinct fibroblasts. In some excavations, ire can even distinguish a very young blood capillary, formed apparently by a number of fibroblasts arranged circularly. These capillaries contain red blood cells (Fig. 5). The interior of the calcareous nodule also contains numerous irregular cavities with sharply defined walls, which in general features and size resemble the excavations described above. Indeed a continuity between these cavities and the surface excavations can in many instances be clearly demonstrated. Whether all these cavities communicate with corresponding excavations it is impossible to say, because the study of serial sections was not feasible. As we shall see, the probability that they do is strong. With the low objective, these cavities also appear to be empty. With the high power, how the same stru, tures visible within the excavations described above are found here: namely, red blood cells, a fine fibrillar connective tissue, interspersed with fibroblasts, and occasionally very fine capillaries containing red blood cells.

The remainder of the ovary shows the familiar changes of the hard, cirrhotic, inactive ovary.

Summary.— A patient, aged 40. with fibroids, adherent tubes and cirrhotic ovaries. The right ovary contains a calcareous concretion, the surface of which is deeply excavated, the interior honeycombed with cavities, many of which are demonstrably continuous with the excavations, all of them probably so These excavations and cavities are occupied by an active tissue, consisting of very young blood vessels, fibrillar connective tissue and fibroblasts, in the meshes of which are main red blood cells.

EpicrUical Remarks.— The source of this active tissue cannot be positively demonstrated without serial sections which, because of the unexpected findings, were not made. That this tissue arose from the peripheral blood supply cannot be gainsaid. The sequence of events is probably this: blood sinuses and attendant young fibrous tissue penetrated through the hyaline covering of the concretion from the periphery. In corroboration of this surmise, we find, in the hyaline fibrous capsule, spaces containing the identical tissues described within the excavations and the cavities. When this highly active


March, 1916.]


tissue making up a blood sinus meets the calcareous concretion, absorption of the lime occurs, resulting in deep excavations into the interior. Coincidently, the formation of young blood vessels takes place, so that part of the blood is carried within these channels.

YVc regard these findings and this interpretation as highly significant for the elucidation of the later processes of bone formation in these calcareous concretions, about to be described.

Case 4. (B. I. H. 2781.) — Rosie I., aged 33, married 9 years; never pregnant. Menstruation began at 14 years; it has been regular, occurring every four weeks and of three days' duration; the ffow has been normal. For the past three years she has been complaining of pain in the lower abdomen. Since then menstruation has been irregular and more frequent. It now lasts one week. On examination, there is tenderness in the left fornix. Operation by Dr. L. J. Ladinski; double salpingo-obphorectomy.

Microscopic Description. — Both tubes are covered with remains of old adhesions. The tubes are short, straight and average 1 cm. in thickness. On section, the lumina are large; the mucosa is pale and honeycombed. The coats are thickened. The right ovary is attached by a broad pedicle to the posterior surface of the tube. It is 2.5'cm. long, 2 cm. thick and 1.5 cm. wide. Microscopir diagnosis of Fallopian tube: chronic salpingitis. The surface of the ovary is covered with the remains of old adhesions. On palpation a hard mass of bony consistence is demonstrable within the ovary. On removal of the mass, which is effected with difficulty owing to its intimate adherence to surrounding tissues, only a shell of ovary, about 2 mm. thick, remains. The calcareous mass is roughly ovoid and measures 1.7 x 1.3 x 1.1 cm. The surface has a brain-like contour with shallow linear sulci.

Section through the center of this mass shows that it is composed of a shell around a central cavity. The shell is 1.1 cm. thick and of bony texture and consistence. The central cavity is about the size of a pea, has a smooth wall and is filled with a soft fattylike material resembling sebacebus matter.

Microscopical Examination of the Bony Mass Within the Ovary. — With a very low power, three fairly well defined zones can be made out: (1) an outer zone consisting of lime-containing connective tissue; (2) an inner zone of pure bone surrounding the central cavity; and (3) between 1 and 2 a narrow zone, in which new osseous tissue is in the process of formation. Each will be described in order.

Outer zone. This is rather broad, covering about two-thirds the diameter of the shell and has the same morphology as in Case 3. In other words, it consists of lime imbedded in a matrix of hyaline connective tissue. The edge is wavy, finely spiculated and sharply defined from the encircling coat of hyaline connective tissue. Especially prominent are the same excavations on the surface as were encountered in Case 3 (Fig. 6). The differenci is that they are deeper ; the fibroblasts are more abundant; tin rt tii liter connective tissue is coarser; and, what is especially conspicuous. the blood vessel has a more mature appearance. The vi ,» I is sharply defined, the coat is firmer, and cells of an endothelial type line the lumen. The red blood cells no longer lie enmeshed in the fibrillar connective tissue, but are all contained within the newly formed blood vessel. The interior of this zone also contains • < i ties, a hit h. as in Case 3, correspond precisely in morphology to the superficial excavations. Here, also, communications between the two can be demonstrated. The same description of the excavations just set forth can, therefore, be applied to these cavities. Inner zone. This possesses all the histological features of mature bone (Fig. 7). There are bone lamellar, bone cells, typical Haversian canals lined with a well defined row of osteoblasts. The Haversian canals contain one, sometimes two blood vessels, fibroblasts and a fine fibrillar connective tissue. The bone trabecular present irregu


lar streaky areas, which take the stain of calcification and which may be interpreted as irregular and incomplete areas of lime absorption.

The most significant observation is tin exact morphological similarity, except us regards the obsteoblasts. to the excavations niul em tins in tin- out, r zone. The blood vessels, the fibroblasts and the fibrillar connective tissue correspond in every detail. The presence of the osteoblasts will now be explained. The middle zone. This is rather narrow, but contains within itself all the various stages of new bone formation. The earliest stage is best represented in Figs. S and 9. Here we note the same excavations and cavities seen in the outer zone. In addition, however, we note that the periphery of the cavity, instead of being comparatively smooth, has a broken-up, moth-eaten appearance. This change is due to two factors: (1) small, irregular scalloped-like absorptions of lime; (2) a tendency for the fibroblasts to arrange themselves along the periphery of the excavation or cavity in the form of one or more layers of obsteoblasts. Distinct transformations of fibroblasts into the round or ovoid cells of the osteoblastic type - an be demonstrated. Another change consists of a process of lime absorption in the trabecular between the cavities and an abundant deposition of cells within these trabecular. The trabecular are more translucent. The stain of the underlying hyaline matrix is more prominent. The cells are round or oval with small nuclei and stain rather faintly. It is quite evident, howen r. that these , ells are of the same typi as those that lie on the periphery of the cavities eini may, therefore, !)i regarded us having the same origin.

The next step in the process of bone formation is represented in Fig. 10. Here we find the earliest form of Haversian canal. The cavities are like those already described; they contain a wellformed blood vessel, reticular connective tissue, many fibroblasts, and in addition, along the periphery, typical osteoblasts. The walls of these canals are composed partly of the calcareous hyaline matrix interspersed with cells of the osteoblastic type similar to those shown in Fig. 9; and party of typical bone foci, consisting of lamellar and bone cells. The bone is sometimes continuous along the greater part of the periphery of the canal; sometimes it is present for short distances in two, three, or more areas of the canal with a calcareous matrix intervening. These bony zones are, as a rule, narrow, sometimes consisting of only two or three lamellar and, peripherally, sharply defined from the surrounding calcareous matrix. This is especially true of the cavities in the more superficial parts of the middle zone. In the deeper portions the lamellar are continuous with the osseous tissue of the inner zone.

Fig. 11 represents the last or final stage of ossification and the formation of a fully developed Haversian canal. This stage differs from the preceding only in the fact the canal is lined along its entire circumference with osseous tissue.

In the lower part of the picture we note a small Haversian canal surrounded almost entirely by osseous lamellar.

It is highly significant for the correct interpretation of the pathogenesis of the new osseous formation, that bone is nowhere found except in immediate relation to cavities or canals. The spaces between the canals are entirely free from bone.

The tissue filling the central cavity contains merely debris and fat.

Summary.— A patient aged 33. Both Fallopian tubes ami one ovary wen I for chronic salpingitis with pelvis

adhesions. A bonj mass is found within the ovary in the center of a corpus albicans. On micrqscopii distinct

zones can be demonstrated: (1) a hyaline connective-tissue capsule derived from a corpus albicans ; i '.' i a calcareous zone, in which are hay-like indentations and cavities i ing a blood vessel and active fibrous young tissue; (3) an

ossifying zone, in which the processes of lime abs< formation of osteoblasts and osseous lamellae, and the conversion of the above-mentioned cavities into mature Haversian canals, are manifest : ( 1 one consisting of mature

bone, with Haversian canals ; (5 ) a central or so-called marrow cavity showing a smooth wall, containing mostly fat.

Our epicritical remarks will lie reserved until after the description of the following case:

... (B. I. H. 2883.)—! am indebted to Dr. W. C. Clarke, of Columbia University, for this specimen.

The only facts obtainable are that the mass was about the size of a walnut and was found within an ovary removed from a patient at the General Memorial Hospital. Xew York City.

Microscopic Examination. — The histology is the counterpart of that in Case 4. the only difference being that the process is more advanced. The three zones, calcareous, ossifying, and osseous, are distinct. The osseous lamellae are more compact; the blood vessels both in the Haversian canals and in the cortical indentations are sharply circumscribed, possess a firm fibrous wall and are lined with " endothelium." The tissue within the forming and mature Haversian canals presents all the characteristics of fatty marrow; there is abundant fatty connective tissue, firm fibrous tissue and abundant fibroblasts, small round cells and spindle-shaped connective-tissue cells. The majority of the Haversian canals are lined with a distinct row of osteoblasts. Neither in this specimen nor in the preceding are we able to find any osteoclasts.

Summary. — With the exception of the clinical findings, the summary of this case is the same as for the preceding, the only difference being that the ossifying process has manifestly attained a more mature age.

Epicritical Remarks Concerning the Pathogenesis of Ossification in - Ovary. — We deem it a fortunate circumstance that we not only possess five cases of a lesion that is unusually rare, but that each illustrates a stage in the evolution of a process, the details of which have so far been a matter largely of speculation. It can be truly said that there are no gaps in the story that these stages illustrate. By them we are enabled to correetlv interpret not only the histogenesis of so-called " osteomata " of the ovary, but also of the majority of abnormal ossifications occurring within the human frame.

Briefly, the process is the following. In the apparently dying or inert tissue of the corpus albicans, there occurs a discrete deposit of lime. This is illustrated in Case 1 (Fig. 1). Bv coalescence these discrete deposits form a solid amorphous calcareous mass within the center of the corpus albicans, the surface of which corresponds in a rough way to the shape of these structures. This is illustrated in Case 2 (Fig. 2). The deposition of the lime does not occur homogeneously, but within the hvaline connective tissue of the matrix of the corpus albicans as a base. In other words, should the lime be dissolved, a cavity within the corpus albicans is not formed thereby, but the underlying hyaline connective-tissue matrix will persist.

Owing to a stimulus, the nature of which is not determinable, ovarian blood vessels arising from the capsule of the corpus luteum penetrate the hyaline connective-tissue membrane and, as they approach the calcareous nodule, are transformed into blood sinuses consisting of a reticulum of delicate connective


tissue and young fibroblasts, both derived from the attendant connective-tissue coat of the penetrating blood vessel. These sinuses erode the surface of the calcareous nodule and, penetrating the interior, form an inter-communicating system of cavities or canals. Some of the fibroblasts arrange themselves circularly and form a very young blood vessel, which eventually carries much of the blood that has hitherto permeated the surrounding loose fibrillar connective tissue. The canals thus formed represent the earliest stages of the Haversian canals. All these steps are nicely illustrated in Case 3 (Fig. 4). The fibroblasts now assume the function of osteoblasts. From irregular delicately appearing cells with a large faintly staining nucleus, they become larger, oval or round, with a strongly defined nucleus, richer in chromatin. These cells tend to arrange themselves along the periphery of the canals and even penetrate into the surrounding areas, in which there has coincidently occurred an absorption of lime. At the same time, the blood vessel of the canal has matured and now consists of a well circumscribed wall of fibroblasts and fibrous connective tissue. The blood vessel now contains all the circulating blood cells, none being demonstrable in the surrounding connectivetissue meshes. The surrounding reticular connective t hardier in appearance, the strands being thicker, denser and interspersed with spindle cells derived from fibroblasts I Pigs. 6, 7, 8 and 9).

A deposition of bone now occurs along the wall of these canals ; the underlying hyaline calcareous matrix becoming converted into osseous lamellse. the osteoblasts becoming converted into bone cells. The ossification begins at one or more areas of the wall, until finally the entire canal becomes surrounded by osseous lamellae (Figs. 10 and 11). The ossification proceeds eccentrically, beginning in the central portions of the calcareous mass and extending peripherally. The bone lamella? are also deposited eccentrically in relation to the individual cavities themselves, the layers becoming more numerous until they meet the lamella? of the neighboring canal. Coincidently with this process of ossification, the contents of the canals mature progressively. The blood vessel enlarges, the fibrous tissue wall is thicker and denser and a distinct endothelial lining is visible. The surrounding reticular connective tissue is also firmer, denser, abundantly interspersed with spindle cells, and has in part become occupied by fatty connective tissue. A distinct layer of osteoblasts now lines these canals. In other words we now find an intercommunicating system of Haversian canals surrounded by osseous tissue. the whole conforming in every detail to normal calcareous adult bone.

The process i- entirely analogous to the physiological endochondral ,rcnce being that, instead of cartilage, the matrix is hyaline connective tissue infiltrated with lime. A description of endochondral ossification taken from Stohr will show how striking this analogy is. " The first indications of this process consist in changes at certain places within the cartilage: a deposition of lime salts takes place within the matrix, in consequence of which it becomes finely granular and dull : it calcines. Such places can soon b<


nized by the unaided eye. and a i iieation,

better perhaps, centers of calcification. Meanwhile, on the

surface of the center of calcification, a tissue rich in blood vessels and young cells, the osteoblastic tissue, has made its appearance. This penetrates into the cartilage, and eai: destruction of the calcified matrix: the cartilage cells are set free and disintegrate. In this way a little excavation arises in the center of calcification; it is called the primary marrow cavity.

" These processes are repeated in the immediately surrounding cartilage: that is, the cartilage ground-substance calcifies. the cartilage cells enlarge, new portions of the cartilage break down, and as a result the primary marrow spare is gradually and continuously enlarged. At the same time the capsules of many cartilage cells are opened, the cells degenerate, and the intervening calcified matrix projects into the marrow space in the form of irregular processes. The marrow cavity is now a bay-like space, filled with blood vessels and primary bonemarrow, that is. with anastomosing branched connect r. cells. Some of these cells, the osteoblasts, grow rich in asm ami apply themselves in the manner of a one-layer epithelium to the walls of the marrow cavity and there produce bone. Some of the branched connective-tissue cells retain their form and later, together with a fine-fibered connective contribute the supporting framework of the bone-marrow. Others of these cells become fat cells. Through the activity of the osteoblasts the marrow cavity is soon clothed with a thin stratum of bone, gradually increasing in thickness; the irregular processes of calcified substance are completely enveloped in young bone. Thus, step by step, the former solid piece of cartilage is transformed into spongy bone, the trabecule of which still contain residues of cartilage matrix."

The analogy between *the pathogenesis of abnormal ossification and endochondral ossification is admitted by many observers. ( Well-. 1 Jiuerger and Oppenheimer, 2 Monckberg,' Ruh,* Kaufmann." and Aschoff." ) All are agreed that the matrix for subsequent ossification is a calcified area.

Relation between Calcification and Ossifica ion. — Calcification is a common pathological phenomenon and has been described as occurring in almost every tissue of the body. In the instances in which the process has been carefully studied, it has been found that it only occurs in areas of tissue that are dead or inert. For instance, we have observed it in tubercles, atheromatous plaques upon the lining of the circulatory system, a necrosed epithelioma of the abdominal wall, the walls of degenerated sebaceous cysts, and in the wall of an old lung

abscess. On the other hand, calcification po

predilection for connective-tissue structure- that have undergone hyaline degeneration, which, owing to their compL of blood vessels, can justly he regarded as inert tissues; our corpora alhieantia may be cited as examples. In addition, we have observed instances of calcification in the hyaline wall of a chronically inflamed Fallopian tube, in the wall of a hernial sac of long standing, in old pleuritic thickenings, in the walls of old hydatid cysts, in old fibroids of the uterus, in the wall of a degenerated ovarian cyst and in the scar of a Lapa


wound. Indeed, this phenomenon has been observed in almost every instance when hyaline degeneration of a com tissue structure may occur.

The chemical process whereby lime is deposited in tissue affords an interesting and fruitful study, but is not germane to our present purpose. For an able discussion of the modern aspects of this theme, the reader is referred to the paper by Wells.

Thus far, every instance of abnormal ossification, exclusive of that directly associated with bony structures, e. //.. exostoses, has revealed a coexisting calcification. In no instance, furthermore, has the writer been able to discover a case of unalloyed ossification. Inasmuch as all observers agree that calcification always precedes ossification, both normal and abnormal, the postulate may be formulated that without ca tion there is no ossification. From this postulate, we may conclude that ossification may occur in any situation where calcification has been observed. A study of recorded cases proves that this deduction is correct, so that a typographical Ii-t of abnormal ossifications becomes merely a duplicate of that of abnormal calcifications. We are not in the position to state (because in the present state of our knowledge it is obviously impossible to determine precisely) that the process of calcification ceases when that of ossification begins. In all probability, howi on of lime occurred on the periphery of our mass, coincidently with the ossification arising within the center. We deduce this surmise, because we have never observed, or seen reported, a case of pathological ossification within the soft tissues ( independent of the bony framework ) without a coexisting area of calcification.

The Relation* of the Development of Xew ISlood

Vessels to the Process of Ossification.

The succession of events comprising the process of ossification, as we conceive it, agrees in its broader features with the conventional view. Our own contribution to the subject is an attempt to resolve the process to its ultimate cellular beginnings; to show how the development of uew blood is the essential activity in the making of hour. This activity applies not only to the making of abnormal bone, bul also (and this is of vaster consequence) to the making of normal bone. To be sure, in the conventional view concerning the development of bone the important role that blood vessel- plaj is well recognized. Their mere presence is accepted as an axiom, their main function being to erode the calcified g substaie orm Haversian canals. shown,

however, it is not the presence, but the development ol vessels that supplies the keynot nation;

furthermore, we have shown that the cellular elements that enter into the process of this development are tl of all the hist omponents of osseous tissue.

The validity of tin- contention obviously depends upi soundness of our exposition of the development of We confess that, at the outset, we felt considerable hesitancy in accepting the interpretation of the histological findings in our specimens, inasmuch as they were entirely inconsistent with [No. 301


ew that we had previously been taught. Never having hitherto made an intensive study of the developments of blood vessels, we were unaware, for a time, that a conception similar own had alreadj been published. By a strange commit into a close and personal touch with such studies. The result lias been that whatever hes we felt at first has disappeared, and we have come to the definite conclusion that the conception, independently worked out by us. is the correct one. This inevitably leads to a discussion of angiogenesis, a subject that has been the source "1 much controversy.

onceming Li -.—The older view* was

first advocated by His and until recently was accepted by most histologists.

In this conception, blood vessels originate a- protoplasmic eords arising from the terminal portion of a previously existing blood vessel. These protoplasmic cords were termed by Brenner angioblastSj and consisted of cellular processes derived from the endothelium of the blood vessel. By the simple process of canalization, these angioblasts become capillaries, the potential element of all blood vessi Is.

This conception necessarily deduces a postulate of tremendous import to cellular ontogeny, the specificity of endothelium. This has been forcibly summarized by Rabl in his dictum " Endothel stammt aus Endothel." The importance of proving whether the endothelial cell is. or is not, specific is obvious. If endothelium is specific, its functional range, both normal and pathological, at one stroke becomes a very limited one. As Schulte ' admirably expresses it: "The doctrine of the specificity of endothelium takes endothelium out of tin' series of mesenchymal derivatives and separates it absolutely from the blood, should that prove to he of mesodermal origin. Consequently thinkers who support this view have seen the importance of assigning an entodermal origin to both blood and endothelium. Could this be established, it would lend a degri e of antecedent probability to the doctrine of the angioblasts, hut strictly speaking, it is not a necessary postulate, for a tissue arising diffusely from the mesenchyme, as development proceeds, may be confined to definite localities or even ultimately be restricted to homoplastic proliferation. Such a tissue would he specific if it yielded no heterogeneous products, and I fed myself that this latter property enters more largely into an idea of specificity as applied to tissues than the continuity or origin of their elements. It would seem, therefore, that the advocates of specificity have charged! themselves rather to prove that endothelium, once formed, produces only endothelium and never any other elements, for example, blood and connective tissue, than that it is peculiar in its origin."

The modern theory of angiogenesis, first proposed by Biickert and Mollier," since then warmly advocated by Huntington," Schulte, McWhorter and Whipple,™ McWhorter and Miller." and Hahn. 1 " assumes that blood vessels consist of ,]. fis


For the best summary of this view see Minot, Kraus and Sabin, in Keibel and Mall's " Handbuch der Entwicklungsgeschichte der Menschen," Leipzig, 1912.


or spaces within the mesenchyme hounded by the indifferent mesenchyme cells. The clefts or spaces enlarge and fuse together to form blood vessels, while the lining mesenchyme cells flatten and form •'endothelium." This theory has bei Q termed the "adaptive" theory as apposed to the "specific." and predicates the postulate that the endothelial cell is a derivative from the widely distributed mesenchyme cell. To quote Schulte again : " This view thus extends the period of development, and enlarges the area in which it is active to practically the whole body of the embryo. It does not deny that endothelial cells undergo mitosis, that vessels after formation lengthen, or that they may branch and send out sprouts, for it by no means implies that endothelium does not grow, but it relegates the phenomena dependent upon endothelial cells to a later period in the life of the embryo."

This is not the place, nor indeed are we in the position, to adjudicate the arguments of the contending exponents. We have contented ourselves with merely stating the opposing views and indicating their possibilities. The data relating to this subject are immense and have been admirably criticized by Schulte, to whose monograph the reader is referred. As Schulte shows, the divergence in viewpoint is due rather to methods of interpretation than to differences in method and technique. Certainly the observations and arguments of the advocates of the adaptive theory are more convincing than those of their opponents. The recent work of McWhorter and Miller." and of Hahn." who showed by delicate operations upon the embryo that blood vessels formed in the area pellucida even when the angioblastic anlage in the area opaca was cut off, affords to our mind irrefutable evidence that the adaptive theory is the correct one.

However, whatever may be said as to the merits of the contending views, the fact that we independently deduced the mesenchymal origin of blood vessels from the histological study of our specimens of calcification and ossification of the ovaries leaves us no choice in the position we shall take. It may seem hazardous to transfer a conception of the development of blood vessels from the domain of the normal to the pathological, but the work of W. C. Clarke," who showed that the adaptive theory of angiogenesis applies as well to the development of blood vessels in granulative tissue, eradicates whatever misgivings we may have had on this score.

The important role that blood vessels play in the process of ossification consists essentially in bringing into heteroplastic activity a dead or inert tissue. In the instances which we report, the tissue is hyaline connective tissue impregnated with lime salts. How is this activity brought about ?

Curiously, the most obvious function of blood vessels, namely, the carrying of nutriment, is only subsidiary in the process of ossification. The main function lies in the production of new connective tissue engendered in the process of development of the blood vessels themselves. As we have demonstrated in Fig. 5, this tissue consists of two elements: (1) young fibroblasts; (2) a fine fibrillar intercellular substance. This is obviously a derivative of the fibroblasts, and its origin, therefore, need concern us no longer. The origin of the


PLATE XVI.


PLATE XVII


fibroblasts is not so easily settled. In ossification of the ovary, these fibroblasts can have only two sources of origin: (a) the endothelium; and (b) the connective-tissue wall of the penetrating blood vessel. Inasmuch as we have shown that fibroblasts later become endothelium, the presumption is strong that the process in its earlier phases is reversed and that, therefore, these fibroblasts are, entirely or in large part, derivatives of the vascular endothelium of the penetrating blood vessel. In embryos, as Huntington, Schulte and others have shown, and in granulative tissue, as W. C. Clarke has demonstrated, these fibroblasts arise not only from the endothelium of the preformed vessel, but also, but in a smaller measure, from the fixed connective-tissue cell. As the hyaline connective tissu mi which the lime is impregnated contains no fixed connectivetissue cells whatever, in our series this origin can be excluded.

However, the problem of the exact origin of these fibroblasts is of academic interest. For our purposes, their ultimate late is a greater issue. As we have shown in our series, the fibroblasts assume three different functions: (1) as vascular endothelium; (2) as osteoblasts; (3) as constituents of the bonemarrow of the subsequent Haversian canals.

In the genesis of ossification their functions as osteoblasts is manifestly the most important.

A study of Figs. 3 to 8 can leave no doubt of the origin of osteoblasts from fibroblasts. In every physical property they are identical with the fibroblasts in their immediate vicinity. Here we note another instance of the close analogy between normal and abnormal ossification, for in developing bone the same origin of osteoblasts is accepted (Stohr).

The exact manner whereby osteoblasts succeed in converting a calcified hyaline matrix into bone-plates is a matter entirely of speculation. Certainly histological data furnish no clue. In all probability, the influence is a physico-chemical one, a process covered with indifferent satisfaction by the term "metaplasia." Speaking in terms of histology, the process may be described as the following. Osteoblasts are ai along the edge of the subsequent Haversian canal, which at this stage is bounded by a wall consisting of a calcified matrix of hyaline connective tissue. These osteoblasts penetrate Eoi a greater or lesser distance into the lime-containing area (Fig. 9). The areas where osteoblasts are found stain much lighter than other areas, indicating a coincident lime absorption. Whether this absorption is due to activity of the osteoblasts or. to a chemical action of the juice- brought by the newly formed blood vessels, cannot be determined. At all events, soon after the penetration of the osteoblasts, boneplates are deposited around the circumference of the future Haversian canal. This deposition is eccentric. As the boneplates form, the osteoblast is converted into a bone cell.

The only detail in the histological picture that now call- for elucidation is the further development of the Haversian canal. As we have seen in Figs. 3 and 3. these are first represented by cavities or indentations on the surface of the lime-containing area, filled with a fine fibrillar connective tissue, fibrobla a blood sinus. In the next stage (Fig. 4). the blood <i become a frank blood vessel with an endothelial wall. The


fibroblasts are more abundant and the fibrillar connective tissue is coarser. The subsequent changes ( Figs. 5, 6 and ~i ) show a gradual senescence of these elements. The blood vessel is accurately shaped and is composed of a firm connectivi wall with a distinct lining of flattened endothelial cells. The fibrillar connective tissue is coarser, the fibroblasts are more abundant, the cell bodies and nuclei are more precise in outline, and the chromatin network is richer. The osteoblastic arrangement of the cells is more pronounced. Finally ( Fig. 8), we have the mature Haversian canals with all their elements attaining their fullest fruition. In addition, we find that some of the connective tissue has undergone fatty change, and we find abundant round cells of the lymphoid type. In other words, the resemblance to the normal Haversian canal of normal bone is now complete.

A curious feature of ossification is the eccentricity of the process, the reverse of what we should expect from the concentric mode of development of the new blood vessels. This phenomenon is the counterpart of that occurring in the di w I opinent of normal bone, in which we find the ossification proceeding from " centers."

Nature of Ossifying Stimulus. — There still remains the question as to the nature of the stimulus that converts a calcified tissue into bone. We must presume there is a stimulus, because not all foci of calcification turn into bone. It is nevertheless still debatable whether ossification is not an invariable consequence of calcification, given a sufficient period of time. ( 'ertainly pathological data indicate that ossification is the rule rather than the exception. For instance, Poscharisky " found bone in all but four of 29 cases of calcification of the eye. Of 38 calcified nodules in the lung, IT contained bone.

Lick " produced bone experimentally in the pelvis of the rabbit's kidney as early as 16 to 20 days after ligating the artery, provided that the kidney was wrapped in omentum to secure a free collateral circulation. Without the collateral circulation, the process required three months. With too free a circulation, therefore, there occurs no calcification or ossification : with to,, little, necrosis o< curs, followed by slow calcification, and either a late or no ossification. Apparently, therelore, a fine adjustment of blood supply is an important factor in abnormal hone production.

Wells believes that the stimulus is probably a tactile one. due to the presence of calcium salts. This is supported by the experiments of Earth."' who healed bone defects by introducing lime or dead bone, whereas, on the other hand, ossification was not stimulated by the introduet ton of decalcified bone.

The stimulus is undoubtedly a physico chemical one. but the precise circumstances suggest an interesting Held for Euture study.

SUMMARY.

A. Three cases of calcification and two of ossificati f the

ovary are described. The process in each instance involved a corpus albicans. The specimens represenl an apparently con tinuous series, in which four cognizable: (1) an

early discrete multiple deposit within a healed corpus luteum; (2) a definitely circumscribed amorphous lime


ra [No. 301


within a corpus albicans; (3) the formation of primary Eaversian canals — which is accomplished by the genesis of an active mesoblastic tissue, both upon the surface and within the interior of such a circumscribed lime deposit. This mesoblastic tissue is derived from the adjacent blood vessels of the ovary, and the predominant activity is the development of new blood Associated with this activity is the development of osteoblasts from the mesenchymal cells; (i) true bone formation — with maturation of all the elements described above, together with eccentric deposition of bone-plates around the primary Haversian canals and the formation of marrow.

B. The development of new blood vessels affords the keynote to the interpretation, in terms of cellular ontogeny, of the

hi ossification. The histological constituents which enter into the formation of new blood vessels are the progenitors of all the histological components of osseous tissue. In other words, blood vessels, osteoblasts, bone cells and marrow (in large pari at least) are merely differentiations of the mesenchymal cell unit.

C. Our specimens furnish strong corroboration of the ' adaptive '* or " mesenchymal " theory of angiogenesis, and to the theory of the non-specificity of endothelium.


D. Ossification does not occur without preliminary calcification, and calcification occurs only in dead tissues.

E. There is no valid reason for regarding bony structures within the ovary as blastomata.

BIBLIOGRAPHY.

1. Wells: Arch. Int. Med., 1911, VII, 721.

2. Buerger and Oppenheimer: Jour. Exp. Med., 1908, X, 554.

3. Monckberg: Virchow's Arch., 1902, CLXVII, 191.

4. Run (quoted by Wells): Vide supra.

5. Kaufmann: Pathologische Anatomie, 6te Aufl., 1911.

6. Aschoff: Pathologische Anatomie, 3te Aufl., 1911.

7. Sehulte: Memoirs of the Wistar Instit. of Anat. and Biol., Phila., 1913.

8. Riickert and Mollier: Handbuch d. vergl. u. exp. Entwicklungslehre d. Wirbeltiere. Herausg. v. 0. Hertwig, 1906, Bd. I, 1164.

9. Huntington: Memoirs of the Wistar Instit. of Anat. and Biol., Phila., 1914, No. 1.

10. McWhorter and Whipple: Anat. Record, 1912, VI, 121.

11. McWhorter and Miller: Anat. Record. 1914, VIII, 203.

12. Hahn: Arch. f. Entwicklungsmech. d. Organ., 1909, XXVII, 337.

13. Clarke, W. C: Personal communication.

14. Poscharisky: Ziegler's Beitr., 1905, XXVIII, 135.

15. Lisk: Arch. f. Klin. Chir., 190S, LXXXV, 118.

16. Barth: Ziegler's Beitr., 1895, XVII, 65.


THE PRESSURE OF BILE SECRETION DURING CHRONIC OBSTRUCTION OF THE COMMON BILE-DUCT.*

By YV. T. Mitchell, Jr. and R. E. Stifel. (From the Hunterian Laboratory of Experimental Pathology, The Johns Hopkins Medical School, Baltimore.)


It is frequently observed in animals with experimental obstruction of the common bile-duct that a rupture of the bile passages may occur with escape of bile into the peritoneal cavity. The following experiments were undertaken to ascertain whether, following an obstruction, there is a rise in pressure within the bile passages from day to day.

A paper by Herring and Simpson ' gives figures for the dog. eat, rabbit, and monkey. The animals were all put under tie- influence of an anaesthetic and the experiments lasted but a few hours at the most. The pressure in millimeters of bile varied in cats from 210 to 375, with a mean of 304.4 : in dogs from 243 to 342, with a mean of 300. These observers found that stimulation of the vagi caused a somewhat prompt fall in bile pressure. Our experiments show no constant reaction following vagus stimulation, and it is possible that the explanation of this difference lies in the duration of the obstruction.


NOTES ON NEW BOOKS.

BOOKS RECEIVED.


Vol. XXVII.— No. 302.


BALTIMORE, APRIL, 1916.

CONTENTS

The Ideal Operation for Aneurisms of the Extremity. Report of a Case. (Illustrated.) By Bertram M. Berxheim, M. D 93


Memorial Meeting to Dr. E. L. Trudeau.

Post-Partum Care of the Perineum.

By E. D. Pi.ass, A. B., M. D. . .


107


The Cases of Gaucher's Disease Reported by Drs. Knox, Wahl and Schmeisser.

By F. S. Makdlebattm, M.D., and Hal Downey, Ph. D. 109

The Role of Certain Florentines in the History of Anatomy, Artistic and Practical. By Edward C. Streeter, M. D .113


Proceedings of Societies.

The Johns Hopkins Hospital Medical Society 118

Report of Cases: Chloroma and Acute Myeloid Leukemia [Dr. .Iohx T. Kixg, Jr.] ; — Chemical Studies in Bichloride Poisoning [Dr. D. S. Lewis and Dr. T. M. Rivers] ; — Experiences with the Epidemic of Typhus Fever in Serbia [Dr. R. P. Stroxg] ; — Spontaneous and Experimental Leukemia of the Fowl. (Abstract.) [Dr. H. C. Schmeisser] ; — The Quantitative Study of Analgesia After Opium Alkaloids [Drs. D. I. Macht, X. B. Herman and C. S. Levy] :— The Action of Papaverin on the Ureter. (Abstract.) [11ns. I). I. Maciit and J. T. Geraghty],

The Johns Hopkins Hospital Historical Club 120

The Rule of Certain Florentines in the History of Anatomy, Artistic and Practical [Dr. Fdward C. Streeter].

Xotes on New Books 120


THE IDEAL OPERATION FOR ANEURISMS OF THE EXTREMITY.

REPORT OF A CASE. 1

By Bertram M. Berxheim, M. D., Instructor in Clinical Surgery, The Johns Hopkins University, Baltimore, Md.


Toward the end of August, 1915. Mr. W. D., aged 13, from Sydney, Nova Scotia, was referred to me by his physician, Dr. Wm. Bruce, for the relief of an aneurism of the right popliteal artery. A definite history of syphilis, practically untreated and of many years standing, was obtained and corroborated by a positive Wassermann reaction. The popliteal swelling had been present only one month, but indefinite pains of a so-called rheumatic character had been observed in the region of the knee-joint for about three months. Once the tumor had made its appearance, however, its growth had been rather rapid, and it had given rise to a considerable amount of pain, and, in addition, a disturbance in the return circulation. manifested by a gradually increasing oedema, bad become apparent in the lower leg. A certain degrei varicosity was

present in the veins below the knee, but. thi ized, "Winn--.

pulsating tumor back of the knee was obviously the prime factor in the impaired venous return.


It was hardly to be expected that an adequate collateral circulation could haw developed, in view of the short duration of the aneurism, and especially in view of the fact that the dorsalis pedis and posterior tibial arteries of the foot pulsated oormally. Most imperative, therefore, was a careful search to determine the state of the collateral circulation: for a definite knowledge of this feature was essential to the selection of an intelligent operative procedure.

At two independent sittings, therefore, the Moszkowicz test,' as given by Dr. Matas, of Tulane University, was carefully carried out, the result being almost totally negative. Occlusion of the popliteal artery proximal to the aneurism left

a limb whose bloodless, cadaveric appearance gave

denceof what would occur if, in the treatment of the am some means wne aol found for preserving the normal a flow. Nor was this a case in which time could be spared for an


' Read before The Johns Hopkins Hospital Medical Society. October 18, 1915.


'Testing the Efficiency of the Collateral Circulation as a Preliminary to the Occlusion of the Great Surgical Arteries. Rudolph Matas: Jour. Am. Med. Assn., Oct. 24. 1914, Vol. LXIII.


94 [No. 302


attempt to develop a collateral circulation, since the aneurism

was increasing in size somewhat rapidly, and the man was very anxious to return to his work.

On September 3. at the Union Protestant Infirmary, I exposed the aneurism, prepared to do any operation that might be indicated. A spindle-shaped tumor, as shown in Fig. 1. presented and was opened on its dorsal aspect, revealing only two openings, the entrance and exit (Fig. 2) of the popliteal artery, the two points being distant about an inch and a half from one another, and only the faintest sign of a groove being apparent between them. The popliteal vein was so densely adherent to the sac that it was impossible to separate it without taking part of the sac wall, which, of course, was done.

To haw attempted a reconstructive Matas endoancurismorrhaphy under the circumstances would have amounted to little more than courting disaster. Hence, keeping in mind the insufficient collateral circulation, without further ado I d about 15 cm. of the internal saphenous vein from the affected leg at the knee and. after proper preparation, interpolated' about 12 cm. of it between the severed ends of the popliteal artery. (Inly the ends of the sac were cui away (Fig. 3), the remainder being left to be folded arouud the transplant as a partial reinforcement (Fig. 4). Carrel'- endto-end suture was used, and the distal end was united to the graft first, because the artery was most deeply situated at that point. It is worthy of note that the wall of the artery was thicker than normal, had numerous pin-head-sized dull-gray plaques iu its intima and was so friable that it tore badly in its preparation for suture, rendering necessary the removal of an additional centimeter and a half from the distal end. The suturing itself was accomplished without great difficulty, and at it- conclusion blood went through the graft in a normal manner, except for the presence of the marked dilatation so graphically illustrated in Fig. 4.* The dorsalis pedis and posterior pulses could be felt at once and remained normally palpable at all times. An uninterrupted conval -• and the patient returned home not only able to walk well but also, as he himself volunteered, "able to get on his shoe with a sock on his foot." whereas, prior to operation, this hail been impossible owing to the oedema. All pain and discomfort in tin/ leg had disappeared and a curious preoperative "dead feeling" of the great toe had given way to a normal feeling. Pulsation could be felt all along the vein graft as well as in the arteries of the foot.

So far as 1 have been able to determine, no case similar to


3 The veiu segment was " reversed " so that its vahi is

foot instead of the heart, as they normally do. This is a most important step in every venous transplant, since the arterial current will be forced to break down the valves, unless they are reversed.

4 It is hardly necessary to add that this dilatation is really a " normal " occurrence in every instance in which a vein is subjected to arterial pressure. The vein wall is thinner and has less muscle tissue than the arterial wall, and it therefore gives. Later on it hypertrophies and undergoes a fibrous change, which enables it to withstand continued arterial pressure without difficulty.


this has been reported from this country, and hardly more than seven from elsewhere * — a rarity that is most discouraging to those who had hoped for real practical developments in modern vascular surgery. 7 Perhaps other cases will be dealt with in a similar way. as the intelligent study of vascular conditions in general and of aneurisms in particular becomes more widespread. Many limbs have been sacrificed because a definite knowledge of the state of the collateral circulation was wanting at the time of operation. Dr. Matas, whose work in the field of aneurisms has brought him such well-deserved renown, has emphasized this point in numerous papers; and the case just cited is an eloquent proof of the necessity for this determination prior to operative interference. Many difficulties will be encountered in carrying out the tests, and they, are not without a certain amount of danger; hence, they will probably have to be modified. Nevertheless, be that as it may, the knowledge is essential and must be had at all costs.

DISCUSSION.

Dr. Halsted: Dr. Bernheim is to be greatly congratulated. The indications for the transplantation seem to have been clear, and the operation was a complete success. It is well termed the " ideal operation." when the indications for transplantation are so definite as they were in the case just reported by Dr. Bernheim.

We are indebted to Alexis Carrel for making such an operation possible. Prof. Lexer, the distinguished director of the surgical clinic of the University of Jena, is responsible for the term, and he was probably the first to transplant a blood vessel in the treatment of aneurism. Many surgical procedures have been called " ideal " and for their time have, perhaps, deserved the appellation. Most of them were, however, short-lived. Some surgeons, myself 8 in the number, have advocated excision of the aneurism under certain conditions. By Bramann and by Delbet excision was termed the " ideal operation. Lexer reported his first case at a meeting of the Deutsche Gesellschaft fur Chirurgie eight or nine years ago. The operation was for an aneurism in the axilla, the result of an attempt by some surgeon to reduce an old dislocation of the shoulder-joint. The operation was successful so far as concerned the patency of the vessels; but the patient died in a few days of delirium tremens.

Four or five years later Lexer reported a second case, also successful. In this a long piece of the saphenous vein was transplanted into the defect caused by the excision of a popliteal aneurism. Lexer has performed his " ideal operation " in a third case, the details of which I cannot at this moment recall. In several other instances in the human subject the transplantation of a vein to replace an arterial defect has been undertaken, usually with unsuccessful result. The surgeon who attempts this operation


5 The first operation of this kind was performed in 1906, by Lexer, who was then in Jena. In a paper appearing in the Arch, f. klin. Chir., 1907, lxxxiii, 45S. he spoke of the procedure as " The Ideal Operation for Aneurisms," and it has gone by this name ever since.

6 Abalos, J. B.: (Fusiform popliteal aneurism; extirpation, circular suture; reestablishment of normal circulation.) Spitalul. Bucuresci, 1914, xxxiv, 183-191.

Surgery of the Vascular System. B. M. Bernheim. J. B. Lippincott Co.. Phila., 1913.

" Ligation of the first portion of the left subclavian artery and excision of a subclavio-axillary aneurism. Johns Hopkins Hospital Bulletin. 1S92. Vol. III. p. 93.


THE JOHNS HOPKINS HOSPITAL BULLETIN, APRIL, 1916.


PLATE XIX.



Fig. 1. — The aneurism and the accompanying vein are exposed, showing dense adherence of the vein to the sac-wall. The small dark bulging area in the sac-wall was the site of a threatened rupture of the sac, evidently caused by manipulations during the application of the Moszkowicz test.


Fig. 2. — The aneurismal sac opened, showing the entrance and exit of the popliteal artery. The drawing greatly exaggerates the groove between these points.


THE JOHNS HOPKINS HOSPITAL BULLETIN, APRIL, 1916.



Pig. 3. — The aneurismal sac cut away from the popliteal artery. The vein was separated from the arterial sac by taking part of the sac-wall with it. With the exception of the ends of the sac, all the remaining portion was left in situ. The ends interfered with the placing of the venous graft.


Fig. 4. — The vein gralt has been sutured to the ends of the popliteal artery and the aneurismal sac wrapped around it for the purpose of reinforcement.


April, 1916.] 95


without having practised it on animals will almost surely fail to accomplish it successfully.

Six years ago I invited Dr. Bernheim to transplant for me a long piece (12 to 14 cm.) of the saphenous vein into an arterial defect caused by the excision of a sarcoma of the popliteal space. In this case the popliteal vein, the internal popliteal nerve and the popliteal artery, from Hunter's canal almost to its bifurcation into the tibials, had been excised. The vascular suture at the lower end of the space was quite difficult on account of the depth of the wound and the relatively small size of the distal stump of the artery. For a time the circulation through the transplant was perfect, but the interpolated vein became thrombosed ' before the wound could be closed. Gangrene did not. however, ensue.

I might mention in this connection that an end-to-end suture of the aorta has been successfully accomplished. In excising a retroperitoneal tumor, Braun tore into the abdominal aorta and ifter excising about 2 cm. of this artery was able to sew the widely separated ends together.

Prof. Kiimmel, of Hamburg, told me of a recent interesting experience of his own. On excising a tumor he made a hole in the abdominal aorta. This he closed with a suture of coarse silk and. if I remember correctly, without the use of oil or vaseline. A second uninterrupted suture of fine silk was taken to reinforce the first.

I should like to be the first to call attention to a possible flaw in my argument for practising the partial occlusion of an artery in the treatment of certain cases of aneurism. As some of you perhaps know, I advocate the employment of a band which can readily be removed and which does not injure the wall of the artery, in order to test and then to encourage the anastomotic circulation. But I realize that it may be possible, even with only partial occlusion, to interrupt the blood flow totally and too quickly. Thus, following the application of a band which still permits a small stream to flow through the artery to the aneurism, the latter might so promptly become solidified by the clotting of its contents that gangrene would be threatened. It is obvious that in such a case removal or loosening of the band might not restore the circulation through the aneurism.

My own experience with vascular suture in the human subject has extended only to veins and to the lateral suture of a defect of the femoral artery in Hunter's canal.

Of particular interest to me is the case of a patient upon whom, with the assistance of Dr. Heuer, I operated four or five years ago. We had about completed the removal of a very large lymphangiomatous cyst of the abdomen. There remained to be freed only its connections with the inferior vena cava. While these were being separated with extreme caution, blood gushed from this vein. There proved to be a linear defect in the vena cava so long that six artery clamps were required to close it. A lateral suture of the vessel with oiled, fine silk was successfully accomplished. The patient's convalescence was uneventful and she is at the present time in excellent health. The defect in the wall of the vein was not an artefact. It represented. I believe, an imperfectly


The most serious objection to the " ideal " or veingrafting operation is perhaps this: that in case of failure the thrombosis which starts in the graft may extend either centrally or peripherally, or in both directions, from the interpolated vein into the artery and thus involve important anastomotic branches which would not have been threatened with occlusion if the artery had been merely ligated, or the sac merely excised or plicated. The transplanted vein is, consequently, a menace, for in at least twothirds of the cases in which the " ideal operation " has been practiced, thrombosis has occurred in the insert.


closed orifice from the vein to a lymph-bud or lymphatic vessel from which the cyst had had its origin. I expect to report, later, this case and an analogous one, in detail, because they may serve to account for the occasional presence, hitherto unexplained, of blood in certain lymphangiomatous cysts, and for the observations that cysts which on the first tapping yielded a clear fluid have, on subsequent tappings, been found to contain more or less blood.

Thus Professor Jordan and Professor Voelcker, 10 of Heidelberg, refer to a case of cyst of the neck, reported by Weil, which had its origin, he believed, in a hemorrhage from the vascular wall of a cystic lymphangioma. In support of Weil's view, the authors instance the observations, repeatedly made, that cysts from which at the first puncture only a clear serous fluid was withdrawn at subsequent aspirations sometimes yielded blood. And one frequently meets with the statement that the serous content of lymphangiomatous cysts may after injury become bloody.

As a possible explanation of the occasional presence of blood in lymphangiomatous cysts I would suggest that a primordial communication between the vein and the lymphatic cyst may not have been completely closed. The presence of blood, at subsequent aspirations, in the content of cysts, which at the first tapping had yielded only a clear serum, might be due to the relief of tension in the cyst rather than to an injury of its wall: for the pressure within the cyst being diminished or negatived, there might be a retrograde flow of blood from the original venous connection.

In one of my cases, a supraclavicular hygroma, a definite relation to a large vein of the neck was demonstrated, and in the other, as I have related, there was an intimate connection with the inferior vena cava and evidence of an opening between the cyst and the vein which may have become closed more or less completely by a cribriform fascia of some sort. It Is, I believe, very improbable that the thin non-vascular walls of either of these lymphangiomatous cysts could have contributed much, if indeed any, blood to their contents; and to continuously furnish blood enough to stain the fluid for possible frequent subsequent tappings would, it seems to me, have been, for such walls, impossible.

Dr. Bernheim: It had not occurred to me to do the Moskowicz test on the other leg, as suggested by Dr. Halsted. We had trouble enough doing it on the one. It seemed quite painful and, to tell the truth, I thought it not devoid of danger. We used a small roll of gauze about 2 inches wide, one end of which was made into the shape of a cone, so as to facilitate the making of pressure between the big muscles just above the knee. With this in the palm of my hand, I clamped down on the artery above the aneurism, but the vein must have been shut off at the same time. I realize that an instrument has certain advantages over the hand in making this pressure, but it also has disadvantages that, to my mind, outweigh the advantages. Any one who has attempted to get the popliteal pulse, and has had the usual difficulty in locating and palpating it accurately, will realize the amount of force necessary to occlude it. This in itself is. perhaps, not so terrible, but one can never be sure that an offshoot of the aneurism is not caught under the pad. Hence I have about decided not to use the test in that form any more. It would seem far more conclusive to make an incision above the aneurism and apply a band which will occlude the artery entirely — but only the artery. With a dressing in place over the small wound, the collateral circulation could be determined with positive accuracy and with great promptness; and, best of all, such a procedure would be entirely devoid of danger. At its conclusion the operative procedure indicated could be carried out with a sense of comfort and confidence that is not felt at present.


"Handbuch der praktischen Chirurgie, Bd. II., S. 117.


96 [No. 302


MEMORIAL MEETING TO DR. E. L. TRUDEAU.


THE LAENNEC.

Dk. Jaxkyvw : Since the Laennec Society last met here a famous figure in the field of tuberculosis study has passed away —Dr. E. L. Trudeau. Not only was Dr. Trudeau the most famous pioneer of tuberculosis investigation and treatment in Ann rira. but he was in a very particular way the hero of all of ns physicians in this country throughout, a long life.

In the year in which 1 was born, Dr. Trudeau. then looking forward to a highly promising career in medicine in New York Citj . came into my father's office and was told by him that he* had very definite signs of tuberculosis of the lungs, and his seemed, in all human probability, a failure. How different he made it ! From that time on. whenever I would become disi ouraged with the way things were going with me, my father

would tak icasion t<> point nut to me what Dr. Trudeau had

accomplished from an apparently hopeless outlook. Nothing was much more hopeless at that period than the outlook for a physician with tuberculosis; but his career lias been one of the most brilliant in the history of American medicine, and one of the most fruitful, both in the quality of his scientific achievement and in what he accomplished for sick men and women.

Dr. Trudeau was not himself a Hopkins man. indeed he could not have been, for the Hopkins Medical School did not exist at that time, but he sent his two sons here ; and while we are all hero-worshippers (everyone worth his salt is. and especially every physician) I have come to believe that Hopkins men are particularly hero-worshippers of the right sort of medical heroes. So it seems especially fitting that this first meeting of the Laennec Society for the year should be given over to an attempt t<> bring before those of us who had the privilege of knowing Dr. Trudeau, and to many of you who only knew him by reputation, the achievements, and still more, the characteristii - which marked his career and which are such a stimulating example to every one of us.

We had hoped that Dr. Welch might he here ami speak from the fullness of his personal knowledge and appreciation of Dr. Trudeau's scientific work, but a meeting of the China Medical Board, which it was imperative he should attend, was called for to-day. We are. however, exceedingly fortunate in having with ns three men who knew Dr. Trudeau intimately; one his senior pupil, as it were, and all three his personal friends, who "ill speak to us on the different aspects of Dr. Trudeau's life and character, so far as it is possible to separate the different aspects from one another. That any of them can think of Dr. Trudeau other than as the man. is impossible, but each will tr\ t" tell ns something of that side of Dr. Trudeau which is ->-He his name mi this evening's program. Of course, if Dr. Osier were here, he would have spoken of Dr. Trudeau with that enthusiasm and insight which we all know how to expect from him. Though absent, he still is with us to-night in spirit, and has sent us a cablegram which I will read to you :


Proceedings of the Laennec Society, January 24, 1916.


Through failure to success, Trudeau passes among the elect. Human sympathy and unfailing optimism made him a strong defense to the stricken. The noble example of his life will remain a permanent inspiration in our profession.

Osleb.

Dr. Walter B. James, of New York, will speak to us of Dr. Trudeau, the physician.

DR. TRUDEAU, THE PHYSICIAN. BY WALTEi: B. JAMES.

It is fitting that this memorial meeting should be held in Baltimore, for Dr. Trudeau cherished a warm affection for The Johns Hopkins, and turned to it for help in some of his periods of greatest suffering, and he knew that nowhere was he more sincerely loved than here, and nowdiere was his work more appreciated. It is fitting, too, that it should be at a meeting of the Laennec Society, for Trudeau and Laennec had much in common.

They both possessed the Gallic temperament and the power to he cheerful under overwhelming vicissitudes, and so, like their nation to-day, snatch victory from defeat. Both were subjects of the very disease that was their life study, and to which they made numerous and valuable contributions, and each, a devout Christian, awaited, with fortitude and without complaint, the coming of the end whose signs he knew only too well.

The brief and impressive document to which each member of our profession must assent before he may enter upon its practice, in spite of its antiquity and its archaic phrases, is still the best epitome of the duties of the true physician ; and the Hippocratic oath remains the standard for the conduct of the medical life. To treat the sick with no thought for himself, hut with every thought for them, and with honesty and truth to teach to those who follow him all the knowledge he has acqui red.

Had the vague yearnings of mankind to know the nature and origin of the maladies that plague them at that time crystallized into the activities that we know now as medical research, this, too, would doubtless have been included in the oath.

This document breathes in its every phrase the highest spirit of medicine and. tested by it. Dr. Trudeau'- life stands nut as a splendid model for the physician.

It is 36 years ago this coming summer that I first heard of him. T had gone to the Adirondacks. to Blue Mountain Lake, to recuperate from the effects of a winter of too great enthusiasm for biology under the stimulating influence of your Newell Martin.

The Adirondacks was a wild region compared to what it is at present, but rumors reached me of a young doctor whose fame was widespread in the northern district, 70 or SO miles away. I heard nothing of his professional renown but only that he was- a splendid hunter and a remarkable shot with the rifle.

Laennec, too, was a sportsman, and it is related of him that his friends accused him of taking more pride in his horsemanship than in his professional achievements.


April, 1916.] r.


A few years later it was generally admitted by us all in the laboratories of New York and elsewhere, that the only man from whom a trustworthy and pure culture of tubercle bacillus could be obtained was Dr. Trudeau. Then we heard that he had built a small sanatorium on a novel plan ; soon, that he was one of the best men in the country to whom to send cases of early tuberculosis.

Not long after, I met him for the first time at Paul Smith's, when on a summer trip through the woods, and I was at once impressed by his tall, straight, alert frame, his keen and responsive interest and the sweetness of his smile. By that time he had begun to be famous throughout the world as a physician. This was the beginning of one of the most cherished friendships of my life.

The exigencies of this evening's program separate the achievements of the physician from those of the investigator and the man, but I suspect that in few men have these three activities been more closely tied together. His professional life was spent in a little village in the woods where distractions and amusements were few and of the simplest and most natural kind. His real friends were his patients, and they paid him occasional visits in the morning for professional advice, then came to spend evening after evening in his cheery library throughout the long winters, a little company closely knit together by the ties of isolation and common misfortune, but a company, than which one will rarely find one more lighthearted and gay.

His experimental laboratory, too, at first in his house, was later a structure so closely adjacent to it that the visitor, from Ms bedroom window, looked across a few feet of deep snow to the sturdy >tone building where the experiments on immunity and resistance were being carried on.

There were no fixed hours for work or for rest, and even the examining office and dispensary of the sanatorium were in his own home. Thus his practice, his hospital and his laboratory were part of his daily life, and inseparable from it, and he never bore well a longer absence from them than one or two weeks.

I first heard from him a quotation which, we used to agree, briefly but comprehensively described the ideal aim of a physician. " Guerir quelque fois, soulager souvent, consoler toujours," and this describes not only his aim but what he made his own life express.

He would have been a distinguished and successful physician under any circumstances and in any circle, for he had the fundamental intellectual qualities that make for success in our profession. He had unusual diagnostic acumen, for be had the faculty of brushing aside or ignoring the little things that so often lead the mind of the unwary clinician from the straight road to truth, and, with an instinct that often seemed like a woman's, he would arrive at a correct diagnosis by means that wen- not easy to follow.

A skeptical stranger once presented himself to him for examination and the doctor found the chest painted with iodine over the right lung apex. After careful search he discovered signs of very slight phthisis in the left apex. He then


asked thepatient why. he had painted the sound side; " To see if you would know " was the reply — a device that might well have tripped a less experienced and wary examiner. He told me this tale with keen enjoyment, for his sense of humor was exceptionally well developed, and stood him in good stead on many occasions of sore trial. A sense of humor seems a necessary part of the equipment of the complete physician.

When we think of how his life was passed in the woods, surrounded by cases of one single disease, his attention focused upon this with singular intensity, for he engaged in but little general practice, it is remarkable that he so rarely erred, and confounded other conditions with tuberculosis. He was especially happy and successful in his relation to that always puzzling group of cases, where lassitude and slight loss of weight with perbaps rapidity of the pulse are the only symptoms that suggest in young people possible tubercular trouble in the lungs ; and he rarely erred.

His invaluable contributions to the rest and fresh air treatment of tuberculosis I shall not describe, for these will be spoken of to-night by one whose relations to Dr. Trudeau's work were even closer than mine, but I should like to say a word about one phase of his therapeutic achievements that belongs to his life as a practicing physician.

Every doctor is conscious at times of a feeling of disappointment, even of resentment, when advice which is founded upon the principles of modern scientific medicine is unheeded by the patient, and we are generally human enough to ascribe it to the vagaries of the individual, rather than to our own delinquencies.

When one has viewed the work of one like Dr. Trudeau from close at hand as I have done, and has marveled at his ability to secure the conscientious performan< e of every therapeutic duty prescribed, exposure hour after hour to cold, the tedium of months spent at absolute rest in bed, with a prescribed diet, one wonders what quality it could be that the man possi ssed enabling him to so override objections and secure the cooperation of his patients. Was it not that indefinable quality which some men have of carrying conviction by simple words, of impelling belief in the wisdom of counsel, of inspirit . fidence through singleness of devotion to their patients' interest ? A quality of inestimable value to a doctor.

The duty of the physician does not stop with the writing of

i wise prescription or the giving of advice, and it is the one who can secure the carrying out of his counsels who fills the full measure of his responsibilities. .Many of Trudeau's clinical victories resulted from this abiln omplete out-of-door rest cure for the patients who had refused such measures until they fell into his hand-.

His unworldlmess and his forgetfulni -- of self were nowhere more in evidence than in his relation to the very poor, who soon flocked to Saranac Lake with a was pathetic.

Trudeau was a bom teacher. He had tie- >j>irit of Erasmus. It was not many months stablishment of his little

home-made laboratory in In- house at Saran bea;an comin- to him to learn how to culture the tubercle


98 [No. 302


bacillus, how to isolate it and, above all, how to design sanatoria and carry out the principles of out-door treatment.

I can remember that during the years when he was enjoying a fair measure of physical vigor, and was able to come to New Fork cine or twice in the winter for 10 days or two weeks at a time, it was always understood between us that he should give uiu of in \ clinics at the college, or possibly a lecture, and during those years I made it a point that every one of my classes should have the opportunity of hearing his views on the early osis and treatment of tuberculosis; and he was never happier than on these occasions.

In his autobiography he tells how a doctor brought, all the way from Australia to Saranac Lake, a young man with tuberculosis, because he himself had heard Trudeau describe the out-door cure and its result on one of the above occasions. Later his voice became so thin that he could be heard only with difficulty in the lecture room, and, to my sorrow and his, he was reluctantly compelled to give up this annual function.

The Ilippocratic injunction to teach was one that he obeyed throughout his entire working life, and Saranac Lake became a Mecca for those in search of information regarding tuberculosis. The sanatorium that he founded and in which he took so much pride soon became a model for such institutions.

The most striking and stimulating phase of his teaching activity was his influence upon young physicians who came to him disabled by the disease. It was an occurrence pathetically frequent for medical students or recent graduates to come to me with the familiar story of a slight hemorrhage, or afternoon fever, or a few tubercle bacilli found in the sputum, always downcast and discouraged, and with a feeling that their profi ssional career was at an end. Generally I had little difficulty in cheering them up when I gave them an account of Trudeau, what he had accomplished and what other men in their situation had succeeded in doing in spite of these obstacles; and I would send them to Saranac with a letter to him and with advice to put themselves entirely in his hands, for I knew what the result would be ; a few weeks or a few months, perhaps even a year, spent on an open porch, later with an electric light over the couch where, presently, medical literature, especially the literature of tuberculosis, would be studied; then, with the absence of fever. and the return, in some measure, of physical vigor, an opportunity to do a few hours' or a half day's work in the laboratory, and so the establishment of an interest that would last for the rest of their lives and leave them further advanced in their profession at the end of their cure than they would have been had they pursued their original course of life.

Many of the most useful and productive workers in the field of tuberculosis, now scattered throughout this country and Canada, are "graduates of Saranac," who there, under Trudeau. found health and at the same time opportunity and encouragement to enter upon a life of research.

I have never known Dr. Trudeau's front door in Saranac Lake to be locked, and every evening for many, many years in his cosy library there was an informal gathering of the younger and older doctors, who sat at his feet, and the discussion was almost always of matters in some way related to


the disease that had brought them there. These gatherings, in which I have from time to time enjoyed the privilege of taking part, constituted a school in the truest sense, and a school that reminds one of what we read in the history of the early days of learning.

His patience in listening to his pupils, his kindliness and complete absence of arrogance, the freedom with which he gave to everyone all that he knew — these qualities, together with the indefinable charm that drew these young men to him, made him a great teacher. Just as an interest in the study of tuberculosis had been of inestimable value to him in stimulating his own recovery, so I am sure did he lead many a young doctor back to health, through the development of a similar interest.

It is a fundamental law of nature that effort is stimulated by resistance, and in some of the recent results of the comparatively new science of anthropogeography, I am often reminded of Trudeau and what I believe his environment did for him. As Huntington shows that in factories the workers put forth their maximum production in periods of greatest climatic rigor, and when he shows that the degree of civilization in Europe now and in the past coincides with areas of maximum climatic storminess, it tempts one to the stimulating and encouraging thought, that perhaps the storminess of Trudeau's fate acting upon his strong nature helped to produce the unusual result that we are celebrating to-night.

As the direct result of his splendid medical life he has left behind him in Saranac Lake a group of institutions that will endure — a sanatorium that is a model for all the world, teaching how cases of early tuberculosis should be managed, with productive research laboratories maintaining high ideals of work and especially utilizing the skill and intelligence of physicians while they are completing their recovery.

But, best of all, he has left a spirit which animates all medical life that is worth while, and which is the soul of modern medical science ; research for the sake of practice, and practice for the sake of humanity.

The value of such a life as Trudeau's to our profession cannot be estimated. For many years an influence has radiated from the village in the woods stimulating men to a fuller and more perfect carrying out of its fundamental precepts. But as matter is indestructible and as force is indestructible, so the power of such a life as his is imperishable. It will go on year after year, helping generation after generation of men to practice medicine better because he lived so complete and so perfect a medical life, even though in so remote a spot.

" So be my passing! My task accomplished and the long day done, My wages taken, and in my heart some late lark singing, Let me be gathered to the quiet West, The sundown splendid and serene."

Dr.. Jaxeway : Dr. James has told us something of the school which gradually grew up around Dr. Trudeau at Saranac Lake, one of the few really distinctive American schools in medicine.

There has come to us to-night from Saranac Lake the oldest pupil of that school, a pupil upon whom the headship must


April, L916.] 99


fall, now that Dr. Trudeau has gone; the man to whom we in this country look for the most authoritative opinion both upon the clinical problems of tuberculosis and those complex and still unsolved problems of immunity to it. Dr. Baldwin, of Saranac Lake, will speak to us od Dr. Trudeau. the investigator.

DR. TRUDEAU, THE INVESTIGATOR. BY DR. E. E. BALDWIN.

It is 1.") years since Dr. Trudeau himself gave a reminiscent talk before tin- society on the history of his experimental work. It is most gracious of your president to grant me the privilege of reviving the memory of that account. It was a story of an extraordinary effort by an extraordinary man. Those now present who listened to him will readily recall his dramatic description of the home-made incubator box. He always spoke humorously nf the bacilli freezing and thawing, but was very proud of his achievement in growing the tubercle bacillus so early with his primitive apparatus. He was. in truth, a pioneer in a field little touched by those not directly concerned with tuberculosis. By that I mean those who never had it themselves. Xo description that I can give will compare with his earnest, entertaining style in relating his early difficulties and experiments. I cannot refrain from quoting his own words found in his autobiography just published (Chapter XVI. pp. 201-203):

In the fall of 18S5, as soon as I had equipped my little laboratory room, I began to work. At first my knowledge was limited to the detection of the tubercle bacillus in the secretions of patients, and my observations to verifying Koch's claim that this bacillus was the cause of the disease and was always found when tuberculosis was present. I made examinations of all my cases, and as a result found only one patient in whom, while the symptoms of consumption of the lungs were present, I could never detect the bacillus. I made a study of this case and proved that it could not be tuberculosis, as the expectoration would not kill animals, while the expectorated matter which contained tubercle bacilli always produced generalized tuberculosis in the guinea-pigs. I published this study under the title of " An Experimental Research upon the Infectiousness of Non-bacillary Phthisis." in the American Journal of the Medical Sciences for October. 18S5, and this was my first publication from my little laboratory room. I am afraid I have been guilty of many others since!

The thing I craved to do, however, was to succeed in cultivating the tubercle bacillus outside of the body and then produce the disease with it in animals. It was the early winter of 1885 when I attacked this problem with great earnestness. I had learned from Dr. Prudden how to make artificial media — beef gelatin, beef agar and other media — but the first growth of the tubercle bacillus direct from animal tissue I knew could be obtained only on solidified blood serum, and then with difficulty. I bought a small sheep for three dollars and a half, and from the sacrifice of this animal I procured the required amount of blood, which, thanks to the pure air and the snow upon the ground, remained tolerably free from contamination and was transferred at once to the ice-box to coagulate. I am afraid my associates at the laboratory to-day would hardly consider the technique I then employed up-to-date, but after many incidents I succeeded in getting some fair plants of blood serum in tubes.

I made plants on this blood serum from a tuberculous gland removed from one of my inoculated guinea-pigs, and put all the tubes in my home-made thermostat. For the next two weeks I watched the temperature of my absurd little oven with jealous


care, and I remember one very cold night getting up in the night and going down stairs to look at the temperature. Many of the tubes turned out at once to be contaminated and a variety of growths appeared on them; but after ten days I still had four tubes free from contamination, and these looked much as when I first put them in the incubator. On the eighteenth day I thought I detected a little growth in the corner of one of these. With every precaution against contamination, with my platinum spade I removed a little of the suspected growth and rubbed it on a couple of clean slides, dried it and stained it. My first intimation of success was when one or two large masses on the slide refused to decolorize when treated with the acid. I washed the slide, put it under the microscope, and to my intense joy I saw nothing but wellstained culture masses and a few detached tubercle bacilli. I at once planted some fresh tubes from the one I had examined, and I knew now I had pure cultures to work with. This little scum on the serum was consumption in a tangible form. With it I could inoculate animals and try experiments to destroy the germ. (An Autobiography, Dr. E. L. Trudeau, pp. 201-203.)

After mastering the culture of the bacillus he naturally made effort- to show the actual effect of therapeutic agents on it. This perfectly obvious and rational procedure, as a prerequisite to the employment of supposed germicidal treatment, indicates that the 10 years of wilderness life had not dulled his intellectual gifts. To quote his own words (Autobiography, ]). -'OH :

As soon as I had pure cultures I began to inoculate rabbits and guinea-pigs, and started some experiments to try to kill the germ in their tissues by the injection of various germicides, such as creosote, carbolic acid, and other substances known to destroy germs. These experiments of mine all failed, and I found, as I expressed it to the students one day at the College, that " the tubercle bacillus bore cheerfully a degree of medication which proved fatal to its host! "

He also tried hydrogen sulphide and hydrofluoric acid gas. the latter forming the subject of his third contribution in print. Later (1888). he published clinical experiments with hot-air inhalations, the conclusions from which were so logical and well-stated as to give an index of his good reasoning faculties and clearness of expression. Hi- summary is as follow-:

First, the therapeutic value of hot-air inhalations in phthisis is doubtful. Second, the evidence obtained by the bacteriological study of the cases does not confirm the assumption that inhalations of heated air can either prevent the growth of the tubercle bacillus in the lungs of living individuals or diminish the virulence of this microbe when it has gained access to them. (Trans. Assn. Am. Phys., 1889, Vol. IV, p. 291.)

The work that probably attracted most attention to Dr. Trudeau as a scientist was the so-called Environment Experiment which he did in 1886 and repeated in 1887. I refer to the really simple hut brilliantly executed experiment whereby he demonstrated on rabbit- three very important truths.

The first one was that confinement, bad air, and restricted

1' 1 without the bacillus could not produce tuberculosis. The

second, that the conditions ,ju-t described plus inoculation with tubercle bacilli led a- a rule to a fatal infection. Finally. rabbits similarly inoculated and turned loo-,- on a little island

near his summer camp, recovered; in fact, lie had to -I t

them to catch them! It must have al encourage ment to him, ami it has rarely happened that a therapeutic


100 [Xo. 302


experiment has received such a widespread demonstration of its value during the lifetime of the author.

Hi re is his own description of the confidence it gave him:

This showed me conclusively that had surroundings of themselves could not produce tuberculosis, and when once the germs had gained access to the body, the course of the disease was greatly influenced by a favorable or an unfavorable environment. The essence of sanatorium treatment was a favorable environment so far as climate, fresh air, food, and the regulation of the patients habits were concerned, and I felt greatly encouraged as to the soundness of the method of treatment the sanitarium represented, even though it did not aim directly at the destruction of the germ. (pp. 204-206.)

The simplicity of this experiment and the novelty of its application made a strong appeal to his friends both lay and medical. I well remember the story of this experiment related to me when a medical student.

During each of the succeeding years until 1896 Dr. Trudeau was able to present some reports of experimental work from his laboratory. The most interesting of his contributions, and the most important, were his experiments with tuberculin. Influenced by the published work of Pasteur on protective inoculations he had engaged in much the same line of experiments simultaneously with Koch. His results were unfavorable and were published on November 22. 1890. shortly after the premature announcement of tuberculin as a cure by Koch in August of the same year. Dr. Trudeau obtained, nevertheless, prolongation of life in his treated guinea-pigs, and from that time until his death held to his faith in the possibilities of tuberculin and other specific vaccines. It must be conceded that this buoyant hopefulness was succeeded by skepticism in his periods of depression, but it was always founded on faith in his observations on animals. Before the discovery of tuberculin I found a short note of his in the Transactions of the \ — eiation of American Physicians, in May. 1890, when, in discussing one of the papers on tuberculosis, he indicated his faith in Pasteur's work. He said :

I think, perhaps, Dr. Shakespeare has not presented the most encouraging side of Pasteur's work. Pasteur has not only taught us that anthrax and chicken cholera are due to a germ, and that hydrophobia is caused by a specific virus which has its seat in the spinal cord, but he has taught us as well that by his methods these diseases are now already somewhat under control of man, and can be prevented to a great extent. TVe need not, therefore, necessarily take too gloomy a view so far as tuberculosis is concerned.

This faith was maintained throughout the quarter-century of life that remained to him. As evidence I will read a letter written last summer to the British Journal of Tuberculosis immediately before his fatal illness :

Nothing has occurred to diminish my faith in the value of tuberculin treatment — a faith which has been manifested by my continuing its use uninterruptedly in my practice and at the Adirondack Cottage Sanitarium ever since it was discovered, and through all the long years I stood nearly alone in my medical environment in its advocacy. If skilfully used, tuberculin stimulates the defensive resources of the organism and is a valuable adjunct to our treatment in many cases. I see no reason why


continued research should not in time give us a better sensitizer than tuberculin.

During the years 1892 to 1895 various tuberculins were introduced that had supposed advantages. Dr. Trudeau expressed the hope that some improvements would be made by which the toxic effects could be eliminated. It was during the period that I began to work with him. Our hopes for the discovery of an efficient vaccine or antitoxin were high at that time. His own time was more than ever occupied with the sanitarium, and his laboratory work was desultory; yet during the winters (the only time he was able to work at all) he continued to direct experiments of the greatest variety. I find on our records over 50 different attempts to immunize animals with dead and living bacilli of varying virulence, and with varying dosage, intervals, etc. These he himself instituted during the years 1892 to 1900, besides numerous other experiments in which he was less directly concerned. At the opening of the Phipps Institute at Philadelphia, in 1903. Dr. Trudeau referred to his successful demonstrations of the immunity reaction obtainable in rabbits as follows :

Most of my own work has been devoted to the study of methods which might tend to produce artificial immunity .... It was only when I began to make use of living cultures as a protective inoculation that I met with any encouraging results, and my experience would indicate that the living germ is essential to what success has been attained in the production of artificial immunity against tuberculosis.

By preventive inoculations of living-bird tubercle bacilli in rabbits, I got undoubted evidence of a marked degree of artificial immunity in experiments which I reported to the Association of American Physicians in May, 1S93. I was able then to demonstrate to the association, by means of living animals, that in rabbits having previously received the preventive injections of living-bird bacilli, the virulent inoculation at first gave rise to a violent reaction of the tissues, which ended generally in cure, while the tuberculous process similarly induced in the controls was accompanied by little or no local reaction. I have many times since confirmed these results by various experiments. (The History of the Tuberculosis Work at Saranac Lake. Med. News, October 24, 1903, p. 8.)

Altogether Dr. Trudeau published but few experimental studies, 1 his periods of ill-health, the sad deaths of his children, and many burdens incident to the sanitarium, made it impossible for him to do more than oversee some of the experiments in which he was most interested. One of his greatest disappointments was the fact that he could not work in the new laboratory generously built for him by Mr. George Cooper in 1894. He often exclaimed that he desired nothing better than a chance to work there and took great pride in showing visitors through.

Onlv those who knew Dr. Trudeau at home and in his laboratory during his prime could appreciate his enthusiasm for scientific investigation. Those who did not know him in the surroundings that he created whereby he was able to attempt experimental work, quite unique in character for the time, cannot know what pride he had in it. His enthusiasm and pride. nevertheless* never led him to much conceit about his knowl


Eighteen in all.


April, 1916.] 101


edge ; this was one virtue that made him so companionable. He was ever modest in assertion, in reality ratlin- timid, even among the young men about him who were naturally deferential. His boasting was too often applied to his associates! A little achievement was always the object of praise from him, and those of us who happened upon some minor point of interest were very likely to hear it enlarged upon by some of our colleagues who had heard of it from Dr. Trudeau.

His manner was irresistibly entertaining to a group of visitors. They often acquired more interest in scientific medicine and were cured of antivivisection heresies by a little talk from Dr. Trudeau about the tubercle bacillus. " Here is a little devil," he would say, " that grows with equal facility in a prince or a pauper," as he exhibited a tube culture to a group of admiring listeners. "Here is what people come to Saranac to be cured of in three months," he would cheerfully remark, as he produced a specimen of extensively cavitated lungs of a rabbit!

While his conversation at such times was dramatic it was never vain or boastful of his own accomplishments ; more often it was of embarrassing predictions of wdrat his assistants were to discover! I can well remember the first weeks in his first laboratory during the winter of 1892 and 1893. He was wont to say: "Baldwin, how does this strike you? If you don't think I'm right I wish you would say so." This was well adapted to increase my conceit in my little stock of knowledge, but it gave a rare impulse to independent thinking. I had never encountered such modesty in any of my teachers and do not think Dr. Trudeau inculcated humility in his associates by this method, though by example this was possible. His belief in research was a passion for its humanitarian service, and he believed in science and humanitarianism joined together. He looked forward to a brighter day when all pain should vanish as a consequence of that union.

In closing I think a favorite expression or aphorism that he frequently used will be of interest to repeat: " The sanitarium represents what we know now, the laboratory what we hope to know in the future."

ARTICLES WRITTEN BY DR. E. L. TRUDEAU. M. D., REPRESENTING HIS EXPERIMENTAL LABORATORY STUDIES.

1. An Experimental Research upon the Infectiousness of Non Bacillary Phthisis. Anier. Jour. Med. Sei., October, 1885.

2. Environment in its Relation to the Progress of Bacterial In vasion in Tuberculosis. Amer. Jour. Med. Sci., July, 1887; Trans. Am. Climat. Assn., 1887, IV, 1.31.

3. An Environment Experiment Repeated. Trans. Am. Climat.

Assn., 1SS8, V, 91.

4. Sulphuretted Hydrogen versus the Tubercle Bacillus. Med.

News, 18S7, LI, 570.

5. Hydrofluoric Acid as a Destructive Agent to the Tubercle

Bacillus. Med. News, May 5, 1888, LII, 4S6.

6. Hot-Air Inhalations in Pulmonary Tuberculosis. Med. News.

1889, September 28; Trans. Assn. Am. Phys., 18S9, p. 2S7.

7. Some Cultures of the Tubercle Bacillus, Illustrating Variations

in the Mode of Growth and Pathogenic Properties. Trans. Assn. Am. Phys.. 1S90, V, 183.

8. An Experimental Study of Preventive Inoculation in Tubercu losis. Med. Record, 1890, November 22.


9. The Treatment of Experimental Tuberculosis by Koch's Tuberculin, Hunter's Modification, and other Products of the Tubercle Bacillus. Trans. Assn. Am. Phys., 1S92, p. 87; Med. News. 1892, September 7.

10. Results of the Employment of Tuberculin and its Modifications

at the Adirondack Cottage Sanitarium. Med. News, 1892, September 10.

11. Eye Tuberculosis and Anti-Tubercular Inoculation in the

Rabbit. Trans. Assn. Am. Phys., 1893, p. 108; N. Y. Med. Jour., 1893, July 22.

12. A Report of the Ultimate Results Obtained in Experimental

Eye Tuberculosis by Tuberculin Treatment and AntiTuberculous Inoculation. Trans. Assn. Am. Phys., 1894, p. 168; Med. News, 1894, September 29.

13. A Chemical and Experimental Research on " Anti-Phthisin "

(Klebs). (In collaboration with E. R- Baldwin.) Med. Record, 1895, December 21.

14. The Tuberculin Test in Incipient and Suspected Pulmonary

Tuberculosis. Med. News, 1897, May 29, p. 687.

15. The Need of an Improved Technic in the Manufacture of

Koch's " TR " Tuberculin. Med. News, 1897, August 28, p. 257.

16. Experimental Studies on the Preparation and Effects of Anti toxins for Tuberculosis. (In collaboration with E. R. Baldwin.) Am. Jour. Med. Sci., December, 1898, and January, 1899; resume in: Trans. Assn. Am. Phys., 189S, p. 111.

17. Artificial Immunity in Experimental Tuberculosis. N. Y. Med.

Jour., 1903, July 18; Trans. Assn. Am. Phys., 1903, XVIII, p. 97.

18. Two Experiments in Artificial Immunity against Tubercu losis. Med. News, 1905, September 30; Trans. Nat. Assn. for Study and Prevention of Tuberculosis, 1905.

Dr. Jakeway : That the president of the New York Academy of Medicine should have left his busy life to come down here to speak to us; that the dean of the Saranac school should have made that long journey to tell us of his knowledge of Dr. Trudeau's career, are eloquent testimony to the esteem and love which Dr. Trudeau, the man, inspired in all who were with him. It has undoubtedly been difficult for the previous speakers to confine themselves strictly to the subject assigned to them.

The last speaker needs no introduction to you. and though he comes but from across the city, he faces no easier task, for his relations with Dr. Trudeau were very close. He will not, however, have to confine himself to any phase of the subject, but will, we all hope, tell us in an intimate way of those sides of Dr. Trudeau's character which, whether we he physicians or not. must appeal to all that is best in us. and must stimulate us to lead in our turn lives which will awake in others those same feelings of respect and of affection which were so universally aroused in everyone who came into any contacl with the great physician of Saranac.

DR. TRUDEAU, THE MAN.

BY II ENT5Y M. TlloM IS.

It is not easy for me to speak at this tune of Dr. Trudeau as a man. He meant more to me than my emotions would stand should I endeavor to tell you. Perhaps the very closeness of our relations obscures my perspective and unfits me for the

task.


102 [Xo. 302


The oft-quoted saying that " no man is a hero to bis valet'*

did not apply to Pr. Trndeau ; indeed, the eloser one got to him, the more one admired and loved him. No one who served him ever voluntarily left his service. Dr. Trudeau's power of understanding and sympathy, and his many-sided nature, made lor him to get close to a very great variety of people, and if I tell you of my first meeting with him at Saranac Lake. I may '"' able to give you some idea of his personality, and how simplj and unconsciously he allowed it to influence those who came near him.

Just 28 wars ago, almost to the day. I went to Saranac Lake. That sounds a simple enough statement now. for many have since traveled the same route. But at that time it may he said that Saranac Lake was practically unknown to the medical - 1. .n in Baltimore : actually. I was the second person from here who had ever gone there in search of health. Dr. Trudeau, in his autobiography, gives a graphic picture of the mental state of one who has been ordered to stop wnrk and go away. but I do not believe that it can be understood until it has been experienced.

The circumstances in my own case were such as for the time to abolish any particular desire to live. Dr. Welch, who was my medical adviser in Baltimore, encouraged me in many ways, and assured me that I should be able to continue my work in neuro-pathology in Dr. Trudeau's laboratory, for he was sure that he had a laboratory, as he had done such good laboratory work. Dr. James in Xew York cheered me on my way, but although I was not very ill. my nervous depression was such that I took three days to make a trip that might have been accomplished in 24 hours. A narrow-gauge railroad from Plattsburg had just been completed to Saranac Lake a few days before, and. if anything could have added to my depression, it was the desolate journey through the snow.

However, it was during this trip that I first became aware of Dr. Trudeau's influence as a man. As I remember it. the only other passenger in the car was. a Mr. Krumholtz. who spoke to me and told me something of the place to which we weir going. I gathered from him that Saranac Lake and Dr. Trudeau meant practically the same thing, and that the doctor would make it all right for me.

Mr. Krumholtz was my introduction to that ever-increasing company of those whose tuberculosis has been arrested lowing the trail blazed by Dr. Trudeau, and I shall never forget his cheerful, helpful talk.

Dr. Trudeau had. in response to a letter, arranged for me to live at the Berkeley, which was then the largest boarding-house for his patients, as well as the village hotel. The talk at dinner on that day among the 15 or 20 guest- was of the kind most interesting to lungers, and I thought how depressing such a conversation might be to a non-medical novice. Some of them had during the morning been examined by the doctor, whom thev called " The King," and it was not hard to see from the way poke and the others listened, and from the questions that tsked, that I had. indeed, come into the domain of a ruler whose word was cheerfully accepted as the law of the land.


That afternoon, while I was unpacking. Dr. Trudeau came to see me. . He was a tall, straight man. weighing more than 180 pounds, and his very dress typified the woods and all outdoors. At his heels was his companion, Nigger, a black mongrel, who went everywhere with him except hunting and to church. Dr. Trudeau would not take him hunting, and he never made any attempt to follow him to church.

I am unable to remember what he said to me on that first afternoon, but looking hack at it now I think of that interview as the beginning of a friendship that has meant more to me than I can express. I remember this, that in a little while Dr. Trudeau took me out with him, showed me the village, and then left me with a group of young people — patients and their friends — who were tobogganing.

The next morning, which was Sunday, he sent his guide over with a note, saying he did not consider it right that a young doctor, engaged to be married, should eat his Sunday dinner alone, and asking me to take dinner with Mrs. Trudeau and himself.

From that time on I became Xigger's rival, and was with Dr. Trudeau as much as possible; indeed, I both hunted and went to church with him.

Dr. Trudeau. when I first knew him. was 40 years old, and his health was as good as it ever became. Indeed the first impression that he made on me, of a man in vigorous active health, abounding in energy and love of life, was only confirmed by a more intimate knowdedge. He was always busy, and the only physical limitation that his disease seemed to have left was his inability to take long walks, skate, run, swim, or row.

His days were full, and he passed quickly from one thing to another, giving to each enthusiastic attention. At this time Saranac Lake was a compact little village in which we were all thrown very closely together. A single stranger in town, or, indeed, a new dog. created remark and had to be explained. There were not many very sick people among us, and as Dr. Trudeau examined his patients only very rarely, some of them only when they came in the fall and when they went out in the spring, and visited them only when there was special need, his winter practice at this time was not very exacting.

The sanitarium was three years old and then contained about 30 patients. The entire management was on his shoulders and. of course, occupied a great deal of his time. He had started almost unconsciously a wonderful institution. and it was amusing to see his assumed consternation at its growth. He would half-jestingly complain bitterly of the load he had to carry, while grasping with avidity every possible chance of increasing it.

He worked some part of every day in his laboratory, which consisted of his narrow office with a boot closet at the end. his barn, and the pit that he had had dug in his backyard. As you can well imagine, the hope that Dr. Welch had encouraged in me that I might continue my own work at Saranac Lake vanished the moment I went with Dr. Trudeau into his office, and verv soon the desire as well, for after being with him for a


April, 1916.] 103


little while 1 had no other thought than that of doing what I could to help him.

Just at this time many cures for tuberculosis were being advanced, most of them based on the supposed germicidal actioD of various agents. He tested these and many other things in the hope that he could find something thai would kill the organism within the body.

A French observer had stated that men who etched on glass with hydrofluoric acid seldom had tuberculosis, and it was supposed that it was breathing the fumes of this chemical that accounted for the supposed effect. This we tried, and it did, indeed, kill the germ in culture. I saw that he would like to try it on a patient as well as on inoculated animals, and I suggested that I try it on myself. He was somewhat loth to let me do so, but finally consented, and thereafter I sat for two hours a day in a room breathing the fumes of hydrofluoric aeid, and with the result that every bit of the glass in the room was etched and that the bacilli disappeared from my expectoration. The rabbits did not fare so well, and although one or two other patients tried it, no further result was obtained.

The deftness and skill which Dr. Trudeau showed in all his actions were very evident in bis laboratory technic. Even though the apparatus was simple in the extreme, it was nicely adapted for its purpose and was used by a master workman. One thing in particular I should like to mention, as it never failed to arouse my astonished admiration. The thermostat was heated by a kitchen coal-oil lamp, and Dr. Trudeau regulated the temperature by turning the flame up or down, and opening one or more of the doors of the wooden cases that surrounded the tin box. This was not hard to do during the day while the fires in the house were kept up, but it required skill to arrange for the whole night wdien the fires went out and everything was apt to freeze. • Before going to bed he would look at the barometer on his table, go out-of-doors and look at the thermometer, make an observation of the heavens, and as a result he would turn the flame up or down, and shut or open the various doors. In this way he was able to keep the temperature of the thermostat within the proper limits. How successful he was is shown by the fact that at Saranac Lake living cultures of the tubercle bacillus could even then always be found, and this could be said of nowhere else in the country.

Dr. Trudeau constantly over-estimated other people's attainments and knowledge, and I discovered later that he had looked forward with high expectations to my arrival, as a man who had worked with Dr. Welch in the laboratory of The Johns Hopkins University. His disappointment must have been keen, for I knew little more about bacteriology than I did aboul hunting.

In later years, when I went with him to the meetings of medical societies, I was often amused, when he had approached some noted physician and told him of the experiments that he was doing and asked for advice about some troublesome point, to note his astonishment when he discovered that it was he himself who was regarded as the authority, and that the other physicians had nothing to offer except respectful attention.


This mo. lot estimate of his own position in the i lical

world he showed also by requesting all of his patients to be examined frequently by Dr. Loomis or some other consultant to have his opinion confirmed, and he only gave up this habit when the patients flatly refused to regard any other advice than his as necessary, and when he discovered that more and more patients were taking the trip to Saranac Lake to get his confirmation of the advice that had been given by others.

Dr. Trudeau tells in his autobiography how much pleasure he took in getting money for his sanitarium and his other charities; indeed, he put into this quest much the same spirit and craft that he used in hunting game. He does not tell, however, how persistently he shrank from any personal profit that might accrue to himself from the growing reputation of the institutions at Saranac Lake. He, of course, could not avoid charging his private patients, but his fees were always most moderate and usually absurdly small, and at no time commensurate with his reputation. Many of his patients were among the very rich, and at the height of his activity the number who applied to him was very large. He distributed them lavishly among the increasing group of younger doctors who had collected about him. and if I told you the largest sum that he ever made from his practice in one year you would find it difficult to helieve me.

Although I am sure that every one of us who was ever associated with Dr. Trudeau in his practice would have been glad to have followed the usual custom in such cases and worked oil a percentage ba>i>. that was not bis way; he never divided fees, the other man got them in full.

He was unwilling to profit by the work of another man. and he carried this unwillingness to such an extreme that it was at times a check to our offering to assist him. I remember on one occasion I was with him when he prescribed for one of the guests at Paul Smith's. His medicine bag was over at his cottage, and he asked me to get it, and then tried to make me take the fee.

It would be impossible to tell you of his endless generosity to everyone about him. He did. indeed, learn how to beg, but he was a born, incurable giver.

He was extremely sensitive to the groundless fear that some one might think that his advice to patients to remain in the Adirondacks might be controlled in any measure by any possible pecuniary advantage to himself.

The rapid development of Saranac l-ake village offered tempting opportunities for investments in real estate, but Dr. Trudeau would never have the leasi interesl in any of the boarding-houses or the many houses that were built for rent to the patients, and. in fact, he got rid of a large tract of land, at no profit to himself, upon which the most extravagant section of the village now stands.

He refused many suggestions by astute business men to become interested m the establishment of private sanitaria. One of these suggestions that particularly aroused his wrath was an oiler of $10,000 a year for his nominal direction of an institution and the use of bis Dame on the circular.


104 [No. 302


The patients at the sanitarium have always paid much less than it costs to maintain them, and as the sanitarium grew, the annual deficit, as well as the expenses, increased in proportion. It was evident to Dr. Trudeau and to everyone else, that if he would accept well-to-do patients and charge them as they were charged at other sanitaria, the much needed money would be assured. The idea of such a change was never entertained, and Dr. Trudeau kept the institution exclusively for the benefit of those for whom it was designed.

Medicine was not a business to Dr. Trudeau. nor was its study a fascinating response to scientific curiosity. The central, compelling force was a strictly humanitarian desire to do everything that lie could to cure tuberculosis, or, if not this, to alleviate the condition of the sufferer as much as possible.

Once having assumed the care of the sick, and having asked and received assistance in his charitable and scientific work, he felt the responsibility very deeply, and gave himself to these objects with absolute unrestraint. It was distressing to him to feel that possibly he might not be measuring up to what he characterized as the "demands of the great public" and he often taxed himself far beyond his strength, in spite of all that his associates and friends could do to shield him. This was particularly so during the summer months when he had charge of the practice among the guests at Paul Smith's Hotel and the campers on the St. Eegis Lakes, as well as the responsibility of the sanitarium and his patients at Saranac Lake. In the early years he lived during the summer in his camp on Spitfire, and was rowed to the hotel and about the lakes to see his patients. When he had to go to the sanitarium or village it entailed a drive of 15 miles. As he became more busy, he gave up his camp and lived in a cottage near the hotel.

I wish I could give you some idea of his incessant activities. and the multitudinous demands that were made upon him during these summer months. It was more than any one man could do, and he had to have assistance. 1 was fortunate enough to be the first to help him, and did so for a number of summers. On the days that he was at Paul Smith's it was possible to relieve the strain somewhat, but on what he came to call the " horrible Tuesdays and "Wednesdays." when he went over to Saranac Lake, little could be done. Mrs. Trudeau always went with him on these trips. They left as early as they could and drove to the sanitarium, and then after luncheon to his office at Saranac Lake, where he saw and examined a seemingly endless stream of people who had collected from all over that region of the Adirondacks and come in from the outside to see him. His office hours were repeated again the next morning, and he also had to visit some of his patients who were bed-ridden.

They usually got hack to Paul Smith's just before dark on Wednesday, and it was always with apprehension that I met them. Dr. Trudeau was often, as he himself described it, a wreck — absolutely worn out nervously. Time and time again we urged that patients who really wanted his advice would come to Paul Smith's or anywhere else to see him, and that it was wrong for him to put himself to this useless strain. We


were entirely unable to convince him. and he persisted until his health made the trips impossible.

His modesty kept him from believing that many people would take the extra journey to Paul Smith's for his advice, and, more than this, he felt that these weekly trips were a duty to the growing community at Saranac Lake and its neighborhood, and especially to those whose finances would preclude their coming to Paul Smith's.

At the end of each summer Dr. Trudeau was usually wretched, at times with fever and other evidences of the renewed activity of his old process, but more often, at the time I am speaking of, as the result of the strain on his highly strung nervous system. He was subject from his boyhood to extremely sharp attacks of ophthalmic migraine, and was liable to such attacks at any time, but he was almost certain to have them when under any very special strain, as on his Tuesdays and Wednesdays at Saranac, and they were very frequent by the end of the summer.

As is not uncommon with such a make-up, Dr. Trudeau had a very remarkable power of going through with what had to be done, in spite of his feelings, on pure nerve, and paying for it afterwards, and it was only those of us who were very close to him who really knew how he suffered.

His intense interest in hunting and other sports was a great help to him at these times, and we always felt that if we could get him down to Little Rapids, and into the woods with his old guide and friend, Fitz Hallock, that his astonishing recuperative power would again restore the balance.

Soon after I first went to Saranac Lake I started hunting with Dr. Trudeau. and two or three times a week his guide, Parker, would appear at the Berkeley, while I was at breakfast, with a note asking me to come over to the house a little earlier, as there was something he had for me to do.

I soon learned that this " something " meant that there was a hunt planned, and I expected to find, when I got across the street, his sleigh at the door, with Bunnie, his favorite hunting dog, hitched to the back, and the guns hidden under the lap robes. There was always a certain amount of secrecy connected with these expeditions, and we got out of the village with as little fuss as possible, the idea being not to reveal tin 1 location of the rabbit swamps to the other sportsmen. It was a rare hunt that was unsuccessful, for we had along'the best shot and the best rabbit dog in the woods, but it was a very rare hunt, indeed, in which I killed the rabbit.

Dr. Trudeau's patience with my clumsiness and awkwardness in the woods was boundless, but at times he could not refrain later from describing to Mrs. Trudeau in his inimitable way how I. by moving my feet, or taking the wrong position, or by missing an easy shot first with one barrel and then with the other, had managed to cheat Bunnie of the satisfaction of finding his rabbit dead at the end of a long and intricate limit.

Dr. Trudeau was a keen hunter and an almost perfei I shot, but even at this time his scientific work, his sanitarium, and his practice, were occupying so much of his time that he had become the physician who hunted for recreation instead of the


April, 1916.] 105


sportsman who occasionally prescribed for a patient because he had to. He had entirely given up fox hunting as that required too much time, but three or four times a week he and I would go into the woods and hunt rabbits for an hour or two. A good rabbit dog was something that he insisted upon having. He tried out every kind of hound that seemed promising, and Fitz Hallock always had two or three dogs in training, many of which were the result of experimental breeding.

At this time of his life he was rarely able to get the time to hunt deer, and it was not until later, when he became part owner of Little Rapids, a hunting preserve, that he did so with any regularity.

Next to hunting and fishing his chief sporting interest was in relation to sailing. He and Mr. Anson Phelps Stokes inaugurated the sail-boat races on the upper St. Eegis Lakes, and were keen rivals for a number of years, but here again his professional duties had interfered by the time I became very familiar with the summer life of the Adirondacks. and he had turned this phase of his activities over to the efficient care of his son Ned. He always loved a good horse and always owned one.

His enthusiasm for almost all kinds of sports and his remarkable skill in most of them made it easy for him to get into close sympathy with many of his patients who cared but little for his other activities, and they took unquestioned his advice about their health and the management of their lives when they learned how good his knowledge was about the tilings that they themselves knew.

Trudeau the man, and that means the physician, the scientist, the philanthropist, and the friend, cannot be understood without some knowledge of his intimate home life. Fortunately, he has himself on many occasions, and most beautifully in his autobiography, acknowledged his dependence on the quiet, -tiuiig. ennobling, unselfish influence of his wife. Without Mrs. Trudeau I do not believe that Dr. Trudeau. as we knew him, would have been possible — she so perfectly supplemented his high-strung, emotional nature. Always, but especially so in times of discouragement, sickness and sorrow, she gave him with perfect understanding just the help he needed.

I cannot brave the attempt to describe the home life of the Trudeau family, nor to estimate the privilege it was to many of us to share it in some degree. Dr. Trudeau's life at home differed in no essential particular from his life that was open to the whole world; indeed, all of his activities wire centered there, and it was there only that one was able to get a clear idea of all the various channels through which his influence went • nit to the public.

Mrs. Trudeau sympathized in all of her husband's aim-, bul she was. I think, the directing force in his work of building churches and maintaining them. Dr. Trudeau was a deeply religious man. but cared little for creeds or doctrinal theology, although he was a consistent Episcopalian. His sustaining optimism was based on his faith, and it was this that he believed enabled him to accomplish some of the tilings that his vision set before him. He has beautifully expressed this as a farewell message to the medical profession in his address on


" Optimism in .Medicine." He radiated this message of i'aith and optimism constantly to his patients and those about him, although he preached it but rarely.

Dr. Trudeau had a remarkable facility for letter writing, and the letters that he wrote were innumerable. When he was well and in full activity, he would occupy every spare moment with his correspondence. It made little difference to him how many people were in the room or what they were doing. One of the clearest pictures I have of him at home is sitting at his desk surrounded by a roomful of talking and laughing people, who would interrupt him constantly while he wrote letter after letter, throwing each finished one on the floor until the rug at his feet began to resemble the snow-covered world outside. For many years he had no secretary and wrote all of his letters himself; indeed, to the end of his life he acknowledged every contribution to the sanitarium with a personal note. He wrote a long letter to his mother every Sunday of the many years that they were separated, and even more frequently t closesl friends refrained from writing to him as often as they wished in order to spare him. and begged him when he wrote to send them dictated letters. Dr. Trudeau never learned to express himself with


the same freedom and ease when dictating as when he wrote by hand. Nearly all of his scientific articles were so written and the whole of his autobiography, and during times of stress and illness he found comfort and relief to his emotional nature in writing unreservedly to his most intimate friends.

The writing of his autobiography was a greal surprise to himself, lie had refused many offers from people who wanted to write his life and had resisted the urging of friends that he should himself write down his own experiences, and only succumbed at last to the kindly insistence of Dr. James, and consented to make the attempt. He began with very little hope of having either the ability or strength to complete it, but. when he had commenced, his wonderful enthusiasm came to his aid, and as the work progressed he became conscious of powers that he had no knowledge of possessing. When asked how be could write so vividly of scenes long past, he said that he recalled them to mind largely as visual images and wrote describing what he saw as rapidly as possible. He wrote on small sheets, often erasing and correcting them until they were almost illegible, and from these his secretary made the typewritten copy which rarely required the least correction.

I am conscious how very imperfectly I have been able to convey to you any adequate idea of Dr. Trudeau's personality. His was a nature that appealed instantly to everyone who net him. and it was easy for him to influence even casual acquaintances. He used this power with great skill in controlling his patients, and getting assistance for his charitable work. Men and women gave him without stint their unremunerated labor, and others delighted to help him with their money. I have time after time watched for and seen this instant response to his personality as he met and talked with strangers. This power which he retained to the last is shown very beautifully in the account which Mr. Clayton Hamilton, in his recent book, " On the Trail of Stevenson." gives of his single interview with Dr. Trudeau. The trail had led Mr. Hamilton to Saranac Lake in the Christmas season of 1911, where he saw Dr. Trudeau, who was then ill and sitting out on his little porch. They talked about Stevenson and of Dr. Trudeau's own work. Among other reminiscences. Dr. Trudeau recounted, as he delighted in doing, Stevenson's remark on the one occasion in which he had been decoyed into the laboratory. Stevenson. after looking for a little while at the cultures and specimens, said about as follows : " Trudeau, we both are bearing lanterns, but I must say yours smells to me most confoundedly of coal-oil."

In relation to this story Mr. Hamilton writes:

The doctor told me this with humor; but it did not seem to me so funny when I thought about it afterward. At present I remember an eager, active-minded man sitting anchored in a lounging chair and muffled among furs: talking with that tense voice of the achieving dreamer; at home in life, though exiled from its laughing and delightful commonplaces; cheerful and alert, though slowly dying; young, clear-eyed, and still enthusiastic, although already ancient in endurance; lying invalided while his City of the Sick grows yearly to greater prominence among the pines: fighting with an easy smile the death that has so long besieged him. to the end that others after him. afflicted similarly, may not die.


April, 1916.] 10;


And the best of our tricky and trivial achievements in setting words together dwindle in my mind to indistinction beside the labors and the spirit of this man.

] »b. Janeway : One impression, which I hope will be a lasting one, I think we will all carry away with us to-night. It 'is that, in our medical heroes it is impossible to separate the -mnal life and the personal character. That is not true in all professions, and certainly not true of all heroes. It lays upon those of us who are their sui i essors in tin- medical profession to see to it that we are true both to their scientific and humanitarian ideals as physicians, and to the legacy of rich character and sympathy with suffering which they have us as men ami women.

I am going to ask Dr. Thayer if he will express our thanks to the gentlemen who have so kindly come here to read these splendid tributes.

Dr. Tiiayei; : May I first add a word about one phase of Dr. Trudeau's activities which has always impressed me deeply ?

Dr. James has spoken of his diagnostic and prognostic abilities. These he used for years with wisdom and skill in determining just who. among the many patients who presented themselves as applicants for admission to the sanitarium, were most likely to he benefited by the advantages which it offered. As he has said himself, this was not an easy task : it was one in the exercise of which he was often criticised : hut it was precisely those patients in whom the process was at its earliest Tn whom the sanitarium was especially likely to give that help which might turn the scale. From this standpoint Dr. Trudeau exercised remarkable ability and discrimination. But often he went farther and exercised an insight and a charity s,, exquisite that those of us who have experienced it can never forget. He knew not only how to choose those whose lives were most likely to be saved ; he knew how to choose those whose lives were most worth saving.

Some of us have had the experience of sending to him patients whose symptoms were not so favorable as. under ordi


nary circumstances, to justify admission to the sanitarium, yet patients whose character and circumstances were such as to appeal to us with peculiar force. We have sent him such patients without, perhaps, even a suggestion that they be admitted to the sanitarium. How quickly under these circumstances did his clear eye and his generous heart detect tl opportunity !

He who has seen the group of men and women gathered in that sanitarium can hardly have failed to realize that this was no ordinary collection of individuals, but a body of the elect. How many to whom all doors of hope seemed closed are now living happy and useful lives, thanks to the skill and insight ami charity of this great and good man.

Those who knew Dr. Trudeau in his latter years were more and more impressed with the beauty of his face. It was not the beauty of line or of color such as one sees in the young, but a beauty brought out by crease and furrow and hollow, that beauty which character brings to age. Bradford tells of a well-known statesman that when spoken to of a certain man. he exclaimed: "I do not like him. I do not like his face." " That is not his fault," said his friend, " he's not responsible for his face." "Yes," he replied, "every man over fifty is responsible for his face." I have thought of that remark when looking into Dr. Trudeau's face. It was a wonderful face with a singular beauty and depth of expression. In the later days when sorrow and illness had settled upon him. it • sometimes as if the body had almost gone, as if nothing remained but the spirit which glowed in the light that shone from his eyes. The body has gone now, but the spirit remains, burning in the hearts of thousands of men and women whom he has taught to live, animating that fine body of students who are carrying on his great work at Saranae and handed on by them to us to-night.

We can hardly express deeply enough our gratitude to Dr. James and to Dr. Baldwin and to Dr. Thomas for what they have said to us. This is an evening that we shall all remember.


POST-PART UM CARE OF THE PERINEUM.

By E. D. Plass, A. B.. M. D.. Instructor in Obstetrics, Johns Hopkins University, Baltimore, Md.


The present treatment of the perineum both alter uncomplicated labor and after primary perineorrhaphy appears to have descended from the antiseptic period, when any addition to the chemical armamentarium was hailed a- a panacea. It would seem that obstetricians have been so absorbed in determining the proper time for, and the technique of. repair, that antiseptic after-care has been handed down unchanged to tin' present generation. Only occasionally a skepl Kronig has dared to doubt the value of these time-honor toms, but in the course of time all of us will be led to o critically the value of antiseptics, and determine to what extent they are useful.


When it is realized that, with the exception of iodine, the usual antiseptics, in concentrations in which they can safely be used on the skin, destroy the usual pathogenic organisms only after a long period of activity, does it appear reasonable to expect that the ordinary irrigations and douches will have more than a mere mechanical action? The false si security engendered by the term "antiseptic" i- danj and when untoward results follow, many individuals seemingly prefer to lay the blame upon the solutions rather than upon their own slip-shod rage uurse t

"antiseptic" spells safety, and she trusts implicitly in the germicidal action of a 1: 1 r a 1: 2 1 bichloride solution.


10S [No. 302


By eliminating the use of snch solutions we do away with this false sense of security, and in my experience the results will be as good or better than those formerly obtained.

There is practically no recent literature upon the routine post-partum care of the perineum, or the after-care of primary perineal repairs. In order to ascertain the general sentiment of the obstetricians of this country in this regard, various textbooks of obstetrics were examined with the following results :

E. P. Davis (Manual of Obstetrics. 19] 1 i advises "a copious irrigation by a small pitcher with an antiseptic solution.*' during the puerperium, and "pouring 1% lysol or sterile salt solution from a pitcher over the parts after each micturition or defecation and whenever>the vulvar dressing has become soiled and has been removed," in the after-care of cases with suture.

Hirst (Text-Book of Obstetrics, 7th edition, 1914) says: " Care must be exercised to remove blood and blood clots from the vulva before putrefaction sets in. This is best done by placing the woman on a bedpan, letting a stream of boiled water run over the parts, and. if necessary, using cotton to wipe them off." Xo reference to any special care after perineorrhaphy was found: but since Hirst advises making all repairs at the end of one week, one can scarcely speak of primary repa i r.

Henry F. Lewis, in the Practice of Obstetrics, edited by R. Peterson, 1907, advises "irrigation with sterile water or sterile antiseptic solution, finishing by drying with some sterile gauze." He mentions no special care following repair.

De Lee (The Principles and Practice of Obstetrics. 1913), under "Aseptic care during the puerperium/' >ays: "The patient is placed on a sterile bedpan, the nurse sterilizes her hands or wears sterile gloves, and gently pours from a narrowlipped pitcher a solution of 1: 2000 bichloride over the vulva. The excess is dried off without rubbing, by touching with dry cotton .... Simple sterile water may be used." After repairs no special care is recommended.

Without exception the text-books examined recommended cleansing at frequent intervals with antiseptic solutions, with sterile water or with saline solution, and frequently the procedure was made very elaborate and time-consuming. There seems to be a widespread belief that some extra care is needed, but the variations in treatment have to do only with the choice of the solutions and in the method of their use.

In order to demonstrate whether such routine antiseptic treatment of the perineum after delivery has any distinctly beneficial effect upon the course of the puerperium or upon the healing of primary perineal repairs, the following clinical experiment was conducted. For a period of nine months — from November. 1914. to August. 1915 — all patients were divided into two groups after delivery, A and B (every alternate patient being placed in group A I . and treated as follows : Those in group A were given the routine perineal care and those in group B were given no special attention. The routine care consisted in bathing the vulva and perineum with cotton pledgets soaked in 1 : 2000 bichloride of mercury solution every four hours, as well as after each defecation and urination during the nine days the patient remained in bed. The patients in


group B were merely kept ruacroseopically clean with warm tap-water and soap and a wash cloth. Xo attention was paid to voiding or bowel movements, unless, as sometimes happened after the initial dose of cathartic, the need of cleansing the parts was apparent. The bloody lochia were removed whenever necessary. Unless the patient was very ill. she was expected to keep herself clean. It was found that the average number of cleansings necessary was as follows : Four a day for the first three days, between the third and sixth days not more than two a day, and after this only one, at the time the morning bath was taken.

Every effort was made to eliminate any factors which might invalidate our conclusions. Since the two series were run simultaneously, the factors of nursing care and surgical ability in repairing the lacerations on the part of the house staff were removed as nearly as possible. The head nurse arranged the lists impartially and none of the staff knew how any particular patient w r as being cared for. Xo exceptions were made to the alternate grouping of the patients. At the end of the experiment, when each group contained 200 cases, the records were carefully tabulated and the following facts discovered:


Group A. Routine Car


Primiparjp 120

Multipara? 80

Full term deliveries 1S1

Premature labors (7-9 months) ... . Iti

Abortions (under 7 months) 3

Spontaneous deliveries 185

Operative deliveries 15

Vaginal examinations 93

Temperature never over 100.4° F.. . . 121

Temperature over 100.4 s F 79

Elevation due to uterine infection.. 30


60% 40%

90.5% 8.0% 1.5%

D2.5%

7.5%

46.5%

00.5% 39.5% 15.0%


Group B. Soap and Wate Care.


102 51% 98 49%


87.0% 10.5% 2.5%

92.5% 7.5%

92 46.0%,

128 64.0% 72 36.0% 29 14.5%


174

21 5

185 15


Reference to Table A shows that the two series are quite comparable as regards operative deliveries and the frequency of vaginal examinations, the two factors which might possibly have had a bearing on the results. The total morbidity ( temperature over 100.4° F.. taken every four hours) is approximately the same (group A, 39.5% ; group B, 36.0%) : nor is there any striking difference ill the incidence of elevation of temperature attributable to uterine infection, as determined by uterine cultures or by the clinical course of the puerperium (group A, 15.0% : group B. 14.5% ). The advantage, if any. is in favor of the series not especially treated (group B).

The low percentage of vaginal examinations is attributable to the fact that the staff attempts to follow the course of labor by means of abdominal palpation and rectal examination, so that ordinarily vaginal examinations are made only for the purpose of instructing students. These, however, probably account, in part at least, for the rather high morbidity, particularly that referred to uterine infection. Fortunately, none of the infections were severe, and there was no mortality.


April, 1916.] 109


The number and character of the repairs of lacerations, as well as the conditions which obtained at discharge (12 to 14 days after labor) are shown in Table B. No particular scheme of repair was insisted upon, but all perineorrhaphies were made with catgut and silk-worm gut, either singly or in combination. Very small nicks were frequently not repaired.



Routine Care.


Soap and Water Care.



Well healed.


Poorly healed.


Well healed.


Poorly healed.


1st degree.. . 2d degree. . . 3d degree . . .


39 92.8% 1 3 7.2% 21 75.0% 7 25.0%


29* 96.6%

19f 95.0% 1 100.0%


1 3.4% 1 5.0%


Totals


00 85.7% 10 14.3%


49 96.1%


2 3.9%


One patient died eight hours after delivery (.eclampsia), t In one case, no repair (eclampsia).

It will be noticed at once that there is a considerable difference in the results obtained. The routine care was followed by many poor results, whereas excellent results were obtained where no antiseptic precautions were taken. Of special interest is the one ease of complete laceration — a forceps delivery of a child weighing 5000 g. in the case of an 18-year-old primipara. She chronologically went into the " no care " list, and the supreme test was made. The healing was per primam, and not only was the sphincter tone excellent, but the perineal body was also in good condition. When one sees a poor result in only 12 out of 400 cases there is a tendency to be satisfied; but a comparison of the results obtained in the two groups — 14.3% and 4%, respectively — clearly indicates that too many failures occurred in group A.


This method of treatment was so successful that on August 1, 1915, the old routine was entirely abandoned. Since that time ~m primary perineorrhaphies have been done as follows: 1st degree, 32; 2d degree, 17; and episiotomies, 8. with only three bad results (5.25%), and these were confined to the first degree tears. The episiotomies were all lateral, single or double, and the wound healed per primam .

To date we have treated 108 repairs in this manner and have had five failures, a percentage of 4.6.

In addition to the better results obtained after the elimination of the more or less complicated antiseptic treatment, there is an economy in the time of the nurses. All who have to do with nursing in large institutions will welcome any change which will free the nurses from the burden of unnecessary routine and give them time to really nurse the patients, provided the result is satisfactory.

Conclusions. — The use of antiseptic solutions in the care of the perineum during the puerperium or in the after-care of primary perineorrhaphies is of no value.

Macroscopic cleanliness alone gives better results and effects a considerable saving of time.

Note. — Since November, 1914, the antiseptic after-care of secondary perineorrhaphies done on the gynaecological service has been discontinued and no attention is now paid to the wound in these cases. Dr. V. N. Leonard, resident gynaecologist, has assured me that the results are excellent; and that, although no statistics have been compiled, the percentage of poor results is even less than previously. The absence of bleeding makes it unnecessary to resort to any special cleaning of the perineum so that the only attention consists of the usual morning bath. Vulvar pads are discontinued after two days.


THE CASES OF GAUCHERS DISEASE REPORTED BY DRS. KNOX,

WAHL AND SCHMEISSER.

By F. S. Mandlebatjm, M. D., and Hal Downey, Ph. D.

{From the Pathological Department, Mount Sinai Hospital Xeic York, and the Histological Laboratory, Department of Animal Biology.

University of Minnesota, Minneapolis.)


Iii the paper by Brill and Mandlebaum mi Gaucher's Disease (1913) an attempt was made to show that this disease is a distinctive clinical and pathological entity, easily differentiated from a large group of diseases whose chief characteristic is an enlargement of the spleen. These authors called attention at the time to a considerable number of cases quoted in the literature as instances of Gaucher's disease without sufficient clinical or pathological data to warrant the diagnosis, and hoped that the subject would not be confused in the future by the addition of other unproven cases.

In the paper by Drs. Knox. Walil and Schmeisser, which has just appeared in the Bulletin of The Johns Hopkins Hospital/ two cases of Gaucher's disease in infants are reported, which, in our opinion, should not have been so cla


Vol. XXVII, Jan., 1916.


We are able to show that the diagnosis is unwarranted, not only by our analysis of the histo-pathology and microchemical tests as reported, but also because we had an opportunity of studying a portion of the material which was kindly sent to us by Dr. Wahl in June. 19] I. At that time we < ame to the conclusion that the case (Case I) 3 disease and called the attention of Dr. Wahl to this fact.

In an analysis of recently reported cases of Gaucher's ' in a paper now in press in the /

not to comment upon the cases which were reported by Knox and Wahl in a preliminary communication while our article was in preparation, but pn rait until their full

appeared.

From the very limited numb reported in infancy one is not warranted in describing stant or definite clinical picture, for the disease at this a


110 [Xo. 302


usually been complicated by intercurrent affections of one sort or another. Still, one must bear in mind the fact that, whenever a reliable history is obtained, it will be found that most, if not all, cases observed in later periods of life, have originated in infancy or childhood. Inasmuch as one of the chief chares of Gaucher's disease is its essential chronicity, it must not necessarily be considered a fatal disease when occurring in infancy, even though the individual may succumb to somi complicating affection. For these reasons it is unnecessary to enter into a discussion here of the clinical features at this period of life, in which the diagnosis may be difficult if not impossible.

We admit that the histo-pathology in any case of Gaucher's at its very inception would probably show but few cellular changes. Inasmuch as no autopsy findings at this • stage have ever been reported, we may assume that the diagnosis might be impossible. In the case just described by Drs. Knox. Wab.1 and Schmeisser, however, the cellular - is so far advanced that the normal appearance of many of the affected organ- is almost entirely effaced. One might reasonably expect, therefore, to find at least some resemblance to the lesions of Gaucher's disease in a process so well established and so widespread in its manifestation.-. This, however, is not the case, as will be shown later. Moreover, in the \ i. pi.ii in. i' v, 1 1 1 • 1 1 lho ih-casc began at the age of two months, the lesion- 15 months later were limited to the hematopoietic organs and the histo-pathology is that of Gaucher's disease. Furthermore, the patient of Erdmann and Moorhead, upon whom a splenectomy was performed at the age of three years and four months, presented an enlarged spleen at the age of 1-1 months, and here also the histological examination -how- the characteristic changes of Gaucher's disease.

From a study of the complete autopsy material in thn e of our own cases ranging from the age of four and one-half years to 42 years, together with the findings of six other observers - cases also came to autopsy, we find it difficult to believe that a definite pathological process, limited invariably to the hematopoietic organs, could have originated in infancy or childhood as a widespread lesion involving the heart, lungs. pancreas, kidneys, adrenals, intestines, thymus, brain, and other organs. It is equally difficult to realize that the lesions described by Drs. Knox. Wahl and Schmeisser, which have no resemblance whatever to those of Gaucher's disease, could localized in later life to the hematopoietic organs and conform to the well recognized picture of this disease.

In considering the histo-pathology of these cases we shall confine ourselves entirely to the results of our study of material from Case I. This consists of spleen, liver, lymph node and adrenal body. In the first place, it is quite evident that all sort- of tissues are involved in the process, particularly the parenchyma of the various viscera, as is freely admitted by the authors. This constitutes one of the most marked differences between these cases and the authentic cases of Gaucher's disease. In the liver there is no question but what the majority of the large, vacuolated cells are derived from the


hepatic cells. A few vacuolated cells are -ecu in the periportal connective tissue, but there is practically no increase in the amount of interstitial tissue, and consequently the number of large cells from this source is very insignificant. The liver from a case of Gaucher's disease presents a totally different appearance. It shows a tremendous increase in the amount of interstitial connective tissue, both perilobular aud intralobular. This interstitial tissue is crowded with the characteristic Gaucher cells, and it is quite evident that these have not been derived from the hepatic cells. Although the hepatic trabecular are more or less broken up by the invasion of Gaucher cells, the liver cells remain quite normal in appearance. In the ease under discussion, the epithelial cells of the larger bile ducts arc very much vacuolated, and conspicuous vacuoles are also seen in some of the endothelial cells of the larger vessels and also in a few of the stellate cells lining the sinusoids. In Gaucher's disease, even in the most advanced stages of the process, such changes in the bile ducts, sinusoids and endothelial cells of the vessels were never seen. The process is limited strictly to the interstitial tissue of the liver.

In the lymph nodes there are many differences between Gaucher's disease aud the case of Drs. Knox. Wahl and Schmeisser. In the latter, the node is packed rather uniformly with the large, clear, vacuolated cells, although in parts of the node there is some grouping of these cells into rounded masses which are surrounded by sinuses or thin layers of connective tissue. These rounded masses seem to lie medullary cords which have become rounded owing to the accumulation of foam-cells. In other parts of the node the large cells are quite uniformly distributed. In Gaucher's disease this grouping of the characteristic cells in rounded masses is much more conspicuous than in this case.

The long strands of modified tissue described by Bovaird. Risel, ami by the writers in their forth-coming paper, are not present in this ease. These long strands, which show clearly that the characteristic cells are derived from the reticulum. are very characteristic for Gaucher's disease, and their total absence in the present case is a strong argument against classifying the case with Gaucher's disease. Another feature which doe- not correspond to conditions in Gaucher's disease is the reduction in the amount of the reticular tissue of the node. To a certain extent this is replaced by many strands of young white fibrous tissue which grow into the node from the capsule, carrying many thin-walled vessels and capillaries with them. The reduction in the amount of the reticulum makes these capillaries appear very prominent. Such a condition has not been reported in Gaucher's disease.

In the node available for our study the process was so far advanced that it was impossible to determine the source of the large cells. However, the presence of a few abnormally vacuolated lymphocytes seems to indicate that some of tin large cells are transformed lymphocyte-.

In the spleen the pathological process is just as far advanced as it is in the early case of Gaucher's disease which has already been reported by one of us. Although the organ is packed with large, clear cells, there are many points of detail wherein it


April, 1916.] ill


differs from the spleens of the Gaucher cases reported. The enormously enlarged sinuses surrounded by rather thick connective tissue walls, which are so characteristic of the Gaucher spleens, arc not seen here. The photomicrographs, figures 1-4 published in the paper under consideration, when compared with those published by Mandlebaum (Jour. Expcr. Med., Vol. Hi. plates 78 and ?'.»). show the difference clearly enough. In the Gaucher spleen there are a few normal sinuses, but most of them are greatly modified and they are usually without an endothelial lining, although they may Lie lined with one or two layers of Gaucher cells. In the case under discussion. although the process is far advanced, most of the sinuses are fairly normal in size and appearance, except for the fact that their endothelial cells are usually somewhat swollen.

In the Gaucher spleens the characteristic cells located between the sinuses are arranged in the form of rounded solid masses, or as alveoli, which are surrounded by thick bands of fibrous tissue. Some such arrangement occurs in the spleen of the case under consideration, but the masses are not nearly so clearly outlined as is the case in Gaucher's disease. In other words, the organ is much more uniform in appearance than is the case in Gaucher's disease. The large cells arc similar to those of the lymph node and liver, but they are very different from the characteristic cells of Gaucher's disease.

In the adrenal body it is clear that all parts of the organ are affected by the process, the cells of the zona reticulosa most. Cells of the zona glomerulosa are vacuolated, and also those of the zona radiata. In the lower portion of the latter zone the nuclei are small and irregular, but the cells are not materially enlarged in these two regions. The cells of the zona reticulosa show the greatest amount of change. These cells are very large and very much vacuolated, and they have the same characters as the cells in the other organs. Eounded groups of these cells are surrounded by bands of fibrous tissue. and in this respect the adrenal bodies suggest Gaucher's disease more than do any of the other organs examined.

The cells of the medulla are also affected, but they have not enlarged to the same extent as those in the zona reticulosa. They are still quite dark and can be recognized as medullary cells. Their nuclei are fairly normal.

It is perfectly evident from the above, as was also pointed out by Drs. Knox, Wahl and Schmeisser, that the large vacuolated cells are derived from the parenchyma of the organ, chiefly the zona reticulosa. But that part of the organ which one would expect to find modified, if this were merely an extension to the adrenal body of the characteristic pathological process of Gaucher's disease, namely the supporting framework, shows little or no change, excepting that it is slightly increased in amount. In Gaucher's disease, no matter how far advanced tin' process, the reticular tissue of the hematopoietic organs and the supporting tissue of the liver are the only tissues involved.

It is claimed that the large vacuolated cells, which characterize the organs of this case, are identical in structure \\ itb those which have been described for Gaucher's disease. Even a superficial examination shows that this is not true. The


nuclei are quite similar in structure and shape, although multinucleated cells are far more frequent in Gaucher's disease. In other respects, however, the cells are quite dissimilar. In Gaucher's disease the large cells present a very peculiar appearance which is not exactly duplicated in any other pathological process. The stainable portion of the cytoplasm occurs in the form of a network composed of rather fine fibrils, the main strands of which take a more or less parallel, wavy course, in the direction of the longitudinal axis of the cell. Even in the more rounded cells the fibrils show a tendency towards a more or less parallel, wavy course across the cell, in case- its nucleus is eccentric : or they encircle the nucleus, if the latter is near the center of the cell. In other cells the course of the fibrils is more complicated, but the main strands of the network show the same tendency towards parallelism. This gives the cells a peculiar streaked appearance which is very characteristic for Gaucher's disease, and which distinguishes its characteristic cells from those of the case under consideration and from those figured by Schultze and Anitschkow. Frequently the bands of fibers appear crowded apart in such a way that they form a rather distinct wall around elongated or irregular colorless spaces. Hounded, vacuole-like spaces are very infrequent, which is another point of distinction between the cells of Gaucher's disease and those of the lipoidemia cases and the case of Drs. Knox, Wahl and Schmeisser. These differences are brought out very clearly by a comparison of the figures published by Anitschkow (Ziegler's Beiirage, Bd. 57, Plate 8) with Eisel's Figure 2 on Plate 6 (Ziegler's Beitrdge, Bd. 46).

The large cells of the case of Drs. Knox, Wahl and Schmeisser are seen to be identical with those figured and described by Anitschkow, Schultze and Lutz, but very different from the cells seen in true Gaucher's disease. The cells are more rounded than are most of the Gaucher cells, and their cytoplasm is filled with rounded vacuoles — a condition which is very rare in Gaucher cells — and the longitudinal striatums are absent. Since the presence of lipoids was demonstrated in these cell-. and in those from the lipoidemia cases of Schultze and Lutz and in the experimental animals of Anitschkow, it seems evident that this type of cell is characteristic for lipoidemia, but not for Gaucher's disease. These cells are never fused into greatly elongated strands and syncytial masses as is the case in Gaucher's disease (Bisel, Bovaird). This constitutes one of the most important differences between the two types of cases and one which, with the streaked appearance of the cytoplasm of the Gaucher cells and the preservation of the non-stainable portion of the cytoplasm after treatment of the tissues by the usual histological methods, permits unfailing diagnosis of Gaucher's disease, especially when it is remembered that the supporting framework of the hematopoietic organs and of the liver are the only tissues involved in the process.

Let us consider for a moment the microchemical examinations which are reported in tip mi ca e only. It is stated that the substance in the large ell- disappears on treatment with absolute alcohol or ether and is slightly ret'ractile. The staining reactions with Sudan III. Nile blue, neutral red,


113


JOHXS HOPKIXS HOSPITAL BULLETIN.


[No. 302


Ciaccio's method, and the Weigert-Pal myelin sheath stain, while not altogether convincing as to the specific type of lipoid matter present, give certain reactions. Anisotropic bodies are seen after the myelin sheath stain. It is stated that these read - ggest the presence of some fat-like so

that may he in the process of transformation into neutral fat and may represent an intermediate stage between ti and a closelj bound molecule of proteid ami fat. In other words, some substance of a lipoid nature, resembling myelin and closely related to tin- fat-. 1- found by microchemical tests.

The material which Dr. Wahl kindly put at our disposal had previously been placed in alcohol, therefore we were unable to make microchemical tests for lipoids. The opportunity of studying the lipoid question, however, was afforded us i the kindness of Dr. Bernstein, from whom we obtained material from two cases of Gaueher's disease in children. Our examinations were made on frozen sections of fresh spleen as well as on material fixed in formalin. The complete results of our studies will appear shortly in the Folia Hcematologica, hut at present we wisli to emphasize the fact that alcohol and ether have no solvent effects upon the substance contained in the large cells. On the contrary, they produce a rather characteristic reaction and make the substance more prominent. No appreciable differences in staining reactions between frozen sections of fresh or formalin-fixed material and the material embedded in celloidin are .-ecu. indicating that the substance remain- in the cells after embedding. For these reasons we have considered that this substance may be of protein nature. Sudan III, Scharlach E, Nile blue, neutral red. and osmie acid were all negative, as well as the methods of SmithDietrich, Fischler. Ciaccio, and Golodetz. Weigert's myelin sheath stain was also negative, and overstating with WeigertVan Gieson, as suggested by Schultze, failed to show a reaction. Furthermore, no anisotropic bodies were demonstrable with the polariscope. Consequently we felt justified in stating that when neutral fats, myelin substances or anisotropic bodies are found by microchi hods in the cells of any proc ess resembling Gaueher's disease, the latter disease may be excluded.

We wish to say here that we fully realized that an appreciable amount of fats and lipoids might be present even though our microchemical tests were negative; therefore, a complete chemical analysis was made. Our results led us to believe that the substance in the cells of Gaueher's disease is not of a pure lipoid nature, but of protein nature possibly in combination with the phosphatids. Any definite theory, however, in reference to the exact nature of this substance is as yet speculative.

In order to avoid any misconception regarding Niemann's case — for Drs. Knox. Wahl and Schmeisser would have us believe that their cases are of the same type — we wish to emphasize that the lesions in Niemann's case were confine' 1 spleen, liver and lymph nodes ( the bone-marrow was not examined by them), and the histological examination showed the typical picture of Gaueher's disease. Furthermore, no i with Sudan III was found, the sections presenting simply a dirty, reddish tinge.


Drs. Knox. Wahl and Schmeisser also believe that the spleen described by Schultze in his case of diabetes accompanied by lipoidemia is like those found in their cases, and consider it very probable that Schultzi 's i as " represents an earlier stage in the same process." It may be stated that Schultz* 'bears no resemblance whatever to Gaueher's disease. It was a case of diabetes mellitus associated with large cell hyperplasia of the spleen, the cells showing certain reactions for lipoids. Such a comparison, therefore, is of no importance in corroboration of the diagnosis of Gaueher's disease.

Since Schultze's presentation at the meeting of the German Pathological Society, two cases of diabetes of similar naturewere reported by Lutz. and through the kindness of Drs. Williams and Dresbaeh we have recently hail an opportunity of studying the material of another case of diabetes, in which large swollen reticular cells filled with fat. lipoids and cholesterin esters were found. The histo-pathology. however, was not that of Gaueher's disease.

Drs. Knox, Wahl and Schmeisser make the following statement : '* Schultze showed that the sections of the spleen of his case reacted to the microchemical tests for fats and lipoids just as did the sections of the generally accepted cases of Gaueher's disease described by Eisel and Schlagenhaufer." This statement is not in accordance with the facts, for fats ami lipoids were not present in the latter cases. In Risel's paper, on page 254, we find the following: " Dass diese Substanz nicht fettartig ist. geht aus dem Fehlen einer Schwarzfarbung durch Osmiumsaure hervor. ebensowenig fiirbt sie sich auch rot bei Behandlung mit Sudan III ": and also, " Bei der Untersuchung im polarisierten Lichte lassen die Zellkorper keine Doppelbrechung erkennen (weder im frischen Zustande noeh naeh Fixierung in Formol)." On page 129 of Schlagenhaufer's article we read : " Spezifische Fiirbungen auf Amyloid und Fett sind negativ. Doppelbrechende Substanzen sind nicht nachweisbar." Schultze studied the slides from the cases of Risel and Schlagenhaufer and aoted ci rtaiu resemblances to his case in the staining reactions, but he makes no mention of having examined their material for fats and lipoids. Schultze assumes, nevertheless, that there is a possibility of some lipoid substance in the cells. This assumption on his part is. of course, entirely unwarranted, as we have shown.

Let us turn for a moment to the question of cellular hyperplasia in general. The literature of the past few years contains quite a number of references to this subject, clinical as well as experimental. It is well known, for instance, that certain specific cells may react to the presence of toxins in the blood and give rise to hyperplastic and proliferative changes, such as are found in typhoid fever or tuberculosis. The injection of foreign substances into the circulation in vital staining also produces a reaction of the reticulo-endothelial cells, as was shown by A-ehoff and Kiyono. The feeding of animals with fatty substances or cholesterin, a- was shown by Anitschkow and others, is also followed by definite cellular changes in the same specific group of cells. In fact, the histological picture produced in these experiments is so significant that Aschoff has called the process " pseudo-Gaucher." We have seen that the


April, 1916.] 113


lipoidemia of diabetes may cause cellular changes in the spleen somewhat similar to those described in Gaucher's disease. Notwithstanding a certain similarity in all of these conditions from the biological and histological standpoints, the nature of the process, a- w< 11 as of the substance contained in the cells, differs in each instance and depends on the underlying etiological factors.

Are we then to call every morbid process accompanied by the presence of " large cells " Gaucher's disease ? Drs. Knox. Wahl and Schmeisser would have us do so, provided the cellcontain lipoids, for they say: "Apparently any disea which the spleen, together with any other organ, shows numerous large, pale granular or finely vacuolated cells, giving the characteristic microehemical reactions for lipoids and showing a tendency to be widely distributed, belong to this group, and any attempt to limit the condition to any -ingle organ or any single set of organs is largely arbitrary."

It would be presumptive on our part to suggest the proper classification of the two unusual cases reported by Drs. Knox. Wahl and Schmeisser. That a widespread cellular hyperplasia, associated with degenerative changes in many organs, exists. cannot be denied. We are unable to suggest the etiological factors, toxic or metabolic, which have produced this unique condition, but we do insist that the cases are not to be classified with a well recognized disease, definite in its clinical manifestations and always accompanied by characteristic changes in a specific group of cells.

We have shown the many points of variance in the cases reported by Drs. Knox, Wahl and Schmeisser, when compared with Gaucher's disease. These authors, in attempting to classify their cases as instances of Gaucher's disease, have built up a theory, assuming some " lipoid metamorphosis," a theory which is not substantiated by scientific facts.

ADDENDUM.

Since the above was written, a paper by Drs. Wahl and Richardson has appeared in The Archives of Internal Medicine, Vol. XVII, Feb., 1916, entitled: " A Study of the Lipin Content of a Case of Gaucher's Disease in an Infant." The spleen and liver of Case I


reported by Drs. Knox, Wahl and Schmeisser were employed for this work.

We wish to emphasize that Drs. Wahl and Richardson have misquoted certain fundamental facts, and their diagnosis and conception of Gaucher's disease, being built upon these misquoted premises, are necessarily erroneous.

In the first place, there is no authentic case of Gaucher's disease in the literature in which microehemical tests for lipoids have been definitely positive. On page 239 they say: " Marchand was the first to note the presence of a peculiar homogeneous substance within the cells which is dissolved in alcohol." We wish to say that nothing can be found in Marchand's article concerning the solubility of this substance.

Secondly, we are told on page 240 that both Schultze and Lutz found lipoids in the material from the cases of Gaucher's disease reported by Risel. Schlagenhaufer, and De Jong and Van Heukelom. This statement is not in accordance with the facts, for Schultze did not examine this material for lipoids, but simply called attention to the morphological resemblance of the cells in his case of diabetes to the cells of Gaucher's disease in the cases of Risel and Schlagenhaufer. Furthermore, Lutz, as well, called attention to the histological resemblance of the two conditions, but was unable to demonstrate the presence of lipoids in material from Schlagenhaufer's case. And, finally, neither Schultze nor Lutz made any microehemical tests on the material from the case of Gaucher's disease reported by De Jong and Van Heukelom. The latter authors, moreover, state that no fat, glycogen, amyloid or fibrin could be demonstrated in their case.

The present status of our knowledge of the chemistry of Gaucher's disease is too meager to warrant any lengthy discussion. An analysis of the figures presented by Drs. Wahl and Richardson shows that three different determinations were made on the same material with variations of more than four hundred per cent in their results. It is obvious that wrong conclusions will be arrived at if one averages, for instance, the figures of 2.5 per cent and 11.3 per cent on the same material.

We fail to see the justification of calling the acetone-insoluble portion of the extract " lecithin," without control nitrogen and phosphorus determinations.

We should like to call attention to the fact that Drs. Wahl and Richardson found a high percentage of total extractives in their case. A high percentage of extractives was also found by us in two cases of Gaucher's disease, but it is quite obvious that such findings may occur in the spleen in many pathological conditions. We do not think, therefore, that one is warranted in drawing any further conclusions from the chemical analyses reported by Drs. Wahl and Richardson.


THE ROLE OF CERTAIN FLORENTINES IN THE HISTORY OF ANATOMY, ARTISTIC AND PRACTICAL.*

Bv Edwakd C. Stkeetek, M. D., Bo-ton. Mass.


If among the cities of Italy Florence holds merelj clary rank as a medical center, or terrain, for anatomical studies, during the Renaissance, at any rate, tie- supreme achievements of her artists in the related realm of artistic anatomy more than made amend-. Here she excited a prepotent influence. The swift revolution in art resulting from the scientific studies of perspective and anatomy was largely


Read before The Johns Hopkins Hospital Historical Club. December 13, 1915.


the work of the Florentine "aurifabers" and artists. The

typical Florentine man of temperament was a hai scientist: consequently, if he was also an artist, he spent much of his energy in pei art on its formal side. He was

a student with high and unquenchable appetencies, r use all the geometry thai lie could muster in solving pn of space, and all the anatomy that be could master in solving the problem of form. lie mixed brains with his paints. Color was not hi- concern, but verisimilitude. He would sacrifice, at any juncture, grace and sentiment for \. i


114 [Xo. 302


vitality. His aim was tutor fidelity to fact — in a word, realism. Now. a realist who recognizes in the use of the human form the supreme decorative principle may not necessarily be an adept in anatomy, but he will be an apt pupil. He will con -- • once, that only by approaching mass beneath contour can we come to apprehend the human figure in its great outlines, the scale of parts, the mutually sustained mechanism. Anatomize you must — there is no alternative. To convey reality and a heightened sense of firm substar.ee. dissection is the only way open to the serious man working, in the figurative art-, upon problems of the human form in movement. Roundness and undulation of body surfaces, certain characters of form and texture, it is true, may be conveyed without a deepgoing knowledge of anatomy, but bodily action introduces a whole train of vital plastic complexities into the problem. Now. by the fourteenth century the Florentine figure artist was ready to cope with these difficulties. He simply had to cope with them. Before Giotto, the medieval Italo-Byzantine conventions required no knowledge of anatomy —all was flat. archaic decoration, submissive to outworn formula?: there was no need here of applying myologic detail or mechanistic interpretation. But it is quite another matter when the great figurative arts bend to the task of portraying high emotional experience. To invest tense thought with sensible shape, to stimulate the moral will of the beholder, in fact, to tell a mov- j ing story convincingly and well in a representative form, at once religious and dramatic, required of the plastic artist that he unfailingly possess all that his forerunners had acquired in the knowledge of processes and materials, and that he keep abreast of his time in subjects such as the chemistry of colors. the mathematics of composition, the geometry of perspective, the illusions of chiaroscuro, and, above all, the science of human anatomy.

Provided he is well drilled in these disciplines, the artist has it in his power, in his very hand, to create a world of sensuous delightfulness framed for the spiritual uses of his kind. He may invest religious emotion with esthetic charm. He must, absolutely must, satisfy the imperious demands of secular art in the matter of faultless drawing and modeling of the undraped human form. From Masolino on. negligent drawing of the figure was a crime no maestro would be guilt v of.

1 »well just fur a moment upon certain incentives to the adoption of forms of art. frankly naturalistic, first observable in Florence in the fourteenth century. What social, civic or economic conditions gave to art on the Arno the specific direction of which we speak ? Well, first of all. the new art was bourgeois by birth, and its appeal to the bourgeoisie must be fresh, simple, ' and immediate. It spoke unvarnished truth. It must avoid the region of abstractions and mystical conceptions, and cleave to the ponderable and measurable objects of sight and In the second place, your realist directs his appeal to the honest, honorable intelligence of his fellows. He is close t<> their farthest-darting apprehension of the world of sense. Thus he becomes the protagonist of science, a self-appointed discoverer of truth. He is the first to feel the quickening to life of new faculties, of fresh intellectual interests, in his own


milieu and time. He is a snapper-up of innovations, always on the alert for some novel way of illuminating the old substance of religious feeling. Symonds has something on this head :

As technical skill increased, and as beauty, the proper end of art, became more rightly understood, the painters found that their craft was worthy of being made an end in itself, and that the actualities of life observed around them had claims upon their genius no less weighty than dogmatic mysteries. The subjects they had striven at first to realize with all simplicity now became little better than vehicles for the display of sensuous beauty, science, and mundane pageantry. The human body received separate and independent study, as a thing in itself incomparably beautiful. commanding more powerful emotions by its magic than aught else that sways the soul.

Now, Art and Science during the Renaissance, "like two stars that held their motion in one sphere," kept trailing each other curiously. Particularly was this true in Florence, where the Medici encouraged all the scientific tendencies of Tuscan art. We have seen that the true creative power of the Florentine artist lay almost wholly on the formal side of his art. With the deepening of his scientific interests he applied himself with more fervent industry to the study of the technicalities of his craft. He appropriated inherited forms of expression more rapidly, and created new ones more readily. Always drawing was his chief concern — good realistic narrators and very fewpainters, in the strict sense of the word, came of Florentine blood. It is characteristic of him to make form alone serve as the living vehicle of the artistic idea. Indeed, he fashions his very ideas plastically. He uses his drawing pen, his modeler's stick, his chisel, casting-mould and chasing-tool, like so many instruments of precision: it is a foregone conclusion that he will use the dissecting knife, too, in the same service. The which he does.

I fear our notion of old Florence is somewhat jejune in one

res t. We picture the city as an aggregation of deep gardens,

and courtly precincts, all peopled with exquisites, whose discourse is neo-platonic nebulosity. The princes, the poet-, the humanists are held too high in our evaluation. As a matter of fact, this city is the very paradise of little bank clerks who com]i(ih'. not amorous rondels, but solid works on mercantile arithmetic : sound craftsmen who measure, balance, calculate, explore, just as Dante did. just as Giotto. Dante"s friend, did. too. iii his rude way. In Giotto are found the seeds of all future development of art in Florence — intimations of a vast abortive inquiry into the physical makeup of man. among other things. Among his followers is found still more curious research in this unblest quarter. His intimate (some say his kinsman), his intimate assistant Stefano is called "the ape of Nature." Billi tells us that this Stefano attained such a pitch of realism in drawing the human figure that the barber-surgeons, preparing to do a phlebotomy, would stand before his subjects and study the detail of the branching of the veins of the arms. His period is 1301-1350.

Reorganization of the study of nature was the issue of Giotto's teaching. The artistic training of a fourteenth century Italian " Primitive " was not so haphazard us we are


April, 1916.] 115


led to believe. Glance for a moment at the " Treatise on Painting," by a pupil of a pupil of Giotto — Cennino Cennini is his name, and he lived at the end of the fourteenth century. In Chapter 70, part 3, he says, speaking of the proportions of the human figure : " I will make you acquainted with the proportions of a man ; I omit those of a woman because there is not one of them perfectly proportioned." A rude beginning and a rude treatise, but it is the best since Vitruvius. " Flesh tints," continues Cennini, " are laid on with verde terra and biacca; go twice over the naked parts. When painting the faces of young persons with fresh complexions this tint should

be tempered with the yolk of a town-laid egg You must

prepare three gradations of flesh color Now we will

speak of coloring a dead man ; that is to say, his face, his body, or any naked part that is visible. Use no rosy tints, because dead persons have no color ; add a little light ocher ; mark the outlines with sinopia, mixed with a little black, which is called sanguine. But, I warn you, use no color which you have not

seen When you have to paint the bones of Christians make

them of the flesh color (' incarnazione '). Having to paint a wounded person, you must lay a tint of pure cinnabar wherever the blood is to appear; then glaze this and the drops of blood with fine lake, tempered in the usual manner."

In subsequent chapters he describes methods of taking a lifecast of the face, casts of the entire figure, of a man, a woman, or an animal ; how to model from life, etc. And so through the whole gamut of that earlier practice among the Giottesschi. Parenthetically, I would say that all the great technical treatises on the science of perspective and the science of bodily proportion, except Diirer's, issued from Florence; Ghiberti, Alberti, Leonardo, Michaelangelo, Eosso de Rossi, and you may add the work of Luca Paciolo, " Divina Proportione." Likewise, in the great outpouring of mathematical works, between the years 1472 and 1500, Florence had her full share (213 mathematical treatises were printed in Italy in those 27 years, 100 of these issuing from press between 1480-1490) . The Florentine artists were, many of them, gifted mathematicians ; this is very true of Brunelleschi and his pupils. Vasari says of Verrocchio, " In his youth Andrea gave considerable attention to science, more especially to geometry ; Ucello likewise." Of Piero della Francesca, Vasari says : " He understood all the most important properties of rectilinear bodies better than anyother geometrician." The greatest mathematical compiler in all Italy, Luca Paciolo, received his training from this same Piero della Francesca, as well as later assistance from Leonardo. Da Vinci himself was a mathematical genius of the purest ray. " Let no man read me who is not a mathematician. No human investigation can lay claim to being true science unless it can stand the test of mathematical demonstration. The man who undervalues mathematics nourishes himself upon confusion. The more mathematics, the more science." A recurring phrase in Leonardo's manuscripts is " la somma certezza della matematica " (the apodictic certainty of mathematics). Certainly the science of quantity had gained a great exponent and protestant in Leonardo, for he was one who was ready to place


his transcendent talent as an artist at the disposal of pure science — almost without reserve.

I have digressed so far only to prove again to you that we here are dealing with unabashed scientists of the brush. Leonardo is merely the end-result of uncompromising realism. His passion for research is the outcome of Verroechio's method. His master, Verrocchio, was taught by Baldovinetti, who in turn derived from Domenico Veneziano, who in turn derived from Andrea del C'astagno. The last named, by the way, is described by a contemporary as " amatore della difficulta del arte." There was no. attempt at evasion of the natural difficulties encountered by the representative arts at Florence after the coming of this man Andrea " of the hung." The scientific impulse found firm lodgment in him. It seems as though the desire were stronger in him than in his fellows to rid himself at once of elusive and symbolic half-statement and gain a share ever greater in the divine truth of form. He is not one to be easily put off with the elementary rules of bodily proportion. He is bitten with corporum intus curiositas. He will take all the hazards of his art, will descend to the charnel-house under the New St. Mary's Hospital and make assay of the " Science of the Sepulchre." In fact, he painted a figure of Saint Andrea " beneath the charnel-house in the cemetery of Santa Maria Nuova," adds Vasari; and he gave such solidity of form to his patron saint that the superintendent of the hospital had him decorate a part of the principal chapel of the church above (1450-52). Domenico Veneziano and Baldovenetti, master and pupil, both first-rate exponents of the new art, were at work there — but I anticipate. Leonardo says that Andrea drew his muscles so boldly that his figures looked like bags of nuts. This was true of his drawings only, not of his painted subjects. Exaggerated myologic detail is constantly met with among the sketches of the early Florentine painters. So it is among their pen and chalk drawings that we find strongest evidence of a taste for anatomy among these masters. Certainly Castagno had such a taste to a degree ! He did not rest content with his knowledge of the superficies of structure. The unclouded drawing of the human figure in action required that he plunge into the complexities of his subject. The muscles, situated immediately under the skin, interest him primarily, but the joints and the skeletal mechanism under the operation of the muscle-groups is a matter of profounder moment to him. Certain aspects of the artist's problem of form are speeding on the way to resolution, under guidance of this man. It looks as though Castagno is under some grim bond to naturalism, whereby he engages to trace no outline that does not express his personal knowledge. Whatsoever his minerver brush relates, he has experienced. The muscles which lie draws so boldly are solidly attached to actual underlying skeletal part-, and are capable of putting solid members into action. Because he cannot render tip-toe movement and the -rare of life, he fails to please Mr. Etuskin. Not that that, matters in the least! The thing to note is Andrea's attempt at an utter fidelity to fact, his portraiture of the body as well as the face, his forthright draughtmanship these he got through anatomies.


116 [No. 302


The manner in which he arrived at a point of serene power. and vastly influenced the Florentine school, is precisely the manner of Leonardo. " Study the - ; then follow

the practice." Better teaching was at hand, perhaps, in Umbria; yet Tuscany proceeded to follow Castagno. He greatly influenced Pollaiuolo and Botticelli, and to a lesser degree Domenico Veneziano who. I repeat, taught Baldovinetti, who taught Yerroechio. who taught Leonardo. Thus the scientific mantle of Castagno passed down in a line of direct descent to Leonardo. These men no longer studied intensively the nudes of Masaccio in those epochal frescoes flanking the Brancacei Chapel at the Carmine — I mean " Peter Baptizing," or "The Expulsion from Eden"; nor did they travel to Castiglione d'Olona. to view Masolino's " Baptism of Christ." Tin y still regarded these pictures as sheer miracles of unimagined power of drawing — precious testimony from the founders of an art that henceforth was to lie grounded not upon intuition but upon perception and knowledge.

I pass to Paolo Fcello. In Paolo Ucello we have an awful example of an artist whose zeal for the house of science hath eaten him up." He had an over-freight of scientific interest. Of adventurous mental temperament, he went squarely to the attack on all the laws governing perspective. As he died in 1475, three years before the first book on practical arithmetic was printed, we may conceive of his difficulties. He turned to Giovanni Manetti for help. "With this philosopher." -ays Vasai i. " Paolo conferred very frequently, and held continual discourse concerning" — what!' The formulae of art? No, " the problems of Euclid." Donatello, pleading possibly in behalf of the neglected wife of the poor science-smitten man, once expostulated with him : " Ah. Paolo, with this perspective of thine, thou art leaving the substance for the shadow." For his own private worship Paolo painted five panels in his bedroom representing his five heroes — Giotto, in painting: Brunelleschi. in architecture: Donatello, .for sculpture; himself, for perspective: Giovanni Manetti, for mathematics. TJcello is truly to be counted a hero — his self-sacrificing labors enabled later painters to proceed from a basis of exact science to the far nobler pursuit of ideal beauty. Those scores of unknown industrial craftsmen like him, in Florence, everywhere eager to impoverish themselves and render up their lives for science, were smoothing the way for our Leonardo.

Much could be said about Donatello. To him. as to any worker " in the round," bred to the processes of sculpture and metal-shaping, bone and brawn construction was the paramount interest. He modeled the body as he modeled thi in a spirit of uncompromising portraiture — to embellish is to falsify. He expresses his hatred of simulacra, in every touch of chaser and chisel. To prove that Donatello assisted at anatomies, at least from the spectators' bench, we have the sole evidence of that Paduan bronze tablet representing " The Anatomy of the Miser's Heart " in the series of Miracles of St. .Anthony. You will recall that the forceful rendering of the human form, the muscular litheness and movement of Donatello's work, were the especial admiration of Michaelangelo, and helped mightily to form him. Donatello's bronze " David "


at the Bargello is the first nude statue of the Penaissance. (It is interesting to note that the first mention of practical schoolanatomies at the Florentine University. coincides with Donatello's birth-date.)

The " Statuta universitatis et studii Florentini," under the date 13ST, deal with dissection of bodies at the school, under six explicit beads, specifying the duties of the Eector and Beadle ; the delivery of the bodies by the officers of the Podesta ; the crying of the anatomy through the school precincts; the choosing of a responsible student whose quarters are large enough to admit the chosen advanced students who pay and the few readers and the Eector who do not pay ; the careful accounting of the costs — the fees to the porters and to those who say mass over the body and bury it, as well as the cost of the good cup of wine given to brace each quasi-valiant heart before and after the ordeal. " In case God grants the Studio to grow, then let the Podesta see to the delivery of not two but three bodies of alien criminals each year ; whatever their foul felonies be, let them be hanged (not burned as the wont is with witches, nor beheaded) and delivered the same day, for corruption comes on apace."

Now, an artist rarely saw such a school-anatomy in Florence — the audience was strictly limited in ways that would naturally exclude him, unless he was a friend of the Rector. However, there were three ways open to him to appease his " corporum intus curiositas " : (1) To wait for a public dissection (which occurred at unconscionably long intervals) ; (2) to go to private dissections performed by his doctor friends : make up little post-mortem parties of his own. Almost invariably would he choose the third method. He went or sent to the gibbet, or to the newly laid grave, if a poor man; if a man of repute and in good odor with the brethren, he could work in the dead-house of the hospitals. I dare say the large majority of Leonardo's dissections were done in the hospitals of Florence, Milan and Eome. Michaelangelo did his anatomies in lordly style: — hired a house in the St. Agata quarter and got Eealdus Columbus to ship him subjects. Michaelangelo's pupil and chief assistant in the Medicean tombs, Montorsoli (who probably did the figures of Cosinio and Damian flanking the monument), worked even more intimately with the anatomists of the schools (Genoa). There is rivalry, almost bitter at times, between the anatomizing artists and the practical anatomists. Hear what Condivi has to say here (Condivi is the pupil and biographer of Michaelangelo) : " From a child Michaelangelo was a hard worker, and to the gifts of nature added study, not using the labor and industry of others, but de-siring to learn from nature herself: he set her up before him as the true example. There is no animal whose anatomy he did not desire to study, much more, that of man, so that those who have spent all their lives in that science, and who make a profession of it, hardly know so much of it as he. I speak of such knowledge as is necessary to the arts of painting and sculpture, not of other minutiae that anatomists observe." So much from the artistic camp — now the other side. Yesalius. on page It J of the work on China root, says that he anatomized a Florentine patrician, Prosper Martellus; and then a few


April, 1916.] 117


pages later comes this very curious outburst: "As for those painters aud sculptors who flocked around me at my dissections, I never allowed myself to get worked up about them to the point of feeling that I was less favored than these men. for all their superior airs."

Now to return to the age of Donatello. There is a largeness of intelligence, a quickness of sympathy, a god-like comprehension in men of the stamp of Ghiberti, Brunellesehi, Donatello, della Eobbia. They were many-sided, like i (rcagna, possessed of eight souls. The task of the revival called for men of amplest powers. Florence contributed men distinguished for their peculiarly versatile genius and the vast variety of their acquirements. The qualities of daring, variety, and brisk vigor are found (as in one of the pupils of TJcello and Donatello, Antonio Pollainolo) sometimes disassociated from breadth of vision, elevation of feeling, and human sympathy. However, as Pollaiuolo was " the first Florentine master to study human anatomy systematically in the modern sense," he will serve to bring our loose account to the tightening point. Born in 1 129, the grandson of a poulterer, apprenticed to U cello, then to Donatello. for whose cruel naturalism he had a keen taste, we see him moving along paths of detailed, severely accurate, technique, in niello engraving and in the casting of little bronzes, lie is painter, sculptoT and jeweler, too. Pretty soon we see him moving along paths more elaborate, of purely objec!• ntific inquiry, in quest of the intimacies of form; and, with a goldsmith's regard for detail and fineness of handling, he begins to anatomize. " He dissected many human bodies," -a\ s Vasari, " to study the anatomy, and was the first to investigate the action of the muscles in this manner, that he might afterwards give them their due place and effect in his works." Buskin has something injurious to say anent this; I quote: " The virtual beginner of artistic anatomy in Italy was a man called the ' Poulterer,' from his grandfather's trade; Pollajuolo. a man of immense power, but on whom the curse of the Italian

mind in this age was set at the deepest Pollajuolo, Cas tagno, Mantegna, Leonardo da Vinci, Michaelangelo, polluted their work with the science x>{ the sepulchre and degraded it

with presumptuous and paltry technical skill Foreshorten

your Christ, and paint him. if you can, half putrefied — that is the scientific art of the Renaissance." This occurs in a note to " Ariadne Florentina." It is a note that does not require any answer. Some day let its learn to shun the frumious Ruskirj 8 we would the bandersnatcb : when he is raw and intern] and turbid and fallacious, at least then, let us not go down in craven submission to him. At any rate, Pollaiuolo got at the mainsprings of bodily movement; he recorded his progre anatomy in a model series of drawings, full of " bizarre energy," which were eagerly passed around among the artists of Ins day. These drawings reveal him, as Berenson declares (in his "Drawings of the Florentine Painters"), as "one of the greatest masters of movement that there ever has been : one of the ablest interpreters of the human body as a vehicle of lifecommunicating energy and exulting power." His influence was as great as it was bracing. He even influenced Germany through Diirer. He affected all schools, all sorts and condi


tions of artists, Botticelli, Signorelli, Piero di Cosimo, possibly Verrocchio, to whom I now turn.

Like "the Poulterer." Andrea del Verrocchio was a pupil of Donatello. He was a goldsmith and general art entrepreneur, of highest renown as a teacher of painters. As a sculptor he was the best between Donatello and Michaelangelo. His great bronze equestrian statue of Colleone will mark him as " ganz apart." Like a colossus he bestrode the crews of bronze-casters in Florence, who were turning otrl objects for household decoration. He was the very man in inspire the young Leonard^. a supreme technicist, whose work was finished ad unguem : a scholar, whose devotion to the mathematical disciplines I have already dwelt upon. Vasari says that he possessed two drawings by Verrocchio "of two horses with various measurements, and the proportions according to which they are to be increased from a smaller to a larger size — all of which are correct and free from error." In the bronzes of Verrocchio, and in his panels and drawings, searching anatomic features can be noted : and if we can entirely trust Mathias Duval (who after all is an authority in the matter), there also exist certain ecorches or flayed figures, purely anatomical in purport, which were used in Verrocchio's " Bottega " and were fashioned by him for the use of his pupils.

There is no doubt as to anatomy being a part of the established curriculum in the Florentine " Bottega " from now on. Men from remote schools came to steep themselves again in Florentine science. Piero della Francesca, and his heavenly appointed spiritual heir. Signorelli, came from Umbria wanting to draw "the nude, the whole nude and nothing but the nude."

There are increasing evidences of an easy intimacy between artists and physicians. Both Piero della Francesca and Ridolfo Ghirlandaio painted a " donna gravida," and we have an occasional scene in a medical ward (Domenico di Bartolo at Sienna), an interior of a bathing establishment (Franciabiagio), a sepulchral monument (Verrocchio Tornabuoni). Bernado Eossellino did a fine portrait bust of the physician Giovanni da San Miniato, signed, and dated 1456 (now in South Kensington). Office consultations are found, in miniatures in manuscripts, and also the well-known low relief by Andrea Pisano on the campanile of Santa Maria del Fiore. It is called Medicina and is second in the series of mechanical arts. The scene is a consulting room : the surgeon is seated to the right, in a cathedra, urine-casting; next him, his assistant holding a mandragora plant in his left hand and rudely pointing with his right thumb to a gra\ id young woman standing at his right. Near the door an' two women carrying urinal baskets. Of course, out of flatter} to Cosimo de Medii i, Florence, from early days, was flooded with representations of the healing saints Cosimo and Damian, in fresco, oil and marble. Hygeia with her serpent is one of the archaic details of the Mandoria portal of the Duomo.

Everywhere throughout the city you will meet with hints of primitive, as well as present, correspondencies between the plastic arts and medicine. The painter Cosimo Eoselli, founder


118 [No. 302


of a school marked by enthusiasm for studies anatomical, should never have become- an artist at all. but a physician; for it was his family that had kept the immemorial " Lily Pharmacy hard by New St. Mary's Hospital. How these easy intimacies arose between physic and the figurative arts would be hard to explain in any other way than the one I shall attempt to use, simple and obvious as it is ! It was by the hazard of association in one and the same guild that the anatomists and artists of Florence made their magnetic contacts. The painters formed a sub-membrum of the " Guild of Physicians and Apothecaries." They all belonged — Giotto. Masaccio, Castagno, Ucello. Verroechio — to the membrum pictorum of the Guild of Physicians and Apothecaries. Masaccio joined the guild first as an apothecary (in 1451. at the age of 19) : then he matriculated under the membrum pictorum (in 1423). You see. the apothecaries included color handlers, the " spetiarii. qui emunt. vendunt et operant colores et alia ad membrum pictorum spectantia memoratum " (apothecaries who buy. sell and deal in colors and other materials needed by the an sts). Bv virtue of tliis affiliation the artists and doctors were thrown together in all the multiform guild functions ; they sat b in the guild Council : walked together under the same banner in pageants. It cannot, therefore, be a matter of surprise to learn that Giotto was the friend of Dino del Garbo and Torrigiana. or that Luca della Robbia (alnn»t -.'on years later) was


a friend of the founder of pathological anatomy, Benivieni, although the latter was almost half a century (-49 years) younger than Luca. (Luca. you will recall, executed the great arms of the Guild of Physicians, a polychrome terra cotta medallion in Or San Michele.)

The opening chapter of artistic anatomic studies at Florence, ending with an account of Verroechio, furnishes us with only a meagre amount of good provable and usable material as compared with the account of Leonardo or Michaelangelo and their followers. With Leonardo, of course, would he grouped Lorenzo di Credi, de Predis, Boltraffio, Sodoma, and Melzi who was custodian of his scientific manuscripts. Michaelangelo's group would be large and difficult to handle, but we would single out Montorsoli and Sebastian del Piombo. There is yet another group to be studied, i. e., Cosimo Roselli. Piero di Cosimo, his pupil, Andrea del Sarto, his pupil in turn, and the entire school of del Sarto (which was under the influence of Michaelangelo), Pontormo, Franciabiago. Rosso Fiorentino.

And to that immortal ruffian, Benvenuto Cellini, who in his diary sums up the tale by remarking that the " essential thing in art is thoroughly to understand how to paint the made," to him separate space might be given, as to one. somewhat isolated from the moral order, but within the pale of an Art that was still in the midst of her traffic-kings with Science.


PROCEEDINGS OF SOCIETIES.


THE JOHNS HOPKINS HOSPITAL MEDICAL SOCIETY. DECEMBER 6. 1915.

1. Report of Cases: Chloroma and Acute Myeloid Leukemia. Dr.

John T. King, Jb. To appear in full in a later number of the Bulletin.

2. Chemical Studies in Bichloride Poisoning. Dr. D. S. Lewis

and Dr. T. M. Riveks. To appear in full in a later issue of the Bulletin.

3. Experiences with the Epidemic of Typhus Fever in Serbia.

De. R. P. Strong. To appear in full in a later issue of the Bulletin.

DECEMBER 20. t915. 1. Spontaneous and Experimental Leukemia of the Fowl.* (Abstract.) Dr. H. C. Schmeisseb.

In this paper was presented the first unit of an extensive study of a transmissible leukemia of the fowl.

Careful examination of a case of spontaneous leukemia of the fowl showed this to confirm in every detail the findings of Butterfield, Mohler, Warthin, Kon, Soshestrenski, Ellermann and Bang. Hirschfeld and Jacoby, and Burckhardt. The blood and anatomical findings closely simulated those of human myeloid leukemia.

By intravenous and intraperitoneal injection of an organic emulsion from this bird the disease was produced in 13 previously healthy fowls, and carried into the fifth generation, giving a blood


Published in detail in the Journal of Experimental Ji1915, XXII, 820-838, and fully illustrated in The Johns Hopkins Hospital Reports, 1916, XVII.


and anatomical picture identical with that of the spontaneous case, and a clinical and anatomical complex which is analogous to that in the human disease. This is in confirmation of the work of Ellermann and Bang, who first successfully transmitted the leukemia of the fowl.

DISCUSSION.

Dr. W. A. Baetjer: I have been much interested in this same subject from the standpoint of human leukemia, where of course no one has been able to progress anything like so far as Dr. Schmeisser has been able to go in the study of fowls. It seems to me that Dr. Schmeisser has opened up the possibility of solving the problems of this disease, which may be of great aid in studying the leukemia of man. It comes at a most interesting time with relation to human leukemia in the sense that there have been, for the past two years particularly, an increasing number of reports which have seemed to suggest the possibility that at least some cases of human leukemia are of an infectious nature. I presume from what Dr. Schmeisser has said that he regards this disease of fowls as being infectious rather than neoplastic. Most of the evidence in the human cases, it seems to us at least, is distinctly in favor of the same conclusion. In that sense it throws a great deal of light on human leukemia and comes at a time when most of those who are working have held back from stating whether they think it is an infection or not. In the last two years, at least three cases have been reported in which an organism has been isolated from the spleen or glands of patients. But in no case have investigators been able to reproduce the disease with these organisms, nor has it been possible in any way to reproduce the typical disease, as Dr. Schmeisser and others have done with the fowl. It seems to me, then, that this offers a very definite advance from the standpoint of human leukemia, in that


April, 1016.] 119


you can get in the fowl a picture that is clinically and pathologically similar to that of human leukemia, but which differs from it, in that it has been transmitted from animal to animal by means of tissue innoculations. Xo one can doubt, I think, that it corresponds in most ways to human leukemia. That it is the same disease, I think is still somewhat open to doubt, because human leukemia presents at the present time a very mixed picture. There are cases which correspond with the cases Dr. Schmeisser has reported in the fowl. Others do not, from the standpoint of blood examination, from the clinical course or from pathological findings. Dr. Schmeisser has brought out that you can have an aleukemic stage coming on in .the same series of animals. In aleukemia the picture is interesting at the present time in connection with the efforts on the part of many to put such diseases as Hodgkin's disease and certain other obscure glandular enlargements into the class of leukemia.

The most interesting feature of the paper is the evidence it offers that a disease which simulates certain types of leukemia in the human being occurs in the fowl, and that in the fowl the disease is definitely infectious. This point gives us far more to go on than we have ever had in dealing with human leukemia in regard to its etiology.

I should like to ask Dr. Schmeisser with regard to the pathology of leukemia, whether he feels that it is a very distinct and specific type of change; i. e., whether the pathology of leukemia in general, acute and chronic, is specific. I should like to ask also whether, from what he has seen in his slides, he could offer any conclusive evidence on a point which has caused a good deal of confusion in human pathology, namely, whether the enlargement of the spleen in human leukemia is the result of an infiltration with the same cells which circulate in the blood, or whether it is due to what is termed a myeloid metaplasia?

Dr. S. R. Miller: I should like to know Dr. Schmeisser's basis for calling structures blood platelets which are larger in size than red blood cells and which contain protoplasm and dividing nuclei.

Dr. Sciimhsslr: In answer to Dr. Baetjer's questions: (It Typical cases of both lymphoid and myeloid leukemia produce pathological pictures which are specific. (2) Whether the presence of the myeloid cells in organs and tissues outside of the bone marrow in leukemia is due to an infiltration and proliferation of the same or due to their origin in loco by a reversion of the vascular endothelium to its embryonic hematopoietic function and then a proliferation, I am not at the present time able to offer any conclusive evidence.

In answer to Dr. Miller's question: The structures referred to were called blood platelets simply as a means of classification and not because they are known to be analogous to the human blood platelet.

2. The Quantitative Study of Analgesia after Opium Alkaloids.

Drs D. I. Macht, X. B. Herman and C. S. Levy. A preliminary communication on the subject was published in the proceedings of the National Acadi my o] Sciences for December, 1915; and the complete paper appears in the Journal of Pharmacology and Experimental Therapeutics for January, 1916.

3. The Action of Papaverin on the Ureter. (Abstract.) Drs. D. I

Macht and J. T. Geraghty. Hi; Macht: In connection with the preceding paper I wish to report a few experiments performed by me within the last few weeks, in order that the same may be recorded in the minutes of this meeting. I have already called attention to the general analgesia produced to some extent by injections of papavfrin This rare alkaloid of opium possesses a number of very interesting properties. I have already shown in the Journal of Pharmacology and Experimental Therapeutics for September, 1915, its action upon the respiratory center, and have also called attention to its


stimulating effect upon the heart and to its interesting action on the coronary circulation in the Journal of thi American Medical Association. Hay 1, 1915.

Perhaps the most interesting property of this drug is the one to which attention has been called by Pal of Vienna and his coworkers Popper and Franckel. These authors point out that papaverin lowers the tonus of all organs composed of smooth muscle. I have been able to confirm their results by personal observations on isolated arteries, uterine strips and intestinal muscle.

Very recently I have had the opportunity of studying, together with Dr. Geraghty, a patient suffering from ureteral calculus, and the idea occurred to us to introduce a solution of papaverin through the catheter directly into the ureter, just below the stone. Knowing from my experiments that papaverin is not toxic, there was no objection to this procedure. Five cubic centimeters of a 2-per-cent solution of papaverin hydrochloride were therefore introduced. On the same afternoon the patient experienced slight colicky pains, and on subsequent examination the stone was found to have descended a considerable distance. After a second treatment with papaverin the patient spontaneously passed the calculus. Dr. Geraghty, while making the injection, could observe with his eye through the cystoscope that the ureteral orifice dilated after the introduction of the drug.

Following this experience I have performed a number of experiments on the isolated ureter of a pig. I was surprised to find that the ring of pig's ureter suspended in oxygenated Locke solution began to contract rhythmically not unlike a frog's heart. These contractions continued spontaneously for several hours at a time. On addition of 5 mg. of papaverin, and even less, there was an immediate relaxation of the ring and a discontinuance of the contractions. Exactly the same observations were made on the human ureter obtained from an operation. So far as I know, these observations have never been made before. It may be further stated that papaverin not only exercises a general analgesic effect, but also acts as a local anesthetic. Attention has been directed to this fact by Pal, and it has been confirmed by me from observations on myself and some of my colleagues.

In this connection I may as well add that even more interesting than the action of papaverin upon the ureter has been found by me to be the effect of epinephrin. The smallest amounts of this drug, I was surprised to find, increased the frequency of the ureteral contractions and markedly increased the tonus of the ureter. Indeed, even a quiescent ureter, that is, a ring which is almost dead and is not contracting, can be revived by the addition of a little epinephrin. A general study of the pharmacology of the ureter is now being carried on.

DISCUSSIOX. Dr. Geraghty: Theoretically, a stone which is sufficiently small to leave the pelvis of the kidney and pass into the ureter should be spontaneously expelled, because the narrowest part of the ureter is its junction with the pelvis. It has been estimated, however, that only about 75 per cent of the stones which enter the ureter are spontaneously expelled. Many of those which become impacted can be removed by manipulative procedures. About 15 or 25 per cent of the stones become arrested in the vesical portion of the ureter and practically all of these stones can be readily removed by intravesical procedures. For stones that become impacted above this point we have heretofore relied upon the passage of an ureteral catheter, with the idea of changing the position of the stone, and possibly its axis, in order to allow its shortest diameter to lie in the ureteral canal. Frequently stones are passed which have been manipulated by the ureteral catheter, even those that have been present for several years. The use of the thermocatheter seems to promise more than the use of the simple catheter, because by means of the heating we not only can


120 [No. 302


manipulate the stone, but also can secure a certain degree of dilatation.

A few months ago I had a most striking example. The patient had a stone impacted at a point 12 cm. from the vesical orifice. A special thermo-catheter was passed as far as the stone, heated to about 115° and then slowly withdrawn. When the catheter was removed from the ureter the stone was found in the vesical portion, having followed the catheter directly down.

Papaverin seems to promise considerable help, because it produces marked relaxation, but some technique will have to be devised by which we can limit the action of the papaverin to the ureter below the stone, or else secure dilatation without paralyzing completely the ureter wall. In order to expel the stone it is necessary to preserve the propelling properties of the ureteral wall itself.

In the case reported by Dr. Macht the stone was very promptly expelled following the injection, without any colic.

JOHNS HOPKINS HOSPITAL HISTORICAL CLUB. DECEMBER 13. 1915. 1, The Role of Certain Florentines in the History of Anatomy, Artistic and Practical. Dr. Edward C. Stbeeter. This paper appears in full in the current issue of the Bulletin.

Dr. H. M. Hukd: Just twenty -five years ago The Johns Hopkins Hospital Historical Club was organized. I suppose I am the only one here to-night who was present at its first meeting, at which Dr. Welch presided and Dr. Osier gave the first paper. Dr. Osier was very much chagrined at the form of the printed programme.


In addition to reading his paper, he had intended to have an exhibition of old books, and had numbered his talks 1 and 2. One of the books he had planned to show was John Morgan's Treatise on Education, which he had numbered 1. Unfortunately, through an error of the printers, the programme read: " I John Morgan. By William Osier." Dr. Welch also gave a talk at that meeting, I think on books. There were not a great many present, and I am afraid we all felt the society was not destined to be very long lived. It was supposed that we should soon see all the old books we could obtain, and that then interest would naturally die out.

It is astonishing, however, how interest in the meetings of the club has been kept up and how much good work has been done. We have had papers of course not displaying any great amount of scholarship, but these have been of a character to indicate where sources of knowledge could be traced. The several papers which Dr. Billings gave us were always extremely valuable. He at one time delivered here, over a period of three or four years, a series of lectures on the history of medicine and used to appear at the meetings and discuss the questions presented. A great many of Dr. Osier's brilliant essays were read before this Historical Club, and also many of Dr. Kelly's. We have had unusual kindness shown us by scholars throughout the country, indeed I may say throughout the world. We have had papers from men whose writings and whose presence have been a great inspiration to us.

We have now begun the second quarter century of our existence. As I have said, I was present at the first meeting, and I am hopeful that I shall be present at the celebration of the second quarter century. If I cannot be, it is my wish that the society will still be in active operation.


NOTES ON NEW BOOKS.

Vol. XXVII.— No. 303.

BALTIMORE, MAY, 19 16.

CONTENTS

Nitrogen Metabolism During Pregnancy. (Illustrated.) By Karl M. Wilson, M. D 121


Functional Significance of Mitochondria in Toxic Thyroid Adenomata. Preliminary Report. {Illustrated.)

By Emil Goetsch, M. D 129

Renal Diabetes.

By D. Sclatee Lewis, M. D., and Herman 0. Mosenthal, M. D 133

Bilateral and Complete Trigeminal Paralysis Without Involvement of Other Cranial Nerves. (Illustrated.) By Charles Metcalfe Byrnes, M. D 138

Digestion: An Historical Survey.

By Raymond J. Cary, M. D 142


Proceedings of Societies.

The Johns Hopkins Hospital Medical Society 152

Seminal-Vesiculectomy in Arthritis [Dr. H. H. Yocng] ; — Tuberculosis of the Tonsils [Dr. S. J. Crowe] ;— Methods and Results of Direct Transfusion [Dr. R. D. McClure and Dr. George Dunn] ;— The Clinical Significance of the Wassermann Reaction [Dr. Arthur F. Coca].

The Johns Hopkins Hospital Historical Club 155

Jonathan Letterman and His Work in Organizing the Medical Department of the Army of the Potomac [Dr. Joseph T. Smith] ;— William Hunter, Anatomist, Physician, Obstetrician [Dr. C. YV. G. Rohrer].

The Laennec 155

Memorial Meeting to Dr. E. L. Trudeau. Notes on New Books 155


mOGEN METABOLISM DURING PREGNANCY.

ilsox, M. D.


By Kakl M. W (From the Obstetrical Clinic

During the past 25 years a number of observers have made contributions to our knowledge of some of the problems of metabolism arising in the course of a normal pregnancy, labor and the puerperium. Unfortunately, practically all of the observations upon women have been made on patients studied only for the last few weeks of the pregnancy, and in some cases only for the last few days, whereas the study of the various phases of metabolism in the early months of pregnancy has been almost wholly neglected.

Various observers have approached the subject through the study of the metabolic processes in pregnant animals. On account of the shorter duration of the pregnancy, together with the possibility of keeping the animal on a fixed diet throughout the entire period of the pregnancy, such studies are naturally more satisfactory than is the case when pregnant women are studied.

Hageman, Jageroos, Ver Eecke and Bar have made extensive studies on the nitrogen metabolism of pregnant animals throughout the entire duration of their pregnancies. Ver Eecke used pregnant rabbits ; Hageman and Jageroos carried out their observations on pregnant dogs (the duration of the pregnancy being 60 days), whereas Bar used both rabbits and dogs, the latter proving to be much more satisfactory for purposes of study.


Johns Hopkins Hospital.)

Hageman found that in the dog the pregnancy could be divided into two distinct metabolic periods, corresponding in time to the two halves of the pregnancy. In the first, the animal was found to be in a state of negative nitrogen balance, storage of nitrogen beginning with the middle of pregnancy and continuing up to the time of labor, this capacity for storage becoming more marked as the pregnancy advanced, according as the needs of the developing ova became greater.

Jageroos obtained similar results in his experiments but concluded, after calculating the nitrogen content of the embryos and their appendages, that, taking the time of the pregnancy as a whole, it is to be regarded as a period of sacrifice on the part of the mother.

"\ er Eecke, after extensive studies on pregnant rabbits, also concludes that the period of pregnancy is to be regarded as a period of sacrifice by the mother, or, as he expresses it. " a sacrifice on the part of the individual for the sake of the species."

Bar, whose experiments were carried out under more nearly ideal conditions than those of the above-mentioned observers, also recognized two distinct periods in the nutrition of the pregnant animal, corresponding in time to the two halves of the pregnancy ; but his findings differ in certain respects from those of Hageman and Jageroos. In common with them, he


122 [No. 303


found the second half of the pregnancy to be characterized by a marked and progressive storage of nitrogen up to the time of labor. In the first half of the pregnancy, however, he distinguished two periods ; first, a period extending from the beginning of the pregnancy to the second or third week, during which there was a storage of nitrogen, this being followed by what he describes as the period of " saturation." in which the retention of nitrogen is less marked or entirely absent, the animal being either in a state of nitrogen equilibrium or even showing a negative balance. This period continued up to the middle of pregnancy and was believed to be due to an increase in the disassimilation processes. In observations made on two pregnant rabbits he found a storage of nitrogen throughout the whole period of pregnancy. Others were studied, but the results were unsatisfactory.

From the whole series of observations made on pregnant animals, he concluded that in the normal, healthy animal, living under proper hygienic and dietary conditions, and going through a normal pregnancy, the period of gestation is not to be regarded as a period of sacrifice on the part of the mother, but may actually be a period of gain, with an increase in her nitrogen capital.

Murlin, studying pregnant dogs, found a loss of nitrogen throughout the first four weeks of the pregnancy, followed by a marked storage in the second half. One of his animals showed a net gain of 8.69 gm. of nitrogen, while another showed a net loss of 55.6 gm. of nitrogen from the mother's body.

All the observations made on the nitrogen metabolism of pregnant women go to show that, in the second half of the pregnancy, we have a period corresponding to the same period observed in pregnant animals, characterized by the marked ability of the organism to store nitrogen. Beginning with Zacharjewsky, this subject has been more or less extensively studied by Schrader, Sillevis. Slemons, Hahl and Bar. Slemons found this capacity for storage to be more marked in multipara?, whereas Hahl and Bar found it to be greater in primiparous women.

Up to the present time, no one ha? made any extensive observations on the nitrogen exchange in the early months of a human pregnancy, and it has been more or less assumed that, inasmuch as the needs of the growing ovum are infinitesimal at this stage, there is either no change at all in the general nitrogen metabolism, or that we have a period of loss, as - i in the first half of pregnancy in dogs, and development of the ovum at the expense of the maternal organism.

The earliest extensive observations are those reported by HofTstrbm, who in a single patient made a very careful study of the nitrogen, sulphur, phosphorus, calcium and magnesium exchange during the last 24 weeks of pregnancy. In this case, personal weekly analyses of the foodstuffs used, and of the urine and feces, were also made.

In regard to the nitrogen metabolism, he found that nitrogen storage occurred throughout the whole period of study. This averaged 1.84 gm. per day, so that the total retention amounted to 310 gm. Of this nitrogen retained, he estimates that 101 gm. were devoted to the development of the ovum, while the balance


of 209 gm. was added to the maternal organism. Of these 209 gm.. he estimates that 51 gm. were utilized in the growth and development of the breasts leaving a balance of 158 gm. of " Restmaterial/' forming a maternal reserve. He is unable, however, to state the exact form which this reserve takes or the manner in which it is utilized by the organism.

From the study of this patient he draws the following general conclusion: "Xormal pregnancy in a healthy maternal organism, living under normal exterior conditions, produces a marked retention of nutritive materials, which suffices for the development of the product of conception and its adnexa, for the modification of the generative organs, and the formation of a reserve fund which will be utilized during labor and the puerperium. Xormal pregnancy does not then constitute for the mother a period of loss, nor yet is it for her a period of gain."

During the last two years, we have had the opportunity to make observations on the nitrogen metabolism in three normal pregnancies : in one patient for a period of four weeks, from the tenth to the fourteenth weeks of the pregnancy. The other two patients were studied for the last 133 and 101 days of their respective pregnancies and also for a short time in the puerperal period.

Method of Study.

The methods adopted in the study of these patients are quite similar to those used by Slemons in the cases studied by him in this clinic and reported in 1904. A fairly liberal diet was allowed, both in quantity and character of foodstuffs used. This was particularly true in the first woman, who was a private patient of Dr. Williams, and she was allowed a very wide selection in the choice of her diet. In all instances the patients were allowed sufficient food to satisfy the appetite, but were not compelled to eat all the food allotted for a given meal when they did not desire it. Each article of food was especially prepared for the individual patient, and was carefully weighed or measured before being given to her. The residue, if any. was collected and again weighed or measured. The nitrogen content of the food ingested was computed partly from the tables of Atwater and Bryant and partly from personal analyses. At all times the patients were kept under as normal external conditions as was possible, particularly in regard to exercise. and were not allowed to lead too sedentary a life.

The urine was collected for 54-hour periods, and carefully preserved : of these specimens daily analyses were made. From these daily analyses the daily average nitrogen content of the urine, for periods of a week at a time was estimated. Daily determinations of the ammonia nitrogen were made on all specimens and the amino-acid nitrogen was also estimated for variable periods. The total nitrogen was determined by the Kjeldahl method, the ammonia by the method of Folin and the ami no-nitrogen by the Van Slyke method. All determinations were made in duplicate. The feces were preserved and analyzed weekly, and from the results obtained, the average daily nitrogen content was calculated. The patients were weighed at frequent intervals.


May, 1916.] 123


Study of Cases.

Case I. — M. V. W., white, age 28 years. Admitted May 30, 1914.

The past history was unimportant.

The present pregnancy is her first, and has been uneventful, except for the fact that the first specimen of urine examined showed the presence of a faint trace of albumin (not in sufficient quantity to give a reading in the Esbach tube). This proved to be a transient phenomenon. Her last menstrual period began on March 7, 1915, and was perfectly normal, lasting for five days. The patient has had no subjective symptoms of any kind since the pregnancy began.

TABLE I, CASE I. Daily Average Nitrogen Exchange.




X. Output.




&





5


| z'j: I"


J


£



|


Weekly Stora


H


O


.^_= £"


,


13.04


8.10 0.70


8.80


+4.24


29.68


29.68


2499


132%


II ....


10.78


8.06 0.69


8.75


+2.03


14.21


43.89


1973



Ill ...


10.73


- 22 0.73


8.95


-1.78


12.46


56.35


2 B]


134%


IV ...


7.88


6.73 0.63


7.36


+0.52


3.64


59.99


1705


130*4


The physical examination showed the patient to be a well developed, well nourished woman, in whom no physical abnormalities were detected. The blood pressure was 120 mm. The weight at the beginning of observations was 128% pounds.

Studies in metabolism were begun on June 2, 1915, and were continued for a period of four weeks. At the time this study was begun, the patient had missed two menstrual periods and was apparently between nine and ten weeks pregnant.

TABLE II, CASE I.

Daily Nitrogen Exchange. Ammonia and Amino-Nitrogen

of Urine.




©


i


»


i


B


E z '


z


A




Date.


[edit] z


Z


1. Z


85

z


= 1



a



J


une 2


915


12.59


7.30


0.71


+4.58


2.8



2273


128%



" 3....


1560


13.30


9.72


0.71


+2.87


3.8


3.2


2578




'• 4....


1000


14.12


4.90


0.71


+8.52


7.1


3.1


2560


130%




1830


12.87


9.48


0.71


2 ii7


5.4


3.6


2251




" 6....


1500


12.86


7.86


0.71


+4.29


3.7


3.8


2572


131%



" 7....


2120


13.28


9.94


0.71


+2.63


4.4


3.8


2739




" 8....


1660


12.29


7.55


i, .,

+4.06


4.0


3.1


2524


132%



" 9....


17:."


11.88


8.09


0.68


+3.11


3.9


4.3


2150


••



" 10....


2030


13.57


9.36


0.68


+3.53


3.9


3.6


2419


133



• 11...


1660


12.28


7.44


0.68


-4.16


4.0



22i a




' 12....


1360


12.82


7.62


0.68


-4.52


4.7


2.8


2360


132V,



" 13....


1140


3.70


7.74


0.68


—4.71


3.5



647




" 14....


1230


10.17


8.44


ii .;.


+1.05


4.2


2.1


1832


131%



" 15...


1460


11.04


7.78


0.75


+ 2.51


4.7


2.4


221 '2




" 16....


1375


10.60


8.00


0.75


+1.85


4.9


3.1


1992


132%



" 17....


1620


10.99


8.39


0.75


+1.85


8.1


2.4


2108




'• 18....


1910


10.2-5


7.48


0.75


- 2.02


6.0


2.5


2<>62


133%



'• 19....


157"


11.87


7.94


0.75


+3.18


2.9


3.6


2323




" 20....


1830


10.01


9.09


0.75


+0.17


3.9


2.6


1961


133%



" 21....


117H


11.01


7.78


0.75


+2.48


3.7


2.7


2196




" 22....


142"


10.39


8.85


0.63


+0.01


6.0


2.3


1926


134' t



" 23....


1620


9.32


8.85


0.63


—0.16


5.1


2.1


1888




' 24....


goo


7.94


6.59


0.63


+0.72


4.6


3.2


1615


132



•' 25....


1100


9.30


6.62


0.63


4 2.05


8.6


2.4


1875




" 26....


860


6.89


5.60


0.63


+0.66


4.8


3.6


1540


132%



• 27...


•HO


7.43


6.11


0.63


-0.69


5.4


2.0


1629




" 28....


900


7.43


7.37


0.63


—0.57


4.7



1855


130%



" 29....


820


6.88


5.97


0.65


+0.26


5.7


3.2


1532




" 30....


750


7.46


4.99


0.65


+1.82


4.7



1534


130%


In the study of the daily nitrogen exchange in this patient it was found, as is shown in the tables which follow, that she stored nitrogen from the time of the beginning of the observations and. with the exception of three isolated days, a plus balance was noted on every day during the period of study. On one of the days when a negative balance was noted, the patient had a gastric disturbance, was nauseated and ingested almost no food, the nitrogen balance


on this occasion being -4.71 gm. On the other two occasions, both in the last week of study, the negative balance was very slight, being —.16 and —.57 gm. respectively. On only the one day during the period of study was there any gastric disturbance present, a point which I wish to emphasize.

In Table I, I have tabulated the actual daily average nitrogen exchange for the four weeks during which the study lasted.

Inasmuch as this patient was only observed for a period of four weeks, it seems that it might be advisable to tabulate the actual daily results obtained for comparison with the preceding. Table II shows the actual daily nitrogen exchange during the period of study, together with the ammonia and free aminonitrogen of the urine for the corresponding days.

Case II. — J. R., colored, age 19 years. Admitted February 5, 1914.

The past history was unimportant.

The present pregnancy is her first, and has been perfectly normal. The patient has had no nausea or vomiting at any time. Her last menstrual period began on November 15th, and was normal. Foetal movements were first noticed about March 14th.

The physical examination showed no abnormalities.

A study of her metabolism was begun on March 4th, and was continued without interruption throughout the remainder of the pregnancy and for the first week after labor. Her weight at the time the observations were begun was 113 pounds. The following table shows the average daily nitrogen exchange for each week of the study up to the time of labor. ( As will be explained later, this patient was delivered about four weeks prematurely, in the 36th week of her pregnancy.) Frequent routine examinations of the urine failed to reveal the presence of albumin, sugar or casts.

TABLE III, CASE II. Daily Average Nitrogen Exchange.



« 


N. Output.



g




B



° ti











iu u.


=


£


£



a


— o


~ o


o


»S


f





=


«ro


o">



£

Z


a


i.


E

z


5=


H


a


18


10.91


9.46


.54


10.0


+0.91


6.37


6.37


1740


112


19


1". Hi


6.40


.36


6.76


+3.34


23.38


29.75


1673


112%


20


12.07


8.54


.63


9.17


+2.90


20.30


50.05


1930


113


21


11.80


7.34


.64


7.98


+3.82


26.74


76.79


1930


114


22


11.70


8.88


.67


9.55


+2.15


15.05


91.84


1955


114%


23


12.50


9.61



10.16


-2.34


16.38


108.22


2023



24


12.15


9.15


.44


9.59


+2.56


17.92


126.14


1916


116



12.30


8.40


.54


8.94


-3.36


23.52


159.66


2012


117%


26


11.87


9.08


.56


9.64


+2.23


15.61


175.27


y,-f,


117%


27


11.72


9.47


.52


9.99


+1.73


12.11


187.38


2153


117%


28


11.76


6.25


.31


6.56


-5.20


36.40


223.78


2"42



29


11.36


8.20


.28


8.48


+2.88


20.16


243.94


1874


n:.'.


30


10.40


7.77


.36


8.13


+2.27


15.89


259.83


1722



31


10.90


7.60


.46


8.06


+2.84


19.88


279.71


1672


121


32


11.95


8.30


.4"


8.70


+3.25


22.75


302.46


1752


122',


33


12.21


7.77


.32


8.09


+4.12


28.84


331.30


1972


123%


34


11.62


6.09


.37


6.46


+5.16


30.96


362.26


1959



35


11.63


7.09


.40


7.49


-4.14


28.98


391.24


2150


125%


36, 6 davs


11.80


6.63


.48


7.11


+ 4.69


28.14


419.38


1683


126%


Dav











Deliv.


1.20


5.96


.63


6.59







Labor pains began at 10.00 p. ni., July 14th, and after an uneventful labor lasting ten and one-half hours, the child was born at 8.30 a. m., July 15th. (Judging from the menstrual history given by this patient, the time when foetal movements first became evident, and the size of the child, which was somewhat under the average, it seems evident that labor occurred between four and five weeks before full-term, apparently in the 36th week of pregnancy; and I have made calculations on that basis.)

The child weighed 2850 gm. The placenta and membranes weighed 540 gm.; the amount of blood lost was 375 gm. The weight of patient before delivery was 126% pounds. The weight of patient immediately after delivery was 117 pounds, a net loss of nine and one-half pounds. Observations were continued on the patient for the first ten days of the puerperium and the following results were obtained:


1-24 [Xo. 303


The nitrogen intake averaged 11.34 gm. X. per day. The nitrogen output:

Urine averaged 10.91 gm. per day

Feces averaged S2 gm.

Lochia averaged 49 gm.

Milk averaged 70 gm.

Total output 12.92 gm. N. per day.

She thus showed a negative nitrogen balance during this period which averaged — 1.5S gm. N. per day. The weight of the patient at the end of the first ten days after labor was 112 pounds, and four days later this had still further decreased to 109 pounds.

Case III.— E. Z.. white, age 18 years. Admitted January 25, 1915.

The past history was unimportant.

The present pregnancy is her first and has been normal in every respect up to the time of her admission to the hospital. There has been no nausea, vomiting, or other gastro-intestinal disturbances. Her last menstrual period occurred in the latter part of August, 1914. Fretal movements were first noticed early in January, 1915.

The general physical examination showed a healthy woman in whom no abnormalities could be detected. The fundus of the uterus was two fingerbreadths below the level of the umbilicus. Active foetal movements were readily appreciated, and the foetal heart-sounds distinctly heard.

Observations on this patient were begun on January 27th and were continued without interruption throughout the remainder of pregnancy and for the first week of the puerperium. Her weight at the time the study was begun was 115 pounds. Frequent routine examinations of the urine throughout the period of study failed to show the presence of sugar, albumin or casts at any time.

From the history of the patient, and the findings at examination, it seems fair to conclude that this woman was apparently in about the 23d or 24th week of her pregnancy and was delivered about two weeks before the expected date of confinement, in the 3Sth week of the pregnancy.

In the following table is tabulated the average daily nitrogen exchange, together with the average and total storage according to the same scheme as that employed in the preceding case.

TABLE IV, CASE III. Daily Average Nitrogen Exchange.




N


. Output.


i


u


j;


^




1





|


3S


- =


z


u i


i~


K


C


i


z


z


•s


fr"


""


i~


U


15.33


11.31


0.S6


12.17


-3.16


22.12


22.12


2310


116%


25


15.65


12.90


1.17


14.07



11.06


33.15


2321


116%


26


15.90



0.80


12.4"



24.5"



2418


120%


27


15.83


13.13


1.60


14.19


+1.64


11.48


69.16


2365


119%


28


15.54


12.41


1.34


13.75


-1.7'.'


r?.53




121%



15.87


13.7"


1.71


15.41


-".4"


3.22


34


2395


VJ'Ji..


30


16.28


13.39


1.39


14.75


+1.50



95.41


2416


123


SI


16.39


13.77


1.40


14.51


+1.58


11. "6


106.47


2448


liv-4


32


16.99


14.20


1.27


15.47


-1.52


10.64


117.11


2522


125


33


18.50


14.06


0.88


14.94


-3.56


24.92


142.03


2765


127



19.72



0.66


13.44


+6.28


43.96


185.99



129


35





13.40


-6.17


43.19



2945



36



l-'.08


1.17


13.25


-6.37






!


'


12.42


1.11


13.53


-6. "4


42.28




134.


Dav Deliv.


19.81


12. "7



13.12


-6.72


20.16


336.21


3003



7.76


11.21


1.05


12.26







Labor pains began at 1.00 a. m., on May S, 1915, the entire labor being uneventful and ending spontaneously after a duration of 15 hours.

The child weighed 2960 gm. The placenta and membranes 4S0 gm. The amount of blood lost was 150 gm. The weight of patient before delivery was 133% pounds. The weight of patient


immediately after delivery was 121% pounds, a net loss of 12 pounds.

The puerperium was perfectly normal, and the nitrogen exchange during the first week after labor was found to be as follows: The nitrogen intake averaged 1S.03 gm. X. per day. The nitrogen output:

The urine averaged 15.96 gm. X. per day

The feces averaged 1.06 "

The lochia averaged 3.40 "

The milk averaged 0.32 gm. "

Total output 20.74 gm. X. per day.

Thus, there was a negative nitrogen balance, which averaged — 2.71 gm. of nitrogen per day.

The weight of the patient at the end of the first week after labor was 117% pounds, and on May 23d. fifteen days after delivery, this had decreased still further to 115 pounds.

Discission of Eesults.

In considering these observations, one point to be emphasized is the fact that all three were made upon perfectly healthy women presenting perfectly normal pregnancies, and that none of them suffered from nausea, vomiting, or any of the other gastro-intestinal disturbances so frequently noted in early pregnancy. Indeed, inasmuch as it has been our experience that at least half of our patients go through the entire period of pregnancy without any of these disagreeable symptoms, the question arises as to whether the women suffering from such disturbances are to be regarded as being perfectly normal.

I ase I, so far as I am aware, is the earliest pregnancy on which metabolism studies have been carried out for any extended period of time. In this patient storage of nitrogen was found to be taking place from the time the observations were begun until their close, and in the actual daily exchange a positive balance was noted on every day except three. The total storage of nitrogen during the period of observation amounted to 59.99 gm. X.

The period of observation in this patient probably extended from the tenth to the fourteenth weeks of her pregnancy at the latest, and it may have been begun slightly earlier. At this period of pregnancy the daily need of the developing ovum for nitrogen can be regarded as infinitesimal. Indeed, the total nitrogen content of the entire ovuru probably does not exceed two or three grams, whence we may conclude that most of the nitrogen stored must have been added to the general maternal organism in some form, possibly to be drawn on later by the developing ovum when its needs became greater. In regard to the place of storage and the form assumed by this nitrogen, it is of course quite impossible to make any positive statement; although we must bear in mind that even at this early stage a portion of it is probably utilized in the growth and hypertrophy of the uterus and breasts.

Storage was found to be most active during the first three weeks of the study and was accompanied by an increase in the body weight of H pounds. In the fourth week the conditions were quite changed, inasmuch as the average daily intake now fell to T.8S gm. X. per day. and with this marked diminu


May. 1916.] 125


tiorf in the intake (the caloric value of the diet at this time was not sufficient for a patient of her body weight i the patient lost four pounds in weight, as compared with the weight at the end of the preceding week. How is this to be explained ?

One explanation might be in the possibility that she may have reached what Bar describes as the " period of saturation," in which disassimilation processes predominate. It is to be noted, however, that this marked change was not accompanied by any gastro-intestinal disturbances. Consequently. I am inclined to believe that the true explanation is much simpler, and that the change was due entirely to the fact that the patient had become thoroughly tired of the diet and regime to which she was being subjected and was suffering from anorexia. The weather, too, at this time had become very oppressive. Confirmation is lent to this belief in the fact that as soon as the patient left the hospital, and lived under home surroundings, her appetite returned and she again began to take her food with relish and increased rapidly in weight.

One very striking feature during the last week of this observation is the fact that in spite of the very low nitrogen intake. as well as the fact that she was losing in weight, she still had the capacity for storing nitrogen, though to a much less degree than during the three preceding weeks.

The second case in our series about corresponds, so far as the period of the pregnancy is concerned, to the case studied by Hoffstrom. Our patient went into labor, however, about a month before the expected date of confinement, so that observations were carried out only for the last 19 weeks of her pregnancy. That she was delivered about four weeks prematurely is, I think, evident when we consider her menstrual history, the time when the fcetal movements first became perceptible, as well as the fact that the child was somewhat under the average weight.

A- is shown in the accompanying table (Table III), in which I have set down the daily average exchange, this patient was also found to be storing nitrogen from the time observations were begun. As in the preceding case, a chart of the actual daily nitrogen exchange was also kept, which shows that on occasional days, as in Case I, there was a slight r* nitrogen balance.

In studying these patients it was thought that possibly

cyclical variations in the nitrogen exchange might be noted at

periods of time corresponding to the time of the menstrual

3, had the patient not been pregnant, but such was not

found to be the case.

Although this patient was ;it all times allowed suffii li to satisfy her appetite, nevertheless, her daily intake throughout the entire period was strikingly low, at no time being greater than ] 2.5 gm. X. per day. Storage became particularly active from the nineteenth to the twenty-first weeks, at the time when fcetal movements were becoming particularly active.

The low nitrogen content of the feces is probably to be accounted for partly by the low nitrogen intake and partly by the easily digestible diet of the patient.

A.s in EToffstrom's case, the most active storage took place during the last nine weeks of the pregnancy when the foetal


needs were at a maximum. The total nitrogen stored by this patient during the period of observation, amounted to 419.38 gm. X. It is interesting to try to determine what became of this nitrogenous material, although this, of course, can only be determined approximately.

The child weighed 2850 gm. Michel, in his anal; human foetuses, found the nitrogen content of a. child weighing 1335 -in. to be 72.7 gm. X. Calculating on this basis, which in this case, however, can only be approximate, the nitrogen content of the child alone ought to be 62.1 gm.

The placenta was not analyzed. Its weight, without cord and membranes, was 500 gm. As shown by Koelker and Slemons, one-half of the fresh weight is made up of fcetal blood, whereas the weight of the dried, water-free material amounts to 7 per cent of the fresh weight of the organ, and the nitrogen content of this dried material to 14.9 per cent. Making use of these findings, we calculate that the nitrogen content of the placental tissue would be 5.21 gm. X., and upon adding to this the nitrogen content of the fcetal blood, which should amount to 9.45 gm., we estimate that the total nitrogen content of the organ is approximately 14.66 gm. We may allow 2 gm. (an extreme figure) as the nitrogen content of the cord and membranes, which weighed 40 gm.

Deducting the weight of the child, placenta and membranes, and blood lost at the time of deliver}-, from the total loss of weight of the patient at the time of labor, we find the amount of amniotic fluid to be approximately 540 gm. which, from the Sgures given by Hoffstrom, would contain 0.19 gm. X.

The nitrogen content of the ovum, then, may be tabulated as follows :

Child 62.10 gm. N.

Placenta 14.66

Cord and membranes 2.00

Amniotic fluid 0.19 gm.


Total nitrogen content of ovum TS.95 gm. N.

Hoffstrom estimates the nitrogen content of the entire ovum at the end of the seventeenth week of pregnancy to be 5. Accepting this figure as being correct, we find then that, of the 419.38 gm. X. stored by this patient, 73.54 gm. have been diverted to the growth and development of the ovum. Tinleaves a balance of 345.84 gm. X. which have been added to the general maternal organism. From this amount, however, we ought to deduct the nitrogen content of the blood losl al the time of labor, and which amounted to 5.56 gm., leaving a balance of maternal storage of 340.28 gm.

A certain proportion of this has. of course, been utilized in the hypertrophy and development of the genital organ dentto the pregnancy, more particularly the uterus and bi

The uterus increases in size up to 800 or 1000 gm. Slemons found the nitrogen content of a uterus removed by supravaginal amputation following Csesarean section, and weighing B50 -in. in the fresh state, to be 38.75 gm.

Assuming the hypertrophy of the breasts to amount to half a kilogram, this would account for approximately another 1" gm. X. We thus have approximate!] of the


126 [No. 303


maternal storage diverted to the development of the genital organs, but we still have left a balance of 284.53 gm. X. added to the maternal organism, which Hoffstrom describes as " Restmaterial."

In the third patient, observations were begun at a rather later period, at approximately the twenty-fourth week of the pregnancy.

One very noticeable feature in this patient is the fact that her nitrogen intake was always greater than in the preceding ,ase. at times almost double: and another very striking feature is the marked increase in the X. intake during the last live and a half weeks of the pregnancy. This was entirely voluntary on the part of the patient, and the diet was simply mereased to the point of satisfying her appetite, no artificial element in the way of forced feeding being introduced. Ser body-weight increased Kif pounds during the time of observation, as compared with 144 pounds in Case II. during a somewhat longer period.

As in Case II, this patient was found to be storing nitrogen to a marked degree from the beginning of the observations (see Table IV). although she also showed an occasional slight negative balance in the actual daily exchange. The most ai tive storage occurred during the last five and a half weeks of the pregnancy as compared with the last nine weeks in the preceding case, and this also corresponded to the time when the diet was at its maximum.

The total storage of nitrogen during the 144 weeks the patient was under observation amounted to 336.21 gm.

Using the same basis for the calculations as in the preceding case. I have estimated below the amount of the stored nitrogen which has been diverted to the development of the ovum:

Weight. Nitrogen Content.

Child 2960 gm. 64.5 gm.

Placenta 420 " 11.73 "

Membranes and cord .... 60 " 2.0

Amniotic fluid 1S45 " 0.68 "

Total 78.91 gm.

Hoffstrom estimates that the nitrogen content of the entire ovum at the end of the twenty-third week amounts to 14.26 gm. Of the 336.21 gin. of nitrogen stored, therefore, we then find that 64.65 gm. have been diverted to the growth and development of the ovum. In this patient, then, we have had 271.56 gm. X. added to the general maternal organism. Again deducting the nitrogen content of the blood lost at the time of delivery, and which amounted to 4. S3 gm., we have a maternal balance of 266.73 gm. X.

If, as in the previous case, we allow 38.75 gm. X". for the development of the uterus, and 17 gm. N. for the breasts, we still have a maternal balance of 210.98 gm. N. as " Restmaterial."

In these two cases, the amounts of nitrogen allowed for the development of the genitalia, and the estimated nitrogen eontent of the ovum are, of course, only approximate. However. I think they are sufficiently accurate to show us that, in normal


human pregnancy, the storage of nitrogen by the maternal organism is far in excess of the actual needs of the developing ovum, and indeed may be several times the amount actually needed for its development.

As to the form in which the '"' Restmaterial " is stored, definite statements cannot be made as yet. A certain portion of it is doubtless made use of in the formation of new blood. As shown by Miller, Keith and Rowntree, the blood volume is very definitely increased at the end of pregnancy. Indeed. in Case III of this series the woman was one of the subjects of their observations, and at a time four weeks before her delivery the blood volume was estimated to be "i408 cc. This, however, would only account for a small portion of the " Restmaterial." A portion also is probably utilized in the hypertrophy of muscles and the various glandular structures affected by pregnancy. In regard to the remainder, Hoffstrom accepts the hypothesis that this is stored as unorganized protein, as a reserve material : and for the present, until definite proof in regard to its disposal can be adduced, this seems to offer a very plausible explanation.

This reserve is probably drawn upon extensively during the puerpermm and period of lactation, during which the entire reserve supply is possibly exhausted.

Cases II and III of our series were both studied for periods of ten and seven days respectively after labor. Unfortunately the observations could not be carried on longer. The results obtained did not differ from those of Slemons and other observers. Both patients showed a negative nitrogen balance, decreased in weight, and both were losing nitrogen when the observations were brought to a close.

Ammonia and Amixo-Acid X'itrogex.

In Case 1. daily estimations of the ammonia nitrogen present in the urine were made by Folia's method, and its percentage was found to be practically normal ; although on one occasion it made up 8.6 per cent of the total urinary nitrogen. The extremes were 2.8 per cent and 8.6 per cent, with an average for the time of observation of 4.8 per cent of the total nitrogen. The daily figures are shown in Table II (see also Chart I).

This is a somewhat lower average percentage of ammonia nitrogen than is generally present in the urine during late pregnancy, as Slemons and ilurlin both found rather higher figures.

In this patient the free amino-nitrogen was also determined by the method of Van Slyke, on every daily total specimen of urine, except on five occasions. These daily percentages of amino-nitrogen are also shown in Table II, and are seen to be somewhat higher than those generally given for the nonpregnant individual (stated by Van Slyke to lie about 1 to H per cent of the total nitrogen). The extreme figures found were 2.0 per cent and 4.3 per cent of the total nitrogen, with an average of 2.97 per tent for the whole period of study. Landsberg, in his series of observations on ten pregnant women, found an average of 3.8 per cent of amino-nitrogen in the urine during the latter part of pregnancy, as compared with 2.8 per cent


May. 1916.] 127


in a series of non-pregnant individuals, his estimations being made by the formol-titration method. Falk and Hesky and Frey also found an apparent increase in the amino-nitrogen.

In Case II, daily estimations of the ammonia nitrogen were also made throughout the entire period during which the








SJ




!? \




^



k


\






Xi



>l|l|





M


1 1 .1. if






J.


• >






< *


<






9


\\S


I I




< \







\ ^


.1 1 !>





3


,r


><i



i !





<


9 J>



i ; ;



S>



V

1 !


y


? !




55



V,o J


i





1^









>


1 \ i


?






^



?





t



. •.






S



\\


>°i




^



I \\\ 1







Il>M





$







<^



l\l





.°Q



!-A !


K




N.



<


i >




<0




^,Q




"0



444M


' i\. !




^t


• «c^5





<0



<;


^P*




i"


>; ;


1 °,




1

3


cfflZ


patient was under observation. In the earlier weeks, the results obtained about correspond to those in Case I and are well within normal limits. During the last six weeks of the pregnancy, however, there was a slight, but still a very definite, increase in the percentage of ammonia nitrogen, although this


never reached what would be regarded as an abnormal figure. On the day on which labor began, July 14, there was a very pronounced increase in the percentage of ammonia nitrogen, which reached 19.8 per cent of the total urinary nitrogen.

The free amino-nitrogen of the urine was determined daily for a period of five weeks from the thirty-first to the thirtyfifth weeks inclusive. The highest figure obtained on any one day was 5 per cent and the lowest 1 per cent of the total urinary nitrogen, while the average daily percentage for the whole period was 2.56 per cent, which practically corresponds to the results obtained in Case I in the early weeks of pregnancy. The daily average ammonia nitrogen and amino-nitrogen percentages for each week are shown in Table V. and the daily percentage of ammonia nitrogen for the last 10 days of pregnancy and day of delivery are given in Chart II.


July


e 7 s


9


10


11


1Z


13


14


15


/6


rr


18


19
















20









































M


~a






















t
















1

%
















I

\















|


%














«i
















/



W




























1



V //\









o>





4' \







!7V>



£~feoL



V





O








°s

















X>

































































Total Urine N., in Gins. % of Ammon. Nitrogen, ( labor.


-o. showing rise before


Chart II, Cask II.


Daily estimations of the ammonia nitrogen in Case III also showed the percentage to be well within normal limits throughout the entire period. In this patient there was no decided increase during the last weeks of the pregnancy, as was noted in Case II. the ammonia percentage remaining remarkably constant throughout the entire period. The absence of such a rise in the ammonia percentage in this ease is probably to be explained by certain differences in the diet of the two individuals, Case III ingesting and eliminating much larger amounts of nitrogen than did Case II; consequently, slight variations in the actual daily amount of ammonia eliminated would produce little or no change in the percentage of ammonia nitrogen. There was a decided rise, however, in the percentage of ammonia nitrogen on the day of delivery, reaching 8.6 per cent of the total nitrogen. The daily percentages of ammonia nitrogen for the last I' 1 days of pregnancy and


128 | No. 303


the day of delivery are shown in Chart III. The fact that this

if ammonia nitrogen was found on the day

of delivery in Case III. and on the day preceding delivery in

1. is to be explained, I think, by the fact that in Case II]


April


May Z8 23 30 1 Z 3 4- 5 6 7 8 9 10 IZ


13




,
























B




_



.e








Is












s:















A

















CJ















/ v.









10


V










































o~


•o
































l






5














o.



v o.




. or


°


% o.



,o










-^ '










^o

+*


































. , .


Total Urine N., in Gms. <fc of Ammon. Nitrogen o


-o, showing rise at labor.


Chart III, Case III.

labor began shortly after the termination of a 24-hour period of observation, whereas in Case II labor had already been in progress for some hours before the 24-hour period had been completed, and in our studies it was not feasible to make analyses of the excreta at shorter intervals than 24 hours. In the cases

TABLE V, CASES II AND III.

Daily Average Percentages of Ammonia Nitrogen and

A mi vo-Nitrogen.



Case II,




Case III.



Week.


Per cent of


Per cent of


Week.


Per cent of


Per cent of


Ammonia N.


Amino-N.


Ammonia N.


Amino-N.


IS


5.66






19


4.80







4.7H






21


1.64






22


4.64






23


3.70






24


3.98



24


5.50


1.82


25


5.22



25



1.75


26


5.02



26


4.45


2.24


27


4.70



27


4.35



28


5.32



28


3.94



29


4.7rt



29




30


5.80



30


--,


31


6.45


3.14


31


3.90



32


5.57


2.4*


32


3.611



33


6.31


1.98


33


3.6H



34


6.85


2.07


34


1.00



35


6.211


3.13


35


4.24



36


8.76



36


4 50



37




37




38




38


4 10



studied by Slemons the highest percentages of ammonia nitrogen were found on the day of delivery, but iu three of his cases there was also a very definite increase ou the day preceding the onset of lahor.

For the first three weeks this patient was undei dailv estimations of the free ammo-nitrogen were also made.


Somewhat lower figures were obtained than in Cases I and II during the earlier and later weeks of pregnancy and a slighter degree of variation in the daily figures was noted. The extremes were 1.1 per cent and 3.2 per cent of the total urinary nitrogen, and the daily average for the three weeks was 1.97 per cent. The daily average percentages of ammonia aud amino-nitrogen for the period during which observations were made are shown in Table V, together with the same figures for Case II.

From the observations made on the amino-nitrogen of the urine in our three patients at various periods of pregnancy, it would seem that there is a definite increase in the percentage of nitrogen eliminated in this form. This increase, however, is largely a relative one. the percentages being higher on account of the decrease in the total nitrogen of the urine.

Conclusions.

1. In the perfectly normal pregnant woman, storage of nitrogen begins at a much earlier period than has hitherto been supposed : possibly the organism may acquire the capacity for storing nitrogen from the very beginning of the pregnancy.

2. In the early months this storage is far in excess of the actual needs of the developing ovum, and the excess must be added to the general maternal organism.

3. Storage of nitrogen continues throughout the entire duration of pregnancy, being most marked during the last few weeks, when the fcetal needs are at a maximum.

4. The nitrogen stored is greatly in excess of the actual needs of the developing ovum, so that, apart from the amount needed for the hypertrophy and development of the genitalia and breasts, a large proportion of the nitrogen stored is added to the general maternal organism as " Restmaterial," though, concerning the form in which this reserve is stored, we are unable to make any positive statement. The nitrogen capital of the maternal organism is thus increased, though the reserve supply may possibly be entirely exhausted during the puerperium and period of lactation.

5. In the healthy woman, who goes through a normal pregnancy, the period of gestation does not necessarily represent a "sacrifice of the individual for the sake of the species

may actually be a period of gain.

6. There is a relative increase in the percentage of urinary nitrogen excreted in the form of free amino-aeids. though not necessarily an absolute increase in this form of nitrogen.

"!. There is also a tendency for the percentage of ammonia nitrogen to become increased during the last weeks of pregnancy, although at other times during the pregnancy there is practically no variation from the percentages noted in nonpregnant individuals upon a similar diet.

In conclusion I wish to express my gratitude to Prof. J. Whitridge Williams for the privilege of carrying out this work; also to the various members of the resident obstetrical staff for much valuable assistance in supervising the regime tinder which these patients were kept.


May, 1916.] 129


BIBLIOGRAPHY.

Atwater and Bryant: The Chemical Composition of American Food Materials. Bull. No. 28, U. S. Dept. of Agriculture, 1906.

Bar, Paul: Lecons de pathologie obstetricale, II, Paris, 1907.

Hagemann, 0.: Beitrag zur Kenntnis des Eiweissumsatzes ini tierischen Organismus. Inaug.-Dissert. Berlin. 1891. (Quoted by Bar.)

Hahl, C. : Beitrag zur Kenntnis des Stoffwechsels wahrend der Schwangerschaft. Arch. f. Gynakologie, 1905, LXXV, 31.

Hoffstrom, K. A.: Eine Stoffwechseluntersuchung wahrend der Schwangerschaft. Skandinavisches Arch, fiir Physiologie, 1910, XXIII, 326.

Une experience sur les echanges nutritifs pendant la grossesse. L'Obstetrique, 1910, 1061.

Jageroos, B. H.: Studien iiber den Eiweiss, Phosphor, und Salzumsatz wahrend der Graviditas Arch. f. Gynakologie, 1901, LXVIII, 527.

Koelker and Slemons: The Amino-Acids in the Mature Human Placenta. Journal of Biological Chemistry, 1911, July, Vol. IX, No. 6.

Landsberg, E. : Untersuchungen iiber den Stoffwechsel von Stickstoff, Phosphor und Schwefel bei Schwangeren. Ztschr. f. Geburtshiilfe und Gynakologie, 1912, LXXI, 163.

Michel: Sur la composition de l'embryon et du foetus humain aux differentes epoques de la grossesse. Comptes rendus de la Soc. de biologie, 1899, 422.


Miller, Keith, and Rowntree: Plasma and Blood Volume in Pregnancy. Jour. Amer. Med. Assn., Aug. 28, 1915, LXV.

Murlin, J. R.: Nitrogen Balance during Pregnancy and Menstruation of the Dog. Amer. Jour. Physiol., 1910, XXVII, 177.

Some Observations on the Protein Metabolism of Normal Pregnancy and the Normal Puerperium. Surg., Gyn. and Obstetr., January, 1913, 43.

Schrader, Th.: Einige abgrenzende Ergebnisse physiologischchemischen Untersuchungen iiber den Stoffwechsel wahrend der Schwangerschaft und ini Wochenbett. Arch. f. Gyn., 1900, LX, 534.

Sillevis: Ueber den Stoffwechsel der Gravida. Centrbl. f. Gyn., 1904, XXVIII, 1471.

Slemons, J. M.: Metabolism during Pregnancy Labor and the Puerperium. The Johns Hopkins Hospital Reports, 1904, Vol. XII.

The Involution of the Uterus and its Effect upon the Nitrogen Output of the Urine. Bull. Johns Hopkins Hosp., 1914, July, XXV, No. 281.

van Slyke, D. D.: Improved Methods in the Gasometric Determination of Free and Conjugated Amino-Acid Nitrogen in the Urine. Jour, of Biol. Chemistry, 1913, October, XVI, No. 1.

ver Eecke, A.: Les echanges materiels dans leurs rapports avec les phases de la vie sexuelle. Mem. de l'Acad. Roy. de Belgique, 1901.

Zacharjewsky, A. U.: Ueber den Stickstoff wechsel wahrend den letzten Tage der Schwangerschaft und den ersten Tage des Wochenbettes. Ztschr. f. Biologie, N. F., 1894, Bd. XII.


FUNCTIONAL SIGNIFICANCE OF MITOCHONDRIA IN TOXIC

THYROID ADENOMATA.

PRELIMINARY REPORT.

By Emil Goetsch, M. D.,

Associate Surgeon, Johns Hopkins Hospital.

(From the Hunterian Laboratory of Experimental Surgery, Baltimore, and the Surgical Clinic of the Peter Bent Brigham Hospital.


Boston.)


It has been customary in the past to group under the designation " thyroid adenomata " new growths 6f benign nature occurring in the thyroid gland in the form of rather welldefined nodules or even encapsulated tumors that are usually readily distinguishable from the adjoining normal thyroid parenchyma. These adenomata are further subdivided upon the basis of their histological structure into colloid, cystic and fetal adenomata. Whether the latter are or are not suitable classifications I shall not discuss at the present time. The terms colloid and cystic are self-evident as applied to their structure, while in the case of those adenomata whose structure is exceedingly variable, and in which atrophic-looking, colloid parenchyma alternates with hyperplastic-looking parenchyma quite different from the ordinary thyroid structure, the term " fetal adenoma " has been applied upon the assumption that these tumors had their origin in embryonic remnants.

The histological structure of these adenomata suggests in the majority of instances relative functional inactivity; that is. if the assumption of functional inactivity as compared with overactivity is based upon the histological criteria ordinarily applied to the study of the thyroid gland. The criteria of overactivity, namely, the increased height and size of the thy


roid cells, the infolding and general hypertrophy and hyperplasia of the thyroid parenchyma and the diminished size of the acini containing little or no colloid, when applied to these adenomata, would lead one almost surely to the conclusion that in the absence of these criteria the tumor in question is an inactive one. Now it is just in these circumscribed tumors that one so frequently finds the parenchyma consisting in the main of low cuboidal or even flattened epithelium, with small, often pycnotic nuclei, a considerable, often very abundant amount of colloid, absence of infolding of the follicular epithelium and of evidence of hypertrophy and hyperplasia generally of the thyroid epithelium. In spite of these facts one frequently encounters clinical states of undoubted hyperthyroidism associated with the occurrence in the thyroid gland of such circumscribed nodules. The hyperthyroidism symptoms may be very mild and hardly perceptible, or in some instances they may be extreme. In certain cases, however, the thyroid lesion may be present without any discoverable symptoms pointing to a condition of hyperthyroidism. To explain these symptoms of thyroid overactivity many have assumed that as a result of the mechanical pressure exerted upon the adjoining normal thyroid gland, the secretion


130 [Xo. 303


latter has been squeezed in excessive amounts into the circulating thuds and has thus caused the symptoms of hyperthyroidism. Another explanation offered is that the mere presence of the tumor acts as a mechanical irritant to the gland, thus exciting the latter to overactivity. By others the symptoms of hyperthyroidism have not been explained at all, the statement simply being made that their origin must be looked for elsewhere than in disorders of the thyroid gland. And lastly, in some instances the adenoma was held responsible, despite the fact that no satisfactory histological evidence of its hyperactivity was apparent.

Patients with evidently inactive adenomata present themselves to the surgeon principally for the removal of the growth for cosmetic reasons or for the relief of mechanical pressure upon the trachea and (esophagus. It is a common experience in the other cases, those presenting symptoms of hyperthyroidism, that, after the surgical removal of the adenoma, such symptoms rapidly subside. This experience lends support to the assumption that the tumor itself is responsible for the symptoms of thyroid overactivity.

An example of this kind may be given, illustrative of conditions in other patients who have recently come for treatment to the surgical clinic of Professor Halsted. A thyroid tumor hail existed for a number of years, at first unassociated with symptoms suggestive of hyperthyroidism, presenting, however, in the last year and a half definite symptoms of moderate thyroid intoxication. At operation upon the thyroid an encapsulated tumor was removed and upon histological examination was found to have the appearance of a simple inactive colloid adenoma (cf. photograph, Fig. 2). Furthermore, upon physical examination of the patient before operation, the thyroid gland itself did not present any findings suggestive of overactivity, such as increased vascularity; nor did the gland at operation siiL r ge>t such a condition. Following the operation, however, there was a marked improvement in the patient's general condition. This fact goes to indicate that the adenoma must in large measure have been responsible for the production of tin- symptoms of hyperthyroidism.

The first patient illustrating these points, whom I had the privilege of observing, was one who came to the surgical clinic of the Peter Bent Brigham Hospital. Boston, Mass.. March 1 1. 19] t. It is for this reason and because of the fact that this case illustrates the findings in several recent cases admitted to the surgical clinic of The Johns Hopkins Hospital that I shall briefly review the history and examination.

The case was that of a married woman, aged 37 years, who complained of a lump in her neck icf. Fig. 1), recent difficulty in swallowing, and nervousness. She was admitted to the surgical clinic of the Peter Bent Brigham Hospital, Marco 11, 1914.

The family history is unimportant. There has been no similar trouble in any of her ancestors.

Past History. — She had scarlet fever at the age of five years, but no other acute illness. She has occasionally suffered with headaches, sore throat and tonsillitis. She has had some dyspnoea. The digestion has always been good; the bowels have been constipated. The genito-urinary and menstrual histories are negative. She has had four children, living and well. Her husband was accidentally killed while at his work one and a half years before


her admission to the hospital. She attributes the onset of her nervous symptoms to this cause. Her habits are good. Weight, March 18, 5S.S K. (129.3 pounds).

The present illness dates back five or six years, to a time just after the birth of her last child. She noticed that the neck was getting larger owing to the appearance of a lump in the lateral margin of the right thyroid lobe. The lump was very small at this time, perhaps the size of a marble. Two or three years ago there was a slight enlargement, and in the past four to five weeks the nodule has been growing more in the direction of the isthmus. The lump has never been painful and has never caused the patient any noticeable trouble until in the past four to five weeks, when there has been slight difficulty in swallowing. Slight hoarseness of the voice has also been noticed recently. Slight palpitation has been apparent for four or five years and has grown distinctly worse since the death of her husband a year and a half ago.

Symptoms of nervousness and worry have been present for the past two years, but have gotten distinctly worse following an attack of tonsillitis four weeks ago.

Increased perspiration, hot and cold flushes, salivation and some loss of weight, have also been noticed during the past four weeks. Asthenia and loss of appetite have been rather marked recently. Constipation has been troublesome for several years.

Physical Examination. — The positive findings, many of which point to a mild degree of hyperthyroidism, may be summarized as follows: The patient is a poorly nourished, restless, rather nervous, middle-aged woman.

There is increased perspiration of the palms of the hands, axillae and soles of the feet.

Eyes. — The Mobius and Dalrymple signs are positive. There is a slight widening of the lid-slits, but no exophthalmos and no von Graefe's sign are apparent. The hair has tended to come out in increased amounts recently. There is some increased pigmentation of the skin.

Neck. — In the region of the right lobe and right half of the isthmus of the thyroid gland is an irregular prominent swelling, about the size of an egg. There is no enlargement of the left lobe. There is no venous distention of the superficial vessels to be noted and no apparent increase in the carotid pulsation or in the pulsation of the thyroid gland itself.

Measurements of the Keck. —

Circumference at level of thyroid cartilage. .32 cm.

Circumference over middle of isthmus 35 cm.

Circumference at root of neck 36.5 cm.

Measurements of Xodule in Right Lobe and Isthmus. —

Transverse diameter 7.5 cm.

Vertical diameter 4.5 cm.

Palpation — There are no thrills palpable over the poles of the thyroid gland or over the tumor itself. The tumor is circumscribed; it can be readily displaced upward into the neck and apparently arises from the right thyroid lobe. It is elastic to the feel, not fluctuant, and has the consistency of a colloid nodule. The left lobe of the thyroid gland is not distinctly palpable. The right lobe, aside from the nodule, is not distinctly palpable.

Auscultation. — No bruits are heard over the poles of the thyroid gland or over the tumor.

Teeth. — The few that remain are in bad condition. Most of the teeth have been extracted.

Chest. — No retrosternal dulness. Heart and lungs negative.

Mammary glands atrophic. Montgomery's glands hypertrophic.

Abdomen. — Edges of liver and spleen just felt. No epigastric pulsation. Adipose tissue lacking in the skin.

Extremities. — Perspiration of hands and feet noticeable. They are quite cold. No edema of legs.

Reflexes. — Superficial reflexes inactive. Deep reflexes active.

Tremor not characteristic. A slight unsteadiness in the hands is perceptible. The patient has been resting in bed for six weeks.


THE JOHNS HOPKINS HOSPITAL BULLETIN. MAY, 1916.


PLATE XXI.



Pig. 1. — Photographs of the patient, showing the circumscribed tumor of the right lobe and isthmus of thyroid gland. Note the absence of exophthalmos.



Fig. 2. — Photomicrograph I aqueous chrome-sublimate fixation. and hematoxylin-eosin stain: 4 mm. in thickness) of a section representative of the gen- ral .innearance of the adenoma in tinthyroid gland. Note the relatively large amounts of intrafollicular colloid and the absence of the common evidences of hypertrophy and hyperplasia of the thyroid epithelium. < X 100. i


May, 1916.] 131


Temperature varies between 97° and 98°.

Pulse averages about 70 per minute.

Urine negative. Output varies between 1300 and 1500 cc. in 24 hours.

Blood Examination— W. B. C, 12.400; haemoglobin, 78 per cent. The differential count shows no abnormal findings.

Blood Pressure. — Systolic, 120 mm. Hg. ; diastolic, 74 mm. Hg.

Pharmaco-dynamic Tests. — The patient gives a practically negative response to the hypodermic injection of 0.00075 gm. of atropin. There was a marked response to the hypodermic injection of 0.0075 gm. of pilocarpine, especially evidenced by the profuse perspiration, salivation and coldness of the extremities produced. The pulse rate was somewhat diminished, but no change in the respirations or temperature was observed.

The tolerance to levulose by mouth is approximately 150 gms. Glucose 100 gms., when given by mouth and followed by the hypodermic administration of adrenalin 0.00075 gm., does not produce a glycosuria.

Operation. — March 21, 1914. Excision of encapsulated -fatal adenoma in the right thyroid lobe and isthmus.

The tumor was found to possess a definite capsule. It was inclosed within the normal-appearing right thyroid lobe, which was considerably thinned out over the tumor. The latter shelled out readily and was about the size of a small lemon. The left thyroid lobe was explored and gave all the appearances of being normal. There were no evidences of hypertrophy or hyperplasia of the thyroid gland, which also failed to show any evidence of increased vascularity.

Gross Pathological Examination. — The tumor is about the size of a small lemon. It possesses a distinct capsule and weighs 33 gms. Attached to it is a section of normal-appearing thyroid tissue. At the right border of the nodule is a separate distinct enlargement, the size of a cherry.

On cross-section the tumor is seen to be composed of a soft pulpy tissue, dark red in color; and interspersed in it are seen irregular islands of whitish, apparently hyperplastic tissue. In one area there is a small cyst, containing a thin straw-colored fluid and lined with a soft reddish granular tissue. In the wall of the cyst is a plaque of calcification. Other granules of calcification are seen scattered through the tumor. In certain areas the parenchyma contains a considerable amount of colloid. Nowhere is there apparent any normal-appearing thyroid gland. The smaller nodule on the right border of the tumor on cross-section is seen to consist of a pale yellowish parenchyma containing small whitish islands of tissue and a moderate amount of colloid.

Microscopic. — Fig. 2 (X100) represents a photomicrograph of an area typical of the greater portion, in fact, of almost the entire adenoma. In certain areas there are aggregations of small follicles, many of which lie free in a matrix of interacinar colloid. The latter does not seem to have resulted from traumatic rupture of intact follicles, for the follicles, in the areas in question, are not broken and there is no evidence of hemorrhage. The follicles vary in size, nowhere being extremely large. There are many small ones. Intrafollicular colloid is present in fairly abundant amount. The follicular epithelium is everywhere of the low-cuboidal and even in many cases of the flattened type, and nowhere is papillary infolding of the epithelium apparent. There are no signs of the characteristic hypertrophy and hyperplasia of the thyroid epithelium. Nowhere does one see tall, columnar epithelium. In certain areas between the larger follicles there are aggregations of smaller follicles, apparently newly formed. The cytoplasm of the cells on the whole is moderately abundant. It stains well with eosin, and in it, upon close observation, is seen a sprinkling of fine pink-staining granulations. (The latter upon subsequent study proved to be mitochondria.) The nuclei stain well in hematoxylin. They are vesicular, oval or flattened, and contain usually a well-marked centrosome and numerous darkstaining chromatin granules. The oval or flattened nuclei are


most often pycnotic. There is no apparent increase in vascularity. Basing one's opinion upon these histological facts, one would conclude that the adenoma is functionally inactive.

Pathological Diagnosis. — " Foetal adenoma " of the thyroid gland.

Upon examination 11 days after operation, except for some feeling of weakness and loss of appetite, the patient's general condition was considerably improved. There was definite improvement in her previous symptoms of nervousness, palpitation, worry, " hot and cold flushes," and increased perspiration. The pulse rate, which before operation was relatively slow, showed a slight fall, being occasionally as low as 65 per minute.

The temperature varied between 97.4° and 98.6°. The respirations were 20.

The skin was drier than before operation.

All the eye signs of exophthalmic goitre were negative, including the Mobius sign, which was positive before the operation. There was no unsteadiness of the eyeballs in the extreme lateral position.

There was no difficulty in swallowing.

The neck, except for the results of the extirpation of the gland, was as before operation.

Reflexes as before.

Tremor, none.

There had been a loss in weight of 1.3 K. (2.86 pounds) since the operation.

The responses to the hypodermic administration of atropin and pilocarpin in the same dosage as before operation were definitely less.

One year following operation patient reports that she weighs 1-12 pounds (a gain of 12.7 pounds), and that she has been definitely benefited by the operation. Her pulse rate is 62 per minute. There is no tremor. Slight nervousness and palpitation persist. She reports also that she is taking care of a large family, a fact to which she attributes several of the symptoms which still persist but to a milder degree than before.

To summarize, then, we have here an illustrative case of a woman of middle age who showed in the thyroid gland a circumscribed swelling which had been present for several years, apparently unassociated with any recognizable symptoms. In the last year and a half a number of symptoms of mild hyperthyroidism had supervened along with the history of more rapid enlargement of the nodule. Before and at operation the thyroid gland itself did not suggest the appearance of overactivity. After removal of the tumor, considerable benefit to the patient ensued not only from relief of mechanical pressure, but also in regard to the symptoms of hyperthyroidism. The gross and microscopic examinations of the customary kind did not reveal evidence of hyperactivity in the adenoma. In fact, the general appearance is represented in the low-power photograph (Fig. 2) of a hematoxylin and eosin section, which is quite characteristic of the whole adenoma.

In the absence of the common criteria of thyroid overacts n\ such as have been mentioned previously in this paper, there remained the possibility that, in spite of this absence, the activity of some or all of the cells of the adenoma might be in excess of the normal, thus producing an excessive amount of active thyroid principle. The latter could then be tie- cause of the symptoms of hyperthyroidism, and still, locally m tie' adenoma, there might be an absence of cellular hypi and no diminution in the amount of stainable colloid in the follicles.


132 [Xo. 303


To determine this point it become* necessary to demonstrate, it' possible, by histological methods evidences of increased cellular activity. For this purpose a technique was employed which demonstrates clearly and fairly easily the presence, in the cell cytoplasm, of structures commonly known as mitochondria. The functional significance of the latter has been considered in a recent summary on this subject by E. V. C'owdry, 1 to which reference should be made for a complete account of these structures. 1 may say briefly that the mitochondria are structures occurring in the cytoplasm of all cells. They occur in the form of granules, rods or filament-. ( Observations made upon living cells in tissue cultures have furthermore shown that they may change their form. They were first observed by Altmann. 5 and more recently their functional significance has been more accurately studied. In their solubilities and staining reactions they resemble phospholipid and to a lesser extent albumins. They are undoubtedly closely related to the life process of the protoplasm of every living cell, and there is ample evidence that mitochondria play an active and fundamental role in cell activity.

A few facte that support this view may be mentioned. They are present in the cells not only of animals, but also of plants. They are more abundant in the active stages of the life of the cell and diminish progressively in number as the cells become senile. This is exemplified in the cells of the different layers of the skin. In the deeper layer where cell division and growth are more rapid, the mitochondria are not numerous, while in the more superficial cells, those either dead or dying, the mitochondria are either very few in number or entirely absent. Moreover, the mitochondria decrease in number as nne passes from nucleated to non-nucleated red blood cells. It is well known also that mitochondria are particularly abundant in immature embryonic cells, in which metabolic processes are very active. Eomeis 3 has found that mitochondria are very numerous in actively regenerating tissues. He used the term plasmosomes, a synonym for mitochondria. They have been observed, furthermore, to be increased in number in kidney cells after the administration of phloridzin. Other facts could be cited, which have been advanced by investigators to support the view that mitochondria participate in the processes involved in cell activity and metabolism. By some the mitochondria are said to be transformed into zymogen granules as in the pancreas, and thus to be the antecedents of the specific secretion of glandular cells.

In accordance with these facts it would seem probable that in glandular cells that are the site of increased secretory activity we should find in the cytoplasm an increased number of mitochondria over the normal. To determine this point a technique which has been devised by Bensley* was applied


1 Cowdry, E. V.: The General Functional Significance of Mitochondria. Am. Jour. Anat., May, 1916, XIX.

- Altmann, R. : Die Elementarorganismen, 1890. Leipzig, Veit & Comp., p. 145.

3 Romeis, B. : Das Verhalten der Plasmosomen bei der Regeneration. Anat. Anz., 1913, XLV, 1-19.

Bensley, R. R.: Studies on the Pancreas of the Guinea-pig. Am. Jour. Anat., 1911, XII, 308.


to the adenoma ami to the adjoining normal thyroid tissue with the results to be described. Before discussing the latter I should like to mention a word in regard to this method. The tissue to be examined should be absolutely fresh, and placed in the fixation fluid in small pieces immediately after removal from the body. If this precaution is observed and the technical steps recommended by Bensley are carefully followed, no difficulty should be experienced in obtaining satisfactory results. The fixation fluid is an osmic-acid, bichromate of potash and acetic acid mixture, and the subsequent staining consists in the application, after mordanting with potassium permanganate, of acid fuchsin with a counter-stain of methylgreen. The sections should be less than 5 micra thick. The mitochondria are stained a brilliant red and are readily recognized, particularly with a sharp counter-stain such as methylgreen.

Xow when the normal thyroid tissue adjoining the adenoma is studied after this technique has been applied, a picture resembling that illustrated in Fig. 3, as drawn by Miss E. Xorris. is obtained. The mitochondria, staining a brilliant red in acid-fuchsin, appear in lower power magnification as small granules, but under the higher power oil-immersion lens they appear as short thick filaments or rods. They are scattered fairly uniformly throughout the cell cytoplasm which is rather scant in amount. In the more flattened cells the mitochondria are more abundant at either side of the nucleus, but in the cells provided with a greater amount of cytoplasm they occur also along the lumen border of the cell. Eelatively rarely one sees cells in which the mitochondrial content is more abundant. In the space between the follicles, small aggregations of thyroid cells, without formation of acini but with the average number of mitochondria, are seen. The cytoplasm, scanty in amount, stains a faint green. The nuclei are vesicular in shape, stain faintly green, and often show the presence of nucleoli, which take on a darker green color.

The intrafollicular colloid stains homogeneously and appears light green which is often tinted a pink color, due to the amount of differentiation of the section in methyl-green or probably also to the age of the colloid. The latter, whenever present in the smaller, apparently younger follicles, is always greenish in color. Xo extrafollicular colloid was seen in the normal thyroid tissue.

If now we compare this picture with that obtained after applying precisely the same technique to the adenoma, results are obtained which are illustrated in Fig. 4. These appearances are quite characteristic of sections made from small blocks of tissue taken from numerous different areas in the adenoma. The mitochondria present essentially the same morphological features as in the normal gland. The strikingly greater abundance of the mitochondria everywhere in the sections of the adenoma, as compared with the normal gland, is at once apparent. This is true of practically all of the parenchymal cells regardless of whether these cells are tall columnar and contain a relatively abundant cytoplasm or whether they are flattened and poor in protoplasm. The cells themselves vary markedly in shape and size. Some are large


THE JOHNS HOPKINS HOSPITAL BULLETIN, APRIL, 1916.



Fig. 3. — Drawing of section (4 mm. thickness) representative of the appearance of the normal right thyroid lohe adjacent to the fcetal adenoma. Note the relatively small number of mitochondria in the thyroid cells. (Aceticosmic-bichromate fixation. Aeid-fuchsinmethyl green. X 390. Oil immersion.)



Fi<;. 4. — Drawing of section (4 mm. thickness) of " foetal adenoma " in right thyroid lobe and isthmus, to show the relatively large numbers of mitochondria in the parenchymal fells as compared with the adjoining normal thyroid cells ( cf . Fig. 3). Note also the large amount of extra-follicular colloid. X 390. (Technique same as in Fig. 3.)


May, 1916.] 133


and columnar: the greater number are low and cuboidal : and others are very much thinned out by pressure of the colloid contained within the follicles. Even the cells of the last type, presenting much the same appearance as the atrophic cells of an inactive colloid goitre, are rich in mitochondria.

The nuclei are on the whole slightly larger and somewhat richer in chromatin. The staining characters of nuclei and cytoplasm are in general the same in each instance. The intra- and extra-follicular colloid stains a homogeneous light green color. In several of the latter, desquamated parenchymal cells are seen containing great numbers of mitochondria. In some areas outside of the follicles colloid is seen in rather large amounts. Here and there solid groups of thyroid cells are -cen. with no indication of follicle formation and containing great numbers of mitochondria.

That analogous conditions are probably present in animal pathology was indicated to me recently in the study of a tumor of a dog's thyroid brought to me by G. B. Wislocki. A circumscribed encapsulated tumor, the size of a cherry, was found enclosed in the center of an otherwise normal-looking thyroid lobe. The findings in the gross and in the general microscopic examinations of the gland were much the same as those occurring in a somewhat similar case described and illustrated by Goodpasture and Wislocki, 5 in their study of the relationship in dogs of old age to cell-overgrowth and cancer. In the present instance, however, there was no degeneration to be observed in the center of the adenoma. The latter was in all likelihood a hyperactive adenoma, for, as compared with the surrounding normal thyroid tissue, it contained in its parenchymal cells mitochondria in far greater number. Furthermore, there was in this case a moderate hyperplasia of the usual type. It would seem from this that there is reason for believing that hyperthyroidism symptoms might readily occur, in the dog as in man, in cases of similar pathological involvement id' the thyroid gland.

In contradistinction to the case reported here, I havi i served several instances of encapsulated thyroid adenomata. unassociated with symptoms of hyperthyroidism, and with no


s Goodpasture, E. W., and Wislocki, G. B.: Old Age in Relation to Cell-overgrowth and Cancer. Jour. Med. Research, XXXIII, No. 3, p. 473.


increase, in fact rather a decrease, in the number of mitochondria present in the follicular cells. In three recent cases of thyroid adenomata associated with marked symptoms of hyperthyroidism, but without exophthalmos, the parenchymal cells have shown a great increase in the number of mitochondria in their cytoplasm. Another evidence, empirical perhaps, that the adenomata of this latter class are hyperactive, is shown by the subsidence of the symptoms of hyperthyroidism almost immediately after the surgical removal of this tissue so excessively rich in mitochondria.

It is evident then that a method or technique is needed that will give us the means for determining whether the individual thyroid cells are functionally hyperactive or not, for without it and with reliance placed solely upon the older criteria of hyperactivity as pointed out above, many clinical cases of hyperthyroidism cannot be correlated with the histological appearance or changes occurring in the thyroid gland. It is the purpose of this preliminary report to call attention to the value of. and the need for, finer cytological studies in determining glandular function, especially in a gland presenting so many variations in its pathological anatomy as the thyroid gland. It is further felt that in the study of the pathological anatomy of the thyroid gland, the mitochondria will prove to be a better index of thyroid activity than the histological criteria heretofore applied. Since the mitochondria occur normally in the thyroid cell, and since they are present in greatly increased numbers in the adenomata associated with symptoms of hyperthyroidism, it would seem probable that they are correlated with an overproduction of an otherwise normal secretion produced by the thyroid cell. It is interesting to speculate why exophthalmos is so rarely if ever associated with thyroid adenomata. It may be that there is a very different form of intoxication in the true Basedow'- disease. In the latter the thyroid gland, just as in the case of the toxic adenomata, shows a marked increase in mitochondria over the normal. There are. however, several differences in these two conditions in the number, morphology, size and distribution of the mitochondria, a description of which will be given in a later report. Interesting results will undoubtedly be obtained when studies are made on the occurrence of mitochondria in hyperplasias and pathologic new-growths occurring elsewhere than in the thyroid gland.


1' mm time to time there have appeared in medical literature reports of "renal diabetes." Under this term is undi a glycosuria which i^ the result of an abnormal permi of the kidney to sugar. The kidney in this pathological stat allow- M small amount of sugar to escape constantly in the


From the Medical Clinic of The Johns Hopkins Hospital


RENAL DIABETES.

I')V D. Si latek Lewis, M. D.,

and

Herman ". Mosexthal, M. 1>.

urine, while tin bl 1 sugar maintains a normal level of between 0.07 ;iik! 0.1 1 per i i ni. The body has lost none of its power to utilize carbohydrate and hyperglycaernia is not Eound as it is in true diabetes mellitus. Consequently, an increase or decrease of the i irbolr drati cons! ituents of the diet has little

tage of sugar in the blood or the qui exi ivied in the urine. These cases have none of the i


134 [Xo. 303


manifestations of diabetes niellitus, due either to a diminished ability of the body to utilize glucose or to the presence of a hyperglycemia ; there is no polydipsia, polyphagia or polyuria,, no loss of weight or weakness, no pruritus or furuncuk>any other symptom of the disease. According to the present conception of this condition, it remains stationary, the glycosuria showing no tendency to increase, nor does diabetes mellitus develop from it ; the subject continues in good health and without any abnormal symptoms or signs except a constant low-grade glycosuria. The data necessary for the diagnosis of renal diabetes are very few in number but sharply defined :

1. A glvcosuria, maintained at a fairly constant level and not markedly affected by changes in the carbohydrate content of the food.

2. A normal percentage of blood sugar while the urine contains glucose.

From this description, it is evident that the term " renal diabetes "' is a misnomer and that " renal glycosuria " would be more appropriate.

Thus far. very few cases of this interesting anomaly have been reported. Von Xoorden/ in his monograph on diabetes mellitus, does not consider the symptom-complex of renal diabetes to be firmly established. His skepticism is no doubt due to the small numljer of cases on record. Allen, 1 in his recent thorough summary, " Glycosuria and Diabetes." admits two cases, those of Bonniger* and Tachau. 5 as indisputable examples of this condition. Since that time, several other instances of apparent abnormal permeability of the kidney to glucose have been published. Bonniger 6 observed a man, aged 37, who on life insurance examination two years previously had shown a glycosuria. After 10 days of irregular sugar excretion, probably influenced by severe alcoholic poisoning, the urine on 33 subsequent days was remarkably constant in its glucose content, which varied within the narrow limits of 0.1 to 0.5 per cent. These percentages were maintained on a carbohydrate-free diet as well as when the food contained an ample amount of the usual starches or included 100 gm. of dextrose or cane sugar. The urine collected in four or five specimens during the 21 hours for a period of eight days showed the same quantity of sugar (0.1 to 0.6 per cent ) in each sample. The blood sugar was 0.0S per cent; some time later it was 0.06 per cent, and the urine which was voided before and after the latter determination contained 0.5 per cent of glucose. Bonniger ' subsequently reports that this case has been observed for six years (eight years since glycosuria was demonstrated by life insurance examination), that he still excretes small amounts of sugar, and is in perfect health. The son of the patient is also afflicted with renal diabet This case furnishes a convincing illustration of the existence of renal diabetes, provided that the sugar excreted was glucose.


-Von Noorden: Die Zuckerkrankheit, Berlin. 1912, S. 37.

Allen: Glycosuria and Diabetes, Boston, 1913, p. 544. 'Bonniger: Deutsche Med. Wehnschr., 1908, XXXIV, 780. -Tachau: Deutsch. Arch. f. klin. Med., 1911, CIV, 448. '• Bonniger: L.c. 7 Bonniger: Verhandl. d. Cong. f. inn. Med., 1913, XXX, 178.


The blood sugar is normal, the glycosuria is constant and does not van- in direct proportion to the ingestion of carbohydrates, the disease is not progressive, and, finally, its hereditary character, upon which some authors have laid stress, is noted. The instances of this condition subsequently reported have shown that the intensity of the glvcosuria is to a great extent, but not absolutely, independent of the carbohydrate intake. This is seen in our patient and is very evident in the following ease, which was published by Tachau : s

E., aged 21, merchant, suffering with transient acute nephritis and gastro-enteritis following an excessive indulgence in fruit.

Days p.. fc Urinary glucose,

observed. • gm. in 24 hours.

4 Carbohydrate free

6 Mixed (15S to 250 gm. carbohydrate)

15 Mixed (124 to 412 gm. carbohydrate) 1.1 to 6.0

3 Mixed plus 100 gm. dextrose 0.6 to 4.2

The days are grouped according to diet and the presence or absence of glycosuria and are not placed in chronological order.

Blood sugar determinations in per cent:

Fasting 0.085 and 0.086

After breakfast 0.061

1 hour after 100 gm. dextrose. .0.076, 0.109 and 0.082

The absence of glycosuria on some of these days can probably be explained by the fact that the level of the blood sugar varied at times and was on occasion depressed below the kidney threshold for this substance. It is known from the publications of Jacobson, 9 Strouse ™ and others, that there is a distinct rise of the blood sugar after meals. Since there is a universal tendency to hyperglycemia after meals, slight fluctuations in glycosuria are to be expected in typical instances of renal diabetes. The criterion of an absolutely constant quantity of urinary dextrose cannot, therefore, be insisted on.

Other cases, which are considered to be true examples of renal diabetes have been brought forward by Graham " and de Langen. 12 The reports of Frank," Eogue and Chalier " and Solomon ,s either lack sufficient data to establish the diagnosis of renal diabetes, or. as in some of Solomon's patients, appear to belong to cases of mild diabetes mellitus. Frank's exposition of increased renal permeability during pregnancy and after poisoning with mercury, uranium, chromium and cantharidin confirms the work of many investigators and furnishes suggestive evidence of the existence of a permanent renal glycosuria.

The question presents itself, why the renal barrier to sugar should be only slightly depressed, causing a renal glycosuria of such mild degree, and why the kidney threshold should not be more markedly lowered in some individuals, and conditions re


s Tachau: L.c.

•Jacobson: Biochem. Ztschr., 1913, LVI, 471.

10 Strouse, Stein and Wiseley: Bull. Johns Hopkins Hosp., 1915, XXVI, 211.

"Graham: Jour. Physiol., 1915, XLIX, p. XLVI (Proceedings*.

12 de Langen: Berl. klin. Wehnschr., 1914, LI, 1792.

"Frank: Arch. f. exper. Path. u. Pharmakol., 1913, LXXII, 3S7.

"Rogue and Chalier: Arch. d. mal de l'apparat digest, 1912, VI. 661.

"Solomon: Deutsche Med. Wehnschr., 1914, XL, 217.


May, 1916.] 135


sembling phlorizin glycosuria be found ? It is vers' likely that such instances do occur, but have hitherto usually been confounded with true diabetes. One example of such a case, however, is on record. Galambos " cites the following data of a patient, a man 50 years old, who has suffered with polyuria and polydipsia ever since he can remember. Observation was carried on over a period of 21 days during which time the glycosuria varied between 66 and 198 gm., and the concentration of urinary dextrose between 2.6 and 7.4 per cent. The carbohydrate content of the diet was between 50 and 354 gm. Frequent collections of urine in this case showed a marked constancy in the hourly excretion of glucose; the administration of 150 gm. of dextrose did not result in any marked deviation from this regularity ; on a day during which the 24-hour specimen was collected in five separate portions, it was found, on making the proper calculations, that 6.4, 4.4, 6.6, 4.8 and 6.6 gm. of glucose were excreted per hour in the various periods. These quantities are very much larger than in any of the cases hitherto reported. The blood sugar values, in per cent, were : During fasting, 0.09 and 0.05 ; If hours after oatmeal feeding, 0.07; and If hours after taking 100 gm. of dextrose, 0.17. The last figure is slightly above that which would be expected in most normal individuals," but is not sufficiently high to invalidate the conclusion that this case is one of renal diabetes. There was a considerable degree of acid isis. This is only to be expected with the enormous losses of glucose in the urine; the carbohydrate balance between intake and output was often negative. This case, therefore, illustrates the possibility of a renal diabetes of severe type, a type which approaches in its characteristics the phenomena observed in phlorizin poisoning. Whether this patient presents an extremely rare anomaly or a condition of more frequent occurrence than has hitherto been suspected can be determined only through further study.

The number of published cases of renal glycosuria or diabetes which stand the test of closer investigation have been relatively few. The following record may, therefore, be of interest :

YV. P. \V., Medical History No. 34774, male, white, age 29, born in the United States, a station agent, descended from Anglo-Saxon ancestry.

Family His tori/. —Father (aged 60), mother (aged 50), 1 brother and 4 sisters are all alive and in good health; one sister died of erysipelas. With the exception of marked obesity in one grandmother and several of her sisters, there is no history of hereditary disease; diabetes mellitus, heart trouble, kidney disease, apoplexy, gout, exophthalmic goitre and tuberculosis have never been found in the patient's family.

Habits. — Smokes 5 to C pipes a day; does not use alcohol; eats a considerable amount of bread but no excess of sweets.

Past History. — Measles and whooping cough In childhood, malaria IS years ago, pneumonia 17 years ago, varicella, complicated by otitis media on the right side, 15 years ago. Venereal infection is denied.

Present History. — Three years ago passed a life insurance examination. This is the only urinary test remembered, until six


"'Galambos: Deutsche Med. YVchnschr., 1914, XL. 1301. 1T Jacobson : L. c.


weeks ago, when the patient applied to his physician for relief from backache. At that time, a glycosuria was demonstrated. The backache cleared up shortly; the glycosuria persisted in spite of a restriction of the carbohydrates in the food. There never have been any other symptoms pointing to diabetes mellitus with the exception of transient paresthesia of the fingers (no loss of weight or strength, no polyuria, polydipsia or polyphagia, no skin involvement — pruritus, furunculosis or other condition— no muscular cramps, no pains in the extremities) ; there have been no evidences of pancreatic disease (no pain in the epigastrium, no fatty diarrhea) ; all indications of exophthalmic goitre have been completely lacking at all times (no exophthalmos, no thyroid enlargement, no vomiting, nervousness, cardiac palpitation or diarrhea) ; there have been no signs of acromegaly or gigantism pointing to hypophyseal involvement; there has been no history of a renal lesion (no headache, visual disturbance, dyspnea, vertigo, edema or albuminuria); there has never been any skin pigmentation to suggest a cirrhosis of the pancreas and liver, that is, a hemachromatosis.

For the last two or three years there has been a tendency to increased frequency of urination during the day but not at night. The quantities voided have apparently not exceeded normal. This is evidently a pollakiuria rather than a polyuria, which is borne out by the ward observations which will be detailed further on.

There has been a slight chronic cough associated with a moderate nasal catarrh and mouth breathing. There have been no night sweats, hemoptysis or " pleuritic pain."

Present Complaint. — The patient feels perfectly well and would not believe himself sick were it not for the persistent, " sugar in the urine."

Physirial Examination. — Height 5 feet 9% inches, weight 152 pounds; appears to be in the best of health and spirits; the skin and mucous membranes are not pigmented, their color is normal, they are as moist as those of a normal individual. The pupils are equal and react to light and accommodation; von Graefe's sign is absent. The pharynx is injected and there is a moderate degree of nasal obstruction, as indicated by persistent mouth breathing. The tonsils are not enlarged or inflamed. There is no pyorrhea alveolaris. The thyroid is barely palpable. The pulse rate averages 75: the pulse is regular in force and frequency and of normal volume. The radial artery can be rolled under the palpating finger, but is soft and elastic. The temperature is normal. The respiratory rate ranges from 16 to 24. The systolic blood pressure is 140, the diastolic 80. The heart's apex beat cannot be seen, it is barely palpable in the fifth interspace, 10 cm. to the left of the median line; the character of the apex impulse is a normal one; there are no thrills over the precordium; the area of relative cardiac dullness extends 3.5 cm. to the right of the mid-line in the fourth space, and 10.5 cm. to the left in the fifth; the heart sounds reveal no murmurs, the second sound over the aortic area is somewhat intensified and is louder than the pulmonic second sound. The lungs are normal except for slight dullness and somewhat prolonged expiration in the right supraspinous fossa, and at times a few dry rales, after coughing, over the same area. The liver and spleen are not palpable and there are no areas of tenderness or increased resistance over the abdomen. The patellar reflexes are very active. There is no edema of the face, back or extremities. On the left thigh there is a small eczematous patcli furrowed by scratch marks. The superficial lymph nodes are not enlarged. The hemoglobin is 100 per cent (Sahli), the red blood cells are 4,600,000 and the white blood cells are 8450 per cu. mm. The Wassermann test is negative. The urine on admission is clear, of reddish yellow color, specific gravity 1035, acid in reaction, negative for albumin, gives a distinct reaction for sugar, and on microscopic examination yields no casts or red blood cells: the qualitative tests for acetone and diacetic acid are negative: the 'phthalein test shows an excretion of 42 per cent in two hours; Ambard's constant determined at various times is 0.07, 0.11, 0.08, 0.10.


186 [Xo. 303


Impression. — The presence of glycosuria was well established. The urine gave a positive reaction with both the quantitative and qualitative Fehling-Benedict reagent, yielded gas on fermentation with yeast, and the unfermented urine rotated the polariscope to the right. The nature of the glycosuria will be subsequently discussed. There may have been a healed tubercular lesion at the right apex; impaired resonance, slightly prolonged expiration and inconstant rales in this region are not pathognomonic of a tuberculous focus; it is certain that in the absence of fever, sputum, night sweats, chills and loss of weight an active process is not probable and therefore of no significance in explaining the glycosuria. Of equally little importance is the nasal obstruction and pharyngitis. The kidneys are anatomically intact as far as the physical and urinary signs are concerned; the functional tests of these organs, however, reveal some impairment as shown by a slightly diminished 'phthalein excretion and an Ambard's constant barely within what has been in our experience the upper normal figure. The connection between such a diminished kidney function and a possible renal diabetes are of extreme interest. The small eczematous patch in this case could not be regarded as a complication of diabetes mellitus, since the hyperglycaemia, which is the direct etiological factor of such a condition, was lacking.

The urinary nitrogen was determined by the Kjeldahl process, the ammonia according to Folin, 1 * the glucose by Benedict's modification of Fehling's method," the acid bodies by Shaffer's procedure. 20 The method of Lewis and Benedict =1 was used in estimating the blood sugar.

In this case the blood sugar levels were normal, though the urine voided at the same time that the blood specimens were taken invariably contained glucose. The first three determinations showed a slight tendency towards a hyperglycemia. 0.11 to 0.13 per cent: these figures are probably too high, since, as noted in the foot-note to Table 1, the standard used to obtain th. in was at fault. This supposition is confirmed K\ the fai t that the IS subsequent results, unless they were carried out at times when abnormal amounts of sugar had been added to the diet, were strictly within normal limits, being either 0.09 per cent or less. It is known that the level of blood sugar in diabetes mellitus after the ingestion of glucose assumes a course different from that in normal individuals and presumably m those afflicted with a renal diabetes. In the present instance (Table 2) after the ingestion of 100 gm. of glucose, a. hyperglycemia of 0.15 per icnt was evident within 35 minute-: two hours and five minutes after the experiment was begun, the

'1 ! sugar level returned to normal and subsequently became

depressed below this figure. This is almost an exact duplicate of the curve which Jacobson 22 produced in normal persons under similar circumstances — a hyperglycemia of an average duration of two hours, a rise of the blood sugar, which reaches its maximum in about 30 minutes, and in many eases a hypoglycemia following the hyperglycemia. The maximum blood sugar values obtained by this author after this test varied from 0.12 to 0.23 per (cut. In diabetes Jacobson found somewhat the same results after the ingestion of 50 gin. of bread and it


14 Folin: Ztschr. f. physiol. Chem., 1902, XXXVII. 161. " Benedict: Jour. Biol. Chem., 1911, IX, 57. ""Shaffer: Jour. Biol. Chem., 1908, V, 211. '-'Lewis and Benedict: Jour. Biol. Chem., 1915, XX, 61. -Jacobson: L. c.


is only fair to assume that the figures would have been very much exaggerated had 100 gm. of glucose been taken instead. Talile :! demonstrates very clearly how the urine in the present case invariably contains sugar, rising as high as 2.2 per cent while the blood sugar maintains a normal level.

The urinary sugar is considerably reduced by restricting the carbohydrates of the diet, but is completely absent only after six days of starvation (Table 1) and reappears with a minimum amount of food. In diabetic patients exhibiting 11 to 13 gm. of glucose in the urine on a mixed diet, a sugar-free state has regularly been obtained after one or two days of starvation. That the amount of dextrose excreted is somewhat dependent on the diet, but to a very much less degree than in true diabetes, is seen in this instance as well as in some of the cases pre\ iously reported. Furthermore, it may he noted from Tables 1 and 3 that glycosuria was below 12 gm. on all the days when the diet was restricted, hut reached 30 gm. when the carbohydrate intake was raised. The two-hourly specimens (Table 3) showed a marked constancy m the amount of sugar eliminated during each day. Here again the amounts varied to some extent in direct proportion with the starchy content of the food. This is accentuated in the urinary collections of October 20-21 and October 21-22. in which 0.5 gm. of glucose was excreted per hour at night, as compared with o.S to 2.; gm. during the day. The direct effect of raising the blood sugar by carbohydrates is thus shown, since the kidney which is permeable to glucose at a subnormal level acts as an indicator of a normal blood sugar increase after meals.

The intensity of the acidosis during starvation, as shown by the quantitative and qualitative tests for the acid substances and the ammonia nitrogen ratio, is moderate in extent. It is difficult to interpret such a finding as indicative either of a true diabetes mellitus or of its absence. That acidosis occurs in normal individuals on carbohydrate as well as on total starvation, is a well-known fact. The observations made on fasting diabetics have shown that in some individuals the acidosis disappears rather promptly, while in others, especially the obese eases, it does not. 53 This has also been our experience. The interpretation of acidosis in fasting diabetics is especially obscure, not only because different patients show varying results due to their own constitutional peculiarities, hut also because the procedure of fasting in diabetes, as practiced up to the present, has demanded the administration of broth, alcohol ami In. arbonate of soda, all of which may either increase or diminish the excretion of acid substances. The studies in this instance would, therefore, make it possible to place this patient either in the category of those suffering with diabetes mellitus or those presenting a normal carbohydrate metabolism.

An attempt was made in our case to cheek the renal glycosuria by in. an- of calcium chloride. Injections of this drug diminish the permeability of the kidney to glucose." Fifteen


" Joslin: Am. Jour. Med. Sc, 1915, CL, 485.

Allen: New York State Jour. Med., 1915. XV. 330. "» Underbill and Closson: Am. Jour. Physiol., XV, 321.


Mat, 1916.1 L31


TABLE 1. URINE ANALYSES, BLOOD SUGAR DETERMINATIONS AND DIET.



Glucose 150 gm. (-30 gra. with each meal) .


Glucose 100 gm. with midday meal.


♦The first three blooil sugar determinations were made with a standard that evidently yielded too high results. A new and carefully controlled standard in the subsequent determinations invariably gave lower readings, even after the administration of dextrose.

t Legal's reaction for acetone and Gerhardt's ferric chloride test for diacetic acid were used, + indicates a trace, + + + + a maximal reaction. I No alcohol was given at any time.

TABLE 2. BLOOD SUGAR DETERMINATIONS AND DEGREE OF GLYCOSURIA AFTER A MEAL CONTAINING

100 GRAMS OF DEXTROSE.


Before the Meal.


A MEAL CONTAINING 100 GRAMS DEXTROSE. After the Meal.


Blood Sugar, per cent.. I'rine Glucose, per cent


...0.00 0.15 0.12 0.12 0.0U 0.U7

TABLE 3. HOURLY GLUCOSE EXCRETIONS AND THEIR RELATIONS TO DIET AND BLOOD SUGAR.



trine.


Blood


sugar.


Diet.



Urine.


B


ood sugar.


1


Diet.






Glucose.







s





Glucose.













£



"S











z









Date.






B ho









Date.















Time.


cc.


1


— 3


1


z


1


•2


bo


- u



Time.


cc.


1


bo


z. '=


1


1


s


I


r -t


- :d







.- a


ft,


H



la


a






a,


H





r

Q,


- ;_


Oct. 13-14 . .


Day.


8-10845


0.16 ,1.4


0.7




6


13


21


3


Oct. 10-2)1 .


Day.


6- 8 102


1.96


2.0


1.0




6


39


82


61




10-12370


0.14 0.5


0.3




10


12


7


1




8-10 110


1.78


2.0 1.0










1-2- 2 21m


0.24 0.6


0.3




12


s


fi




10-12 108


1.51


1.6,0.8




10


2







2- 4275


0.16 (J. 4 0.2









12- 2196


1.76


3.4


1.7




12


2.",


72


55




4- 6168


0.38 (j.6 0.3




5


'0


18 5




2- 41170


1.61


2.7


1.4










6- 8130


0.59 0.80.4









4- Its


2.08


2.0


1.0




>

46


72


32



Night.


8- 8325


0.64 2.1 ".2








Night.


6- 8 88

S- 6 455


2.94 2.18


2.. 5


1.3








Oct. 15-16 . .


Day.


li- 8133


0.69 0.9'0.5




6


29


.").> 6
















8-10220


0.79 1.80.9


9


0.09





Oct. 20-21 .


Dav.


0- 8 122


2.3


2.8


1.4


5


0.08


6


36


7S


►95




1II-12 1H4


i». 40 0.80.4




10


12


6 1




8-10132


1.2


1.6


o.s


0.08




..





12- 2 213


0.66 1.40.7




1:'


51


31 7




10-12 136


1.6


2.2


1.1




10


2


o





2- 4 1 2S


1.08 1.4 0.7









12- 2 170


2.3


4.0


2.0



0.11


12


i;i


71


•on




4- 6 <>

1.50 1.5 0.8


4


0.09


5


35


42 14




2- 4 114


1.8


2.0


1.0










6- 8131


1.20 1.60.8










4- 172


1.3


2 - 2


1.1





45


SO


85


Night.


8- 410


1.25 .-,.2ii.."i










6- 8106


., >


2.:;


1.2



o.os


















Night.


8- 8300


1.5










Oct. 10-17 . .


Dav.


6- 8


S2


o.S4 0.70.4




6


31


oil :il
















8-10


170


1.00 1.80.9


9


0.09





Oct. 21-22 .


Dav.


8-10280


1.02


7.4


2.7





33


,1


20




10-12


210


0.72 1.80.9




10


2


1




10-1224.3


1 . 2.5


3 . l


1.6










12- 2 200


1.08 3.1 1.6




12


r,

42 ;::




12- 2255


1 .56


i.n


2.n




In


5



1




2- 4 144


1.35 2.0 1.0









2- 41190


1.52


2.9


1.5




12


58


I::


24




4- 6110


1.66 1.80.9




•~>


36


42 30




4- 610H


1.64


2 7


1.4










6- 8 34


2.22 0.80.4









6- 8140


2.27


3.2


1 .6




.)


2,


41


45



Night.


8- 6197


2. 38 4.7'i.;,






' •



Night.



1 . .".4


...2 0.;,








50 gm, carbohydrate given as dextrose.


138 [No. 303


grams of calcium chloride by mouth on October 26, and 24 gin. on October 27 and on October 28. had no effect in reducing the sugar output. Further experiments in this direction were contemplated but could not be carried out because of the limited stav of the patient in the hospital.

SUMMARY.

From these studies it becomes apparent that this patient showed glycosuria, but none of the other abnormalities characteristic of an impaired carbohydrate metabolism. This case, therefore, may be added to the small list of those that point to the existence of a so-called renal diabetes or renal glycosuria. The slightly diminished phenolsulphonephthalein excretion, the slight elevation of Ambard's constant above the normal, as well as the glycosuria, point to a depressed kidney function. The absence of any further subjective or objective signs, pasl or present, leads to the conclusion that a renal glycosuria is an interesting anomaly, but of no importance to the organism, as a whole.

The question of prognosis in this condition is the most important problem which remains to be solved. It is well known that instances of true diabetes may persist for years without


changing from a mild to a severe type in spite of the lack of any systematic efforts at dietary restriction, thus resembling renal glycosuria. It is not certain that what is termed renal diabetes may not develop into diabetes mellitus, especially since comparatively little is known of the early stages of true diabetes. The number of cases of renal glycosuria thus far observed has been small and none of them has been followed for a sufficient length of time to ascertain whether renal diabetes is congenital, and not an acquired anomaly, and whether it may persist indefinitely without changing its characteristics. The intensity of renal glycosuria should vary with the degree of kidney permeability to dextrose. With a threshold only slightly depressed, an intermittent glycosuria often of an apparently unexplained origin may be present; with a very marked depression, changes approximating the conditions found in phlorhizin poisoning should develop. Intermediary degrees of kidney involvement should have glycosurias of corresponding intensity. If the present ideas of the relations of a diminished kidney threshold for sugar are true, all the grades of intensity indicated should be demonstrated in the course of time.


BILATERAL AND COMPLETE TRIGEMINAL PARALYSIS WITHOUT INVOLVEMENT OF OTHER CRANIAL NERVES.*

By Charles Metcalfe Byrnes, M. D.,

Instructor in Clinical Neurology, Johns Hopkins University.

(.From the Janus Buchanan Brady Uroloc/ical Institute.)


The anatomical relations of the trigeminal nerve as it emerges from the pons, its short intracranial course, and the protected position of its ganglion within the dural sheath suggest a probable explanation for the frequency with which this nerve escapes in diseases of the cerebral meninges.

Different opinions have been expressed, however, concerning the incidence of syphilitic affections of the fifth nerve, and Uhthoff ' claims that this nerve is involved in 14 per cent of all cases of cerebral syphilis. Forster 5 states that neuralgic disturbances are not uncommon, and that motor and sensory paralyses have been observed. Oppenheim = has also seen involvement of the motor root in one case, and von Ziemssen ' - a case with sensory changes, implication of other cranial nerves, and motor paralysis. In Lowenfeld's ! case, there was sudden isolated paralysis of the muscles of mastication upon one side, and Xonne 6 has frequently observed syphilitic. trigeminal affections, but usually in association with other cranial nerve symptoms. Hutchinson " makes the surprising statement that he has " scarcely seen paralysis of the fifth nerve except as the result of syphilis"; and, although only one fifth nerve is affected, " it shows no tendency to become complicated by involvement of other cranial nerves." He has, however, observed two cases in which both trigeminal nerves were affected.


Read before the Philadelphia Neurological Society, February 25; and before the Baltimore Neurological Society, March 17, 1916.


Unilateral motor paralysis has been observed in two cases by Spiller and Camp. 8 Sensory changes in the trigeminal area were not present, but in one case associated hemiparesis and bilateral oculomotor paralysis were noted. In the second case, fibrillary tremor of the right masseter muscle had been noted and there was a history of pain in the right trigeminal area; but the patient's condition was such that a satisfactory sensory examination could not be made. Other cranial nerves were not involved, but there was a recent right hemiplegia discovered at autopsy to be due to meningitis and temporal lobe softening, and the pontile and spinal tracts of the fifth nerve were degenerated.

Although various combinations of symptoms have been described in syphilitic affections of the trigeminal nerve, there are certain features of the disease which are more or less characteristic : The more common symptoms are confined to sensory disturbances in one or two branches of the nerve, and rarely involve all three branches; the affection is almost always unilateral and associated with implication of other cranial nerves; the motor fibers are rarely affected; complete motor and sensory paralysis is rare even when other nerves are involved, and extremely rare as an isolated paralysis: and lastly, the disease is sometimes bilateral.

Complete syphilitic paralysis of the fifth nerve has been described by Neiding' who refers to a similar observation by Kuttner. In Neiding's case, the symptoms, which were con


May, 1916.] 139


fined to the right trigeminal area, were attributed to syphilitic disease of the Gasserian ganglion. Other cranial nerves were not affected and there was no evidence of involvement of the central nervous system. Complete insensibility and motor paralysis were present upon the affected side, and taste was lost upon the anterior portion of the tongue. Examination of the blood showed a strongly positive Wassermann reaction, but a study of the spinal fluid was not made. After three months of active specific treatment there was marked improvement and the patient was considered clinically well.

Total syphilitic paralysis of the trigeminal nerve, either alone or in combination with other cranial nerves, is of sufficient importance to make even a clinical record of such cases valuable; and the peculiar syndrome observed in the patient whose illness is related in this paper is, I believe, unique in medical literature.

F. M., a male, unmarried, aged 29, who complained of " syphilis." was admitted to the service of Dr. H. H. Young at the Johns Hopkins Hospital, January 19, 1915. The family history is unimportant, and there is a personal history of the usual diseases of childhood, several attacks of malaria, and at the age of 19 gonorrhoea complicated by a double epididymitis. Six weeks ago, December 4, 1914, he noticed a sore upon the left side of the foreskin which was diagnosticated as a chancre, but for which he received only local treatment from his family physician. The primary lesion healed, and the patient considered himself well until January 9, 1915, when he began to complain of severe headaches, sore throat and a profuse skin eruption.

Examination upon admission to the hospital shows the presence of a hard chancre on the foreskin slightly to the left of the median line. Its center is covered by a small scab, beyond the edges of which there is an indurated area, measuring 1x2 cm. The inguinal glands are indurated and enlarged, and over the trunk and forearms there is a maculo-papular eruption.

Salvarsan, 0.6 gm., was administered intravenously, January 19, 1915; it was followed by a somewhat severe constitutional reaction. A second dose, of 0.6 gm., was administered January 26, to which he reacted only slightly. Business affairs called the patient away from Baltimore, and on February 2, without receiving further injections of salvarsan, he left for Porto Rico, with directions for taking " mixed treatment " by the mouth. The treatment was faithfully adhered to during his absence, until the following symptoms made their appearance.

Upon returning from a long automobile ride, March S, 1915, three months after the primary lesion, he complained of ringing in both ears and severe headache. The next morning these symptoms had subsided, but after another long drive he went to bed because of a return of the intense headache associated with a chill, fever, nausea and vomiting. He was treated for " la grippe " for three or four days, after which all of the symptoms disappeared except the headache, which persisted and gradually became more intense; there was also a severe pain in the left side of the face " resembling facial neuralgia."

These neuralgic attacks continued until about March 14, when the patient noticed that the entire left side of the face felt numb, and chewing upon this side was difficult. Numbness in this region was so pronounced that movements were not fully appreciated, and he felt, when smiling, as if the face were drawn to the right side; but when this act was performed before a mirror he could notice no difference in the movements of the two sides of the face. Six days later, March 20, the right side of the face became slightly numb, without, however, any preceding pain, and it was almost impossible to masticate anything solid. Within two days the condition had so progressed that the entire front of


the head and both sides of the face were completely numb, and it was impossible to chew or even close the jaws. There has been no difficulty in the movements of the eyes or lids, nor is there a history of diplopia. Taste, swallowing, speech and movements of the tongue have not been impaired, and control of the arms, legs and sphincters has not been disturbed.

The patient became alarmed about his condition and decided to return to Baltimore, where he arrived March 30, and was admitted for the second time to the service of Dr. Young, who, on April 3, asked me to see the patient, when the above history was obtained. At this visit it was also learned that headache, nausea and vomiting, which had been prominent symptoms during the journey to Baltimore, since admission, had been less frequent; but that within the past two days he had experienced severe pain in the right thigh and difficulty in moving the right foot.

Physical examination by Dr. Cameron reveals no abnormality in the thorax or abdomen, and a laboratory report upon the blood and urine states that in the former there is a leucocyte count of 13.600, and that in the latter sugar and albumin are not detected. Since admission the temperature has varied from 99 to 101.4° F.

Examination of the nervous system is as follows: The patient is lying in bed with the mouth partly open, and is unable to close it when requested to do so. He looks ill, and complains of headache and pain in the face.

There are no subjective disturbances of the olfactory nerve, and when tests are made with valerian and oil of cloves, these substances are correctly named.

There is no disturbance of vision and the optic disc in each eye is of good color, the margins are well defined, the veins are not engorged, and the lamina cribrosa is visible.

Both pupils are slightly dilated, but equally so, and respond promptly to light, directly and consensually, and during accommodation. The extrinsic ocular muscles act normally in all movements of the eyes, and there is no nystagmus or strabismus. The left upper lid shows slight ptosis and there is consequent narrowing of the left palpebral aperture. It is stated, however, that this condition has existed since birth, and that it has not increased since the onset of the present illness. Movement of the upper lid is unimpaired.

The Fifth Nerve. — The patient complains of almost constant headache, pain in both ears, and numbness of the entire face. Objectively, there is complete loss of tactile, thermic and pain sense in the entire sensory area of both trigeminal nerves, except that in the distribution of the left maxillary nerve a pinpoint is occasionally recognized as such, although it does not produce a sensation of pain. Corneal sensibility is completely lost upon both sides, and when the eyes are closed, irritation of the nasal and buccal mucous membranes produces no response from either side, nor is the patient cognizant of what is being done. All forms of sensibility, except deep pressure, are lost upon both sides of the tongue in its anterior portion.

The motor portion of each fifth nerve is completely paralyzed and the lower jaw hangs drooping from its articulation, and cannot be closed voluntarily or moved in either lateral direction (Fig. 1). Tremor of the temporal and masseter muscles is not observed, but these muscles, upon both sides, fail to respond to faradic stimulation, and their reaction to the galvanic current is slow and lazy.

At rest the face is symmetrical and the nasolabial folds are of about equal intensity. In wrinkling of the brow, frowning, closing the eyes, and showing the teeth, the movements are equally well performed upon the two sides (Fig. 2). Taste, when tested with solutions of sugar, salt, acetic acid, and quinine, shows no impairment upon either side of the tongue, anteriorly or posteriorly.

A watch is heard slightly better with the right than with the left ear; and, because of this auditory defect, the patient was later referred to Dr. Jas. Bordley, who examined the ears and reported


140 [Xo. 303


that moist eczema was present in both external auditory canals. The vestibular portion of the eighth nerve was not examined minutely, but there were no definite subjective or objective evidences of disturbance in this division of the nerve.

There has been no difficulty with speech or in swallowing except that due to inability to move the lower jaw; and fluids do not regurgitate. The soft palate, although insensitive upon its oral surface, moves equally well on the two sides when saying " Ah," and the palatine muscles respond promptly to faradic and galvanic stimulation. The sternomastoid muscles and the trapezeii function normally and show no weakness or atrophy upon either side.

The tongue is protruded promptly and in the median line, it is slightlv tremulous, but is under good control; the motor power is not diminished, and the response to both forms of electrical stimulation is prompt and vigorous.

A jaw-jerk is not obtained. The biceps and triceps tendon jerks are easily obtained and are equally active upon the two sides. Both knee-jerks are slightly hyperactive, and the left is greater than the right. The tendon Achillis jerks are present, but this reflex is more active at the right ankle. There is no ankle or patellar clonus. The epigastric, abdominal and cremasteric reflexes are equally active upon the two sides. Plantar stimulation and decending tibial irritation produce plantar flexion of the great toe upon each side.

There is no evidence of ataxia, weakness, or loss of voluntary control in either upper extremity, and sensation in the arms is normal. When standing with the feet together and the eyes closed, there is some unsteadiness; but the heel-tibial test is accurately performed with either leg. Walking is slightly impaired because of pain in the right leg and difficulty in flexing the right foot, which gives the characteristic "steppage" quality to the gait. Motor power in both legs is well preserved, except that upon the right side there is weakness in the tibial and peroneal group of muscles, and these muscles show diminished excitability to both forms of electrical stimulation and respond slowly to the galvanic current. Deep pressure over the right peroneal nerve is definitely painful, and there is moderate diminution of cutaneous sensibility in the area innervated by this nerve. Sensory changes other than those already noted in connection with the head and outer portion of the right leg are not detected.

Lumbar puncture.— March 31. The spinal fluid is slightly cloudy and under increased pressure. Cell count, 740 per cu. mm. A stained smear shows that the majority of these cells are lymphocytes, but a few polymorphonuclear and epithelial cells are observed. The globulin is greatly increased, and the Wassermann test is strongly positive. Serum Wassermann, positive. (Dr. Cameron.)

A clinical diagnosis of syphilitic meningitis with bilateral involvement of the trigeminal nerve, and syphilitic peroneal neuritis was made.

Treatment and Subsequent Course— April 3. Salvarsan, 0.4 gm., was administered intravenously. The reaction was moderate.

April 5. The headache is less intense and the patient is generally more comfortable. There is no involvement of other cranial nerves, and the neurological examination is the same as at the first visit. Mercurialized serum (Hydrarg. bichlorid. gr. 1/25) administered intradurally. An examination of the spinal fluid at the time of administration is as follows: Fluid, slightly cloudy; pressure 220 mm.; cell count. 510 lymphocytes; globulin increased; a Wassermann test was not made. Reaction to the treatment was moderate. The temperature did not rise above 99.6° F., there was some pain in the legs for 24 hours, but no nausea or vomiting.

April 10. General condition much improved. The headache and pain in the face almost entirely absent. Salvarsan, 0.6 gm., administered intravenously. Reaction moderate.


April 12. General condition improved. No involvement of other cranial nerves. Neurological symptoms unchanged. Mercurialized serum (Hydrarg. bichlorid. gr. 1/25), administered intradurally. Spinal fluid examination: Fluid clear; pressure 220 mm.; cell count 165; globulin increased; Wassermann, not made. Reaction similar to that following the first treatment, except that the temperature rose to 101.4° F.

April 17. Salvarsan, 0.6 gm., administered intravenously. Reaction moderate. The patient was discharged from the hospital two days later, with instructions for stimulating, electrically, the paralyzed muscles, and the request to return at intervals for further treatment. Examination at this time shows that the neurological condition is unchanged. The headache and pain in the face have entirely disappeared, but there is still complete sensory and motor paralysis of both fifth nerves and right foot-drop.

April 20. Admitted to the Church Home and Infirmary for further treatment. Examination to-day shows a very slight return of sensation in each mandibular and lingual division of the trigeminal nerves, but the entire area supplied by the two upper branches of each fifth nerve is still completely anaesthetic. Mercurialized serum (Hydrarg. bichlorid. gr. 1/25), administered intradurally. Spinal fluid examination: Fluid clear; pressure 190 mm.; cell count 70; globulin, trace; Wassermann test, not made. The treatment was followed by a rise of temperature to 101° F., intense pain in the legs and slight headache.

April 21. The corneal reflex in each eye is absent, but the patient says he can feel the cotton when it is drawn across the cornea.

April 26 and May 3. Salvarsan. 0.6 gm., administered intravenously.

May 4. Examination to-day shows that there is still complete insensibility in the ophthalmic division of each trigeminal nerve, and the corneal reflex is absent in each eye ; but there is a slight return of sensation in the maxillary and mandibular distribution upon both sides, although portions of these areas are still com paratively anaesthetic. The lower jaw can now be moved so that approximation of the teeth is possible. Because of the marked reaction following the previous intradural treatment, and the definite improvement in symptoms, it seems advisable to discontinue radical treatment for a while, and mercurial inunctions are ordered. .

May 26. The patient's general condition shows marked improvement, and he states that he can now feel drafts of air upon the face, or in the nostrils when respired, and that he knows when he has his hat on. There is still pronounced weakness of the muscles of mastication, and objects cannot be held between the teeth, although the upper and lower jaws can be approximated. Bilateral corneal anaesthesia persists, and sensibility in the distribution of both maxillary and supraorbital nerves is still greatly impaired; but in each mandibular area sensation is practically normal The right foot-drop is still present.

May 28. Lumbar puncture and intradural administration of mercurialized serum (Hydrarg. bichlorid. gr. 1/25). To these he reacted onlv slightly. Spinal fluid examination at this time: Fluid clear; pressure 240; cell count S: globulin, faint trace; Wassermann negative; serum Wassermann negative.

The following dav the patient was discharged from the hospital, and it became necessary for him to leave Baltimore two weeks later without having received further treatment except the continuation of mercurial inunctions. In the course of eight weeks, then five doses of salvarsan intravenously, alternating with four doses of mercurialized serum intradurally, were administered at the intervals recorded in the hospital notes.

A letter from the patient dated November 26. 1915, states: " My health has been splendid. My foot is normal again and my jaws allow me to eat everything now. The left side, which as you know, was hit hardest, is still without the fleshy muscle. My eyes, nose and upper lip are still very numb.'"


THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1916.



Fki. 1.— Photograph of the patient, April 5, 1915, showing complete jaw-drop from bilateral fifth nerve paralysis.


PLATE XXIII



Pia. 2.— Photograph of the patient, April 5, 1915, showing his ability to perform ordinary facial movements. The lips cannot be closed completely because of immobility of the lower jaw.


May, 1916.] 141


Complete motor and sensory paralysis of both fifth nerves,

without implication of other cranial nerves has. I believe, not been previously recorded in medical literature. It is true Hutchinson, Leudet. and Uhthoff have reported instances in which both nerves were involved, but an analysis of their cases shows that the affection was quite different from that which I have just described.

In Hutchinson's cases, the two nerves were not simultaneously affected, and he does not state to what extent they were involved, or whether there was implication of other cranial nerves. Leudet's™ patient, when first examined, showed disturbance of vision, ptosis, strabismus in the left eve. muscular disorders of the right eye, and anaesthesia in the entire distribution of the left trigeminal nerve. He was seen at intervals during a period of four years, after which, at the final observation, it was noted that the condition upon the left side of the face bail remained practically unchanged: that, in addition, the right eye was totally blind and the entire right side of the fare was anaesthetic. Xo note was made upon the condition of the motor portion of either fifth nerve. An autopsy was secured and it was found that the left Gasserian ganglion, which was pale, contracted, and reduced in size, had been invaded by an exostosis of the temporal bone.

Seventeen years later Labarriere" refers to a case of syphilitic involvement of both trigeminal nerves, which, by some students (if the subject, appears to be regarded as an additional instance of the affection, but the case in question, Xo. 1:! in Labarriere's studies, is identical with one described by Leudet. to whom full credit is given in the author's thesis.

Although it is impossible, without anatomical evidence, to determine the exact character and location of the lesion in my case, the syphilitic nature of the affection is evident. Haemorrhage into, or. acute inflammation of both trigeminal nuclei would, of course, produce bilateral fifth nerve paralysis : but the subacute onset of the disease does not suggest haemorrhage, and it is improbable that a pontile lesion of this extent could occur without neighborhood symptoms, or even a fatal termination.

That intense meningitis was present is indicated by the unusually high cell count in the spinal fluid; but it is unusual to witness this degree of meningitis without implication of other cranial nerves. Bilateral syphilitic ganglionitis suggests a probable explanation, but such a condition, if confined within the dural covering of the ganglia, makes it difficult to explain the marked lymphocytosis in the spinal fluid. Diffuse meningeal inflammation upon the surface of tin' pons might involve tin- trigeminal roots upon each side, and account for the cytological changes in the spinal fluid. It is not probable, bowever, that the sixth nerves would have such a

lesion. Local meningitis upon each lateral aspeel of tl bul imt extending across the mid-line, might produce bilateral trigeminal radiculitis and resulting paralysis of both without implicating the sixth nerve, or those lateral fifth nerve. Such a lesion would account for the lympho and at the same time explain the long duration, and perhaps


permanency of some of the symptoms, from central deg tion of the sensory fibers. While it may be difficult to locate, exactly, the lesion in this case, there is little doubt that the symptoms were due to intracranial involvement of both fifth nerves.

There are two important clinical features which deserve especial emphasis. Trophic disorders following lesions sory ganglia are not infreqently observed, and it is not improbable that the bilateral auricular eczema may have bi this origin. In Xeiding'> case, furunculosis of the nasal cavity upon the affected side was attributed to the same i

A.i i ording to Nonne, Itumpf has been unable to find in the literature a single instance of syphilitic disease of the fifth nerve in which taste was lost. This statement is, however, contradicted by Xeiding. in whose patient taste was lost upon the anterior two-thirds of the affected half of the tongue. I □ view of Rumpf's studies and the preservation of taste in the case which I have studied, it appears that the centripetal fibers conducting this special sense do not enter the central nervous system by way of the Gasserian ganglion. It is not improbable that the loss of taste in Xeiding'- rase may be explained by an extension of the inflammatory process into the trunk of the mandibular nerve with involvement of the incorporated fibers of the chorda fcympani.

It is a pleasure to acknowledge my indebtedness to Dr. Hugh H. Young for referring the patient to me. and for the privilege of conducting tin- study in the Brady Crological Institute.

BIBLIOGRAPHY.

1. Uhthoff, W.: Die Augenveranderungen bei den Erkrankungen des Gehirns. Graef-Saemisch Handb. der gesamt. Augenheilkunde, 1911, Bd. II, Aufl. II, 1088; also, Ueber die bei der Syphilis des Centralnervensystems vorkommenden Augenstbrrungen, Leipzig, 1893.

2. Forster, E.: Die Syphilis des Centralnervensystems. Lewandowsky's Handb. der Neurologie, 1912, Bd. Ill, Spec. Neurol. II. 395. Springer, Berlin.

3. Oppenheim, H.: Die Syphilitischen Erkrankungen des Gehirns. Nothnagel's Spec. Pathol, u. Therap., 1896, Bd. IX. Th. 2. 4G ff. ; also, Lehrbuch der Nervenkrankheiten, 1908, Bd. I. 544; Bd. II. 1103.

4. Von Ziemssen: Leber Lahmung von Gehirnnerven durch Affektionen an der Basis cerebri. Virch. Arch., 1S58. XIII. 210. 376.

5. Lowenfeld, L. : Die Syphilitische Erkrankungen des Xervensystems. Lehrbuch der Geschlechtskrankheiten. Letzel, 1892, 240

6. Xonne, M.: Syphilis and the Xervous System. 1913, 142. Lippincott & Co.

7. Hutchinson. J.: Syphilis. 1904,214. Cassell & Co.

8. Spiller and Camp: Syphilitic Paralysis of the Trigeminal Xerve. Amer. Jour. Med. Sci., 1910, CXXXIX, 402.

9. Xeiding, M.: Die Isolierte Lahmung des X. trigeminus. X' u rol. Centralis., 1914, XXXIII, 615.

10. Leudet, E. : Recherches cliniques pour servir a 1'histoire des lesions viscerales de la syphilis. Moniteur des sc, med. et pharmaceut., 1860, II, 1188.

11. Labarriere, E.: Essai sur la meningite en plaques ou sclereuse. These de Paris, 1ST:


142 [No. 303


DIGESTION: AN HISTORICAL SURVEY.

By Raymond J. C.uiy, M. D., Lake View, Wash.


Anv survey of the views that have been held by mankind in the past on the subject of animal digestion and bodily nutrition must necessarily be synchronous with the history of medical science.

The majority of ancient medical records that have come down to us are largely occupied with references to diet and descriptions of imaginary causes of ill-health. In the absence of direct testimony as to the conception held by the ancients with regard to the manner in which the food they ate nourished their bodies, we are forced to rely upon statements throwing a side-light on the general subject.

The ancient Egyptians held the belief that food was the chief source of disease, and they followed precept by practice in taking a purgative and an emetic three times a month. However, there was also present in the Egyptian mind the idea that the body was ruled by demons, and that digestion was performed by the aid of a "demon" or spirit, whereas indigestion was due to the anger of the spirit.

The authors ' of the great epic poems of the Hindus have given evidence, however, of the existence of other theories related to demonology, according to which principles or humors were supposed to reside in the body and to direct the natural digestive processes. Thus the Aryan writers recognized three principle humors: Vata — situated between the feet and the navel — or Wind; Pitta — between the navel and the heart— or Bile; Kafa — between the heart and the top of the head — or Phlegm.

Kafa was predominant during the period when the food was in the mouth ; Pitta, during the course of digestion; and Vata. after the food in the stomach was fully digested. If from any cause any one of these principles became unduly prominent, the condition of the bowels was affected. Thus, when Vata exercised too strong an influence, the bowels were costive; when Pitta, or the bile, was in the ascendant, they were loose; whereas they acted normally when Kafa was the most powerful.

These writers also describe a Pachaka, or fire of digestion, situated between the stomach and the small intestine, which assisted digestion and imparted heat to the body. Pachaka was also able to separate the nourishing portions of the food from the dejecta. 2

Among the Chinese the medicine and physiology of yesterday are the same as that of to-day. They and their civilization, like mountains, have attained a certain limited height, have existed there, inflexible and almost unchanged, for thousands of years. Physiology occupies the lowest grade in Chinese medical science and nothing of value or interest relating to the subject of digestion is to be found in their medical literature.


1 See Jee: History of Aryan Medical Science, London, 1S96.

- By some this body was looked upon as being identical with Pitta, or bile. The author of the " Rasa-pradipa " imagined it to be a minute heating substance situated in the centre of the navel.


Among the ancient Chaldeans, Babylonians and Persians we find that medicine probably presented the lowest form that has ever existed in civilized communities. The Chaldeans appear to have contributed absolutely nothing to the general stock of medical knowledge.

The medicine of the Medes and Persians resembled somewhat that of the Chaldeans, but had a still closer analogy to that of the Hindus, with the important difference that it produced no Susruta or Charaka.

Turning our attention to early Greece, we find that their philosophy exercised so essential an influence upon their medicine that the fundamental doctrines of the former formed the theoretical principles of the latter, and we cannot well keep the two separate. In fact, the whole medicine of the Greeks bears the special character of a philosophical science, if we except that of Hippocrates alone.

Nevertheless, from quite an early period, the medical writers of the ancients recognized that the stomach was one of the chief organs concerned in digestion and they paid considerable attention to it. According to these Grecian natural philosophers, the food, after it was taken into the stomach, putrified or was cooked. Anaxagoras (500-428 B. C), a member of the Ionic school (600 B. C.) and teacher of Pericles, imagined that the animal body, by means of a kind of affinity, appropriated to itself from the nutritive supply the portion similar to itself. His philosophical influence was great, but a more important influence, especially later, was exercised by Empedocles (504443 B. C), whose assumption of the four elements — water, air, fire, and earth — formed a foundation stone for the doctrines of Hippocrates II of Cos, justly named the Father of Medicine.

It is not within the province of this paper to extol or to magnify the achievements or failures of medical celebrities, except in so far as they may be related to the historical development of our knowledge of digestion. Hippocrates taught that gastric digestion was brought about by a sort of internal cooking or coction — " pepsis " (digestion) — possibly through the agency of the " innate heat " s of the body. The views of the Hippocratists were based upon the assumption of the four elements of Empedocles — fire, water, earth and air — whose mixture and cardinal properties (warmth or heat, coldness, moisture and dryness) formed the body with its constituents. To these corresponded the cardinal fluids, blood, phlegm, black and yellow bile, in the order mentioned. The heat or warmth from the blood caused digestion of food. The liver formed blood and bile and assisted the process of coction in the stomach by increasing its heat. To certain foods were ascribed qualities corresponding to the four humors, and such foods were recommended for maladies due to excess or defect of the humors. Thus to Hippocrates and his followers we owe the


3 Callidum innatum, the " animal heat " of later physiologists. (See Harvey.)


May, 1916.] 143


foundation of a science of dietetics. But about their ideas on the physiology of digestion nothing further need be said.

Next there appeared the philosophy of Plato (427-347 B. C), which, paying slight respect to all facts and holding all observation by the senses as deceptive, won a controlling influence over medicine. Plato, though the noblest of philosophers, has hardly deserved well of the profession of medicine. As so often happens, the enunciation of a rational doctrine by Hippocrates tended to cause a reaction, and men now began to seek to deduce the underlying principles of physiology and disease, not from the study of facts, nor from the evidence of the senses, but from purely mental speculations. Eeflection ranked higher than experience. The hold which this method of solving physiological problems obtained on the physicians and thinkers of that time retarded the advance of physiological knowledge by a period only to be reckoned by centuries. Plato, for instance, gravely propounded the theory that some of the fluid drunk passed through the wind-pipe into the lungs, and there served to cool the heart ; the liver served the lower desires ; the spleen furnished an abode for the impurities of the blood. The intestine was long and tortuous, in order that the food need not be renewed so often and thus disturb the contemplations of the mind.

Aristotle (384-321 B. C), the teacher of Alexander the Great, exercised no such important and immediate influence upon the views of ancient medicine as did Plato. He did not, like Plato, call about him a numerous school of followers: nevertheless, his great mind supplied for centuries the principles of thought and observation, and the material for the extension of all branches of knowledge, but especially of the natural sciences, of which he is considered the creator. He did much to break down the excessive idealism current in the system of Plato, and to bring thought back into more realistic grooves. Like the Father of Medicine, he looked upon digestion as brought about by a process of coction in the stomach, the resulting chyle proceeding to the heart. He looked upon the blood as the medium by which the nutritive material for the growth and warming of the body was conveyed through the vessels. Bile he regarded as a useless excrementitious product.

The school of Alexandria, founded by Herophilus and Erasistratus (about 330-280 B. C.) covered a period, which when compared with the preceding dogmatic tendency of medicine, must be regarded as an epoch of realism. 4 It was distinguished by the appearance of the famous founder of human anatomy, Herophilus of Chalcedon, and of Erasistratus of Inlis, a physician valued no less highly than his contemporary. They, however, differed widely in their tenets.

Herophilus possibly discovered the chyliferous and lymphatic vessels, and the duodenum, which he named; he also describi d the liver quite accurately. He was a follower of Hippocrates and of the humoral doctrine. Erasistratus, however, discarded the humoral system, and propounded one of his own, based upon the theory that the arterial vessels and heart contained " vital

4 Called by Baas, without much error — " The epoch of antique scientific, or exact, medicine."


spirits "" (pneumata). He ascribed digestion to the result of trituration of the food between the stomach walls (Iatrophysician!), nutrition to the addition of new particles, and secretion to the action of what he termed the non-attractive force. He thought that the bile was useless, the spleen superfluous, and showed that fluids did not enter the air passages.

Few records have come down to us of the medical opinions current among the inhabitants of early Bome, but in so far as we can speak of such an art, it did not rise above the very first rudiments. Gradually with the advent of Grecian medical influence some advancement was made.

At a much later time (200-131 A. D.) flourished the most famous of all the Roman physicians. Claudius Galen, of IVrgamus. He was a man who not only knew all there was to know in his age, but who also possessed sufficient talent and originality to acquire the position of a medical dictator, and to maintain it for more than a thousand years. His physiology, though somewhat marred by excessive theorizing, was admirable. Following Hippocrates and the Alexandrians, he emphasized the great importance of the study of anatomy and physiology, and performed many experiments in both of these sciences.

Galen believed that the food, after it reached the stomach, was digested by the process of " coction "; the results of digestion were then carried to the liver by the portal vein, where they were transformed into blood (an important error which was not discarded until the 17th Century). This blood, now called " natural spirits," was then carried to the heart where by the aid of the innate heat of this organ, it was laden with " vital spirits." The heart then drove into the lungs, through the pulmonary artery, as much of the blood as was required for their nutrition. At the same time the remainder of the blood was driven through the veins to all parts of the body, supplying its various portions with nutriment. Galen, therefore, considered the venous portion of the circulation as the seat of nutrition. The arterial blood (blood laden with vital spirits), upon reaching the brain, there generated the " animal spirits."

Little of interest or of value can be gathered from the writings of those who followed Galen. For a period to be measured only by centuries the current opinions were only variants of Galen's views. In the dark ages of Medieval Europe the tendency of all knowledge was to recede rather than to advance; indeed, the influence of Christianity tended to hasten the decline of medicine instead of advancing its progress.

The standard of Arabic medicine, it is true, was at its highest development from the 8th to the 10th Century, but it offers us little or nothing in the way of advancement in physiological knowledge.

Early in the history of the Middle Ages, we find medicine and religion more or less firmly united together, and, from the 6th Century onward, everything medical gradually fell into the hands of the Church, and especially of the monks, whose ignorance of medical science is only too well known to medical historians. The authority of the Church in all branches of knowledge soon became paramount, and for many centuries it controlled more or less absolutely the gates of learning. The search for truth ceased to be the study of natural phenomena


144 [Xo. 303


and the search for the reason why : it narrowed itself down to asking, " What does the Church say about it!' " Truth and science came to mean simply that which was written, and inquiry became mere interpretation.

However, with the dawn of the Renaissance, the various medical sciences — anatomy, physiology and chemistry — again began to develop and the writings and teachings of such men .1- Vesalius (1514-1564). Servetus (1509-1553). Paracelsus | 1 193-1541 i. and Borelli (1608-1679), were in part the instrument- which served to shatter to pieces the idol of authority, which was never to be put together again.

Vesalius contributed little or nothing, directly,, to the science of physiology, but by his anatomical dissections he paved the way for many future physiological discoveries; and in truth we may look upon him not only as the founder of modern anatomy, but also as the distant forerunner of the English physiologist, William Harvey ( Ki>-1m,; i. whose discovery of the circulation of the blood opened up the avenues for scientific physiological and chemical research which has given so many us discoveries to the world.

Paracelsus exerted a great influence upon the development of medicine, especially chemical physiology, through his! ings in mystic alchemy, so that by some historians he is called the founder of chemical physiology.

Borelli. likewise, by his numerous experiments and discoveries in the new and infant science of physics, of which he was the real founder, hastened the development of physiological knowledge.

The 17th Century saw the birth of two distinct sciences — physics and chemistry — the latter emerging from a mystic alchemy. It was not long before they were pressed into the e of physiology, sometimes unwisely, whereby the school of physiology proper was split up into the school of those who would explain all the phenomena of the body on physical and mathematical principles, the iatro-mathematicdl or iatrophysical school, and into the school of those who proposed to explain all the same phenomena as mere chemical events, tin 1 iatro-cht micai -ehool.

In the study of the historical development of our knowledge of digestion, it is necessary to inquire into the manner in which chemistry came to the aid of those who were studying the problems of life, and thus gave rise to the chemical physiology which we know to-day.

Among the medical celebrities whose influence in the advancement of chemical physiology was paramount, the names of the chemical mystics. Basil Valentine ( 1450-?)." Paracelsus or irastus Bombast von Hohenheim. 6 and van Helmont must be considered first of all.


According to historians, Basil Valentine was probably a Benedictine monk living at Erfurt about the middle of the loth Century. He was one of the alchemists and apparently the author of certain conceptions which played an important part in the development of chemistry and physiology.

c Paracelsus, born at the close of the 15th Century in Maria Einsiedeln, Switzerland, was the son of a physician and, at the age of sixteen, is said to have entered the University of Basel and


Basil Valentine is generally credited with the conception of the three " elements," replacing the old idea of the ancients of the four elements — earth, air. fire and water. He designated these three elements, sulphur, that which is combustible; mercury, that which is volatile; and salt, that which remains after burning. To this conception of the properties of matter he added his archaius, or archcei, which were to him the spiritual forces governing and determining the phenomena of the universe, chemical changes included.

Apparently the doctrines of Basil Valentine obtained a firm hold upon the mind of Paracelsus. He greatly enlarged and developed them by the new light he had gained by his own researches, observations and studies. He was a chemist through and through, but delighted to enshroud his chemical conceptions with the veil of mysticism.

According to him, the two important facts of Xature were visible matter and invisible forces. The former consisted of the three elements — sulphur, mercury and salt, with their properties, which were capable of bringing about changes in this visible matter. The latter were spiritual forces, prominent among which were the arch mi, to which matter was subject and by which its changes were governed. All chemical and physiological processes were governed by the arch (bus. He looked upon digestion as carried out by this presiding force or spirit within the body. Its home was in the stomach and it separated the material useful for nutrition, the " essence," from the useless, the " poison," and thus became the alchemist of the body. Digestion was to him a kind of putrefaction, by which, on the one hand, the assimilation of the nutritive slime, on the other, the formation of the excrement, was rendered possible. Health was recognized by the regular action of this archceusj disease, i. e. indigestion, was the failure of the archwus to govern aright. Such conceptions as these were considered by Vesalius and his followers as the ravings of an ignorant charlatan. X' • rtheless. after a lapse of nearly one hundred years they were taken up by a man, who so handled them that, in a modified and developed shape, they found lodgment in ordinary medical teachings and served as the starting point of that chemical investigation of the problems of living beings, which since that time, and especially in these later years, has been so fruitful of results. As Paracelsus, with the aid of some fifty year- of increased knowledge, extended and developed Valentine's ideas, so his doctrines were in turn extended and developed with the aid of one hundred years of increased knowledge by van Helmont.

Jean Baptiste van Helmont T ( 1577-1644 ) is almost as strik


soon afterwards to have studied under Bishop Trithemius at Wiirzburg. Later he traveled extensively and finally settled at Bale, as a physician, in 1527. Regarding his personal history, however, there is much uncertainty. Many of his writings, discoveries, theories, and even his language, in places, are so exact reproductions of Basil Valentine's, that it is not difficult to presume that lie had seen his predecessor's works in manuscript and made extensive use of them. There is also the probability that he was taught his doctrines while a pupil of Bishop Trithemius.

7 Born at Brussels in 1577, some thirty-six years after Paracelsus' death and thirteen years after that of Vesalius.


May, 1916.] 145


ma a figure in medical history as Paracelsus, whom he resembled in many respects, though he surpassed him both in genius and also in learning.

In studying the writings and character of van Helmont we -.Tin to be brought face to face with a dual personality — with two intellects of quite different kinds. There is the patient, careful and exact observer, a child of the new learning, who takes advantage of all the new discoveries and teachings; but beneath it all we cau see the mystic, speculative dreamer and philosopher, weaving a fantastic scheme of the powers and forces ruling the universe, and calling in the aid of invisible supernatural agencies to explain the occurrence of natural phenomena. Throughout all his writings may be seen the continued endeavor to weave his exact chemical and physical knowledge and his spiritualistic views iuto a consistent whole.

Van Helmont's conceptions may be regarded as a peculiar remodeling of the pantheism of Paracelsus into a mystic and pietistic system, based upon more or less exact chemical principles. Throughout his writing we find the use of two new terms, " Bias " and " Gas." By the former he meant in all probability the archceus of Paracelsus; by the latter he clearly disentangles himself from all the mystic Paracelsian Lore and earns for himself the title of the first of modern chemists, and at the same time the first of chemical physiologists. By " Gas " he probably meant, what we now call carbonic acid gas or carbon dioxide. "Gas" he observed to be formed in various fermentative processes by the action of a ferment, as in the making of wine or bread. He was deeply impressed with the idea of the action of ferments and makes it the basis of his system of physiology. Digestion, as well as all other changes in the body, was looked upon as a process of fermentation. And he reconciled this view with his acknowledgment of the influence of the "Bias" or archceus by putting forth the hypothesis that these spiritual agents worked, not by acting directly on matter, but by making use of the ferments, which were thus their servants or instruments.

The current teachings of the day regarding digestion and nutrition were in substance those of Galen. The food absorbed from the stomach and intestine was imbued with natural spirits in the liver: in the heart the natural spirits were converted into vital spirits : and in the brain the vital spirits were converted into animal spirits.

A., ..riling to van Helmont this teaching was entirely wrong; instead of three there were six conversions or digestions, by which the food was transformed into the living body tissue.

To him the whole body was under the influence of an tin-hit ns influus or vital principle, which resided in the stomach, while every organ had its own individual archceus insitus directing the processes natural to it. During the process ..I' digestion in the stomach, his so-called first digestion, the local archceus generated a ferment whereby an acid was produced to dissolve the food. This ferment, he believed, had its origin in the spleen and it was from this organ that the stomach drew all it< energy. The ferment was an acid ferment, fermentum milium, but the acidity was not the ferment itself, it was only tlie organ or instrument of the ferment.


The food, as acid chyle, then passed into the duodenum where it at once acquired a saline nature — it was the change of an acid into a salt. This duodenal change constituted his second digestion and was affected by a ferment furnished by the bile. 5

The third digestion was that of sanguification, taking place in the mesenteric veins, liver and vena cava, ana consisted in the conversion of the chyle into crude blood, brought about by the aid of another hepatic ferment,"

We might, with much truth, compare these three digestions with what even now-a-days we sometimes call primary and secondary digestion.

It is difficult to differentiate clearly between his fourth and fifth digestion, the former consisting primarily in the conversion in the heart of venous into arterial blood, while the latter " changes the blood of the arteries into the vital spirit of the archceus."

The sixth and last digestion took place in the kitchens of the several members, for there were as many stomachs as there were nutritive members. In this sixth digestion a spiritus, a ferment innate in each place, cooked its food for itself. " A vein," says van Helmont, meaning probably an artery, "may be considered as a vessel containing aliment prepared for the kitchens of the tissues, but it is not their kitchen. Each tissue maintains its own individual kitchen within itself." In other words, all the tissues live upon the common blood, and the power of assimilation lies in the tissue itself; it is the tissue and not the blood which primarily determines assimilation, the qualities of the blood have only an indirect influence.

Van Helmont's exposition of the mechanism of the digestive process exerted a great influence on investigators who followed him. It showed that many of the problems of the living body were chemical problems to be solved by chemical knowledge, and also a large number of the processes taking place in the living body were more or less akin to the process by which yeast produces alcohol, as in wine-making, and therefore may be spoken of as fermentations. The idea of fermentations had long been known, but its definite introduction into physiological thought is due to van Helmont.

Francois De le Boe (or Dubois), better known as Pranciscus Sylvius, 10 was one of the direct successors of van Helmont in the field of chemical physiology. He was the foremost and most typical representative of the iatro-chemical school.

Van Helmont was but little influenced by the new discoveries in physiology, chemistry, anatomy and physics, whereas Sylvius was well versed in all these matters. In contrast to van Helmont, he would have nothing to do with mystic speculation about invisible agencies and spirits, lie followed \an Helmont. however, in considering many of the changes


"Van Helmont knew nothing of pancreatic digestion. Wirsung had not yet made his discovery of the pancreatic duct (1643).

' No mention of the lacteals is made, although he certainly must have been cognizant of Aselli's discovery in 1622.

10 Born in Hanover in 1614: died at Leyden in 1672. He became professor of Medicine at Leyden in 1658 and for twelve years exerted a most powerful influence by his teaching.


146 [No. 303


within the body as being of the nature of fermentative processes ; but to him. this fermentation was a true chemical change — an " effervescence," and he saw no reason for any additional intervention of subtle agencies, as did van Helmont.

The 17th Century was rich in new discoveries, with many of which Sylvius was by no means unacquainted. You may recall thai Aselli discovered the lacteals in 1622; Harvey, the circulation of the blood in 1628 ; Wharton, the submaxillary duet in 1655; Stenson, the parotid duct in 1661; Wirsung, the pancreatic duct in 1612; he also appears to have observed the pancreatic juice. De Graaf made investigations on the pancreatic juice in 1604, as well as on saliva and bile. Jean Pecquet, in 1651, made known his discovery of the receptacle of the chyle and its continuation as the thoracic duct and traced it into the venous system at the junction of the jugular and subclavian veins. Two years later. 1653, Rudbeck, of the University of Upsala, described the vessels which we now call lymphatics. He saw them first in the liver and intestines and traced them to the thoracic duct, of whose existence, he says, he had become aware in 1650, before the publication of Pecquet's book. In 1673, one year after Sylvius' death, Peyer published a little tract, in which he described certain new glands of the intestines, now known as Peyer's patches. And finally, in 1682, Brunner succeeded several times in removing from a dog nearly the whole of the pancreas, and in keeping the dog alive afterwards for a considerable time. Five years later he described the glands in the duodenum, since known by his name.

Van Helmont knew nothing of either salivary or pancreatic ducts, but Sylvius with this added knowledge was led to attach the greatest possible importance to saliva ; in fact, it was to him a type of the fermentative juices, and he attributed many of the changes taking place in the stomach to the saliva swallowed with the food rather than to the ferment provided by the stomach itself. The first stage of the fermentation, called chylifieation. was brought about chiefly through the action of this salivary secretion, according to Sylvius' view; the second stage of digestion was due to the interaction of the bile and pancreatic juice. De Graaf, his eminent pupil, had convinced himself that the pancreatic juice was of an acid nature, and this supposed truth became a foundation stone of Sylvius' views on digestion. Apparently, led away by a preconceived theorv. he failed to recognize the alkalinity of the pancreatic juice and persistently insisted that it was acid, believing its use in digestion was to effervesce, to ferment, with the bile. But neither Sylvius nor his pupil seemed able to clearly explain just how it promoted digestion. De Graaf tells us that the " effervescence attenuates the viscid mucus lining the interior of the intestine, the presence of which might hinder the absorption of chyle by the lacteals ; while it also assists the separation of the useful parts of the food from the useless " ; but there is no explanation given how this is brought about.

According to Sylvius, in the next stage of digestion, the chyle, or the nutritious part of the food, passed into the lacteals and was conveyed through the thoracic duct into the venous system. The blood carried to the right heart by the upper great veins was chylous blood. In the right side of the heart it


met with the blood of the vena cava, which he termed bilious blood, because he believed that the bile was secreted by the gallbladder and that that part of it which was not needed in digestion was carried by the cystic duct back to the liver, where it passed into the venous system, whence, mixed with the blood, it was carried by the vena cava to the heart.

Glisson ( 1597-16: 7) and later Malpighi (1628-1694) disproved this erroneous view, but it greatly aided Sylvius in the explanation of his views of digestion and he clung to it tenaciously. According to him, the " chyle assumes the form of blood (a superficial initial change) owing to the bilious blood ascending to the heart, meeting in the right auricle and especially in the right ventricle with the lymphatic blood (of the superior vena cava) with which the chyle is mixed, and so, on account of the different or rather opposite disposition of each (kind of blood), in certain of their parts provoking an effervescence of great moment." But the " chyle reaches the ultimate perfection of blood through the continued and tempered effervescence, which by reason of the breathing of air takes place in the lungs, in the left auricle and ventricle of the heart and in the large trunks of the aorta. By the energy and help of this effervescence we think that there bursts out and springs forth the vital fire, which by rarefying the more fatty and oily parts, not only of the chyle added to the blood, but of the blood itself, and by loosely uniting together at the same time all other parts, reduces the whole into a heterogeneous, homogeneous mass and so converts the chyle into true blood."

His exposition is vague indeed, but beneath it all we can recognize his efforts to explain, in the light of added chemical knowledge, that it is unnecessary to take refuge in subtle influences and occult agencies ; that all changes taking place within the body are more or less purely chemical in their nature and can readily be reproduced by experiment in the chemical laboratory.

We must at least give to Sylvius the credit of showing that there was no connection between chemistry and spiritualism; that, on the contrary, the newer chemistry in its attempt to solve vital problems was treading the path of the most naked materialism. In all probability, it was to this opening up of a line of inquiry into chemical physiology free from any taint of mysticism, that the great influence, which as a teacher he undoubtedly exercised, was largely due.

In contrast to the iatro-chemical school of which we have been speaking, there was developing during this period the so-called iatro-mathematical or mechanical school of which Giovanni Alphonso Borelli (1608-1679) of Naples was the founder, with such followers as Redi (1626-1697), the sagacious naturalist, Archibald Pitcairn (1652-1713), the British representative of the school, Lorenzo Bellini (1643-1704) of Florence, and Giorgio Baglivi (1668-1707), a pupil of Malpighi.

This school based the phenomena of digestion and other physiological processes upon the action of mechanical laws. After the manner of Erasistratus the whole process of digestion was referred to trituration by the interaction of the stomach walls.


May, 1916.] 147


Borelli had pointed out the great grinding, crushing force which was provided for by the muscular coats of the stomach of birds, and thought he had proved his point by feeding turkeys idass o-lobules, hollow leaden tubes, etc., and the next day finding the leaden masses crushed and eroded and the glass pulverized. He admits that birds of prey and fishes, which are destitute of teeth and possess a membranous stomach rather than a muscular one, digest hard food in a different maimer. " These animals consume flesh and bones by means of a certain very potent ferment much in the same way as corrosive liquids corrode and dissolve metals. Such a corrosive juice is poured forth by the small glands with which the membranous substance of the stomach is crowded." "

Archibald Pitcairn (1652-1713) like the English school generally, was far more exclusively mechanical than the Italians, and would hear nothing of acids or ferments even in digestion. " That the stomach is fully able to comminute the food may be proved by the following calculation." says Pitcairn. " Borelli estimates the power of the flexors of the thumb at 3720 pounds, their average weight being 122 grains. Now, the average weight of the stomach is 8 ounces, therefore, it can develop a force of 117,088 pounds, and this may be further assisted by the diaphragm and abdominal muscles, the power of which, estimated in the same way, equals -461,219 pounds." Well might Pitcairn add that this force is not inferior to that of any millstone !

The futility, indeed, of this mode of viewing the subject, is signally illustrated by the fact. that, whereas Pitcairn had allotted to the stomach fibres such an enormous power, Borelli thought that 1350 pounds was more correct. Hales believed that 20 pounds would come nearer the truth, and Astruc valued its compressive force at 5 ounces.

It was many years, in fact the greater part of a century, before further contributions were made to the knowledge of the subject of digestion. It is true that at the close of the 17th Century and the beginning of the 18th Century, there flourished two men who achieved great eminence as chemists and wlui were assiduous in applying their chemical knowledge to physiology : but. so far as digestion is concerned, their influence was rather that of expositors than that of discoverers. I refer to George Ernest Stahl, born in 1660 at Anspach, and Hermann Boerhaave, born near Leyden in 1668.

Stahl, employing the term Animism, ascribed the force used in digestion, as well as in all the chemical changes taking place in the living body, to the " sensitive soul." His conception had not a little kinship to van Helmont's ; indeed, his views may to a certain extent be regarded as a development of it. The sensitive soul of Stahl is that of van Helmont with two differences only. It works directly on chemical processes, without the intervention of archm, and is not a mortal something


11 Regarding the presence of this corrosive juice in the stomach and its influence upon digestion, we find that the followers of Borelli went beyond their master and were prepared to deny chemical action in all cases and to maintain that digestion was in reality a mere trituration of the food by the muscular mill of the stomach into the creamy mass known as chyle.


associated with, and as it were the shell of, an immortal mind, but it is itself the immortal principle, spiritual and immaterial, coming from afar, and at the death of the body returning whence it came.

Speaking of the physiology of digestion, Stahl seems to admit fermentation as a property of non-living things and to regard putrefaction also as a sort of fermentation, possible in and belonging to non-living things. Apparently, he regards the ferments of saliva and pancreatic juice as non-living agencies, although he refuses to believe in a gastric ferment.

Boerhaave (1668-1738), the teacher of Haller, was a man of wholly different mind and, although a learned scholar ami a sound scientific thinker, he cannot be said to have made any striking contribution to our knowledge of digestion. Essentially eclectic in nature he combined in his conceptions of physiological processes many of the doctrines of earlier systems.

He recognized that digestion was. in part at least, a solution of some of the constituents of the food by means of various juices. Saliva, the juice from the esophagus, the gastric fluid, which consists in part of a viscous secretion poured out by the glands of the stomach, and in part of a thin fluid secreted by the arteries, the bile, the pancreatic juice, and the intestinal juice, each of these contributed to the result. But he regarded the solution effected by means of these juices as of the nature of an ordinary solution, and not of a fermentation. He denied the acidity of the gastric juice. In common with his contemporaries, Boerhaave regarded the nerve supply to the stomach as out of all proportion to the movements or sensations of that organ and believed that a nervous fluid, having some share in the digestion of food, was poured into the cavity of the stomach from the endings of the nerves.

He joined with the mechanical school in believing that the more fluid and nutritious parts of various articles of food were expressed from them by trituration in the stomach. In particular he thought that bones were not digested, only crushed. He was more or less antagonistic to the doctrines of fermentation, and regarded the action of the juices as a mere solution, not as a proper fermentation. Nevertheless, he held that solution and trituration are, in digestion, aided by something else. He thinks that the stomach contents, being exposed to considerable heat, undergo " an incipient fermentation by means of which the chyle is impressed with the primary principle of vitality."

These doctrines of Boerhaave became the dominant ones for many years: indeed they were taught by his illustrious pupil. Haller, nearly fifty years later.

Albert von Haller was born at Bern in 1708 and in 1725 went to Leyden to work under the renowned Boerhaave, where he undoubtedly laid the foundation of all his future work. Haller was a universal and indefatigable savant, of ingenious natural endowments, a marvelous, almost unique, capacity for work, absolutely conscientious, a man of inextinguishable love for science and ait. and one of the greatest medical thinkers of all times, as well as a notable poet, botanist and statesman.


148 [Xo. 303


In 1757 he began to publish his " Elementa Physiologise,"

the eighth and last volume having the press m 1765. This great work may he taken as a trustworthy aecount of the knowledge of the time with regard to the questions therein stated.

In his exposition of digestion he considered the saliva to be neither acid nor alkaline and regarded its use as being that of softening the food and helping deglutition. He recognized the importance of the tunica villosa of the stomach, but says that the glands therein contained furnished the mucus of the stomach only, the true gastric juice, the succus gastricus, being secreted by the arteries. He discarded the idea of Boerhaave that a nervous fluid, oozing from the endings of the nerves, intervened in gastric digestion. He believed that pure gastric juice was neither acid nor alkaline, and while speaking of it as a macerating liquor which softens and dissolves the food, he refused to regard it as a ferment. He held that it was not a corrosive liquid, like many acids, and. though at times it might lie acid, the acidity was a token of the degeneration of the digested food, not of digestion itself.

He regarded trituration as a useful aid. especially where hard grains form a part of food, as in that of birds, but only an aid. "They have done well who have brought back to its proper mediocrity the power of trituration so immensely exaggerated."

He looked upon bile not as a mere excrement, as some had done before him, but as a secretion from the liver substance. It was a fluid viscid and hitter, but not acid, and indeed not alkaline, a fluid which had the power of dissolving fat. He added that the bile must have some other function than that just described; "for animals deprived of their gall-bladder very rapidly perish, the exact cause of their death not being clear."

In considering the pancreas he says, " A part at least of the usefulness of pancreatic juice will be to dilute and soften the cystic juice, so that this mixes better with the food." He adds, " There may be other functions of the liquid not as yet well known to us " — a sentence perhaps prophetic of the work of Bernard a hundred years later.

In this brief review of the opinions and theories of the eminent men of science living before the middle of tin isth Century regarding the subject of digestion, we find that to van Helmont the stomach with its acid character was the important organ of digestion ; that others following him insisted that other juices were of more importance but that most of them, though they admitted a certain potency to the gastric juice, either doubted or denied its acidity. The veil of doubt was, however, soon to be lifted, and thus to reveal the true nature and function of the gastric juice.

The year 1752 is indeed a red-letter year in the history of our subject. In that year were published two treatises upon the " Digestion of Birds " by Rene Antoine Ferchault de Reaumur, which mark an epoch in the history of digestion by indicating the dividing line between modern ideas of physiological processes and all that had gone before. Reaumur was one of the iii"-t striking men of science of the 18th Century. Born at


Rochelle. France, in 1683. he moved to Paris at the beginning of the 18th Century. He was a wealthy man and used the opportunities thus afforded him in carrying out many and varied scientific experiments. But it is only of his work on digestion of birds that I shall now speak. In these experiments he attempted to learn whether the digestion of food was due to trituration, putrefaction, or to solution, brought about in some way by means of the gastric juice secreted by the stomach. He devised a means of determining whether the comminution and solution of food is effected by the action of the gastric muscles. This he accomplished successfully by obliging animals to swallow metallic tubes opened at both ends, save that each end was secured with a grating made of threads or fine wire, and filled with their natural food, such as grains, etc., for granivorous fowls. He argued that if these grains, after remaining in the stomach, were broken down and decomposed, we must assign a dissolving liquor as the cause of the phenomenon, since the sides of the metallic tubes must have presented an insuperable obstacle to the action of the gastric muscles upon the contents; but that if they were returned in a sound and entire state, it must be acknowledged that in these animals digestion does not depend on a solvent, but on muscular action. His first memoir deals with digestion in granivorous birds — those possessing a gizzard or muscular stomach.

A few hours after they had swallowed the grains, Reaumur killed the animals and removed the tubes for examination. He found barley grains, etc., quite entire, whence he inferred, that in these animals, the food was not broken down by a solvent, but by the strong action of the muscular stomach. He further observed that if the tubes were quite thin, they were frequently broken, crushed or distorted in a most singular manner. These results need not surprise us if we but recall the observations of Redi and Borelli, that ducks, fowls, and pigeons pulverized hollow globules of glass in a very short time. 12

" This hypothesis of Vallisnieri is evidently groundless." says Spallanzani, " for seeds remain unaltered whenever they are defended by tubes. As when pigeons, fowls and turkeys are forced to swallow several balls of glass at once, some in tubes and others naked, the latter are reduced to small fragments as usual, while the former remain entire. The gastric muscles are the chief cause of this effect."

It had been long known that fowls always have a supply of pebbles in the stomach. It was observed by Redi, Borelli and others, when members of the Academy of Cimento, which was established in 1657 under the patronage of Prince Leopold, that the ducks and fowls that had the greater number of stones in their stomachs more quickly reduced spheres of glass to powder. Redi thought that the stones performed the office of


12 It may also be of historical interest to mention that Vallisnieri of Padua (1661-1730) stated in his anatomy of the ostrich, that the hardest substances, such as stones, wood, glass and even iron are reduced to pieces in the stomach of these enormous birds by a solvent. Moreover, he was inclined to think that glass was attacked and broken by a similar liquor, which he believed existed in the stomach of fowls, without the concurrence of muscular action.


May. 1916.] 149


teeth, while Reaumur believed that they were necessary to -i ion.

The greatest part of Reaumur's first memoir deals with the great force of the gizzard of fowls in triturating the food ; in the remainder he endeavors to prove that this viscus contains ii,i menstruum of sufficient efficacy to produce solution. In support of this he mentions the following points based upon experiments: (1) Barley grains remained unaltered within the tubes; and (2) ducks were given small particles of meat in tubes and on removal from five to twenty-four hours laid. some pieces had retained their red color (some, however, had lost it) and there was also no appreciable diminution m amount. From this he inferred that no menstruum had acted on the meat, since it was not comminuted or much dissolved. and he even concluded that the gizzard contains no solvent capable of decomposing and digesting the aliment.

In his second memoir he inquired into the nature of the function of digestion in carnivorous birds, whose stomachs are membranous in type. He chose a kite as the subject of his experiments, taking advantage of its well known habit of vomiting indigestible things which it had swallowed. He used tin tubes filled with different substances, especially meat, which were thrown up, after a certain time; and that the meat was more or less digested, according to the time it was in the stomach, was the general and invariable result observed. Hence, he justly inferred, that here digestion is produced by the gastric fluid, without the concurrence of any triturating power. From other additional experiments he also concluded that digestion in other birds with membranous stomachs is produced in a similar manner.

On several occasions he had observed that when his tubes containing flesh and grain were rejected, they were filled more or less completely with a yellowish, somewhat opalescent fluid, which to the taste was salty and bitter. Obviously it was this fluid which had dissolved the food and he asks himself these questions : " What is this liquid which acts on flesh, but has not the same power on starch? To which of the solvents which chemistry offers us can this liquid be compared ? " To answer these questions he filled his tubes with small pieces of sponge, from which, when rejected, he squeezed out the fluid which they had imbibed. In this way he obtained a small amount of an opalescent fluid, salty to the taste, rather than sour. By this means he was the first to obtain gastric juice in an approximately pure condition.

With the fluid he attempted a few experiments in artificial digestion by allowing it to act upon particles of meat at 32° R. for twenty-four hours, using meat placed in water as a control. He found that, while the meat in the control putrefied, the portions placed in the gastric juice, though not very much dissolved, were hardly at all putrefied. Hence, he concluded that digestion was not putrefaction, but something quite opposed to that process. He lamented, however, that, from the death of his kite and his neglecting to substitute other animals in its stead, he could not adduce facts sufficiently numerous to illustrate the subject more fully, lie promised to supply the deficiency on some future occasion, but his death a few years


afterwards ( 1757 ) prevented him from fulfilling his promise.

Of course, these experiments of Reaumur still left a great deal to be investigated, but their value lies chiefly in the following : He employed an entirely new method in the investigation of gastric digestion. He further established the fact that the gastric liquor possessed a distinctly solvent power, dissolving various constituents of food, not by inducing or favoring putrefaction, but by a process which w T as quite antagonistic to it.

The next solid contribution to the subject of gastric digestion was made by Spallanzani, u some twenty-five years after the epoch-making investigations of Reaumur.

This scientist contributed much to our knowledge of physiology and natural history, but it is of his work upon the physiology of digestion that I wish to speak. Practically all his experiments and discussions are contained in his " Dissertations Relative to the Natural History of Animals and Vegetables," the original Italian publication first appearing in 1782.

Spallanzani's methods of experimentation were those of Reaumur, but he greatly enlarged upon them. He employed thin metallic and wooden tubes opened at one or both ends and covered with wire grating. He perforated the sides also of the tubes to allow freer access of the gastric liquor. He also used hollow brass globules divided into hemispheres, which were pierced like a sieve, and which he could open and shut at pleasure. In some cases he employed small linen sacs, using one to four thicknesses of cloth whereby he thought to partially prevent, or to increase, the action of the gastric liquor according to the thickness of the cloth. In other cases he introduced into the stomach or esophagus, meat, etc., tied to a wire or string, fastening the free end around the animal's neck. This method permitted him to withdraw the food at any time during the process of digestion, and examine it. He even introduced long cylinders containing meat, bread,- etc., allowing one end to rest within the stomach and the other in the lower esophagus, and in this way was able to observe digestion in the stomach and esophagus at the same time. He employed, as did Reaumur, small sponges to obtain the gastric liquor, with which he made numerous experiments in artificial digestion. On himself he experimented by swallowing these small, thin linen bags, containing various kinds of food, examining the contents after they had been voided per anum. He even dared to swallow wooden tubes. Finally, he obtained gastric liquor by making himself vomit on an empty stomach before breakfast. He employed a great variety of foods in these experiments, such as grains of all kinds— wheat, corn, maize, rye, etc. ; flesh of every description : also animals, including fishes, frogs and earthworms; and finally, ligaments, cartilage, hard and soft bones, teeth and coral.


13 Born in 1729, at Scandiano, in Southern Italy. He became professor of Logic, Mathematics and Greek at Reggio at the age of 25, but in 1760 was transferred to Modena, where he filled the chair of Natural History. In 17GS, he became professor of Natural History at the famous University of Padua, where he labored until his death in 1799.


150 [Xo. 303


His experiments were very numerous and included practically all species of animals. He first investigated digestion in

animals that possessed muscular stomachs or gizzards : these included common fowls, turkeys, ducks, geese, doves, and pigeons. His second dissertation deals with animals that possess the so-called intermediate stomach, namely, crows and herons. The experiments outlined in the third, fourth and fifth dissertations were performed upon animals with membranous stomachs, these including frogs, newts, earth and water snakes, vipers, fishes, sheep, oxen and horses : also, the little owl, screech owl, falcon, eagle, cat, dog, and finally man. His last dissertation deals with the question, whether food ferments in the stomach, and also with the question of the acidity of the gastric juice.

SpaOanzani by innumerable experiments carried on in the various ways which I have mentioned, confirmed and greatly extended Reaumur's results. His conclusions were many, and I shall state them as briefly as possible:

SPALLANZANI'S CONCLUSIONS. Is Animals with Muscular Stomach ok Gizzards.

1. Trituration by means of the muscular walls of the stomach is the chief factor in the digestion of grains and the like, though the gastric liquor undoubtedly assists it.

2. Trituration and the action of gastric juice mutually assist each other in the digestion of flesh; the former breaking down the aliment, acts as a predisposing cause: the latter, when it is thus prepared, penetrates into it, destroys the texture, dissolves the particles, and disposes them to change their nature and to become animalized.

3. The stones that are always found in the gizzards of these animals are not at all necessary for the trituration of firm food and even harder substances, contrary to the opinion of many anatomists and physiologists, ancient as well as modern. When, however, they are put in motion by the gastric muscles, they are capable of producing some effect upon the contents of the stomach.

4. The digestion of flesh and bread may take place solely by the action of the gastric juice without any assistance from the triturating action of the gastric muscles.

5. Gastric liquor retains outside the stomach the power of dissolving animal and vegetable substances in a degree far superior to water. ( He advises the use of heat and fresh gastric juice.)

In Animals with Intermediate Stomachs.

1. Gastric liquor of crows is a solvent of flesh without the aid of trituration.

2. The digestion of food is proportional to the quantity of gastric juice acting upon it.

3. Bones are undigested by the gastric juice of crows, except soft ones, like cartilage, which are digested very slowly.

4. Flesh is very slowly digested by esophageal liquor.

5. Crows' gastric liquor is of a transparent yellow color, which deposits very little sediment on standing, possesses a bitter and salty taste, has very little volatility and is non-inflammable.

6. Gastric juice, outside the body, digests flesh without the production of putridity. Digestion is enhanced by heat and is more rapid when gastric liquor is allowed to flow slowly over the flesh and constantly renewed. Digestion is retarded by cold.

7. Gastric juice is secreted by small arteries, which open into the stomach. (He was not sure of the presence of any gastric glands which might serve such a purpose.)


8. Some power of trituration is present in the stomach of the heron, but digestion here is not the effect of the trituration, but of the solvent power of the gastric juice. It has even the power of digesting bones.

9. The bitter taste of the gastric liquor derives its origin from the bile which regurgitates through the pylorus into the stomach cavity.

Ix Animals with Membranous Stomachs.

1. In frogs, gastric juice was found to have slow digestive powers.

2. Water-newts digest fish-worms in twenty-four to forty-eight hours without the intervention of trituration.

3. Digestion of food in frogs, serpents, water snakes, vipers, eels, carps, barbels and pikes is performed by the gastric juice, though somewhat slowly. No trituration is present.

4. In sheep and oxen the process of rumination precedes the solvent action of the gastric liquor. No triturating power is present.

5. The gastric fluid of the little owl can digest bones as well as flesh. It does not become putrid even when exposed for months in hot weather. Esophageal liquor from this animal also digests flesh quite rapidly. (He obtained similar results with the tawny owl. )

6. The gastric juice of the falcon digested bone and tendon quite rapidly, as well as flesh, but did not have much effect upon teeth, enamel or horn. Trituration is not a factor.

T. In the eagle such substances as bread and cheese and flesh and even bone were quite readily acted upon by the gastric juice outside of the body. The gastric juice of this bird digested animal and vegetable substances. It produced an incipient solution of bone and almost a complete one of cartilage.

S. The gastric fluid of the dog and cat is the efficient cause of digestion in these animals, independently of any triturating power. In the dog it also acts upon bone, but not so speedily as upon flesh, because of its hardness.

9. There is a peristaltic motion of the stomach of dogs and cats and some other animals, which was demonstrated by opening the abdomen shortly after feeding. It was easily excited by irritating the stomach with a knife point, which produced contraction followed by an undulating wave across the stomach and by a dilatation of the contracted portion. This gradual movement of contraction and dilatation began at the upper end of the organ and extended to the lower and (he felt that) this motion was calculated, not to triturate the food, but to carry it slowly from the superior to the inferior orifice of the stomach, and thence to expel it into the duodenum.

10. In the experiments upon himself he found that flesh and bread were rapidly digested by his gastric juice independent of trituration, and that it could dissolve muscle fibres, membrane, and even tendon, cartilage and soft bone, though the time consumed in digesting the latter substances was somewhat longer than in the case of the former. " Before quitting the subject," he says, " let me observe that though I have mentioned the gastric juice as the efficient cause of digestion in the experiments upon myself, yet I mean not to exclude those of the intestine from their share. We know that the small intestine completes the process of chylifieation, which is but begun in the stomach. I must allow, therefore, that the digestion of animal and vegetable substances in the bags and tubes is perfected in the intestine. But this is not in the least repugnant to the results of those experiments that show the human stomach to be destitute of any triturating force, and digestion to be the effect of the gastric juice alone, though the fluid which is secreted by the side of the small intestine may complete the process."

11. The gastric fluid obtained from his own stomach was a little salty to the taste but not especially bitter, and possessed no prop


May, 1916.] 151


erty of inflammability. Gastric juice left in a phial one month did not become putrid. Beef was quite readily dissolved when kept at a definite heat and did not putrefy, but the control in water became excessively putrid in a short time.

12. The gastric juice is probably provided with an antiseptic principle. When acting upon flesh, etc., outside (or inside) of the body, it rarely, if ever, putrefies. In fact, it impedes putrefaction and in some cases may even restore putrefied substances. None of the three species of fermentation (sweet, acetous or putrid) takes place in digestion.

13. There is present in the stomach of man and some animals an acid principle, but it is not constant and depends on the quality of food. This temporary acidity is not produced by the gastric fluid, but by the food. (He sent a specimen of the crow's gastric juice to Scopoli, the eminent chemist, for analysis — apparently the first detailed analysis on record. The results of this and his own examination led him to the conclusion that the gastric fluid was neither acid nor alkaline, but neutral. He thinks, however, that there may be a latent acid in this fluid, though it cannot be detected by any of the ordinary means. His reason for this was the observation that it readily curdles milk — a fact held by Macquer and others to be a sign either of a manifest or occult acidity.)

We thus owe to Spallanzani, after Reaumur, the definite experimental proof of the solvent power of the gastric juice upon various constituents of food, but he was unable to go much beyond this, because he failed to recognize its acid character. He, however, conclusively disproved the older theories of digestion, especially that of trituration, putrefaction, fermentation and maceration.

I have dwelt at some length upon the investigations of these two men because it seemed to me that they were pregnant with many suggestions for future scientific lovers of truth. Their work is in reality the germ from which many of our more modern ideas concerning the physiology of digestion have sprung. During the next fifty years numerous monographs appeared dealing with various phases of digestion, and I deeply regret that I could not have brought the subject up to a more recent date. But, before closing, it might be of interest to mention briefly some of the more important additions which were made during the half century following the work of Spallanzani.

In his physiological inaugural dissertation, entitled " De Alimentorum Concoctione," Stevens of Edinburgh, in 1777, adopting the methods of Reaumur, substantiated the work of the French and Italian inquirers. In 1772, appeared a paper by John Hunter, published in the Philosophical Transactions, " On the Digestion of the Stomach after Death." This was followed, in 1786, by his " Observations on Digestion," both of which papers contain many interesting facts and observations relative to our subject. It is very evident, from a perusal of these articles, that Hunter entertained views on digestion which are very similar to those of Spallanzani, though modified by the vitalistic Stahlian conceptions, in which the latter did not share. Hunter at first was inclined to attach considerable importance to the acidity of the gastric juice. In 1772, he writes, " In all the animals, whether carnivorous or not, upon which I made experiments to discover whether or not there was an acid in the stomach (and I tried this in a great variety I . I constantly found that there was an acid, though not a strong


one, in the juice contained in that viscus in a natural state." But in his later communication he says, "It is only found occasionally." And, indeed, the 18th Century passed wholly away before the " acid ferment " on which van Helmont had, in the early years of the 17th Century, laid such great stress was rightly appreciated ; for the observations of Carminati, who in 1785 found the clue to the problem of the acidity of gastric juice, by showing that m carnivora at least the juice, though neutral when the animal is starving, is undoubtedly strongly acid after it has been fed, fell on barren ground.

We have seen that numerous theories as to the nature of the digestive process, before the time of Spallanzani, were held by physiologists. That of coction was entertained by Hippocrates. Oalen and others; putrefaction by Praxagoras of Cos, and apparently, even by Chelseden (1688-1752); trituration bj Erasistratus. Redi, Borelli. and others; while the theory of fermentation had many partisans, amongst whom may be mentioned, van Helmont, Sylvius. Willis, Grew and Lower. Even Haller adhered to the theory of maceration, supposing that the food is merely diluted and softened by the stomach fluids. Finally, we have the theory of chemical solution, proposed by Spallanzani, a theory which met with more favor from physiologists than any of the others.

To such a turbulent state of knowledge, the well known pithy and laconic observation of William Hunter was certainly not out of place, " Some physiologists will have it, that the stomach is a mill, others that it is a fermenting vat; others again, that it is a stew-pan ; but in my view of the matter, it is neither a mill, a fermenting vat, nor a stew-pan, but a stomach, gentlemen, a stomach."

In 1803, Young, of Baltimore, experimenting upon frogs, snakes, and other animals, demonstrated that the solvent power of the gastric juice is due to its acid content, which turned litmus paper red. He further showed that it had its origin in gastric secretion, and that it did not originate from any kind of fermentative process, vinous or otherwise. He also deduced the important fact that the flow of gastric juice and saliva are associated and synchronous, a point which has but recently been demonstrated by Pawlow and his collaborators. He made the error, however, that it was phosphoric and not hydrochloric acid that was present. It was not until twenty years later (1824) that Prout (1T85-1850) of England proved that hydrochloric acid was the free acid in the gastric juice.

Prout was speedily followed and his statement affirmed by Tiedemann (1781-1861) and Gmelin (1788-185.1) in their notable monograph " Die Verdauung nach Versuchen," which appeared in 1826-27.

Six years later, in 183.°), there was issued from the press a volume entitled, " Experiments and Observations on the (lastrie Juice and the Physiology of Digestion," which contains the classical and far-reaching investigations of William Beaumont (1785-1853) a surgeon of the United States Army, upon the young Canadian voyageur, Alexis St. .Martin, who was accidentally shot in the stomach (1822), the wound healing after a year or more with the production of a gastric fistula.


152 [Xo. 303


the aperture being about two and one-half inches m circumference. Beaumont at once seized the opportunity which preitself in this remarkable case, and at different periods during the following nine or ten years he performed numerous experiments. 238 in all, with this Canadian half-breed as the subject of his investigations.

- : ral cases of artificial gastric fistula had been reported before the time of Beaumont's work, but the case in point stands out pre-eminent above all others on account of the accuracy and care with which the experiments were performed.

As we have seen, much uncertainty existed in the minds of men as to the exact nature of the phenomena occurring during digestion in the stomach, the precise mode of action of the juice, the nature of the juice itself and its action outside the body. On all these points Beaumont's investigations brought clearness and light where there had been previously the greatest obscurity. Perhaps, the most important observation was his study of the digestibility of different articles of diet in the stomach, which remains to-day one of the most important contributions ever made to practical dietetics. His observations are probably the most important ones until the time of Pawlow and his school who, chiefly by perfection in technique of experimentation, were able to carry the work further. Beaumont was truly the leader and pioneer of experimental physiology in our own country.

In looking back over the centuries and tracing the historical development of the various systems and theories which were formulated from time to time by the greatest physicians, scientists and philosophers of their day, we are unable at the present time to appreciate at their true value the circumstances under which they were formulated, and the advantages or disadvantages attendant on their conception. But it must remain an element of surprise and disappointment that the views current up to the close of the 18th Century should show so slight an advance over those formulated, with less particular knowledge, two thousand years before.

Xo less surprising is the wonderful advance which has made since the beginning of the 19th Century in the elucidation of physiological problems. Coincident with the onward ss of science our knowledge of the chemical and physiological processes which serve to support life has remarkably increased. Thanks to the patient investigation of the infinitely little, and to the gathering together of the results, theories of


vital processes can now be based upon multitudes of observed facts, giving both positive and negative evidence.

By following the teaching of Hippocrates in 400 B. C. teaching which was until lately disregarded, or at least spasmodically and superficially followed, we have penetrated many of the mysteries connected with bodily processes, though much still remains to be done.

REFERENCES.

The following references have been freely drawn upon in the preparation of this paper:

Adams: Genuine Works of Hippocrates. New York. Win. Wood and Co.

Baas: History of Medicine. Translated by Handerson, New York, 1889.

Beaumont: Experiments and observations on the gastric juice and the physiology of digestion. Plattsburg, 1833.

Carminati: Richerche sulla natura e sugli usi del succo gastrico in medicina, e in chirurgia. Milano, 17S5.

de Reaumur: Sur la digestion des oiseaux. Hist, de L' Acad., roy. d. sc. an. 1752, pp. 266-307, pp. 461-495.

Foster: History of Physiology. Cambridge, 1901.

Garrison: History of Medicine. Philadelphia, 1914.

Haller: Elementa physiologic corporis hurnani. Lausanne, S vol., 1757-66.

Hunter, John: Observations on certain parts of the animal economy. 2d ed., pp. 129-143, London, 1792.

On the digestion of the stomach after death. Phil. Trans.. London, 1772, LXII, p. 447.

Myers: Life and letters of Dr. William Beaumont. St. Louis, 1912.

Osier: A Backwoods Physiologist. An Alabama Student, N. Y., 1909.

Pawlow: The work of the digestive glands. London, 1902.

Prout: On the nature of the acid and saline matters usually existing in the stomachs of animals. Phil. Trans., London, 1S24, 45-49.

Schafer: Text-book of Physiology. 2 vol., London, 1898.

Spallanzani: Dissertations Relative to the Natural History of Animals and Vegetables. London. 1784.

Stevens: Dissertatio physiologica inauguralis de alimentorum concoctione. Edinburgh!, 1777.

Stirling: Some apostles of physiology. London, 1902.

Tiedemann and Gmelin: Die Yerdauung nach Yersuchen. Heidelberg and Leipzig, 1S26-27.

Yan Helmont: Ortus medicinae. Amsterodami, 1648.

Withington: Medical History from the Earliest Times. London. 1894.

Young: An experimental inquiry into the principles of nutrition and the digestive process. Philadelphia, 1S03.


PROCEEDINGS OF SOCIETIES.

THE JOHNS HOPKINS HOSPITAL MEDICAL SOCIETY. JANUARY •;. 1916.

1. Seminal-Vesiculectomy in Arthritis. Dr. H. H. Young.


DISCUSSION.


Dr. Quinsy: I can only call your attention to one or two further points with regard to the seminal vesicles. I have felt that the development of the surgery of these organs is a subject of which American surgeons should be very proud, because, although they


were described, as were so many other structures of the human body, by Fallopius in the sixteenth century, and of course were known by all subsequent anatomists and surgeons who were not afraid to attempt surgery on them, still it remained for American surgeons, and above all for the present generation of American surgeons, to demonstrate a successful surgical approach to these organs. As one looks over the literature of the subject to-day one finds instead of a long list of German, French, Italian, Polish, and Russian names, that the contributors are almost entirely American. This is due to the fact that American ingenuity was applied at the time when the European surgeons had given up serious, radical


May. 1916.]


JOHNS HOPKIXS HOSPITAL BULLETIN.


153


attempts on these organs. The work, as Dr. Young has mentioned to you, was started first in this country by Dr. Belfield of Chicago, and by Dr. Fuller of New York, but it was not until such deft operators as the president of this society directed our attention to the subject, that successful excision of the vesicles was made possible.

Some may ask if the seminal vesicle, when normal, is of any special value except as a reservoir; or whether it has some function which should be preserved if possible. For a good while the idea prevailed that the vesicle was simply a reservoir for portions of the spermatic fluid. More recent physiological observations, especially on animals, have shown that, though this is true, it has other intrinsic functions. In some species the secretion cf the seminal vesicle has agglutinating properties. For instance, in the rodents, more especially in the guinea-pig, the secretion of the seminal vesicle causes the prostatic secretion to coagulate. By this method nature provides in two ways for successful impregnation. By coagulation the material is prevented from leaving the vagina after coitus, while at the same time the spermatozoa are squeezed outside the coagulum so that they can exert their normal activity unhampered. In various other ways also the secretion of the vesicle is important. For instance, it has been shown that reproduction is not impossible after extirpation of the vesicle, but that the fruitfulness of such an animal is decreased.

I quite agree with Dr. Young's conclusions that if one is operating on a vesicle which is so diseased as to necessitate exploration, it should be removed in the large majority of cases.

Dr. Hunneb: It does not seem necessary to emphasize the importance of this subject — the role played by the genito-urinary organs in furnishing a focus for widespread infection. In the female we do not see many cases in which arthritis can be traced directly to the genitro-urinary organs. Of course, the genitalia have the deep glands of the cervix and the Fallopian tubes, which, becoming infected with gonococci, occasionally form foci for infections of the joints. In the urinary tract we do not have to deal with the deep glands characteristic of the male, and for that reason we see far fewer cases of general infection or arthritis derived from the urinary tract of the female.

I have been particularly interested for the past few years in infections which come to the genito-urinary tract from other foci, such as tonsils, teeth or sinuses. I hope in a short time to bring before the society a series of 50 cases of stricture of the urethra, in a good many of which, I am satisfied, the infection that started the infiltration about the urethra came from some distant point, such as the tonsils, teeth or sinuses.

I have been interested in the male side of this question, more particularly because of the women who have come to me complaining of sterility. It seems strange that, even to-day, women go about from gynecologist to gynecologist being treated and curetted because they are sterile and anxious to become pregnant, while the logical and simplest method of finding out what the real trouble is in a good many cases is to have the male examined. In from 40 to 50 per cent of these cases, on examining the secretions of the male, we find the sterility in all probability is due to blocking or obstruction of the spermatic organs.

Certainly those interested in genito-urinary work in the male will feel a great debt of gratitude to Dr. Young for these methods which he has presented to us to-night.

Dr. Guthrie: It is, of course, a matter for congratulation that another possible focus of infection has been discovered. We have felt for a long time that there were foci that were not being approached, and particularly ones which were apparently cryptic and which do not present symptoms which would lead to suspicion being cast upon them. One great difficulty which is encountered by all those who try to arrive at a diagnosis in infectious arthritis


is the multiplicity of possible foci and sometimes of actual foci which may exist. The question then arises as to which one is the seat of the trouble. In a recent case on the wards, the patient was discovered to have abscesses about the roots of the teeth. Despite the protests of the patient, these were removed. The next thing was an examination of the sinuses and the remains of the tonsils. One diseased tonsil was discovered and also eliminated. Following that an examination of the digestive tract revealed a difficulty about the appendix. This was investigated and, the suspicion that there had been trouble in this area having been confirmed, the appendix was removed. Following each one of these procedures, the patient improved considerably, but I have a letter to-day saying that her symptoms have returned. Apparently the search for the guilty focus must be resumed.

2. Tuberculosis of the Tonsils. Dr. S. J. Crowe.

JA2HJAKY n, 1916.

1. Methods and Results of Direct Transfusion. Dr. R. D. McCluke

and Dr. George Dunn.

To appear later in the Bulletin.

2. The Clinical Significance of the Wassermann Reaction. Dr.

Arthur F. Coca.

DISCUSSION.

Dr. Miller: I am extremely interested in the message brought this evening. It brings up the question in one's mind as to whether the Wassermann reaction is worth anything, or any treatment is worth anything in lues. From the scheme drawn on the board, 1 am not prepared to answer, off hand, which of the conclusions one can justly arrive at.

There are a few points I would like to take up briefly. First, Dr. Coca made the statement that the reagents employed in the Wassermann reaction are very unstable and vary from day to day. I think that is open to some argument. Patients' serum is an unknown variant. The amboceptor which has been suitably prepared has, I believe, usually been regarded as quite a stable thing. That is, given an amboceptor of a given titre, it does not vary much from time to time provided it is kept under suitable conditions. The suspension of sheep's red blood cells, freshly prepared, is a presumably stable reagent. Each new lot of complement is stable during the period in which it is used, and its power is determined by suitable preliminary titrations. Any given antigen suitably titrated from time to time is constant, in that you know what it will do. at least relatively. If, however, one takes the various short cuts designed to be useful and time saving, then a number of these preliminary titrations are omitted and one is dealing with a number of variable reagents, and presumably some of them at times are absolutely inert. So I should think a possible criticism of the statement of their variability might be taken into consideration from that standpoint. Out of the first 1200 cases admitted to the Phipps Psychiatric Clinic, all cases were routinely tested against three different antigens — the cholesterinized extract of human heart (.04 cholesterin), a similar extract of the same heart not cholesterinized, and the acetone insoluble lipoid fraction prepared according to the Noguchi method. These were all tested for their binding powers, and we knew what each antigen would do in terms of the other two. Out of the first 1200 cases, the results with these three different antigens, in all cases of known, unknown or suspected lues, were identical, except in seven cases. In those seven, the cholesterin extract gave a positive fixation, while the other two were negative. This was in our minds suspicious enough to warrant the repetition of the Wassermann on those individuals' blood taken a week later, and also a control done by someone else who had known nothing about the condition. In all seven instances, the result came back the second


154 [Xo. 303


time exactly the same and was confirmed from one or two other sources. In my experience even two antigens are not enough to be invariably useful, for there are differences between antigens that apparently bind equally well with a known positive serum, which we do not yet know.

As regards the one particular point that interested me most — the finding of the uselessness of the Wassermann reaction in nonluetic and in unsuspected cases — it seems to me that there may be fallacies (and I am not by any means certain that the Wassermann reaction is free from fallacies), yet all the weight of evidence is against the statement. There have been too many instances where a definite luetic process has been confirmed by the subsequent course of the case, either at autopsy or by following suitable therapy. I do not believe that the Wassermann reaction is a biochemical one. I believe it will be shown to be a purely chemical process, essentially a colloidal chemistry affair. There is evidence for this that has apparently been buried away in the literature. It has been definitely suggested by Paul Schmidt that the sera of luetics differs colloidally very markedly from the sera of normal individuals. It seems to me that discrepancies in results will ultimately be explained on the basis of colloidal chemistry. 1 simply throw out the suggestion as being a possible source of hope in this apparently hopeless tangle.

Dr. Keidel: I would like to say that I agree with Dr. Miller's remarks on the various reagents that we use; and to add that with our titration of the complement I think we can always eliminate that as a source of error, provided we maintain a high standard for it. We have always felt that we must be continuously making new antigen preparations. While we do not adopt a unit of titre, we, nevertheless, use a comparative method of investigating them. We run more than one antigen in the series and try always to have a new antigen running with the others. If the new one does not come up to the standard of the antigens we have been using, we discard it. In this way we keep up an antigen standard which it seems to me must always be, if anything, slightly on the increase so far as efficiency is concerned. These antigens, of course, are always controlled for objectionable qualities such as would give a false positive. There are differences which have not been mentioned so far, which might account for some of the lack of uniformity in results, for we have observed that the sera of syphilitic patients reach a stage, particularly in treated cases, where there is a great variation from day to day in the amount of fixing body in the sera, that is to say, there is a zone in which the patient may vary, so that one day his sera may contain more fixing bodies, sufficient to give a positive Wassermann, and another day these may fall, so the Wassermann result would be a doubtful reaction. Another time they may fall so low that the reaction is completely negative. We have seen this repeatedly, in fact in almost all our treated cases this variation occurred. This would not, of course, be brought out unless a great many tests were made. We make frequent Wassermann tests. Our patients on treatment are in many cases tested every week, and always once a month.

With regard to the indictment of the Wassermann reaction, I do not think we are prepared to agree here with Dr. Coca's list of answers. We would certainly treat a typical hard chancre, with a history and with no secondaries, although the spirocha?tes are absent. In the first place such a lesion might easily not have spirochetes, because we know they tend to decrease in number as the lesion tends to heal, so that, even though the chancre may be typical, it may be perhaps at a late period, and we might fail in such a case to get spirochastes. In the second place, we know from experience here, and I am sure they do in other places, that the effect of treatment, particularly that of salvarsan, is so striking that we can make a diagnosis of a chancre practically by that alone, and with that as an aid we find we are justified in reading a positive Wassermann as an indication for immediate treatment in those cases. In such a case with a negative Wassermann, while


the chancre may appear to be a typical one, we have still to remember that it may be a chancre redux or a tertiary lesion. Some cases of chancre I am sure are overlooked which at least should be recognized as chancre redux. In those cases there would be no spirochetes, and, the lesion being tertiary, there might be a negative Wassermann. I would be in favor of treating those cases at least as a diagnostic means.

In the second group of cases, we probably agree. In cases of typical chancre and secondaries, we would undoubtedly treat under A. Under B we would treat tentatively at least, with the idea that if we got no result from treatment, we would suspect some other condition.

In the third instance, we would not treat, because we would insist upon having a Wassermann test first. In the third group, we make our diagnosis clinically, regardless of the Wassermann reaction, if we feel sure enough to diagnose a lesion as a tertiary syphilide. There is a chance, of course, that the Wassermann may be negative in about one-third of the cases. If we made a diagnosis clinically, we would undoubtedly treat the case whether the Wassermann was positive or not. In obscure cases, I can only say this, that several years ago I analyzed with Dr. Frontz some 4000 cases in which we had made Wassermann reactions for diagnosis. We divided our cases into several groups according to the history and manifestations. Each group was subdivided into treated and untreated cases. While I am sorry to say I cannot give the figures exactly, I can state, however, that as the presumptive evidence of syphilis increased from group to group, so did the presence of the positive Wassermann. In the groups of treated cases there was always a lower percentage of positive Wassermanns than in those untreated. This analysis showed us that, when using the Wassermann reaction as an aid to diagnosis in a large series of cases, the percentage of positive Wassermanns increased as the evidence in favor of syphilis increased.

I quite agree with Dr. Coca that it is an extremely difficult matter to pick out non-syphilitic cases and test them and get 100 per cent negative. Tjaere are bound to be so-called clinically latent cases which would fall in that group and give a positive Wassermann. In the treated cases, there is difficulty, because we use the Wassermann as an indication for treatment as long as it is positive. If the Wassermann reaction becomes negative, we have lost a means of following the effect of the treatment. Our rule here, as a general thing, although we do not regard the degree of positiveness of the reaction as an indication of the severity of the disease, is to give a patient treatment and follow his Wassermann at frequent intervals. We know the time necessary to produce a negative Wassermann and use that as a basis on which to figure the amount of treatment that patient should have subsequently. The Wassermann undoubtedly then is of great assistance in treating those cases.

Dr. Miller: In this series of 112 cases in which the same two antigens were used by all five observers, it would be interesting to know if all five observers used a uniform technique. I think that makes a very material difference. It can readily be demonstrated that, given the same two antigens, two people in the same room at the same time, by different methods of mixing the antigens with salt, may get diametrically opposite results. Therefore, the series to have been of any value must have been comparatively the same all the way through, or else it cannot hold.

Dr. Coca: There is only one question that I have to answer — the question of Dr. Miller with regard to the technique used by the different men. You can anticipate what the answer will be — that it was humanly impossible for each one of these men to be under constant supervision in order to see that they did not put one thing in before the other, or the other before the one. It is, however, significant that Dr. Miller admits that two men standing side by side, using the same reagents, may get opposite results. His statement agrees with practically everything I have said.


May, 1916.] 155


THE JOHNS HOPKINS HOSPITAL HISTORICAL CLUB. JANUARY 10, 1916.

1. Jonathan Letterman and His Work in Organizing the Medical

Department of the Army of the Potomac. Db. Joseph T. Smith. To appear later in the Bulletin".

2. William Hunter, Anatomist, Physician, Obstetrician. Dr. C. W.

G. Rohkeb. To appear later in the Bulletin.

THE LAENNEC.

JANUARY 24, 1916.

Memorial Meeting to Dr. E. L. Trudeau.

The proceedings of this meeting appeared in full in the April number of the Bulletin".


NOTES ON NEW BOOKS.


Vol. XXVII.-No. 304

BALTIMORE, JUNE, 1916.


CONTENTS

Thorium — A New Agent for Pyelography. (Illustrated.) By J. Edward Burns, M. D 157

A Statistical Study of 035 Lahors with the Occiput Posterior. By E. D. Plass, A. P., M. D

A Letter of Edward Jenner Containing a Brief Account of His Discovery of Vaccination. (Illustrated.)

By Charles M. McBryde, M. D

A Report of Sixty-Four Cases of Epilepsy in Patients from Fourteen Years to Forty Years of Age.

By L. R. Waters

Severe Anemia with Eosinophilia.

By Arthur F. Beifeld, M. D., and Milford E. Barnes,

M. D The Possible Role of Books in the Dissemination of the Contagious Diseases.

By C. A. Laubach, M. D . . .


Proceedings of Societies.

The Johns Hopkins Hospital Medical Society 186

Presentation of a Possible Case of Heat Cramps [R. L. Hade.n] ; — The Diagnosis and Treatment of Umbilical Concretions, with Report of a Case [Dr. S. V. Irwin] ; — Medical Aspects of the European War. (Abstract.) [Dr. A. M. Faunti.eroy, U.S.N.]; — Wound Infection and Treatment. (Abstract. i [Dr. Kenneth Taylor] ; — Nerve Conduction in the Non-Medullated Nerves of Medusa Cassiopea. (Abstract.) [Alfred Goldsborough Mayer]; — A System for Following Postoperative Patients [Dr. Frederick W. Bancroft] ; — Thorium — A New Agent for Pyelography [Dr. .T. Edw.vrd Burns].

The Johns Hopkins Hospital Historical Club 190

Medicine in Japan and China [Dr. William H. Welch].

The Laennec IPO

Tuberculosis in Early Childhood. (Abstract.) [Dr. Alma Rothholtz] ; — Carcinoma of Pleura [Dr. Stanhope I'.aym Jones] ; — Choroidal Tubercles in General Miliary Tuberculosis [Dr. R. L. Randolph and Dr. A. C. Schmeisser]. Books Received 191


THORIUM- A NEW AGENT FOR PYELOGRAPHY. 1

By J. Edward Burns, M. D.,

Assistant Resident Urologist, James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Hullo., Mil.


Ever since the introduction of pyelography by Voelker and Von Lichtenberg 2 in 1906, its prime importance in the role of renal diagnosis has readily been recognized. Although various attempts have been made to replace eollargol, the medium recommended by them for injection, it has proven the pyelographic agent par excellence up to the present time. The various colloidal solutions of salts of heavy metals, which have been tried as substitutes, are those of silver, iron, bismuth, copper, lead and mercury, as have suspensions of the salts of bismuth, calcium and magnesium. All of these solutions sediment on standing, and while being for the most part quite opaque to the Roentgen ray, are viscous; moreover, a great many are quite toxic and irritating.

The chief objection to eollargol is its irritant action when it into the tissues, and, as a matter of fact, there have been


1 A Preliminary Report on " Thorium — A New Agent for Pyelography " was published in the J. A. M. A., Vol. LXIV, pp. 21262127. This paper was read before The Johns Hopkins Medical Society, Feb. 21, 1916. From the James Buchanan Brady Urological Institute.

2 Voelker & Von Lichtenberg; " Pyelographie (Rontgenographie des Nierenbeckens nach Kollargolfullung " Munch, med. Wchnschr.. 1906, LIII, 105-107.


a number of deaths reported following its use. Its elimination from the urinary tract is somewhat prolonged on account of its viscosity. The fact that it stains everything with which it comes in contact makes it objectionable. It is also quite expensive; for this reason its use for cystograms and large hydronephroses is often prohibitive.

An ideal solution for use in pyelography should be nontoxic, (within the ordinary limits of usage) non-irritating, quite opaque to the Roentgen ray. and give not only a good shadow but one of clear delineation ; it should possess a marked degree of fluidity, permitting its ready escape from the urinary tract, and be inexpensive 50 as to lie generally used.

Since the opacity of ;i substance to the Roentgen ray depends upon its atomic weight, thorium, being next to the heaviest known element, was quite ideal theoretical!] and seemed worthy "i' careful invest igal ion.

The nitrate am! chloride of thorium are quite readily soluble in water. gn in-- a clear, markedly acid and astringent solution^ These solutions precipitate insoluble salts in the urine and also precipitate proteins, this latter characteristic making impossible their intravenous introduction in greater degrees of concentration than two per rem. These soli also quite irritatdng. All of these qualities render them unfit for clinical


158 [Xo. 304


However, on account of the ready solubility of these salts a very concentrated solution can be made, the nitrate having been used in as high concentration as fifty per cent ( Fig 1). These solutions are particularly valuable for the injection of pathological specimens, the finest hair-line vessels and ducts being readily seen in the roentgenograms ol these specimens. The plate below (Fig. 2) shows the seminal vesicles, ampulla- and vasa deferentia, injected with a fifteen per cent solution of thorium nitrate. After this injection the specimen was fixed in Kaise'rling's solution, which latter caused a precipitation of thorium salts in the walls of the ducts, markedly accentuating their outline in the roentgenogram.

Regardless of the fact that the above mentioned properties render these salts unsuitable for clinical use. it is quite evident that thorium in some form would he ideal for use in pyelography. It is very well known, however, that different salts of the same metal vary greatly in their irritating and toxic action, these latter characteristics seemingly varying indirectly with the size of the molecule, and being sometimes especially reduced in a complex ion formation. After a careful series of chemical studies of the various combinations into which thorium may



Fig. 1. — Renal pelvis and ureter of rabbit injected with a 50 per cent solution of thorium nitrate.

enter, a solution containing a double citrate of sodium and thorium, together with an excess of sodium citrate and some sodium nitrate, was found to possess the qualities enumerated above a- being necessary for an ideal pyelography medium. The solutions used contain ten per cent and fifteen per cent of thorium nitrate, and are made in the following way:

To make 100 cc. of a ten per cent solution, in gm. of thorium, nitrate are dissolved in as little distilled water as possible; to 1 this solution, kept hot on a water or steam hath, are added 30 cc. of a fifty per cent solution of sodium citrate, the additions being made in small quantities, and care being taken to shake the solution thoroughly after each addition. At first, after the addition of the citrate solution, a white gummy precipitate is formed, which later become- granular, and finally dissolves on the addition of all the citrate solution. This solution is


then made neutral to litmus by the careful addition of a normal solution of sodium hydroxid, and made up to the required volume of 100 cc. with distilled water. On filtration, a clear, limpid solution is obtained, which, when sterilized, either by boiling or steam under pressure, is ready for use. The stability of the solution is not affected in the least by sterilization.

The chemical reactions involved in the preparation of this solution are probably as follows :

Th (X0J 4 + H.,0 = HX0 3 + TH (X0 3 ) 3 OH. H 2

HX0 3 + TH (X0 3 ) 3 OH C-CO,Xa + XaOH =

HO-C-COJSTa

C-GCLXa


H, ^our possibilities : Th (X0 3 ),.O.C fi H 4 7 Xa, + C fi H,0 7 Xa 3 + Xa N0 3 +H 2 0.

Th (X0 3 ),(O.C,.HAXa ; ), Th (X0 3 ) (O.C 6 H 4 T Xa 3 ) 3

Th (<>.C, ; II 4 7 Xa,) 4



FlG 2— From a series of vesiculograms by Dr. E. M. Watson, Assistant Resident Urologist, James Buchanan Brady Urological Institute.

This solution contains approximately fifteen per cent of thorium nitrate, about nine per cent of sodium nitrate, and twenty-one per cent of sodium citrate, the thorium being most probably in the form of a double citrate of sodium and thorium, as shown above.

As the thorium content of the solution alone is responsible for its shadow-casting properties, it- percentage strength has to be greater on account of the large size of the molecule ot this double citrate than if the solution contained thorium nitrate alone, in which the molecules are much smaller ami in consequence the atomic concentration much greater. The outline of the renal pelvis and ureter, as given by the shadow east by this solution. ,- not only quite definite, but the shadow itself is of remarkably clear delineation.


THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE, 1916.


PLATE XXIV.



Fig. 3. — Kymographic tracings (Dog IX), showir crease in respiration, after intravenous injection ol cc. The increase in magnitude of the respiratorj iue to muscular twitching.


in blood pressur r cent thorium s iu two places


increase in pulse rate and dedution in small amounts — 1" ward the end of the tracings



Fig. 4. — Kvmographic tracings I Dog XIX i, showing rise in blood pressure, increase in pulse rate, decrease in respiration, and periods of apnoea, after small injections of 10 cc. or less, of 15 per cent thorium solution intravenously, both vagi having been cut before the injection was begun.


Jr\E. 1916.1 1 59


In addition to its great opacity to the X-ray, the solution, either by it- adhesive properties, by its capability of absorbed by calculi, or by means of its comparative density, accentuates the shadows of calculi in the urinary tract when they arc not ordinarily seen in plain Roentgen ray plates.

The marked degree of fluidity of the solution is of great advantage, for it so rapidly escapes from the kidney pelvis. ureter and bladder, that a plate, made a few minutes after the injection has been discontinued, gives no suggestion of a slimlow. thus showing that the solution has been completely eliminated from the urinary tract.

That tin- solution i- not irritating to the mucous membranes of the bladder, ureters, and pelves of the kidneys, has been demonstrated by the fact that no urinary symptoms have been observed in the cases in which it has been used. Subsequent cystoscopic examinations have shown no evidence whatsoever of any inflammation of the vesical mucous membrane: the examination of the bladder, ureters and kidney pelves, in cases which have come to operation within a few hours or days after it- use, have shown no evidence of any irritative action. In the animals into whose peritoneal cavities this solution ha- been

introdui ed, there has I n no sign of any peritonitis at autopsy,

and all of the fluid has been absorbed in most instances. The careful neutralization of the solution has been emphasized previ iusly, and it i- due to this fact that no irritating action ha- been observed.

The solution, although exerting an inhibitory action on the growth of the ordinary bacteria, is not bactericidal. Mouldgrow in it upon standing; therefore, it must be sterilized ami kept sterile while being used.

A word may be said in regard to the introduction of the solution into the renal pelvis and ureter. This is done by the gravity method by means of a burette with a rubber-tubing connection and a properly fitting nozzle for the end of the ureteral catheter, the burette being held slightly above the level of the patient. This method is recognized by urologists at the present time as being the least dangerous and most successful fur completely distending the renal pelvis. Injection by mean- of a syringe has fallen into disuse because of the great danger of over-distension of the pelvis, and the forcing of tin' solution into the renal parenchyma or into the peri-renal tissues. In practically all the cases of death reported to the use hi' ollargol, tin- latter procedure was employed.

Pharmacologic Action or nn-: Solution. Thi' pharmacologic action of tin- solution has been studied experimentally in dogs, cat-, rabbits and guinea p animals having been used altogether. In these animals doses, given intravenously, intraperitoneally, intramuscularly ami subcutaneously, produced no effect. Larger dose- have in a few instances produced diarrhoea, while still largei have caused death preceded by muscular twitchings, clonic convulsions and coma. These fatal doses, of course, wi

above tl dinary limits of clinical usage. In a few tnstani es

'-' '<. of tin- fifteen per cent solution per kilogram (intraperitoneally ami intramuscularly) proved fatal in these animals, much larger doses being required intravenously to p


death. Even these figures in the ease of an ordinary man of 70 kg. would allow the use of 140 cc. of the solution, which

would he ten lilnc- a- -real a- that used ill a -11 II pie pyelogram,

and hundred- of turn- greater than any small amount that mighl he absorbed during the procedure. A- a matter o much larger amounts than this have been used in the renal pelvis without any ill effe< ts.

The tolerance of these animals for the solution seemed to vary greatly with the method of administration ; dugs, for in-iain i . being much more tolerant of the solution intravenously than when it was given intraperitoneally. The reverse, however, was found to lie true in the case of rabbits. Guinea-pigs tolerated the solution in much larger doses intraperitoneally than cats.

Outside the body the solution prevents the coagulation of the blood. When introduced into the circulation it causes no change in the cellular elements of the blood. The numbei of red and white blood cells and the hemoglobin content remain the same after its introduction.

In studying the effect- of the intravenous injection of the solution, twelve dogs and two rabbits were used. In only one of these dogs did the solution prove acutely fatal. 5 cc. per kg. having caused death in five hours in Dog XXVII. One of the rabbits died three days after the injection and at autopsy marked parasitic infection was found, so that it is impossible to say whether the thorium solution was in any way responsible or not.

The intravenous injection of this fifteen per cent thorium solution, in dug-, in small amounts (10-15 cc. ). cause- first a rise in blood pressure with an increase in pulse rate, the respirations being also increased. All three quickly return to normal. However, if the small doses be repeated over a period of several hours, the animal being etherized by intratracheal insufflation, there will be a decrease in the depth of the respirations after cadi injection. These period- of dei rease in respiration later become priods of apnoea, the respit finally ceasing quite a while before the ventricular contraction- -tup. The ventricular contractions, as a rule, become quite irregular before they cease altogether. Tl final drop in blood pressure, a- would be expected. The cutting uf the vagi has no effect upon these phenomena. By this method a- much as 12 cc. per kg. (Dogs IX and XI) have been required to produce death. In a few of these dog- muscular twitchings followed by clonic convulsions were observed toward the end uf the experiment i Pigs. -' and 1 1.

As much as -I cc. per kg. i Dog XVIII) have been given at a single dose without any symptoms being observed, and Willi

iffed mi the phenolsulphonephthalein output or on the

blood urea content. This animal was sacrificed in day-: the autop irovei ] • "" demo]

change in kidney function, a- indicated bi iln- two methods of investigation, in any of the dogs to which ten and fiffc cent thorium solution was administered intravenously I and 6). In some of the dogs there was diuresis of short duration. In rabbits, 3 cc. per ;g. of this ft tion. when given in a single it V 1 1 I . produced


[No. 304


immediate muscular twitching and clonic convulsions followed by rapid and complete recovery, no untoward effect being observed afterward. Autopsy in this instance was also negative. Two ce. per kg. ( Rabbit VIII) caused death in three day-. At autopsy a generalized parasitic infection was found.

The solution was injected into the peritoneal cavity of five

three cats, seven rabbits, and three guinea-pigs. It

caused death in one instance in each of the different animals.

Three and a half ec. of this fifteen per cent solution per kg.

in Dog XXI prod u - - I diarrhoea; no other effects were

ed. Three cc. per kg. (Dog XIX) caused a bloody


ilf^fl. r-y t 1 1 1 1 1 \jLJ^\ 1 9 u li .'. a i4 si at .•/ .-s e x j> i z 3 <



m — i ii i i i i i i i n











Z - ,<='*








^~~-«- *




_p* .




























Fig. 5. — Chart of Dog VI, showing no change in phenolsulphonephthalein output or blood urea content after injection of 1 cc. per kg. of 10 per cent thorium solution.

X = phenolsulphonephthalein output for two hours and ten minutes.

° = blood urea, grams per liter.


Do* .


m


8/oedt/rt








.

n




»


t9






\


4



'



»


»


»




13





'


>a


-*





























































































































































































'

















.

























































Bf








f
























-*

















































































































































































































































































Fig. 6. — Chart of Dog VII, showing no change in phenolsulphonephthalein output or blood urea content after intravenous injection of 1.5 cc. per kg. of 10 per cent thorium solution.

X = phenolsulphonephthalein output for two hours and ten minutes.

c = blood urea, grams per liter.

diarrhoea for twenty-four hours following the injection, with prompt recovery; the animal was sacrificed in thirty-six days for a kymographic experiment. The autopsy showed central necrosis of the liver. All the other organs were normal. Two cc. per kg. ( Dog VIII ) proved fatal in eighteen hours after the injection. At autopsy this animal showed hemorrhagic gastroenteritis and congestion of all the organs. Xo fluid, however, was present in the peritoneal cavity and the peritoneal surfaces were smooth and glistening. Microscopically central necrosis of the liver was found. In cats, three cc. per kg. (Cat III) caused death in three days. This animal loss of appetite : it was dull and apathetic. At autopsy a small


amount of clear fluid was found in the peritoneal cavity: the peritoneal surfaces were normal. All the organs were normal in gross appearance. Microscopically cloudy swelling of the liver was seen. Two cc. per kg. 1 1 at IV I produced no effect. This animal was sacrificed in eighty-four days, the autopsy showing generalized parasitic infection. One cc. per kg. (Cat II) produced no effect. This animal was sacrificed in ninetyfour days, the autopsy showing nothing abnormal. In rabbits 10 cc. per kg. (Eabbit VII) produced death, preceded by convulsions, in twelve hours. The autopsy showed a small amount of bloody fluid in the peritoneal cavity ; the peritoneal surfaces were normal. Seven and a half cc. per kg. in Eabbit IX produced no effect. In guinea-pigs 8 cc. per kg. ( Guinea-pig IV ) caused death in forty-eight hours. Some clear fluid was found in the peritoneal cavity at autopsy : the peritoneal surfaces and organs were normal in appearance. Three ec. per kg. (Guineapig III) showed no effect.

Intramuscularly, small quantities distributed over different portions of the body were absorbed, no effect being produced. In dogs. 2 cc. per kg. given deeply into the lumbar muscles (Dog XXXI) caused death in three days. Hemorrhage and necrosis were observed at the site of the injection and at autopsy congestion of all organs was found. In cats, 4 cc. per kg. (Cat VI) caused death in twenty -four hours. The autopsy showed a slight hemorrhage at the site of the injection, and bloody fluid in the pleural and pericardial cavities: microscopically central and midzonal necroses of the liver were seen.

Subeutaneously, small doses were well absorbed, producing no effects whatever if well distributed over the body. In dogs, 2 cc. per kg. (Dog XIV. who four days previously had received 1 cc. per kg. intraperitoneally ) were followed by death in forty-eight hours. Muscular twitchings were observed for twenty-four hours preceding death. The autopsy showed hemorrhage at the site of the injection ; there was no free fluid in the peritoneal cavity : all the organs were congested. In cats. 4 cc. per kg. (Cat V ), caused death in twelve hours. The autopsy showed acute congestion of the spleen, petechial hemorrhages in the heart muscle, and central and midzonal necroses of the liver.

Modifications of the Solution.

With the idea of a possible simplification of the solution, various attempts were made to modify it, but these modifiea-. tions, when tested experimentally, have either shown an increase in toxicity, or have been responsible for the production of certain symptoms that are not observed when the original solution is used.

Since the thorium content of the solution is alone responsible for its shadow-casting properties, as noted above, it was thought that a solution containing only the double neutral citrate of sodium and thorium would be a great step towards simplification. 3 This, however, in fifteen per cent concentration, proved


3 1 am indebted to Dr. H. A. B. Dunning, of the firm of Hynson. Westcott & Co., of this city, for the preparation of this double neutral citrate and the modified solutions employed in these experiments.


THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE, 1916.


PLATE XXV.




Fig. 7. — Normal renal pelvis and ureter.


Fig. 10 — Accentuation of the shadow of a renal calculus by the thorium solution, a plain roentgenogram having shown no shadow.


Fig. 13. — Bilateral hydronephroses, and hydroureters, dilated and trabeculated bladder, dilated internal sphincter, due in congenital obstruction in posterior urethra.



Fig. 8. — Slightly irregular pelvis due to old chronic inflammatory

process.



Fig. 11. — Moderate grade of hydronephrosis due to a calculus in the lower end of the left ureter.


Fig. 14. — Double pyelogram showing a slight hydronephrosis in the lower portion of the pelvis of the left kidney.



Fig. 9. — Kink in upper ureter dun in aberrant vessels to lower pole of kidney, with a slight grade of hydronephrosis.



Fig. 12. I. arm' hydronephrosis due to a congenital stricture of the ureter.


Fig. i i i louble i i logram, showing similar types of renal pelvis on both

sides.


THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE, 1916.


PLATE XXVI.




Fig. 16. — Double pyelogram showing a bifid pelvis on the left; kink in lower end of right ureter.


Fn;. 19. — Plain roentgenogram of bladder showing indefinite shadow in the bladder region due to numerous small calculi.


Fig. 22. — Cystogram. Case of tabes dorsalis showing trabeculated bladder with diverticulum, dilatation of the internal sphincter and funnel-shaped posterior urethra.




Fig. 17. — Horseshoe kidney; case of Dr. Guy L. Hunner.


Fig. 20. — Cystogram (same case as Fig. 19), the bladder being filled with ten per cent thorium solution.


Fig. 23. — Congenital hydronephrosis in a boy 11 years of age.





A



Fig. IS. — Cystogram showing trabeculated bladder with diverticulum, dilatation and kinking of right ureter.


Fig. 21. Si se as in Figs. 19

and 20 after thorium solution had been allowed to How out of the bladder, showing sponge-like shadow due to the differing degrees of opacity of the calculi and thorium solution.


Fig. 24.— Double pyelogram showing a double renal pelvis with a calculus in the upper pelvis and ;< bifurcated ureter cm the

left side.


June, 1916.] 161


quite toxic as is shown by the following experiments : An intravenous injection of 4 cc. per kg. (Dog XX) caused a bloody diarrhoea for twenty-four hours, beginning six hours after the injection, the diarrhoea ceasing by the beginning of the third flaw The dog was dull and apathetic, and bad no desire for food. Death occurred in seventy-two hours. The chief autopsy finding was central necrosis of the liver with congestion of the kidneys. Three cubic centimeters intravenously (Dog XVI) caused a marked diarrhoea for forty-eight hours following the injection, during which time the dog was very sick and stupid. This animal showed marked loss of appetite and weight. The total phenolsulphonephthalein output for two hours and ten minutes dropped from 88 per cent at the time of injection to 50 per cent on the thirty-fourth day, at which time the animal was sacrificed. At autopsy no unusual findings were observed grossly. Unfortunately, the sections were lost.

These experiments show that a solution containing the double neutral citrate alone could not be used. Sollman and Brown 1 investigated the pharmacologic action of the double citrate of sodium and thorium; these authors found that one gram per kg. given intravenously caused death immediately and that .5 gm. per kg. caused death after twenty-four hours. The results of the studies of these authors agree with mine, excepting in the autopsy findings. They report ulceration of the buccal mucous membrane and deposits of calcium in the organs; no such changes were found after the use of various doses of any of the thorium solutions that I have investigated. These authors furthermore state that the toxic effects of the double citrate may be largely accounted for by the sodium citrate content, for their experiments with sodium citrate alone gave practically the same results.

A solution made in the same way as the original solution, but in which thorium chloride was used in place of thorium nitrate in its preparation, caused diarrhoea for twenty-four hours in Dogs XXIII and XXVI. In each instance 4 cc. per kg. were given intravenously. These animals were sacrificed in forty-four and thirty-seven days, respectively, and the autopsies in both instances were negative.

A solution containing the double neutral citrate of sodium and thorium, fifteen per cent, and ten per cent of sodium citrate, caused immediate death in Dog XXIV, after 2.5 cc. per kg. had been given intravenously. The autopsy was negative. In Dog XXVIII, 4 cc. per. kg., intravenously, caused death in eighteen days. For twenty-four hours following the injection there was marked muscular twitching and diarrhoea. However, there was prompt recovery from these symptoms, but the gradual loss of weight and appetite continued until death ensued. The autopsy findings in this instance were negative.

A solution containing fifteen per cent of the double neutral citrate of sodium and thorium and ten per cent each of sodium chloride and sodium citrate caused death in sixteen days after the intravenous injection of 4 cc. per kg. (Dog XXV). This dog was apparently well until three days before death, when he began having convulsions and was very dull and apathetic.


Sollman & Brown: " Pharmacologic Investigations on Thorium.' Amer. Journ. Physiology, 1907, XVIII, 426-456.)


Dog XXIX died at the end of an intravenous injection of 3 cc. per kg., the respirations ceasing before the ventricular contraction. The autopsy showed congestion of all the organs. Dog XXX. given 4 cc. per kg. intravenously, hail diarrhoea i'm- twenty-four hours with prompt recovery; there were no other symptoms. This animal was sacrificed in thirty days. The autopsy findings were negative.

From these observations, it is seen that the withdrawal of any of the component parts of the original solution would be harmful. The substitution of the chloride for the nitrate of thorium in the original solution produced diarrhoea.

Clinical Uses.

Since the introduction of this solution into the Urological Clinic of this hospital eight months ago, it has been used in one hundred and twenty-live cases without any untoward effects whatsoever having been observed.

From the table of eighty-seven pyelograms (pp. 162-163) it will be seen that there were nausea and vomiting following its use in four cases. These symptoms could be readily accounted for by the ureteral catheterization alone, for they occur fully as frequently in case- where this alone has been done and no injection has been made into the renal pelvis or ureter. In one of these cases, on account of the irritability of the bladder, the patient had to be etherized before ureteral catheterization could be attempted : the etherization could account for the nausea and vomiting in this case. In the table of cystograms it is seen that nausea and vomiting occurred in one case, and slight nausea and frequency of urination in another. In the first case the nausea and vomiting occurred some hours after the cystogram had been made and was due in all probability to some indiscretion in diet. In the second case the patient was quite nervous, this condition possibly being entirely responsible for the symptoms.

The largest amount used in the entire urinary tract in a. single case was 600 cc. of a ten per cent solution introduced into the bladder, ureters and renal pelves of a boy twelve years of age. The roentgenogram (Fig. 13) in this instance showed a dilated and trabeculated bladder with dilatation of the internal sphincter, double hydroureters and hydronephroses, due to a congenital obstruction in the posterior urethra. This patient showed no change in the phenolsulphonephthalein output or blood urea content; nor has there been any interference with kidney function demonstrated in any of the cases. For pyelograms, from 5 to 150 cc. of a fifteen per cent solution have been used, and for cystograms from 30 to 930 cc. of a ten per cent solution.

Conclusions.

1. Thorium solution fulfils all the conditions necessary foi an ideal pyelographic medium.

2. Clinically, there ha- never been the slightest evidence of

toxicity in a series of one hundred and twenty-five case.-, the amounts used in a single case varying from a few cubi meters to almost a litre. This alone is proof of its non-toxicity.

3. Experimentally, although in a few instances death has followed tlie injection of large doses into the peritoneal cavity


[Xo. 304


TABLE OF PYELOGEAMS. FIFTEEN PER CENT THORIUM SOLUTION.


Quantity of thorium sol. injected.


4466 C. C. . .

4474 T. J. F... 45

4491 [l. M 45


273 4499 ;E.H 50

275 4519 P. C. H.. ..


Ureteral calculus Pyelogram (S) .

Pyelitis— left Pj elogram (S) ,

Renal calculus Pyelogram (S)

Hydronephrosis Pyelosrram (S)

Ureteral calculus Pyelogi

Renal tuberculosis Pyelogram ( S)


27- 4521 G. B 32 Hydronephrosis


Pyelosrram (D) L150cc.


! , W. H .

M. V....


346 4676 R. McA.


3!


W. S

1'. S. M... T. L. C...

1591 T. J. W . .


.1. .1. McG P.B


4355 F. X . . . .

J. B

3106 W. L. C .

443' .1. \V....

4439 J. W....

221 443- J. W....


222 4426 R. M

23;' 4416 R. M.... 23* 4443 K. F. H .

2:33 4435 D. S. B..


i- logram (S)


Symptoms fol- Phenolsulphone- Phenolsulphone lowing injec- phthalein output phthalein output

tion. before injection. after injection.


None None Xone Xone Xone Xone

Xone


41%, half hour. 50%, half hour.

Half hour, 14%, R. ; Right nephrectomy.

30%, L.


Xone


19 Hemorrhagic nephritis Pyelosrram (D)


Pyelosrram (S) 8 cc.


Xone


Xone


Pyelonephritis

Pyelonephritis Pyelogram (D) . . . • Xone

Pyelitis Pyelogram (D)


SI. nausea and vomiting.


Prostatic hypertrophy Hydronephrosis


Pyelogram (D) Xone

. Pyelogram (S) Xone


Hydronephroses Pyelogram (D) 600 cc SI. nausea and

Hydrcureters. Septum post. Cystogram 1 i vomiting.

urethra.

Essential hematuria Pyelogram (D) R-5ce.

L-occ. Prostatic hypertrophy. Vesi- Pyelogram (S)

< al calculus. Prostatic hypertrophy. Pye- Pyelogram (S) 16 cc. .

litis. Ureteral calculus. Pvelone- Pyelosrram (S)

phritis. Ureteral calculus. Pvelone- Pyelogram (S)

phritis. Ureteral calculus. Pyelone- Pyelogram (D)

phritis.

Ureteral calculus Pyelogram (Si Xone

Ureteral calculus Pyelograi i (S Xone

Chronic prostatitis a n d Pyelogram (D( > Sonc

seminal vesiculitis. L-6cc...

llrer of bladder. Cystitis Pyelogram (S)

and prostatitis.

Renal calculus Pyelosrram (D)

Hydronephrosis. SI. Pros- Pyelosrram (D)

tatic hvpertrophv.

Pyelitis Pyelogram IS)

Hydronephrosis Pyelosrram (D)


Half hour, 10%, R. : Total, 62%

30%, L. Total, . :

R.; 0%, 1 Half hour, 15%, L Half hour, 20< ,. U.

15%, L. Half hour, 6i . ,1

R.:12%,L. TransHalf hour. 17V i . Total, 61%.

R.; Trace. L. Half hour, 15%, R. :

9 .. L. Half hour, 18%, R.;

.V , , L. Trans.... Half hour, 14%. R.; Total, 60%.

IV-,. L. Half hour. :

10%, L.

Blood Total, 26%

3 gms. Bl. urea, 0.6


. Pyelitis, right.

. Right nephrectomy.

. Plastic operation on pelv

kidney. . Right pyelotomy.


Tonsillectomy. Lavage of renal pelves with AgXO s . Injection of




Lavage of renal pelv

solution. Lavage of renal pelv


with AgXO, l with AgNO»


Xone Xone. Xone

Xone

Xone

Xone

Xone


Xone


Total, 61% Total, 62%

Total, 59% Total, 59%

Total, 49%

Total, 60% Total, 62%

Total, 62%

Total, 60% Total, 62%


Etherization tor cystoscopy. Suprapubic cystotomy with division of urethral septum.

Lavage of renal pelvis with AgNOi solution.

Perineal prostatectomy and lithotomy.

Lavage of renal pelvis with AgKOs solution.

Left nephrectomy.

Left nephrectomy. Left nephrectomy.


L-25CC,


245 4463 G. W. L.. 42

259 4535 F. Y 31

2:'7 4565\V.S 55

321 456? \V. S 55

350 456- H 2J3 4574 H. A. M.. 55

295 4560 C.B 48

' G 57

323 4579 H. H. E.. 45

324 4617 R. T. D... 56

325 4615 \\

265 4454 A. M. H.. 26


Cystitis. Prostatitis Pyelogram (D) .1.

Pyelitis (rt) Pyelogram (D) ...

Pyelonephritis. Periurethral Pyelogram (S) —


R-14cc. L-14CC.


Pyelonephritis. Periurethral Pyelogram (S)

abscess. Pyelonephritis. Periurethral Pyelogram (S)

abscess. Renal calculus Pyelogram (S) R-15CC.

Chr. prostatitis and Veru- Pyelogram (S)

montanitis. Ureteral calculus Pyelogram (S) L-!3ec.

Pyelitis (rt.) Pyelogram (D) ....

Pyelonephritis Pyelogram (S) R-4 cc...

Pyelone- Pyelogram (D) . .


Renal calculus.

phritis. Ureteral calculus Pyelogram (D)


R-13c Lace


1530 J. H. B... 35 chrome prostatitis a n d Pyelof seminal vesiculitis.

43 2«4536J. L 36 Ureteral calculus. Hydrone- Pyelogram (S) R-13oc..

phrosis. 317 4602 W. H .... 27 Renal and seminal tubercu- Pyelogram (S) .

Dtial hematuria Pyelogram (S)


211 4420 326 4632

333 1549

334 4369

356 4707


G. O.

G. B.. L. A.. B. G. J. M.. L.C..


24 Hydronephrosis. Double Pyelogram (D)

pyelitis. 39 Chr. prostatitis and seminal Pyelogram (D)

vesiculitis. 21 Vesical ulceration. Leuco- Pyelogram (D)

plakia. 63 Pyelonephritis. Cystitis ... Pyelogram (D)

- of kidney fit) Pyelogram (D)


F. S..


R 171

1.-2" c H-7cc...


Chr. prostatitis Pvelosrram (S) R - Xone

Renal tuberculosis Pvelosrram (S) Xone

Hydronephrosis. Double Pyelogram (S) R-2S cc. . . Xone

pyelitis.

Hydronephrosis Pyelosrram I'D) . None.

Renal tuberculosis Pvelogram (D) ... R-4 i None


Xone Xone Xone Xone Xone Xone Xone Xone Xone


Xausea and vomiting.

Xone


Xone None Xone Xone

Xone Xone Xone Xone Xone None


Total,- 639! Total, 63%

Total. 55%

Half hour, 14%, R.: Total, 52%.

iv .. 1-.

Half hour. 22%, R. ; Total. 63%

12',. L. Half hour, 21%, R. : Total, 59%.

a%, l.

Half hour, 27%, R.: 22%, L.

Total, or; Total. 709!

Total, 61% Total, 70%

Total. 70%

Half hour, 16%, R. ;

23%, I.Half hour, 16%. R. ; Total, 63%.

22%, I.. Half hour, 22%, R. :

Total, 5S%


Half hour, trace

R.; S89i I-

Half hour. 21%, R. ; Total, 60% T ital, 70%.


Etherization for cystoscopy. Pyelotomy.


Left nephrectomy


ind drainage of periurethral ;ii

Incision and drainage of periureThral .

Incision and drainage of periurethral abscess.


. Lavage of renal pelvis

solution. . Syringe injection.

. Right nephrectomy.

Left ureterolithotomy.


Total, 64%

Half hour, 35%, R. : Half hour,

trace, L. trai e, I Half hour, 22%, R.

Total. 73'


Half hour. 15%, R.i

1



Right ureterolithotomy.

36,' ; . R. ; Left nephrectomy.


Lavage of renal pelvis with .

solution. Exploration of right kidney.


Half hour, 51%. R.: Total, 42%

0%, I..

Total, 55%

Half hour.


Left nephrectomy.


Right nephrectomy.

.':.- Exploration of right kidney.


June, 1916.] 163


TABLE OF PYELOGEAMS. FIFTEEN PEE CENT THORIUM SOLUTION— Cont'd.


s


371 4719 377 57-16 382 1772

38! 1806

S87 1777

31)5 4S93

41(1 4793

336 4S0S 4nl 4808

3 il l-m


443 4892

447 4916

1611 1916


ll« 


I.. C. H .. P. H

c. c

S. K

B. O. B . .

H. K

H. K

C. H. R...

C. II- K

r. w. G

\V. M. P.. \\ .E.McG

A. S. H... K. K. H..

H. W . F. .

F. H

P. F...

C.J

W. H. K .

H. M. S .

J. G

J. G

B. G

F. M. B ..

P. M

J. X

C. F. P. . .


Quantit s

of tho i rium sol.

in ieett d.


Renal tuberculosis

Pyonephrosis

Renal tuberculosis

Ureteral calculus

Renal calculi

Pyelitis <rt)

Pyelitis (rt)

Ureteral calculus Ureteral calculus (rt)

Prostatitis and seminal vesiculitis.

Nephralgia

Renal calculi. Double renal pelvis and ureter.

Chr. prostatitis

Nephralgia

Cnr. prostatitis. Verumontanitis.

Median bar hypertrophy

Median bar hypertrophy. . . .

Prostatic hypertrophy

Chr. prostatitis

Chr. Cystitis. Prostatic

Hypi r. i Median bar. i Essoin nil hematuria

hematuria

Perinephritic abscess (rt >

Gonorrhceal pyelitis

Chr. Cystitis and Chr. Pros tatitis. Double pyelitis

Renal tuberculosis


Pyelogram (S) R-£

Pj-elogram (S) . Pyelogram (S) ,


Pyelogram (Si .. R Pyelogram (S) ... R


Pyelogram I Pyelogram I S I

Injection of seminal

vesicles. Pi elogram (S)

in (D) ....


Svmptoms Phenolsulphone- Phenolsulphonelollowing phthalein output phthalein output

injection. before injection. after injection.


X. me

None. None

None

None


. Half hour, 2( '•, , R : [total, 53% Right nephrectomy.

24' 7. L. .Half hour, ie , R.;Total, 68 1 Right nephrectomy.

28%, I..

. Half hour, 33%, R. : Total. 65< ; Left nephrectomy.

I

. Half hour, 30%, R. ; Total. 627c Left pvelotomy.

21', L.

. Half hour, 35% Half hour, 3S7< Lavage of renal pelvis

solution.

. Half hour, 35% Half hour, 38% Lavage of renal pelvis

solution.

I'li-trp. lull. .1, .im


uli \k\<> ; . nh lgN0 3


gram (S) ... Pyelogram (D) . . Pyelogram ( D 1


R. H 53 Essential hematuria

R. H 53 Essential hematuria

C.S 28 Double pyelitis ...


D. C. B... 3S Pyelitis (rt.)

H. K. B.. 29 Renal tuberculosis bilateral.


Pyelogram (S) ... im (D) ..

Pyelogram (D) .. am (D) . .



R-llcc. Ii-9cc...

R-5CC.

R-20CC,

L-16 cc. R-lOcc. L-12 i


. Half hour, 12%, R 22%, L. Total, 4"' ,


Half hour, 18%, R 13%, L. ; transves., 25%.

Half hour, 15%, R.; I., . . I

Half hour, 22%, R. : transves., 5 1 ,.

Half hour, 0%, R. ; Total, 15' , . L.

Half hour. 7%, R.: Total, 1"'.. I.-; transves., 7 : ' ,,

Total,



Ureterolithototm .


Pyelogram (S) . Pyelogram (S) .

Pyelogram (D) Pyelogram (S) .


None.

None . None .

None .


Incision and drainage oi phritic ab

Lavage of pelvis with AgNOs solution.


None None


Half hour, 11',. R.

Half hour. V ,. R. 8' . . L. ; trans


Half hour, 20%, K.

8%, L, : trans

ves.,8%. Half hour. 20%, B.

- , I . : t r a n s

ves . -' , Half hour, 17' ,. R

13 r ; , L. ; t r a n s


1st half ho

2d, li"

42',.


Lavage of pelves with AgNOa solution. Right nephrectomy.


nh AgNOs ith IgNO


L = Left kidne


teal collection of phenolsulphonephthalein output. Total=Phenolsulphoni p)


TABLE OF CYSTOGRAMS. TEN PEE CENT THOEIUM SOLUTION'S.



- a






Jl^


Symptoms



Z


K





il-:


S : mp o



OJ



Diagnosis.


Cystogram.


folio



~




Diagno ' stogram.


~ = 2


following



~. ~







injection.























5-z .=



s


— X


Z


<




5-72 =



17


33 7


4641


Z





1


1S5 ....


S. V.




Cvstogram. . .




J. J. w.


67


Prostatic hypertrophy. Cystogram...


I'll.


None.



213 1173


W. v..


19


Tabes dorsalis


Cystogram.. .


,


None.






ilculi.






G. C. T.


66


Prostatic hypertrophy.


Cystogram. . .


930 . ,


.. and





37 42








19


362


1715


V. w.



1'iM CC.


None.


4


229


1438


D. s. B.


22


Ulcer of bladder, evsti

Cvstogram. . .



None.



364


4,23


D i .0


38


Cerebro-spinal lui


. I . I








tis, contracted blad




21



1773


S P. I:



Prostatic In pertroi



None.















\ esical calculi.




.

.,-,,;


443(1


P. H.


45



Cvstogram.





400


4S11 R. L.


.",1


Retro-vesical sarcoma. Cystogram...










Rt. kidney




23


413


4592 A. B.


13


Tuberculous pvo- Cystogram...



None.


6


234


4136


M. K.


.is


Prostatic hypertrophy,


Cvstogram. . .


250 cc.


None.






nephrosis (right).




.


249


1778


J. B. C.


4','


Prostatic hypertrophy,


I , stogram .



None.


M


411


4088 K. E. K.


la


Bar hvpertro- Cystogram. . .








cerebro-spina] lues.










phj .




s



4459


P.H.


62





None.



415


4K4M


1 M S


55


Carcinoma of prostate. Cvstogram...



None.


ii


256


4493


H.H.H.












Vesical calculi.









pertrophv.





-.'6


434


48S5


S. R. D.


48


Hvpertrophv of trigone. Cystogram...


750 cc.


None.



260


13,6


\V. l .


nH


Cerebro-spinal lues


Cvstogram. . .


275 cc.


None.







Contracted vesical





203


1369


B. G.


•',1


Cystitis. Leukoplakia.



30o None.







neck.





244


44611


J. M.


?,4


Hydronephrosis



Norn




4-1


H. F.


4N


Diverticulum



None.


13


330


I'll

J. G.


W.


Tabes dorsalis



47,(i cc. Non<



-l.,u


4664


W.K.C.


no


Prostatic hypertrophy. Cystogram.. .




14


29

4523


M. S.


55


Cerebro-spina] lues


Cvstogram...


425 cc.


None.



la3


4927


A. B.


47


Prostatic hvpertrophv. ( lystogram.. .


250 cc.


None.



310


I,,,':


J. F. H.


1

Cerebro-spinal lues


Cvstogram. . .


725 cc.


None.












4o9I


T. W.


6n


Prosi at i' h\ pertrophv. Vesical calculi.


Cystogram. . .



None.










n;i [Xo. 304


and tissues of animals, larger doses intraperitoneally and intiavenousl] iced no ill effects.

1. That the solution is non-irritating is shown by the absence of urinary .symptoms after its use. and the absolute lack of any such evidence cystoscopically, and at operation.

.'.. The pyelograms and cystograms made with this solution show a splendid shadow which possesses an unusual clearness of delineation.

(J. The solution is clear and watery ; therefore it possesses a great degree of fluidity, permitting its ready elimination from the urinary tract.

7. It is perfectly clean and does not stain the linen. In this particular it possesses another marked advantage over other solutions, particularly those of the silver salt-.

B. It is quite inexpensive, being about one-third as costly as collargol.

I desire to express my sincere thanks to Dr. Hugh H. Young, Director of the James Buchanan Brady Urological Institute . for his constant and enthusiastic interest throughout the course of this work : to Dr. C. A. Waters, of the Department of Boentgenology. for his invaluable assistance in the roentgenographic to Dr. E. K. Marshall, of the Department of Bharmacology, and to Dr. George Pierce, chemist of the James Bu


chanan Brady Urological Institute, for their helpful sugges tions; to Dr. Montrose T. Burrows, of the Department of Pathology, for his kind assistance in reviewing the pathological material: and to Dr. W. S. Gorton, physicist of the James Buchanan Brady Urological Institute.

DISCUSSION'.

Db. Honkeb: We ought to congratulate Dr. Burns on this very important contribution for those who work in urology. In working in a special line, as I have been doing for some time: viz., on ureter stricture, I have regretted often not having X-ray pictures of the condition of the dilated pelvis and the dilated ureter above the point of stricture. I have not felt justified in using the older solutions, such as collargol, because of the actual danger to the patient, and because in those particular cases it was not going to do the patient any good. A diagnosis could be made with the means at hand and it did not seem justifiable to go further. Now, from the experience I have had with thorium solution, I feel that we are perfectly justified in going further and getting an actual picture as a matter of record and to demonstrate to others the condition, without any added risk to the patient. I have always felt we were not justified in using collargol except in rare instances where perhaps there was doubt as to whether we were dealing with a tumor of the kidney, or in some such case where we actually needed an X-ray picture. The thorium method described by Dr. Burns this evening will be of great value in many cases.


A STATISTICAL STUDY OF 635 LABORS WITH THE OCCIPUT

POSTERIOR.

By E. D. Plass, A. B., M. D., Instructor in Obstetrics, The Johns Hopkins University, Baltimon . Md.


Introduction.

The recent American literature on the subject of obliquely posterior positions of the occiput has indicated such a widespread belief in the unfavorahleness of this common occurrence, and such radical opinions with regard to the proper methods of treatment, that this study was undertaken for the purpose of learning from our clinical experience whether there is any justifiable basis for such views. We have always viewed these cases with perfect equanimity and have been impressed with their benignity, but so far without any definite statistical evidence of our own in favor of such a view. The occiput obliquely posterior presentations have always been a stumblnc_ r block for physicians, and only somewhat recently have the conservative obstetricians come to the conclusion that they are little, if any, worse than the anterior varieties. However, this view seems not to be universal, for, only within the past year, an American author has advocated Cesarean section in certain cases of this class, even in the absence of any other indication, and the majority of writers refer repeatedly to the marked difficulties encountered in these cases.

The following points have been studied and will be considered in order: Frequency, internal rotation, time of rupture of the membranes, character of the delivery, necessary operative measures, indications for operations, infant mor


tality, duration of labor, type of pelvis, size of the child, and maternal morbidity and mortality. The first portion of the article is devoted to the presentation of the statistical findings ; in the second portion the historical aspects are considered and a short discussion of the various findings is attempted.

Statistical Findings.

M<iti rial. — The histories of the first 7500 patients admitted to the Obstetrical Ward of the Johns Hopkins Hospital up to November, 1915, were examined and a note was made of the position of the child, as determined by abdominal palpation and by vaginal touch. The latter was always given preference over the former as being more accurate, but where no vaginal examinations were made the findings on palpation were considered final. Of the total number of admissions, 1730 were not available for our study. This group includes patients that were classified as " not pregnant." " not delivered." " admitted post partum." etc.. as well as those in whom no definite diagnosis was made, usually because the patient was admitted very late in labor. Accordingly. 5770 cases, representing 58 children, were available for analysis, and the following table >li<i\v~ the frequency with which the various presentations were noted


June, 1916.] 165


Table 1. — Frequency of the Various Presentations.

Percentage.

94.60 .34 .13 3.87 .96 .07


Vertex 54S8

Face 20

Brow 7

Breech 226

Transverse 56

Compound 4


5801 * 99.97

Thirty-one cases of twin pregnancy are included. Table 2 shows the incidence of the various varieties in the 5488 vertex presentations.

Table 2. — Incidence of Varieties oi Vertex Presentations.

Position. Number. Percentage

L. 0. A 2613 47.61

R. O. A 1046 19.06

L. O. T 706 12.86

R. O. T 488 8.89

L. O. P 181 3.30

R. O. P 437 7.96

O. P 17 .31

Frequency. — From Table 2 it is seen that there were 635 i ases of occiput posterior among 5488 vertex presentations, an incidence of 11.57 per cent. The division into right and left varieties i- also indicated. These figures are considerably lower than those usually given. The discrepancy is probably explained by the fact that the majority of the patients applied for admission only when labor was well advanced, and after a eei tain amount of internal rotation had taken place.

Except in the cases complicated by contracted pelvis, in which the head usually engages with the sagittal suture transverse, it is probable that a large proportion of the cases, registered as L. O. T. and R. 0. T., originated as obliquely posterior positions. The only objection to such an assumption is the greater incidence of the former in our series, which would indicate that almost as many cases had originated in L. 0. 1*. a-s in R. 0. P., which is contrary to the general experience. Consequently, it has seemed advisable to limit our consideration to the cases in which a positive diagnosis of an actual posterior position had been made.

Internal Rotation. — A study of our histories gives the following information concerning this cardinal movement in the mechanism of labor:

Table 3. — Character of Internal Rotation (Spontaneoi s

and Operative).

Spont. Oper. Total

Rotation through 135 3 to symphysis I O. A.) . . 419 77 496 Rotation through 45° to hollow of sacrum

(0. P.) 70 10 80

489 87 576 No rotation permitted (version or Caesarean

section) 46

No note on direction of rotation 7

No rotation (born in oblique diameter) 6


635


With regard to the question of internal rotation, interest settles on the cases of spontaneous rotation as giving an index of the normal incidence. This was observed in 487 cases, and in 419 or 85.8 per cent, the occiput turned toward the symphysis, while m the remaining 70 or 1 t.2 per cent the occiput was toward the sacrum.

A certain amount of information was gathered with regard to the influence of the factors that are usually brought forward to explain rotation.

In 22 cases it was noted in the histories that the head was "poorly Hexed." Of these, 11 rotated spontaneously. 1 to (). A. and 4 to 0. P. This finding substantiates the observation long since made that poor flexion interferes with rotation of any kind and tends to cause posterior rotation in a certain number of cases.

Of the 70 cases in which spontaneous posterior rotation was observed, 35, or 50 per cent, occurred in primiparse (women who had never given birth to a viable child). As the number of primiparse in the entire series was 316, or 49.76 per cent, it is apparent that the parity of the patient, and consequently the multiparous condition of the pelvic floor, cannot be held accountable for posterior rotation.

A factor which seemed to bear a causal relation to rotation of the occiput into the hollow of the sacrum was discovered in studying the direction of rotation in the various types of contracted pelves.

Table 4. — Direction- and Method of Rotation in Cases With Contracted Pelvis.



Rotated to symphysis. (0. A.)


Rotated to hollow of sacrum. (0. P.)


Type of pelvis.


Spont.


Oper.


Spont.


Oper.



No.


%


No.


'


No.


%


No.


%


Generally contracted


49 7 10 15

fi


81.6

77.7 71.4 44.1

54.5


8

1

3

10

4


13.3 11.1 21.4

20.4

36.3


2 1 1

8

1


3.3 11.1

7.1 23.5

9.1


1


(1 1



l.G





2.9


Generally contracted and





From this table, considering spontaneous rotation alone, it is seen that in the usual types of contracted pelvis, the occiput rarely rotates posteriorly. In the group of cases marked by inlet contraction alone (generally contracted, simple flat and rachitic), rotation was noted in 83 cases, and in 70 of these it occurred spontaneously. Of these 70, in only 4, or 5.71 per cent, did the occiput rotate posteriorly; whereas in the 23 cases of typical funnel pelvis, in which spontaneous rotation occurred, it turned toward the sacrum in 8 cases, a percentage of 34.7. When the outlet contraction was complicated by a contraction at the brim (generally contracted and flat funnel), one case out of 7, or 14.3 per cent, showed posterior rotation. From the table it is very evident that funnel pelves, in addition to predisposing toward rotation into the hollow of the sacrum, have a marked tendency to interfere


[No. 304


with rotation in any direction, and consequently the incidence of operative rotation is considerably increased. In the group of inlet contractions, out of S3 cases operative rotation was j in 13, or 15.6 per cent, while in 4-"' eases of typical tunnel pelvis it was necessary in 15, or 33.3 per cent.

That this is more than a coincidence is indicated by the findings for the normal pelves. Here there are two divisions, separated at the period when outlet mensuration became a routine procedure. In the former, outlet contractions were usually overlooked, while in the latter they were recognized and placed in a separate category.

Table 5. — Rotation in Normal Pelves.


Rotate..! to svmphvsis.

... \.



Spout. Oper. Spont.


Oper.




', No. ', No. ',



Before outlet mensuration was instituted

After routine outlet mensuration was instituted .


114

217


68.6 2<; 15.0 24 14.4 77.2 25 S.9 ".2 11.:!


2 1.2 7 2.5


From Table •"> it. appears that, in the former period when funnel pelves were not recognized, there was a smaller percentage of spontaneous anterior rotations and a larger percentoperative rotations than in th> - up. in which funnel pelves were recognized and classified as such. Considering spontaneous rotation alone, it is seen that, in the first group, consisl \ 3 cases, posterior rotation occurred in 24. or 17.4 per cent, whereas in the second group, consisting - -. this outcome was noted only 32 times, or 12.9 nt.

These observations on the effect of pelvic contraction upon internal rotation would indicate that resistance at the superior strait favors anterior rotation, but resistance at the inferior strait tends t. tate 1 occiput into the hollow of the sacrum and to increase the necessity for operative rotation.

The observations made upon rotation in premature and mature feruses emphasizes the well-known fact that children with small heads tend to rotate posteriorly. Of the Tl cases in which the children weighed less than 2500 gm.. rotation was observed in 58 ; in 10 then :sarean

section or version was done, and in 3 no note was made as to the direction of rotation. Of these 5$ cases, in 19, per cent, the occiput rotated posteriorly, and in 39. per cent, anteriorly. This makes the occurrence of the former nearly three times as frequent in premature as in mature children.

It is thus seen that faulty flexion of the head, funnel pelvis, and the small size of the child are three factors that favor posterior rotation and that contraction at the superior strait prevents such rotation.

Rupture of the Membranes. — In each cast.- the t rupture of the membranes was noted, together with the size of the cervix when rupture occurred. In 33 . ita were


not given and could not be inferred from the histories. In 2S additional cases the membranes were artificially ruptured «arly in labor, at the time of operation, and before there had been any reasonable chance of their spontaneous rupture. Excluding these two groups, there remained 574 cases m which there were satisfactory data concerning the time at which the membranes ruptured.

It was found that in 449 rases, or 78.2 per cent, the membranes had remained intact until the cervix was more than half dilated ( 5.0 cm. ) . whereas premature rupture had occurred in 125 cases, or 21.8 per cent. (It was thought that the term "* premature rupture " might well be limited to rupture before half dilatation of the cervix, inasmuch as rupture of the membranes after the cervix is that size is rarely a complication of any moment. ) Furthermore, it is interesting to note that in 179 i ases, or 31.2 percent, artificial rupture was resorted to after full dilatation.

In order to determine whether contraction of the pelvic inlet had any additional effect upon the incidence of this accident, the 121 cases associated with contracted pelvis were analyzed, and 101 cases were found in which data were available. Of these, in 25. or 24.7 per cent, spontaneous early rupture occurred. It is somewhat surprising that the difference is not more marked.

icter of Delivery. — Spontaneous delivery occurred in - -. TT.l per cent of the entire series. In reviewing the movement of internal rotation in these cases the following facts were discovered:

Table 6. — Rotation in the Cases of Si'ontaneoi s Delivery.

Rotated through 135 : to the symphysis 414 Rotated through 45 : to the hollow of the sacrum . . 62

Rotation not noted S

No rotation — born in the oblique diameter 5

4S9

By reference to Table 3, in which the direction of the rotation in all the cases is noted, it will be observed that spontaneous rotation through 135 c to the symphysis occurred and from the table above it is found that in 414, - 3 ;.er cent of these, spontaneous labors occurred, whereas, among the 70 cases with spontaneous rotation into the hollow of the sacrum. 62, or 88.6 per cent, of the women were delivered without assistance. Thus it is evident that, when the usual anterior rotation occurs spontaneously, there is a minimal chance that artificial delivery will be indicated, whereas the anomalous spontaneous rotation into the hollow of the sacrum is followed by the need for interference in about 10 per cent of the cases times as frequently as in the usual anterior

rotation. In spite of this, rotation into the hollow sacrum is not so serious a complication as is generally thought, beeausi ; is comparatively a very low operative inci dence.

itive delivery was required in 146 cases, or cent. The following operations were performed:


June, 1916.]


„ JOHNS HOPKINS HOSPITAL BULLETIN.


icr


Table 7. — List of Opekative Pbocedubes.

Version and extraction 39

Cesarean section (abdominal) 7

Forceps. Rotation to symphysis ( 0. A. i

("high G Scanzonian ( double application l J m j(j g

[low 1

Single application — occiput still posterior (R. O. P. lg

andL. O. P.). 1 mid 4

[ low

("high After complete spontaneous anterior rotation (0. A.).J m j,j q

( low 5

After spontaneous rotation to an obliquely anterior I _

position (L. O. A. and R. O. A.). 1 mid 1

[low 14

After spontaneous rotation to a transverse position J _

(L. O. T. andR. 0. T.). 1 mid 10

[low 1

After manual rotation to an obliquely anterior posi- J _

tion (L. 0. A. and R. O. A.). } mld 1

(_ low 4

After manual rotation to a transverse position (L. 0. ) g

T. and R. 0. T.). 1 mid 10

[_ low 8

Rotation to hollow of sacrum I 0. P.I.

After complete spontaneous rotation into the hollow | ni f h ° of the sacrum. 1 mid

[ low 7

After accidental instrumental rotation into the hoi- I hi f n ° low of the sacrum. 1 mid 3

[low

After intentional rotation into the hollow of the j hi f n °

sacrum. | mi( ^ 3

I low 3 Incomplete rotation. Accidentally delivered in R. 0. T. from an original

R. O. P. low !

The various accessory operations, such as manual dilatation, vaginal hysterotomy and induction of labor, have been disregarded.

The number of patients delivered by the various types oi forceps operation is of interest a- showing the course of development of our present treatment. When the clinic first opened. the Scanzonian operation was usually performed when rotation had not occurred spontaneously, but after a short period the method of manual rotation followed by a single application of forceps was given a trial and proved so successful that it is now the usual method of treatment. In the latter half of the series there were only two cases of double application, the procedure being reserved for the rare cases m which manual rotation is impossible. In the course of my five years' association with the service I have never even seen the operation performed. An account of our present methods of treatment will be presented in the latter part of this article.

Indications for Delivery.— -The following table gives the indications for operative delivery as stated in the histories.


In some instances more than one indication were given, but usually by reading the preliminary note it was possible to estimate their relative importance, and the classification has been made according to what seemed to be the most important in the individual case.

Table 8. — Indications fob Opebatio.ns.

Group A— Possibly due to the position. Nlftllber . p erC e„tage.

Delay on the perineum 34 23.29

Delay in mid-pelvis 31 21.23

Maternal exhaustion. 23 15.75

Group B — Not due to the position.

Pelvic dystocia 17 11.64

Eclampsia and toxemia 13 8,90

Placenta praevia and premature separation

of the placenta 6 4.11

Cardiac disease 5 3 42

Fetal asphyxia 6 4.11

Prolapsed cord 4 2.74

Twin pregnancy 2 1.37

Ventro-fixation of uterus 1 0.68

Various rare conditions 4 2.74

146 99.98

Of these, only the cases in Group A can possibly be considered as being due, even in part, to the position itself. Moreover, in the 88 operative cases in this group, there were 18 forceps deliveries performed after spontaneous rotation to the symphysis or to the obliquely anterior position had occurred. This fact of the spontaneous conversion into the favorable anterior variety removes these cases from the category of those in which the original posterior position was a factor in determining the need for intervention. This reduction leaves TO cases in which the need for operation could possibly be attributed to the posterior position. This represents 47.94 per cent of the 146 operative cases, or 11.02 per cent of the entire series, but it must be remembered that other factors, such as inertia uteri and rigid perineum, were undoubtedly responsible for a certain rather large share. Any attempt to divide the cases of delay in mid-pelvis and on the perineum, on the basis of inertia or rigidity, introduces such a large personal element, unless all observations are made by the same individual, that no such classification was attempted. Even disregarding the possible reduction in this direction, it is very apparent that occiput posteriors should rarely of themselves offer definite indications for operative procedures.

If our series of cases is divided into two parts approximately at the middle, we find that the operative frequency in the second half is appreciably smaller than during the years preceding, and that the three indications for operations in Group A, possibly indicative of dystocia due to the position, are less in evidence. Thus, in the first part — 326 cases — the operative frequency was 25.1 per cent (82 operations), and 55, or 67.0 per cent, of the operations were done for Group A indications. In 12 of these cases there had been a spontaneous anterior rotation, which reduced the percentage to 52.4 per cent. In the second part — 309 cases — there were 64 operation-. 20. 1 ! per cent, and :!:!. or 51.6 per cent, were done for Group A indi


[No. 304


cations. In 6 cases there had been spontaneous rotation anteriorly and the corrected percentage is only 42.2 per cent.

I - interesting reduction in operai acy is indica tive of the greater conservatism which has come with a fuller appreciation of the resources of Xature in dealing with eases with the occiput obliquely posterior. At the present time, all vertex presentations are viewed as equally benign, ami absolutely no apprehension is felt when an occiput posterior is diagnosed. As is seen, the great majority of the uncomplicated eases terminate in spontaneous delivery. With the exception of low forceps, which is viewed as an almost uniformly successful operative procedure, operations are usually deferred until there is a maternal or fetal indication and, unless the duration ior is very markedly prolonged, operations are not done on a pure time indication.

ity. — The gross infant mortality, including all children in the series which were still-born or died during the first two weeks, was 52, or S.1T per cent. The causes of death, as accurately as could be determined, are shown in the following table:

Table 9. — Causes of Infant Deaths.

Number. Percentage.

Prematurity 12 23.1

Operation (no other cause evident) ... . 11 21.1

Syphilis (macerated fetuses) 9 17.3

Still-born (spontaneous labor) 5 9.6

Eclampsia 3 5.7

Prolapse of cord 3 5.7

Placenta prsvia 3 5.7

Congenital anomalies 3 5.7

Died after birth (cause unknown) 2 3.9

Premature separation of placenta 1 1.9

52 99.7

Of this total of 52, 24 weighed less than 2500 gm., and consequently may be excluded, leaving 28 deaths in the 564 mature children — a percentage of 4.96. When this i- compared with Williams' figures for the total infant mortality in the first 10,000 cases in the Obstetrical Service of the Johns Hopkins Hospital, it is seen to be not much greater. He found •.", 1 per cent of deaths among the mature children, using 2500 gm. as the lower weight limit for maturity. A comparison of these figures would indicate that the infant mortality i? increased about 1.0 per cent in the cases of occiput posterior.

An analysis of the 28 deaths among the mature infants shows :

Table 10. — Causes of Death in Mature Chtldken.

Operation (no other cause evident) 11

Still-born (spontaneous delivery) 5

Eclampsia 3

Placenta praevia 3

Prolapse of cord 2

Syphilis 2

Died after birth (cause unknown l 1

Congenital anomaly 1

In this series, only those deaths incident to operation, 11 in number, and those due to asphyxia in which labor was spontaneous, 5 in number, can be regarded as in any way dependent upon the position. Thus, 2.83 per cent of the mature children


perished as a result of delivery. Considering that five of these cases were complicated by contracted pelvis, it is seen that the child presenting with the occiput obliquely posterior has a chance of survival that is but little smaller than if the laws of gravitation or accommodation had ordained an anterior variety. Duration of Labor. — The total duration of labor and the duration of the second stage were noted, whenever given, and the averages in the various classes of cases appear in the following tables. In the first place the usual arithmetic averages were computed and then an attempt was made to establish the various modes. Statisticians prefer the latter method as indicating much more closely the probabilities in any particular case. The arithmetic average is computed by adding the durations of the labors in the series and then dividing by the number of cases, whereas the mode is established by separating the cases into groups according to the duration of labor and determining in which group the greatest number of cases appear. If there is a sufficient number of cases the curve, if one be plotted, will rise gradually to the mode and then fall away on the other side.

Table 11. — Arithmetic Averages for Duration of Labor and Second Stage.


Para.


Rotation.


Labor.


No. of Cases.


Duration of Labor.


No. of Cases.


Duration

of 2d Stage.


Primipara?


Anterior


Spontaneous


186


In hr. 27 m.


1S6


1 hr. 29 m.


Primipara?



Operative


55


29 hr. 11 m.


52


3 hr. 1 m.


Primipara?


Posterior


Spontaneous


311


17 hr. 13 m.


30


1 hr. 30 m.


Primipara*


Posterior


Operative



15 hr. 30 m.


S


3 hr. 17 m.


Multipara

Anterior


Spontaneous


221


12 hr. 00 m.


222


5" m.


Multipara?


Anterior


Operative


16


21 hr. 23 m.


17


2 hr. 53 m.


Multipara 1


Posterior


Spontaneous


29


11 hr. 36 m.


2'


1 hr. -t m.


Multipara?


Posterior


Operative


9


12 hr. 32 m.


8


2 hr. 33 m.


It is noted that in all classes the arithmetic average of the duration of labor is somewhat longer than the figures usually given for normal labor, but still the difference is very moderate. It is interesting that, in those cases in which spontaneous labor followed rotation of the occiput into the hollow of the sacrum, the duration of labor was shorter than in the cases of anterior rotation with spontaneous delivery. In the primiparae, the duration of the second stage was almost identical whether the occiput rotated anteriorly or posteriorly, and in the multipar* posterior rotation only "sliurhtly prolonged this stage. It was thought that backward rotation would considerably delay delivery, but these figures would indicate that there is no basis for the frequent statement that this anomaly of mechanism seriously prolongs labor.

The arithmetic average of the duration of the second stage in the various groups of operative cases is more than twice as great as the duration of this stage in the spontaneous cases. Each case is given a definite test of labor before operation is considered, and this test consists of a reasonably long second stage. Realizing that a moderate prolongation of the stage of expulsion often makes possible a spontaneous delivery, the patient is given every reasonable chance to deliver herself. In the presence of a maternal or fetal indication, prompt delivery is effected, but in the normally progressing case a very conservative course has been followed, and with gratifying results.


June, 1916.] 169


A further analysis was made to determine, in eases of spontaneous delivery, what percentage of labors were protracted beyond the average and what the duration of the longest and shortest labors was in the various groups. The average figures given in Table 11 were employed as a basis for comparison.

Table 12. — -Showing the Number of Labors Above and Below the Average Duration, Together with the Duration of the Shortest and Longest Labors in Each Class of Spontaneous Delivery.



Primipara-, anterior rotation.


Multipara?, anterior rotation.



Labor.


2nd Stage.


Labor. 2nd Stage.



No.


'

No.


No. ', No.


.

Above average. . . Below average .. .


73 113


39.25

00.75


74 112


39.7! 60.21


85 38 . 64 82 L36 61.54 136


37.10 62.90


Shortest duration Longest duration.


2hrs. 10 in. 85 hrs. H m.


10 m. 22 hrs. m.*


4.") in. 5 m. 90 hrs. m. 4 hrs. 20 m.


A neglected case brought into the Hospital as a last resort.



Primipara*, posterior rotation.


Multipara , posterior rotation.



Labor.


2nd Stage.


Labor. 2nd Stage.



No.


'.


No.


No. ', So.


Above average. . . Below average. . .


12 18


40.11 00.00


11 10


36. 61

03 . 34


10 34.49 l'J 05.51 20


31.03 08.07


Shortest duration Longest duration.


4 hrs. lo in. 72 hrs. (1 in.


15 m.

5 hrs. o in.


2 hrs. 15 m. 15 m. 39 hrs.O in. 2 hrs. 4."> m.


Approximately two-thirds of all the cases fall below the average in the, various groups, indicating no general prolongation of labor or of the second stage. Moreover, the fact that (inly about 40 per cent of the cases rise above the arithmetic average would indicate that a true average would fall somewhat below that figure. Because of this fact an effort was made to establish a mode in the various groups of spontaneous labors, but on account of the comparatively small number of cases this was not entirely satisfactory. Table 13 indicates the results obtained by dividing the various types of labors into groups, each group representing three hours of time.

Table 13. — The Mode in the Duration of Spontaneous Labors.


Primipara?, anterior rotation. . Primipara', posterior rotation. Multipara-, anterior rotation.. . Multipara-, posterior rotation..


Under


6-9


i — 12

6 hrs.


hrs.


hrs.


14


24


25


3


5


6


01


48


27


8


!l


4


1>-21 hrs.


21-2-1 24-27 hrs. 1 hrs.


27-30

hrs - 311 hrs.


Primipara?, anterior rotation l!l 11 11 Primipara?, posterior rotation. .. . 4 12 Multipara?, anterior rotation 14 5 In Multipara-, posterior rotation 1 3


14


1


l!l 3

i 1


Table 13 well illustrates the difference between the arithmetic average and the mode, and shows how the latter indii ates the probabilitie- in a given ease much more accurately than the former. For example, the arithmetic average in primipara? with anterior rotation and spontaneous delivery (Table 11) is 18 hours 2? minutes, and yet from Table 13 it is evident that there is a greater probability of such a labor ending after 12 to 15 hours than during any other 3-hour period, and that this period consequently more nearly constitutes an average than does any other. Likewise, in the cases of multipara- with anterior rotation and spontaneous delivery the arithmetic average is 12 hours, whereas, disregarding the period up to 6 hours (Table 13), it is seen that more labors end in the (i- to 9-hour period, and consequently this is more nearly the correct average. In the smaller groups of cases with spontaneous labor following posterior rotation, tin- mode is not very clearly defined, but there is evident the same tendency for it to fall below the arithmetic average.

Table 14 illustrates the results of an attempt to find the mode in the duration of the second stage in the various types of cases. Fifteen-minute intervals have been arbitrarily chosen.

Table 14. — The Mode in the Duration of the Second Stage.


15 m.


16 m.


31m.


46 m


1 hr. 1 m.


or


to


to


to


to


less.


1 30 m.


45 m.


lhr.


lhr. 15 m.


Primipara?,

anterior rotation !l 13

Primipara?,

posterior rotation 1 5

Multipara;,

anterior rotation 40 59

Multipara?,

posterior rotation 5 4


lhr. 16m


lhr. 31m. lhr. 46 n

to to

lhr. 45 m. 2 hr.


Primipara?,

anterior rotation . . Primipara?.

posterior rotation. Multipara-.

Anterior rotation . . Multipara?,

posterior rotation.


Here again the value of the mode as evidencing possibilities is brought out. In the primipara? with spontaneous delivery following anterior rotation, the arithmetic average for the duration of the second stage is 1 hour 29 minutes, whereas the mode (Table 14) falls in the period between 46 minutes and 1 hour. Also, in the multipara? with anterior rotation and spontaneous delivery, the mode falls between 10 and 30 minutes, whereas the arithmetic average is 50 minutes. In the other two classes the number of cases is too small for the satisfactory determination of the mode, but the general tendency for it to be below the arithmetic average is to be noted.

Type of Pelvis. — In an attempt to determine whether any particular type of pelvis is more apt to produce the occiputposterior positions, the incidence of the various varieties of


L70 [Xo. 304


peh i( deformity in the present series was determined ami compared with the figures r ntly published by Thorns for a

series of 4000 unselected consecutive cases from the Johns Hopkins Hospital :

Table 15.— Incidence of Various Types of Contracted Pelvis.


No. Per Cent.

Generally contracted 66 10.39

Simple flat 14 2.20

Typical funnel 36 5.67

Generally contracted tunnel 15 2.36

Rachitic 26 4.09

157 24.71


No.


Per Ci


391 9.77

59 1.47

211 5.27

S7 2.17

186 4.65

934 23.33


It is seen that the frequency of the various types of contracted pelves in the cases with occiput posterior is within 1.0 per cent of the frequency observed in the largeT series of unselected cases. This indicates that the character of the peh is has no influence upon the production of these positions.

Size of II" 1 Children. — All the cases of definite occiput posterior were used for the study, irrespective of the size of the child. For the sake of completeness, the following table is introduced to show the weights of the children in the series :

Table 16. — Weights of the Children in the Serifs.

1000 g. or under 4

1001 to 1500 g 8

1501 to 2000 g 13

2001 to 2500 g 46

2501 to 4000 g 504

4001 g. and over 54

Weight not recorded 6

635

The only bearing that the size of the child seems to have is that, as has already been mentioned, in the ease of small children the occiput tends to rotate into the hollow of the sacrum.

Maternal Morbidity and Mortality. — Our morbidity statistics are based upon a standard of 38° ('. (100.4° F. ) . the temperature being taken by the mouth every four hours, day and night, for nine days, and then twice daily (8.00 a. m. and 8.00 p. m.) for the next five days. Special conditions may make advisable the taking of the temperature more frequently, but it is never taken less frequently. Only a single elevation above the standard is needed to have the case classed as febrile. Xo elevations after the 14th day are included, as they very rarely can be attributed to the labor. The following table shows the findings as regards morbidity :

Tahle 17. — Morbidity.

Total cases with temperature 100.4° F. or above at

any time 233 36.7?

Single initial rises (normal 24 hrs. after delivery).. 37 5.8V

Other single rises (elevated less than 24 hrs.) 66 10. 4*

Probable uterine infections 105 16. 5^

Various other causes (eclampsia, pneumonia, mastitis, etc. ) 25 4.0*


The term "single initial rise" refers to that temporary rise of temperature which so frequently occurs after a normal labor and which disappears within 24 hours, not to recur. The single rises occurring later in the puerperium and persisting for less than 24 hours can not be classified etiologically. Usually there are no symptoms and no objective findings, and within 24 hours or less the elevation has disappeared. It seems permissible to say that they are not due to a local infection of the generative tract. The 105 cases, grouped as " probable uterine infections." include all the cases which showed more than a single rise and in which a definite cause for the elevation could not be located elsewhere. That they were essentially very mild in character is indicated by the fact that there were no deaths attributable to infection. Many cases were put in this class, even when a uterine culture had failed to give any evidence of an infection, but since they could not clinically be placed elsewhere, they are included here, on the theory that a temperature elevation during the puerperium means infection of the generative tract, uules? some other cause can be found.

There were in all 10 deaths in the series, a percentage of 1.57, but none of them can be attributed to the position, as the list below will show. It was not to be expected that there would not be any mortality connected with these cases.

Table IS. — Causes of Maternal Deaths.

No. 1177. Died two hours after spontaneous delivery. Chronic nephritis with convulsions.

No. 1297. Died a few hours after delivery from internal hemorrhage due to incomplete rupture of the uterus caused by manual dilatation of the cervix in the presence of a complete placenta prtevia.

No. 2229. Died on the second day from toxemia and myocarditis. Confirmed by autopsy.

No. 3287. Died on the second day from acute lobar pneumonia. Confirmed by autopsy.

No. 3928. Died three days after delivery. Eclampsia. Confirmed by autopsy.

No. 5043. Died a few hours after delivery. Eclampsia.

No. 5237. Died less than 24 hours after admission. Eclampsia.

No. 5736. Died two hours after delivery. Diabetic coma.

No. 5863. Died two hours after delivery. Eclampsia. Confirmed by autopsy.

No. 5911. Died five days after Caesarean section for partial placenta praevia and grave chronic nephritis in a 40-year-old primipara. The autopsy showed chronic diffuse nephritis.

History axd Discussion". Introduction. — It is only within the last century that the ancient fanciful descriptions of the position of the fetus in utero and during birth have been generally discarded. Until 1742. when Sir Fielding Ould stated that the occiput was usually turned toward one side of the pelvis during the early stages of labor, it was taught that the fetus descended through the pelvis in the position in which it was finally born, that i>. usually with the occiput directly anterior under the symphysis pubis. Ould incorrectly stated that the head was turned so that the chin rested on the shoulder, but in 1752 Smellie corrected this ami asserted that the trunk and head retain their usual relations, and that there i> no twisting of the neck. In


June, 1916.] 171


1 ! i 1 Saxtorph and Solayres, Independently, advanced the view that the head usually enters the pelvis in the right oblique diameter.

Baudelocque, the famous pupil of Solayres de Renhac, recognized six varieties of vertex presentations, the usual four oblique and two antero-posterior. Up to that time, e: ment with the occiput directly anterior was generally thought to be the most common : but Baudelocque insisted that it was very rare. He said : " It has appeared to me that the proportion of the first (L. 0. A.) to the second (B. 0. A. i i- a- 1 i to 1. and to the fourth (B. 0. B.) and fifth ( L. 0. I'i as 30 01 even 100 to 1 ; as to the third ( 0. A. ) and the sixth I 0. P.), they are excessively rare: although most accoucheurs have thought, and still think, that the third (0. A.I is the most natural and usual."

Xaegele was the first .to insist upon the frequency of occiput posterior positions and their eventual rotation to the symphysis pubis. His predecessors had recognized these positions, but had thought that they were not only very rare, but that the usual outcome was rotation to the hollow of the sacrum. He showed the incorrectness of these views and attempted the first objective description of the mechanism of labor. Most of the results of his careful work have stood the test of time, but his views on the mechanism of internal rotation have from time to time been assailed. Xaegele's work really marks the beginning of our modern conceptions of the mechanism of labor.

Frequency. — The figures adduced by various authors with regard to the frequency of occipito-posterior positions vary so much that it is impossible to arrive at any very definite conclusions from the literature. The older authors, as might be expected, had very divergent views concerning the relative frequency of the various varieties of vertex presentations. Thus Xaegele found 29 per cent of his vertex cases in R. 0. B. : whereas Madame La Chapelle found only .0777 per cent and Madame Boivin .05 per cent. Simpson noted 22.7 per cent, and Swayne 1.04 per cent. The figures for the incidence of L. 0. B. also varied markedly: thus. Xaegele noted only .03 per cent, while Simpson had .60 per cent, and Swayne reported 2. 79 per cent.

More recent writers have reported somewhat more comparable figures, but the percentages still vary considerably. Thus, Darbyshire found 16.0 per cent occiput posteriors in 276 vertex cases : Geddes had an incidence of 10.5 per cent in multipara and 20.8 in primiparae. Botkowskaia reported an incidence of 18.5 per cent, and Ingraham one of 12.03 per cent. The last author states that Biuard observed 49.8 per cent and P. Dubois 26.33 per cent. Dimitroff. in 1056 presentations, noted 29.54 per cent. 26.23 per cent in R. 0. P., and 3.31 per cent in L. 0. P., and quoted the following figures :

R. 0. P. L. 0. P.

P. Dubois 25.60", 0.63?

Pinard and Battaillard 26.70? 10.47?

Herrgott and Vallois 33.50? 0.45?

Corbiere 26.22? 7.95?

Sentex 2.03? 0.95?

Several authors (Darbyshire. Geddes and Massini) state tha occiput posterior is more common in primiparae than in multipara?.


The actual frequency of the obliquely posterior position of

the occiput is especially hard to determine because of two factors. In the first place, there is a difference of opinion with regard to the status of the transverse positions of the occiput, and in the second place, with regard to the occurrence of B. 0. A. as an original position.

Most authors do not recognize the transverse position of the occiput as an original engagement, but rather as a trans stage in the anterior rotation of the occiput which was originally directed obliquely posterior. While it is generally admii ted that, in certain forms of contracted pelvis, especiallv the flat varieties, engagement usually occurs with the sagittal suture directed transversely, the tendency is to consider this impossible, or at least unusual, when the pelvis is normal.

There are several objections to this view, but until transverse engagement is a generally admitted fact, it will be wise to disregard the possibility of its occurrence in any but contracted pelves. The first objection is the undoubted occurrence of transverse positions in normal pelves, while the head is .-till too high to have been affected by the factors that are usually advanced to explain internal rotation. Various abdominal and high pelvic structures have been brought forward as factors in the mechanism of rotation, but they have generally been discarded, and rotation is usually considered as occurring low in the pelvis. If it is admitted that the sagittal suture is sometimes transverse while the head is at the brim, we must either believe in high rotation or original transverse engagement, and the latter idea seems the more tenable.

A second objection was discovered in our statistics. Our figures show that the transverse positions are more frequent than the posteriors and the L. 0. T.'s are more common than the B. 0. T.'s. B. 0. B. is generally believed to be much more common than L. 0. B., and yet the relative frequency of the supposed transitional transverse positions is reversed and a combination of the posterior varieties with the transverse gives the same total for both the right and left positions.

Among the statistics reviewed, those of Yoorhees alone contain any reference to transverse positions of the occiput, and he found very much the same figures as those reported here.

If we had added the transverse positions (21.75 per cent) to the posteriors (11.57 per cent ) . we could have reported an incidence of 33.32 per cent, which would more nearly agree with the figures reported by the majority of writers and with the general teaching; but in the presence of the two objections raised above, it was determined to disregard the tra i positions in this study and to consider only those in which actual posterior positions were first seen.

With regard to the status of the B. 0. A. positions, very much the same difficulty appear-. Xaegele and those who followed him have stated that B. 0. A. is an exceedingly rare primary position, and that the vast majority of the i s which this position is diagnosed are seen late in labor after there has been partial rotation from an original R. <>. P. We noted this position in 19.06 per cent of our vertex pn tions, and here again find it difficult to consider them all as


172 [Xo. 304


ating merely a stage in the mechanism of internal rotation. The chief objection to the view that they are trans in character is their undoubted presence high in the early in labor and the inability to explain this except by sum.' abdominal factor which can produce partial rotation but never complete turning.

If the B. 0. A~'s are added to the posteriors, we have a percentage of 30.63 ; but in the absence of direct evidence to show that the former are no! primary, they were nol considered in this study. It is quite obvious that, if both the transverse and the right anterior positions were added to the posteriors, the incidence of the latter would be 52.38 pi or more than half of the vertex positions. It is certainly no! a fact that the occipito-posterior positions are as common as this, and yet very good authority could be brought forward to show why both of these additions should be made.

If, in our series, all the right positions are added together, we have 35.91 per cent, and the left positions total 63.1 '. peT cent. Thus:


R. 0. A. ...


19.061:


L. 0. A. ...


47.61?


K. 0. T. ...


8.89


L. 0. T. . . .


.... 12.86*


R. 0. P. ...


.... 7.96?


L. 0. P. ...


3.30*


Total


35.91?


Total


.... 63.77?


These figures agree closely with the usual statement that left positions occur in 70 per cent of all vertex eases and right positions in 30 per cent. The proper division into varieties is in a confused state, however, and more study is needed to settle some doubtful points concerning the mechanism of labor and the possibilities of engagement and rotation of the fetal head.

Many of the variations in the percentages reported for the posterior positions undoubtedly are to be explained by the fact that the various authors have assumed that either the transverse or the right anterior positions represent transitional stages in the mechanism of originally obliquely posterior positions, or, on the other hand, as has been done in this study. have disregarded all the cases that did not have an actual posterior position when first seen.

Internal Rotation. — The frequency with which rotation into the hollow of the sacrum has been noted is of considerable importance; and the following figures have been gathered from the literature :


Percentage.


Percentage.


Xaegele 3.12 Halsey 2.00

Edgar 4.00 Harrar 14.00 ( computed )

Massini 4.00 Dupre 4.00

Tweedy 4.10 Dimitroff 1.2S

Mosher 2.00-7.00 Bataillard 1.61

Ingrahani 7.00 Corbiere 2.71

That we found such a high percentage of cases in which the occiput rotated posteriorly may be explained by the fact that in our service operative interference is postponed as long as . and therefore even- chance is given for spontaneous rotation in one direction or the other. Our figures (14.2 per cent ) would indicate that this anomaly is somewhat more common that it is usually considered to be.


In some studies, persistent occiput posteriors (obliquely and in the hollow of the sacrum) have been noted, and it is interesting to see how the results vary. Harrar says that 20 per cent remain posterior. Stark gives 50 per cent, whereas Yoorhees found 104 such eases in 5000 deliveries, approximately 10 per cent, if vertex presentations are reckoned at 95 per cent and occiput posteriors as 20 per cent of these. Bill says that 50 per cent fail to rotate, and Eice noted 162 failures in 400 cases of occiput posterior, or 40.5 per cent.

By reference to Table 3, it is evident that there were 1ST eases out of 576 in which the occiput failed to rotate, t. e., stayed transverse or obliquely posterior, or rotated into the hollow of the sacrum. This would give us a percentage of 27.25 of so-called persistent occiput posteriors. This is a very considerable number, but it must be remembered that in nearly half of these cases the occiput rotated into the hollow of the sacrum, and this was followed in a large majority (88.6 per cent) of the cases by spontaneous delivery. If the term " persistent occiput posterior " be used only in referring to those cases m which the occiput rotates neither to the symphysis aor to the sacrum, we can very readily realize their importance, for internal rotation is one of the cardinal movements in the mechanism of labor and under ordinary conditions delivery can very rarely occur without it.

The Mechanism of Internal Rotation. — It was found, as previously stated, that the parity of the patient and the condition of the pelvic floor have no influence upon the occurrence of posterior rotation, but that the three factors which apparently do play a part are the type of the bony pelvic outlet, the flexion of the head, and its size.

An attempt was made to correlate these observation- with some line of the theories of internal rotation that have been advanced. From the fact that anterior rotation is as common in multipara; as in primiparae, it may be argued that the muscular and fascial pelvic floor plays a minimal part in the mechanism. It is conceivable that these soft pelvic structures may act to accelerate or complete a rotation already begun, but it is impossible to make this theory of Veit explain all the vagaries of rotation under the conditions which we have observed. It is very difficult to conceive a mechanism whereby the pelvic floor alone can cause anterior rotation from an occiput obliquely posterior position. On the other hand. although the failure of this usual occurrence can be explaii when the head is poorly flexed or small, these explanations do not cover those case- in which a narrow pubic arch is apparently responsible for the lack of anterior rotation.

Sellheim's otherwise attractive theory falls short when he attempts to explain posterior rotation. He assumes a spastic condition of the child's neck, which makes it more readily bent backward than forward, so that, as a consequence, the occiput turns into the hollow of the sacrum. It is difficult to substantiate this by clinical observation, and the unprejudiced obstetrician cannot detect any difference in tone in the neck musculature of children born by this anomalous mechanism. Moreover, this theory offers no explanation for the more frequent occurrence of posterior rotation in those conditions which, as we have shown, conduce to its appearance.


June, 1916.] L73


The various abdominal and high pelvic theories offer no assistance. In view of the fact that they have been so generally discarded, thev need not be discussed here in detail.

Although none of the theories will explain absolutely all i , Eodge's idea of the inclined planes and ischial spines will at least explain anterior rotation from an obliquely posterior position and also the phenomenon of posterior rotation in the three conditions which, according to our experience, most conduce to this anomaly. Hodge says: "Hence, when the head descends in the fourth position (B. 0. P.), if the point of the occiput should strike upon the spinous process of the ischium or extreme boundary of the anterior inclined plane, it will be reflected anteriorly toward the arch of the pubis, and delivery will be effected as in an original second position (E. 0. A.) . If, however, the point of the occiput should strike posteriorlv to the spines of the ischium, it will be reflected backward to the hollow of the sacrum." In this connection it is interesting to note that Baudelocque and Deventer observed that posterior rotation was more frequent when the ischial spines protruded.

Let us now attempt to determine why it is that the three conditions mentioned have such a tendency to cause posterior rotation. In the first place, when the head descends through the pelvis poorly flexed with the occiput obliquely posterior, it is evident that the occiput is somewhat nearer the sacrum than usual and the brow is well up against the symphysis. The ischial spines will impinge upon the head considerably in front of the occiput, and the brow will be influenced by the anterior planes, while the occiput is affected by the posterior planes. Under these conditions it is easy to understand why the occiput should go backward.

When the fetal head is smaller than usual or the pelviccavity much more roomy than normal, there is a tendency for the head to advance through the most capacious part of the pelvis, where the resistance is least. This would tend to bring the occiput behind the spines and thus to cause posterior rotation. Or, the head being very small, it is conceivable that it would not impinge upon the spines at all and consequently, by a process of accommodation to the opening in the pelvic diaphragm, it would eventually rotate backward.

Finally, when there is a narrow pubic arch, the proximity of the tubera isehii prevents the head from getting well up under the symphysis and it must find a passage more than normally behind the protruding spines. This will mean that the head will strike the spines in such a manner that the occiput will meet the posterior inclined planes and will rotate i" the hollow of the sacrum.

Where the pubic arch is wider than the arbitrarily chosen upper limit for funnel pelves (8 cm.), the ischial spines may still protrude somewhat more than usual and give a pelvis which, as regards the mechanism of rotation, should still be classed as funnel. This probably explains some of the cases of posterior rotation in normal pelves.

Anterior rotation can occur in a funnel pelvis if the anterior planes are sufficiently long to cause the occiput in it- deso to strike upon them and be deflected anteriorly. In these


cases the capacity of the posterior portion of the lower pelvic cavity is restricted, and the head is often molded considerably in order to accommodate itself between the approximated tubera.

If the posterior planes and the spines, rather than the soft pelvic tissues, are responsible for posterior rotation, this phenomenon should never occur after the head is visible. This is in accord with our observations. On the other hand, anterior rotation frequently happens after the head is crowned 1>\ the partially separated labia. The anterior planes and the spines are near enough to the vaginal orifice so that, when the vertex is visible, the widest portion of the head — the biparietal diameter — is in the region of these planes and their effect is then made evident. The position of the head at the time of internal rotation should, therefore, and does, vary not only with the length of the pubic bones, but also with the width of the pubic arch. The wider the arch, the lower the head must be before the spines and planes become effective, and the greater the possibility of visible rotation.

It is not claimed that Hodge's theory and its application in the previous paragraphs explain all the vagaries of rotation in the cases of occiput posterior, but it certainly seems to be the most attractive. In the elaboration of the theory to explain the observed facts, certain assumptions and conjectures have been indulged in which may not prove wholly acceptable. As a matter of fact, it is more than probable that no one theory will satisfy all the demands made upon it, and that the final word in the mechanism of internal rotation will embrace a skillful combination of several factors.

Rupture of the Membranes. — Although practically all writers assert that premature rupture of the membranes is more common in the posterior than in the anterior varieties of occiput presentations, very few actual statistics were found. Harrar found premature rupture 1776 times in 5496 occiput anterior cases, or 32 per cent, and in 348 out of 804 occiput posterior cases, or 43 per cent. Eice noted first stage rupture in 40 per cent of occiput anterior and in 60 per cent, of occiput posterior cases. Massiiri insists that premature rupture is more common among primiparae with occipito-posterior positions than among rnultipara3 with the same positions. Some authors even say that premature rupture should immediately suggest occiput posterior because of the fact that it i- so frequent in that position. Attempts to explain this relation have been mostly on the basis of a poor accommodation between the head and the pelvic inlet. Our figures — 21.8 per cent of rupture before half dilatation of the cervix — fail to substantiate the usual opinion, and furthermore we cannot see why, theoretically, there should be any difference in the behavior of the fetal envelopes whether the occiput is anterior or posterior. If the head is well Hexed when it enters the |"'l\ is, as it undoubtedly is in the majority of i ases, the same diameter engages at the superior strait and. that being the case, the fit must be the same whether the back of the child happens to be anterior or posterior.

Character of Delivery — Treatment. Man} articles have been written upon the correct course of treatment in o


174 [No. 304


i many methods have been devised for overg the difficulties which have been so greatly emphasized. The very diversity of these procedures is indicative of the confusion which exists in the whole subject. Several of the methods advocated are based on sound principles, but the majority have tended only to confuse a subject which is really i omparatively simple.

CD. Meigs, in speaking of these cases, said: "Beware of meddlesome midwifery and. if one is to err in these cases, better err on the side of waiting." This bit of advice i^ just as tin. 11. iw as when it was written, but the improvements in aseptic t& bjiique, by eliminating many of the former horribly fatal -. have led to haste in obstetrical work. The knowledge of when to interfere is as important as the mere technique of performing the usual forceps operations, but good judgment is much rarer than good operative ability. The profession generally- seems to have been so impressed with the statement that occipul posterior positions will very frequently need operation that they do not wait to see whether the individual case will make that demand, but proceed to deliver instrumentally on the smallest provocation, and often on none whatever.

The more conservative writers have reported a small operative incidence. Thus, Naegele noted 11.8 per cent forceps deliveries, P. Dubois 7 per cent. Battaillard 10 per cent. Dupre 3.64 per cent. Botkowskaia 10.75 per cent in primipara? and 2.5 per cent in multipara?. Corinin gives the incidence of spontaneous labor as 96.23 per cent, Dimitroff as 93.9 per cent, Mosher as 90 per cent, and Lacrotte as 87 per cent. In these series, the figures were taken from cases which were normal in every other respect, and indicate the interference necessary in uncomplicated occiput posterior labors. In an early section we have considered 11.02 per cent of our operative deliveries as possibly due to the position.

1 n contrast to these figures indicating that the uncomplicated occiput posterior should nine times out of ten he delivered spontaneously, Bill reports that 50 per cent of his cases of occiput posterior needed forceps, and details rather incompletely 137 cases in which the double application of forceps was employed. Many of these operations were done with the head still high in the pelvis and, judging from the context, through a partially dilated cervix. Again, Lukins has recently stated : " The ideal plan of management in occiput posterior positions, provided the patient can be seen and the diagnosis made sufficiently early, is to hasten cervical dilatation by manual means and accomplish immediate version by combined internal and external manipulations."

The statements in the last paragraph illustrate what an unenviable reputation the position in question enjoys, and what radical method> are introduced ill order to obviate difficulties which really do not exist. Evidence might, indeed, be introduced to show that there are physicians who seriously advocate the employment of the Cesarean section in the absence of any other indication. In the light of our experience, n is difficult, to see how such errors have arisen.

i if the many published methods of treating the complication, if there really be one, very few have any sound reason in


commend them. Postural treatment, with the patient lying on the same side as the occiput or on the other side, as is variously recommended, is certainly of little value, as is attested by the lack of unanimity of opinion with regard to which side is preferable. Correcting the obliquity of the uterus by means of pads and binders seems futile. Manual rotation of the head at the superior strait and the correction of improper flexion digitally have a sound basis, but are rarely indicated. O'Brien's method of rotating the mother around the child, by fixing the latter manually, seems not only awkward, but useless, when one considers how readily the reverse can be accomplished. The double application of forceps distinctly has a place in the treatment of the unrotated occiput, but is indicated only when rotation cannot be accomplished manually. The single application of forceps with the blades reversed or reversing has no distinct field of usefulness when there are so much simpler methods that have not the obvious disadvantages of these procedures.

The chief point in the treatment is to give Nature a chance, and not to fall into the common mistake of thinking that the position itself will cause trouble. A large portion of the cases will need no assistance, and the majority of those that do demand help will offer no great difficulty. Spontaneous rotation will usually occur, but if it does not, at least 90 per cent of the heads can be rotated manually to the t