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THE JOHNS HOPKINS HOSPITAL BULLETIN

VOLUME XXX

BALTIMORE THE JOHNS FK)PKINS PRESS

BALTIMORE, UD., U. 6. A.

Entered as Second-Class Mntter at the Baltimore, Maryland. PoatofDee Acceptance for mailing at special rate of postace pn^viil.'d fnr in s.-rtinn llo.^. Art ..f Ortnht^r :i 1^17 Anthori^.^.i ..t, ,i.,k :i. ijjig.

Vol. XXX-No. 335]

BALTIMORE, JANUARY. 1919

Clinical Observations on Epidemic Influenza. (Illustratcil.) By Abtiiub Bi.oomkield and George A. Hakrop. Jr.

Tlie Beliavior of tlio Blood Toward Oxygen in Inlliicnziil In feetions. (Illiistratod.)

Bv (iEOBGK A. Harbop, Jr

## Contents

Bacteriological Findings in Epideniie Inllneiiza. 1 By S. K. Howard, Jf. D 13

Ectopic Pregnancy. By H. M. X. Wynnk . . . l.O

1 Notes and News 25

10 I Notes on New Books 27

ECTOPIC PREGNANCY

By II. M. X

Hes'ideitl (li/necoloriisl. Thr

INCIDENCE In the 2t years from 18!t0 to l!tl(i inclusive, there iiavc Ijeen 303 patients with ectopic pregnancy in the tiynecological Service of The .Johns Ho])kins Hospital who were operated upon. There have been 22,fi88 patients admitted to the Gj-necological Service during the S'i years, of which 303 had extrauterine pregnancies, an incidence of l.:W.

Table Showino the Nimbeb ok Patients with ExTRAi'n':Ri.NE PREOXANCIE.S Each Year

^ *

1990

2

18«!

6

1902

8

1908

23

1014

14

1891

3

18(t7

1

1003

15

190U

23

1915

13

1892

4

1 898

8

1!X)4

23

IftlO

13

1010

13

isns

8

18it!t

7

HI05

23

I91I

16

I8»4

7

lOOO

10

1900

13

1912

11

1895

'

1901

10

1907

10

1913

11

Total

.103

Race— Negroes, 101; white, 202. Total, 303.

Of the.s(. 22.688 patients. i:.H2 were wliit.- and .">2:(i wer.' negroes. There were 202 eases of extrauterine pregnancy among the whites (1.16:^) and 101 among the negro» (l.'.il^).

Wynne.

Johns Ilopkins IlosjiHa]

AGE

(»f this .series of cases the age was rccnnlcil :>()() tunes. The youngest patient was a 1 ."i-ycar-old white girl, married .seven months previously to admission and never pregnant Ix'fore. .\n unruptured left tubal |)rcgi»Hncy was removed at operation. The oldest jjaticnt was a l.")-year-old ncgress, who had given birth to three full-term chihircn. .\t operation a fullterm litiiopedion. which iiad been in thf aiidomcn for four years was removed ( Kcjiorted by .1. (i. Clark, The .lohns Hopkins Hospital Bulletin. l«!i:. Vlll. and in Kelly's Operative Gynecology, Vol. 11). Of this series 182 (GH) occurred in the decade 24 to .5.3 years inclusive. Seven patietits were under 20 years and ten were over 10 years of age.

TAni.K Showixo Aokh ok 300 Patik.nth

MARITAL HISTORY

In a series of 284 there were 14 unmarried, two widows and nine twice married.

Table Showing Time of Admission Aftee

Marriage

Time

Number

of patients

Time

Number

of patients

Time

Number

of patients

Time

Number

of patients

married

married

married

married

yrs.

yrs.

yrs.

2 wks . . .

1

9

9

8

18

9

4 wks...

2

22

10

14

19

3

6 wks...

3

18

11

9

20

7

2 mo8. . .

4

13

12

17

21

6

4 mos. . .

5

I.i

13

11

22

2

5 mos. . .

6

12

14

8

23

3

7 mos . . .

7

21

1.5

9

20

1

8 mos . . .

8

13

16

6

27

1

17

8

Total

268

PREVIOUS PREGNANCIES

In the histories of 375 patients, the number of pregnancies prior to the ectopic pregnancy was recorded. In 57 (31^) there had been no previous pregnancy and of the 218 (79^) who had been pregnant before, 307 (95;?;), 75^ of the whole series, had given birth to full-term babies and 11 (5^), 4^ of the whole series, had had only miscarriages. Instrimiental deliveries had been performed on 19 patients (9;^ of those who had had full-term pregnancies). Histories of prolonged puerperia associated with chills, fever and abdominal pain were obtained from 38 patients (17.5^ of all patients previously pregnant) .

Table Showing Number of Previous Pregnancies

Number

Number of

Number of

Number of

Total

Number of

carriages

patients

children

patients

patients

1

65

1

77

57

2

25

2

32

1

67

3

8

3

27

2

42

4

5

4

21

3

22

5

2

5

17

4

22

6

2

6

14

o

16

7

8

6

16

Tola

1 107

8

2

7

13

9 .

2

8

8

10

3

9

11

1

10

3

12

11

1

13

1

12

1

14

2

13 14

1

1

Tota

1 207

15 16

1

Total 275

The interval between the last pregnancy and admission to the hospital for an ectopic pregnancy was noted in the his Table Showing the Interval Between the Last Pregnancy and Admission to the Hospital for Ectopic Pregnancy

"oS

•5Z

- »i

• a

»- n

aj S

fc. g

t- g

tM C

b. a

1

ft

1

i

It

1

it

1

B

z

B

z

B

S5

B

§.

E

Iz

mos.

mo:.

yrs.

yrs.

yrs.

3

9

5

3

23

9

5

15

3

4

10

1

4

22

10

8

16

1

5

11

2

5

13

11

4

17

1

6

12

20

6

20

12

6

18

1

7

18

15

7

19

13

1

19

2

8

2

36

8

5

14

1

Total

226

tories of 226 patients, the shortest interval being three months and the longest 19 years. The interval was between one and seven years iu 168 patients (74^).

PREVIOUS OPERATIONS

Dilatation and curettage had been performed on 15 patients for bleeding caused by the ectopic pregnancy; two of these operations were done in this hospital. One patient was curetted twice before admission for bleeding caused by the ectopic pregnancy.

Curettage was performed on 13 patients, from one to five years before their admission and simple dilatation of the cervix twice for sterility.

Incision of Bartholin gland abscess, five years before; one patient.

Pelvic puncture for inflammatory disease; three patients.

E.rplorafori/ laparotomy five years before; one patient.

Multiple myomectomy five years before; one patient.

Ovarian tumor removed; one patient.

Tu.nior removed and appendectomy; six years before; one patient.

Parovariancystectomy, right; suspension of uterus; appendectomy; two years before (Gyn. No. 16,409).

Suspension of tderus and appendectomy ; 18 months before (Gyn. No. 15,751).

Salpingo-oopliorectomy, left, and appendectomy; one and two years ago, for chronic pelvic inflammatory disease; two patients.

Salpingo-odphorectomy, right, and appendectomy ; one patient.

Appendectomy (only) ; three patients.

Appendectomy and nephropexy were done in another city on one patient for the symptoms caused by a right tubal pregnancy about six and eight weeks prior to admission to this hospital.

Five patients have been operated upon twice in this hospital for ectopic pregnancy.

Pelvic puncture, once.

Salpingectomy (alone), twice.

Salpingo-odphorectomy, twice.

COMPLAINT

The symptoms that patients complained of on admission were as follows :

Bleeding 93

Pain, general abdominal or not specified 99

Pain in lower abdomen 69

Pain in riglit lower quadrant of abdomen 33

Pain in left lower quadrant of abdomen 33

Pain in back 20

Pain designated as "bearing-down," 4 times: and as "cramplike," 4 times.

Tumor in abdomen 17

Tumor in right lower quadrant of abdomen 1

Tumor in left lower quadrant of abdomen 4

Swelling of abdomen 3

Tenderness of abdomen 4

January, 1919]

17

Pregnancy 2

.Miscarriage I

Amenorrhea 1

Dysmenorrhoea 2

Vomiting 9

Nausea 6

Diarrhoea 1

Pain on defecation 1

Dysuria 2

PoUakiuria 1

Fainting 1

From the foregoing list we see that the most i-oiumon causes for which these patients seek medical attention are pain, complained of by 254 (84;^) bleeding, complained of by 93 (31j^) and tumor, complained of by 28 patients (7^).

SYMPTOMS Onset (1) Acute without prodromal symptoms other

than bleeding or a missed period 14(> (48%)

(2) Acute with prodromal symptoms 72 (247c)

(3) Gradual without acute attacks 84 (28%)

Irregular bleeding 229 (76%)

Nausea 146 (48%,)

Vomiting 126 (42% )

Tumor 45 (15%)

Fainting 38 (137c)

Fever 29 (IO70)

Chills 12 (47c)

Weakness 87 (29% )

Defecation painful 28 (9% )

Urinary frequency 40 ( 13% )

Burning on voiding 27 (9% )

Pain on voiding 87 (29%)

Loss of weight 6 (2% )

Bad taste In mouth 3 ( 17c )

Patients believing themselves to be pregnant 11

Patients not suspecting pregnancy 3

Patients suspecting an abortion 1

Patients who had felt life 1

Patients having a sensation of fluid in the abdomen. ... 1 Patients who had passed complete casts of the uterus. . 2 Patients complaining of pain in the abdomen not otherwise qualified 131 (437o)

Pain, general abdominal 21 (7%)

Pain, limited to the lower abdomen 28 (9%)

Pain, limited to the lower left quadrant 43 (14% )

Pain, limited to the lower right quadrant 41 (137o)

Abdominal pain over pelvis, with pain in the epigastrium 2 Abdominal pain over pelvis, with pain In the umbilical

region 1

Abdominal pain over pelvis, with pain in the bladder. . . 1 Abdominal pain over pelvis, with pain in the rectum. ... 2 Abdominal pain over pelvis, with pain in the flanks. ... 2 Abdominal pain over pelvis, with pain In the thighs. ... 1

Abdominal pain over pelvis, with pain In the legs 2

Abdominal pain over pelvis, with pain in the right

shoulder 2

.\bdominal pain over pelvis, with pain in the chest 1

Patients complaining of backache 19

fowl. — The symptoms that a patient considers as sufliriently unusual to cause her to seek medical attention an' produced in the vast majority of cases by intraperitoneal bleeding. A history of abdominal pain was procured from

300 patients (yiW), the other three patients stated positively that there had been no abdominal pain or discomfort and they came to the clinic on account of irregular bleeding. In each of these three patients an unruptured tubal pregnancy was found at operation, but no evidence of any clot or free blood in the jicritoneal cavity.

The onset of the symptoms may be acute without other prodromal symptoms, although there is usually a history of a missed period or of irregular bleeding. In a second type there is an acute attack following prodromal symptoms, which the patient sometimes ascribes to her pregnancy. A third type of patient gives a history of gradual onset without an acute attack.

Recurring attacks of pain occurred in 102 cases (34^) ; seventeen patients complained especially of soreness and tenderness, ratlier than of definite pains. In several instances the pain was of several years' duration, generally with a recent exacerbation, but in each instance at operation some other condition, usually chronic pelvic inflammatorj- disease, was also present.

The pains seem rarely to radiate. Tlie character of the pain was described as violent, agonizing or severe in 90 cases, cramping in 41, colicky in four, bearing down in 14, laborlike in nine, shooting, cutting or sticking in si.\ and as dull or aching in 29.

Pain or irritation in the rectum and l)ladder occur after intraperitoneal hemorrliage, most often when clots have collected in the pelvis and adhesions have formed. Pain and vaginal bleeding often occur about the same time. Myssey (St. Paul Med. Jour.. ]!)14, XVI, 588) states that pain on defecation is almost pathognomonic of the condition, but in our experience, this symptom is also frequently present in cases of pelvic inflammatory disease.

MENSTRUAL HISTORY One hundred and three patients (34'ii) stated definitely that they had missed one or more periods; and 31 (10;^) said that their last period had been overdue for from one to five weeks, while 52 (IT"^) had noticed that the last period was abnormal in some other respect.

Number

Number

Number

of periods

ol

o( period!

ol

mined

patienta

mined

patients

1

42

7

1

2

14

8

2

<

14

9

4

2

lU

3

5

4

11

1

(t

U

Total

. .1U3 patients.

Increased frequency of menstruation 14

Constant bleeding since last period 60

No irregular bleeding 49

No irregular bleeding and no periods missed 18

Periods normally regular 210

Periods normally irregular 30

18

[No. 333

Last menstrual period :

Overdue 1 week 11

Overdue 2 weeks 1 1"

Overdue 3 weeks 2

Overdue 4 weeks 1

Overdue 5 weeks 1

Shorter than usual 5

Longer than usual 2ii

Flow decreased 1^

Flow increased 9

Color abnormal 5

Xausea and vomiting occurred in a few cases, as in normally pregnant women and the patients with these symptoni> considered themselves pregnant. In the great majority, however, there was a history pointing to intraperitoneal hemorrhage before nausea or vomiting had occurred.

Abdominal masses were noticed by the patients in cases of advanced pregnancy and wliere a walled-otf hematocele was present.

Fainting occurred in some cases wliere there was profuse intraperitoneal hemorrhage.

Chills and fever were unusual .symptoms and always suggested the gravest complications.

Weakness is generally present in the more anaemic.

Loss of weight was noticed only in advanced tubal pregnancy, as also was the complaint of a bad taste in the mouth.

The notes in our histories as to whether the patient considered herself pregnant are very incomplete, and no conclusions can be drawn from them except that not all believed that they were pregnant.

SIGNS

In the following tabulation of physical signs, it is notable that many of the presumptive signs of intrauterine pregnancy are not present in the majority of this series of ectopic pregnancies. In the larger percentage of the cases in which the table gives " a softened and enlarged cervix or fundus " the notes Avere " slightly softened " or " slightly enlarged " and often there was a difference of opinion in those cases examined by two men. We believe that most cases of tubal pregnancy show no very definite gross changes in the cervix and uterine body, unless the foetus is living. In no case was a positive Hegar's sign recorded. Vaginal cyanosis was not marked in any case.

The usual aksence of definite muscle spasm or rigidity is in accordance with the signs of most pelvic diseases and, where present, there was invariably blood in the peritoneal cavity, not confined to the pelvis. Voluntary resistance to deep pressure was a very common sign.

Abdominal tenderness was frequently alj.sent in cases of pelvic hematocele ; in unruptured tubal pregnancy and in advanced cases, but in patients who had had a recent severe hemorrhage, the abdomen was generally exquisitely tender.

The figures recorded on pelvic tenderness are undoubtedly too low. Certainly in those patients that have been under my ob.servation, there is usually marked tenderness, and. especially when the pelvis is filled with recent clots, tliere is an

even greater degree of tenderness than is found in cases of pelvic abscess. I have seen two eases of unruptured tubal pregnancy in which firm bimanual compression of the mass elicited no tomplaint or discomfort, but they are very unusual.

Signs ox Physical Examination Shock (extreme) 15

Breasts:

Lactating 7

Colostrum present 46 (15%)

Abdomen:

Distention 90 (30%)

Free fluid 33 (10%)

Mass 72 (24%)

Tenderness, general 21 (7%)

Tenderness, limited to lower abdomen 71 (23%)

Tenderness, limited to lower right quadrant 52 (17%)

Tenderness, limited to lower left quadrant 39 (13%)

Muscle spasm 11 (4%)

Rigidity 17 (6%)

Pelvis:

Vaginal cyanosis 6 (2%)

Bloody discharge from vagina 85 (25%)

Cervix softened 85 (25%)

Cervix enlarged 48 (16%)

Fundus softened 15 (5%)

Fundus enlarged 86 (25%)

Mass, boggy 83 (24%)

Mass, firm 38 (12%)

Mass, cystic 40 (13%)

Blood clot crepitus 21 (7%)

Tenderness 146 (48%)

HEMOGLOBIN AND LEUCOCYTE COUNT

Unfortunately, hemoglobin determinations and leucocyte counts were not done in many of the cases. It is to be remembered that the lowest point of the hemoglobin curve is not obtained until from 48 to 72 hours after an acute hemorrhage (Dunn & AVynne, John Hopkixs Hospital Bulletin, XXIX, No. 323, January, 1918). On this account, the degree of ananiiia caused by the acute hemorrhage is not determined as a rule before operation. A high leucocyte count is usually found shortly after acute intrajieritoneal hemorrhage and cannot by itself be considered an indication of infection. In our small series of leucocyte counts, there were between 20,000 and 30,000 leucocytes in 8 cases (10^) and between 10,000 and 20,000 in 39 cases (-17.5^). Tliis observation agrees with those reported by other authors.

Hemoglobin

Before Operation

Per cent of

hemoglobin

Number of

patients

Per cent of

hemoglobin

Number

of patients

15

20-30 30-40 40-.')0 50-60

1 3 13

7 19

60-70 70-80 80-90 90-100

18

20

16

9

Total number of patients on whose blood hemoglobin determinations were done prior to operation, 106.

.I.\NIUHY, 1919]

19

LEfcocvTE Count Before Opebatio.n

W. B. c.

No. of patienta

\v. B. r.

No. of patienta

\V. B. C.

No. of patients

3.000

5,000-6,000

6,000-7 ,00t)

7,00ft-8.0OO

8,000-9,000

9,000-10.000

1

2

6

.;

10.000-11.000 11,000-12.000 12.00(UI3.00() 13.0<K»-14,00«1 14.000-l.i.llOO 15,000-16,000

12

I 8

4

t>

Ifi. 000-17. 000 W.OOO-IS.IMHI IS.OOO-lO.tKMt 20,000-21.000 22.000-23,000 30.000

3

1

1 5 2

Total number of patients on whom leucocyte counts were made before operation, 82.

TEMPERATURE AND PULSE

The temperature on ailnii^t^ion to tlie hospital was less tliaii 101° F. ill 164 (9H) of a series of 180 eonsci-utive adiiiissions for ectopic jrestiition and the pulse was loss tlian I'iO jH?r minute in the same number of patients. The majority sliowed .some increase in both ]iulse rate and temperature.

Temperatire axi> Pfi-.sK ON Akmissiox to the Hospital of 180

Co.NSEClTIVE PaTIE.NTS

Teraperalure

No. of patienta

Temperature

No. of patienta

Temperature

No. of patients

Did not reginter. . . 97.0-98.0 98.0-98.5 98. .5-99.0 99.0-99.5

1

.10 26 41

99.5-100 100.0-100.5 100.5-101 101.0-101.5 101.5-102

2!) 30 8 5 3

102.0-102.5 5 102.5-103 103.0-103.5 i 1 103.5-104 2

Pulae

No. of patienta

Pulie

No. of patienta

Pulae

No. of patients

60-70 70-80 80-90 90-100 100-110

4

9

46

110-120 120-130 130-140 140-l.iO

16 21 7 5

150-160 160-170 2 170-180 1 Could not be 1 counted

pre-operative diagnosis The pre-operativc diagnosis wa.s recorded on the history in 212 cases. The correct diagnosis was made on admission in !)8 cases (4G<) and confirmed on examination after the patients had l)een anu'sthetized for oi)erntion. Twelve additional ca.«es were diagnosed correctly oidy after the patients were under ana-sthesia, while a probable diagnosis of extrauterine pregnancy was made in five other ca.ses, one of whicii had a jwsterior vaginal coeliotomy performed before the laparotomy for confirmation of the diagnosis. In 28 othc i-ases the condition was suspected but not definitely diagnosc(l until some operative procedure had been performed. In <>!• ca.^es (•iS'i) the extrauterine pregnancy was not diagnosed, although in a number of these cases some other pathologiciil condition pre.«ent was diagnosed correctly. The diagnfiscs recorded were made by some member of the resident staff in the large majority of the ca.«es.

Table of Diaonosfs Before Opkratiox Extraulprinp pregnancy (on admission examination I . . . . 98 cases Extrauterine pregnancy (on examination under aniesthesis 12 cases

Extrauterine pregnancy (probable diagnosis)

Extrauterine pregnancy (after exploratory puncture) ....

Retained membranes of extrauterine pregnancy

Pelvic abscess or extrauterine pregnancy

Chronic pelvic inflammatory disease or extrauterine pregnancy

Appendix abscess or extrauterine pregnancy

Chronic appendicitis or extrauterine pregnancy

Cystoma of ovary or extrauterine pregnancy

Myoma uteri or extrauterine pregnancy

Calcified myoma or lithopedion

Flbro-cystoma

Ovarian cyst with twisted pedicle

Multilocular cystic ovary

Ovarian tumor

Ovarian tumor ( malignant )

Papillomatous cyst of ovary

Parovarian cyst

Myomata uteri

Myomata uteri with pregnancy

Myomata uteri, cystic, or sarcoma of uterus

Myomata uteri, cystic, or angioma of uterus

Myomata uteri with adherent dermoid cyst

Pelvic abscess

Pelvic abscess with general peritonitis

Pelvic abscess or appendix abscess

Chronic pelvic inflammatory disease

Subacute pelvic inflammatory disease

Acute pelvic inflammatory disease

Chronic appendicitis

General peritonitis

Retained membranes

Abortion, infected

Miscarriage due to retroposition of the uterus

Pregnancy

Retroposition of the uterus

Chronic pelvic inflammatory disease..

Tubo-ovarian abscess

Ovarian cyst

Submucous myoma, cystic

Ovarian tumor

Extrauterine pregnancy

Chronic pelvic inflammatory disease. .

Papillocystoma of ovaries "

Tuberculous pelvic inflammatory disease

Pelvic inflammatory disease with ovarian cyst. . " No diagnosis made "

4 cases 1 case

11 cases 6 cases

<! cases 1 case 1 case 1 case 1 case 1 case 1 case 1 case 1 case 1 case 1 case 1 case

1 case

5 cases

2 cases 1 case

1 case

1 case

11 cases

1 case

1 case 20 cases

2 cases

1 case

2 cases

1 case

2 cases 1 case 1 case

1 case

2 cases

1 case

1 case

! cases

We do not believe that the Hat-footed diagnosis of extrauterine pregnancy is as simple as many writers consider it. Ill making an estimate of the percentage of faulty dingiio.^es, we should al.<o include those cases diagno.'Jed as extrauterine pregnancy which, at operation, prove to be another condition. Ill this clinic the latter class of cases is nunierous. In jirivate jiractice among more intelligent patients, there sliould be a higher percentage of correct diagnoses made than in a free clinic. The classical case of an acute ruptured ectopic pregnancy is usually clear if a .satisfactory history can be olitained, but there are a great many cases in which the history points equally well to jielvic inflammatory disea.se. The latter ili.sease also gives .symptoms that not infrequently strongly suggest extrauterine pregnancy. Cases with unilateral intlammatory di.-^ea.se are .«een in this clinic fully as often as extrauterine pregnancies and may be very puzzling. Thi'

differential diagnosis in this class of cases is often difficult even when a careful history has been taken.

Very often there are other conditions present that make a positive diagnosis practically impossible. Another stumblingblock is encountered occasionally in patients who have had an early abortion with retained membranes and have a cystic ovary on one side. We have seen three cases of this cliaracter which were correctly diagnosed by one or more members of the staff, but which were considered to be unruptured extrauterine pregnancies by other members who examined the patients under equally favorable circumstances.

There are occasional cases in which the diagnosis is in doubt even after operation has been performed, as in the following :

Gyn. No. 22180. The patient was a white woman, age 33 ; she was admitted to the hospital May 16, 191G, complaining of "bowel trouble."

Married 18 years; three children, youngest six years of age. No miscarriages. Labors normal. Fever for two weeks beginning in the fourth week following the first labor ; otherwise the puerperia were normal.

Last menstrual period February. 1916; last preceding October, 1915. Miscarriage on January 1, 1916, after slight vaginal bleeding for the preceding week. A curettage was done by her family physician January 2 and the patient was told that " the afterbirth was perfect." No foetus was seen. A period normal, except slightly prolonged, began on February 7 and lasted seven days. On February 21 an appendectomy and a curettage were performed. The surgeon who operated said that the uterus, tubes and ovaries were normal at that time. No pain followed the operation until April 6, when she had a gradually increasing pain in the lower abdomen and back. This became quite severe, but lasted only one day. The abdomen felt sore for the following three days. She had no further abdominal pain until May 13 at 6 p. m., when she began to have pain in the left lower quadrant of the abdomen, similar to the previous attack. There had been slight vaginal bleeding for three days prior to this attack, during which the bleeding increased considerably. This attack of pain lasted 36 hours.

P. .E.— Pulse 100. Temperature 99.6°, May 15, 1916. W. B. C, 19,000. Hbg. 95;?;.

Abdominal tenderness marked in the left lower quadrant and less marked in the right lower quadrant. ^Moderate rigidity below the umbilicus. A firm, smooth mass can be felt about half way between the umbilicus and pubis.

Pelvic Examination. — A bloody vaginal discharge is present. Cervix slightly softened and slightly enlarged. The tumor described above seems to be the uterus. A moderately firm mass, which is tender, can be felt in the left fornix. Blood clot crepitus in the cul-de-sac.

Diagnosis. — Extrauterine pregnancy, left, probablv witli beginning tubal abortion.

February 17, 1916. — Operation. A pelvic puncture was performed and about three ounces of old black blood was evacuated from the pelvis. The patient was immediatelv

prepared for laparotomy. There was a considerable amount of old blood in the abdomen. The tubes were found densely adherent in the cul-de-sac, the fimbriated ends were open, both tubes were considerably enlarged and oedematous. No foetal or placental tissue could be found, nor was there any visible site of an ectopic pregnancy in either tube. The tubes were released from adhesions and a cigarette drain placed through the cul-de-sac. There was a good deal of fresh bleeding during the operation. The patient was discharged June 16 after a rather prolonged convalescence. At the time of discharge the uterus was still enlarged, but there were no pelvic masses or tenderness.

TREATMENT The treatment of our cases has been operative, either by the abdominal or vaginal routes. In several cases posterior vaginal coeliotomy has been performed for diagnosis. Pelvic puncture has been employed for pelvic hematocele in a number of cases, although in 60^ of these cases a laparotomy was performed immediately afterwards.

Table of Operatioxs

Vaginal (only ) 24 cases (S%)

Pelvic puncture (only) 16 cases

Pelvic puncture with laparotomy (for hemorrhage

following puncture, 4 ) 24 cases

Pelvic puncture with dilatation and curettage. ... 3 cases

Dilatation and curettage with laparotomy 5 cases

Vaginal salpingectomy 1 case

Exploratory above Poupart's ligament into sac ... 3 cases Laparotomy 279 cases (92%)

Abdominal incision of sac with drainage 5 cases

Removal of fcetus and placenta 6 cases

Salpingectomy (unilateral) 180 cases

Salpingectomy (bilateral ) 56 cases

Resection of one tube 1 case

Puncture of hematosalpinx 2 cases

Total extirpation of sac and CONTENTSs. 12 cases

Partial extirpation of sac 1 case

Oophorectomy (unilateral) 108 cases

Oophorectomy (bilateral) 24 cases

Resection of one ovary 11 cases

Ovarian cyst tapped 1 case

Hysterectomy 30 cases

Resection of uterine cornu 7 cases

Myomectomy 5 cases

Excision of accessory tube 1 case

Ligation of remaining tube 1 case

Excision of abscess sac 1 case

Suspension of uterus 10 cases

Excision of mesenteric cyst 1 case

Excision of umbilical hernia 1 case

Resection of omentum 1 case

Release of intestinal adhesions 5 cases

Suture of rectum 3 cases

Suture of sigmoid 1 case

Resection of ileum 3 cases

Lateral anastomosis 3 cases

Additional: Perineal repair with suture of rectal sphincter 2 cases

Laparotomy by tlie abdoniiual rout4j has beeu preferred in all cases except those in which there was a pelvic hematocele with symptoms and signs indicating infection. In such cases, pelvic puncture and drainage is usually a safer procedure, althougii a secondary laparotomy may be necessarj' later for continued pain.

The majority of our patients have entered the hospital after examination in the Out-Patient Department and have l)een operated upon on the day following admission, unless they were in serious condition at the time of admission, when immediate operation has been performed, with very satisfactory results. One patient whose case has been previously reported by Richardson ( JoHxs Hopkins Hospital Bulletin ) was in very extreme shock when admitted to the hospital and was treated expectantly. However, three days later, operation became imperative on account of marked abdominal distention and she died on the third day after the operation. Richardson thought this patient could have been operated upon the day following admission, when she had recovered somewhat from the primary shock and before serious distention had set in.

Whenever other pathological conditions demanding operation were present, they were included in the operative treatment, when the patient's condition justified a prolongation of the procedure.

Peritoneal Toilet. — In the majority of our cases the peritoneal cavity had been cleaned of blood and clot as well as possible. In 259 cases the peritoneal cavity was cleaned of blood and clot, and in eight cases no attempt was made to evacuate blood. We believe that the convalescence is more satisfactory when the blood is carefully removed.

Irrigation. — The peritoneal cavity was irrigated in 3^ cases, sterile normal salt solution being used in 35 ca.ses and sterile water in two cases. In recent years this practice has been discontinued.

The sac ha.s been irrigated following pelvic puncture in nine cases, but this procedure has been abandoned on account of the danger of breaking through the wall and filling the peritoneal cavity with the fluid, as occurred in one case and resulted in a general peritonitis. This patient recovered after a secondary operation for drainage of the abdomen.

Drainage. — Primary drainage has been used in 150 ca.«t glass tubes were employed twice and in the remainder gaui / usually in the form of a cigarette drain. The drains arc l)referably placed through the cul-de-sac into the vagina, rather than through the abdominal wall (38 cases were drained through the abdominal incision). At the present time drains are not employed unless there is .some evidence iif infection in the pelvis or a general ooze following the release of adhesions.

Stimulant.^. — Salt solution administered subcutancously \y depended upon for stimulation during operation and halieen employed in 5fi cases. Salt solution by rectum has been used in 13 cases and with equal parts of coffee in four rase.-. The peritoneal cavity was filled with salt solution In'fore

(losing the abdomen in 34 cases, but this procedure has been discontinued, as it seems to favor post-operative distention and generally increases the patient's discomfort, as well as spreading infection over the entire abdomen, if any should be present. In the case of one patient with very serious shock, an infusion of normal .^alt .solution was administered through the radial artery and resulted in gangrene of the hand. In a few cases drug stimulants have been used hypodemiically, strychnine in 16 cases, digitalis in three cases and brandy and ether in one case.

Transfusion of blood has not been used in any case included in this series. Very satisfactory results, however, have been reported by others who have used both direct and indirect transfusion, but sometimes there is no time to match the bloods of donor and recipient and a severe reaction following the transfusion may be fatal. The majority of these acutely ruptured cases can be stimulated sufliciently with subcutaneous infusions of large quantities of salt solution to tide them over the immediate shock. As all the.se patients are of ages most favorable for operative risk and as a rule have been in good health prior to the acute onset, they usually will recover if stimulated with salt solution for the first few hours.

Lichtenstein (Muench. Med. Wchnschr., 1915. LXII, 1597) reports eight cases treated by reinjection of the blood found in the patient's abdomen after defibrination and dilution with salt solution 3:2, a procedure open to criticism.

The intravenous injection of 7^ acacia in distilled water, filtered and sterilized by boiling, will probably prove to be of great value in those cases in which there is severe shock due to great loss of blood volume (Rous-Wilson, Jour. Am. Med. Assn., January 26, 1918). We have used this preparation in one case in which there was an abundant hemorrhage at operation and severe shock, with gratifying results.

There are, of course, patients in such serious shock when first seen that operation is contra-indicated. In these cases shock must be combated by some of the methods mentioned above, but as soon as the patient is in condition to stand operation, it should not be delayed.

The time consumed in operating is shown in the table for 255 cases.

Table Siiowixo the Dr

RATION ay

OrERATIONS

Number

Number

Timt

of

Time

ol

Time

ol

cues

C*Mt

cue*

mi».

An. Mill.

krf. ndi.

S

3

45

22

1 25

4

10

6

60

23

1 30

4

16

4

55

14

1 40

2

20

10

21

1 45

4

26

14

1 6

11

1 SO

2

30

21

1 10

17

1 65

2

35

29

1 16

2

2

40

23

1 20

8

2 10 2 26

2

1

Total, 256 operations.

All operations consuming less than 20 minutes were pelvic punctures only.

22

[No. 33.

Thirty operators performed 267 operations.

One operator performed 44 operations

One operator performed 35 operations

One operator performed 27 operations

One operator performed 21 operations

One operator performed 15 operations

Two operators performed 14 operations (each)

One operator performed 12 operations

One operator performed 11 operations

One operator performed 10 operations

One operator performed 9 operations

One operator performed 8 operations

Two operators performed 6 operations (eacli)

One operator performed 5 operations

Four operators performed 4 operations ( each )

One operator performed 3 operations

Six operators performed 2 operations (each)

Four operators performed 1 operation ( eacli )

Ancesthesia. — Iii the large majority of these cases, nitrous oxide followed by ether, administered by tiie open drop method, lias been used. Some patients have been given chloroform or ether only, and a few chloroform and ether.

Diagnosis at Operation

Ruptured with free blood in peritoneal cavity 100 -, .„^ .

Ruptured with encapsulated blood in peritoneal cavity 66 r Tubal abortion with free blood in peritoneal cavity ... 381 Tubal abortion with encapsulated blood in peritoneal I (19%)

cavity 13 J

Unruptured , 55 (20%)

Total 272

Interstitial pregnancy, right 2 '

Tubal pregnancy, right 135

Tubal pregnancy, left 131

Ovarian pregnancy, right 2 '

Total 270

' Wynne, J. H. H. Bull. XXIX, No. 324, February. 1918. - CuUen & McAll. Surg., Gyn. & Obst.. 1912; M.ver & Wynne, to be reported.

In one case the pregnant tube was ruptured during the examination under ether. Active hemorrhage at time of operation occurred in 20 cases.

The peritoneum was noted as blood stained before bcinu opened in 43 cases.

The blood in the peritoneal cavity was designated as fluid in 66, clotted in 24 (infected, three) ; there were fluid and clots in 55 cases.

The opposite tube was noted to be normal in 15 cases.

The opposite ovary was noted to be normal in 12 case.s.

The appendix was described as normal in 31 cases.

The appendix was involved in the sac in 11 cases.

The appendix was adherent to a myoma in one case.

A CASE OF PREGNANCY IN A RUDIMENTARY HORN Gyn. No. 16T27. The patient was a white woman, age 30, admitted to the hospital June 9, 1910, complaining of vaginal l)leeding and pain the left .side of the abdomen. Married five vears; one child two years old. One miscarriage at two months, one year ago. Labor and puerperia normal. Last menstrual period January, 1910.

P. I. — The patient considered herself pregnant, but noticed that the uterus had not enlarged as rapidly as during her former pregnancy and that the enlargement was more on the left side than on the right. For a month she has noticed tenderness over the left side of the abdomen. At 6 a. m. on the morning of admission, she was awakened by pains in the pelvis, similar to labor pains and shortly after, passed blood and bits of tissue resembling placenta. There was slight bleeding afterwards, but the pain subsided. She was nauseated this morning.

Phi/gical Examination Under Ether. — On abdominal examination, a mass can be felt in the lower abdomen, which is rather soft and boggy and about the size of a large orange. The mass is movable and seems to be attached to the uterus.

Gyn. No.

Race

Age of patient

Date

Fre-operative diagnosis

Operation

Placenta

Result

Feetus

Years 114

B.

29

1890

Fibrocystoma.

Laparotomy.

Removed.

Died. Shock.

101

B.

28

1890

Abdominal pregnavicy (several mos. past term) .

Lai "•^'tomv

Removed.

Recovery.

Wt. 2800 grms. Male. Dead. Fully developed. Crown rump 30 cm.

1,705

W.

42

1893

Ectopic, two months past term.

Lapatpitomy.

Removed.

Died. General peritonitis.

Dead. Length. 42 cm.: wt., 4 lbs.

4,564

B.

45

1896

Calcified myoma or litliopedion four years past term.

Laparotomy. (Reported by

Removed. J. G.Clark).

Recovery.

Lithopedion. Weight, 43 lbs.

7,182

W.

34

1899

M u 1 1 i 1 c u 1 a r cystoma

ovarii. Ruptured tubal pregnancy,

Laparotomy.

Removed.

Recovery.

12.207

W.

41

1905

Laparotomy.

Removed.

Recovery.

Macerated. Weight, 12.')0

two months past term.

13.272

B.

28

1906

Laparotomy. Laparotomv.

Recovery. Recovery,

Full term, female. Living. Six months. 33 cm. long.

13,546

W.

35

1907

Extrauterine pregnancy.

Removed.

ruptured.

13.673

B.

30

1907

Laparotomy. Laparotomy.

Recovery. Recovery.

13,806

B.

33

1907

Abdominal pregnancy.

Removed.

Macerated remains of foetus.

(Reported by CuUen,

Surg., Gvn. cS:

b.st., 1915, X

X, 261.)

17,056

W.

35

1911

Laparotomy.

Removed.

Recovery.

Dead. Intraligamentary, rt. Weight, 6A lbs.

19,092

B.

22

1913

Extrauterine pregnancy, infected.

Laparotomy.

Removed.

Died. General peritonitis.

Macerated. Femur, 5.2 cm. Humerus, 4.8 cm.

21,494

B.

29

1915

Ovarian tumor, right.

Laparotomy.

Removed.

Recovery.

Dead. Weight, 1911 grms. 44.5 cm.

Januabt, 1919]

23

Pelvic Examination. — The vagina and cervix are normal. The fundus of the uterus is soft and boggy and, attached to it by a pedicle, is the mass described above.

Pre-Operative Diagnosis. — Extrauterine pregnancy or pregnancy in a rudimentary liorn.

Operation. — The mass was found to be a pregnancy in thi; rudimeutarj' left horn of a bicornat* uterus and was attached to the right side of the uterus by a small pedicle. The left tube was stretched over the pregnant horn and togetlier with the left ovary was so intimately associated with it as to necessitate their removal. The left horn was amputated close to the right side and there remained a practically normal uterus.

The patient was discharged on the 13th day after an uncomplicated convalescence.

Diagnosis. — Pregnancy in a rudimentary horn, left.

Pathological Xo. 15,150. — The specimen has been opened anteriorly in the operating-room and measures 7x8x5 centimeters. The walls measure 1.5 centimeter in thickness. Foetus of 4 to 5 months in unruptured membranes.

Patholooicai, Retobts

The tissues removed at operation have been studied histologically and the diagnosis has been verified. We are unable at the present time to give a thorough report on this interesting side of the disease.

The routine preparations, where the endometrium was examined, have been reported as follows:

Normal endometrium 13

Gland hypertrophy of the endometrium 5

Endometritis, chronic 5

Endometritis, acute 1

Decidual reaction of the endometrium 7

Cast of uterine cavity with decidual reaction 2

In addition to ectopic pregnancy the following diagnoses were made at or before operation :

Atrophy of the opposite tube 1

Hematosalpinx of the opposite tube 3

Hydrosalpinx of the opposite tube 16

Chronic salpingitis of the opposite tube 8

Pyosalplnx of the opposite tube 6

Tuboovarian abscess of opposite tube 1

Ovarian abscess •. 3

Chronic pelvic inflammatory disease 92

Cystic ovaries 13

Ovarian cyst, follicular 9

Ovarian cyst, corpus luteum 3

Parovarian cyst 1

Retroposition of the uterus 6

.Myomata uteri 17

.Membranous dysmenorrhoea 1

Mesenteric cyst 1

General peritonitis 1

Pre-operative rupture of abscess Into rectum 1

Meckel's diverticulum 1

Umbilical hernia

2

Appendicitis, chronic

52

Appendicitis, sub-acute

5

Appendicitis, acute

2

Periappendicitis

7

Complications before operation : Pulmonary tuberculosis

2

Diabetes i

Insanity i

Arthritis deformans i

Chronic nephritis i

Ascaris lumbricoides i

Uncinaria Americana l

Post-operative Compucatioxs

The complications following operations have been as follows:

Acute bronchitis 2 cases with recovery.

Bronchopneumonia 2 cases with recovery.

Lobar pneumonia 2 cases with 1 death.

Fecal fistula, abdominal 2 cases with 1 death ")

Fecal fistula, vaginal 1 case with death. . . ll patient.

Urinary fistula, abdominal 1 case with death. . . J

Atonic ileus 1 case with recovery.

Peritonitis, general G cases with 5 deaths.

Infected drainage cavity with

collection of pus 3 cases with recovery.

Cystitis 2 cases.

Phlebitis (of left leg) 3 cases.

Tetanus 1 case with recovery.

(Reported by Casler at Southern Medical Association meeting in 1917.)

Gangrene of the hand following intraarterial (radial) salt infusion 1 case.

Mastitis, right 1 case.

Acute follicular tonsillitis 1 case.

Influenza 1 case.

Erysipelas (facial) 1 case.

Shock and antcmia have been omitted from this list, as accurate data for all cases are not available.

SuBSEQfE.XT Operations for Co.mplicatio.vs Abisino erom the Prim.\by Operatiom

Gyn. No. 2,612. Abdominal drainage for peritonitis following rupture of sac by Irrigation after pelvic puncture. Symptoms of peritonitis 11 days after operation. Recovery.

Gyn. No. 7,901. Exploratory laparotomy for localized poritonitta 36 hours after left salpingo-oophorectomy and vaginal drainage. Death on the sixth day from lobar pneumonia.

Gyn. No. 11,473. Pelvic puncture for drainage, 23 days after salpingo-oophorectomy. Recovery.

Gyn. No. 11,491. Dilatation of drainage tract and evacuation of pus 10 days after pelvic puncture. Recovery.

Gyn. No. 12,380. Rupture of abdominal incision 22 days after laparotomy. Recovery.

Gyn. No. 15,529. Right salpingo-oophorectomy and release of adhesions 1.J days after pelvic puncture and drainage of infected hematocele. Recovery.

34

[No. 335

Gyn.No. 17,251.

January 16, 1911, at the first operation, during hysterectomy, left salpingo-oophorectomy and release of adhesions, the rectum was torn. Abdominal fecal fistulae resulted.

April 29, 1911. Excision of- fistulous tracts, suture of rectum and bladder. Appendectomy. Failure.

September 18, 1911. The patient was readmitted to the hospital (Gyn. No. 17,804) for abdominal fecal fistula and a recto-vaginal fistula following her first operation.

September 30, 1911. Excision of abdominal fistula, resection of sigmoid, end-to-end anastomosis, suture of bladder. Shock.

October 5, 1911. Enterostomy for ileus.

October 6, 1911. Enterostomy for ileus. Death on the table.

CAUSE OP DEATH There have been 13 deaths in our scries of 303 cases and autopsies were performed on six of these.

Gyn.No. 114. (Autopsy No. 72.) Shock 12 hours after operation. This patient was in a very critical con

dition when operated upon. No anatomical cause of death was found at autopsy.

Gyn.No. 521. (Autopsy No. 181.) Died 24 hours after operation. The anatomical diagnosis at autopsy was: Acute general peritonitis (pure culture B. coli from bloody peritoneal fluid), perforation of appendix with circumscribed abscess.

Gyn.No. 1,795. (Autopsy No. 38S.) Died 10 days after operation. At autopsy an acute fibro-purulent peritonitis, chronic diffuse nephritis and gallstones were found.

Gyn.No. 7,901. (Autopsy No. 1562.) Death 6 days after operation, of lobar pneumonia.

Gyn. No. 10,678. (No autopsy.) Death 3 days after operation. On admission the hemoglobin was 15 per cent and on the day of death 10 per cent.

Gyn. No. 12,042. (No autopsy.) Death 9 hours after operation. This patient was operated on by the vaginal route and a large amount of clot and fiuid blood evacuated, followed by a gush of bright red blood. Laparotomy was immediately performed. Shock.

Table Showing Pbegnancies Since Operation

Character of operatit

No. of years since operation

of ciiildren and miscarriages since operation

1,636

1,710

2,805

4,120

6,482

8,441

9,740

9,746

10,258

10,544

11,215

11,244

11,592

11,830

11,834

12,236

12,268 12,398 14,167 15,309

15,644

15,955 17,428 18,744

19,781 20,777 21,017 21,082 21,483 22,303 22,445

Incision of sac with drainage

Enucleation of sac

Right salpingo-oophorectomy

Pelvic puncture with drainage

Right salpingectomy

Right salpingo-oophorectomy

Left salpingectomy

Right salpingo-oophorectomy

Left salpingectomy

Left salpingectomy with resection of right ovary

Right salpingo-oophorectomy

Pelvic puncture and exploratory laparotomy

Right salpingectomy

Pelvic puncture •

Left salpingo-oophorectomy

Right salpingo-oophorectomy

Right salpingectomy

Right salpingo-oophorectomy

Left salpingo-oophorectomy and resection of right ovary. . Left salpingo-oophorectomy

Right salpingo-oophorectomy

Left salpingo-oophorectomy

Right salpingectomy

Right salpingectomy

Right salpingectomy

Resection of right cornu

Right salpingectomy, resection of right ovary, myomectomy

Right salpingectomy

Right salpingectomy

Right oophorectomy

Left salpingo-oophorectomy

23 months 20 months

15 months

16 months

5 full-term children. 2 full-term children.

1 full-term child.

2 full-term children.

1 miscarriage at 2% months 4 years after operation.

2 full-term children, 1 miscarriage. 1 miscarriage.

5 miscarriages, the first 2 years after operation.

1 full-term child.

2 full-term children. 2 full-term children. 1 full-term child.

6 full-term children.

1 tubal pregnancy 8 years after operation.

1 full-term child.

2 miscarriages 10 and 8 years ago at 3 months;

1 full-term child 6 years ago.

1 miscarriage.

2 miscarriages.

1 full-term child.

1 full-term child 2 years after operation; 1 miscarriage 6 years after operation.

1 miscarriage and 1 full-term child 3 years after operation.

1 full-term child.

1 full-term child.

1 full-term child 14 months after operation; 1 fullterm child 32 months after operation.

8 months pregnant when heard from.

1 full-term child 1% years after operation.

1 full-term child 1 year after operation.

1 miscarriage (induced) 6 months after operation.

3 weeks from term when heard from.

1 full-term child IS months after operation. 1 full-term child 11 months after operation.

F^VE Patients Opekated on fob Second Ectopic Pregnancy in This Clinic

Second operation

4,147

9,781

13,776

15,771

16,230

Pelvic puncture in 1896

Right salpingo-oophorectomy in 1902

Left salpingectomy in 1907

Right salpingectomy in May, 1909

Right salpingo-oophorectomy in November, 1909

Right salpingectomy in 1904

Left salpingo-oophorectomy in 1905

Right salpingectomy in 1908

Left salpingectomy in November, 1909

Hysterectomy; left salpingo-oophorectomy in January, 1911

11,590 12,290 14,895 16,188

17,251

January, 1919]

25

These six fatalities were reported in Kelly's Operative

Gynecology, Vol. II.

Gyn. No. 12,830%. (No autopsy.) Death 4 hours after operation. The patient was in serious shock when operated upon. About 2 liters of free blood were evacuated from the abdomen.

Gyn. No. 15,314. (No autopsy.) Death 3 days after operation from shock. (Reported by E. H. Richardson.)

Gyn. No. 17,119. (No autopsy.) Death 2\i hours after operation. The patient was in good condition after the operation until 3 minutes before death. Probably embolus.

Gyn. No. 17,211. (.\utopsy No. 3489.) Death 8 days after operation. Anatomical diagnosis at autopsy: Acute general peritonitis.

Gyn. No. 17,251. (No autopsy.) Death S days after secondary operation tor fistula following primary operation. General peritonitis.

Gyn. No. 18,731. (No autop.sy.) Death 2Vi hours after operation. Shock. This patient had diabetes.

Gyn. No. 19.092. (Autopsy No. 38S4.) Death 12 days after operation. .\t autopsy acute general peritonitis and embolic pneumonia were found. At operation the sac containing foetal bones and infected material was ruptured.

Immediate Resvlts

Well 271 (89.4%)

Improved 19 (6.3%)

Died 13 (4.3%)

Ultijiate Results Letters were sent to the 290 patients who recovered from the operations for ectopic pregnancy. Answers to the fol

low-up letters were obtained from 118 patients and nine, who did not answer the letter, were later readmitted to this hospital. Of 120 patients, 100 have been well since operation, five have had poor health since operation, .seven report fair health and two no change in general health since operation. Four had good health for several months or years, and afterwards died, one of pulmonary tubenulosis, one of acute intestinal obstruction, one of post-operative pneumonia. In one ease the cause of death was not stated.

Of the series of 127 cases, there was no possiltility of future pregnancy in 33. Of the remaining 9G in whom there wa.s a possibility of future pregnancy 36 (38°) have since become pregnant one or more times; 61 pregnancies have resulted in •?7 full-term children ; two patients were pregnant almost at term when heard from. In 16 cases the pregnancy ended in miscarriages and six patients had a second extrauterine pregnane}'.

Opeuatioxs Subsequent to Operation fob Ectopic Pbeonaxct Post-operative ventral hernia has occurred in eight cases; four have been repaired in this hospital and one in another hospital, and three patients have not been submitted to another operation. One patient was operated upon for intestinal obstruction and one had a vaginal panhysterectomy performed in this hospital for carcinoma of the cervix. In all 14.5 patients have been followed on this point.

I wish to thank Dr. Howard A. Kelly for permission to publish this report.

NOTES AND NEWS

Dr. George Blumer is Chairman of the Medical Advisory Board, Yale University, New Haven, Conn.

Dr. Montague Boyd is Associate Professor of Surgery (Genitourinary), Emory University: Andrologist, Wesley Memorial Hospital and Visiting Genitourinary Surgeon, Grady Hospital, Atlanta, Ga. Government service: Captain. M. R. C, on duty in France.

Dr. Walter V. Brem is .Major .M. C, and Chief of the .Medical Service, U. S. Army Base Hospital, Camp Fremont, Cal.

Dr. Helen Smith Brown is Lecturer In Social Hygiene for the Commission on Training Camp .Activities, Washington. D. C.

Dr. S. W. Clausen is Instructor in Pediatrics, Washington University Medical School and Assistant Physician to the St. Louis Children's Hospital. He Is First Lieutenant, M. R. C, and is in active service.

Dr. Malvern B. Clopton is Major, M. R. C. He is a member of Washington University Hospital Unit No. 21, and is stationpd with General Hospital No. 12, B. E. F., Rouen, France.

Dr. Stanley Cobb is First Lieutenant. M. C, Division of Brain Surgery.

Dr. Sydney M. Cone Is Captain, M. R. C, and is stationed at the Alder Hey English Military Orthopedic Hospital. England.

Dr. Henry Wireman Cook is Associate Director of the Bureau of Medical Service, American Red Cross, Washington, D. C.

Dr. W. L. Cousins Is Surgeon-in-Chlcf of St. Barnabas Hospital, Portland, Me. Government service: Major, M. R. C, and Chief of the Surgical Staff U. S. Army Base Hospital, Camp Gordon, Ga.

Dr. J. Stalge Davis is Captain, M. C, U. S. Army, and is on active duty in Baltimore.

Dr. Ernest C. Dickson Is Associate Professor of Medicine, Iceland Stanford University School of Medicine. Government service: Captain, C. A. M. C, stationed In Basingstoke, England.

Dr. Richard N. Duffy Is Surgeon to the New Bern General Hospital, New Bern, N. C.

Dr. C. B. Dunn Is Chief of Staff, Southeastern Hospital for the Insane, Madison, Ind., and on the teaching staff King's Daughters Hospital, Madison, Ind.

Dr. Arthur B. Emmons Is Captain. M. R. C, and Is stationed In Evacuation Hospital No. 2, A. E. F., France.

Dr. W. L. Estes, Jr., la Director of St. Luke's Hospital, South Bethlehem, Pa. Government service: Captain, M. R. C, attached to Mobile Operating Unit No. 1. Section No. 1, A. E. F., France.

Dr. William W. Farr Is Captain, .Medical Corps, U. S. A., stationed at U. S. Base Hospital. Camp Shelby, Hattlesburg, Miss., with title of Chief of Subsection of Otolaryngology.

Dr. A. L. Fisher is Captain, M. C, and is In charge of the Surgical Service, U. S. Base Hospital No. 30, A. E. F.

26

[No. 335

Dr. J. M. T. Finney is Brigadier General, M. C, U. S. Army, and is Surgical Consultant, A. E. F., France.

Dr. Simon Flexner is Lieutenant Colonel, Medical Corps, U. S. A. He is on duty at the Rockefeller War Demonstration Hospital, New York City.

Dr. James R. Garber is Instructor in Obstetrics South Highlands Infirmary Training School for Nurses, Visiting Obstetrician to the Hillman Hospital, Attending Obstetrician to the Salvation Army Home, Birmingham, Ala., and Acting Secretary of the Southern Medical Association.

Dr. S. McPheeters Glasgow is Captain, M. C, and is stationed at Camp Zachary Taylor, Ky.

Dr. L. W. Gorham is Captain, M. R. C, and is stationed with I\ S. Base Hospital No. 33, Portsmouth, England.

Dr. F. F. Gundrum is Vice-President, California State Board of Health, and Consulting Physician, Sacramento County Hospital. Government service: Chairman Medical Advisory Board No. 7, Sacramento, Cal.

Dr. Louis Hamman is Acting Physician-in-Chief to The Johns Hopkins Hospital and Acting Professor of Medicine, Johns Hopkins University.

Dr. F. M. Hanes is connected with Base Hospital No. 65, A. E. F., France.

Dr. Henry Harris is Instructor in Medicine, University of California. Government service: Member of Medical Advisory Board, District No. 5, California.

Dr. R. F. Hegeman is Captain, M. R. C, and Is Assistant Chief of Base Hospital'No. 96.

Dr. Campbell P. Howard is Professor of Theory and Practice of Medicine and Clinical Medicine, State University of Iowa, and Physician to the University Hospital.

Dr. Henry T. Hutchins is Major, M. C, and is Surgeon-in-Chief, Evacuation Hospital No. 49, A. E. F.

Dr. J. Edwards Kerney is Visiting Urologist, Memorial Hospital, Pawtucket, R. I.; Visiting Urologist to Rhode Island State institutions; Associate Visiting Urologist to St. Joseph's Hospital, Providence, R. I.: and Surgeon in Urology to Rhode Island Hospital, O. P. D., Providence, R. I.

Dr. Clarence F. M. Leidy Is Captain, M. C, 62d Pioneer Infantry, Camp Wadsworth, S. C.

Dr. Hans Lisser is Instructor in Medicine, University of California Medical School, and Assistant Visiting Physician, University of California Hospital. Government service: Chief Examining Physician, Local Draft Board No. 4, Oakland, Cal.

Dr. Herbert M. Little has taken up again his work as Assistant Professor of Obstetrics and Lecturer in Gynecology, McGill University, after two years' duty overseas with the Canadian Army Medical Corps. He is also Assistant Attending Obstetrician, Montreal Maternity, and Assistant Attending Gynecologist, Montreal General Hospital.

Dr. David Russell Lyman is Medical Superintendent, Gaylord Farm Sanitarium, and Clinical Lecturer on Tuberculosis, Yale Medical School. He was for six months with the Rockefeller Commission for the Prevention of Tuberculosis in France, and with the Tuberculosis Bureau of the American Red Cross.

Dr. W. G. JlacCallum is Contract Surgeon, U. S. Army.

Dr. J. D. Madison is Captain, M. C, and is stationed in Milwaukee, Wis., as President of the Examining Board for Medical Officers' Training Camp, etc.

Dr. W. McK. Marriott is Professor of Pediatrics, Washington University Medical School, Physician-in-Chief to the St. Louis Children's Hospital, and Consulting Physician to the St. Louis City Hospital and the St. Louis Isolation Hospital.

Dr. Robert T. Miller is Lieutenant Colonel, M. C, Director U. S. Base Hospital No. 27, and Chief of Surgical Staff Mobile Hospital No. 1.

Dr. Ralph G. Mills, Assistant Resident Pathologist Johns Hopkins Hospital, is Professor and Head of Department of Pathology, ' Peking Union Medical College, Peking, China (absent on leave).

Dr. George R. Minot, Jr., is Assistant Professor of Medicine, Harvard Medical School; Associate in Medicine, Massachusetts General Hospital, and Assistant Consulting Physician to Collis P. Huntington Memorial Hospital of the Harvard Cancer Commission. Dr. Roger S. Morris is Forchheimer Professor of Medicine, Medical Department University of Cincinnati; Director of the Medical Division Cincinnati General Hospital, and Director of the Outdoor Dispensary. Government service: Major, M. C, on duty abroad.

Dr. W. Bean Moulton is Captain, M. R. C, and is stationed at Camp Greenleaf, Chickamauga Park, Ga.

Dr. C. D. Parfitt is Lecturer on Medicine, University of Toronto, and Advisor to the Tuberculosis Clinic, General Hospital, Toronto. Dr. Francis W. Peabody is Assistant Professor of Medicine, Harvard Medical School; Physician to the Peter Bent Brigham Hospital, and Consulting Physician to the Collis P. Huntington Memorial Hospital. Government service: Major, M. C, on active duty in France.

Dr. Louise Pearce is Associate in Pathology at the Rockefeller Institute for Medical Research, New York City.

Dr. Clement A. Penrose is Major, M. R. C, at present on inactive duty.

Dr. H. W. Plaggemeyer is Captain, M. C, and is on active duty in France.

Dr. Alexander Randall is Captain, M. R. C, and is stationed with the 6th Army Corps, France.

Dr. George K. Rhodes is First Lieutenant, Medical Corps, U. S. A., on duty at U. S. Base Hospital, Camp Meade, Md.

Dr. Hunter Robb is Major, M. R. C. He is stationed in the Medical Officers' Training Camp at Camp Greenleaf, Ga.

Dr. Peyton Rous is Associate Member, Rockefeller Institute for Medical Research, New York City, and Vice-Chairman, Division of Medicine and Related Sciences, National Research Council, Washington, D. C.

Dr. W. G. Sexton is First Lieutenant, M. C. He is on duty with U. S. Base Hospital No. 158, Camp Greenleaf, Ga.

Dr. W. F. Shallenberger is Associate Professor of Gynecology, Emory University; Visiting Gynecologist, Wesley Memorial Hospital; Visiting Gynecologist, Georgia Baptist Hospital, and Assistant Visiting Gynecologist, Grady Hospital, Atlanta, Ga.

Dr. Frank J. Sladen is Captain, M. C, and is Assistant Chief of Medical Service, U. S. Base Hospital, Camp Sherman, Ohio.

Dr. J. Morris Siemens is Major, M. R. C, and is Chief of the Surgical Service, U. S. Base Hospital No. 92, Cape Greene, N. C.

Dr. F. Janney Smith is Captain, M. C. He is Chairman, Cardiovascular Examining Board, and President, Certificate of Disability Board, 155th Depot Brigade, Camp Lee, Va.

Dr. Winford Smith is Colonel, Medical Department, U. S. A., and Chief of Bureau of Administration, Hospital Division, Surgeon General's Office, Washington. D. C.

Dr. Richard P. Strong is Major, M. C, and is stationed in France. Dr. Solomon Strouse is Assistant Professor of Medicine, Northwestern University; Attending Physician, Michael Reese Hospital; Director, Department of Medicine, Michael Reese Hospital Dispensary. Government service: Secretary and Member of Medical Advisory Board 3 J, Michael Reese Hospital.

Dr. Adrian Taylor, Assistant Resident Surgeon, The Johns Hopkins Hospital, is Professor of Surgery and Head of Department of Surgery, Union Medical College, Peking, China.

Dr. W. S. Thayer is Physician-in-Chief to The Johns Hopkins Hospital and Professor of Medicine, Johns Hopkins University. Government service: Brigadier General, M. C, U. S. Army, and Chief Medical Consultant, A. E. F., France.

Dr. Charles B. Thompson is Executive Secretary, Meulal Hygiene Society of Maryland: Psychiatrist at the Hebrew Hospital Dispensary, and Lecturer on Psychiatry to the Training School of the L'nion Protestant Infirmary.

Dr. Douglas Vanderhoof is Professor of Medicine in the Medical College of Virginia, Physician-in-Chief to the Virginia Hospital, Senior Attending Physician to the Memorial Hospital, and consulting Physician to the Johnston-Willis Sanatorium. Government service; Secretary Medical .-\dvisory Board No. 2. Richmond, Va.

Dr. Cecil \V. Vest is Captain. .M. C. and is stationed at Camp Meade, Md.

Dr. Carl \V. Waldron is Captain. C. A. M. C. O. C. The Canadian Unit. He is stationed at The Queen's Hospital, Frognel. Sidcup. Kent, England (for facial and jaw restorations).

Dr. Louis .M. Warfield is Major. M. C. and is Chief of the Medical Service, Jefferson Barracks. Mo.

Dr. S. Shelton Watkins is Lieutenant, M. C. U. S. Navy.

Dr. Ernest M. Watson is Instructor in I'rology. .Medical Department, University of Buffalo; Attending Urologist to Buffalo City Hospital, Municipal and Ernest Wende Hospital: Assistant Attending Urologist to Erie County Hospital, and Assistant in Clinical Urology, Buffalo General Hospital.

Dr. Charles W. Webb is Chief Surgeon to the Clifton Springs Sanitarium and Hospital. Clifton Springs, N. Y.

Dr. Harry 1. Wiel is Assistant in Medicine, University of California, and .Assisting Visiting Physician, San Francisco Hospital, San Francisco, Cal.

Dr. Gordon Wilson has taken up again his work in Baltimore after serving as Major, M. R. C. having been assigned to Camp .Meade as Tul>erculosis Specialist.

NOTES ON NEW BOOKS

The liuntgcn Diagnosis of Diseases of the Alimenlary Canal. By Ri'sstax D. C.vKMAN, M. D., and Auiebt Miixeb, M. D. (Philadel/ihia: W. B. Saunders Company. 1917.)

It Is quite refreshing to read such a splendid description of the various methods and means of diagnosis as are put forth by Carman and Miller.

After a description of apparatus, technic and interpretation they take up the different organs and the various manifestations of disease as evidenced by rcpntgon examination.

Of especial value is the liescription of the normal findings before each chapter on the various organs, thus giving the student a much clearer conception of the pathologic states as outlined later. The idea of giving classified lists of roentgenologic signs in various diseases is noteworthy and a splendid idea.

Among other things which make the book graphic and impressive is the fact that practically all cases shown have been verified by operation and noted in the text— also the references at the end of each chapter prove to be another great asset.

Altogether the book is of great value — easy to read and understand because of the clearness of the text — the various points are graphically portrayed by splendid illustrations, and every subject receives thorough consideration from all points of view. It is a book which should be read by every rrentgenologlst as well as all practitioners interested in the roentgenologic diagnosis of gastrointestinal conditions, as It Is undoubtedly by far the foremost publication on the subject to-day. E. H. G.

PUBLICATIONS.

The following six monographs :

Free Thrombi and Ball-Thrombi in the Heart. By J. H. Hewitt, M.D. 82 pages. Price, $1.00. Benzol as a lyeucotoxin. By Laurence Selling, M. D. 60 pages. Price,$1.00.

Primary Carcinoma of the Liver. By M. C. Winternitz, M. D. 42 pages. Price, 75 cents.

The Statistical E.\perience Data of The Johns Hopkins Hospital, Baltimore, Md., 1892-1911. By FitEDi:itiCK L. Hoffman, LL.D., F.S.S. 161 pages. Price, $2.00. The Origin and Development of the Lymphatic System. By Florknce H. Sauin. 94 pages. Price,$2.00.

The Nuclei Tuberis Laterales and the So-called Ganglion Opticum Basalc. By Kdward F. Mai.one, M. D. Price, $1.50. are now on sale by The Johns Hopkins Pre.ss, Baltimore. Other monographs will ajipear from time to time. THE JOHNS HOPKINS HOSPITAL REPORTS. Volume I. 423 pages, i)y plates. Volume II. 570 pages, with 28 plates and figures. Volume III. 766 pages, with 69 plates and figures. Volume IV. 504 pages, 33 charts and illustrations. Volume V. 480 pages, with 32 charts and illustrations. The Malarial Fevers ot Baltimore. By W. S. Thayer, M. D., and J. llEWETSON. M. D. „ „ ,r T> A Study of some Fatal Cases ot Malaria. By Lewellts F. Barker, M. B. Studies in Typhoid Fever. By William Osleb, M. D., with addlUon.il papers by G. Blomer, M. D.. Simon Flbxnee, M. D., Walter Keed, M. D., and H. C. Parsons, M. D. Volume VI. 414 pages, with 79 plates and figures. Volume VII. 537 pages with illustrations. Volume VIII. 552 pages with illustrations. Volume IX. 1060 pages, 66 plates and 210 other illustrations. Contributions to the Science of Medicine. Dedicated by his Pupils to William Hbnrt Welch, on the twenty-flfth anniversary of his Doctorate. This volume contains 38 separate papers. Volume X. 516 pages, 12 plates and 25 charts. structure of the Malarial Parasites. Plate I. Bv Jesse W. Lazbab. M. D. The Bacteriology of Cystitis, Pyelitis, and Pyelonephritis in Women, with a Consideration of the Accessory Etiological Factors in these Conditions, and of the Various Chemical and Microscopical Questions Involved. By Thomas R. Brown, M. D. Cases of Infection with Strongyloides Intestinalis. (First Reported Occurrence in North America.) Plates II and III. By Richard P. SxRUNf:, M. D, On the Pathological Changes in Ilodgkin's Disease, with Especial Reference to Its Relation to Tuberculosis. Plates IV-VII. By Dorothy M. ItKED. M. D, Diabetes Insipidus, with a Report of Five Cases. By Thomas B. Fctcher, M. B. (Tor.). Observations on the Origin and Occurrence of Cells with Eoslnophlle Gn.ij ulations in Normal and Pathological Tissues. Plate VIII. By W. T. Howard. M, D.. and R. G. Perkins. M, D. Placental Transmissions, with Report ot a Case during Typhoid Fever. Bv Frank W. Lynch. M. D. Metabolism in Albuminuria. By Chas. P. Emerson. A. B., M. D. Regenerative Changes in the Liver after Acute Yellow Atrophy. Plates IX-XII. By W. G. MacCallcm, M. D. Surgical Features of Typhoid Fever. By Thos. McCrae, M. B., M. R, C. P. (Lond.), and Jasies F. Mitchell. M. D. The Symptoms, Diagnosis, and Surgical Treatment of Ureteral Calculus. By Ben.iamin R. Schenck, M. D. Volume XI. 555 pages, with 38 charts and illustrations. Pneumothorax ; A historical, clinical, and experimental study. By Charles I'. E.MERSON. M. D. Clinical Observations on Blood Pressure. By Henry W. Cook, M. D„ and John B. Briggs. M. D. The value of Tuberculin in Surgical Diagnosis. By Martin B. Tinker. M. D. Volume XII. 548 pages, 12 plates and other illustrations. The Connective Tissue of the Salivary Glands and Pancreas with its Development in the Glanduia Submaxillaris. Plates I-III, By Joseph Marshall Flint. M. I>. A New Instrument for Determining the Minimum and Maximum BloodPressures in Man. Plates IV-X. By Jcseph Erlanger, M, D, Metabolism in Pregnancy, Labor, and the I'uerperium. By J. Morris Slemons, M. D. An Experimental Study of Blood-Pressure and of Pulse-Pressure in Man. Plates XI and XII. By Joseph Eklangke, M. D., and Donald R. Hooker, A. B., M. S. By Typhoid .\li.uiugitis. By RuFus I. Coi.e, M. D. The Pathological Anatomy of Meningitis due to Bacillus Typhosus. William G. MacCallum. M. V. A Comparative Study of White and Negro Pelves, with a Consideration of the Size of the Child and Its Relation to Presentation and Character of Labor in the Two Races. By Theodore F. Riggs. M. D. Renal Tuberculosis. By George Walker, M. D. Volume XIII, 605 pages, with 6 plates, 201 figures, and 1 colored chart. studies in Genito-ITrinary Surgery. The Seven-Glass Test. By Hugh II. Young, M. D. The Possibility of Avoiding Confusion by Bacillus smegmatis (Smegma bacillus) in the Diagnosis of Urinary and Genital Tuberculosis. An Experimental Study. Bv Hugh H. Yoong. M. D., and John W. Churchman. M. D. Urethral Diverticula in the Male. By Stephen H. Watts, M. D. An ITnusual Case of Urethrorrhagla. Bv H. A. Fowler, M. D. Paraurethritis. By John W. CHrRCHM.iN. M. D. Use of Ointments In the Urethra in the Treatment of Chronic Urethritis. By Hugh H. Young, M. D. Treatment ot Stricture of the Urethra. By Hugh H. Yoono, M. D., and John T. Geraghtt, M. D. The Treatment of Impermeable Stricture of the Urethra. By Hugh H. Young. M. D. The Treatment of Bacterlurla by Internal Medication. By John W. Churchman. M. D. Use ot the Cystoscope In the Diagnosis ot Diseases ot the Prostate. Bv Hugh H. Y'oung, M. D. Chronic Prostatitis. An Analysis ot 358 Cases. Bv Hugh H. Young. M. D.. John T. Geraghty, M. D., and A. R. Stevens, M. D. Modern Method for the Performance of Perineal Lithotomy. By Hugh H. Young. M. D. Operative Treatment of Vesical Diverticula. Bv Hugh H. Young. M. D. Case of Double Renal Pelvis and Bifid Ureter, By Hugh II. Young, M. D. I'yonephrosis Due to Bacillus Typhosus. Bv Hugh H. Young, M. D., and Louis C. Lehr, M. D. The Use of the X-ray in the Diagnosis of Renal and Ureteral Calculi. Bv F. II. Baet.ier. M. D, Nephritis and H.-ematuria, By R. A. Fowler. M. D. The Microscopic Structure of Urinary Calculi ot Oxalate ot Lime. By II. A. FOWLER, M, D, Cystinuria with Formation of Calculi. By H, A, Fowler, M. D. Post-Traumatic Atrophy of the Testicle. By John W. Church.man, M. D. A Description of the Dispensary for Treatment of Genito-Urinarv Surgical Cases at The Johns Hopkins Hospital. By Hugh H. Young, M. D, Volume XIV. 632 pages, with 97 figiires. Studies in Genito-TJrinary Surgery. The Treatment of Prostatic Hypertrophy by Conservative Perineal Prostatectomy. An analysis of cases and results based on a detailed report of 14.5 cases. By Hugh II. Young, M. D. Recto-Urethral Fistulse. Description of New Procedures for their Prevention and Cure. By Hugh II. Young. M, D. The Early Diagnosis and Radical Cure of Carcinoma ot the Prostate, being a study of 40 cases and presentation of a radical operation which was carried out In four cases. By Hugh H. Young, M. D. Volume XV. 542 pages, with 87 illustrations. Twelve papers on pneumonia. By Drs. Chatard, Fabyan, Emerson, Marshall, McCeae. Steiner, Howard and Haines. A Study ot Diarrhoea In Children. By J, II. Mason Kso.k, Je., M. D., and EiiwiN II, Schorer. M. D. Skin Transplantation. By John Staigb Davis, M. D. Epidemic (jerebrospinal Meningitis and Serum Therapy at The Johns Hopkins Hospital. By Frank J. Sladen, M. D. Volume XVI. 670 pages with 151 figures. studies in the Experimental Production of Tuberculosis In the GenltoTlrinary Organs. By George Walker. M. D. The Effect on Breeding of the Removal of the Prostate Gland or ot the Vesiculie Seminales, or ot Both : together with Observations on the Condition ot the Testes after such Operations on White Rats. By George Walker. M. D. Scalping Accidents. By John Staige Davis. M. D. Obstruction ot the Inferior Vena Cava with a Report of Eighteen Cases. By J. Hall Pleasants, M, I), Physiological and Pharmacological Studies on Cardiac Tonicity in Mammals, By PERCIVAL Douglas Cameron, M. D. The set of sixteen volumes will be sold, bound in cloth, for ninety dollars, net. Volume II will not be sold separately. Volumes I, III, IV, V, VI, VII, VIII, X, XI, XII, XIII, XIV, XV, XVI will be sold for$5,00, net, bound in paper, and $5.50, net, bound in cloth. Volume IX will be sold for ten dollars, net. Orders should be addressed to The Johns Hopkins Press. Baltimore. Md. The Johns Hopkins Hospital Bulletins are issued monthly. They are printed by the LORD BALTIMORE rRESS, Baltimore. Subscriptions. .$3.00 a year {foreign postage, 50 cents), may be addressed to the publisher-t, THE JOHXS HOPKIXS PRESS, BALTIMORE; single copies will he sent by mail for fifty cents each. Single copiet may also be procured from the BALTIMORE KE]VS CO., Baltimore.

## Contents

Fluoroscopy of the Cerebral Ventricles. (Illustrated. t A Pliarmacological Appreciation of a BIhliral Reference to

By WAi.TtB E. Dandv J'J Mass Poisoning, 11 Kings IV, 3S-41. (Illustrated.)

Stereoroentgenogranis of tlie Injected Lung as an Aid to the B.v Uavid I. Maciit. A. B.. LL. B., M. D., F. S. .!.A. . 38 Study of the Lung Architecture. (Illustrated.)

By William Snow Miller 34 Titles of Papers Appearing Uurini; the Year. Elsewhere than in

An Electromyographic Study of Chorea. (Illustrated.) the Bulletin, by Present and Former Members of the Hos By Stanlet Cobb, M.D 35 pital and Medical School Staff 42

TITLES OF PAPERS APPEARING DURING THE YEAR. ELSEWHERE THAN IN THE BULLETIN, BY PRESENT AND FORMER MEMBERS OF THE HOSPITAL AND MEDICAL SCHOOL STAFF

Abel, J. J., and Pincoffs, M. C.

On the presence of albumoses in extracts of the posterior lobe of the hypophysis cerebri. — Utiid. Kockejeller Inst. M. Research, N. Y., 1918, x'xyiii, 193-203.

Atchley, D. W.

A study of eight cases of acute nephritis. — Arch. Int. ilcd.. Chicago, 1918, xxii. 370-408.

Renal action in acute nephritis. — Proc. Soc. Exper. Biol. A lied., X. Y., - 1917-18, XV, 85-88.

AUEB, J.

Generalized analgesia in cats after exposure to a war gas (CH3);S0,. — Proc. Exper. Biol, d Med., N. Y., 1918, xv, 104-106.

Localized pulmonary edema in cats after the inhalation of \yar gas I CH,)2S0,.— Ibid., 106-107.

AuEE, J., and Gates, F. L.

Experiments on the causation and amelioration of adrenalin in pulmonary edema. — Stud. Rocketeller Inst. M. Research, N. Y.. 1918, xxviii, 131-150.

AuER, J., and Kleixee, Isabel S.

Morphine hyperglycemia in dogs with experimental paucreatic deficiency. — J. Exper. M., Bait., 1918. xxvii, 49-03.

AuER, J., and Meltzer, S. J.

Lantern slide demonstration of the effect of magnesium sulphate upon tetanus. — Proc. Soc. Exper. Biol, d Med., N. Y., 191T-1S. xy. 36-37. The administration of epinephrin by intraspinal injections in acute or subchronic cases accompanied by a low blood pressure. — J. Am. M. .\ss., Chicago, 1918, Ixx, 70-71.

Baer, W. S.

Arthroplasty with the aid of animal membrane. — Am. J. Orthop. Surg.,

Host., 1918, xvi. 1-29: 94-115; 171-199.

Primary and delayed primary suture in the treatment of war fractures.

— Am. J. Orthop. Surg., Bost., 1918, xvi, 513-519.

Also: J. Am, M. Ass., Chicago, 1918, Ixx, 1530-1533.

Baetjer, F. H.

Differential diagnosis of bone tumors. — Am. J. Roentgenol., X. Y., 1918, y, 261-264.

Baetjer, W. A., and Miller, S. R.

Bence-Jones proteinuria : some observations on its occurrence, with particular reference to nephritis and hypertension. — J. Am. M. Ass., Chicago, 1918. Ixx, 137-139.

PoIIinosis or hay-fever : its specific treatment. — South. M. J. Birmingham, Ala., 1918, xi, 341-345.

Baetjer, W., Strong, R. P. let ah].

Report on progress of trench fever investigations. Trench Fever Commission of Medical Research Committee, American Reti Cross. — J. Am. M. Ass., Chicago, 1918. Ixx, 1597-1598.

Barker, L. F.

Heart murmurs. — Canada Lancet. Toronto, 1918, 11, 545-551. Endocrine functions and the digestive apparatus. — Med. d Surg., St. Louis, 1918, ii, 655-678.

The general diagnostic study by the internist. — -V. York M. J. [etc.], 1918, cvii. 489-493; 538-542; 577-582. Also: Med. Rec, N. Y., 1918, Nervous and mental symptoms in exophthalmic goiter. — J. Am. it. Ass., Chicago, 1918, Ixxi, 327-329.

The value of the classics as a part of the studies preparatory to medicine. — South. M. J., Birmingham. Ala., 1918. xi. 391-394. Address in Medicine. On the significance of " heart murmurs " that may be found on examination of candidates for military service. — Canad. M. Ass. J., Toronto. 1918, viii, 577-585.

Oral sepsis and the digestive apparatus. — South. M. J., Birmingham, -Ala., 1918. xi, 481-484. The first ten years of the National Committee for Mental Hygiene, with some comments on its future. — Ment. Hyg., Concord, N. H., 1918, ii. 557-581.

Barker, L. F., and Miller, S. R.

Perforating ulcer of the hard palate resembling tertiary syphilis. — J. Am. M. Ass., Chicago, 1918, Ixxi, 793-797.

Barker, L. P., and Rowntbee, L. G.

A report of a case of myrtol poisoning with comments upon the toxicity of eucalyptus oil and myrtoi in human beings and in animals. — Tr. Ass.

Am. Physicians, Phila., 1918, sxsiii.

Beall, K. H.

The diagnosis of nephritis. — Texas State J. M., Fort Worth. 1918, xiii. 349-351.

Berey, J. M.

Action of the gluteus maximus strain. — AZftonj/ if. Ann., 1918,

Blackfan, K. D.

-Midland M. J., Birmingham. 191S, xvii.

Blackfan, K. D., and Maxcy, K. F.

The intraperitoneal injection of saline solution. — Am. J. Dis. Cliild., Chicago, 1918, xy, 19-28.

Block, E. B.

The relation of oral sepsis to the nervous system. — South. If. ./., Birmingham, Ala., 1918, xi, 606-609.

Bloodgood, J. C.

Some hernias that disqualify for military service, whether operated on or not. — J. Am. M. Ass., Chicago, 1918. Ixx. 515. A warning against operations for varicocele on applicants for enlistment, registrants for the selective draft and soldiers. — J. Am. M. Ass.. Chicago, 1918, Ixx, 409.

Medical preparedness and medical and surgical problems in this war. — Penn. M. J.. Athens, Pa., 1918. xxi. 389-394.

Medical preparedness in the great drive for democracy. — South. M. J., Birmingham, Alabama, 1918, xi, 51-56.

Aluo: Muruland M. J.. Unit.. T.HS. Ul. 1-0.

.ll»o; J. Florida it. Ast., St. Augustlue & .IiKksonvlllc, 1918. Iv, 2.-5 How the iniliisirliil surgodii <'iin host co-operate with the GoTornniPut

ilurlog the war.--NoM/fc. M. ./., BlrmlnKhain, Ala.. 1918. xl. 45:t-4ri4.

The liiiportiince of recocnlzlng the weakness or the obllteralinn of the

ronjolneil temlon In operations for Infrulnal hernia. — South. H. ./..

BlrmlDKhnm, Alabama. 191S. il. 3e«S(i9.

AKo: ">»f. il. Kr<-.. Omaha. Neb.. 1918. xilll. SOl-.W".

Soldiers illsableil In the war. (Letter). — South, il. J., BirinlDgham.

Alabama. 1918. xl. r,-2i;X , „ ,

Some principles Involvlne the treatment of Infeeteil wounds. — ./. J/.rf.

At: Georgia. Augusta. 1918. vlll, 9-i:i.

Bloomfield, a.

Typhoid bacterlemla during the course of miliary tuberculosis. — .liii. Kei: Tuberc, Bait.. 191S. 11. 28-35.

Brem. W. v.. Rolling. G. E. and Caspee. E. J.

Pandemic Influenza and seiondarj- pneumonia at Camp Fremont. Calif. —J. Am. il. .!»».. Chicago, 191S. Ixxl. 21.38-2144.

Bribgman, E. W., and Hibose, K.

The effect of diuretics on the general blood pressure in animals with constriction of the renal arteries. — Arch. Int. Ued., Chicago, 1918. xxi. 3.-1-.3.J3.

Brooks. B.. and Allison, N.

Arthroplasty: exp<TimentaI and clinical methods. — Am. ./. ()ilhiii>. Surg.. Boston. 1918, xvi, 83-93.

Brooks. B.. ScmMAciiER. H. W., and Wattenbero, J. E.

Intestinal obstruction: an experimental study. — Anil. Surg., I'hilii.. 1918. IXTll. 210-214.

Bbowx, T. R.

studies on some unusual tvpes of diarrhea. — ilcd. d Surg., St. I^ouis. 1918. II. 640-«4.".

BiSTixG. C. H., Martin. H. G.. and Loeveniiabt. A. S.

The mori'hologlcal changes In the tissues of the rabbit as a result of reduced oxidation.—^, i'j-pcr. J/., Bait., 1918. xxvii, 399-412.

BlBNS, J. E.

The diagnosis and treatment of urlnarr Ilthlasls. — llVst Virg. it. J., Huntington. 191s. xli. 280-291.

BfBNs, J. E.. and Hopkins, P. B.

A comparative study of the effects of thorium and other substances on the renal parenchyma when retained.— >/. Vrol., Bait.. 1918. 11. 145-1.')9.

BiBBOws. M. T.

A note on the mechanism of heart muscle contractions. — J. ilisaouri if. Atf.. St. liOUis. 1918. XT, 13S.

Why should autopsies be held? The argument to be used with relatives and friends. — Interstate it. J., Chicago, 1918. xxv. 700-763.

Burrows, M. T., and Neyjiann, C. A.

Studies on the metiiboilsm of cells In vitro. The toxicity of ilipeptiils for embryonic chicken cells. — i'ror. .S'oc. ICrpcr. Hiol. it iled., .N. Y., 1918. XV. 1.38139.

Camac, C. N. B.

Clinical report upon cases of lobar pneumonia treated with nnti Sieumococcus serum as observed at general hospital no. 6. Fort cFherson. Georgia. October. 1917. to May, 1918.— .4m.. J. M. Sc, Phila.. 1918. civi. 887-893.

Cameron. D. F.

Aqueous solutions of potassium and sodium iodlds as opaque mediums in roentgenography. Preliminary re|)ort. — /. .l»i. il. Asa., Chicago. 1918. Ixx. 754-7.—I.

Camebon, D. F.. and Gbandy. C. C.

Sodium ami potassium Iodlds In roentgenographv.--./. .4m. .1/. Ana., Chicago. 1918, Ixx. 1,'.I0-1.J17.

Campbei.l, C. M.

The r<^le of Instinct, emotion and personalllv in disorders of the heart.

With suggi-sllons for a clinical record. — ./. Am. il. .4»«., Chicago, 1918.

Ixil. 1021 1020.

A city school district and its subnormal children: with a discussion

of some soilal pmlilems lnv(dved and suggestions for constructive

work. — ilrnl. Iliig.. Concorii. .\. II.. 1918. li. 232-244.

A case of chlldhond conflicts with prominent reference to the urinary

system: with 8<ime general considerations on urinary symptoms In the

psyrhonru roses and psychoses. — I'fuchoanalut. Her., Wash., 1918. v.

269 290.

Carter, E. P.

F^irther observations on the aberrant electrocardiogram associated with sclerosis of the atrioventricular buniile branches and their tenninal arborizations, rilnical and histologic report of a case in which such aberrant complexes were obtained. — Arch. Int. iled.. Chicago. 1918. xxil. 331 3.'-,3.

Carter, E. P. and Wedd. A. M.

Report of a case of paroxysmal taehycarilia characterized by unusual control of the fost rhythm. — Arch. Int. iled., Chicago, 1918, xxil, 571!)80.

Casler. DeW. B.

Tetanus fnllnwlng laparotomy for ectopic pregnancy. Treatment hr subarachnoid injections of magnesium sulphate and anll-tetonlc serum — recovery —.Voiil A. il. ./,. Birmingham. Alo.. 1918, il, .-,12 ..n;.

ider.- /ii; Hod. frol. (Cabot), 8°, Phila. Jt .V. Y. St. Uiuls

Cailk. J. R.

Infectious of the bla

1918. 11. 80-131.

The treatment of undescended testicle. — Interstate il.

1918. xxv. 2S.'.-2S0.

The diagnosis of diseases of the central nervous system by means

of the cystctscopic appearance of the bladder. — Interstate il. J.,

St. lyouis. 1918, xxv. 102-104.

Remarks on kidney surgery. — South, il. ./., Birmingham. .Ma.. 1918.

xi. 299-305.

Caclk, J. R., and Greoitzer, H. C.

Occluded renal tuberculosis, nutune])hrectomy. — iled. d Sun/., St. Louis. 1918. ii. 4:.3-450.

Cecil, A. B.

An unique type of urethral obstrucllou.384.

^/. t rol. Bait.. 1918. 11. 379

Eiper. il.. Bait..

Chesxey. a. II.. and CtLij^N, G. E.

A note on the production of acid l)y pneuiiuic 1918. .\xvlil, 289-29i;.

Chesxey, A. M., and Moore, H. P.

A further study of cthylhvdrocui>rein toptochini In the treatment of acute lobar pneumonia. — Arch. Int. iled., Chicago, 1918, xxi, 059-081.

Churchman, J. W.

Melanosnrcoma of the rectum, with the report of a case. — .4m. J. il. Sc., Phila.. 1918. dr. 039-044.

Treatment of acute infections of the joint bv lavage and direct meditation.—./. .4m. .U. .4«».. Chicago. 1!>I8. Ixx. 1047-10.')0. Fibroma of the tongue with consiileratlon of other tumors of the tongue anouis, 1918. ii. 173-177.

A new incision for exposure of the lower abdomen and pelvis. — .liin. Surg., Phila., 1918, Ixvil, 180-182.

Clakk. a. H.. and Feltox, L. D.

A flltrable toxic product of the hemolytic streptococcus. — J. .4m. il. Ass., Chicago. 1918. Ixxl. 1048-1049.

Clark, J. G.

Medical teaching and research nftiT tli< 1918. Ixxvlii. 220-2.30.

The therapeutic use of radium in gyncci Chicago. 1918. xxvi, 019-024.

Clarke, T. W.

The baby that •

war.— tm. J. Obtt., S. Y.. ilogy. — Surg. Oynec. d Obst.,

ininot take milk.— trcd. Pcdint., X. Y.. 1918, xxxv, 193

Clausen. S. W.

a method for the estimation of potassium in blood. — .1. Biol. Chem..

Bait., 191.S. xxxvi. 479-484.

The effect of injections of pituitary solution on (he urinary output in

a case of diabi'tes Insipidus.- .4 m. ./. Dis. Child., Chicago. 1918. xvi.

195-204.

Clausen. S. W.. and Mo.senthal, H. O.

The malntinance diet In diabetes meliitus as determined by the nitrogen equilibrium.— .Irc/i. Int. iled.. Chicago. 1918. xxl. 269-281.

Clausen, S. W., Mosentiial, H. O., and Hii.i.eb, Alma.

The effect of diet on blood sugar in eliabetis meliitus. — Arrh. Int. ilrd.. Chicago, 1918, xxl, 93-108.

Cobb, S.

A note on the supposed relation of the sympathetic nerves to dccere hrate rigidllv. muscle tone, and tendon reflexes. — .Im. J. Physiol. Bait.. 1918, xlvl, 478-482.

Cole, R.

I'revenllon of pneumonia. — J. Am. il. Ass., Chicago. 1918. Ixxl. (',3.-i

0.39.

Pneumonia as a public health problem. — Kentucky il. J., 1918. xvi.

563-505.

Cole. R., and MacCallum, W. G.

Pneumonia ut a base hospital. 1140-1 l.'.O.

CoxE, S. M. a methoil

42-43.

if studying nerv<

(^hlcago. 1918, ixx.

Im. ./. Orlhnp. Surg., Bost., 1918. xvi.

Some of the results of work on the pathology of peripheral nerve

Injuries- Im. ./. Orthop. Surg., UnDt.. 1918. xvi. 319.322.

Surgliiil pathology of the peripheral nerves. -Ilrit. .1. Surg . Bristol.

-mal nervi's and war injured nerves rath, d llaclcrlol, xxil, 1051 II.

1917 IV,

lllstolnglcal observations on

with the neurokeratin slain.

Corner. G. W.. and Ht bni. F. H.

The non effect of corpus iuleum preparations on the ovulation cycle of the rat.— .4m. ./. I'hysiol., Bait., 1918. xlvl. 48.3486.

Cusiiiso, H.

A study of a series of wounds Involving the brain and Its enveloping

structures.- /Ir(». -1. Surg., Bristol. 1917-18, v. 5.1«.«84.

Notes on penetrating wounds of the brain. — Brit. il. J., Ixinil.. 1918. I.

221-220.

Dandy, W. E.

Extiniallon of the choroid plexus of the lateral ventricles In eommunl.nilng h^dnM ephalu". -.Inn. Surg.. Phila.. 1918. Ixvili. .-,09 .'.79. Ventriculogrnpbv folbiwlng the injection of air Into the cerebral ventricles— . I nil". Surg., Phila.. 1918. Ixvlii. 5-11.

Davis, E. G.

Duodeno urptei-al fistiilii of spcmtanpoiis oriRin : report of a case. — J. Am. M. Ass.. Chicago. lOls. Ixx. ;;7(! ::7s.

Urinary antisepsis: a stiul.v of tlie antisi'ptic properties and the renal excretion of compounds related to phenolsulphonephthalein : preliminary report.— .7. Am. M. A.1S., Chicago, lOlS. lx.\, 581-585.

Davis, E. G., and Hain, R. F.

Urinary antisepsis. The antiseptic properties of normal dog urine. — J. Viol. Bait., 1918. ii, ;'.0S)-320.

Davis, E. G., and Harrell, B. E.

.Acriflavine in the treatment of gonorrhoea — an experimental and clinical study. — J. Urol., Bait.. 1918, ii, 257-27G.

Davis, E. G., and White, E. C.

Urinary antisepsis, further studies of the antiseptic properties and the renal excretion of compounds related to phenolsulphonphthalein. — J. Urol, Bait., 1918, ii. 107-127.

Urinary antisepsis. The secretion of antiseptic urine following the Intravenous administration of acriflavine and proflavine ; preliminary report. — J. Urol, Bait.. 1918. ii. 299-^07.

Davis, E. G., White, E. C, and Rosex, R.

Urinary antisepsis. The secretion of antiseptic urine following the intravenous administration of an organo-mercury phthalein derivative.—,/. Urol, Bait.. 1918. ii. 277-297.

Davis, E. G., and Young, H. H.

The surgery of the douhle kidney. Report of a case of resection of upper segment for calculous pyonephrosis. — Surg., Giincc. d Obst., Chicago, 1918, xxvii. 1-l.S.

Davis, J. S.

The use of the pedunculated flap in reconstructive surgery. — .liiii. Surg., Phila., 1918. Ixviii, 221-230.

Davison, W. C.

The superiority of inoculations with mixed triple vaccine (B. typhosus. B. paratyphosus A. and B. paratyphosus B. ) over successive inoculations with the single vaccines, as shown by agglutinin curves in men and rabbits. — Arch. Int. Med., Chicago. 1918, xxi. 437-509.

Dawson, P. M.

I'nlversity ideals Pa.. 1918. n. s..

Sci€7ice, y. Y. and Lancaster.

-,r. Am. If. .Iss.. Chicago,

ilf. Ass.. Chicago. 1918. Ixxi. 63S-G39.

Dick, Gladys H., and Murray, Eleanor. The morphology of the inlluenza bacillus 1918, Ixxi, 1568.

Dickson, E. C.

Botulism ; a further report of cases occurring In the Pacific Coast

States. — Arch. Int. lied., Chicago. 1918. xxii. 483-495.

Botulism. A clinical and experimental study. — Monogr. Rockefeller

Inst. it. Research, X. Y.. 1918. no. 8.

Botulism.— Bh//. Canadian Army M. Corps. 1918. i. 85-87.

Al.w: Canad. M. .4.i.s-. ,/., 1918, vill, 903-909.

Dickson, E. C, and Burke, G. E.

Botulism : a method of isolating Bacillus Botullnus from infected materials. — J. Am. M. Ass., Chicago, 1918, Ixxi. 518-521.

Felton, L. D., and Clark, A. H.

A Bltrable toxic product of the hemolytic streptococcus. — •/. .Im. J/. Ass., Chicago, 1918, Ixxi, 1048-1049.

Flexner, S.

Control of meningitis. — .7.

Dr. p-ranklln P. Mall ; an appreciation. — Science. N. Y. & Lancaster,

Pa.. 1918, n. s., xlvli. 249-2.54.

Flexner, S., and Awoss, H. L.

The passage of neutralizing substance from the blood into the cerelirospinal fluid in actively immunized monkeys. — J. Exper. M.. Bait.. 1918, xxvlii. 11-17.

FLEXNER, S., Amoss, H. L., and Eberson, F.

Physiological stimulation of the choroid plexus and experimeutal poliomyelitis. — J. Exper. M., Bait., 1918, xxvii. 679-687.

Flournoy, H.

Notes sur 4 cas d'obsessions et impulsions a debut instantan^. — ( Coinmunication a la Soci^te Medicate de Gen&ve), Geneve, 1918. Kiludig. 24 pp. 8°.

l.'alcoi.iismt' et les enfants anormaux. — Extrait du xiii rapport de la Soriet*^ g^uevoise de patronage des Alleu^s. 1918, 16 pp. 8"^.

Ford, W. W.

I'tirther observations on the bacteria of the intestinal tract. — Tr. Ass. Am. Physicians, Phila.. 1918, xxxlli.

Fowler, H. A.

Anatomy, anomalies and injuries of the penis. — In: Mod. Urol (Cabot), 8°, Phila. & N. Y., 1918, I. 193-222.

FroNTZ, W. A.

Presentation of device facilitating the introduction of the cystoscope in certain difficult cases. — J. Urol, Bait.. 1918. ii. 39-41.

Froxtz, W. a., and Geraghty, J. T.

A study of primary hydronephrosis. — .7. Urol. Bait.. 1918. ii. 161-209.

Futcher, T. B.

Chronic hypertrophic pulmonary osteo-arthropathy following bronchiectasis. — Bull. Canad. Army Med. Corps. 1918, i. 38-40.

Career, J. R.

.\ iilea for prenatal care and the end-results of the h.vgiene of pregnancy.— Am. J. Obst., N. Y., 1918, Ixxviii. 506-575.

-.7. Indiana M.

Mod. Urol (Cabot). 8°, Phila. & X. Y.. Mod. Urol (Cabot). 8". Phila. & X. Y.. Radium. Pittsburgh. Pa.,

Phila.. 1917-lS. ngham, Ala.. 1918. xi.

locytic leukemia.

Gatch, W. D.

Some observations on the surgerV of the thyroid gland. Ass., Fort Wayne. 1918, xi, 13-17.

Geraghty, J. T.

1918. ii. 187-244.

Tests of renal function

1918, Ii. 337-376.

The results of treatment of bladder tumor

1918. X, 77-85.

Geraghty, J. T., and Fbontz, W. A.

A study of primary hydronephrosis. — J. Urol, Bait.. 1918. ii. 101-209.

GiBBES, J. H.

Ilodgkin's disease; primary involvement of mediastinal glands with presentation of tumor mass over sternum. Blood-picture characteristic of well-advanced disease. Differential diagnosis. Etiology. Pathologic

anatomy. I'rognosis. Treatment. — Med. Clin *'

i. 1587-1594.

Oral sepsis an<l arthritis. — Sonth. M. ./.. Bii

489-492.

GiFFIN, H. Z.

Splenectomy following radium treatment fo Med. Rec, X. Y.. 1918, xciv, 1020-1023.

GiFFiN, H. Z., Sanford, a. H., and Szlapka, T. L.

Estimation of urobilin and urobilinogeu in the duodenal +++++ CONTENTSs. — Am. J, M. Sc. I'hila.. 1918, civ. 562-579.

GOETSCH, E.

-Vewer methods in the diagnosis of thyroid disorders : pathological and clinical. — .V. York State J. M., N. Y.. 1918, xvili. 239-207. Also: Clifton Med. Bull, Clifton Springs, 1918. 1-12.

GOLDBAOH, L. J.

Nasopharyngeal tibro-myxoma. undergoing sarcomatous changes. — Laryngoscope, St. Louis. 1918, xxyiii. 106-108.

GOODPASTURE, E. W.

An anatomical study of senescence iu dogs, with especial reference to the relation of cellular changes of age to tumors. — J. Med. Research, Bost., 1918. xxxviil. 127-190. Observations on mitochondria of tumors. — Ibid., 213-224.

Goodpa.sture, E. W., and Jacobson, V. C.

Occlusion of the entire inferior vena cava by hypernephronm. with thrombosis of the hepatic vein and its branches. — Arch. Int. M.. Chicago, 1918. xxii. 86-95.

GORHAM, L. W.

Xote on the diagnostic use of the X-ray in pneumonia, with especial reference to the position of the diaphragm. — .ilhany M. Ann., 1918. xxxix. 58-65.

.7. Physiol.

ulogy. — South. M. -/.. Birmingham.

eluding bands. —

Grey, E. G.

Observations on the postural activity of the sto Bait., 1918, xlv, 272-285.

Griffith, F. W.

Some of the common errors in gyne Ala.. 1918, xi. 40-42.

Gundrum, F. F.

Rat bite fever with report of two cases. — Calif. State J. M., San Fran..

1918, xvi, 16-18.

Nitro-benzol poisoning. — Calif. State J. M., San Fran.. 1918. xvi, 2o2

253.

Hain, R. F., and Davis, E. G.

Urinary antisepsis. The antiseptic properties of normal dog urine. — ,J. Urol. Bait.. 1918. ii. 309-320.

Halsted, W. S.

Dilation of the great arteries distal to partial

Proc. Nat. Acad. Si:. Bait.. 1918, iv, 204-210.

Cylindrical dilation of the common carotid artery following partial

occlusion of the innominate and ligation of the subclavian. — Tr. .im.

Surg. Ass.. Phila.. I'.US, xxxyi.

Ijetter to Dr. Keen. Communication on the subject of the Carrel Dakin treatment of wounds. In: Keen, \V. W. The treatment of war

wounds, Phila.. 2. ed.. 1918, 252-259.

Harrell, B. E., and Davis. E. G.

Acriflavine in the treatment of gonorrhoea — an experimeutal and clinical study. — •/. Urol Bait., 1918. ii. 257-276.

Harrop, G. a., and Mosexthal. H. 0.

The comparativi- food yalue of protein, fat and alcohol in diabetes mellitus as measur. d bv the nitro.cen equilibrium. — Arch. Int. .Med., Chicago. Iill8. xxii. 7.50-75S.

Hazex, H. H.

Syphilis and the war. — .4»i. ./. Syph., St. Louis. 191s

A more intensive form of arsphenamine therapy.

St. Louis. 1918, ii. 778-779.

More contract surgeons (Letter). — J. .\ni. M. Ass.

Ixx. 1184. „^„

Duties of the dermatologist. — J. Am. M. Ass.. Chicago. 1918. Ixx. 1989 1990.

Dermatology and the war. — Med. if- Surg., St. Louis, 1918. ii. 145-l,.l.

Hiller, Alma, Mosenthal, H. O., and Clausen, S. W. The effect of diet on blood sugar in diabetes mellitus. — Chicago, 1918, xxi, 93-108.

. 144 135. im. ./. Syph..

Chicago. 1918.

Arch. Int. Med..

Februabt, 1919]

45

Chi.ni:.!. 1!US. Ixxl.

Hl.NMAN, F.

Thi" nianagpiiicnt of siirKlcal risk: n review of 100 klilney iinil prostate 0[H>rations. auil 50 eases of enlnr^d prostate Dot operated iipou. — Call/. Stole J. M.. San Fran.. 1!>1S. xvl. 2tl-::i."i.

A niodlfleatlon of CltzmaDH's syringe for iMSterlor urethral Insilllatlons.^. Am. .U. .!»«.. Chicago. lOlS. \x\. l:;!>i.

His.MAN, F.. and Lissek H.

Srpbllls of the epliUil.rmls without Involvement of the testicle : Itcporl of cage.— .Im. .;. S„i>h.. St. Louis. 1018, II. 4»i.'>-471.

HlBSCIIFELDEB, A. D.

The leaching ni pharmacology. — ,/. Am Jl tiU'.l-tilL'.

HiRscHFELDER. A. D., and Caxtwei.i,, W.

KITiMts of sonic aminii acl.ls upon the e.\clse<l segments of Intestine. — J. Pharmntol. d f.'j-pcr. Thcrap.. Bait.. 1018. xl. ITS.

HrrzBOT, J. M.

The effect of spleneetomv on the normal Imllvhliial and In certain pathological eoDilltlons.—' .4nn. Hurg.. I'hlla.. 11118. Ixvll. .i4()-."in. Myeloma of the clavicle.— -Inn. b'urg., Thlla.. 1018. IxvUl. ICIM.

HoL.MES, J. B.

Keccnt work In anatomy, physiology and pathology of childhooil.- Am. ./. l>iH. Ihil.. ('hlcuga, IftlS. xv. L'78-308.

Hooker, D. R.

The veno-pre.

mechanism. — .liii. ./. I'hijHiol.. Bait.. lOlS. xlvl.

Hooker, D. R.. and Maciit. D. I.

Coueerning the action of the lodlile. bromide and nltnite Ions on the respiratory center. — ./. I'hnrmncol. A Expcr. Thcr<ii>.. 1018. xl. 113-G7.

HoPKixs, J. G., and Parker, Jilia T.

The effect of Injections of hemolytic streptococci on susceptible nnd insusceptible animals.—./. Exprr. J/.. Bait.. 1018. xxvU. 1-20.

Howard, C. P.

.Some of the medical lessons of the present war. — /. loira Sliitc U. .S'oc. Clinton. 1018. vlU. :t.-2.

Howard, C. P.. and I.ngvali>.sen-, T.

The mlm-ral metabolism of experimental s<urvy i<( thi- monkey. — L'vif. Iowa UonogrnphM, Studies In Med.. 1018. 1. 111).

Howard, C. P., and Steve.ns. F. A.

The Iron metabolism of hemochromatosis. — fiiir. loicii ilriHognipln-. Studies In Med.. 1018. 1. 1 IT.

Howell. W. H.

The coagulation of blood.— //nrrci; Lict.. lOli; IT. I'hila. & I,ond.. I'.Hs. JT2-:t2:t.

HowLAXD. J., and Marriott. W. M.

Ad.losls.— /'rnn. .1/. !.. Athens. I'a.. 101,8. xxl. 4i;0-4:!l!.

The Influence of a< Id phosphate on the elimination of ammonia hi I he

urini'.-.l rcA. Int. .Mrd.. Chicago. 1018. xxll. 4T7-48-.>.

Dbservatbms upon the calcium +++++ CONTENTS of the hlood In Infantile tetany

anil upon the effeil of treatment by calcium. — Quart. ./. .Med.. Oxford.

1018, xl. 280-tlO.

Hf.NXEB, G. L.

Anatomy, abnormalities. Injuries and diseases of the ureter. — In: .Mud.

I rol. (Cabotl. 8°. Phlla. & N. V., 1018. II. 24."i-:tll.

A rare type of bladder ulcer. Further notes, with a report of eighlicMi

cases. — /. .On. .1/. !»».. Chicago. 1018. \xx. 2();t 212.

Kluslve ulcer of the bladder. Further notes on a rare type of bladder

ulcer, with a reiiort of twenty-live cases. — Am. ./. Obxf., N. Y.. 101s.

ixxviii. :it4-:hi.-..

The etlologv of ureteral lalculus. — .S'lirtf. (Ifinrr. .{ olml.. Chicago. I'.ils. xxvll. 2.'>2-2Tn.

HtRWITZ, S. H.

The value of renal functional studies In the prognosis and Ireiiliinnt if nephritis.- f'liUf. State ./. U.. San Fran.. 1018, xvl. 28T-20:i.

HtRWITZ, S. H.. and Falconer, E. H.

The %nlue of Unehtgen rays and benxene In the treatment of poly cythemla vera. — /. Am. .M. Afn., Chicago. 1018. Ixx. 114:!lU.-i.

HtRwiT7, S. H.. Meyer, K. F.. and Tacssio, L.

Studies on the Mooil proteins. III. Alliumln-globulln rallo In anillnxli Immunity. — /. Infrrl. /ii«.. Chicago. I'.ils. xxll. 1-2T.

.Iack, W. D., and Balleiil, L. C.

The use of fascial transplants in war surgery. — -.Inii. Sinu . I'bll.i . 1018, IxvlU. 14.

Jaxe>vay, T. C. Richardson, H. B., and Park, E. A.

Kiperlmenis on the vasoconstrictor action of blood serum. — In/i fi;(. -Ved.. Chicago, 1018. xxl. .-.tl.'i-l!o:<.

Keidel, A.

rorasltologv anil serologv of syphilis. — .tin. ./. Suph.. St. I.<iuls. IOI>. II. 2Tii.2.sT. I No; South. .1/. ./., Birmingham. Ala.. 1018. xl. 2117 2T1.

Keidel, A., and Zim.mermann, E. L.

Tattooing and syphilis.— .tm. J. Spph.. St. Louis. 1018. I. 8.1. 00.

Keith, N. M.. and Thomson, W. W. D.

War nephritis, a clinical, functional, and pathological study. — (jiinri t. Sled., Oxford. 1018. xl. 220-200.

Kelly, H. A.

Fibroid tumors of the uterus treated with radium. — Charlotte |.V. f'.j

.U. ./.. 1018. Ixxvll. l.'i.-il.'lT.

Fibroid tumors and radium. — Virginia J/. Slonth.. Kichmouil. Va..

lOLs. xlv. IT,

Two hundn-d and ten fibroid tumors treated by radium. — 7'r. Am.

Olinrr. Soe.. rhila.. 1018. x||||.

The.Hlore Caldwell Janewav. 18T2-101T. — lloiton \l. Jt S. J.. 1018.

clxxlx. .-.'.iT-.-iO'l,

.loseph Trice. 18.-.:t-inil.— «o«foii, if. rf S. J.. 1018. dxxlx. 081-084.

.lohn llerr Miisser. 18.'i0-1012.— «osf. U. <t S. ./., 1018. clxxlx. 7T2.

lir. Kec nieillcal research. — Nciciicc. X. Y. & l.<incaster. Ta.. 1018.

n. s.. xlvli. 41!i.

Kempf, E. J.

Social and sexual behavior of monkeys with some comparable facts in human sexual behavior. — lAbstr.) Am. J. I rol.. .\. Y., 1018. xlv, 82-80.

Kino, J. T.

.\uscultation of pnlmonary apices in young men. — Mil. Surg.. Wash., lois. xlll. ou r,.-.

Knox, J. H. M.

.Vjnericas debt In Iranci. -.1 m. ./. /»i«. Child.. Chicago. 1018. xvl, 212

Kracse, a. K.

Itest.— .Im. Iter. Tuhrrc. Halt.. 1018. I. 080-082.

Klenientarv concepts of tuberculosis.— .4m. Urr. Tuberc.. Ball.. 1018.

il. o:t-Ti.

I'redlsposllliin. < IMltorial.l— Im. Rer. Tubere.. Bait.. 1018, II. 43-48.

Tobacco smoke and pulmonarv tuberculosis. (Kdltorlal.) — .4in. Ker.

Tnlnre.. Hall.. 1018. II. OO-lO.-i.

Autlliiberculosls measures.— .4m. Her. Tubere.. Bait.. 1018, II. 037-0.":;.

Fssays on tuberculosis :

1. Before the tiitiercle bacillus.

2. Before Itobert Koch.

(. Hubert Koch.

4. The tubercle bacillus.

.'•. Infection: Introdiulory considerations.

0. Sources of infection : Cornels theory of dust Infection.

T. Infeclioii by inhalation : Fliigge's theory of droplet Infection.

8. Infection by Ingestion: part one.

!i. Infection by ingeslion : part two: the lirst experiments.

10. Infection by Ingestion: I'urt three: The occurrence of iMVlne bacilli in man.

11. Infection: special characteristics of tuberculous infection.

— /. Outdoor l.i/e. N. Y.. 1018. xv. 1-0: 30-41: fl.->-73 : 80; 101 100: 120: 1201.17: 1031CO: 100.204.

— ./. Outdoor Lite. X. Y.. 1018. xv. 22ij-2:{0 : 24fl-2.'>0 : 20n-27.'i :

20."i-3OO.

^/. Oufrfooi- Life. X. Y.. 1018. xv, .{27-320: 342-344: :i03-:!fl7 :

374.

Lange, Linda B.

The complement Hxatlon test for tuberculosis.— Iwi. Iter. Tubere.. Bait.. 1018. II. .-.41 ..4.".

Lawrence. J. S.

.\ studv of the aerobic bacteria found In wounds received on the batllellelil o^ the Somme.— i/iJ. Surgeon, Wash.. 1018. xlll, 140-1.13.

Levy. R. L.

The effect of thvrold secretion on the excitability of the endings of the cardiac vagus. — .4rr)i. Int. Ued.. Chicago. 1018, xxl. 203-208.

Levy. R. L., and Alexander, H. L.

The predisposition of streptococcus carriers to the compllcatlonH of measles. Uesults of separation of carriers from non-carriers at a hniie hospital.^/. .Im. .1/. Axu., Chicago. 1018. Ixx. IN2T I8:io,

Lis.'iER. H.

Svphllls of Ibe lung.— Im. ./. il.'Se.. I'hila.. liils. civ. :i.-.0-380.

The prevention of congenital svphllls by aullluellc prenatal Iberapy. Cnli). state .1 . M.. .San Fran.. 1018. xvl, 384:t88,

A not 1 the use of corpus luteum to prevent the palurul breasts

of menstruation. — F,ndoerinolog)i . (llendale. Cal.. lois. II. 12 l.^i.

L18SER, H., and Hin.max, F.

Svphllls of ihc cpl.lldvmls without Involvement of the lesllde: Keport of case.— Im. ./. s,iph.. SI. Louis. 1018. II. 40.% 4T1.

LoEVEXHART, A. S., BiNTiNo, C. H., and Martin. H. O.

The morphological changes In the tissues of the rabbll as a result of reduced oxidation.- ./. Kxper. J/.. Bull., 1018. xxvll. 3011 412.

Lyman, D. R.

The control of the careless consumptive.— Ira. Iter. Tubere.. Bait.. 1018. II. 30-42.

Following up the discharged sanatorium palleiit.- Im Her. fulirre.. Ball.. 1018. 11. 01.-, (121.

MacCalli M, W. G.

I'albologv of the epidemic Hireptococcnl bronchopneumonia In lb.' army camps.—:/. Im. M. Am.. Chicago, 1018, Ixxl. 704-707.

MacCalli M, W. G., and Cole. R.

I'neumonia at a base hospital.-^/. .Im. M An,.. Chicago. 1018. In, 1140.I1.-.0.

McCli RE, W. B., and Sai er. L. W.

Observations regarding Ihi' loss of water vapor through the skin In Infants.- Irr/i. Int. Sled . Chicago. 1018. xxl. 428-430.

MiCrae, T.

Tuberculosis am

iddler. — .Im. He

Ball.. lOIM. II. 372

46

[No. 336

Macht, D. I.

Jewish food problems. — Jenish Forum, 1918, Nosi, l-U. A case of aspirin habit.— J/ed. Hec N. \. 1918. xciv, 't"- ,„,„.,„.,,

On the absorption of apomorphm and morphin through "uiji"-" channels.— Fcoc. 8oe. Exper. Biol. <C Med N Y., 191 --18, ^,y-,-^-- ' ,, On the comparative absorptive power for drugs of the bbuUler and urethra (male). — Proc. Soc. Exper. Biol. <C Med., N. \., lUli-lb. xv,

On the relation of the chemical structure of the opium alkaloids to their effect on smooth muscle and on the discoveiy of a new thHrapeutic a°ent as a consequence thereof. — Proc. Soc. Exper. Btol. d Med., >. 1.. 1§18. XV. 63-66. , ^ r ..t • 11 i,;,u On the relation between the chemical structure of the opium alkalouis. and their physiological action on smooth muscle with a pharm.iiological and therapeutic study of some benzyl esters : I. On the relation of the chemical structure of the opium alkaloids to their action on smooth muscle. II. A pharmacological and therapeutic study of some benzyl esters. — J. Pharmacol, d Eiper. Tlierap., Bait., 1918, xi, 389417 ' 419-446 .

On the absorption of drugs and poisons from the bladder and the urethra : I. Absorption of apomorphin and morphin. II. Absorption of various alkaloids, antiseptics, local anesthetics and salts. — J. L rol.. Bait, 1918, 11, 43-49 ; 211-226. ,, ., „ x- v ims

On parotitis as a complication of influenza. — Mca. Hec, .^. i.. iJis, xciv, 1117.

Macht, D. I., and Hooker, D. R.

Concerning the action of the iodide, bromide and nitrate ions on the respiratory center. — J. Pharmacol, d- Exper. Thernp.. Bait., l.ilS, si, 63-67.

Macht, D. I., Isaacs, S., and Gbeexberg, J. P.

On the influence of some opiates and antipyretics on the field of vision —Proc. Soc. Exper. Biol, d Med., N. Y.. 1917-18, xv. 4b-4S. On the influence of some antipyretics on the neuromuscular coordination test of •' tapping." — Proc. Soc. Exper. Biol, d Med., N. \., 191(18, XV, 61-62.

OS M. Soc, Topeka, 1918, Gynec. <f Obst., Chicago.

the presence of the meningococcus in the blood, birago, 1918, xxiii. 470-474.

Major, R. H.

Importance of focal infection in diseases of obi Herald, St. .Toseph. 1918, xxxvii, 159-163. Uremic ulceration of the intestine. — J. Kai xvlii, 136.

A study of the Krukenberg tumor. — Surg 1918, xxvii, 193-204.

Major, R. H., and Black, D. R.

A huge hemangioma of the liver associated with heniangiomata of the skull and bilateral cystic adrenals. — .Iwi. J. M. Sc. Thila., 1918, clvi, 469-483.

Marriott, W. M., and Howland, J.

The influence of acid phosphate on the elimin.ntion of ammonia in the urine. — Arch. Int. Med., Chicago, 1918, xxii, 477-482. Acidosis. — Penn. M. J., Athens, Pa., 1918, xxi, 429-436. Observations upon the calcium +++++ CONTENTS of the blood in infantile tetany and upon the effect of treatment by calcium. — Quart. J. Med., Oxford, 1918, xi. 289-319.

Marriott, W. M., and Sissos, W. R.

Variations in the lipoid ("tat") +++++ CONTENTS of the blood of infants under certain nutritional conditions. — ^iii. J. Dis. Child., Chicago, 1918, xvi, 75-82.

Marshall, H. W.

Structural deformities versus functional efficiencies as objects of treatments —BosfoH M. & 8. J., 1918, clxxviii, 708-712.

Revised ideas concerning toot defects and orthopedic footwear. — Boston M. d S. J., 1918, clxxviii, 428-432.

Maxcy, K. F.

Observations J. Infect. Di.

Maxcy, K. P., and Blackfax, K. D. The intraperitoneal injection of salin Chicago, 1918, xv, 19-28.

Mendenhall, Dorothy R.

Milk, the indispensable food for children. — T". S. Dept. I,abor. Children's Bureau. Care of Children Ser. No. 4, Bureau I'ubl., No. 3.i, Wash., Gov't I'rintlng Off., 1918.

Meyer, A.

Modern views and propositions on enforced treatment of mental diseases. — Maryland Psychiat. Q., Bait., 1918. vii. The mental hygiene movement.632-634.

Meter, A. W.

To Franklin Paine Mall. Ave Magister ! — Johns Hopkins Alumni May..

Bait., 1918, vi. 140.

Some observations on megacytes in lymphatic tissues. — Am. J. Anat.,

Bait.. 1918, xxiv, 91-104.

Studies on hemal nodes : VIII. The absence of hemal nodes in the

domestic pig. — Am. ./. Anat., Bait., 1918, xxiv, 109-120.

Miller, S. R., and Baetjeb, W. A.

Pollinosis or hay-fever: its specific treatment. — South. M. J., Biimiughani. Ala.. 1918. xi. 341-345.

Bence-.Tones proteinuria ; some observations on its occurrence, with particular reference to nephritis and hypertension. — J. .im. M. Ass.. Chicago, 1918, Ixx, 137-139.

Miller, S. R., and Barker, L. F.

Perforating ulcer of the hard palate resembling tertiary syphilis. — J. Am. M. Ass., Chicago, 1918, Ixxi, 793-707.

Miller, W. S.

A study of the nerves and ganglia of the lung in a case of pulmonary tuberculosis.— Am. Rev. Tuberc, Bait.. 1917-18, i, 123-139.

solution. — Am.

Vhild.,

-banad. M. Ass. J., Toronto, 1918, vlil.

Mills, C. W., and Hendersox, J. T.

The effect of pulmonary tuberculosis on renal function. — -4m. Aei;. Tuberc, Bait.. 1917-18, i, 573-597.

Mllls, C. W., and Forster, A. M.

The treatment of laryngeal tuberculosis by reflected condensed sunlight.— -Vat. Ass. Study d Prev. Tuberc, Tr., 1918, xiv.

Mills, R. G. . ,. , u h,

.lapanese medical literature. Review of current Pf^^'o^'cals by the staff of the research department. Severance t nion Medical College. Seoul. Korea.— Chino M. J., Shanghai, 1918, xxxu, 49-6o , 2o6--bi . An'^unSsuarcaseof double carcinoma with extreme resistance to one and death from the effects of the other.— C7mia M. J., Shanghai, 1918. xxxii.

Mills, R. G., Ludlow, A. I., and Vax Biskirk, J. D.

A simple method of water purification tor itinerant missions other travellers.— CftiJiO M. J., Shanghai. 1918, xxxu,, 13.-14o.

'^Pathologic hemorrhage. A group of cases illustrating this condition with a note on the early diagnosis of pernicious anemia.— Metf. tlni. X. Am., Phila., 1918, i, 1102-1124.

MixoT, G. R., and Loeb, R. F. „ , ,/ .

An attempt to prevent influenza at Harvard College.— Boston if. cCS. J., 1918, clxxix, 665-669.

ries and

-Surg.

' ""p^^mature separation of the .norm.allv implanted placenta. Oynec. Ob.it., Chicago, 1918, xxvi. 133-138.

Morris, R. S., and Friedlaxder, A. . ,. - i,- ,„

The significance of presystolic thrill in the examination of soldieis.— J. Am. M. Ass., Chicago, 1918, Ixxi, 3.o-3(i.

^"'RenaTJ'unf.^io^- as measured by the elimination of,^fl"^;^|- /"J^ ?nd nitrogen, and the specific gravity of the tivine. H- !«« ejie" -if, inS low and normal diets.— .Ircft. Int. Med. (^^^'^"SO. l^H-J^"- '-O^SO^,War nephritis, by P Ameiiille ..Transl. from the French by H. t. Mosenthal.— J^. Urol., Bait., 1918, ii, d1-106.

Mosexthal, H. O., and Clausex, S. W. • , k h, „»,„

The maintenance diet in diabetes mellitus as determined by the nltiogen eQuilihrium.— .liTji. Int. Med., Chicago, 1918. xxi, 269--S1.

MO.SEXTHAL, H. O., ClAUSEX, S. W and HiLLER ALMA

The effect of diet on blood sugar in diabetes mellitus.— lif/i. /»' Mca.. Chicago, 1918, xxi, 93-108.

MOSEXTHAL, H. 0., and Harrop, G. A. , , ^,. ,:,,„.„- „,pi

The comparative food value of protein, f«^-XV'^» ™h" ' 'l'-'"';** f"^'" litus as measured by the nitrogen equilibrium.— .liOi. Int. ilea., Chicago, 1918, xxii, 750-758.

Neymaxx, C. a., and Burrows, M. T. . . ^ ,- . ,

studies on the metabolism of cells i""", ,, The toxicity of dipept.d, for embryonic chicken cells.— Proc. Soc. Lxpc. Biol, d ilea., -n. i., 1918, XV, 138-139.

-Ann. Surg.. Phila.. 191S. Ixvii,

Nrsox, P. I.

Inflammatory tumors of the abdoinen.306-311.

Infantilism and other hypoplastic conditions of the uterus.—/. Am. M. Ass., Chicago, 1918, Ixxi. 1101-1107.

^'rhe^ pathological effects of Phthirus pubis.— Porasitoioffi/, London. 1918. X. 375-379. .^ , , j i oi c ., -ja^ jn".

The biology of Phthirus pubis.— Pai-asi<o7off!/, Lond., 1918, x, 3S3-4Uo.

War-time problems of the nursing profession. — lohns Hopkins .\uises Alumna: Mag., Bait., 1918, xvii, 93-100.

Opie. E. L., Baetjer, W. [et all. . ^. ,^ . „ ^^^

Report on progress of trench fever investigations. Trench lever Commission of Medical Research Committee, American Red Cross.— J. Am. M. Ass., Chicago, 1918. Ixx. 159i-lo98.

Opie, E. L., and Wobus, R. E.

Elephantiasis : report of a case.9S7.

OsLER, Sir W. ,„,„ • -^i -..

Typhoid spine.— B"». Canadian Army M. lorps l^l;^- i- 'S.;-'Graduated exercise in prognosis. — Lancet, ixinii., i.iis. i, -oi. The rimary examination for the F R. C. S. Eng. ; an appeal to the President of the Royal College of Surgeons.— Lancet, Lond.. 191S, i.

Medicine in America (Speech to University Extension Stiidents, summer meeting at Cambridge).- The Hospital, Lond., 1918, Ixiv, 43o.

The utility of artificial pneumothorax in the treatment of phthisis. — Canada Lancet, Toronto, 1918-19, Hi, 64- 1 2.

P\rk, E. a., Jaxeway, T. C, and Richabdsox, H. B.

Experiments on the vasoconstrictor action of blood serum.— 4rc/i. Int. Med.. Chicago, 1918, xxi, 565-603.

Patox, S. ,.,.,,,

Effects of low oxygen pressure on the personality ot the aviator. J Am. M. Ass., Chicago, 1918, Ixxi, 1399-1400.

Am. M. Ass.. Chicago. 1918. Ixx.

Februakt, 1919]

47

Peabody, F. W.

Ciinliuc ilfspnea.— Jm. J. J/. iV., Phlln.. 1918. civ. 100117.

Cardiac dyspnea. — Harvey Led., 1910-17. Phlla. 4 lA>nd.. lOlS, 24S •J71.

Peabody, F. W., Clovgu, H. A., Stubgis, C. C. {ft al.\ Effects of tbo Injection of eplnepbrln In soldiers with " irritable heart." rrelimlnary report. — J. Am. J/. Aat., Chicago, 1918, Ixxl, 1912-1913.

Peabce, Louise, and Bbowx, W. H.

Kxporiiiioutnl ir.vp;iutiiioiiii:isis : its application in chemotberapeiitkInvestlgations. — J. Exper. 11., Bait., 1918, IxviU, 109-147.

Pesbose, C. a.

Plaooemeyeb, H. W.

Kadicnl treatment for veslco-vaginal flstuln. — Grate Hasp. Bull.. Detroit. 191718. 11. 17-19.

QUINBY. W. C.

Anatomy and pbTsiolog; of the cidney. — In: Hod. fro/. (Cabot), 8°.

r-bila. & N. Y.. lins. 11. 312-3.-16.

Anutumv and phvslologv of the prost;ite and seminal vesicles. — In:

Mod. Int. (CalMiti. S . Phlla. Jt N. Y.. 1918. 1, 541-552.

The treatment of genital tuberculosis in the male. — J. Am. if. Ass..

Chicago. 1918. Ixxl. 1790-179G.

Richaedsox, E. H.

Note on saphenous varljt simulating a femoral hernia. — Ann. Surg.,

Phlla.. 1918. Iivll. 471-472.

Interpretation of lumbo-SJicral backache in women. — South, if. J.,

Birmlngliam. Ala.. 1918. xi. 139-144.

The effect of hysterectomy upon ovarian function. — Tr. Am. Oynec.

Soc, I'hila.. 1918. xliii.

Richardson, H. B., Jaxeway, T. C, and Pabk, E. A.

Experiments on the vasoconstrictor action of blood serum. — Arch. Int. Hcd., Chicago. 1918. xil. 565-003.

Roses, R., Davis, E. G., and White, E. C.

Urinary antisepsis. The secretion of antiseptic urine following the intravenous administration of an organo-mercury phthaleln derivative. — J. Crol., Bait.. 1918. II, 277-307.

Rocs, P.

Method for Intravenous Injection of guinea pigs. — ./. Exper. it.. Bait .

191, <(, xivll. 4.->9-462.

I'rinary slilcmsls. Hemosiderin granules In the urine as an aid In

the diagnosis, of pernicious anemia, hemochromatosis, and other dis

eases causing slilerosis of the kidney. — J. Exper. if.. Bait., 1918. xxvlil.

645-659.

Rovs, P.. and Olheb, J.

Experimental hemochromatosis 644.

Exper. if., Bait.. 1918, xxvlil, 02;

Rois, P.. and Robebtso.n, O. H.

Free antigen and antibody circulating together in large amounts (hemagglutinin and agglutinogen In the blood of transfused rabbits). — J. Exper. .1/.. Halt., r.iis. xxvli. 509-517.

Autobemagglutluutlun experimentally Induced by the repeated withdrawal of blood— J. Exper. J/., Ball., 1918. xxvll. 563-508.

Roi s. P., and Wilson, G. W.

hiuld substitutes for transfusion after hemorrhage; first communica tion. — J. Am. it. Aat., Chicago, 1918, Ixx, 219-222.

Rowxtree, L. G.

Syphilis in its medical its general, and its sociological aspects — Therap. Qai., Detroit, 15»1S, n. s., xxxTiti, 222-225.

Row-ntbee, L. G., and Bakker. L. F.

a report of a case of myrtol poisoning with comments upon the toxlcltv of eucalyptus oil and myrtol In human beings and In animals. — Tr. Alt. Am. Phyticiant, I'hila., 1918, xxxlli.

Rl'SIIMORE, S.

Progress In gynecology. — Boston if. <f S. J., 1918, clxxviil, 633-539.

Sabix, Fi.OBExrE R.

Franklin Paine Stall: a review of bis scientific achievement. — Science, N. Y. & Lancaster, Pa., 1918. n. s., xivll, 254-261.

Sampson. J. A.

The escape of foreign material from the uterine cavity into the nl.Tlii.veins.— .tm. J. Obst., N. Y., 1918, Ixxvlii, 161-175.

SeM-ards, a. W.

Viii. Ill- .lis. nrery and associated conditions. — ifed. Clin, X. Am.. Phlln.. 1141.

• if tropical sunlight with special reference to phot"

— J. Hcd. Research, Bost.. 1918. xxxvlll, 293-334.

•n of dilute sodium hydroxld on certain races of the pri, ,11,,,,, .„ , ,i.._v. .4m. .If. Ass.. Chicago. 1918. Ixxl. 1301-1.303. The treatment of amcrblc dysenterv with chaparro amargosa casli'ln nicholsonl. — J. Pharmacol, rf Exper. Therap., Bait, 1918. xl, 331.

Sellabds. a. W.. Spooseb, L. H., and Wyman. J. H.

Serum treatment of type I pneumonia. — J. Am. if. Ass., Chicago. 19I.K Ixxl. 1310 IMll.

Sharpe. W.

Diagnosis and treatment of brain Injuries with or without fracture of

the skull.— .4m. ./. Surg., X. Y.. inis. ixxll. 109-114.

The operativ., treatment of trifacial neuralgia. — Ann. Surg., Phlla..

19IS. Iivill. .".71-.T7S.

Kecent advances In neurological surgery and especially in the diagnos!"

and treatment of brain Injuries— CJiorfoMc (.V. CI If. J., Ixxvll. 2.T1

erlpheral facial

the time of labor. — Am. J. Obst..

Operative treatment In selected cases of chronic perl paralysis. — J. Am. it. Ans., Chicago. 1918. Ixx. 13541357. Recent advances In the surgery of the brain and spinal cord.— ./ourriar. I.ancct. .Minneapolis. 1918. xxxvlll, 313-318.

Fractures of the skull : the resulting intracranial pathology and the treatment.— .»/cd. rf Surg.. St. Ixiuis. Mo., 1918, 11. 319-333 Observations regarding neurological surgerv. and especially the diagnosis and treatjnent of brain injuries. — J. Tenn. if. Ass., .Nashville.

Observations regarding the iliagnosis and treatment of brain Injuries with or without a fracture of the skull. .l/iiiiir»«f<i I/.. I'MS. I. ;;n,-, SlMON, C. E.

A manual of clinical diagnosis by means of laboratory methods. — 9. ed.. Phlla. & Lond.. 1918. Lea & Feblger. 851. p. 80. The probable association of amino-aciduria with Bence- Jones |iroteinurla. — J. Am. it. Ass., Chicago, 1918, Ixx, 224.

SiSSOX, W. R.

A critical review of intestinal bacteriology in relation to certain diarrheas of infants.- f<o»(on if. rf ,S. J., 1918. clxxviil. 492-408.

Sissox, W. R., and Mabriott, W. M.

Variations in the lipoid ("fat") +++++ CONTENTS of the blood of Infants under certain nutritional conditions. — .4m. J. Dtt. Child.. Chicago, 1918 xvl 75-82.

Sladex, F. J., and Friedlandeb, A. [et al].

The epidemic of Influeniia at Camp Sherman, Ohio. — J. Am. i/. .4<r».. Chicago. 1918. Ixxl. 1052-1650.

Slemons, J. M.

The significance of fever 1918. Ixxvlii. 321-328. Analysis of the blood In 06sf.. N. Y.. 1918. Ixxvll.

S.MITII. W. H.

How nurses are meeting the present needs. — Im. ,/. Surging. Uorhester.

N. Y.. 1917-1918, xvlll. 979-989.

The civil hospital ami its duties in war time. lAbstr.l. — Trained

Xurse [etc.), N. Y.. 1918. Ix. 1315.

Medical aspects of the war. — Johns Hopkins Alumni Hag., Bait., 191S

vl, 348-307.

Some ospects of the nrognim of the medical department of the armv

and their effect on civil hospitals. — ifod. Hasp., St. Louis. 1918 xl

334-330.

Si'EBBY, J. A.

Results following operative treatment of pelvic inflammatory tilsea«e in the Standford University Clinic. — Calil. State J. .»., San Fran 1918 xvl, 388-390.

Stevens, A. R.. and Petebs, J. P., Jb.

A study lu war nephritis; a new condition associated with henior rhages in the bladiler wall and urinary symptoms: prellminarv report.^T/. Im. J/. Ass., Chicago. 1918. Ixx. 1760-1703.

Stboxo, R. p.

Etiidogy and method of tninsmlssion of trench fever. — Bull Arad dc it(d. Par., 1918. 3. s, Ixx.

Stboxo, R. P.. Swift, H. F. fef at].

Trench fever. Report of Commission Medical Research Committee. American Red Cross. [London], 1918. Ox/ord Vnirersity Press, 446.

Report on progress of trench fever Investigations. Trench Fever Commission of Medical Research Committee, .\merlcan Red Cross. — J 4m if. Ats., Chicago. 191S. ixx. 1597-159S.

Report on progress of trench fever Invesllgations of Trench Fever Commission of Medical Research Committee. American Red Cross. — ifrd ItuU. Par.. 191,s. I, 370-383.

Strovse, S.

.Juvenile diabetes in twins, (he Karell treatment of edema. The Importance of details In the treatment of angina pectoris. — .Ifrd. VUn. X. Am., Phila., 1917-18. I. 12411259.

Stbouse. S., and Bi.ocii, L.

Notes on the present epiilenilc of respinitorv disease. -./. .Im. Jf. .4»» Chicago. 1918. Ixxl. l.')08 1571.

Tiieoiiai.d. S.

Chief function of oblique tnuscles of the 1918. xil. 57.59.

VoKGTLix, C, and Mvkiis. C. N.

Phosphorus as an lnc|lcator of the vitamin

-iird .standard. Chic

+++++ CONTENTS of corn and

products. -/'Mil. Health Itep., Wash., 1918. xxzlll. 911-911 Wabfield, L. M.

vilhout acute onset. — J. Am. .If. Ass..

Chronic emiocardltis ' I91S. Ixxl. 970!iil. The eti..li>gy of nrlerlo III. 115<11i. I.<ictosurla : case pn-f ronsln it. J., 1917IS,

onset. clerosls.-^f. fall, rf fl(»i. .v., St. IjO\i\». 1917-18. nting unusual fentiiri's. cllnlrni n-porl. — Mis

Warfield. L. M.. and Smith. F. M.

Studies on Irritable heart; preliminary report. Chicago. 1918. Ixxl. 1815-1816.

Watson. E. M.

The development of the semlDit T(»IcIp(i In man.— xxlv. 305-435

wl.. 191 s bacilli ill

conslileralli.n of th<- methods for di'moiislrnilng tubercle the urin.-.— .4m. J. .W. Sr , Phlla.. lOIS elvl, 6.36-643. Xoten iin the recognition of certain le»ions of the male bladder. -.4nn Hurg.. Phlla., 1018. Ixvil. 06102.

The human seminal vesicles at birth, with observations on their fetal development. — Ann. Surg., Phila., 1918, Ixviii, 416-419. Also: Tr. . Hect. Oenito-Urin. Dts. Am. M. Ass., Chicago, 1918, Ixix. The essentials of success in prostatic surgery. — Canad. M. Ass. J., Toronto, 1918, viii, 327-332.

The place of Intraspinal therapy in urology. — J. Am. M. Ass., Chicago, 1918, Ixx, 296-300. ,

The developmental stages of the human seminal vesicles. — J. Urol,, Bait., 1918, ii, 129-139. '<

The structure of the verumontanum — a study of the origin and devel- • opment of its inherent glandular elements. — J. Urol., Bait., 1918, ii,(f 337-351. j;

Watts, S. H.

.\cute and subacute pancreatitis. Report of seven cases. — Ann. Surg., I'hila., 1918, Ixvii, 278-292.

The treatment of certain forms of subacute pancreatitis. — Surg., Oynec. d out., Chicago, 1918, xxvii, 286-288.

Weeb, C. W.

Surgical treatment of goiter. — N. York State J. il., N. Y., 1918, xviii, 272-278. Also: Clifton Med. Bull., Clifton Springs, 1918, 12-18.

Welch, W. H.

Letter to S. Adolphus Knopf, M. D. An introduction to " What the American soldier now fighting in France should know about tuberculosis," by S. Adolphus Knopf. — J. Outdoor Life, N. Y., 1918. xv. 14.

Whipple, G. H., and Cook, J. V.

Proteose intoxications and injury of body protein. IV. The metabolism of dogs with sterile abscess, pancreatitis, and pleuritis. V. The increase in non-protein nitrogen of the blood in acute inflammatory processes and acute intoxications. — J. Expcr. 11., Bait., 1918, xxviii, , 223-241 ; 243-252.

Whipple, G. H., and Van Slyke, D. D.

Proteose intoxications and injury of body protein. III. Toxic protein catabolism and its influence upon the non-protein nitrogen partition of the blood. — ./. Exper. M., Bait., 1918, xxviii, 213-221.

White, E. C, and Davis, E. G.

Urinary antisepsis. The secretion of antiseptic urine following the intravenous administration of acriflavine and proflavine preliminary report.—./. Urol., Bait., 1918, ii, 299-307.

White, E. C, Davis, E. G., and Rosen, R.

Urinary antisepsis. The secretion of antiseptic urine following the, intravenous administration of an organo-mercury phthalein derivative. — J. Urol, Bait., 1918, ii, 277-307.

Williams, J. W.

.\ consideration of some of the anatomical factors concerned in the production of deformed pelves. — Am. J. Obst., N. Y., 1918, ixxvii. 714758.

WOLFSOHN, J. M.

The predisposing factors of war psychoneuroses. — J. Am. M. Ass., Chicago, 1918. Ixx, 303-308. Also: Lancet, Lond., 1918. i, 177-180. The treatment of hysteria ; successful results of a rapid re-education methoi' — ./. Am. .U. Ass., Chicago, 1918, Ixxi, 2057-2062.

WOOIXEY, P. G.

Three cases which illustrate the consequences of coronary lesions. —

J. Lab. t£- Clin. M., St, Louis, 1917-18, iii, 192-198.

-Meningitis at Camp Greene. — ./. Lab. & Clin. M., St. Louis, 1917-18,

iii. 409-412.

Three cases of parietal aortic thrombosis. — J. Lab. <G Clin. Med.,

St. Louis, Mo., 1917-18. iii. ,-i39-347.

Convulsions. ( Editorial, i—-/. Lab. .£ Clin. M., St. Louis, 1917-18, iii,

719-720.

Yates, J. L.

Surgical methods in the treatment of malign affections of superficial lymphatic tissue. — Surg. Oimec. it Obst., Chicago, 1918, xxvii, 156-162. Observations of a Wisconsin medical officer in France. — Wisconsin M. J., Milwauliee, 1917-18, xvi, 476-477.

Young, H. H.

Cancer of the prostate. —

1918. i, 657-719.

Sarcoma of the prostate. 1918, i. 720-722.

Calculus disease of the prostate. — In: Mod. Urol. (Cabot), 8°, Phila. &

N. Y.. 1918, i, 723-724.

The employment of the high frequency current for the extraction of

calculi incarcerated in the lower end of the ureter. — J. Urol., Bait.,

1918, ii, 35-38.

A new operation for epispadias. — ./. Urol.. Bait.. 1918. ii, 237-251.

Recent progress in the treatment of cancer of the prostate, seminal

vesicles and bladder. — South. M. J., Birmingham, Ala., 1918, xi, 120 129.

Excision of vesical diverticula after intravesical invagination by

suction ; a new method. — Surg. Gynec. <t- Obst., Chicago, 1918, xxvi,

125-132.

Presentation of a radical operation for tuberculosis of the seminal

tract. — Surg. Oynec. A Obst.. Chicago. 1918. xxvi, 375-384.

Changes in trigone due to tuberculosis of kidney, ureter, and bladder.

Bridge formation and floating trigone. — Surg. Gynec. cC Obst., Chicago,

1918, xxvi, 608-615.

Young, H. H., and Davis, E. G.

The surgery of the double kidney. Report of a case of resection of upper segment for calculous pyonephrosis. — Surg. Gynec. d Obst., Chicago, 1918. xxvii, 1-13.

Zimmerman, E. L., and Keidel, A.

Tattooing and syphilis. — Am. J. Syph., St. Louis, 1918, i, 83-96.

2Iod. Urol. (Cabot), 8°, Phila. and N. Y. i; Mod. Urol. (Cabot), 8°, Phila. & N. Y.,

PUBLICATIONS.

The following six monographs :

Free Thrombi and Ball-Thrombi in the Heart. By J. H. Hewitt, M. D. 83 pages. Price, $1.00. Benzol as a Leucotoxin. By Laurence Selling, M. D. 60 pages. Price,$1.00.

Primary Carcinoma of the Liver. By M. C. Winternitz, M. D. 42 pages. Price, 75 cents.

The Statistical Experience Data of The Johns Hopkins Hospital, Baltimore, Md., 1892-1911. By Frederick L. Hoffman, LL.D., F.S.S. 161 pages. Price, $2.00. The Origin and Development of the Lymphatic System. By Florence K. Sabin. 94 pages. Price,$2.00.

The Nuclei Tuberis Laterales and the So-called Ganglion Opticura Basale. By Edward F. Malone, M. D. Price, $1.50. ## Contents Antituberculosis Measures. By Allen K. Kraisi: 49 Insusceptibility of Monkeys to Inoculation With HlooJ From Measll•^ Patients. (Illu>tiiitcd.> By Andrew Watson Sellards ami John A. Wentwortii S" The Production of Tetany by the Intravenous Infusion of Sodium liicarbonate. Report of an Adult Case. By George A. Harrop, Jr 6 Changes in the Blood Immediately Following Transfusion. By John G. Huck, M. D. 03 Elizabeth Fry — Quaker Reformer. (Illustrated.! Bv Henry M. Thomas 72 ' .... < , , , . ^_ . . . 1 1 1 1 1 : 1 1 1 1 1 1 i 1 ^ ^^ 1 1 1 1 i 1 1 1 <V,p.< ...17 3 f 6 j & 7 8 3 [4 5 i . 7 & 9 !L: 2,o.i i'"] r: T 1 ^ • ' •  • ' ' ' • ' .. .. -? i ^ i j J 3 -?. s. w ' 1 y V 1 \ y '^ ' 1 . ! " J J / \ ^ / I \. s^ i_ '^ k \ 1! p n o .c t Pa .e. 1- H, e. t Pn ic t Po. t\f A B c D E ' ' '!,. . ;. ijj ,v.r,_| icmperature curves of mt asies pancnTS.' J 1 1 1 1 1 UJ Ij LJ L_L J_l _l -J _J _ 1 1 1 1 1 1 62 [No. 337 Sixteen days after this injection, this animal was reinoculated with measles blood taken from a patient (C) wirhin from four to six hours after the rash had appeared. The blood was mixed with an equal part of 2 per cent sodimn citrate in physiological saline. Of this mixture 15 c. c. were injected intraperitoneally. On the following day, 24 hours later, another injection was made with blood taken from a patient (D) 12 hours after the appearance of the rash. This specimen of blood was diluted with an equal part of physiological saline and dcfibrinated ; 20 c. c. of this defibrinated mixture were injected intraperitoneally. After another interval of 24 hours a final injection was made with the blood of Patient E, taken not later than 12 hours after the rash had appeared. One part of blood was mixed with two parts of physiological saline and 20 c. c. of the defibrinated mixture were injected intraperitoneally. The efPect of these injections is given in Chart I. The temperature charts of these patients are also given. (Chart IV.) Monkey II was kept under observation for 10 days. Blood for injection was taken from Patient B within from 6 to 12 hours after the first appearance of the rash. The specimen was mixed with an equal part of physiological saline and 20 c. c. of the defibrinated mixture were injected intraperitoneally. The white blood counts and temperature of this animal are given in Chart II. The temperature of the patient is recorded in Chart IV. Before injection this animal had a marked erythema o\ er the face and eyebrows ; a few macules were also present. This ra.sli faded during the first week of the incubation period, but increased somewhat 10 days after inoculation, mough its intensity was not so great as during the period before injection. Since this time it has fluctuated considerably. At present, two months after the last injection, it is more marked than at any time during the incubation periods. Twelve days after the first injection of blood this monkey received injections of measles blood on three successive days ; these injections were exact duplicates of those just recorded for Monkey I, the same specimens of blood being used. Monkey III. This animal, a young adult, was given a series of three injections simultaneously with Monkeys I and II. The same specimens of blood were employed though the details were different. The injection on the first day consisted of 8 c. c. of the mixture of citrated blood injected into the heart and 12 c. c. intraperitoneally. On the second and third days 30 c. c. of the defibrinated mixtures were given intraperitoneally. Tlie results in this monkey are recorded in Chart III. REFERENCES 1. Hektoen: Jour. Infect. Dis., 1905, II, 238. 2. Anderson and Goldberger: Public Health Reports, 1911. XXVI, 847 and 887; Jour. Am. Med. Assn., 1911, LVII, 113, 476 and 971. 3. NicoUe and Conseil: Compt. Rend. Acad. Scien., 1911, CLIII, 1522. 4. Hektoen and Eggers: Jour. Am. Med. Assn., 1911, LVII, 1833. 5. Tunnicliff: Jour. Infect. Dis., 1912, XI, 474. 6. Lucas and Prizer: Jour. Med. Research, 1912, XXVI, 181. 7. Ricketts and Wilder; Jour. Am. Med. Assn., 1910, LIV, 463. 8. Tunnicliff: Jour. Infect. Dis., 1918, XXII, 462. 9. Plotz: Jour. Infect. Dis., 1915, XVII, 1. THE PRODUCTION OF TETANY BY THE INTRAVENOUS INFUSION OF SODIUM BICARBONATE REPORT or A'm ADULT CASE By George A. Hakrop, Jr. (From the Medical Clinic of The Johns Hoiiki>is Hospital) Many drugs and chemicals have been mentioned as causing tetany in adults. Following Frankl-Hochwart,' it has been customary to classify all these conditions in one group, as due to toxins or poisons. The clinical history of a patient with tetany which was produced, or at least precipitated, liy intravenous infusions of sodium bicarbonate follows : L. H. Medical No. 39293. Colored. Aged 22. Domestic. Admitted, March 8, 1918. Died, March 18, 1918. The family and past history were unimportant, except that the patient remembered no previous attacks which in any way suggested tetany, and the members of her family corroborated her statement. Present Illness. — At 7.30 a. m. on the day of admission, before she had taken any food, she swallowed two 7%-grain tablets of bichloride of mercury, dissolved in a glass of water. Shortly afterward she vomited, and within an hour commenced to vomit ' Frankl-Hochwart: Die Tetanic der Erwachsenen, Leipzig, 1907. blood. She was admitted to the hospital about noon. At this time she was vomiting dark colored material, and was very dull and drowsy. Physical Examination. — Nothing abnormal was made out aside from tenderness and slight muscle spasm in the upper abdomen. The throat was red, but otherwise it showed nothing. All of the deep reflexes were normally active. No stigmata of rachitis could be found. Weight, 130 pounds. Mercury was recovered from the urine, feces, and vomitus. Blood Examination. —W. B. C, 19,000. R. B. C. 5,624,000. Hemoglobin (Sahli), 90 per cent. Differential blood count normal. The Wassermann test was negative. Course in the Hospital. — From the time of her admission the patient passed blood in her urine and stools. The usual energetic measures were taken to secure a large fluid intake and to eliminate the mercury. On March 9 she became totally anuric and continued so until her death. On this day the plasma bicarbonate capacity (Van Slyke) was 45 volumes per cent, and the carbon dioxide tension of the alveolar air (Marriott) was 28 mm. of mercury. She was March, 1919J 63 given 500 c.c. of a 5 per cent sodium bicarbonate solution intravenously.' No untoward effect was noted and she said that she felt more comfortable afterwards. Twenty-four hours later (March 10). another intravenous infusion was given of 700 c.c. of a 5 per cent sodium bicarbonate solution, prepared as before. This made in all 60 grams of sodium bicarbonate given intravenously. A small amount given by mouth on March 9 had not been retained. About five minutes after this last infusion, which had been given slowly and had been apparently well taken, the patient's face suddenly grew pale, she commenced to have great inspiratory difficulty, and became very apprehensive. She complained of numbness and tingling of tlio fingers, and begged to have them rubbed. The hands assumed the typical obstetrical position, there was pedal spasm, and a first degree facial phenomenon (Chvostek's sign) was obtained. The pulse was accelerated to about 130, and the extremities became cold. There was no elevation of the blood-pressure. The acute attack lasted for about 15 minutes, after which the breathing became easier and she was less apprehensive. The main d'accouc/icur position was maintained for about two hours. On March 11 a blood sample was taken for the calcium and phosphate determinations recorded below, and at the same time for a determination of the plasma bicarbonate capacity (Van Slyke), which was found to be 80 volumes per cent. This sample was taken about 20 hours after the original attack. On this day a second degree Chvostek's sign was obtained and Trousseau's phenomenon was easily elicited. The further history of the case has no bearing on the present discussion, except that Trousseau's phenomenon was present until March 15, and Chvostek's sign was obtained the night before her death. March 18. Commencing on March 12 there was pitting edema of the lower legs, and on March 15 evidence of the accumulation of a moderate ascites. She became very anemic from the continued bleeding from the bowel, the hemoglobin (Sahli) on March 17 being only 20 per cent. 'This was prepared by boiling a sodium bicarbonate solution made up with freshly distilled water, and then reconverting the carbonate so formed back into the bicarbonate by passing a stream of carbon dioxide through the solution until it was no longer colored by a few drops of phenolphthalein. The writer has been unable to find any clinical reports of tetany ocourring in adults followin-; the administration of sodium biiarbonato. Among the nuiny accidents following its use in the treatment of diabetic coma, the occurrence of convulsions, especially clonic in type, is frequently mentioned.' These convulsions have usually knl to a rapidly fatal termination, often in a few hours. Tetany, however, lias not been mentioned or identified as such, Ilowland and ilarrioic have observed tetany in young children following the therapeutic administration of sodium bicarbonate for acidosis and cite three cases.* During the period of tetany their patients showed a low calcium +++++ CONTENTS of the blood serum, a condition which they have shown to be pre.<ent during the active period of infantile tetany, particularly during or shortly after the occurrence of convulsions. The amount is usually tiien less than 7.0 mg. per 100 c. c. In the present case of adult tetany, analysis of the calcium +++++ CONTENTS of a blood serum samjile taken 20 hours after the original attack showed a value higher than 9.0 mg. per lOO c. c., iience about normal, and there was no marked accumulation of pliosphates (the phosphate +++++ CONTENTS of the blood serum was less than 6.0 mg. per 100 c. c.).* It shoidd be noted, however, that in this case there had been no actual convulsions. It seems clear that the condition here was associatetl with, if not directly precipit^ttod by, the suddenly increased alkalinity of the blood due to the sodium bicarbonate infusions. In conclusion, it is desired to call attention to a danger, not too remote, attendant upon the intravenous u.se of sodium bicarbonate in conditions in which the renal excretory function is markedly impaired, and particularly when extreme oliguria or anuria is present. 'L. Blum: Ergeb. der inn. Med. u. Kinderh. 1913, XI, 480. " SjTuptomatologie und Therapie des Coma diabeticuni." •Quart. Jour. Med., 1918, XL. 289. 'The calcium and phosphate determinations were kindly made by Dr. Howland and Dr. Marriott CHANGES IN THE BLOOD IMMEDIATELY FOLLOWING TRANSFUSION ]?y John- G. Hick. M. D., Baltimore (From the Cliniral Laboratory of the Medical Department, The Johns Hopkins Univcrsilj/ and Hospital) The ever-increasing use of transfusion as a therapeutic measure has stimulated interest to seek a clear explanation for the various changes that follow the introduction into one individual of the blood of another. Nevertheless, some of the simplest questions raised by this procedure remain still unanswered. For instance, although it is generally knowTi that after a transfusion the hemoglobin and the red corpuscle values are increased, the exact way in which the increase occurs is not understood. ^lany have assumed that the immediate effect is entirely mechanical, that is, that the blfjod of the recipient- is altered in direct proportion to the quantity of the blood introduced, just as though the two had been mixed in a vessel outside of the body; that, later, reactions on the part of the blood-forming organs come into play, and these then take a part in detennining the succeeding changes. No doubt the mechanical and reactive effects are both important, but the relative importance of each is not clearly defined, and the decision has practical value, because the outcome may influence us to use either small transfusions frequently repeated or larger transfusions at longer interv'als. Certain observations already at hand cast consideraiilc iloubt upon the view that the immediate effects of transfusion are purely mechanical and lead us at once to anticipate that these effects will be neither constant nor quantitative. T>am8on ' has shown how quickly and markedly the number of red cells in the circulation may be altered by the injection 64 [Xo. 337 of adrenalin. He is convinced by his experiments that the liver acts as a reservoir from which large numbers of red cells are poured into the circulation. No doubt other influences may act in the same prompt way upon this reservoir. Sellards and Baetjer,* from their experiments and a review of the entire subject, conclude that there is no constant nor quantitative response to the injection of foreign abnonnal elements into the blood. The object of the present study is to obtain detailed and exact infomiation upon the changes that occur in the blood elements immediately after transfusion. METHODS Transfusion was performed in each instance by a modification of the citrate method of Lewisohn, as described by Sydenstricker, Eivers and Mason." The details of the technique need not be repeated here. Especial care was taken in testing the donors to be'certain that the bloods were compatible. The amounts of blood given in different cases varied from 250 c. c. to 1250 c. c. Studies of the blood were made immediately before the injection, immediately after the injection, two hours, five hours and aboiit twenty-four hours later. These time intervals were followed rather closely in practically all of the cases. Each examination consisted of counts of the red cells and of the white cells, with a difEerential count of 300 white cells. Platelets were estimated in the smears and the hemoglobin was determined. Notes were also made on the moipliology of the blood cells. Counts were always made with the same instrmnents and by the same observer, with the same reagents ; and care was taken to draw the blood from the same part of the body, with uniform punctures. The effect of transfusion was studied in seven cases of pernicious anemia, two cases of idiopathic purpura, four of benzol poisoning, five of secondary anemia and two of Banti's disease. RESULTS Eesponses to transfusion were so variable that it seems desirable to append the detailed protocols. A few of the niaiu points only will be summarized here. Red Blood Cells. — In general, following the injection of blood, there was an immediate increase in the red cell count, the striking point being the marked increase in many cases apparently out of proportion to the quantity of blood introduced. Thus, in Case 2, the red coimt rose from 880,000 to 1,488,000 immediately after the injection of 500 c. c. ; and in Case 5, from 480,000 to 1,300,000, following the injection of 650 c. c. Such remarkable changes indicate apparently a rapid redistribution of blood following an injection. In some cases the initial increase continued for several hours, usually falling, so that at the end of 24 hours the count had fallen to approximately where it was before transfusion. In other cases, however, there was a marked increase at the end of 24 hours. In several instances, after injection of blood, the count fell for a few hours and then rose slightly. Hemoglobin. — The hemoglobin in most cases showed a uniform rise following transfusion, usually reaching its maximum at the end of 24 hours. In some cases the hemoglobin fell slightly after the initial rise. Changes in hemoglobin did not run parallel with changes in the red count, as may be seen best from the variations in the color indexes. Leucocytes. — In practically every case following transfusion there was some increase in leucocytes. In several instances, however, they remained practically stationary or even fell. These relations do not seem to be constant in any particular type of case. The most striking change in the differential count is the increase in the polymorphonuclear neutrophiles, which was striking even in some cases where there was little change in the total leucocyte count. Occasionally a neutrophilic myelocyte was seen following transfusion, but they were not constant. In these cases no outpouring of nucleated red cells occurred, although in four instances a few were seen following transfusion, but not before. The numbers are so small, however, that this may have been accidental. DISCUSSION A general review of the immediate effect of transfusion upon the blood count in twenty cases does not reveal any constant changes following this procedure. The point of practical interest and importance seems to be that no exact mechanical effect can be demonstrated following the introduction of definite quantities of blood. Whereas, in a general way, it may be said that the introduction of blood raises the count, the effect is essentially a biological one involving the redistribution of blood in the body and its exact nature is not at present understood. REFERENCES 1. Lamson: Jour. Pharmacol, and Exp. Therap.. 1915, VII, 169. 2. Sellards and Baetjer: Bull. Johns Hopkins Hosp.. 1918, XXIX, 135. 3. Sydenstricker, Mason and Rivers: Jour. A. M A., 1916, 117, 719. M.VRCH, 1919J 65 BLOOD CHART— CASE 1 Patie-nts Name, Bbant; Wabd F; Age, 47; Medical No., 124 S33: Diagnosis, Per.nicious Anemia; Transfusion, 1250 c. c. 5-S1-I8 Before Transfusion 4.00 p. m. P. M. N 143 47.e^< P. M. E 4 l.SSri P. M. a L. Lrm I 0.33% S. Ljrm 146 48.e9<> L. Mono 7 2.33% Tnaa. 4 1.33% K. Myelocytes E. Myelocjtes B. Myelocjtes Mreloblasis I O.SS% Smudtres 14 4.66% Platelets Markedly decreased. Nucleated R. B. C 2— Intermediate, 1 Normoblast. 1 Moderate anisocytosis. Moderate poikilocytoeis. Basophilia Slightly diffused anc punctate. No. Cells Counted and %. 300 99.91 lib 80% R. B. C I 2.2SI.O00 W. B. C 3.200 C. 1 1.3 Condition of Patient No chill: no fever. Blood Obtained Little fin^r left hand. 5-31-18 .31-18 5-31-18 8-1-18 After Transfusion 5.00 p. ni. T.wt p. m. 10.00 p. m. 4.00 p. m. n ni IV ^ lOfi 55.3% 141 47.095, 180 60.0% 227 75.6% 5 1.68% 5 1.60% II II 1 0.33% 4 1.33% 2 0.66% 113 37.8% 97 32.3% S» SS.0% 40 1.13% 6 2.0% 8 2.66% fl 3.09'r 3 1.0% 0.66% 4 1.33% 1 0.33% II 8 2.60% 6 2.0% 6 2.0% 43 15.0% 5 1.68% 17 5.68% Markedly decreased. Markedly decreased. Markedly dccreaflcd. 1-Megaloblast, 1 T) — Normoblasts, 5 Moderate anisocytosis. Moderate anisocvtoeis. Moderate anisocytosis. Moderate poikilocytoeis. Moderate poikiloc>'tosis. Moderate poikilocytosis. Moderate poikiloc.vtosis. Slightly diffused and Slightly diffused and Slightly diffused and Slightly diffused and punctate. punctate. punctate. 300 99.96 300 99.98 300 99.98 65% 65% 70% 70% 3,424,000 3,a12.000 2,960.000 2,688,000 4,200 3,340 S,W0 4.440 1.0 1.2 1.3 No chill: no fever. Slight fever. Slight fever. Slight fever. Third finger left hand. Little flngcr left hand. Third finger left hand. Little finger left hand. BLOOD CH.\RT— CASE 2 Patient's Name, Pa vuK ; Ward G; Age, 30; Medical No., 123834; Diagnosis, Pernicious Anemia; Transfusion, 500 c. c. 2d Transfusion Date Time 3-26-18 Before Transfusion. 3.55 p. ni. 3-26-18 .\fter Transfusion 4.15 p. m. 3-26-18 6.15 p. m. 3-26-18 ).30 p. m. 3-2718 1.55 p. m. P. M. N 1 187 62.3% P. M. E 9 3.0% P. M. B 1 0.33% I. Lvm ! 8 2.66% 8. Lvm 68 22.8% L. Mono 4 1.33% Trans, 7 2.33% N. Myrlocvtes 2.0% E. MvelocVles B. Mvclocvtes MveloblasU 3 1.0% Smudges 7 2.33% Platelets Practically absent. Nucleated R. B. C 1— Normoblast, 1 Marked anisocytosis. Marked poikiloc^'tosis. Bsjiophilia Slightly diffused. N'o. CelU Counted and %. 300 99.98 Hb. 19% R. B. C. 880.000 W. B. C. 3,800 C. 1 1.1 Condition of Patient .... No chill; no fever. Blood Obtained Little Anger right hand. 16 5.33% 4 1.33% 3 L0% 10 3.33% 57 19.0% ^r, 5.0% 30 10.0% 45 15.0% 8 2.66% 10 3.33% 7 2.33% 2.0% 10 s.ssr/c 11 3.66% 1 0.33% 6 IS 5.0% II D 1 n.S3% 8 2.60% 2 0.60% 8 2.68% 2 0.68% Moderatcl.y diminished. Markedly diminished. Moderately diminished. Moderately diminished. 1 — Normoblast. 1 l-Normoblast, 1 .J-N irmoblasts. 3 Marked anisocytosis. Slight anisocytosis. Marked anisocvtosis. Moderate anisocvtosis. !l(oderate poikilocytosis. Slight poikilocytosis. Moderate poikilocytosis. Moderate poikiloc}'loai9. Slightly diffused and Slightly diffused. Slightly diffused. Slightly diffused. punctate. 300 99.94 300 99.95 300 99.99 300 99.92 25% 30% 30% 32% 1,488.000 1.512.000 1.410.1"! 1,688.000 4.300 8,700 5.4.^11 3,700 0.89 1.0 1.0 1.0 No chill; no fever. Slight fever. Fever. No chill; no ferer. Third Bngrcr right hand. Little flngcr right hand. Third finger right hand. Little finger right hand These cells are very I large in si7.e, the I majority with many lobed nuclei. Patient's Name, Pavck; Ward G; Age, 30; BLOOD rH.\RT— CASE 3 Medical No., 1L'S834; Diagnosis, Pebsiciocs Anemia; Transfusion, 500 c. c. 3-12-18 Before Transfusion 11.00 a. m. 312-18 After Transfusio 12.25 p. m. 3-12-18 .2.') p. ro. 3-1218 6.25 p. m. 3-13-18 11.00 a. n P. M. X 194 54.6% P. M. K n P. M. B 1 0..'«% I.. Lym » 1.68% S. Lvm 80 26.8% I.. Mono S 2.68% Transitional 8 2.68% N. MvelocTtes I n K. Mvclocvtes , B. Myelocytes Mvrlohlasts ; 2 0.68% Smudges 2 0.80% Platelets Moderately decreaaed. Nucleated R, B. C. 6— Sormohlast, 4 I Intermediate, 1 I MegalohlasI, 1 Basophilia Moderately diffused am punctate. Marked aniwocvtosis. Marked poikilocytosis. No. Cells Counted and %. 300 99.83 lib 10% R. B. C 824.000 W. B. C 1,877 C. I I 0,83 Condition of Patient No chill; no fever. Blood ObUined Little finger left hand. 10.0% 1.60% 1,60% 0.38% 2.0% atcly decreased. Marked aninocytosls. Marked poikilocytosis. Slightly diffused and punctate. O.XVfr 7.33% 0,80% 0.60% 30n 99.93 l.V^o 920,000 .1,040 0.83 No chill; no fever. Third finger left hand. M,rl:.-I nniaocTtosIs, Mark. I fiikllocytosis. I :<!•' 99.98 10% I (ca.noo 3,160 1.0 M;,rkc d animcytosls. MarkiMl poikilocvlosls. ir«i 99.81 l.C.WI I " Krver. Tliird finger left hand. 2.0% 14.0% .3.0% 2.33% 1.60% Practicall.r abflent. ThrMe seen larger in size' and liirarre in shape. I l-lnlcnne<liatc, 1 Slightly diffused and punctate. Marked anisocytosis. Markcfl poikilocytosis. .mo 99.96 15% 1,096,000 1.800 0.75 No rhill; no fever. I Little finger left hand. 66 [No. 337 BLOOD CHART— CASE 4 Patient's Name, Alexander; Ward F; Age, 33; Medical No., 125655; Diagnosis, Pernicious Anemla; Transfusion, 750 c. c. 2d Transfusion Date Time 6-29-18 Before Transfusion 11.00 a. m. P. M. N P. M. E P. M. B h. Lvm S. L.vm L. Mono Transitional N. Myelocytes E. Myelocytes B. Myelocytes Myeloblasts Smud,?es Platelets Nucleated R. B. C. . . Basophilia No. Cells Counted and %. Hb R. B. C W. B. O C. I Condition of Patient Blood Obtained 3 1.0% Markedly diminished. Marked anisocytosis. Marked poikilocvtosis. Slightly diffused and punctate. 300 99.92 44951 2,080,000 2,600 6-30-18 11.00 a. m 0.33% 43.0% 1.0%, o.e Markedly diminished. 1 — Normoblast, 1 Marked anisocytosis. Marked poikilocytosis. Slightly diffused and punctate. 300 99.95 73.0% 2.66% 0.33% 20.6% 1.0% 0.66% 1 0.33% i 1.33% Markedly diminished. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. Markedly diminished. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. 2,706.000 3,040 67.3% 1.66% 0.66% 0.33% 19.0% 4.0% 0.66% 2.33% 0.33% 11 3.66% Practically absent. 4 — Megaloblast, 4 Marked anisocytosis. Slight poikilocytosis. Slightly diffused. 30O 99.93 No chill; no fever. Little finger right hand. Ft. transfused slowly in left arm. A few pathol. lymphocytes seen in I, II, III. Patient's Name, Bailet, Irwin; BLOOD CHART— CASE 5 Ward M; Age, 30; Medical No., 121999; Diagnosis, Pernicious Anemia; Transfusion 650 c. c; 2d (1st Transfusion 12-15-17, 500 c. c; Washed Cells) Date Time P. M. N P. M. E P. M. B L. Lym S. Lym L. Mono Transitional N. Myelocytes E. Myelocytes B. Myelocytes Myeloblasts Smudges Platelets Nucleated R. B. C. 12-18-17 .\fter Transfusion 3.45 p. m. 12-18-17 12-18-17 8.45 p. m. No. Cells Counted and %, Hb R. B. C W. B. C. I Condition of Patient Blood Obtained — Megaloblasts, 2 Normoblasts, 3 Microcytes and macro cytes. Megalocytes. Slightly diffused and an occasional punctate. .\nIsocytosis. Poikilocytosis. 300 99.91 Estimated (Sahli). 3% 480,000 6,080 0.37 No chill; no fever. Little finger right hand. Greatly decreased, large in size. 3 — Normoblast, 3 Microcytes and ' macro cytes. Megalocytes. Slightly diffused. 300 99.98 12% 1,360,000 5,640 0.47 No chill; slight fever. Third finger right hand. 12.3% 0.33% Microcytes and macro cytes. Megalocytes. Slightly diffused. 0.71 Slight fever. Little finger right hand. Microcytes and macro cytes. Megalocytes. Slightly diffused. 300 23% 1,324,000 6,000 0.84 Slight fever. Third finger right hand. 12-19-17 2.30 p. m. 89.0% 0.66% 0.33% 1.0% 8.0% 3 1.0% Markedly decreased, not large in size. Microcytes and macrocytes. Megalocytes. Slightly diffused and punctate. Marked anisocytosis. Marked poikilocvtosis. 300 99.99 0.88 Slight fever. Little finger right hand. Blood transfused in left arm slowly. BLOOD CHART— CASE 6 Patient's Name, Ceockett; Ward G; Age, 65; Medical No., 120650; Diagnosis, Pernicious Anemia; Transfusion, 500 c. c. 10-22-17 Before Transfusion 11.45 a. m. I 10-22-17 After Transfusion 12.40 p. m. n 10-22-17 2.40 p. m. m 10-22-17 5.40 p. m. rv 10-23-17 11.45 a. m. V Remarks P. M. N 108 36.0% 3 1.0% 1 0.33% 75 25.0% 79 26.3% 4 1.33% 4 1.33% 2 0.66% 24 8.6% Normal; large in size. 8— Mieroblasts, 3 Normoblasts, 5 Many microcytes and macrocytes. Markedly diffused and punctate. Marked anisocytosis. Marked poikilocytosis. 300 99.95 20% 1,176,000 5,000 0.90 No chill; no fever. Little finger left hand. 98 32.6% 1 0,33%! 60 20.0% 100 33.3% 1 0.33%, 3 1.0% 2 0.66% 35 ll'.6% Normal; large in size. 18— Mieroblasts, 4 Normoblasts, 14 Many microcytes and macrocytes. Markedly diffused and punctate. Marked anisocytosis. Marked poikilocytosis. 300 98.72 35% 1,432,000 6,320 1.2 No chill; no fever. Third finger left hand. 212 70.6% 2 0.66% 15 5.0% 53 17.6% 1 0.33% 3 1.0% ii 4.66% Increased; large in size. 13— Mieroblasts, 3 Normoblasts, 9 Intermediate, 1 Few microcytes and macrocytes. Markedly diffused and pimctate. Sliirht anisocytosis. Slight poikilocytosis. 300 99.85 34% 1.. '592,000 7,800 1.1 No rhill; no fever. Little finger left hand. 238 79.3% ft 14 4.66% 32 10.6% ft 3 1.0% 13 4.33% Increased; large in size. 5 — Mieroblasts, 1 Normoblasts, 3 Intermediate. 1 Few microcytes .-uid macrocytes. Markedly diffused and punctate. Slight anisocytosis. Slight poikilocytosis. 300 99.89 32% 1,856,000 7,840 0.88 No chill; no fever. Third finger left hand. 108 36.0% 3 1.0% 4 1.33% 46 16.3% 77 25.6% 1 0.33%, 5 1.66% 1 0.33% 55 18.3% Normal; large in size. 6— Mieroblasts. S Normoblasts, 1 Intermediate, 2 Diffused and punctate. Slight anisocj-tosis. Slight poikilocytosis. 300 99.85 31%, 1,368.000 8,200 1.1 No chill; no fever. Little finger left hand. P. M. B S. Lym Nucleated R. B. C. No. Cells Counted and %. R. B. C W. B. C C. I Condition of Patient right arm, slowly, then rapidly. March, 1919] G7 Patiest's Name, White; Ward F; Age, 50; BLOOD CHART— CASE 7 Medical No., 1226 IH, Diagnosis, Pebmcioi-s A.nemia; 2d Tbaxsfisiox, 600 c. c. (1st Transhsion. 2-3-18) 2-17.18 Before Transfusion 217-18 After Transfusion 2-1718 217 18 2-1818 Remark* Time 10.45 «. m. I 12.20 a. m. n 2.20 p. m. in S.25 p. m. IV 10.4S a. in. V 140 46.9% 161 SS.OT'r .>» 74.0% 246 82.0^0 21» 73.0% 3 1.0% 1) 1 0.38% .< I.O^c 1 n.ss^'c 6 2.0% '1 1 !!& 8 2.«8rt 84 28.0% 11 3.68% I 6 O.SS% 16.8% 2.0% 4 \.3S% 27 O.IKT, 8 2.00% 2 0.66% .11 17.0% 4 1.3;i% U Mono ! 8 2.as9e> 11 3.66% 4 1.33% 9 8 S.0% 2.68% 1 0.337e i.6e7<> .1 1.6870 N. MrelocytM E. Mjeloc.vtes " 1 1 0.33% II 12 4.0% 17 5.68% 3 1.0% 5 1.88% 10 3.33% Platelrts Decreased slightly; some verj- large. Norma some Urge in Markedly decreased. Some large in size. Normal; some Urge In 2— NormobUsts. 5— Normoblast, 4 27— Normoblast, 21 2— Nonnoblast. 1 8— Normoblast. 7 Intermediate, 1 Intermediate, 6 Intermediate, 1 Megaloblast. 1 SliKhtly diffused. Diffused and punctate. Slightl V diffused and Slightly diffused and Slightly diffused and Slicht anisocvtosis. Slight anisocvtosis. punc ate. punctate. punctate. Slight poikilocj-tosis. Slight poikilocjtosis. Slight anisoc.vtogis. Moderate aniso^-tosis. Moderate anisocvtosis. Slight poikiloc>'t06i9. Moderate poikilocvtosis. .M.Klt-ratc poikilocvtosis. 300 98.92 300 99.70 3(XI 99.92 300 99.97 300 99.97 Hb S5% 1,288.000 44% 2,184.000 4870 2,64(1,000 48% 2.748.000 48% 2.448.000 W. B. C 3.720 2,760 2.400 3,560 1.4 1.0 No chill: no fever. Severe (I.S8 chill ; fever. 0.85 Fever. 1.0 No chill; no fever. Blood ubuined Little finger right hund. Third finger right hand. Little finger right hand. Third finger right hand. Little finger right liand. Blood transfused slowly in left arm. BLOOD CHART— CASE 8 Patient's Name, Hopkins; Ward M; Age, 52; Medical No., 121133; Diagnosis, Banti's Disease; Transfusion, 400 c. (I.ST Transfusion, 500 c. c.) (Same Donor as 1st) ll-*'-17 11-22-17 After Transfusion 11.43 a. m. II 11-22-17 1.4.1 p. m. Ill 11-22-17 5.45 p. m. IV 11-2S-17 10.40 a. m. ' V Before Transfusion 10.40a.m. Remarks I 1 P. M. F,. P. M. B. Lym. S. Lvm U Mono Transitional . . . N. Myelocyte* E. Myelocvtes . B. Myelocvtea . MyeloblaaU ... Smudge* PUteleU Nucleated R. B. Basophilia i.S% 1.66% 2.33% 2.33%! 6.33% 2.68% 4.33% 0.33% 38 12.8% Increased; large in size. 99.87 Diffused. Marked anisocvtosis. Marked poikilocytosis. 300 99.88 Diffused. .\nisocytosis. Poikilocvtosis. 300 81% 3,488,000 3,384.000 i 11,560 I 11,380 0.45 I 0.57 'Good; no fever; no chill. .No chill; no fever. Little finger right hand. Third finger right hand. 72.3% 5.0% 2.66% 1.68% 4.0% 1.66% 6.0% 20 6.69% Increased ; markedly en Urged in size. Diffused. Marked anisocytosis. Marked poikilocytoeis. 300 99.94 40% 3,552,000 ll>,380 0.57 Slight fever. Little finger right hand. 83.0% 3.0% 2.sa% 1.33% 4.0% 0.66% 4.33%, 86.0% 2.3.1% 3.0% 1.0% 0.3.1% 4.60% Greatlv increased. Diffused. Ani8oc>.t08is. Poikilocytosis. SOU 98.65 3.496.000 10.600 0.57 Slight fever. Third finger right hand. 300 99.98 38% 4.352,000 10,049 0.44 No chill; no fever. Little finger right hand. Blood transfused In left arm, rapidly. BLOOD CHART^CASE 9 Patibnt'8 Name, Thomas Hopkins; Ward M; Age, 52; Medical No., 121133; Diagnosis, Banti's Disease (?); Transfusion, 500 c. c. Dale Time 11-917 rnre Transfusion 11.20 a. m. 11-9.17 ter Transfusion 1.35 p. m. P. M. r. P. M. B L. Lym S. l^ U Mono Transltlnnal ... K. Myelocytes K. Myelocytes . B. Mvelocvtes . HyelohlasU ... Smudges Platelets Nucleated R. B. C. No. CelU Counted and %. 78,6% 3.0% l.SS% 2.33% 8.86% 0.69% Increased markedly. Large in size. 2 — Normoblasts, 2 Macroc)-tcs aitd microeytes. Diffused. Marked anisocvtosis. Marked poikilocytosis. »nO 99.81 19% 2,890,000 9.940 .« 73.3% 2.99% 2,0% 2,99% .1,99% 2,69% 14 469% InfTcased markcdl.v. Large in size. 4— Normoblasts, 2 Microblasts, 2 Macrocytcs and micro cytei Diffused. Markeil anisocvtosis. Marked priikilocytosis. 300 99,gS 23% 2.68fl.flfl0 7,000 ,44 Good; DO fever; no chill. iNo chill; no fever. 81,8% 2.88% 1.98% 1.38% 1,69% 5,0% 1.0% 17 S.<S% Increased markedly. Large in <ize. 4— Normoblast*, 4 Macnvytes and microcytes. Diffa«c<l, Markcl anlaocytaria. Marked puikilocjtaris. 300 W.M 2»% 2,880.000 7,000 .41 Slight fever. Rlood ObUined LiUle finger right hand. Little finger right hand. Little finger richt hand. 76.0% 1.60% 2.3.1% 3.00% .1.60% 1.3.1% 3.0% Increased greatlv. Li in size. 3— Normoblasts. MacTocytes and mlcro cyte*. Diffused. Marke<l anisocytosis. Marked poikilocytosis. 800 99.98 24% 8,416,000 8.120 .15 Slight fever. ,rhird finger right hand. 59.3% a 69% 0.60% 2.38% 890% 1.69% 7.69% 11.0% Large In size. Diffused. Marked anisocytosis. Marked poikiloc>.tosls 3110 99. 22% 2.840.000 9,000 ..19 No chill; no fever. Little finger right hand. del. cytcs. These cells were seen in slide n, Clamifled under Trans. Seen in slide IV. Classified under Trans, jPt, hsd no reaction after transfusion except fever of lflO°, Blood transfused In I left srm, rapidly. G8 [No. 337 BLOOD CHART— CASE 10 Patient's Name, Petee Skafidos; Wakd F; Age, 24; Medical No., 120S04; Diagnosis, Echinococcus Cyst of Right Lung; Transfusion, 500 c. c. 10-25-17 Before Transfusion 2.45 p. m. I 10-25-17 After Transfusion 3.15 p. m. n 10-25-17 5.30 p. m. in 10-25-17 Before Operation 8.15 p. m. IV 10-26-17 After Operation (18 hrs.) 3.30 p. m. V Remarks p. M. N P. M. E P. M. B 228 7G.0% 5 1.66% 2 0.66% 8 2.66% 27 9.0% 5 1.66% 17 6.66% 's 2.66% Normal. Diffused very little. 300 99.96 25%, 1,856,000 10.560 .69 Small hemoptysis and blood-streaked sputum. Little finger right hand. 227 75.6%, 1 0.33% 2 0.66%, 14 4.66% 16 5.33%, 3 1.0% 17 6.66% !! '.'. 20 6.66%, Normal. Diffused very little. 300 99.90 35% 2,184,000 12,640 .83 Small hemoptysis and blood-streaked sputum. Third finger right hand. 248 82.0% 1 0.33%, 1 0.33%, 10 3.33%, 18 6.0%, 6 2.0% 9 3.0%; '9 3.6% Increased. Diffused very little. 300 99.99 35%, 2,496,000 13,080 .73 Small hemoptysis and blood-streaked sputum. Little finger right hand. 247 82.3%, 3 1.0% 5 1.66%o 19 6.33%, 6 2.0% 14 4.66%, '6 2.6% Increased slightly. Diffused very little. 300 99.95 33%, 2,160,000 14,800 .78 Small hemoptysis and blood-streaked sputum. Third finger right hand. 251 83.6%, . 2 0.66%, 5 1.66% 9 3.0% 6 2.0%, 10 6.33% ii 3.66%, Increased slightly. 2 — Normoblasts, 2 Diffused very little. 300 99.91 32%, 2,776,000 20,120 .59 Fever. Some *' old " blood-streaked sputum. Little finger right hand. Pt. died from hemorrhage on 10-31-17. S. Lvm L Mono Cell seen in slide UI classified here. Nucleated R. B. C No. Cells Ckjunted and %. Hb R. B. C W. B. C C. I Condition of Patient left arm, somewhat rapidl.v. BLOOD CHART— CASE 11 Patient's Name, Stlvia McMillian; Wabd O; Age, 26; Gyn. No., 122424; Diagnosis, Post-Operative; Transfusion, 300 c. c. 1-13-18 Before Transfusion 10.00 a. m. I 1-13-18 After Transfusion 1.00 p. m. n 1-13-18 3.00 p. m. m IV V Remarks 227 75.6% 1 0.33% 29 9.66%, 2 0.68% 12 4.0% 6 2.0% 1 0.33% 22 7.33%, Practically absent. 144— Normoblast, 144 Markedly diffuse; slightly punctate. Moderate anisocytosis. Moderate poikilocytosis. 300 99.91 5%, 1,112,000 37,700 0.22 Fever. Little finger left hand. 126 42.0%, 3 1.0% 84 28.0% 6 2.0% 15 5.0% 42 14.0% 3 1.0% 21 7.0% Practically absent. 1329-Normoblasts, 1000 Intermediate, 329 Markedly diffuse; slightly punctate. Moderate anisocytosis. Jloderate poikilocj'tosis. 300 100.0 22% 1.216.000 26,360 0.91 Fever. Third finger left hand. 210 70.0% 3 1.0% 42 14.0% 3 1.0%, 6 2.0% 30 10.0% 3 1.0% 3 1.0% Moderately diminished. 849— Normoblasts, 809 Intermediates, 40 Markedly diffused; slight punctate. Moderate anisocytosis. Moderate poikilocvtosis. 300 100. 19% 2.480,000 24,500 0.39 Fever. Little finger left hand. To give transfusion rt. arm was used and had to cut p. M. E P. M. B S. Lvm p. m. Nucleated R. B. C No. Cells Counted and %. Hb R. B. C W. B. C C. I Condition of Patient BLOOD CJHART— CASE 12 Patient's Name, Charles Thomas; Ward D; Age, 43; Surgical No., 121146; Diagnosis, Sinus Tract in Old Wound; Transfusion, 500 c. c. Date Time 11-25-17 Before Ti'ansfusion 12.00 m. 11-2517 (er Transfusion 2.00 p. ni. 11-25-17 4.00 p. m 11-25-17 7.00 p. m. 11-26-17 12.15 p. m. P. M. N P. M. E P. M. B L. Lvm S. Lym L. Mono Transitional N. Myelocytes E. Myelocytes B. Myelocytes M.veloblasts Smudges Platelets Nucleated R. B. C. .. Basophilia No. Cells Counted and Hb R, B. C W. B. C. I Condition of Patient . Blood Obtained 14 4.66%, Normal. Slight anisocytosis. Slight poikilocytosis. 300 42% 3,144,000 17,280 0.67 M chill; no fever. .ittle finger right hand. 0.33%, 3.33%, 0.33%, 1.33%, 31 10.3% Slightly increased. Slight anisocytosis. Slight poikilocytosis. 63% 3,296,000 14.640 0.82 Slight chill. Third finger right hand. 30 10.0% Slightly increased. Slight anisocytosis. Slight poikilocytosis. Diffused. 300 99.95 62% 3,696,000 12,160 0.72 \o rhill; no fever. Little finger right hand. Greatly increased. Slight anisocytosis. Slight poikilocvtosis. 300 99.95 53% 3,656,000 14,5(X) 0.73 No chill; no fever. Third finger right hand. 0.33% 2.33%, 3.0% Greatly increased. Slight anisocytosis. Slight poikilocytosis. 300 99.91 52%, 4,288,000 11,620 0.61 No chill; no fever. Little finger right hand. Pt. was operated on Sept. 20. 1917, for gastric ulcer. 50 c. c. blood injected when needle became clogged; interval of half hour before continuing. Seen in slide I. Classified under Trans. Pt. was operated on again on Nov. 28, 1917. Found tubercles throughout abdominal cavity. Pt. died on Nov. 29, 1917. March, 1919] 69 BLOOD CHART— CASE 13 Patient's N.\me, M. STRrzYKOwsKi; W.\rd G; Age. 14; Medical Xo., 120599; Diao.nosis, Typhoid Fe\'eb; Tbaxsfcsiox, 300 c. o. (10-8-17 1st TR.\NSFnsioN, 400 c. c.) 10-11-17 After Transfusion 1.50 p. m. n Date 101117 Before Transfusion Time 12 m. I I P. M. X 138 46.0% P. M. E 4 1.33% P. M. B P L. Lvm S6 18.6% S. Lvm 70 23.3% U Jiono 3 0.66% Transitional : 17 5.66% N. Myelocytes E. Myelocytes | B. Myelocytes , Myeloblasts ' Smudges 13 4.83% Platelets Decreased slightly; large Normal; large. in size. Nucleated R. B. C. Basophilia Diffused. .\nisocytosi8. Poikilocrtosis. N'o. Cells Counted and %. 300 99.S8 Hb 33% B. B. C 1,872,000 W. B. C 2,320 C. 1 0.91 Condition of Patient Slight fever. Blood UbUineU Little finger left hand. 1011.17 3.15 p. m. 1011-17 5.15 p. m. 10-121 11.15 p. 65.0% 10.3% 21.6% 1.66% 2.33% 11.3% is.e% 2.33% 2.83% 8 2.66% Decreased; large in size. Large in size. 7.SS% 2.5.3% 2.33% 3.33%) Diffused. Slight anisooytosis. Slight poikilocvtoeis, 3i<0 99.82 Slight fever. Third Bngcr left hand. Diffused. Slight anisoc}-toei& Slight poikilocytosis. 300 99.88 39% 2,168.000 5,200 0.93 Slight fever. Third finger left hand. Diffused. Slight anisoc.^iosis. Slight poikilocytosis. 300 99.87 40% 2,376,000 3,640 0.87 Fever. Second finger left hand. Decreased; large in size. Diffused. Slight anisoc.vtoeis. Slight poikiloc^-tosis. 3U0 99.32 42% 2,352,000 3,240 0.91 Slight fever. Tliird finger left hand. Blood transfused left arm, v< 1 slowly. BLOOD CHART— CASE 14 Patiext's Name, Marie Zahbodka; Ward G; Age, 29; Medical No., 120464; Diagxosis, Ttphoid Feveb; Transfusion, 250 c. c. 10-10-17 .\fter Transfusion 12.05 p. m. Dale 1010-17 Before Transfusion Time 11.00 a. m. ' I P. M. N 9S 32.6% P. M. E 2 0.6% P. M. B L. L»-m 46 15.3% S. L.vm. 122 4a6% U Mono 6 1.6% Transitional 15 6.0% N. Mrelorytes E. Myeloc}-tes B. Mvelocvtcs | Mveloblaats Smudges 12 4.0% Platelets I..arge in size; decreased. Large in size Nucleated R. B. C. None. None. ' Slight anisocytosis. Slight Doikilocytosis. Bcaophilia Diffused and punctate. Diffused. Many cells seen. No. Cells Counted and %. 300 99.7 Hb. 30% R. B. C I 2,128.000 W. B. C. 6,360 C. L 0.71 CondiUon o( Patient ....! Slight chill. Blood Obuined 'Liule finger right band 10-1017 5.30 p. m. 10-lM 11.30 a. 13.3% 22.09<. 0.66% 9.6% I Many cells seen. 38% 1.768,(100 7,440 99.89 51.3% 0.33% 20.6% 12.0% 1.0% 9.6% I*arge None. Slight nnNoc.\-tosis. Slight poikilocytosis. Diffused; very few. 99.83 23.6% 10.0% 0.66% 7.0% 38.3% 10.3% 2.8% 9.8% 6.0% 14 4.6% 2 0.66% size; decreased. r<arge in size; decreased. Slightly increased. None. None. Slight anisoc.vtosis. Slight anisoc.vtoeis. Slight poikilocytosis. Slight poikilocytosis. Diffused and punctate; Diffused; few. few. 800 99.86 800 99.86 40% 39% 1,648,000 1,872,000 5,120 6,660 Chill. ' Fo Third finger right hand. Third flngo 1.2 Fever. 1.0 38% 2,384,000 6,380 0.82 Slight feve right hand. { Little finger right hand. : Little finger right hand. Blood transfused in left arm— rapidly. BLOOD CHART— CASE 15 Patient's Name. Baceb; Ward G; Age, 28; Medical No., 125383; Diagnosis, Benzol Poisoning; Transfusion, 600 c. Date Time 520-18 Before Transfusion 3.15 p. m. I 5-2018 After Transfusion 4.10 p. m. II 520-18 6.10 p. m. m 5.2018 9.10 p. m. IV 5-21-18 3.16 p. m. V Remsrks P. M. N P. M. E P. M. B 60 16.6% 2 0.66% 230 76'.^° 5 1.0% 6 l-etfH, 1 0.13% 2 0.68% 3 1.0% PrartirallT absent. Slight anUocTtosis. Slight poikilocj-toris. 2— Normoblast, 1 Megaloblast, 1 Slightly diffused and punctate. 300 99.94 38% l.9R4.nno 1.160 1.0 No chill: no ferer. Little finger left hand. 62 20.6% 8 2.66% 192 64.0% 20 6.66% 10 3.33% 2 0.66% 6 2.0% Practically absent. Slight ani«ooto»is. Slight poikilocytosis. Slightly diffused and puncute 300 99.91 4.1% 1.768,000 2,640 1.2 No chill; no ferer. Third finger left hand. ft-. 81.6% 2 0.66% n n 1S7 62.3% in 3.83% n 2 0.66% 4 1.83% Practically absent Slight aniwcylods. Slight poikilocytosis. Slighily diiruacd and punctate. 300 t».«e 47% 2,240,000 1.38) 1.0 Slight fever. Utile finger left band. 62 2n.69i 5 1.66% 220 73..1% 4 1.83% 4 1.83% (1 3 1.0% 2 0.66% Prarticallv absent. Slight ani.oK-vtnsis. Slight iK.ikil<<-yto<iis. 2— Normoblasts. Slightly diffused s n d puncUte. 300 99.98 45% 2,796,000 1,280 0.83 Slight fevor. Tliiril finger left hand. 47 l.'>.6% 3 1.0% 7 2.33% 218 72.6% 10 3.33% 8.0% 2 0.66% 1 0.33% 3 L0% Pnireically absent. Slight snisocylosis. Slight iKiikilocytosli. Slightly diffused s n d puncUle. ant 99.96 4.1% 2,.176,n00 2,000 0.96 No chill ; no fever. Little finger left hsnd. h. Mono. V. Mrelorytes r.. Mvplocytes n. Mxlocrtes MielnhlijU Smudgm rialelels Nucleated R. B. C. Buophilia No. Oils Counted and %. Hh R. B. C. W. B. C C. I Tondition of Pittent Blood Obuined Pt. transfused slowly in right arm. 70 [No. 331 BLOOD CHART— CASE 16 Patient's Name, Chas. Webek; Waed F; Age, 17; Medical No., 122256; Diagnosis, Benzol Poisoning; Transfusion, 275 c. c. p. M. N p. M. E p. M. B L. Lym S. Lj-rn L. Mono Transitional . . . N. Myelocytes E. Myelocytes . B. Myelocytes . Myeloblasts . . . Smudges Platelets Nucleated R. B, Basophilia Ifo. Cells Counted and * Hb R. B. C W. B. C 1-11-18 Before Transfusion 10.00 a. m. 1-1-18 After Transfusion 11.30 a. ni. 1-1-18 4.30 p. m 20.0% 22.6% 1.07o 10.3% Practically absent. Slightly diffused. Slight anisocytosis. Slight poikilocytosis. 300 99.86 54% 2.648,000 2,400 Practically absent. Practicallj' absent. Slightly diffused. Slightly diffused. Slight anisocytosis. Slight anisocytosis. Slight poikilocytosis. Slight poikilocytosis. 300 99.79 3WI 99.88 59% 57% 2,272.000 2,512,000 3,160 1,880 1.3 1.9 No chill ; no fever. Slight fever. Third finger right hand. Little finger right hand. Practically absent. " Slightly diffused. .flight anisocytosis. Slight poikilocytosis. 300 99.92 67% 3,216,000 1,800 0.89 Slight fever. Third finger right hand. Practically' absent. 300 99.84 Slightly diffused. Slight anisocytosis. Slight poikilocytosis. 54% 2,368,000 1,720 Blood transfused in left arm slowly. BLOOD CHART— CASE 17 Patient's Name, Chas. Weber; Ward F; Age, 17; Medical No., 122256; Diagnosis, Benzol Poisoning; Third Transfusion, 300 c. c. 1-9-18 Before Transfusion 2.00 p. m. I 1-9-18 After Ti'.insfiision 4.00 p. m. n 1-9-18 6.00 p. m. m 1-9-18 9.00 p. m. IV 1-10-18 2.00 p. m. V Remarks p. M. N P. M. E P. M. B 96 32.0% 1 0.33% 32 10,6% 115 . 38.3% 16 5.33% 28 9.33% 1 0.33% II n 11 3.66% Practically absent; those seen large in size. 110 36.6% 1 0.33% 18 6.0% 129 43.0% 7 2.33% 28 9.33%, 1 0.33% 6 2.0% Practically absent; those seen large in size. Moderately diffused. Slight anisocytosis. Slight poikilocytosis. 300 99.92 42% 2,704,000 2,680 0.77 No chill; no fever. Third finger right hand. 111 37.0% 1 0.33%, 11 3.66% 127 42.3% U 3.66% 23 7.66%, 5 L66% U 3.66% Practically absent; those seen large in size. Moderately diffused. Slight anisocytosis. Slight poikilocytosis. 300 99.93 43% 2,752,000 2,080 0.79 Slight chill; slight fever. Little finger right hand. 90 30.0% 1 0.33%, 13 4.33% 162 54.0% 8 2.66% 18 6.0% 1 0.33% 1 0.33% 6 2.0% Practically absent. Moderately diffused. Slight anisocytosis. Slight poikilocytosis. 300 99.98 40% 2,120,000 1,880 0.90 Slight fever. Third finger right hand. 90 30.0%, 3 1.0% 1 0.33% 17 5.66%, 130 43.3% 14 4.66%, 37 12.3%, 1 0.33% 7 2.33%, Practically absent. 1 — Normoblast. Moderately diffused. Slight anisocytosis. Slight poikilocrtosis. 300 ' 99.91 41% 2,296,000 1,840 0.93 No chill; no fever. Little finger right hand. Many patho. lym. in S. Lym I, n, V. Nucleated R. B. C No. Cells Counted and %. Slight anisocj-tosis. Slight poikilocytosis. 300 " 99.88 39% 2,232,000 1,920 0.88 No chill; no fever. Little finger right hand. R. B. C W. B. C. C. I Condition of Patient left arm slowly. BLOOD CHART— CASE 18 Patient's Name, Ellen Foppino; Ward G; Age, 36; Medical No., 125109; Diagnosis, Benzol Poisoning; Transfusion, 750 c. c. 5-11-18 Before Transfusion 2.0O p. m. I 5-11-18 .\fter Transfusion 3.45 p. m. n 5-11-18 5.46 p. m. m 5-11-18 8.45 p. m. IV 5-12-18 2.00 p. m. V Time Remarks P. M. N P. M. E P. M. B L. Lym S. Lym L. Mono Transitional . . N. Myelocytes E. Myelocytes B. Myelocytes MyelobLists . . Smudges Platelets Nucleated R. B. C. Basophilia No. Cells Counted and %. Hb R. B. C W. B. C C. I Condition of Patient . , . , Blood Obtained 36.0% 56.3% 4.0% Practically absent. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. 300 99.96 Occasional ; those se&n large in size, bizarre in shape. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. 300 99.94 46% 2,856,000 640 Little finger left hand. Third finger left hand Practically absent. Moderate anisocytosis. Moderate poikilocytosis Slightly diffused. Little finger left hand. 'ractically absent. 1 — Megaloblast. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. 300 99.99 45% 2,464,000 800 Third finger left hand. Practically absent. Moderate anisocytosis. Moderate poikilocytosis. Slightly diffused. Little finger left hand. PL transfused slowly in right arnu March, 1919] 71 Patient's Name, Stbombebger; Ward G; BLOOD CHART— CASE 19 Age, 19; Medical No., 126431; Diagnosis, Idiopathic Purpura; Transfusion, 700 c. c. Date Time 5-12 IS 512 s Before Triuisfusion .\ft er Transfusion 2.00 p m. 3.10 p m. I n 247 82.3% 233 77.6% 6 2.0% 6 2.0% 1 0.3S7c 2 0.66% 2 0.66% SO 10.0% SO 10.0^,^ 4 1.33% 13 4.33% 8 2.68% 6 2.0% 1 O.SS%, 1 n.3S% S 1.0% 8 2.66% 5 1218 8.M p. in. n' 230 7a 6% 7 2.33% 2 0.66% SO 10.0% 14 4.66% 12 4.0% 1 0.33% 4 1.33% Practically absent. Slight anisocytosis. No poikilocytogis. SISIS i.OO p. m. P. M. E. P. M. B. S. Lym L. Mono Transitional .... X. Myeloc>-tcs . E. Myelocytes .. B. Myelocytes . . Myeloblasts Smudges Platelets Nucleated R. B. 78.0% 1.33% 0.66% Prnrt ically absent. I.^lifrht anisoc>'to6)S. No poikilocytosis. , ... 99.95 7S% 1 5.014.000 I 8.200 ' 0.73 No chill; no fe\*er. Little finger right hand. Practically absent. 81% 5,120,(X» 12,r>(K) Practically absent. Slight anisocytods. No poikilocytosis. .i.lK.OOO 12.600 ('.S3 Slight fever. Little finger right hand. 79.0% 1.33% 0.33% 13.6% 3.0% 1.66% Practically absent. Slight anisocytosis. No poikilocytosis. 81% 5.474.000 14,200 300 ! 84% 5,616.I»K) 13,400 0.75 Slight fever. No chill: no fever. Third finger right hand. Little finger right hand. Pt. transfused slowly ' in left arm. BLOOD CHART— CASE 20 Patient's Name, Mary Stromuergeb; Ward G; Age, 19; Medical No., 126431; Diagnosis, Idiopathic Purpura; 1st Transfusion, 600 c. c. Date Time P M. X P. M. E P. M. B L. Lvm L &.::::: Transtitional .. N. Mvelocyles E. Mvelocvtes B. Mvrlocvtes Myeloblasu .. Smudges Platelets 4-29.18 Before Transfusion 12.30 p. m. 4.29-18 After Transfusion 1.55 p. ni. 4-29.18 >.5S p. m. 4-30-18 12.30 p. m. 65.3% 1.33% 22.0% 3.0% 4.0% 65.6% 0.66% 0.66% 2.33% 15.0% 2.66% 5.667e 2 7.33% Practically absent; those Markedly diminished; seen large in size. those seen large in size I and bizarre in shape. Nucleated B. B. C. !»— Normoblast, 3 I Marked ani!<ocytosis. | Marke<l poikilocytosis. I Basophilia Moderatelv diffused. Moderately diffused. No, Cells Counted and %. ' 300 "300 lib I 40% 46% R. B. C 3.492,000 3,9(10.000 W. B. C I 7.600 8,100 C. I I 0.66 0,58 Condition of Patient ....|No chill; no fever. No chill: no fever. Blood Obuined iLittle finger left band. Tliird finger left hand. Markcdlv Tliose 5C( size and shape. 85.0% 0.33% 0.33% 0.66% 4.66% diminished ; n large in bizarre in .Slightly diffused. 300 49% 3,904.000 11.200 0.02 Severe chill. Little finger left hand. 0.33% 8.33% 4.33% 8.0% 3 1.0% Practic-ally absent; those' seen lar^c in size and bizarre in shape. Slightly diffused. sno 49% 3.912,000 11,680 0.62 Fever 103°. Third finger left hand. ).66% r.0% 1.33% >.6e7o Practically absent; seen large in size. 33% 33% those Marked anisoc.vtosis. NLirkcd poikilocvtosis. Sliglitly diffused. 0.«f No chill: no fever. Little finger left hand. Path. Lym. (Reider) Tu-o seen in I, one seen in V. BLOOD CHART— CASE 21 Patient's Name, William Meyer; Ward F; Age, 52; Medical No., 121243; Diagnosis, Hypertension with Myocardial iNsumciENCY; Control; No Transfusion Date Time 11-30-17 Before Transfusion 2.20 p. m. 11.3017 r»cr Transfusion 4.30 p. m. 11-30.17 &30 p. m. 12-1-17 2.30 p. m. P. M. B U Lvm S. Lvm U llono Transitions) ... N. Myelocytes E. Myelocyte* . B. Myelocyte* . M.velohlasts ... Smudges Platelets Nucleated R. B. C Basophilia No. Cells Counted and %. 3.33% 17.0% 1.60% 3.60% 10 3.33% Norma t Vc anisocytosis. No poikilccyt'.sjs. 1 — Normoblast, 300 9».n 73% 4,384,000 7,300 0.84 No chill; no fever. Little Anger right hand. S.0% 17.8% 2.83% 3.60% Normal. 1 No anisocytosis. j No poikilocytosis. 74% 4.376.000 7,.1B0 0.86 Vo chill; no fercr. Third finger right hand. 6.3S% ie.0% 3.0% 2.00% Xormal. No anisocytosis. No poikilocytosU. No chill; no fercr. Little finger right hand. ).0% ).66% )..'«% 5.66% r.0% J..33% 1.0% Xormal. No snisocytosis. No poikilocytosis. 300 »B.»1 74% 4,392.000 7,240 0.86 No chill: no fever. Third finger right hand. 73 [Xo. 33: ELIZABETH FRY-QUAKER REFORMER' By Henhy M. Thomas 111 speaking of Elizabeth Frj- to my friends I am struck with how little is kllo^vn about her, and yet one hundred years ago she was beginning in London a career that made her the most influential woman of her time, certainly in philanthropy and, I believe, in general. To understand Elizabeth Fry and her struggles it is necessary to know something about Quakers, or the Society of Friends, to which sect she belonged. Most of you know that the Society of Friends was founded by George Fox in 1647-48 as a protest against the formality and abuses which he believed had affected the Church at that time. He taught that true religion is a direct personal experience, and that there is in every man's soul something that responds to the truth as revealed in the Bible, which, when properly regarded and attended to, is a safe guide for conduct. This view led to a personal interpretation of the Bible and did away with creeds and the authority of priests or ministers. He and his followers " bore testimony," as they would say, against many customs and beliefs that they disapproved of. They took many of the injunctions of the Bible literally and felt it wrong to call any man master and to show more respect to one than to another, and they therefore refused to take off their hats before the great and keep them on before the lowly, said " thee " and " thou " to their equals and superiors as well as to those usually called inferiors, adopted a manner of dress which they did not change with the fashions, refused to take legal oaths, and many other such things. From the first they acknowledged the complete equality of women and gave them equal influence in the conduct of the Society. George Fox was a powerful, persuasive preacher, and influenced many people particularly among the lowly, but not a few among the well-to-do and learned. Among these latter were William Penn, Eobert Barclay and John Gurney. John' Gurney, the ancestor of Elizabeth Fry, was put into prison with other Friends and remained there for three years because he would not take the oath of allegiance, his testimony being against taking any oath. All the Gurneys appear to have been prosperous, and were interested in woolen weaving and in banking. John Gurney, Elizabeth Fry"s father, married Catherine Bell, the great granddaughter of Robert Barclay, the Quaker apologist, and so the Gurneys of Earlham could trace their ancestry on both sides through an unbroken line of influential Quakers to founders of the Society. John Gurney had inherited quite a large property and had himself prospered. In 1786 he leased from Edward Bacon the estate of EarUiam in Norfolk near Norwich, and it is ^ Read before The Johns Hopkins Historical Society, Pel)nuiry 12, 1917. from this estate which stayed in the Gurney family for nearly 100 years that the Gurneys of Earlham took their name. Augustus Hare's book (The Gurneys of Earlham) is by far the most attractive account of this remarkable family. John Gurney and his wife had 13 children, 11 of whom grew up. Of these 11 there were seven daughters and four sons. Mrs. Gurney died when her youngest child was only a little over a year old, and tlie eldest, Catherine, who from that time took charge of the family, was only 17. Mr. Gurney and his wife were not strict Quakers, and although they conformed in some respects to the customs of the Society, they were very liberal in their manner of life and I have no doubt were the objects of deep concern to their plainer relatives and other members of the Society. At the time of Mrs. Gurney's death, Elizabeth, the third daughter, was just 12, having been born on the 31st of May, 1780. There was one sister between Catherine and herseK and next to her came a boy, John, then four girls bom in three years, and three boys ending the flock. These 11 children, deprived of their mother, were drawn closely together and developed themselves and each other into a wonderfully united family. Catherine, who when still very young, was known as Mrs. Catherine Gurney, felt the chief responsibility of their bringing up, and with the help of the older girls guided them as l^est she could. The father interfered but little, requiring only that they go to Meeting on First Day at least once and sometimes twice. Even this slight conformity was resented by the young people and many are the disparaging remarks recorded in the journals of the children, for keeping of journals appeared to be one of the methods of education in this family, and, indeed, in general at that period. In " The Gurneys of Earlham " we find interesting abstracts from these journals and I wish that I might read you some of them. Indeed, I must read one note written by Louisa Gurney when 11 years' old, particularly as it refers to the subject of our study and gives us a glimpse of one phase of the family. Aug. 14 (1796). Betsy is so ill, I look forward with the most gloomy ideas concerning her A great many Friends came to tea. I did all I could to please tliem. How charming it is to feel one is giving pleasure: though I can never say how stupid they were to me After tea Kitty chose we should work again; this was rather a tug to me, but I bore it pretty well, only Kitty did provoke me by making me give up something to Chenda, merely because she was the eldest; there is nothing I hate so much as this sort of partiality; it does provoke me so. We read a little Sacred History; I like the Old Testament amazingly. The house at Earlham was very large and the Gurneys entertained freely, and as the girls grew older it must have been a most attractive place to visit. The seven girls dressed as gaily as possible, and were often seen in a band riding THE JOHNS HOPKINS HOSPITAL BULLETIN, MARCH, 1919 msjs^ ELIZABETH, MRS, FRY. After the Portrait by George Richn Makch, 1919] 73 over the country on their ponies, wearing scarlet ridinj; habits. The literary- and scientific youufr men of the neighborhood came to the house and tlicre was much discussion on the subjects of the day. particularly in relation to the philosophy of Rousseau, Voltaire and other free-thinking autliors of tliose times. Among this group there were only two young men who took a serious view of life — one the Baptist minister, the other a Roman Catholic chemist named Pitchford, and strangely enough it was this latter who was the one steadying influence to this flock of Quakers. Among this band Elizabeth was probably the gayest and in many ways the most attractive. She sang sweetly, danced beautifully, and was a remarkably independent character. From a very early age slie appears to have been delicate and to have suffered from marked nervous symptoms. She was dreadfully afraid of many things, particularly of the dark and of the water. She also kept a diarj-, but, unfortunately, when she read it over towards the end of her life she felt it wise to destroy all the early years. Judging from what she wrote later, it would have been a most valuable accomit of the feelings and experiences of a nervous child. She herself when 48 recorded her impressions of herself at an early age : Dagenham. Eighth Month, 23d, 182S. My earliest recollections are. I should think, soon after I was two years old; my father at that time had two houses, one in Norwich, and one at Branierton. a sweet country place, situated on a Common, near a pretty village; here. I believe, many of my early tastes were formed, though we left it to reside at Earlham, when I was about five years. The impressions then received remain lively on my recollection; the delight in the beauty and wild scenery in parts of the Common, the trees, the flowers, and the little rills, that abounded on It, the farm houses, the village school, and the different poor people and their cottages: particularly a poor woman with one arm, whom we called one-armed Betsy; anotlier neighbor, Greengrass, and her strawberry beds around a little pond; our gardener, who lived near a large piece of water, and used to bring fish from it; here, I think, my love for the country, the beauties of nature, and attention to the poor, began. My mother was most dear to me, and the walks she took with me in the old-fashioned garden, are as fresh with me, as if only just passed; and her telling mo about Adam and Eve being driven out of Paradise; I always considered it must be just like our garden at Bramerton. I remember that my spirits were not strong; that I frequently cried if looked at, and used to say that my eyes were weak; but I remember much pleasure and little suffering, or particular tendency to naughtiness, up to this period. Fear about this time began to show itself, of people and things: I remember being so much afraid of a gun. that I gave up an expedition of pleasure with my father and mother, because there was a gun in the carriage. I was also exceedingly afraid of the dark, and suffered so acutely from being left alone without a light after I went to bed, that I believe my nervous system was injured in consequenre of it: also, I had so great a dread of bathing (to which I was at times obliged to submit) that at the first sight of the soa, when we were as a family going to stay by it, it would make me cry; indeed, fear wa.s so strong a principle in my mind, as greatly to mar the natural pleasure of childhood. I am now of opinion, that it would have been much more subdued, and great suffering spared, by its having been still more yielded to; by having a light left in my room; not being long left alone; and never forced to bathe; for I do not at all doubt that it partly arose from that nervous susceptible constitution, that has at times, throughout my life, caused me such real and deep suffering. I know not what would have been the consequence, had I had any other than a most careful and wise mother, and judicious nurses, or had I been alarmed, as too many children are, by false threats of what might happen. Even though treated so carefully by otliers her vivid imagination tormented her, and her early diaries must have contained many outpourings of her spirit. These are lost and we can only guess their character by her later struggles and the records of her sisters and friends. John Pitchford records ' that she told him of being so impressed as a child by the story of Abraham and Isaac that she was afraid to go to fleeting for fear that her parents would be required to sacrifice her. The state of her health secured her many privileges. She was allowed to sleep later than the other children and was usually excused from going to Meeting on Sundays — a much prized privilege. The meeting house in Xorwich was reached through Goat's Lane and the children always spoke of the meeting as " Goat's," and recorded in their journals their feelings with such remarks as " I stayed at home from Goat's which I was most glad of," "A long, dis(di.<gusting) meeting at Goat's," etc. (Louisa. 11 years.) Mr. Gurney was "labored with" about liis indulgence of Elizabeth, and when she was older he required her to attend Meeting more regularly. There were no paid ministers among the Quakers and they depended for the " spoken word " upon certain of their members feeling called; that is, having a sense that they must either pray or preach. Certain members who spoke frequently and acceptably were acknowledged Ity the fleeting and designated as ministers, and certain of them traveled from Meeting to Meeting and were called Public Friends or Visiting Friends. It was to hear one of these that Elizabeth Gurney went when slie was 17 years old. Her diary, which has been presened from about this time, reads : Sunday, Feb. 4th, 1798. This morning I went to Meeting, though but poorly, because I wished to hear an American Friend, named William Savory. Much passed there of a very interesting nature. I have had a faint light spread over my mind, at least I believe it is something of that kind, owing to having been mucii with, and heard much excellence from, one who appears to me a true Christian. It has caused me to feel a little religion. My imagination has been worked upon, and I fear all that I have felt will go off. I fear it now; though at first 1 was frightened, that a plain Quaker should have made so deep an Impression upon me; but how truly prejudiced in me to think that, because good came from a Quaker, I should be led away by enthusiasm and folly. But I hope I am now free from such fears. I wish the state of enthudiasm may last, for to-day I have felt that there Is a God; I have been devotional, and my mind has been led away from the follies that it is mostly wrapped up In. We have had much serious conversation; In short, what he said and what I felt, was like a refreshing shower, falling upon earth, that has been dried up for ages. It has not made me unhappy: I have felt ever since Augustus Hare: Gurneys of Earlham. Vol. I, p. 47. 74 [Xo. 337 humble. I have longed for virtue. I hope to be truly virtuous; to let sophistry ily from my mind; not to he enthusiastic and foolish; but only to be so far religious as will lead to virtue. There seems nothing so little understood as religion. A most interesting struggle had begun of which I can only give the bare outlines. She records two days following, on the 6th: My mind has by degrees flown from religion. I rode to Norwich, and had a very serious ride there; but meeting, and being looked at, with apparent admiration, by some oflicers. brought on vanity; and I came home as full of the world, as I went to town full of heaven. However defective the education of the Gurney children may have been; it had at least led to a remarkable independence of thought. Of all of them Elizabeth seems to have been the most independent, and she then and all through her life showed a ver}' clear insight into her thoughts and feelings. She records on Sunday, the 11th: It is very different to this day week (a day never to be forgotten whilst memory lasts). I have been to Meeting tnis morning To-day I have all my old irreligious feelings: my object shall be to search, try to do right, and if I am mistaken, it is not my fault; but the state I am now in makes it difl5cult to act. What little religion I have felt has been owing to my giving way quietly and humbly to my feelings: but the more I reason upon it, the more I get into a labyrinth of uncertainty, and my mind is so much inclined to both scepticism and enthusiasm, that if I argue and doubt, I shall be a total sceptic; if. on the contrary, I give way to it. and as it were, wait for religion. I may be led away. But I hope that will not be the case; at all events, religion, true and uncorrupted, is of all comforts the greatest; it is the first stimulus to virtue; it is a support under every afiiiction. I am sure it is better to be so in an enthusiastic degree, than not to be so at all, for it is a delightful enthusiasm. There are many other records of the struggle. She was so determined not to be carried away by her emotions that she got her father's consent to send her to London so that she might see for herself the attractions of the world and decide whetlier she could be +++++ CONTENTS in their enjoyment. Wliile in London she took music and dancing lessons, went to the plays and to the opera, and saw as much of gay society as her opportunities allowed. Her diarj' for March 26, 1798, reads : This morning I went to Amelia Opie's and had a pleasant time. 1 called on Mrs. Siddons, who was not at home: then on Dr. Batty; then on Mrs. Twiss, who gave me some paint for the evening. I was painted a little, 1 had my hair dressed, and did look pretty for me. Mr. Opie, Amelia, and I, went to the Opera concert. I own, I do love grand company. The Prince of Wales was there: and I must say, I felt more pleasure in looking at him, than in seeing the rest of the company, or hearing the music. I did nothing but admire his Royal Highness; but I had a very pleasant evening indeed. On the other side, William Saverj- was also in London and she went to Meeting to hear him preach and had some conversation with him, and when she returned after two months she began to feel pretty sure that she was going to turn into a plain Quaker. She regarded the change with great interest, but with not a little apprehension, as she knew what a trial it would be to her father as well as to the rest of the children. In May, to distract her mind, her father proposed another visit to London, and she writes in her journal on the 24th : I wrote to my father this morning. I must be most careful not to be led by others, for I know at this time I have so great a liking for plain Friends, that my affection being so much engaged, my mind may be also by them. I hope as I now find myself in so wavering a state, that I may judge without prejudice of Barclay's Apology. It was about this time, when she was just 18, that she began her first independent philanthropic venture — the establishment of her school at Earlham for poor children. She had always fotmd it easy to do for others, and even before her religious awakening she had been her father^s instrument for the distribution of his charities. She took such a delight in doing for people and giving help that she recognized very clearly that she deserved no great praise for so doing. Her development into a plain Quaker progressed deliberately and she took no step in that direction without much thought and travail of spirit, but she adopted one peculiarity after another in spite of the open opposition of her immediate family and often against what seemed to her the dictates of reason. She gave up dancing — a pleasure she delighted in — and singing, gradually changed the manner of her dress, and used thee and thou, the so-called singular form. To counteract all this Mr. Gurney took her with some of the other children on trips, and she seems to have enjoyed what she saw, but the Quakers whom they met at various places interested her more. She on her part was the object of the deepest interest to the Friends, as indeed was natural. At one time, when 19, she was appointed on a committee to in\-estigate the Ackworth School, and afterwards, wb.en the young people were encouraged to speak and nothing was said, she spoke. Of this she writes: "As it appeared to me it was delaying the meeting I took courage (as I thought it was more right than wrong to speak) : and said what I thought of the grammar and ciphering; I felt glad I had done it though i trembled at doing it not a little." She was then asked her opinion of other matters about the school. This seems to have been her first service on a committee of investigation. During this visit she records on July 4, 1799 : " This morning we walked to York and saw its wonders. We .*aw the Friends' Retreat for crazy people which my father thought extravagantly kept." This institution had been founded in 1792 by Friends, under the guidance of William Tuke, and was the first place in England where the humane treatment of the insane was attempted. I have fotmd no other references to her having visited it again, but she was doubtless quite familiar with the ideas and methods carried out there, as the proper care of the insane was a common subject of discussion in the Society. In America the Friends had long been interested in the subject. In 1709 the Philadelphia Monthly fleeting took steps towards the establishment of a hospital for the sick and the insane, but it was not until 1751 that the Pennsylvania Mabch, 1919] 75 hospital wiis founded. This institution among other sick cared for patients "distempered in mind and deprived of their mental faculties." In 1813 the Philadelpliia Friends, stimulated by the success of the York Retreat, founded at Frankford a Friends' Asylum. Upon returninjT to Earlliani, Elizabeth befjan to take a more active part in the ileetin<r, and in the fall of 1709 was appointed a representative. Her Sunday school for cliildren increased rapidly, and here she began to show her remarkable power over audiences. She paid great attention to the manner of reading (for she objected to the way the Bible was usually read), and it must have been here that she be^an lo develop the very remarkable style that was so effective throughout her life. She was married when just 20 to Joseph ¥r\, the son of another prominent Quaker family. The Frys were also wellto-do and were in business in London. Unlike the Gurneys, they were the strict-est of plain Friends. You well imagine that this important step was not taken without due deliberation. Elizabeth felt that she had a distinct work, and like so many young women of to-day she was loath to give it up. The sisters helped in the decision by filling their diaries with hopes and prayers that Betsy might make no mistake. Joseph Frvs first proposal was refused, but thinking from the tone of a note that he might receive a different answer, he went back to Earlham. Augustus Hare, from whom I quote, gives a most amusing account of the outcome. Joseph Fry did not dare risk a second proposal so " he bought a very handsome gold watch and chain and laid them ujmu a white seat. .... * If Betsy take up that watch,' he said, ' it is a sign tiiat she accepts me, but if she does not take it up by a particular hour, it will show that I mu.«t leave Earlham.' The si.\ sisters concealed themselves in si.x laurel hushes, in different parts ol" the grounds, to watch." When Betsy first discovered the watch she retreated to the house, but the sisters kept up their vigil from the laurel bu.'shes. Just where Joseph Fry was tile account does not state, but continues: " Once again did the an.xious sisters see Bct«y emerge from the house, with more faltering steps this time, but still inwardly praying. and slowly, tremblingly, they saw her take up the watch, and the deed was done." Upon going to London Elizabeth Frv' was thrown into quite new surroundings, and it is amusing to find that, altliDUgli she was considered austere and plain among the Gurneys, among the Frys she was looked upon as far too gay and too much given to worldly customs. Her children came rapidly, and by a most unusual circumstance in exactly the numlier and order as to se.x as her mother's, and as each one came it was given the name of the corresponding Gurney child. Her health was not good, and these first years were largely taken up in adapting her^lf to her new surroundings. She was always helping those in want when they came to her attention, but took no special part in public charities. An interesting incident occurred shortly after her first child was born, and we find in her journal (A Memoir of the life of Elizabeth Fry, 1847, Vol. I. p. 108) the following: Mildred's Court, Eleventh Month. 25th (1801). My cough has been so poorly that my husband called in Dr. Slmnis. I asked his advice about our little one being inoculated; he strongly recommended the cow-pox, and said that he would undertake the care of her if we liked: I think higlily of his judgment, and I believe it to be our duty to avoid evil, both bodily and mentally. So trifling a complaint as tlie cow-pox, being likely to prevent so dreadful a disease as the small-pox, at least it appears justifiable to try it; although the idea is not pleasant, it almost looks like taking too much on ourselves to give a child a disease. But 1 altogether was easy to do it. I felt a good deal about the operation, which was very little and easily performed. What a wonderful discovery it is if it really prevents the small-pox. You may remember that the first vaccination with cow-pox was done by Jenner in 179G, just six years before this incident. She became an ardent advocate of vaccination, and when, after the death of her father-in-law, in 1811, she moved to the large country place at Plashet, in the parish of East Ham, she herself vaccinated the cliildren of the parish, having been taught the method by Dr. Willan, an early and earnest exponent of the practice. She inspected the children from time to time to see that none were left unvaccinated. In these villages small-pox became practically extinct. Elizabeth Frv- .^oon became the philanthropic Lady Bountiful of the parish, and there was nothing for the good of the people that she was not busy about. She saw that the sick and injured were visited, estiiblishcd a depot for the distribution of clothing, and in winter she had soup prepared at her house in such quantities as to supply hundreds. With the help of the clergyman and his wife she established a school in which 70 girls were taught. From the first, after moving to London, Elizabeth Fry was iictive in the Society of Friends. She spoke more and more frequently in Meeting, and in 1811 her gift was formally acknowledged by the Meeting and she liecame a recommended minister. The Frys ciitcrtainiMl Friends constantly, and it was not often that they did not have one of Elizaiictii Fry's brothers or sisters from Earlham staying with them. After moving to Pla.<het the hou-sehold became still more complicated, and there are many notes in her journal telling of the thought that she gave to her household, particularly to the proper treatment of servants. Her first 10 children were liorn in K! years, and the last child six years aftenvards, Novemljer 1, 1822. In 1813 she paid her first visit to Newgate Prison where she was much impressed by the misery of the women. There is nothing in her journal, however, that suggests that at that time she felt prison reform to be her great work, and it was not until three years later that she made her second visit, this time at the instigation of two of her brothers-in-law. The condition of this prison was most lamentable and some of the descriptions are hard lo briieve. Years before John [No. 337 Howard had called attention to the prisons in England and had had laws passed by Parliament for their betterment, but these laws seem to have been at this time almost completely disregarded. The part of Newgate in which the women were confined was the worst part, and the conditions were those of utter squalor, misery and vice ; indeed, they were so terrible that the governor himself went there as rarely as possible, and it had for one of its titles " Hell above ground." All the women were herded together without any attempt at classification. There were many children among them, filthy and half-naked. It was in these discouraging surroundings that Elizabeth Fry and her companion requested to be left alone with the women. I doubt whether upon going there she had any plan formed in her mind, biit with her quick instinct she made the one appeal that was most likely to be effective. She spoke to the women of their children and showed them how their behavior was affecting them, and she suggested that, if they would co-operate with her, she would form a class to instruct the children, but that this must be with tlieir cO-operation and that they themselves were to select one of their number to be the teacher. The women immediately grasped at the plan and by the next visit they had chosen Mary Connor, a young prostitute convicted for stealing a watch, to be the school-mistress. It was in these discouraging circumstances that the work began. The prison authorities were entirely skeptical as to the outcome, but allowed Elizabeth Fry and her associates to try it. The plan succeeded from the first and it was not long before numbers of the older women were clamoring to be allowed to attend the classes. Other ladies joined Elizabeth Fry and visited tlie prison daily, and it then became possible to extend the work to the older women. The women were divided into different groups, a monitor from among their number was chosen for each group, and occupation was provided for them as well as daily Bible readings and other instruction. A matron over the women prisoners was also introduced. To do all this required a considerable sum of money which was provided by the committee, especially by Elizabeth Fry and her brothers. The visiting committee of ladies became later the British Ladies' Society for Promoting the Eeformation of Female Prisoners, with many branches throughout the kingdom. The changes that followed these reforms on the women's side at Newgate were so marked and occurred so quickly that they attracted widespread attention, and two years after their inception, in 1818, Elizabeth Fry and her brother, Joseph John Gurney, visited many of the prisons in Scotland and the north of England. The notes (Notes on a Visit Made to Some of the Prisons in Scotland and the North of England in Company with Elizabeth Fry, etc., London, 1819) of this visit were published by ]\Ir. Gurney. The state of each prison they visited is recorded and at the end of the book he has brought together their ideas as to prison management. Later, Eliza beth Fry published her views on this subject (Observations on the Visiting, Superintendence, and Government of Female Prisoners, London, 1827), and they can also be learned from the reports of various Parliamentary Commissions before which she gave testimony. In brief, she believed it essential that the women prisoners should be entirely separate from the men prisoners, that they should be under the direct care of only women, and should be visited by the men officers only in the presence of women; that the women prisoners should be classified, the tried from the untried, the more hardened ofllenders from those less so, etc. ; that they should be properly clothed, fed and warmed; that the uniform of each class should be difl'erent, and that prisoners should be graded according to behavior. She insisted upon the importance of instruction, particularly religious, and urged that the Bible be read to them daily and that it should always be within easy access. Useful occupation she regarded as of first importance, the occupation being so planned as to bring them some remuneration while in prison and to help them to earn their living when they were released. She did not feel that the lot of the prisoners should be made too easy, but she insisted that the first idea must be that of reformation. Solitary confinement she believed to be open to grave dangers, although she advocated strongly that each prisoner be alone at night. She earnestly opposed capital punishment in general, and especially when it was administered for trifling offences as it was at that time. The importance of the supervision of prisoners upon their release was also insisted upon, and the ladies of the committee gave special attention to those women who were to be transported to the penal colonies in Australia. The condition of these women had been most deplorable and their residence in the colony a scandal. The committee was instrumental in providing work for the women to do during the voyage, matrons to have charge of them and proper methods for their recej)tion and care upon arrival. Elizabeth Fry had the great satisfaction of seeing practically all of her suggestions adopted, and it was not long after she had begim her work for the prisoners that to her consternation she found herself famous. Few distinguished people visited London without accompanying her to her claSvS at Newgate. Her advice was asked by very many people; she appeared before committees of Parliament and many Societies. Her influence was little short of marvellous. Correspondence was established with philanthropic persons in various countries in Europe. She gave advice as to the niana,gement of prisons and the care of the insane. She had long correspondence with the philanthropic Venning brothers, John and Walter, who were living in St. Petersburg. It was through them that she sent advice as to the improvement of the lunatic asylum at St. Petersburg, in which the Dowager Empress had become interested and which she had taken under her special care. Elizabeth Fiy recommended east-iron window frames instead of the clumsy iron bars which had been used in the old institution. She also recommended that all except the Mabch, 1919] violent lunatics dine together at a table covered with a cloth and furnished with plates and spoons. Here, as cvenwhere, she felt the importance of the Bible, and the Xew Testament was introduced into this institution. To show how closely Elizabeth Fn-'s suggestions were followed, I shall quote portions of a letter from Mr. Venning written after her death (Memoir, Vol. 1, p. 387) : When I received a letter from your mother I always wrote It out in French and presented it in that language to the Empress, and when she had read it, it was very encouraging to see with what alacrity she ordered one of her secretaries to translate it into Russian, and then deliver it to me to be conveyed to the asylum, and entered into the journal there for immediate adoption. I remember, on one occasion, taking a list of rules, at least 14 in number, and the same day they were confirmed by the Empress; and these rules introduced the following important arrangements, viz.: The treating the inmates, as far as possible, as sane persons, both in conversation and manners towards them — to allow them as much liberty as possible — to engage ihem daily to take exercise in the open air — to allow them to wear their own clothes, and no uniform prison dress — also to breat up the inhuman system of permitting the promiscuous idle curiosity of the public, so that no one was allowed to see them without permission ; a room on entering the asylum was prepared for one at a time, on certain days to see their relations. The old cruel system drew forth many angry expressions from the poor lunatics, " Are we wild beasts to be gazed at? " . . . . Another important rule of your mother's was, most strictly to fulfil whatever you promise to any of the inmates, and above all, to exercise patience, gentleness, kindness and love towards them; therefor, to be exceedingly careful as to the character of the keepers you appoint. These are some of the pleasing results of your mother's work. The Dowager Empress on one occasion, conversing about your mother, said, " How much I should like to see that excellent woman, Madame Fry, in Russia." Her health was never ver}- strong, but even when ill she could not restrain herself from trying to put right what she thought was wrong. On one occasion, in 1824, when resting at Brighton, she noticed the great number of beggars and how the charity was given indiscriminately, and seemed to be doing more harm than good. To meet this she organized the charitably disposed among the different religious denominations into the " Brighton District Society," which was, in effect, a charity organization society, and, so far as I know, the first one ever formed. After this slie was instrumental in establishing similar ones in many other places. It was during this stay at Brighton, while she was suffering from frequent attacks of faintness at night, for the relief of which she was often taken to the window of lier room overlooking the sea. tliat her s_\-mpathy was aroused by the constant sight of tlie blockade man, or coast-guard, pacing the beach. She thought how lonely and isolated his life was and wondered how she could help him. She took the first opportunity of speaking to one of these men, but discovered that it was against orders for the men to speak to any stranger, as their duty was to prevent smuggling. To protect the man she gave him her card with the request that he give it to his superior oflHcer. Some days later she was much pleased to receive a visit from the naval lieutenant in charge of the sta tion and he explained to her the nature of the service. Mrs. Frj' with her clear insight at once thought of a plan, probably the best, that might alleviate the hard lot of the coast-guards — .<lie established libraries containing tiie Bible and other books. The libraries became very popular and were distributed throughout England. Another national society was formed to look after tlie interest of this work. Official sanction was given and certain grants allowed. The report of tho committee in 1836 shows the magnitude to which the work had grown. This report ends as follows (Memoir, Vol. II, p. 229) : The means thus so liberally afforded, have enabled the committee to provide and forw^ard to the coast, 198 libraries for the stations on shore, containing. .25,890 vols. 74 libraries for the districts on shore, containing. 12,880 48 libraries for the cruisers, containing 1,867 School books for the children of the crews of stations 6,464 Pamphlets, tracts, etc 5,357 in No. Making a total of 52,464 vols. and thereby to afford a body of deserving and useful men and their wives and families (amounting to upwards of 21.000 persons) with the means of moral and religious instruction, as well as profitable amusement, most of whom, from their station in life, liave not the means of procuring such benefits from their own resources, and who. in many instances, are so far removed from places of public worship and schools, as to prevent the possibility of themselves or their families deriving advantage from either. Mrs. Fry's interest in public institutions spread over the whole of England, Scotland and Ireland, and many branches of the British Ladies' Societj' were started in all of these countries. In 1835 she extended her influence to the Channel Islands and visited them again in the following year. The acts of Parliament pertaining to prisons did not apply to tliese islands, and their prisons were in a lamentable state. As usual, she was able to suggest many improvements in their management that could be and were carried out. Many of lier correspondents urged her to visit the Continent and give them the aid of her experience and personality. She felt it lier duty to comply with this call, and in 1838 she began her Visits of Gospel Love " to Europe. Siie made five such visits, and, as Friends would say, the way was wonderfully opened for her. Tliose in authority were nearly all more than anxious to have her visit their institutions to suggest improvements. Tlie various royal families received her most cordially ind appeared to delight in her society. She must have made a picturesque figure in such surroundings, dres.scd as she was in the simple elegance of the plain Friend whicii harmonized -o perfectly with her erect carriage, her dignified l)caring an<l lier earnest, sympathetic face. Her principles did not allow her to do many of the things that were considered neces.«ary in court, but this seems to have made no difference. Royalty in general seemed more pleased that she advi.sed them and prayed with them than if she had ki.«sed their hands. She ^uggested many things about the conduct of their prisons, asylums and hospitals, told them of her views as to the [No. 337 religious state of their kingdoms, and when there was religious persecution — as was frequently the case — she pleaded for religious freedom. All this she was able to do with such wisdom and tact that her counsel was accepted in the spirit in which it was given and very frequently was acted upon. She visited the Prussian Court twice, in 18-10, where she was received with peculiar consideration, and when the King of Prussia, Frederick William IV, visited England in 1843, to stand sponsor for the Prince of Wales (the late King Edward VII), he insisted, somewhat to the consternation of those who had charge of his entertainment, in spending much of his time with Elizabeth Fry. He requested that she dine with him at the Mansion House, went with her to visit Newgate Prison, and then took dinner with her and her family. He was heard to say, " She is the best friend I have in the world." Little did Betsy Gurney think when, she renounced the pomps and follies of the world and adopted the customs of plain Quakers, that the path she had chosen was to lead her so often to the seats of the mighty ! Although Elizabeth Fry saw many things to criticize in her journeys to Europe, she also found things to commend and she met with many earnest workers for the amelioration of the distressed. It was during her first visit to Germany that she visited Pastor Fliedner's establishment at Kaiserwerth — • an establishment for the training of nurses, the first secular one that had ever been established. Fliedner had corresponded with Mrs. Fry, had visited her on two occasions and seems to have been much influenced by her example. Mrs. Fry, on her part, upon returning to England followed his example and established the first band of professional nurses in Great Britain. She herself could not take a very active part in it, but her sister, Mrs. Samuel Gurney, and some other ladies took the management of it. When not engaged in nursing, the " Nursing Sisters " resided at " The Home," in the city. They wore a plain but inconspicuous dress and were maintained and paid by the institution, but were not permitted to receive any money or gifts under any circumstances for their attendance in illness. The funds of the Society were small and were derived partly from subscriptions and partly from the liberality of those who were benefited. The intimacy between Elizabeth Fry and the other members of the Earlham family never waned and she paid frequent visits to Norfolk. Her sisters for the most part difl'ered from her in religious matters, but this difference was never allowed to cause any break between them. Whenever there was illness, Elizabeth Fry, when possible, nursed the suft'erer in a peculiarly sympathetic, skillful manner. However strict she may have been with herself, she was more than lenient with everyone else and had a never-failing sympathy. This to some extent must have been due to the fact that she herself suffered frequently from bodily ills, particularly those most troublesome ones of a nervous nature, and she had a most unusual insight into such troubles. In the Memoir " her daughters have included in the extracts from her Journal a number of notes which bear on her bodily state. These give some idea how, in her case, a peculiarly nervous, sensitive nature was controlled and directed and made most wonderfully effective by a firm religious belief. These extracts are probably only a few of many similar ones to be found in the original journal, but they are, I am afraid, too many to be included in this paper, and so I have been forced to select some which seem most interesting. I have already read you her own recollection of her childhood in which she speaks of her childish fears and nervousness. When she was 18, during her religious awakening, she shows in the following extract how she was struggling against her morbid fears : Jan. 4, 1799. A plan, at least a duty, that I have felt for some time, I will now mention. I have been trying to overcome fear; my method has been to stay in the dark, and at night to go into those rooms not generally inhabited; there is a strange propensity in the human mind to fear in the dark, there Is a sort of dread of something supernatural: I tried to overcome that, by considering as far as I believed in ghosts, so far I must believe in a state after death, and it must confirm my belief in the Spirit of God; therefore if I try to act right, I have no need to fear the directions of Infinite Wisdom; I do not turn away such things as some do. I believe nothing impossible to God, and He may have used spirits as agents for purposes beyond our conceptions; I know they can only come when He pleases, therefore we need not fear them. But my most predominant fear is that of thieves; and I find that still more difficult to overcome, but faith would cure that also, for God can equally protect us from man as from spirit. Before and after the birth of each child she usually suffered a period of depression, accompanied by great bodily weakness and a terrifying apprehension of death. After the birth of her second child, when 23, she writes : Plashet, Fifth Month, 21st, 1803. I have long been prevented writing in my journal, by a severe attack of indisposition. It is difficult exactly to express what I have gone through, but it has been now and then a time of close trial; my feelings being such at times as to be doubtful as to whether life or death would be my portion. One night I was, I believe, very seriously ill; I never remember feeling so forcibly how hard a trial it was in prospect to part with life. Much as my mind, as well as body, was then tried in this emergency, still I felt forcibly an inward support, and it reminded me of that text of Scripture, " Can a woman forget her sucking child, yea they may forget; yet will I not forget thee." And then I told those around me, that I was so ill, I could almost forget my child, but I felt the existence of a power that could never forget. I have gone through much since, in various ways, from real bodily weakness, and also the trials of a nervous imagination: no one knows but those who have felt them, how hard they are to bear, for they lead the mind to look for trouble, and it requires much exertion not to be led away by them; nothing I believe allays them so much as the quieting influence of religion, and that leads us to endeavor after quietness under them, not looking beyond the present. But they are a regular bodily disorder, that I believe no mental 'Memoir of the Life of Elizabeth Fry. Edited by two of her daughters. London, 1847. March, 1919] 79 exertion can cure or overcome, but we must endeavor not to give way to them. Again six years later she records: Seventli Month. 27th, 1S09. I am much better than I was, but I have believed, in these trying complaints to which I am liable, that the less I look outwardly for help the better; as I do not believe any doctor can do much for me. I feel the best satisfied when I simply endeavor to bear them patiently; I think I know myself, wliat is the best to take for them: they appear to be principally nervous, which I consider to be beyond the power of man either to understand or cure; but how often have I experienced true spiritual support and help, when I have endeavored patiently to wait on the source of good: and the mind being so nearly connected with the body, whatever tends to tranquillize it, really helps the complaint. She often was pursued by the tlioujiht that possibly lier nervous depression might be due to a lack of faith, and an evidence that she was in some way untrue to her religious standards, although her intelligence told her that the condition was largely a physical one as is sliowTi by the following extract : Plashet, Fourth Month, 30th, 1S14. None know but those who suffer from them the deep humiliations such disorders create, as those I have lately had; I mean great bodily weakness, accompanied by nervous lowness of spirits, and mucli mental fear. In the first place, how deeply do they try us, being in their own nature so painful: in the next, from the difficulty in doing strictly right in them, how far to endeavor to divert by cheerful amusement, or by taking such things as may soonest relieve them; and added to these, I think many are apt falsely to accuse themselves, and to mistake the painful restlessness and fear occasioned by them, for impatience and mistrust; I have sometimes a hope that this is not my case, thougli at others great fear arises, lest I should in any degree let go my hold, or be impatient after having so abundantly known the goodness, the loving-kindness of the Almighty. Oh, saith my soul, may He once more revive the spirit of His poor unworthy one. and breathe upon these dead bones, that they may live. The neurotic disposition seems to have been an inherited tendency in this remarkable family, and Elizabeth Fry, when 53, wrote to one of her daughters, who was evidently suffering, the following helpful and encouraging letter: (1833.) I feel in the first place, earnestly desirous that thou shouldst think as little as possible of thy nervous feelings. I luiow how extremely painful they are, but experience' has taught me. the less I think of them the better. It is most important to look upon them as much as possible like the toothache — that it must be endured while it lasts, but it is not dangerous in its nature. As for the discolored view, the imagination may at times give to things, nothing is more important than to set it down as a clear and fixed thing in the mind, that whilst this nervousness lasts it is not sound, and must not be believed or taken heed to. I would not have thee discouraged at this return of it. I believe I never had death brought home very closely. without being brought into a low nervous state, it is after all so awful: though I increasingly see. that this is real weakness, and that those who are believers In the Lord Jesus, however unworthy, need not fear it, as through Him its plague and sting will be done away. But it is folly in one sense to look ahead, we have enough to do to seek for help and grace for the present time to do our present day's work. When the day comes that we have to give up "this mortal life." we may and ought humbly to trust. that through the unmerited mercy and love of our Lord, His grace will be found suflicient for us. I observe, for my great encouragement, that what we call nervousness often proves no common blessing, if made a right use of, and not given way to. It so wonderfully humbles, prevents the creature glorying, and makes willing to do anything to come to that peace, which quiets every storm. Thy uncles and aunts have nearly all been striking instances of this: and I believe, hard, very hard as it is to bear, it is a baptism to fit for a fulness of joy and glory rarely partaken of; but it in no common degree calls for patience. I always think both David and Paul largely partook of this sort of humbling experience. Therefore my dear .... if tried this way, possess thy soul in patience, and look upon it as a suitable, though bitter, medicine prescribed by the Physician of value to promote thy health and cure. She always, wJiile engaged in her various philanthropic activities expended her strength most lavishly, and afterwards she usually had periods, often long ones, of great .suffering. Together with the physical weakness, the accompanying menXaI depression was often combined with the fear tliat she had received far too mucli personal adulation, and that she had ])erhaps put herself forward unduly. She was glad to use the power of her reputation and position in the furtherance of her ]irojects, but was very fearful that she might take to her.self — the instrument — the credit that was due to her Lord, and she at times looked upon her illnesses as corrective agencies. As she was returning from her second visit to Germany, when 61, she WTites, in a letter to her husband and children, the following: Cassel. Ninth Month. 26th. 1841. I have continued very far from well, with latterly a considerable stiffness in my limbs, so that I am obliged to be assisted to walk upstairs, and helped into the carriage, sometimes by one or two men. I might have had the same attack at home; but one thing is certain, we may fully trust in our Heavenly Father, who is constantly protecting us under the wing of His love, and who knows what is best for us, I have sometimes thought that after being so helped on my way, from the palace to the prison, it was likely that the poor instruments should need a little further refining and purifying, for our works are to be tried as by fire. I have very earnestly desired not to repine, or to be unwilling to drink the cup that may be given me to drink. We travel witli six horses to make the greatest speed home. I have a board in the carriage, tliat when your uncle and Anna are outside. I can quite rest and make a real sofa of It, when I need it, which I do for one or two stages In the day. Mary and Francois are very attentive and kind; indeed how differently am I cared for to many poor missionaries. I wish you to feel for me, but not to be too anxious about me; •ommil mo entirely to Him wuo only knows what is best for me. Ynur aunt lOlizabeih's Iflter wi.n very seasonable and acceptable. I wis!) her and all my children to know how it is with me. for I need their sympathy and prayers, at the same time that I feel the best help to be near, and the Power that says to the waves " So far shall ye go and no further." Often In my wakeful and at times distressing nights, a sweet peace comes over me to calm my troubled spirit. We hear from newspapers, that the poor Baptists In Copenhagen are to be released from prison, a small sum being paid by way of fine. What a comfort! and the poor Lutherans In Prussia say they are now so well off, that they do not wish us to ask for any more liberty for them from the King. After this visit Mrs. Frj's health improved but slowly and, although far from well, she felt it her duty to go again to 80 [No. 337 Fraufe in ]S43. Upon returning from this visit her health failed rapidly and she was practically an invalid from then until her death, although she was able to continue her correspondence and at times to take part in the various national societies she had founded. Among the number of interesting references in the Memoir to this time I can only include the following : One afternoon, when one or two members of her family were reading to her, she was unable to attend to a very interesting religious biography, saying, it was too touching to her — too aftecting. She added, after a pause, "How I feel for the poor when very ill, in a state like my own, for instance, when ' good ' ladies go to see them. ' Religious truths so strongly brought forward, often injudiciously.' " As she became weaker her fear of death decreased and to one of the " Nursing Sisters " she thus expressed herself, " I am of the same mind as Paul, I can say, 'to me to live is Christ, but to die is gain.'" Shortly before her death her daughters record a marked change in her dominant disposition: There was another wonderful change. Her powerful understanding and great capacity had given her the habit of control — she was accustomed to power. During her long illness, this continued more or less to show Itself, and it was not always easy to distinguish how far her opinions about her own treatment and capabilities were well founded or not. This feature of her character had disappeared. The will seemed wholly broken, the inclination to resist, or even strongly to desire anything, passed away; and she was +++++ CONTENTS to leave little things and great to the direction of others. It was inexpressibly affecting to see her look of meek submission, to hear her plaintive answer, " Just as you like," to those about her. These extracts that I have read show clearly how much Elizabeth Fry suffered throughout her life from her peculiar nervous organization. For two years before her death in 1845 she was an invalid, confined practically to her bed or chair. Exactly what organic trouble she had, I have been unable to determine, for her daughters speak only in very general terms of the symptoms. She became less and less able to take any active part in the various movements she had been instrumental in starting. She, however, attended Meeting whenever possible, often when she was too feeble to leave her wheelchair, and it is said that her mind remained remarkably clear in regard to her ministry, even when she found it very diflBcult to concentrate her attention on other subjects. During the last months of her life she appears to have suffered intensely, and her strong will seems to have become passive, but her condition did not become acutely alarming until three days before her death when, I think, she must have had a thrombosis of the cerebral blood vessels. Slie gradually became unconscious and died October 12, 1845. Elizabeth Fry's religious faith never wavered, nor did she ever regret having become a plain Quaker. She suffered much for her principles, particularly from the fact that many of her sisters and brothers could not see as she did and that most of her children separated themselves from the Society. Her eldest son renounced his membership and others were disowned for marrjing out of Meeting. She believed most strongly that young people should be left free in their choice in marriage and encouraged her children in this by her svTnpathy and love. She felt as a minister of the Society of Friends that she could not go to their weddings, but she did attend the Meetings in which their names were taken from the list of members. She was thrown much with earnest people of all denominations and had no trouble in uniting with them all. Her attitude to others was one of love and helpfulness, but of herself she was a severe critic. Although she felt it right for herself to confonn rigidly to the customs of Friends, she regarded it as a personal matter, and saw clearly that such conformity might be a stimibling block to others, particularly to the young. She had little patience with the empty forms of piety, whether in plain Quaker or in the most ritualistic of priests. Her religion was one of service and she truly followed George Fox's injunction, " That which Friends doe speake they must live in." Augustus Hare (Gurneys of Earlham, Vol. II, p. 201) writes of her wonderful tenderness: Mrs. Fry used pathetically to say at this time that she had been " undermined by excessive love," an expression touchingly significant of the secret spell of Elizabeth Pry — the spell which unlocked the hearts of kings to her, and caused the prisoners' chains to fall off at her approach. She had been no professional philanthropist, too much absorbed in humanity at large to care for the human item, but the public work had been, as it were, only the overflow of her woman's heart, the expression of the fulness that remained after children, grandchildren, brothers, friends, had been loved with an intensity which to her eyes seemed " excessive," almost sinful. This marvellous tenderness it was. thrilling in the tones of a voice whose natural music would have been almost sufficient to melt and convince, which had been the key to her influence and power — this, and her sweet humility of soul, her child-like, single-eyed devotedness. This certainly accounts for the charm and appeal of her personality, but her effectiveness was due, I think, to the fact that she had a most remarkable faculty of grasping a situation and knowing, seemingly intuitively, what under the circumstances should be done to meet it. This is genius, and when genius is activated by Christian love what may it not do and who of us would not gladly follow ? THE JOHNS HOPKINS HOSPITAL BULLETIN. It is issuod monthly. 'N'olumo XXX iy in progress. Tlie sxibscription prico is$3.U0 per year. iForeign postage, 50 cents.) Price of clothtxnind volumes. $3.50 each. A complete index to Vols. I-XVI of the Bulletin has been issued. Price. 50 cents, bound in cloth. Orders should be addressed to Thd Johns Hopkins Press, Baltimobb, Md. The Johns Hopkins Hospital Bulletins are issued monthlp. They are printed by the LORD BALTIMORE PRESS, Baltimore. Subscriptions,$3.00 a vear (foreign postage, ,'50 cents), may he addressed to the publishers, THE JOHXS HOPKiyS PRESS, BALTIMORE ; single copies jpili be sent by mail for fifty cents each. Single copies may also be pi-ociircd from the BALTIMORE NEWS CO., Baltimore.

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Vol. XXX— No. 338]

## Contents

DcKi'tieration tJranulcs and Vacuoles in the V'ibroblasts of Clii|>ital .M.Mli.al Society

Clinical Dliscivaf ions on Epideniie InlUiriiza [1)1!. .\. I.. Bloo.mkiki.h and Dr. (;. A. Harrop] ;— Comments on the Pathology and Bacteriology of Fatal Inlliienza Cases, as Observcil at Camp Devens. Massaclmsetts [Dr. S. B. WoLUAi ii] ; — .-\ Kiinctioiial lie-education Clinic: Organi/.ation and Methods (Dr. W. (i. Tho.mp.so\) ; — Malaria in the Federated .Malay States. A Coriection | Dr. W. (J. MacCallusi j.

DEGENERATION GRANULES AM) OF CHICK EMBRYOS C

VACUOLES IN THE Fir,HOBLASTS TILTIVATEI) IN VITRO

By Wahukx (From the llfpnrtmrnt of Anatomti.

l.NTKODrCTIO.N

Tlu' riirniiititiii ul' ;rriiiiuii'.s am! nT tluid vacuoli's within lin' lil>ri)l)la.tt.>< of ti.ssut'-fulturi'.s is of fn-qui'iit owurrcncc in |il)i.<iiia iinti in IxK-kcV .solutinn, witli or without tho ailditiun i>f othtT siihstaiiws. TIrtc arc other t\in'.>; of licfjciu'ratidii. Thi.>i vat-iioli/.utioii of the fytophLsni i.s one of the more coinnnin iiUMles of cell (lefieneratioii unil (K-iitli in tissiie-<-iilture.«. It liiis, however, reeeived very little eoiisiilenition, partly hecaiisi> the vacuoles have often lieeii eonfu.seil with fat ilr<i|is ami ])artly heeause iiivesti;:ators have heeii reaihinj; out in other tlireetion.*!.

I.icwis and Ix'wi.s ('!.")) eon.sidereil .somewhat hrietly tin fn"aniiles and vacuole.s H|i|)earin;; in the eell.s of eiiltiires. especially the ^rranule.** which .«tain with neutral red, Nile lilii. B extra, and lirilliant eresyl hlue 'ih. In the normal cell tli«'

raiiule.s were few in number, hut were plentiful in cells with

many vacuole,*. It wa.* al.«o noted that they accumulate ahout tho central liody (centrosphere) and are similar to the ;rraiiulcwithin the vacuoles. Xo relation.ship was founil between these in-anules and mitochondria.

H. Lewis The Johns Hopkitm Mcdiral S' hool)

'J'he aulliors al.sii (Icalt sipmcwii.it brictly witii the vacuoles found in the cytoplasm, recoj^niziiifj that they were si^nis of ilegeneration of the cylo))lasni and that there was a prof,Tt'i'-'*ive accimiulation in some types of defreneration until most of the cyto])lasm was useil up and only a framewurk remained. At first it was .sdiiicwhat dillicult to distin<;uish the vacuoles from tho fat ^.'lobule s|)aces in li.xi'd and staineil |)reparatioiis, but in the living cells no such ililliculty was encountereil. Small ihincinj,' oranules, varyinj,' in numiier from one to many, were seen within the vacuole; sometimes the ^franules were motionle.>Js and adherent to the wall of the vacuole. It was al.so ftuind that at times th(\v were colored jiale jfreeii with janus jfreen. With Nile blue B extra anil brilliiint cresyl blue 'ih the +++++ CONTENTSs of the vacuoles stained ])ink', and the jrrannles blue or purple. ('han;:es in the shape of the vacuoles and the formation of very unstable, thread-like processes exteiidin;: out from them were also ob.served. We were unable to trace any relation liotwoen mitochondria and vacuoles, although it wan often noted that the niitochondria chanfred from threads and rods to {.Tannics and vesicles, jiarallid with the increase in tin

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number of granules and vauuoles, and that in extreme vacuolization the mitochondria were lodged in the eytoplasmic framework between the vacuoles.

Maximo w ('IG) noted in plasma cultures of subcutaneous tissue of the adult rabbit, fixed with Zenker-formol, embedded in celloidin, cut into histological sections, and stained with cosin-azur, that the fibroblasts contain singular gi-anules which stain bright pink — i. e., are slightly acidophilic. At first these are minute and irregularly scattered in the cell body in small groups. The number of gi-anules varies, but increases with the age of the culture. " In old cultures vrithout cell proliferation all fibroblasts are often crowded full, up to the very end of their outgrowth, with large, round, closely packed

granules Besides the above granules the protoplasma

of many fibroblasts of the same preparation contains small and large vacuoles." In some vacuoles a large or small acidophilic granule of the same character was occasionally detected. ilaximow states that the impression produced is that the granules dissolve from the outside inward and form the vacuoles, and that the granules become permanent constituents which are transmitted to subsequent cell generations. He further finds that " the whole cell-body and its processes are then crowded full of spherical, occasionally very large, granules, so that but little is seen of the protoplasm itself." He regards this as an adaptation for life outside the organism. The vacuoles usually present are either scattered singly or joined in groups. " In the fibroblasts embedded in the masses of the old fibrin the majority of the large granules are substituted by vacuoles and the structure of the cell-body appears therefore coarsely foamy." These granules and vacuoles fomid by Maximow in the fixed and stained cultures of the subcutaneous tissue of the adult rabbit correspond to the granules and vacuoles previoush' described by Lewis and Lewis, and are probably similar to the ones considered more in detail in the present paper.

JIaximow concludes, from cultures fixed in Zenker-formol and stained ^vith iron hematoxylin after sectioning, that the above-described acidophilic granules represent the product of the direct transformation of the chondriosomes. He bases this view upon the very distinct pictures secured by the above method. He says : " The black chondrioconts change into round granules — the mitochondria, which increasing in size seem to transform themselves into the acidophilic granules." This theory regarding the derivation of the above-considered granules and vacuoles from mitochondria is probably cjuite incorrect. The two types of cytoplasmic inclusions have nothing to do with each other. Maximow's conchtsions are such as might be expected from the methods employed by him. He introduces the article under consideration by the statement that heretofore tissue-culture has lacked exact, authentic, systematic researches of a histological character, and that " we lack till now precise information concerning their microscopic structure, their correlation, and, above all, their origin from determined, well-knowTi elements of normal tissue." After this introduction he proceeds to show how cultures should be studied. What could bo more absurd than

to base practically all conclusions upon observations made on tissue-cultures that have not only been cut into sections, but have also been fixed in the same old mixtures that have so often led observers astray in normal tissues. The very thing we are trying not to do in tisstie-cultures is what ^Maximow seeks to introduce with his histological technique. The absurdity of depending ahuost entirely upon histological teclmique, section cutting, etc., ^\-ill, I think, be obvious to most American observers familiar with cultures. The greatest value of the tissue-culture method lies in the fact that it admits of a study of the living cell, and affords an opportunity actually to watch some of the changes which take place therein, both under the usual conditions of the culture and under various experimental conditions through the introduction of knowTi factors, such as vital stains, various chemical substances, drugs, poisons and other alterations of the mediimi. Maximow gives little or no attention to observations on the living cell, at least as far as one can judge from liis article. This is partly due, no doubt, to the fact that living cells are not so easily observed in plasma as in fluid media. I do not wish to undervalue the use of fixed and stained material, especially total mounts (we use them extensively) ; but the pictm-es found in fixed and stained material should be interpreted and controlled from extensive observations upon the living cells. The emphasis, in fact, should be laid on the study of the living cells, and this we have constantly done. It is, of course, more easily accomplished when fluid media are used and the culture grows out on the under surface of the cover-slip, than with the use of plasma. The fixed specimens are of great help in the construction uf illustrations, and some structures are more clearly revealed than in the living; but tmless they are to be seen also in the latter, their existence in the living cell, as seen in the fixed specimen, must always be open to question.

Maximow criticizes our methods very severely : "' In view of the imperfection of their methods (the preparations were made by vapors of osmie acid and examined in ioto, without making sections) their results are of but little importance." In the first place, osmic acid vapor, wdth the virtues of which Maximow is apparently not familiar, is a most excellent fixative for cultures in fluid media, far better than any of those employed by him — we have tested them all. It may not answer as well for plasma ctiltures, but with that we are not concerned. In the second place, there is little point in making sections of cells that are already flattened out on the coverslip, unless one wishes to trace their origin from the old piece ; for that purpose we have, of course, occasionally made sections.

Maximow also criticizes, as have others, the tise of Locke's solution. We have never claimed that this solution alone contained all the necessary food-stufEs, but with the addition of dextrose and bouillon or egg-yolk the need can be partially met. Just how complete a supply of food can be given in this manner has not yet been determined. Cultures have been kept alive for a month by washing and changing the medium every day or two, and possibly they might be carried on much lono-er. The cultures in plasma degenerate somewhat more slowlv, as a rule, than those in our solutions, but here also

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replantation is necessary for long continued growth. Burrows and Xeymann ('IT) believe that food materials for the growing cell^. in both i.-iotonic .<alt solutions and jilasma, come directly from tissue fragments in the explanted piece through disintegration caused by unfavorable environment. \Ve have long thought tliat some of tlie food elements might be sup])lied in this manner. The conditions, of course, are not normal either in ])lasnni or in Locke's solutiou, but tlu' first fibroblasts that grow out into the media show no al)normal cytologic chaugi^s. The conditions in these embryonic chick filirohlasts undoubtedly ditTer somewinit from those found in the aduh mammalian fibrol)lasts studied l)y Maximow.

Burrows and Xeynninn find that the cells in rilro " come to rest after a short ])eriod aiul .«how evidences of deterioration through vacuolization and failure to stain deeply." These authors evidently recognize that vacuolization is a sign of degeneration. We have not found that the process interferes with the staining of the c-ells unless they are ilead before fixation. A cell may be almost completely filled with vacuoles ami yet stain brilliantly with iron hematoxylin and a counter stain.

Luna ('IT) found small vesicles or vacuoles aj)pearing in the pigment cells of the retina, cultivated in ritro, and as their number seemed to increase with a corresponding decrease in the mitnchiuidria, he thought it probable that they were derived from the latter. Vesicles such as he pictures in his Fig. 7 correspond to the mitochondrial vesicles already figured and described by us in degenerating cells (1915). They do not correspond to the degeneration vacuoles described in the present paper.

M.\TERI.\I> A.NI) METHODS

Most of the observations were nnule on small explants from the leg& of G-, T-, and S-day chick embryos cidtivated in the usual manner in Ix)cke's solution plus 0.5 per cent dextrose. Such cultures show fibroblasts, clasmatocytes, and often ectodermal membranes and muscle-buds. The cultures of this special series usually rc^iched the maxinnim growth in about 48 hours. Some of them showed more or less degeneration at T2 hours, and at 0(! hours most of the cells were ccmipletelv degenerated an<l dead.

I wish to emi)hasi/.e liere tiiat the particular series of cultures (several hundred) used for these observations were made by an inexperienced a.ssistant and that the number of cultures showing granular and vacuolar degeneration was far in excess of that shown in any of our other series where such a mode of degeneration is not by any means the rule. Not only did most of the cultures show such degeneration, but the growth was usually below the average and sometimes there was no growth. I have not been able to analyze the factors responsible for this excessive amount of granular and vacuolar degeneration. The process is, however, essentially the same as that ob.served in other series except that in the latter case the cultures lived longer with normal appearing cells before degeneration liegan and that this particular type of degeneration was not so common.

The cessation of growth, of mitotic division, and degenerative changes, may depend luit so much on the exhaustion of the food supjdy as upon the accumulation of waste jjroducts in the medium. There was very little Huid in the small drops used in these cultures, and it is possible that it did not take very long for the accumulated waste |)roducts to exert injurious effects upon the cells.

Mitotic figures were found in some of lhe.<e cultures, often many in the same culture at the same time. Such dividing cells are found in the 24-, 48-, and T2-hour cultures. On the other hand, some cultures do not contain a single mitotic figure, and these are usually the ones which show degeneration changes, some even as early as the second day. We are still ])uzzled by the great differeiurs in the vitality of the cultures, ilue, perhaps, to unknown factors during the manipulations. This is more especially true when the method is used by an inexperienced worker. The rate and extent of growth are often equal to that seen in ])lasnui.

The living fibroblasts were observi'd over varying lengths of time in cultures of various ages, both with and without the use of vital stains and various other substances. The vital stains most frequently employed were neutral reil and janus black Xo. 2. The combination of these two stains proved the most satisfactory of all. We have, in the past, frequently used the combination of tun \ il;d stains, more especially neutral red and janus green. Tiie latter combination has been u.sed also liy Coghill ('15) on fresh amphibian material, and by Mrs. Lewis ('IT) on certain eggs and embryos. The neutral red is rapidly taken up by the vacuoles and certain granules of the fibroblasts, while the janus black No. 2 stains only the mitochondria a deej) blue-i)lack. Neutral red was used in strengths varying from 1-5000 to 1-800,000 in Locke's solution. For most of the observations I use 1-20,000 or 25,000. The janus black No. 2 was usually of the strength of 1 j)art of janus black No. 2 to 10,000 or 20,000 part,s of Locke's solution. Brilliant cresyl blue 2b and methylene blue (Ehrlich rect. or Ilarmer Lab.) were also used. These stain the same granules and vacuoles that take up the neutral re<l.

Until recently we contiinied to use osmic acid vapor as a fixative with excellent results. l.ately, however, the osmic acid in the market has not given satisfaction, and we therefore substituted Zenker's solution without the glacial acetic acid (2.5 per cent bichromic acid solution plus 5 per cent corrosive sublimate plus 1 per cent sulphate of sodium). This has given most excellent pre])arations when followed, as were the osmic acid specimens, with the iron hennitoxylin stain. The trover-slip with the attached growth is innnersed in the bichromate corrosive sublinnite mixture from i to 12 hours, washed and carried through the alcohols with a little TiUgol's solution. It must be borne in mind that fhe |)rocedure here used is suitable for cultures grown in Tiocke's .solution and not necessarily for jdasma cultures where the clot aits as a buffer through which the fixatives must penetrate. In cultures in Ijocke's soluiton the naked cells are exposed to the action of the fixative and the process is correspondingly rapid, reducing post-mortem changes to a minimnm. Comparatively few

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cultures were fixed, as we relied upon living material for our (onelusions. With the iron hematoxylin stain it was often impossible to disting-uish between small granular mitochondria and the degeneration granules, as both are stained black. The study of the living culture aids in the interpretation of the fixed material and vice versa. Some jioints would undoubtodlv liave been missed if only one method had been cniploycil.

DEGENERATION GRANULES AND VACUOLES Degeneration graniiles may be characterized brietiy as follows :

(1) They are rare or non-existent in tlic more normal, vigorous fibroblasts of the verj' young cultures.

(2) They vary in size from the ultramicroscopic grannies to ones larger than mitochondrial gi-anules.

(3) They increase in number with the age of the culture.

(4) Tliey tend to accumulate about the centriole or centrosphere.

(5) They are often moved about actively (by cytoplasmic currents), usually in paths from the periphery to the centriole or centrosphere, or vice versa.

(6) They take the neutral red stain with great avidity, also brilliant cresyl blue 2b and methylene blue (Ehrlich).

(T) They are not stained by jan\xs black Xo. 2 which stains the mitochondria.

(8) In fixed specimens stained witli iron hematoxylin many of these granttles are not distinguishable from mitochondria.

(9) They do not arise from the mitochondria.

(10) The degeneration vacuoles develop al)out tln'ni.

(11) Tliey are probably waste products.

(12) They accumulate under certain conditions in degenerating fibroblasts, and hence might be called degeneration granules.

The degeneration vacuoles show the following characteristics :

( 1 ) They are not found in tlie normal, vigorous fibroblasts of the cidtures.

(2) They are first apparent after there lias lieen a considerable accumulation of granules.

(3) They always seem to form about the granules and almost always contain one or more granules.

(4) "When first recognizable the vacuoles arc small and contain a relatively very large granule.

(5) They vary much in size.

(6) They tend to accumulate about the centriole or centrosphere.

(7) They often move in paths from the ju^ripbery to the centriole or centrosphere, or vice versa.

(8) They stain avidly with neutral red. l>ut not as deeplv as the granules; they also stain witli mctliylenc Idue and brilliant cresyl blue 2b.

(!>) They are not stained liy janns black Xo. 2.

(10) They often change shape in the living cell, all gradations from spheres to long thread-like channels being seen.

(11) They do not arise from the mitochondria.

(12) They are probably waste products.

(13) They accumulate under certain conditions in degenerating fibroblasts until the latter are often crowded full of them, and then as the cell dies they disappear and the dead cell has a moth-eaten appearance.

The granules and vacuoles especially considered here are most readily singled out from other cytoplasmic inclusions by their property of rapidly absorbing the neutral red dye. It is well known that neutral red stains certain granules in various types of cells in other animals, and the fact that they absorl> neutral red does not necessarily indicate that the granules are identical in composition : very likely they are not. We do not know whether the union of the dye with the granule is a physical or a chemical one. Such grantiles, however, probably have certain characters in common.

The determination of the presence of such granules in the normal, living embryo or animal is most easily aecomplisheil in small, more or less transparent forms that live in an aqueous environment. In embryos, such as the chick, it is more difiiciilt to ascertain with certainty if such granules are normal in any particular type of cell, such as the fibroblast. The mere act of isolating the fibroblast by separating it from the organism in teased preparations, in spreads, or in cultures, immediately alters the environment. Changes in the normal metabolic activity probably follow immediately, and the formation Qf such granules may result from the changed environment through alterations in the normal supply of gases, salts, carbohydrates, protein products or through the inadequate elimination of waste products from the immediate environment of the cell.

For the present, at least, we are micertain whether such granules actually exist in the fibroblasts under the normal conditions of the embryo. Occasionally one finds here and there, in cultures less than 24 hours old, fibroblasts entirely free from granules that take the neutral red stain. If these granules do exist normally they are probably small and few in number. Such filiroblasts exhibit a marked contrast to those found in many of the older cultures.

fiRAXULES IX THE TOUSG FIBROBLASTS

Tlu' liealthy vigorous fibroblasts of the young cultures are free from vacuoles and contain very few scattered granules that stain red with the neutral red. In the ordinary cultures there are usually to be fotmd, at the end of 24 hours — in the fibroblasts that have migrated from the explant, or other fibroblasts that have arisen from these by mitosis — scattered, clear, refractive g-rannles. They vary in number, often quite markedly, in difl'erent cultures and also in cells of the same culture. After 24 hours none of the fibroblasts are entirely free from such granules and many of them also contain small vacuoles with relatively large granules.

niSTRIBt'TIOX OF GE.VXILES IX THE HEALTHY FIBROBLAST.S

The comparatively few grantdes seen in the fibroblasts of the very young cultures are scattered through the cytoplasm without any definite arrangement, so far as I have been able to determine. Those in the body of the cell, however, a]iproacb

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to within varying distances of the edge of the much flattened cells. (Jriuiules are not uncommon in the lari;i'r iiroi-csscs, and here sometimes, since they may be nearly as larjje as tlic diameter of the i)rocess, they come close to tlie surface. It is not surprisinji that the granules are irregidarly and apiJarently indiscriminately scattered through the cytoplasm, as under the best conditions tlicy often move about, usually in a patJi from the periphery to the nucleus, or riVe cersu, and are tliu;! constantly changiutt ])osition. As we shall .^ee later, in tlu' fibroblasts of older cultures the granules and vacuoles come to have a very definite relation to the ccntriole, and their paths of movement are between the ccntriole and the ]icripliery, rather than between the nucleus and the periphery. The position of the ccntriole is dillicult to determine until there has been a considerable acciunulation of granules, but T think if it could be located in the younger, healthy tihrohlast.s wc should find that the granules were moving in jiaths between it and tlic j)eriphery. rather than between the nucleus and the ])eri|ilicry. Its close proximity to the nucleus makes it a])]>ear as thougii it were the nucleus that was the center for such activity.

IXCRKASK IN rilK XI .MBER .VXD SIZK OF THE GRAXfl.ES .\NI) VACUOLES

As the cultures get older there is a gradual increase in the number and size of the granules and vacuoles. In spite of great variations in the rate of accimiulation and the ultimate size of the granules and vacuoles in ditferent cultures, an accurate picture can be given of the more usual process found in the majority of cultures that undergo vacuolar degeneration.

As the granules increase in number it soon becomes noticeable that |)art of them accumulate at one side or at one end of the nucleus. In fixed material and in later stages this accumulation at the side of the nucleus is clearly seen to take ])lacc about the ccntriole or centrosphcre. It is rarely possible to recognize in the living cell, during the early stages of the accumulation of the granules, the ccntriole or centrioles at or near the center of the granular mass. Since, however, it is possible to do so in fixed material, and at later stages also in the living cell, I have not the slightest doubt but that this accimiulation of granules at one side or at one end of the nucleus always takes place about the ccntriole. This is a very interesting and im|)ortant ])oint. It is the centricde, then, ami not the nucleus that is most directly concerned in the accumulation or location of degeneration granules and vacuoles.

The ccntriole or the ap|iaratus surrounding it is the determining factor that in name manner governs, by its ju'culiar metabolic activity, the accnnndation of the granules and vacuoles about it. I shall speak of an accumulation of graindes about the ccntriole in these earlier stages, even though in the great majority of instances the centrifde was not positively recognized in the living material.

As the granules and small vacuoles increa.«e in nHnd)er, then, they accunndate nmre and more about the ccntriole. The nniss is den-^er at the center than at the iieriphery, and there arc always a few granules scattered through the cytoplasm. With the increase in number of the grannies the presence of snndl

vacuoles about many of them becomes more ajiparent. The granules also show more variation in size, in that nniny of them are larger than before. As the jjrocess goes on. the number and size of the vacuoles grailually increase, so tlial they form an ever-widening hah) about the centriule and centrosphcre. Most of the granules iieconie enclosed in vacuoles or show more and more distinctly their va<-uolar envelope. Vacuolization may continue until tiie entire cytoplasm i> crowded lull ol vacuoles except for the enlarging centrosphcre and a narrow peripheral nuirgin which usually renunns more or less clear. The cytoplasm in such highly vacuidized cells is reduced to a thin framework between the vacuoles, and to a dear, well-defined centrosphcre about the ccntriole tliat is entirely or almost entirely free of granules or vacuoles. I.,ong s])indle-shapcd fibroblasts, with the nucleus exten<ling nearly the full width of the cell, often have the ccntriole at one end of the nucieus, and the cytoplasm between the nucleus and that end of the cell may become ])acked with vacuoles lielore any appear in the other einl of the cell.

The rate of increase in the nundier of granules and vacuoles varies greatly in different cultures, ami also somewhat among the cells of a single culture. There is. however, usually more variation between different cultures than among the cells of the same culture. No two fibroblasts are ever exactly alike, even in the same culture: yet in sjiitc of this <lissimilarity among the individual cells tliere exists enough uniformity t^i give a peculiar character to each cidture. Since the rate of accumulation of tlie vncmiles :ni(l granules varies in different cultures, often quite niarkedly. one finds occasioindly in a "i-i-hour culture an accunnilation of vacuoles and granules as extensive as in the average 48- or even T2-hour culture. On the other liand, it sometimes hajipens that a 48- or a 7"<?-hour culture presents no greater accumulation of grainiles than the average 24-hour culture.

There are many other variations in the minilicr. size, inequality of size, etc., of the granules and vacuoles. It is the control ami production at will by enviroimiental alterations of such variations that will enable us to analyze more fully the processes that arc taking ]ilace. It <loes not seem beyond the realms of po,<sibility that some day we may be alile to jiroduce at will any desired variation.

The above conclusions in reganl to the increase in the number and size of the vacuoles and granules were not drawn from the continued observations of imiividual cells over long periods of time, but from shorter observations on thousands of cells in hundreds of cidtures. It would i)roiiably be possible so to rcgidate the comlitions of ob.servation that one conlil follow in a single cell this accumulation of granules and vacmdes from the condition foumi in the healthy fibroblasts, with few scattered graindes. to tin- completely viiciiolized cell, and r-vcn to the death of the cell.

Often during the observations, through the manipulation of the culture and the apfdication of neutral red and janns black Xo. 2, the c(dls were found to live hut an hour or so after the observations were begun. Such cells do not exhibit (hiring that hour or two anv niarkeil increase in the nnndicr of

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granules or vacuoles. Their death may ensue at any stage in the granular and vacuolar formation. Death may also take place at any stage in the cultures that are not thus manipulated. Several factors imdoubtedly contribute to the death of the cell, and sometimes one and sometimes another may predominate. In the highly vacuolated cells stained with neutral red the final death process is often quite rapid. The behavior of the colored vacuoles is quite striking; one after another, in rapid succession, they suddenly lose their color and flash out of siglit. When the process is complete, the cell has a peculiar, clear, unstained, moth-eaten appearance. Changes in the mitochondria and in the nucleus are also to be seen.

SIZE AXD SHAPE OF THE GRANULES

The granules vary iu size in the same cell. Some are barely visible with the highest powers, even with the neutral red stain; others are of considerable size and maj' measure onequarter or one-half the diameter of the nucleolus. The extreme minuteness of some of the granules indicates that other still smaller, ultramicroscopic ones are probably scattered tlirough the cytoplasm. Within certain limits it can be safely stated that the more healthy the cell the fewer and smaller are the granules. The granules undoubtedly increase iu size. One cannot actually see this increase, since the process is probably slow and the difficulty of following the same graiuile through any considerable length of time is too great.

Most of the granules are somewhat angular in outline, suggesting a crystalline formation. There is but a suggestion of this, however, since they are usually irregularly angiilar. I suppose an irregular angular mass might result from crystallization or from the accumulation of ultramicrosco[)ic particles. Such granules are difficult to distinguish, by their shape alone, in unstained cells, from the small gra:udar mitochondria (when the latter are present). In most healthv cells, however, the mitochondria are in the form of rods and threads which can be easily distinguished from the degeneration granules. In fixed specimens stained with iron hematoxylin it is likewise difficult or impossible to distinguish between granular mitochondria and degeneration granules. There is a method, however, by which the two types of granules can be distinguished in the living cell; i. e., the combination of neutral red and janus black No. 2, by which the granules are stained bright red and tlie mitochondria blue-black. Some of the special mitochondrial stains also enable one to distinguish the two types of granules in the fixed specimens ; on the other hand, certain fixatives, especially those containing acetic acid, destroy the mitochondria, but leave the granules miaffected.

Maximow noted that the griinules described by him were at first minute and irregularly scattered in the cytoplasm. This extreme minuteness of some of the granules is an important point, especially in relation to their possible origin from mitochondria, as alleged by some authors; for it would be logical to assume, if tliey do arise from mitochondria, that the latter first become reduced iu size to a minuteness which renders them invisible, and that this is followed by a change in constitution and a gradual increase in size. Mitochondria are

sometimes minute to the limits of visibility and yet retain the characteristic staining reaction with janus black No. 2. The most minute degeneration granules, on the otlier hand, exhibit the same characteristic coloring with neutral red seen in the larger granules. It is perhaps importtmt to note in this connection that those minute mitochondria are not always or usually found in fibroblasts that are just beginning to show the minute neutral red granules. It is only in the later stages of degeneration that the normal mitochondrial threads and rods tend to break up into granules.

THE RELATION OF GRANULE AND VACUOLE

It is not always possible to distinguish the granule from the small vacuole, as the granule may occupy practically all of the vacuole with only a thin rim of fluid. It may be that all the granules we are considering are included in vacuoles. The fact that granules are often irregular in outline would not nullify such a +++++ CONTENTSion, since vacuoles themselves are sometimes irregular. It is conceivable that even the smallest granule may be surroimded by a rim of fluid too thin for detection. In our present state of knowledge concerning these bodies it is of no particular consequence whether all granules lie within vacuoles or all vacuoles contain granules. Practically all vacuoles do contain granules, one or several, and it is vmcertain whether vacuoles exist that are entirely free from granules. We do not know why the vacuole should develop around the granule. It may be that minute vacuoles appear first and granules develop within them, or the granule may appear first and the vacuole develop about it. Since we arc not certain of the exact relations when the granules have attained visible sizje, the idtramicroscopic condition must necessarily be still more uncertain. The impression one gets from the study of uiunerous specimens is that many of the granules in the healthy cell are free from vacuoles, and that the latter subsequently develop about them. The granules in the smaller vacuoles often appear to be larger than those in the large ones. The larger vacuoles, however, usually contain several granules, with perhaps an aggregate of material equal to the larger granules of the smaller vacuoles.

In vacuoles of the same diameter containing solitiiry granules, the latter often vary in size. The amoimt of fluid in the larger vacuoles is much greater in proportion to the size of the gTanules than that in the smaller vacuoles.

Multij)le granules within vacuoles can be conceived of as arising in at least four ways: (1) By the coalescence of smaller vacuoles each with a single granule, the number of granules in the larger vacuole depending upon the number of smaller vacuoles which coalesce; (2) large granules may split up into small granules; (3) new granules may develop in vacuoles, by a process of crystallization, for example ; (4) granules free in the cytoplasm might be taken info the vacuole as it enlarges.

THE rOSITioX OF ORIGIN OF THE GRANULES AND VACUOLES

We have not been able to determine the position of origin of the granules and vacuoles. In the earlj' stages tliey are

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scattered, but as tlicy become more numerous, most of tlieiii are located in the immediate rejrion of the centriolc. Since they move about freely in the cytoplasm, either towards the centriole or away from it, one mifrht conclude tluit they form in the more i>eriplieral rej^ons of the cytoplasm and arc carried towards the centriole where they tend to accumulate, or that they arise near the centriole and arc carried outwards into the more peripheral rejiions of tiie cytoplasm. The ditliculties of the problem are increased by the fact that the smallest firanules are on the boundary of visibility, and from that one must conclude that they begin their existence in tlic cells as dustdikc jrraiiules invisible even with the hijflicst powers. Such •rranules in cyto])lasm would be unlikely to lie found in their position of orijrin when they attain the size of visibility. The fact that they accumulate about the centriole may indicate only that they are carried tiiere, as they form, l)y cyto])lasmic currents, if such currcntjj exist; and that tlie.^e currents tend, during degeneration, to flow more towards tlic centriole than away from it. Such a view receives some sujiport from tiie changes which oci-ur al)out the centriole. W'p have noted elsewhere that the centrosome increases in size during degeneration, and that about it a centrosphere develojis which gradually increases in size until it may become as large as the nucleus. The enlarging centrosphere is usually free or nearly free from granules and vacuoles, the latter surrounding it in a zone of varying thickness.

In cells with many vacuoles and a large centrospbcre, the latter is sometimes tilled with enormous numbers of the finest, du.«t-Iike granules which stain red with neutral red. What relation the.<e l)ear to the granules under discussion is not known, but very likely they represent a similar degeneration ]>ro<!uct. We have seen that the ordinary degeneration granules begin to form before the centrosphere apjiears; tlms they may arise independently of it.

TIIK MOVEiLEXTS OF TIIE ORAXILES .WD VACKH.ES

The granules and vacuoles exhibit a considerable amount of movement, ditfercnt from an<l more extended than the ordinary mit(H-hondrial movements. It is irregxdar, sometimes rapid and jerky, sonu-times slow and of varying speed. The distances traveled differ greatly; in general, the direction is from the region of the centriole or centrosphere to tiir |)eri[>hery, or lire \erxii. The amount of activity varies in ilifferent cultures and in cells of tiie same culture, and is apparently easily affectcfl liy environmental factors. Under certain conditions no movements r)f the granules are to l)c seen. Thes«' movements are probably not de|(cndi'nt upon the activity of the granules themselves, but upon either cytoplasmic currents in which the pa.ssive gramdes are carried or metabolic changes. It has not l)cen possible to .see cytoplasmiicurrents.

As statcfl aitovi', the movements of the granules are somewhat dilTerent in character from the mitochomlrial movements ; the amplitude is often greater and they are more lively. The movements are best followed in cells where the granules are stained red with neutral red and the mitochondria

blue with janus black No. 2. .\ red granule is sometimes seen passing along close to a blue-black mitocbondrium, .sometimes extending beyond the extremity of the mitocbondrium. Again the granules may pass back and fortli in paths that are some little distance from a mitocbondrium, and nniy cro.ss at varying angles above or below a mitocbondrium. Sometimes granules are detiected by the initocliondria as the latter are bent, or a])pear to l)e bent, i)y the tlowing granules. These appearances are such as to suggest that the granules arc located in a more fluid, streaming jiart of the cytoplasm, while the mitochondria arc in a less Huid part, tiie movements of which would be of a different ciiaracter, thus giving to tlic mitocbondrium and to the granule eacii its own peculiar tyjie of motion. On tiie otiicr iiand, tiie different types of motion may ijc due entirely to tile differences in I'cmijiosition of the mitochondria and of tiie granules, witii a resulting dill'ereiicc in tile inter-action tictween tlicin and tlie enclosing cyto|dasm.

niAMJKS IN IllK IDlfM OK THE VACUOLES

The viicuolfs Miry not only in size and jiosition. liut ai.so in sliape. In some ceils tiiey are constantly altering tlieir form such changes often occurring coincidently witii ciiange of position. Frequently many or almost every cell in a culture will show vacuoles tiiat are constantly ciianging iiotii form and position. -Vgaiii, viTy few if .uiy of tlic ceiis wiii siiow sucii changes.

The variations in siiajie wiiiili tiie vacuoles may assume arc quite remarkable. The usual form is spherical. Tiiis is the most staiiie condition and such vacuoles may remain unciianged for a long time. In contrast to this may iie found a complicated, tliread-like network of channels, very unstaliii' and constantly changing. Between tiiese two extremes a multiiilicity of forms occur in different ceils. The most common change is the sending outward from a \acuole of a long tiiread-like channel or process. Tiiis apparently cont^iins fluid similar to t.liat within tlie vacuole. These processes arc likewise constantly changing tiieir ])osition and length. The entire vacuole may iie converted into such a channel, wiiicii in rare instances may brancii and anastomose with other similar ciianneis to form a more or less comjdex network witii granules .scattered here and tliere witiiin the ciianneis. In such sjiecimcns the granules fre<|ucntly are larger than the diameter of tiie ciianncl and produce a distinct i»ulge in its wall. Tile granules are often oijscrved to sliift along tiie channel.

These vacuolar ciianneis are vi-ry unstaiiie and ciiange niucli more rapidly tiian tiie mitochondria. Many of tiiein are aiiout llie same size and siiape as tiie mitochondria, and at first may prove to be somewiiat confusing; but witii tlie use of neutral red and other vital dyes (methylene blue and brilliHul cre.syi lilue) tiicy can lie sliarply an<l clearly .separated from tiie mitochondria. Their ttehavior, too, is so difTerent tliat one soon comes to recognize that tiiey are entirely different. The vacuolar channels may change back into splitrical or oval vacuoles.

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I should suppose that these various changes iu the form, and ]ierha]is also in the position of the vacuoles, are dependent upon the metabolic activities, or upon the interchang-e of substances between the exterior and interior of the cell. The longprocesses and networks also suggest that there may be some relationship between vacuoles and the canalicular ai)]iaratus found in some other types of cells.

MITOCHONDRIA AND MITOCHONDRIAL VESICLES

Iu the vigorous, healthy fibroblast the mitochondria are usually scattered throughout the cell as long threads or rods, often branching or anastomosing and running in lines more or less parallel to the long axis of the cell; in others, radiating somewhat from the nucleus and centriole towards the periphery. As the granules and vacuoles increase in number the radial arrangement of the mitochondria about the centriole becomes more and more marked. In the earlier stages the mitochondria extend beyond the granular and vacuolar area into the clear cytoplasm. In some of the cultures the mitochondria come to lie in the cytoplasmic net between the vacuoles, and also partly in the clear peripheral regions at the ends of the cells. In such cells, even though the entire cytoplasm becomes packed with vacuoles and granules, the mitochondria may remain as short threads or rods until the cell is about to die.

Otlier cultures show fibroblasts in which the mitochondria midergo much more change. As the vacuoles and granules increase in number the mitochondria show more of a tendency to break u]) into short rods and granides, and these in turn may swell u]) into spherical bodies or vesicles of various sizes. The granules form very minute vesicles and the longer rods may form \esicles as largo as the neutral red vacuoles.

These changes apparently begin first in the mitochomlria lying immediately about the centrosphere and gTadually extend toward the periphery. They are usually preceded by changes in the mitochondria which give them an irregular appearance, and the longer threads seem to he broken up into short rods. The irreg-ularities of the mitochondria gradually become more marked and arc chiefly characterized by differences in the diameters of the various tlireads and of the different i)arts of the same thread or rod. These clianges are also accompanied by irregularities in the staining; that is, the mitochondria exhibit lighter and darker areas, especially w ith such stains as janus black Xo. 2. Under ordinary conditions of the culture, these changes in the mitochondria indicate degenerative changes in the cell. Similar changes can be brougiit about in a relatively short time in the long thread-like mitocliondria of Iiealthy fibroblasts by the use of potassium jiermanganatc. Witli a 1-20,000, 1-40,000, or 1-80,000 solution there takes place with varying degrees of rapidity, depending upon the strength of tho sohition, changes in the mitochondria similar to those observed in the more slowly degenerating cells of the cultures.

During these cliaiigcs both the thread and rod-like mitochondria and tile niitochoiulrial vesicles stain bluish witli janus l)l;ick Xo. 2. and ncxcr at any time do they take up tlie

neutral red. In fact, there is always a sharp distinction between the staining of the ntitochondria and the mitochondrial vesicles with janus black Xo. 2 and the staining ol' the degeneration vacuoles, the granules, and the processes of the vacuoles with neutral red. There are undoubtedly at times certain similarities between the two types of vacuoles when unstained, and in our earlier observations we were uncertain as to the relationship existing. For example, one often sees a small vacuole with a long mitoehondrium-like process that is continually changing in shape, size and position. Xow both the mitochondria and the neutral red vacuolar processes

I are subject to constant changes in form, size, and position.

I As mitochondria form vesicles the vesicular enlargement often takes place first at one end of the mitochondrium; the length of the unchanged narrow portion would vary, of course, with the length of the original mitochondrium and the size of the vesicle at the time of the observation. In unstained living cultures it might be impossible for the untrained eye to distinguish between such a changing mitochondrium and a neutral red vesicle with a mitochondrium-like process. With the application of a 1-10,000 solution of janus black No. 3 the mitochondria and the mitochondrial vesicles are stained bluish, whereas the neutral red vacuoles and granules remain unstained. If this stain is folloAved by a 1-25,000 solution ol' brilliant cresjd blue, it will be seen in a few minutes that the color in the mitochondria rapidly disappears, while the previously ixnstained vacuoles and granides take up the brilliant cresyl blue and appear bluish or violet in color. If, however, the janus black Xo. 2 is followed by neutral red ( 1-20,000 or 1-25,000), the blue color of the mitochondria and the mitochondrial vesicles is often increased in depth, while the previously imstained vacuoles and gi-anules take up varying amoimts of the neutral red dye. Then, too, the differences in the behavior of the two types of vacuoles when stained and followed with the application of potassium permanganate oichloroform indicate that we are dealing with two quite different things.

In some cells with almost complete vacuolization the mito- I chondria may show very little sign of degeneration or change, but apj)ear as rods and short threads in the cytoplasmic network between the vacuoles. In some of the long spindle cells \acuolization may be complete at one end of the cell and the mitochondria be more or less broken up into rods and granides ; while at the other end, the nucleus lying between the two parts, there may be almost complete absence of vacuoles and granules, and very little change in the long thread-like mitochondria. The degenerating end of such a cell seems to be always the end containing the centriole.

CHANGES IN THE REGION OF THE CENTRIOLE

As the cultures get older there is a gradual increase in the number and size of the granules and vacuoles. Parallel witii tliis increase very important changes take place in the region of the centriole. As the granules increase in number, they tend to accumulate about the centriole, which is located near one side or one end of the nucleus. This gradual accumulation

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of the granules, and later of the viuuolcs, about the eentriole gives a very characteristic picture, especially when tlic granules and vacuoles are stained with neutral red. One is often unable to recognize the centriole in the earlier stages in the living cell. In lixed material the centriole can usually l)c seen at the center of the mass of granules and vacuoles. Later, as these accumulate, the centriole becomes surrounded by a more or less dear area (the centrosphere) near the center of the mass of granules and vacuoles, and near one side or one end of the nucleus, with which it is more or less in contact. As the granules increase in number, the centrosphere increases in size, and at its center can usuallv be detected the double centriole. The centrosphere is usually entirely free from neutral red granules and vacuoles. It gradually increases and may eventually attain a diameter equal to, or even greater than, that of tiie nucleus. With its enlargement tiie granules and vacuoles api>ear to be pushed farther and fartb.cr away from tile centriole. The centrosphere usually presents a clear medullary zone immediately about the centriole or centrioks, and a much wider cortical zone, which often shows radiations. Occasionally one or two small neutral red granules appear td lie within the centrosphere. In some cultures which have been stained with neutral red the centrosphere .shows many very line, red, dust-like granules. Since this seems to occur only in c-ells that show somewhat advanced vacuolar degeneration, it may be that it is indicative of the beginning degeneration of the centrosphere.

We have already considered the radial arrangement of the mitochondria about the centriole and centrosphere; the i^ranules and vacuoles, lying between the mitochondria, also at times assume a more or less radial arrangement. We have considered also the movements of the granules and vacuoles which take place more or less in paths between the centriole or centrosphere and the perii)iiery. The accunudation of granules, vacuoles, and mitochondria about the centriole, and the accumulation or building up of an increased amount of what .«(H'ms to be a special type of cytoplasm about the centriole, would indicate that its activities are in some nninncr increased during the degeneration of the cells.

DISCUSSION

I venture to suggest that in due course of time it will lie found that the living part of the cell cannot be stained by any of the so-called vital dyes, since the combination of the dye with the living protoplasm would so upset the delicate molecidar constitution of the latter as to kill it : and because living ]>roto}>lasm is so eonstituteil that it cannot combiiu', either jihysically or chemically, with any other substances exce[)f such as are synthetically built up into itself. The corollary will be that till' so-raIle<l vital dyes stain only the non-living cytopla-smir inclusions, such as granules, vacuoles, secretion granules, food-glol»ules, mitochondria, etc.

One might well hesitate to ela.«s the mitochondria witli nonliving c.\-toplasmic inclusions, in view of the many claims tluii have been set forth as to tiie r«"ile of mitochondria in the transmission of hereditari- qualities, and above all as to their part

in the formation of various cell structures during histogenesis. They are supposed to form the coUagenic libers (Meves). myolibrils (Benda, Meves, Duesberg, Hoven and others), epidermal fibers (Firket and Uuesbcrg), neurofibrils (Uoven, Meves and G. Arnold), and .secretion granules (Grj-nfeltt, Bobeau, Kegaud and Marvis, Nicolas. Kegaud and Favre, Hoven and others) — a formidable list of authors imbued with the idea that the mitochondria po.s.scss magic qualities. I'owdry, in his recent excellent contribution, " The Mitochondrial Constituents of Protoplasm," states that " the radical claims concerning their role in histogenesis have forced the reinvestigation of the entire field." He is inclined to believe that the mitochondria are concerned, either directly or indirectly, witli nu>tabolism or with proto|)lasmic respiration. The mitochondria may well play an important role in the general metabolism of the cell, more especially in that particular part of the metabolism which is common to all cells, such as respiration, perhaps, as has been suggested by several authors (Kingsbury, Mayer, Kathery and Schaetler). The mitochondria niight jilay such a role in the general metabolism of the cell and still not be considered as a part of the living cytoplasm, any more than are the stored-up yolk-granules found in many eggs.

t'oghill suggests that during the i)rocess of digestion and assimilation of yolk in amphibian embryos certain end-products of the process segregate into what he calls alpha bodies and beta bodies, and that the former, proltably undergoing some chemical change, become free as mitochondria in the process of assimilation into protoplasm. AVlietluT this be true or not, more interesting still is the suggestion that the more toxic action of janus green (whicii st-siins the mitochondria), as compared with that of neutral red (which stains the bctn bodies), is due to the fact that tiie proces.«es leading up to tiie construction of protoplasm arc oi)structed i)y the reaction of tiiis stain ; whereas, only the residue, so to speak, of these processes is attacked liy tiie neutral red. If the mitochondria are concerned in tiie respiration of the cell, the action of jaiiu.green on the niitociiondria. for which it has a special alliiiity. might obstruct the rcs])iration to such an extent as to kill tiic cell. Coghill's suggestion as to the less toxic action of neutral red would apply to our conception tiiat neutral red stains only llie non-living matter, such as accumulated waste products or stored-up food-stuffs, or .some partially digested food-stuffs that are not iminediateiy essential to tiie ceil.

(Jranules witli a special affinity for neutral red iiavc been described in many iliffercnt types of cell in many different species of animals, and it will be interesting in tiiis connection to consider a few of the more striking cases. Fischel ('01) found in the living ectodermal cells of ampiiiiiian larva; many such granules. He considered tliem as living elenient.s, in conformity, perhajis, with the views of .\ltmann prevalent at that time. We know that tlie ectodermal cells of various vertelirates deposit witiiin themselves substances which are usually <-onsidered as non-living elements, and which in many ca.ses ultimately accumulate to such an extent as to finally transform the cell into a non-living scale. The fact that such

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deposits may serve a useful purpose in the organism does not invalidate the view that they are non-living inclusions.

The Clarks have described in the lymphatic endothelial cells of the tadpole's tail numerous gi-anules which take up the neutral red in the living. E. R. Clark has shown that the lymphatic endothelium is actively phagocytic, and since these cells possess the power of taking up particulate matter it may well be that they also take in ultra-microscopic particles and segregate them into granules that take up the neutral red. Whether these granules are of this nature, or whether they consist of waste products, is of course impossible to determine at present. Other phagocytic cells, such as the clasmatocytes and leucocytes, are especially rich in vacuoles and granules that have a great affinity for neutral red. The clasmatocytes are especially interesting in this connection, as they are abundant in most of our cultures. Certainly the vacuoles, and [irobably all the granules which stain so avidly with neutral red, are non-living inclusions, the granules for the most i)art being derived from cellular debris taken up by the cells.

It is well known that the partially digested dead +++++ CONTENTSs of the food vacuoles of protozoa stain with neutral red (Plato, Stole) and that disintegrating bacteria and cell debris in leucocytes stain in a similar manner (Plato, Arnold). Many eggs contain nmnerous granules and globules, probably foodstuffs, and perhaps accumulated waste products also, that stain with neutral red. The eggs of Cerebratulus, of the sanddollar, and of Lojthius piscatorius (M. R. Lewis), as also the amphibian egg (Coghill), have recently been studied with the aid of neutral red, and all were foimd to contain numerous neutral red-staining granules probably of the nature of storedup food-stuffs.

There are reasons for believing then that the granules and vacuoles considered here are non-living cytor()lasmic inclusions. Since the granules and vacuoles accumulate without noticeable enlargement of the cells, they must be formed in greater part from the cytojilasm rather than by the diffusion into the cell of substances and fluid from the outside ; moreover, thev are formed from the cytoplasm, ])resuniably as jiroducts of the metabolism of the living cell. Tliese products of metabolism may be divided into two classes — food products and waste or secretion products. The former are found most abundantly in egg and embryonic cells, and we should scarcely expect to iind cells cultivated in Ijocke's solution storing up food-stuff's. We are led, therefore, to accept the alternative theory, i. e., that the granules and vacuoles are accumulated waste products and that they are formed in part, at least, hy the breaking down of the cytoplasm. This process may be looked upon as a degeneration j)henomenon. since it ultimately leads to the death of the cell.

The altereil environmejit of the fibroblasts in the cultures pr<ibably sooner or later interferes in many ways with their normal metabolism, either from the absence of oxvgen, salts, or food-stuffs, or through the accumulation in the culture medium of waste products in suificient amount to prevent their normal elimination from the cells by osmosis. This altered environment M'itli its lack of certain essential salts, food-stutfs, and

perhaps of oxygen, would favor the breaking down of the cell protoplasm through starvation, and the accumulation of waste products. We have no method of determining whether the +++++ CONTENTSs of the vacuoles and granules are identical with the normal waste products excreted from the cell. An alteration in the composition of the waste products, however, might he expected to accompany the starvation of the cell.

Since the cells do not appear to increase in size as vacuolization spreads, we are more or less forced to conclude that part of the cytoplasm is broken down into granules and vacuoles. This process maj' use up most of the cytoplasm, leaving only a slender framework between the vacuoles. The enlarged centrnsphere usually remains intact and does not become vacuolated. The cytoplasmic framework is continuous with the centrosphere, radiating out from it in all directions.

The relationship of the gTanuoles and vacuoles, and likewise of the mitochondria, to the centriole and to the gradually enlarging centrosphere is not at all dear, if we attempt to explain it in physiological terms. The anatomic picture is plain enough, but why the granules and vacuoles should surround the centriole and centrosphere is miknown.

The centriole and its centrosphere have long been considered by many authors as the dynamic center of the cell, the focal point of the more active archoplasm of Boveri, the kinoplasni of Strasburger, the spongioplasm of Leydig, etc. This peculiar cytoplasm, which accumulates about the centriole during degeneration and which I have also seen much augmented in amount in giaait cells in certain cultures, seems to be different from the ordinary cytoplasm that occupies the bulk of the cell. Whetlier there is an actual increase in the amount of the stuff" forming the centrosphere or merely a concentration of already existing material about the centriole, is difficult to determine. There appears, however, to be an actual increase.

Conklin speaks of the spongioplasm of the egg of Crepidula as " the interalveolar or continuous substance within which are found enchylemnni, microsomes, mitochondria, as well as yolk, oil, and other inclusions." He finds that " large inclusions such as yolk spheres are forced out of regions where the spongioplasm concentrates." A somewhat similar phenomenon seems to take place about the enlarging centrosphere. where the vacuoles and granules are forced away hy the concentration or increase in the archoplasm or spongioplasm about the centriole in the degenerating fibroblasts. The framework of cytoplasm, which extends from the centrosphere to tlie peripheral layer in these highly vaciiolized fibroblasts, corresponds, perhaps, to the spongioplasmic framework in Crejiidula that remains throughout the entire cell and connects the nucleus and centrosphere of the resting stages to the peripheral layer after the centrifugal force has displaced the more fluid part of the cytoplasm, tiie yolk, and the other cytoplasmie inclusions. It is the spongioplasm that seems to be the living part of the cytoplasm, the ])art which determines the polaritx of the cell. In the normal fibroblast the cytoplasm, except for the mitochondria and a few granules, appears homogeneous. Does this a|)parent homogeneous cyto])lasm consist of two ])arts.

THE JOHNS HOPKINS HOSPITAL BULLETIN. APRIL. 1919 ' <« :.'•=.•;

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a sponorioi)la.«mic framework ami a more fluid enchvlemma y Or is it all H|)(iiijri(i|>la.-;mii- material. cxeeiJt for tlie iiKJusioiis above iiotinl 'i

The eauses of. or faetors eoiicemed in, the firadual enlar<,'emeiit of the eentrosphere are not known. It is well reeojjnized that in many ejijrs where food aceiimulations are eonsiderahlc tile attraction sphere is larjre. It is also larger in cells that are about ready to divide tluui in the restin<r cell. There is undoubtedly a relationship between the accumulation of foodstuffs in the eg-r and the size of the attraction sphere; and again, between the growth in size of cells which are destini'd to divide and the increase in the size of the attraction sphere.

Is the accumulation of granules and vacuoles about the centriole the factor that causes the enlargement of the eentrosphere?' Such an accumulation of granules and vacuoles would naturally alter the usual relation.ship of the centriole to the periphery of the cell, ujjsetting the metabolic balance in such a manner as to eaiise. perhaps, the building iip of the enlarged eentrosphere, since the metabolic activities which are centered in the centriole probai)ly de|)end upon a constant interchange of materials i>etween the centriole and periphery. The accimiulating waste products about the centriole in the form of granules and vacuoles would certainly tend to alter this.

BIBLIOGRAPHY

Burrows. M. T.. and C. .-V. Xey'raann: 1917. Studies on the metabolism of cells in vitro. Jour. Exp. Med., XXV.

Clark. E. L.. and E. R. Clark: 1919. On the reaction of certain colls in the tadpole's tail toward vital dyes. Anat. Rec.. XV.

Coghill. Ct. E. : 1915. Preliminary studies on the intercellular digestion and assimilation in amphibian embryos. Science. N. S., XLIII, 347.

Conklin. E. G.: 1917. Effects of centrifugal force on the structure and development of the eggs of Crepidula. Jour. Exp. Zool.. XXII.

Cowdry, E. V.: 1918. The mitochondrial constituents of protoplasm. Contributions to Embryology, VIII. Carnegie Institution of Washington, Pub. No. 271.

Fischel. A.: 1901. Untersuchungen liber vitale Farbung. Anat. Hefte, Bd. XVI. 417.

L^wis. .\I. K.: 1917. The effect of certain vital stains upon the development of the egg of Cerebratulus lacteus. Echinorachniu.s parma, and I..ophius piscatorius. Anat. Rec, XIII.

Lewis. .\l. R.. and \V. H. Lewis: 1915. Mitochondria and other cytoplasmic structures in tissue cultures. Am. Jour. Anat., XVII.

Luna, E. : 1917. Note citologlsche sull" epltello pigmentato della retina coltlvato " In vitro." Arch. Ital. di Anat. e dl Embr . XV.

.Maximow. Alexander: 1916. The cultivation of connective tissue of adult mammals in vitro. Russian .Archiv of Anat., Hist. and Embryology. I.

Plato, J.: 1900. feber die " vitale " Karbarkeit der Phagocyten des Menschen und einigen Saugethiere mit Neutralroth. Arch. f. mikr. Anat . LVI. 868.

Stole, A.: 1902. L'eber das Verhalten des Neutralrots ini lebendigen Protoplasma. Zeit. f. allg. Phys.. I. 209.

EXPLANATION OF FIGCRES

The figures are all drawn free hand from living cells stained with neutral red. and many of them with janus black No. 2 in

addition. The original drawings gave only vague outlines for the cells, as the author's attention was concentrated on the relations of granules, vacuoles, mitochondria, centriole. eentrosphere, and nucleus. Since then the borders of similar cells, both in living and fixed material, have been examined, and appropriate outlines added to the original cell drawings. Thus the greater number of the figures are composites. The edges of most of the fibroblasts present a peculiar scalloped condition, with slender processes of varying lengths extending from the points, much longer, as a rule, than those shown in the figures.

Figs. I, 2. 3, 4. and 5 are from 78-hour-old cultures; explants from the legs of 8-day chick embryos. Figs. 2 and 3 are from the same culture, the others are each from a different culture.

Fig. 1.— Healthy fibroblast with few granules. Figs. 2. 3, 4, and 5 show the gradual accumulation of granules about the centriole and the increasing radial arrangement of the mitochondria. In Fig. 5 are also seen many small vacuoles. Fig. 4 and 5 show small centrospheres.

Fig. 6. — A 74-hour-oId culture; explant from leg of 9-day chick, showing' increased number of vacuoles and granules about an enlarged eentrosphere. Mitochondria broken up into short rods.

Figs. 7 and S. — 54-hour-old cultures: explants from leg of 8-day chick. In Fig. 7 the centrospliere is at the side of the nucleus and the granules, vacuoles and mitochondria are arranged more or less symmetrically and radially about it. In Fig. 8 the eentrosphere is at one end of the nucleus. Very few granules or vacuoles are seen in the opposite end of the cell.

Figs. 9 and 10. — 7S-hour-ol(l cultures: explants from leg of 8-day chick. The eentrosphere either has not developed or is obscured by the crowded granules and vacuoles. The centriole was not seen, but its position in both cells is undoubtedly at the side of the nucleus.

Fig. 11. — A 78-hour-old culture; explant from leg of 8-day chick. Large eentrosphere surrounded by granules, vacuoles, and mitochondria. Wide cortical zone of eentrosphere shows radiations. The vacuoles in this cell were constantly sending out long processes.

Fig. 12. — A 4S-hour-old culture: explant from the leg of a 7-day chick. Cell crowded full of large vacuoles, except at the thin edge. Mitochondria broken up Into short rods which seem to lie in the cytoplasmic framework — eentrosphere obscure.

Fig. 13. — A 48-hour-old culture; explant from leg of 7-day chick. Very large eentrosphere surrounded by many large vacuoles. Radially arranged mitochondria, rather long rods and threads. No vacuoles or granules in the opposite end of the cell.

Fio. 14.— A 2-day-old culture: explant from leg of 7-day chick. Large eentrosphere: entire cell crowded with large vacuoles; mitochondria in form of short rods.

Fig. 15.— A 3-day-old culture: explant from leg of 7-day chick. The vacuoles showed much motion and were constantly sending out long processes or changing into channels, which are seen to anastomose at one end of the cell.

Fig. 16.— a 24-hour-old culture from the leg of a 7-day chick. The vacuoles and gianules showed considerable motion, and the vacuoles were constantly sending out processes and changing In form.

Fig. 17.— a 3-day-old culture from intestine of a 7-day chick. The mitochondria have all changed Into vesicles. Degeneration has progressed to such an extent that the vacuoles have begun to disappear.

Fic8. 18, 19, and 20.— 2-day-old cultures; explants from the legs of 7- and 8-day chicks; showing variations In the vacuoles, eentrosphere, etc. eentrosphere full of dust-like granules.

Fio. 21— A 3-day-old culture; explant from leg of 9-day chick. Mitochondria arc changing into vesicles.

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[No. 338

SOME ASPECTS OF 0\ ARIAN PREGNANCY. WITH REPORT OF A CASE

By A. W. Meyer and H. M. X. AVyxxe

From the Department of Gyneeology of The Johns Hopkins Medical School, the Department of Embryology of the Carnegie Institiition.

and the Department of Anatomy of Stanford University

Although the first case of ovarian pregnancy under that heading in the Index Medicus is that of Kouwer ('97) (van Tnssenbroek, '99), careful scrutiny of the titles listed for the last decade reveals the fact that 5 cases of ovarian pregnancy were reported in 1908, 4 each in 1909 and 1910, 7 in 1911. 13 in 1912, 9 in 1913, 7 in 1914, 3 in 1915, 1 in 191G, and 5 in 1917. This makes a total of 58 cases apparently reported \vithin this decade. Since the reports on some of the cases were published in three different Journals, these were, of course, counted merely as one, and although the authenticity of four of the cases must be questioned on the basis of the titles alone, the series, nevertheless, is a large one in spite of these facts and of a marked decline in the number reported during the war. Since Norris ('09) stated that only 19 certain cases, a])proximately only one-third as many as all cases Usted in the last decade, were reported in the decade between 1899 and 1909, it would seem that ovarian pregnancy not only is receiving increasing attention, but that a change in attitude probably is in progress. Tliis conclusion would seem to be justified even though a careful examination of the descriptions of the cases reported in the decade between 1908 and 1917 would reduce somewhat the number listed.

Loekyer ('17) accepted as authentic only 22 cases of those reported between 1910 and 1917, but his review is only a partial one. Even so, it shows that there is a decided increase in the number of cases which have been regarded as genuine from decade to decade. The marked increase in the number of genuine cases re])orted in recent decades becomes still more evident if one recalls that Williams ('10) found only 13 positive cases up to 1906, whereas Norris found 19 positive cases in the single decade between 1899 and 1909. That is, ISTorris foimd more positive cases reported in this decade than had been reported in all previous medical history up to 1906. This surely is a significant fact.

The opinion that many, even if not all, cases of so-called hematocele, hematoma, apoplexy, blood cysts, and rupture of the ovaries, probably are nothing but cases of ovarian pregnancy in disguise, has been held by various investigators for some time. Hence, if hematocele of the ovaries repeats the history of hematosalpinx, it is not tmlikely that the near future will see a marked increase in the reported frequency of " a fact so curioiis and important in itself," as Granville aptly put it a century ago. This would seem to be true in spite of the fact reported by Norris and Mitchell ('08), that only a single case of ovarian pregnancy was found among 44 extra-uterine specimens and 58 hemorrhagic cysts contained in the collection of 1700 gynecological specimens at the hospital of the University of Pennsylvania. At any rate, a careful microscopic examination of all such eases would seem

to be indicated in the future in order to determine, if possible, which cases are, and which are not, conceptual in origin.

To-day it is no longer true, as stated by Freund and Thome ('06) and by Sencert and Arom as late as 1914, that authentic cases of ovarian pregnancy belong to the great rarities. Yet the fact that many of our states, as well as many large clinics, have not a single case on their records seems to suggest that the condition still is seldom recognized, a century after Granville observed his first case. Moreover, a nimaber of continental gynecologists and obstetricians, for a quarter of a century, have regarded the oceiu-rence of ovarian pregnancy as undoubted. Anderson ('17) stated that German writers began to report eases of ovarian pregnancy with some frequency after 1901, and Gilford ('01) also called attention to the fact that continental opinion long had accepted ovarian implantation not only as possible, but as proven. Gilfonl further referred to the often quoted opinion of Tait that ovarian pregnancy is as rare as " A blue lion or a swan with two necks," and in his article in 1899 also called attention to the opinion of Bland-Sutton, that ovarian pregnancy not only has no existence, but that it is impossible. These opinions are particularly interesting in view of the carefitl reports made by Granville (1830 and 1834), in connection with the two cases which he then and which others since have regarded a.< cases of undoubted ovarian pregnancy, in spite of the absence of microscopic examination. In view of this lack it is particularly fortunate that both of these reports of Granville are accompanied by splendid illustrations by Bauer, which also won his praise and admiration and which greatly strengthened his cases. It may be recalled in this connection that Werth ('01) accepted Granville's case recorded in 1820, but said nothing about his second more convincing instance reported in 1834.

Although there is as yet no agreement as to what constitutes an authentic case, a re\'iew of the literature justifies the growing and apparently well-founded belief that in the past too much emphasis has been laid on certain criteria wliich later experience has shown to be partly inapplicable. It is becoming clear that some cases, formerly excluded for reasons regarded as sufficient, with our present knowledge could no longer be rejected. Moreover, it does not seem at all improl>able that some cases listed as tubal really were orarian in origin. Xor must it be forgotten that not even the entire absence of remnants of the conceptus can positively exclude a case from the category of true ovarian pregnancy. In a number of cases in the literature, and also in the present case, the clinical history and gross anatomic findings suggest the conclusion drawn by Scott ('01) on a priori grounds alone, that the conceptus may be completely resorbed. It may, of course, also be aborted and disintegrate completely. That such an

April. l!il!t|

i:s8umptiuii is justified is indicated by the lysis of tlie emljiv" or fetus in a large number t)f eases of ovarian jtrejrnancy, and also by the very degenerated condition of some of the vesieles and of the surrounding ovarian stroma. The |)ossil)ility ol' such an occurrence is estal)lislied also by similar events in tlic uterine and tubal jiregnancies discussed elsewhere (Meyer. '19), and ])robal)ly is illustrated by such cases as those of Anning and Littlewood {'01 ). in which no mention is made (if an embryonic disc in a translucent conccptus the size of m

• ' pea." Then, to be sure, there are the cases of unruiiturcil

ovarian ])regiinncies containing villi only, as well as the rare case, probaltly of double ovarian pregnancy, of Holland ('11 ). Although one cannot be certain that embryonic tissue was removed from the left ovary with the blood-clot which was forcibly c.\]ielled at the time of operation, it is not at all improbable that the small jdasmodial masses found in the Icli ovary were the only remnants of the concejitus. 1 realize fully that the conclusion that young concejjtuscs may be wholly dissolved is fraught with great uncertainty, but I am quite sure that it is justified by the facts, and that it therefore is in the direction of truth. It could oidy fail to be so if every ovum that beconu's implanted within the ovaries were al)orted or were removed by operation before lysis was possible.

One cannot rightly refuse to recognize the i)<)ssil)ility of tlie spontaneous disap])earance of an ovarian pregnancy. Sinee implantation in the ovary occurs under such al)normal conditions, it would .seem that for this reason alone the gn^at majority of .such implantations inevitably must succumb. This would .>;eem probable wholly aside from considerations regarding the development of the corpus luteum, although lack of, or interference with, the development of the latter also woulil .'ieem to condition early death of the conceptus if the results of the long series of experiments on rabbits by Frankel ('0.3-'10) are indicative of the role iilaycd by the ••orpus luteum in early imidantations in nian also. It surely is didicult. if not impo.ssible, to see liow implantation witbii: the (Jraalian follicle, and esj)ecially the later development ol the conceptus, can fail to interfere with the development of ii normal corpus luteum. Ca.^es in the literature, and also in tlie present case, did not reveal the presence of any well-pre.'<er\eil or even true luteal cells at the time the pregnancy was terminated. Although this fact does not presu|)pose an entire lack of developnu'ut of these cells in the earliest stages of tlu' implantations, it undoubtedly does im|)ly a defective development, which in it.*elf nniy have become responsible for tbi> death of the conceptus. \or should the jiossiide toxic eti'ect upon the conceptus of luteal lells be forgotten in this i-onnection.

I do not assnnu'. to j)e svire. that the eliiiieal symptoms mikI signs alone should suflice finally to group a s|)ecinien as truly ovarian, but when these arc indicative of the pre.«ence of an ectopic gestation, and when undouiitcd intra-uterine decidual changes are present, in the absence of abdominal pregmincy or tubal involvement and a normal corpus luteum. and the presence of a blood-dot within the ovary, there would seem to he little reason for doubting the authenticity of the ovarian implantation even in the absence of cnd)ryonic remmint.-.

Siiu-e i-hanges suggesting decidual reaction in the ii\ary ha\e l)eeu reported so seldom it is doubtful whether nnich emphasi^ can be laid on them. One seems justified in saying this in spite of the fact that the presence of decidua in the ovary formed the only anatomic evidence U])on which Kantorowic/ ('04) confidently classed his two rather atlvanced cases of ectopic pregnancy anumg the authentic. Moreover, if it be true, as stated by Webster ('04 ) that changes which cannot be distinguished from true decidual changes not infrequently occur in the ovary in connection with normal uterine pregnancies, then the ])rescnce of islands of decidual cells in an ovary surely cannot be regarded as indicative of ovarian pregnancy. 1 wonder, however, whether it woidd not be po.ssible to distinguish genuine decidual cells by modern histnchemical methods. In making this observation, 1 am fully aware that various criteria have been advanced from time to time by means of which to judge ovarian pregnancies, and that many of these have met with objection and have hence been nu>dified. Such modifications would seem to be inevitable as long as there is progress in the sulutinii nf mm unsettli'd question.

The absence of tlie iCtus in inanv of the recorded cases in itself demonstrates tlie entire inapplicability of the criterion addeil by .lacobsoii ('(I.S). .Moreover,' the histologiiappearance of the ovarian tissue around certain jiortions of the blood-clot in the present, ami also in some of the ca.ses in tinliterature, would seem to suggest that it may be very diflicull to find remnants of ovarian tissue at several points in a casi' of pregnancy which has ailvanced far. Hence, this criterion of Spiegelbcrg ('7S) cannot be regarded as necessarily crui-ial. Whenever the implantation is developed at the outer instead of at the inner margin of a follicle, as in the ca.^e of Banks ('12), early destruction, even if not early rupture, of the overlying ovarian stroma and cajisule would seem to be inevitable. Indeed, whenever the layer of ovarian stroma overlying the pliuiiita is thin, very early death of the fetus would seem to lie inevitalde from defective nutrition alone. On the other hand, when jdaccntal development occurs in the region of the follicle directed toward the body of the ovary, great destruction of the ovarian stroma woulil seem to be unavoidable, even if something akin to normal decidual formation actually took ]dace. In the case of Kngelking ('lU), f<ir exani])le, not a trace of an ovary was found in an ovarian pregnancy which had become interstitial. Kven without assuming the complete aidhenticity of this rather ecpiivocal case, it W(uild seem highly probable that the presence of ovarian tissue later in the pri'gnaiiey probably is determined very largely by the location of the fertilized follicle within, or by the e.\act location of the im|ilanta1ion upon the ovary.

Werth ('8T) is said to have collected 12 ca.srs. among which he regarded only that of Leopold ('S2) as authentic. Ix-opolil ('1)9) reported 14. (Jilford ('01), in a splendid succinct review of tlu' literature gave 28 cases. Hi of whi<h he regarded as nndoubteil and 12 as ]>robalile. Koclie {'02) accepted only 12 ca.<es. Filth {'02) accepted 21. Kantorowicz {'04), using the criteria of I.,eopold {'99), together with a microscopic examination as a basis, groujied the cases in the literature a

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[No. 338

certain, probable, and uncertain. He considered 17 as certain, 10 as probable, and 13 as uncertain. And to the 17 cases regarded as certain by him, Kantorowicz then added two of his own, basing his decision, however, mainly upon the presence of deeidua in the ovaries, thus making 19 cases regarded as authentic by him. Freund and Thome ('06) regarded 23 of all the cases reported up to that time as certain. Norris ami Jlitchell ('08) considered 16 as positive, 15 as probable and !) as fairly probable. Warbanoff ('09) collected 3-t cases and iSTorris ('09) regarded 19 of those contained in the literature of the previous decade as positive; but Williams ('10), from a critical review of the literature up to 1906, and upon tlic l)asis of the criteria of Spiegelberg, regarded only 13 as positive, 17 as highly probable, and 5 as probable. Mapes ('14) collected 30 cases, but wholly from secondary sources, and Lockyer ('17) 42, from the years 1910 to 1917. Of these eases Lockyer accepted 22 as authentic and 20 as questionable ami undecided from the evidence available to him.

This short summary suffices to show that there is as yet no consensus of opinion as to what constitutes an ovarian pregnancy. Although this fact finds its explanation partly in our lack of sufficient knowledge, it is due also to the meagerness of some of the reports. Besides, if complete disintegration and lysis of intraovilrian conceptusps can occur, then it must always remain a. question of opinion in the future wliether some of the cases so rejiorted really were or were not true ovarian jiregnancies. This must remain true no matter how thorouuh the microscopic examination, unless the clinical history or changes in the maternal organism can afford us crucial tests in such cases.

Anyone who reads far into the literature of ovarian pregnancy also nnist become aware of the fact that even very recently skepticism has been carried too far. Jacobson ('08), for example, placed the case of Ivouwer-van Tussenbroek (a ease which finally convinced Bland-Sutton) and that of Webster ('01) in the doubtful class! Furthermore, .Tacobson also insisted upon the presence of an cndiryo or fetus as absolutely essential.

It must be emphasized, however, that even a liberal attitude on the part of a reviewer would not justify him in accepting all cases reported as genuine upon the basis of the reports themselves, for they — especially the older ones — often are too meager to enable one to form a reliable opinion. This is illustrated also by such recent reports as those of (iarrard ('16), Martin ('17), Sweeney ('17), and of Mills ('17). Although it must he remembered that from the very nature of tilings it sometimes is impossible to make a report which in itself carries conviction, it is regrettable that in a niunber of relatively recent cases in which such a report apparently could have been made, this was not done. ^lills' case seems to have been an instance of ovarian implantation in a region other than the Graafian follicle, and hence recalls the first ease of Granville and the cases of Franz ('02), Norris ('09), Paucot et Debeyre ('13)?, and perhaps also that of Kouwer ('97) (van Tussenbroek, '99).

From evideiu'e contained in the literature, it is clear that further re|)orts of single cases are not needed for the purpose

of emphasizing the occurrence of ovarian pregnancy, yet such reports nevertheless may help in the determination of the relative frequency of this novel and sinister condition, and also throw further light upon its genesis and the finer relations of the implantations, as well as upon other matters. Moreover, since the cases which are accompanied by a careful histologic examination and wliich for this reason alone are wholly unequivocal from an anatomic standpoint still are relatively few, the report of an additional case would seem to be justified. The present specimen (Carnegie Collection, No. 1322) was donated by Wynne to the Department of Embryology of the Carnegie Institution of Washington, and the following clinical report furnished by him :

CLINICAL HISTORY

Gy.n. No. 22303. — The patient, an Italian woman of 37 years, was admitted to, the Gynecological Service of The .Johns Hopkins Hospital July 12. 1916, complaining of pain in the lower abdomen, nausea and vomiting.

Famil)/ History. — Negative.

Past History. — General health good. She has never had any serious illness. For the past five years following a labor she has had recurring mild attacks of pain in the abdomen without nausea or vomiting.

Menstrual History. — Always regular every month except when pregnant or lactating. Duration four to five days; painless, moderate flow. Last period ,Iune 25, 1916. Last preceding period March 16, 1916. No intermenstrual bleeding before present illness.

Marital. — Married IS years; seven children, oldest 16, youngest born IVa years ago (died. 1915). Has had three miscarriages. History of labors and puerperia vague.

Present Illness. — Began five days ago (July 7, 1916) with sudden pain in lower abdomen, nausea and vomiting. She has had marked dysuria and painful defecation. For 12 hours after onset there was rather profuse bleeding from the vagina and there has been a bloody vaginal discharge since.

(The patient does not understand English and her husband acted as interpreter. )

Physical Examination.— T. 101.6° F. P. 96. R. 20. W. B. C. 8400. Hbg. 46 per cent.

The patient lies in bed grunting with pain. The skin is pale. The lips and raucous membranes are quite pale. There is a systolic blow heard at the apex and increasing toward the base, being loudest over the pulmonic area.

A drop of clear fluid was expressed from the right breast.

The abdominal respiratory movements are limited, although she does not complain of pain on deep inspiration. The flanks bulge somewhat. There is no demonstrable movable dulness. There is tenderness all over the abdomen, most marked over the lower left quadrant. There is increased resistance over the lower abdomen, but no muscle spasm. No masses can be made out.

There is a profuse bloody vaginal discharge. The cervix is pushed up behind the symphysis by a soft, exquisitely tender mass, filling the cul-de-sac. No crepitus is made out. Rectal examination confirms the vaginal. The fundus of the uterus is not felt.

July 13. Ifiia. — Ether examination.

There is a dark, bloody discharge from the vagina. There is no vaginal cyanosis. The cervix is lacerated, firm, and normal in size. The fundus of the uterus is about normal in size and is in anteposition. A boggy mass fills the cul-de-sac and to the right of the uterus a fairly firm mass, the size of a small orange, which is somewhat movable, can be felt. Definite blood-clot crepitus can be felt on rectal examination.

Pre-Operative Diagnosis. — Extra-uterine pregnancy, ruptured.

Operation (Dr. W. R. Holmes, Resident Gynecologist). — A free midline Incision was made below the umbilicus. The peritoneum

Al-KIL. I'.IUtJ

95

was blood-stained. The abdomen contained 200 to 300 c. c. of dark fluid blood and clots, and a large clot filled the cul-de-sac. Active bleeding had ceased. The left tube and ovary were normal and free of adhesions. The ri,i;ht tube, which was quite normal in appearance, lay over a mass which had replaced the right ovary. This mass was roughly spherical. 5 to 6 cm. in diameter and semisolid in consistency. Over the surface there were six or eight nodular projections, about 1 cm. in diameter, .^t the top of one of these projections there was a very small opening, from which bloody fluid could be squeezed. The surface of this mass was white with spots of bluish-black discoloration.

The appendi.x was normal except at the lip. where it was adherent to a blood-clot.

The tumor was removed by clamping, tying, and cutting into the^ right iiifundibulo-pelvic ligament and the right utero-ovarian ligament. The right tube was not removed. The appendix was also removed and all blood and clots were cleaned out of the abdomen. The incision was closed without drainage. At the close of the operation, the uterus was curetted. The uterine cavity measured 7.5 cm. in length.

A subcutaneous salt solution infusion was started on the table and continued on the ward until 2000 c. c. had been absorbed.

The patient was in good condition at the end of the operation and made an uneventful recovery.

The urinr on admission contained red blood cells, white blood cells, no casts, acetone, a trace of albumin and no sugar. Several days after the operation it was negative, except for a faint trace of albumin.

August J, V.Hi't. — Discharged in good condition.

Oyn. Path.. \o. i^.?}'i". — Normal endometrium from curettage.

A letter from the patient dated February 12. 191S. said that she had remained in good health since the operation and had given birth to a full-term child January 29. 1918.

Several features in this cliuit-al history ikviTvo coninu'iit. First amoii<^ these is the menstrual a<;e as eoni|)ared witli the size of the chorionie vesiele. Since the eross-seetions of t!u' latter measure 15 x 18 mm. and since it and the amnion are degenerateil and devoid of an enihryo, it is evident that the latter must have <lied a jjood while before the time of o|)eriition. Hence, the menstrual period rei«)rted for June 25, l!)l(i. very evidently wa.s not the lii.it period before prejrnancy supervened, but the lirst jteriod which recurred after the death of the coiHej)tus. Consequently, tiiis prejrnmuy undoul)tedly dates from near April 13, the time of the first omitted period. Moreover, the conceptus must have died long enough before Jtine 25 to have niatie iidiiltition of the succeeding period impossible. It shoidd lie noted, however, that the original menstrual cycle n f) pure nil i/ was broken, for with the customary inter-menstruar period of 28 days, menstnuition normally would have fallen due on June 7 instead of .June 'i'>. Hence, the mainteimnce of the original cycle woidd have brought rufiture of this ovarian pregnancy, as indicated liy the symptoms, on July 7. in direct relation with the on.*et oi menstruation. Nor does it seem unlikely that the hyperemiii accompanying the return of menstruation on June 25, if sudi it really was, may have been jiartly responsii)le for the on.<el of a sufficiently large and persistent hemorrhage to cause tiie slight rujiture indicated by the symjitoms on July 7. It must also be rcmembere<l in this connection that cases of ovarian ()regiiancy have been reported in which menstruation was uninterrupted. But in the ca.«o of Chiene ('13), fi>r example, the death of the conceptus may have occurred .«o early that tli

succeeding period was not inhibited, and the same thing may be true of the case of Lea ('10).

Since the material from the curettage, done al ihc time of operation, showed the presence of a normal endometrium, the uterine deeidua as.sociated with this ])rcgnancy nnist have been shed some time jireviously. Such a conclusion also woulil seem justified iiy the condition of the conceptus. which apparently was unai)le to |)revent a return to the normal. Tinabsence of deeidua at the time of operation al.^o suggests thai what was re|)orted as a return of imrmal menstruation on June 25 may have iiecii licniorrhage accompanying the expulsion of the deeidua.

Since, in the present ca.-:c, the .iKiriunic vesicle was so degenerated and .<o completely isolated in a large clot, and especially since no well-iin|)lanted villi were found in the .sections and gross jiortions examined, it is not at all jirobahle that the hemorrhage that caused the rupture \va.< due to a contemporaneous invasion of the ve.-ssels by the fetal trophoblast, such as occurs in uterine and tubal im|ilantations, and as has been actually described also in ovarian implantations by Franz ('02) and by others. In the present, and in similar cases in the literature, it would strm that hemorrhage was made jiossihle also by degenerative changes in the highly va.«cular stroma of the ovary which ha<l been greatly com|ircssed and stretched by the proportituiately large blooddot, the organization of whieli would seem U> iiare been precluded by its size alone.

The fact that relatively few unruplured ovarian pregnancies are recorded suggests that the old tenet that rupture is le.>is likely the more advanced the jiregnancy becomi-s. probably is open to .serious doubt, as suggested by Hanks ('12), who bclievetl that the lubes can accommoilatc themselves more readily than the ovary. Hanks stated that in the majority of cases of ovarian jiregnancy rupture occurred in the lirst two or three weeks, and Caturani ('11) also cxjinwed doubts regarding the dictum that rupture of the ovary is lc.«s likely the more advanced the pregnancy. .No one will di'ny, 1 prc.sume, that the .symiitoms of rupture nniy have been totally absent, as rejiortcd in the ca.^es of .N'nrris ('OK) ami (Jrimsdale ('13), but this does not imjily that the ovarian stroma or the germinal cjiithcliuni still surrounded the lull-term i-onceptus. Such an occurrence would be possible only if tlu' ovarian stronni and the overlying germinal c|iithcliinn undi-rwent an astonishing hyperplasia. Although such a thing is conceivable it is decidedly significant that no one has reported any such finding or observed the presence of mitotic figures.

Insteail of undergoing hyperplasia the ovarian .stroma in this ca,«e is found invaded, stretched, compre.<.-<cd, anil degenerate, and the germinal epithelium is entirely absent. The fact that several observers have seen what they took for the fibrin layer of Xitabuch also shows that degenerative changes in the ovarian impbinlations may be extensive. Heur-e, it would seem to follow that the absence of symptoms of rupture merely nniy mean that the ovarian stroma and epithelium which ha|ipcned to overlie the fetal membranes gradually have died and degenerated before being forced apart by the expanding conceptus or the increasing hetnorrhage. That such

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[No. 338

a sequence of events is possible would seem to be undoubted, and merely distension of the ovarian stroma until it com])letely surrounded a full-term pregnancy ' is hardly conceivable ; whereas, the absence of pain upon the yielding of an exceedingly thin degenerate layer of ovarian stroma is quite conceivable.

That rupture may occur very early is exemplified also by the cases of Chiene ('13), Seedorff ('15), and especially by that of Aiming and Littlewood ('01) and of Holland ('11). In such curious instances as that of Grimsdale ('13) one can hardly assume that the ovarian tissue was preserved about the entire .•onceptus, and it is not at all unlikely that full-term ovarian ]iregnancies, which, according to WarbanofE, supplied a sur])risingly large percentage of all cases collected by him, will form a far smaller percentage in the statistics of the near future. Indeed, they already form a far smaller percentage of those reported up to the present, and the advances in diagnosis alone make it very imlikely that in the future many cases of ovarian pregnancy will advance far before being detected.

The present specimen, which had been hardened and cut before it came to my attention, is a firm, nodular, dark-colored mass, 26 X 16 X 11 cm., shown in Fig. 1. In the gross, it especially recalls the specimens of Freund and Thome, Giles ('14-'15), Jaschke ('15), and Lockyer's ('17) second case. The exterior is smooth though bosselated and formed by a rather injected layer which is extremely thin, showing tlie blood-clot beneath, aroimd the greater extent of the specimen. The surface layer is eroded over several small elevated areas in which the blood-clot imderneath is exposed. Hence, the capsule may have been ruptured in several or only in one ol' the areas as noted at the time of the operation. Xear the region of amjjutation through the mesovarium shown to the right in the figure and marked by the corrugations of the hemostat, the tissue overlying the clot becomes more opaque, thicker, and also more yellowish. Here it is studded with small cysts, the character of which in itself suggests ovarian tissue. The color of the area to the right also is suggestive, and the cysts later were foimd to contain a clear viscid fluid, so characteristic of cysts of the ovary. The location of the main portion of the ovarian stroma shows that implantation occurred near the mid-point of the free convex or posterior border of the ovary, and that the stroma forming the sides gradually was forced apart, not by the growing conceptus, except perhaps at the lieginning, but mainly by the liemorrhage itself.

The major ]iortion of the surface of the divided specimen shown in Fig. 2 is composed of blood-clot, the presence of which confirms the " blood-clot crepitus " spoken of in the history. This clot contains an empty vesicle, the wall of which is formed for the greater part of its extent by a thin fibrous layer, except near the proximal or lower portion in the figure, where a thicker portion of ovarian tissue hoods the clot. Approximately only about one-third of the ovarian stroma seems to be preserved.

Xear the exterior of the thicker portions of the latter, a small cvst with clear +++++ CONTENTS is fomid directlv beneath the

surface, as indicated in Fig. 4. The distal or upper portion in the figure shows the clot to contain an empty, smoothwalled, degenerate chorionic vesicle, such as is frequently seen in tubal clots.

Examination of the cut surface with the binocular microscope shows the presence of only a few isolated, degenerated, and some hydropic villi scattered through the clot. Examination of the chorionic vesicle shows the presence of only a few attached villi and that the amnion is fused to the chorion. Since the entire sjjecimen obtained at operation is still covered by a layer of ovarian tissue which is unbroken save in a few very small areas, it is e^ddent that we are dealing with a very good example of an undoubted ovarian pregnancy in spite of the absence of an embryo. The latter undoubtedly did not escape through the small rupture in the capsule, for the chorionic vesicle seems entirely intact. Although the absence of a corpus luteum in the opposite or left ovary was not especially mentioned, lack of comment would seem to suggest that none was present, for the ovary very evidently was examined. Hence, this implantation probably took place within the Graafian follicle itself, and not in some other area of the ovary.

Celloidin sections of the excised portion show that the bloodclot contains no fibrin and that it is composed of relatively fresh and fairly well-preserved blood in the region near the main body of the ovarian stroma. The latter is quite normal although decidedly vascular, and contains ova. The layer of the ovarian stroma which surrounds the clot becomes thinner and thinner the nearer the free border is approached. It also becomes more trabeculated, hemorrhagic and degenerate. No overlying layer of smooth muscle, as mentioned by Yoimg and Rhea ('11) and also by Kantorowicz, was seen. Some infiltration with pohauorphonuclear leucocytes is noticeable. Degenerate villi are scattered about in the blood and a few others are apparently still attached to the equally degenerate ovarian stroma. Trophoblast is absent on these, although some of the villi that lie isolated in the clot possess a very e\\dent epithelium and also are associated \\'ith a few small masses of very degenerate syncytium. Only a few degenerate nonvascular vilU are still seen on the chorion. Very little evidence of epithelial proliferation is present on these, despite the fact that the blood in which the vesicle is eml^edded is not very degenerate. This seems to suggest that the hemorrhage wliich caused the rupture of the ovary was comparatively recent, although the conceptus had been dead for some time. Some of the villi scattered about in the blood-clot are outlined by degenerate syncytium only, and nothing but small degenerate masses of the latter are seen on the chorionic membrane or lying about isolated in the degenerate blood foimd in other places. Nevertheless, the epithelium of the chorionic vesicle is thickened at several points. The amnion is fused -nith the chorion and both membranes are very degenerate and destroyed almost completely in several places. The surroimding ovarian tissue, which is markedly vascidar and degenerate, shows infiltration in jdaces, especially where it is stretched over the large clot. No fibrous layer bounds the implantation cavity, as in the case re]>orted by Seedorff. The ovarian stroma merely

THE JOHNS HOPKINS HOSPITAL BULLETIN, APRIL, 1919

Fn;. 1. — External appearance of the reconstituted gross specimen (Carnegie Collection, No. 152'^). Natural size.

Fiu. 2. — Appearance of cross-section of specimen shown in Fig. 1. X 1.

Fin. 3. — Photograph of a section from a part of the specimen showing the clot largely surrounded by ovarian stroma and containing the empty vesicle. The arrow points to the portion near which degenerate masses of what may have been lutein cells aro found. X 2.

I"i(.. 4 l'liotopra|)h of a section t;il<in from the thick portion of the ovarian stroma near the mesovarlum, showing a well-developed Graafian follicle. X 3.

April, 1919]

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is slightly i-ondenscil here ami thero. and in places contains areas of hyaline ilegeneratioii, tlie exact origin of which conld not be definitely determined. A few of these are found near tile thin bounding layer of the ovarian stroma, hut no lutein layer or even luteal cells could i)e recognized. Tiie only objects seen which might be regarded as ])ossibly luteal in origin arc two microscopic rhoniboidai areas which lie near a small depression upon tiie surface, indicated in Fig. 3. The.se areas, which were covered by a very thin layer of ovarian stroma only, were made up of parallel, ilegenerate, slightly separated cords consisting of a syncytium containing numerous rather pycnotic unequal-sized nuclei. No pigment was seen in these areas, and were it not for the arrangement of the syncytia! cords, one would not be reminded even remotely of a ])ossil)le luteal origin. Although the germinal epithelium was wholly absent in the areas examined, these questionable areas nevertheless may have had such an origin. In the absence of lutein cells the present ca.se corresponds to that of Freund and Thome luid others, and stands in marked contrast to the ca.se • if van Tussenbroek, Franz, Anning and Littlewood ('01 ) and Thompson ('0^). As in the tase of Seedorff, no decidua was jircsent and nothing suggestive of an attempt at decidual formation, as rejwrtcd by Franz, Webster ('04 and '07), and by Caturani and Kantomwicz, was seen in the jiortioiis examined.

In describing his ca.se, .Sccdorif declared that in some places "f c-ontact between the fetal and maternal tissues he could not discriminate between trophoblast and connective-ti.ssue cells which looked like decidual cells and lutein cells. It is interesting that Sudortf al.«o spoke of villi which were almost Idled with Langhans' cells, an observation which naturallv makes one wonder whether by any possibility these cmdd not have been Ilofbauer's cells.

The pre-served ovarian tissue which was found near the amputation stumji contained hemorrhagic follicles, as observed al.so by Mall and fuUen ('13). A Graafian follicle 3 mm. in section, shown in Fig. 4, protruded above the rest of the .-troma ajid was quite mature. The presence of this follicle might be taken as an evidence of the occurrence of ovulation during pregnancy, were it not for the fact that the pre'sence of so degenerate a conceptus shows that as far as any effect u|)oii the maternal organism was conc-erned, the pregnancy virtually had been terminated long before. That both ovulation and menstruation can and do return after the death of an ovarian conceptus, but before its removal from the ovary, is illustrated also by ca.ses in the literature, especially by that of Xorri^ ('09). One must assume, however, that few, if any, surviving fetal element.* can be present under these circumstances. This concliLsion also would seem to lie confirmed by the remarkable case of Sencert and .\ron ('14). These authors reported a case of ovarian pregnancy in which nothing but a portion of an umbilical cord ."> mm. long containing Wharton's jelly, two arteries and a vein, and what was regarded as a placenta, remained. The latter was said to be composed of a narrow layer of plasmodiuni and a much thicker layer of trabeculat..! syncytial trophoblast containing blood between the trabecula-.

Because of the singidar structure of this placenta and also because of the failure to find villi or any remnant of the membranes, the authors concluded that the chorionic vesicle therefore could not ha\e reached the villous sUige. How such a supposition can be reconciled with the survival of a portion of an umbilical cord entirely nornnd in structure, it is dilHcult to see. The ovary concerned was brown, of the size of a " large fresh walnut," and contained a tumor, apparently the socalled placenta, which was 2 cm. in diameter. Although these fetal remnants had brought about not only almost complete amenorrhea for two years and also atrophy of the ovary and uterus, ablation of the affected ovary was followed not onlv by a return of the menses, but by a normal pregnancy within .seven months.

A sec-ond instance of ovarian pregnancy of sjiecial interest was that of Giles. Xo fetus was found, although the jtregnancy was unrujitured, and Giles estimati'd that the conceptus had died in the third or fourth week. The operation was not done until five months after the onset of the pregnancy. What is particularly interesting in this case is that Giles s])eaks of the mucoid degeneration of the connective tissue of the villi. The latter were found to be large, much branched, and had ramified in the clot. Since Giles also spoke of one of the illustrations as showing a vascular state of some of the villi, it seems possible that this was a case of hydatiform degeneration, even though there were no signs of activity of the syncvtium. Since the fetal membranes were isolated in a bloodclot very much degenerated and the villi without a Langhans' layer, one scarcely could exi)cct to find much evidence of epithelial jiroliferation .so common (but not essential) in hydatiform degeneration. Giles estimated that four months had elapsed since death of the conccptu-s, and if this specimen really was a hydatiform degeneration, it is the first one observed in ovarian ])reginincy and hence of particular interest for this reason alone.

REFERENCES

Anderson, S.: 1917 Primary ovarian sestation. Intern. Clin., XXVII, ser. 2.

Anning, G. P.. and Harry Littlewood: 1901. Primary ovarian pregnancy willi rupture 14 days after last menstruation. Trans. Lond. Obst. Soc, XLIII: and Lancet. 1901. I.

Banks, A. G.: 1912. A case of ovarian prcRnancy. .Tour. Obst. and Gyn. Brit. Emp.. XXI.

Caturani. M.: 1914. Ovarian pregnancy with report of a case. Am. Jour. Ob.st.. XLI.X.

Chiene, G.: 191:!. A case of raptured very early primary ovarian pregnancy. Edin. .Med. Jour., N. S.. X.

Engelking, Ernst: 19i;{. Intraligamentar entwickelte Eierstockschwangerschafl. Eln Beitrag zur anatomlschen Dlagnoatlk vorgeschrlttener Falle. .Monatschr. f. Gcb. u. Gyn.. XXXVII.

Franz, K.: 1902. Teber Einbottung und Wachstum des Eies Im Elerstock. Beitr. z. Geb. u. (Jyn.. VI.

Fraenkel, L. : 1903. Die Function des Corpus luteum. Arch. f. Gyn., LXVIII.

Idem: 191ii. Noue experlmente zur Function des Corpus luteum. Arch. f. Gyn., XC.

Fiith. H.: 1902. Ueber Ovarialschwangcrscbaft. Beitr. z. Geb. u. Gyn., VI.

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Freund. H. W., u. R. Thome; 1906. Eierstockschwangerschat't. Arch. f. path. Anat., CLXXXIII.

Garrard, J. I.: 1916-17. A probable case of ovarian pregnancy. ,Tour. Med. Assn. Ga., VI.

Giles. A. E., and C. Lockyer: 1914-15. Case of ovarian pregnancy. Proc. Roy. Soc. Med. Lend.. VIII; Obst. and Gyn., Sect. 2-10.

Gilford, Hastings: 1901. Ovarian pregnancy. Brit. Med. Jour., II.

Idem: 1S99. Two further instances of extra-uterine (one tubal and one ovarian) gestation in which rupture occurred before the first month; operation. Lancet, I.

Granville, A. B.: 1820. A case of a human fetus found in th.^ ovarium of the size it usually acquires at the end of the fourth month. Philos. Trans. Roy. Soc. Lond., Ft. 1.

Idem: 1834. Graphic illustrations of abortion. J. Churchill. Lond.

Grimsdale, T. B.: 1913. Case of ovarian pregnancy with fulltime fetus. Jour. Obst. and Gyn. Brit. Emp., XXIII.

Holland. E.; 1911. A case of ovarian pregnancy; probably bilateral. Jour. Obst. and Gyn. Brit. Emp., XX.

Jaschke, R. T. ; 1915. Ovarialgraviditat mit wohlerhaltenem Embryo. Ztschr. f. Gebh. u. Gyn., LXXVIII.

Jacobson, S. D.: 1908. True primary ovarian pregnancy ; operation; recovery. Contributions to the Science of Medicine and Surgery, N. Y. Post-Grad. Med. Sch. and Hosp.

Kantorowicz, Ludwig: 1904. Eierstocksschwangerschaft. Samml. klin. Vortr.. Volkmann, N. F., Nr. 370, Gyn. 136, Leipzig.

Kouwer, B. J.: 1897. Ein geval van ovarlalzwangerschap (zwangerschap in ein Graafschen follikel ) Nederl. Tijdschr. v. Verlosk en Gynaec. Haarlem, VIII.

Lea, S. W. W. : 1910. A case of ovarian pregnancy with diffuse intraperitoneal hemorrhage. Jour. Obst. and Gyn. Brit. Emp., XVIII.

Leopold. G. : 1882. Ovarialschwangerschaft mit Lithopadionbildung von 35-jahriger Dauer. Arch. f. Gyn., XIX.

Idem: 1899. Beitrag zur Graviditas extrauterina. Arch. f. Gyn., LVIII.

Lockyer, C. : 1916-17. Two cases of primary ovarian pregnancy, with a review of the literature 1910-1917. Proc. Roy. Soc. Med. Lond., X; Sec. Obst. and Gyn.

Mall, F. P., and E. Cullen: 1913. An ovarian pregnancy located in the Graafian follicle. Surg., Gyn. and Obst., XVII.

Mapes, Chas. C: 1914. Ovarian gestation — being principally a review of the literature. Amer, Jour. Surg., XXVIII.

Martin, R. S.; 1917-18. Three interesting cases. Va. Med. SemiMonthly, XXII.

Mills, H. M.; 1917. Probable ovarian pregnancy. Am. Jour. Obst., LXXVI.

Meyer, A. W. : 1919. Uterine lysis, tubal and ovarian, and resorption of conceptuses. Biol. Bull., XXXIII.

Norris, C. C: 1909. Primary ovarian pregnancy and the report of a case combined with intra-uterine pregnancy. Surg., Gyn. and Obst., IX.

Norris, C. C, and C. B. Mitchell: 1908. Primary ovarian pregnancy with report of a case. Surg., Gyn. and Obst, VI.

Paucot, H., et A. Debeyre: 1913. Etude sur les grossesses ovarlennes jeune. Ann. de Gynec. et d'obst. 2s, t. 10.

Roche, J.: 1902. De la grossesse ovarienne. These de Lyon.

Scott, N. S. : 1901. Ovarian pregnancy; is it an explanation of ovarian hematomas? Am. Med.. II.

Seedorff, M.: 1915. Ein Fall von geborstener Ovarialgraviditat. Monatschr. f. Geb. u. Gyn., XLII.

Sencert, L., et M. Aron: 1914. De Tindependance qui existe entre le development du placenta et celui de I'embryon (t propos d' un cas de grossesse ovarienne.) Bibliog. anat., t. 24.

Spiegelberg, Otto: 1878. Zur Kasuistik der Ovarialschwangerschaft. Arch. f. Gyn., XIII.

Sweeney, Thompson: 1917. Ovarian pregnancy. Med. Rec, XCII; Am. Jour. Obst., LXXVI.

Tussenbroek, van, Catherine: 1899. Un cas de grossesse ovarienne (Grossesse dans un follicule de Graaf). Ann. de gyn. et d'obst., t. 52.

Thr same: 1899. Ovarialschwangerschaft (ein Fall von Schwangerschaft in einem Graafschen Follikel). Intern. Gynak. Kong. zu. Amsterdam; Centralbl. f. Gyn., XXIII.

Thompson, J. F. : 1902. Ovarian pregnancy, with report of a case. Trans. Am. Gyn. Soc, XXVII.

Warbanoff. Peter: 1909. Ein Beitrag zur Graviditas ovarica. Inaug. Dissert.. Miinchen.

Webster, J. C: 1904. Study of a specimen of ovarian pregnancy. Am. Jour. Obst., L.

Webster, J. C: 1907. A second specimen of ovarian pregnancy. Trans. Amer. Gyn. Soc, XXII.

Werth, R.: 1887. Beitrage zur Anatomie und operativen Behandlung der Extrauterinen Schwangerschaft. Stuttgart.

Werth. R.: 1901. Ovarialschwangerschaft. Handb. der Geb.. von Winckel, Bd. II. Th. 2, Wiesbaden.

Williams, J. W. : 1910. Ovarian pregnancy. Gynecology and abdominal surgery, Kelly-Noble, Phil, and Lond.

Idem: 1917. Obstetrics; A text-book for the use of students and practitioners, N. Y. and Lond.

Young. E. B., and L. J. Rhea: 1911'. Ovarian pregnancy. Report of a case. Bost. Med. and Surg. Jour.. CLXIV.

GRANVILLE SHARP PATTISON

By AVii.Li.VM .Sxdw iliLLEE, University of AViscoiisin

Gro.ss, in his biojiraplucal sketch uf Pattison, say,< :

It is no exaggeration to say that no anatomical teacher of his day, either in Europe or in this country, enjoyed a higher reputation; his forte as a teacher consisted in his knowledge of visceral and surgical anatomy, and in the application of this knowledge to the diagnosis and treatment of diseases and of accidents, and to operations.

Being a man ui' iiitunsc feeliiii;' and .-^tvoni; pn-juiHces he did not easily brook oppositimi. Because of tlic^e characteri.sties

'Read before The Johns Hopkins Hospital Historical Club. December 2, 1918.

tlie early years of his career were stuvniy and his reputation as a teacher was fully acquired only after many bitter controversies, one of which was so acrimonious that it was fought out on " the field of honor."

The year of Pattison's birth is usually given as IT!)], Imt he says in his " Refutation," addressed to Dr. Nathaniel Chajinian, of Philadelphia, under date of November 28, 1820, " 1 shall soon enter on the 28th year of my age " ; this ap]>areutly makes 1793 tlie more correct date. He died November 12. 18.52, after a short illness, of nlistrtictiim of the ductus eonimunis choledochus.

THE JOHNS HOPKINS HOSPITAL BULLETIN. APRIL. 1919

GRANVILLE SHARP PATTISON. Courtesy of Dr. J. M. H. Rowland.

THE JOHNS HOPKINS HOSPITAL BULLETIN. APRIL, 1919

PLATE VIII 7i V

NATHAMEL CHAPMAN. Courtesy of Dr. Howard A. Kelly.

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Granville Sharp Pattison was the youiijjest sou of John Pattisoii, of Kelvin Grove, Glasgow. Of iiis early eilueatioii we know nothing eseept the statement tiiat he was probaliiy edueated at the I'niversity of Glasgow. That he was a hanlworking student is shown by his being, when hut 18 years old. assistant to Allen Burns, and on the death of Burns, in 181:!. l)ec<)niing his suecessor to the Chair of Anatomy, I'hvsiology and Surgery in the Andersonian Institution, a recently organized medical school in Gla.'Jgow. Here he made quite a reputation as a lecturer, and had it not been for his naturally indolent nature and love of ea.se, would, no doubt, have attained in his later years preeminent re]iutation as an anatomist.

In Novend)er, 181S, charges were brought against him liy Dr. Ure. one of his colleagues, of having committed adultery with his wife, and a divorce was obtained by Dr. I' re on that ground. The divorce laws of Scotland were at that time iwpuliar; all divorce |)roeedures were brought in the consi.story court, which was an ecclesiastical organization. It was not newsisary that the parties charged with adultery liad ever seen each other ami the reputed paramour might not have ever existed. In any event, the accu.«ed ])aramour could not appear and defend himself. If the husbaiul obtained a divorce from his wife on the ground of improper conduct, he could immediately bring a .<econd action for damages and the accused party could then appear in court and endeavor t" disprn\r the charge.

This second action was never instituted by Dr. I'rc. .Vftcr the arrival of Pattison in this country. Dr. Ure attemjitcd \<y publish an octavo volume dealing with the case. One of liis witne.s.ses, however, having confessed that her declaration was false and that she had been induced to make her statements by means of threats and i)ribcs. Dr. Ure suppre.s.sed the volume, for he could not sustain his charges, and had he attempt^'d under the.<e circumstances to circulate the publication he would have subjected himself to criminal prosecution. This epi.sode was unfortunate for Pattison and it j)layed an im|)ortant role in the turbulent years which f(dlowed : for, although generally known to be luifounded, many venrs cla])sed before it ceased to be recalled.

In Glasgow the charge was generally discredited, for Dr. L r. did not poss<'ss an enviable reputation ; in fact, a statement is made that he barely escaped transportation to Botany Bay " for fraudulently stealing and destroying his father's will." In spite of this accu.<ation Dr. Ure retained his position in the .Vndersonian Institution. Pattison explains the situation in the following statement :

The Andersonian Institutinn of which Dr. I're is a member is an establishment of late date. The funcis which were ol)tain>(l for the erection of its buildings were procured by sul)scrlptioii : and as Dr. fre was very active, at the time when the niom-y was raised, in obtaining it. an(i gra<ite<l to the subscriber of t20 :i perpetual ticlcet of admission to one of the courses of his lectures, it has become a question, wliether the money was bestowed on him as an Individual, he granting personally an equivalent, or to the Corporation of the Institution.

When Dr. Cre. about six years asio. fraudulently stole his father s will for the purpose of defrauding his family, an attempt was niadi

to expell him from the institution: but as the Trustees, upon taking advice, learnt that his expulsion would involve them in a tedious liti!;ation. a litigation which would require to be carried on by money advanced by them as individuals, the attempt was abandoned.

IJejdying tu tliis. Dr. t'liapman shows that the institution was incorpordtctl on June !t, Kyti; when the buildings were ready for occu])ation he does not state, but he docs infer that Pattison was guilty of a misstatement in that he considered an in.stitution 21 years old as an " fstabli.shment of late date." The founder of this Institution was .lohu Anderson, a Scottish naturalist, who in his will provided I'or its establi.shment; he died January 13, 17!)6, and the incorixtration on .lune 9, 1790. was undoubtedly the first step in carrying out tiie iirovisions of the will. The mcclical dc|)artnicnt gave its (irst courses in 1799.

Dr. Chapman attempts to offset the stateinciit in regard to the will of Dr. Fre's father by saying:

.\'ot long before he came to this country. .Mr. Pattison was tried

for a felony, in stealing a body from the grave Mr. Pattison

merely escaped from want of evidence that he had taken the clothes of the deceased: the part of the offence most penal under the Scotch law.

In this instance Patti.son was in the lii>i nf cinnpany. for .Tohii Hunter. Sir .\stley Cooper and nearly every teacher of amitomy up ti> the ])as.<age of the "Anatomy Act" in ]S.i2. might with more or less justice be termed an " acquitted fellon."

The occasion of Pattison's coming to Pliiladclpbia was the e.xpectation of occtijiying the Chair of .\mitomy in the Medical Departnu'iit of the I'niversity of Peinisylvauia. nuide vacant by the death of Profes.sor Dorsey and temporarily lilled i)y Prof. Philip Syng Physick. That he was given to understand before leaving England tiiat the position was ojicn to him is certain, but that this was unofficial is also certain.

On Deceml)er 24. 1818, I'attison received a letter from his In-other, .lohu Pattison, who at that tiiue resided in Philadelphia, in which he .states that his legal adviser. Mr. Chauncy. agreed with him that there was an opportunity for a man of talent lo be appointed to the |)osition left vacant by the death of Dr. Dorsey. The fact that he was a foreigner was certainly against him. but he was " inclined to think tiiat the trustees will be more guidecl iiy talent, than l)y any otlier consideration." He advised that letters be obtained from Astley Cooper and others and " you had better say the extent of your museum. etc.. wiiich I know Mr. Bnrns considered invaluable."

liider date of April 20. 181!l. Dr. Dcwees. of Philadelphia, wrote Pattison a letter which eonlained the following statement :

I have, contrary to any right, taken the liberty to advise upon the subject. As far then as a firm belief that you would succeed (and that belief founded on pretty certain data) will offer an inducement lo pay us a visit, I have no hesitation to declare, that no question remains In my mind, that were you on the spot, your election would he certain. It Is unquestionably the opinion of two of the most intlucntial and best informed men here. Your visit should be as prompt as possible, that you might have the necessary time for the preparatory arrangements here. .My opportunities

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to judge of the sentiments of those, who have this gift in their power, will be best explained by your brother.

Acting on thi.s advice Pattison arranged his affairs as qiiickly as possible and sailed from Liver])ool for New York, where he landed Jnlv 6, and on the evening of Jnly 7. 181 '.i, reached Philadeljihia.

The two " most infiueutial and best-informed men " referred to above were Drs. Chapman and Physiok. Each of these denied having authorized the use of his name. ('ha])maii .states :

The trustees, after postponing the appointment for six months .... had publicly advertised that they would receive applications from any quarter. But we soon discovered our mistake — for at their first meeting which took place not many days afterwards, when all the testimonials of Mr. Pattison were submitted to them, so far from a favorable impression being made, these recommendations were treated contemptuously, as extravagant and hyperbolical — it being quite manifest, that no individual with halt the merit which they set forth, would sacrifice his actual possessions, to embark in so adventurous a scheme!

Chapman evidently forgot that Philadelphia and the country in general was peopled with those who had left the old countrv and settled in this country because they thought that tlu'\ had here an opportunity to improve their condition — that they were adventurers.

Shortly before sailing, while he was in London, Pattison Avas made a member of the Medicq-Chirurgieal Society of London and a Fellow of the Eoyal College of Surgeons. Had there been the stain on his character which was charged against him, it seems doubtful if these honors would have been bestowed on him. The " testimonials " were written by Prof. John Barclay and Dr. Thompson, of Edinburgh : Francis Jeffrey, editor of the Edinbvrgh Revieu' : James Wardrop and Astley Cooper, of London; the Eev. Dr. Love, of Glasgow, a celebrated clergj-man of the Kirk of Scotland : Sir James McGregor : Sir William Adams ; and others.

Just at this time there was a good deal of intrigue taking place in the faculty of the University of Pennsylvania, and in 1819 Philip Syng Physick,

Yielding up his own better judgment to the schemes of others, for perhaps the first time in his life, allowed himself to be transferred — for the act was not of his own choice — from the chair of Surgery, to that of Anatomy, from the place where he was emphatically at home, to one in which he was comparatively a stranger.

Pattison did not accept any appointment in tlie L'uiversity. though one was offered to him : he also declined a professorsliip in the Transylvania L^niversity at Lexington, Ky. Cha])man makes Pattison's declination of the call to Lexington appear in a false light and says :

The College, were, moreover, as I am told, justly indignant at the disrespectful manner in which they were treated, considering the only motive of Mr. Pattison, in procuring the appointment, was to have it published as an early recognition of his consequence in this country.

He also states that Dr. Caldwell was furnished witli all of Pattison's documents, and had a distinct miderstanding with

Pattison that if lie were elected he would accept. If such «ere the case, Dv. Caldwell would not fail to make mention of it in his " Autobiography," for such episodes as this are favorite themes in his narrative. A careful reading of Peter's " History of the Medical Department of Transylvania University " also fails to reveal a single reference to this incident. In 1820 Pattison was elected Professor of Surgery in the University of ilaryland, and he looked forward to leaving behind him all the intrigue and malevolence he had encountered at Philadelphia, fostered in a large degree by Dr. Xathaniel Chapman. This did not materialize, for One of the faculty, a Professor in the University of Pennsylvania! came to Baltimore immediately after my settlement in that City, apparently for the purpose of shutting me out from the hospitality of the citizens, by the most foul, the most malignant, the most false asperations against my character.

The animosity existing between Pattison and Dr. Chai)man. who seems to have been the moving spirit in the campaign against Pattison, soon reached an acute stage and Pattison issued a challenge to Dr. Chapman, which he did not accept. This led Pattison to go to Philadelphia, and on October 23. 1850, he put up in two jntblic places the following post:

To THE Pviu.ic Whereas Nathaniel Chapman, M. D., Professor of the Theory and Practice of Medicine in the University of Pennsylvania, etc. etc. has propagated scandalous and unfounded reports against my character; and Whereas when properly applied to. he has refused to give any explanation of his conduct, or the satisfaction which every gentleman has a right to demand, and which no one having any claim to that character can refuse, I am therefore compelled to the only step left me, and Post the said Dr. Nathaniel Chapman, as a liar, a coward and a scoundrel.

Granville Sh^vbp Pattison.

Following tlie European custom Pattison resolved to stay two days in Philadelphia ; but, he says :

My stay, however, was not long. left to my option I was

arrested at 11 o'clock A. M. of the day on which I had put up the post. Dr. Chapman denies all agency in the matter, be it so.

When the case came before the grand jury, all the correspondence in the case was furnished by Chapman, and Pattison says :

Perhaps he did this that I might be convicted, in order that an opportunity might be furnished him of displaying his (lenerosity and magnanimity, by applying " instantly in person to the Executive " for my " pardon."

In his letter refitsiug to meet Pattison, Chapman gives as his reason, " tlie character and conduct of Mr. Pattison, as well in relation to the causes which compelled him to leave Scotland, as to events which have subsequently happened." Xot satisfied with this, in Xovember, 1820, Chapman issued a pamjihlet in which he attempts to Justfy his conduct. To this Pattison replied in a like manner November 28, 1820. Pattison " had the good fortune and address to enlist the sympathy of his colleagues and a large part of the community in Baltimore in his behalf, and presenting his side of the case to a committee of prominent citizens, he was exonerated from all blame."

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This was iu)t Chapmiiirs first "affair"; hi- had soim- ycar^: ln't'oro i-halleii<.0(l Dr. Dewecs. In rogaril to this alTair ( liii|iiiiau says :

It happened fifteen or sixteen years ago: and if my conduct was reprehensible. I hope I have since atoned for it, by a friendship warm, cordial and sincere. What, however, will be thought of tln' nialiBnity of a man. who thus endeavors to disturb the hnpplnes> of families, by references of this nature! ! I

Patti.soii r('|ilyili;r to tliis does not |mt (liainnaii in :ni "•nviahle lijrlit :

I have not a " numerous family," I admit, and here I allow there is ii distinction. But did Dr. Chapman before he had a family, when he challenged Dr. Dewees. who had a numerous one. think this excused him?

The quarrel lietwoon Chapman anil I'attison was finally taken up hy General Thonuis Cadwalailer, Dr. t'haiimanV hrother-in-law, and four years after Pattison's arrival in thi> <Miuntry (IS'iS?) they met somewhere in Delaware. Cailwalader received the ball from Pattison's pistol in his " pistol iirm " which was disabled thereby durini; the remainder of lii> life. Pattison was uninjured, " but a ball i)assed tlu-oiii:]i the skirt of his coat near the waist."

In 1820 Pattison resigned his professorship at Baltimore and returned to England. Why he resigned a position whiib with liis professional services he states was bringing him ^10,000 a year is not clear; for, as a teacher, he had a successful record while in Baltimore, and the University ot Maryland enjoyed its greatest prosperity. On the one liand. is tile statement that he " led a very gay life " in Baltimore jind that his health was thereby impaired and that after he left it was doubtful whether he recovered; on the other hand. there is Pattison's flat denial and 'Hi additional years of activr life.

In July, 1827, Pattison was ap]>ointeil Professor of AnatoniN in the newly organized University of London. Before long Inbecame involved in difficulties, different from those at Philadelphia, but equally disastrous. Pattison was a Scotchman and had taught in Scotland and "America"; he had iiifroduced as a te.\t-bo(»k Fyfe's anatomy, written by a Scotchman : he had for his demonstrator a Mr. Bennett, an Englishman. who had conducted a school of anatomy in Paris which had. very properly, been refused credit at an English institution : he had iiicurrecl the displeasure of Wakley, editor of tlu' f.iincet, who supjjorted Bennett; hut chief of all he was a Scotchman. If any one doubts the attitude of London at thitime towards Scotchmen let him read Pichot's " Life ami Labors of Sir Charles Bell " and the " Lett^'rs of Sir Cbiirli Bell " by his brother Tieorgc.

Wakley began his attjick on Pattison by a sharp criticism of Fyfe's anatomy ; it must be acknowledged, however, that tln' criticism was justified. Wakley was a friend of the mclii jl students an<l supported them in most of their comjilaints ami. |)0ssibly, promptetl .<ome of them. That he was responsible fm many reforms in medical in.struction and medical i)racticcs ito his credit, and he deserves all the credit accorded to him. but he sometimes overshf>t bis mark; take, for e.\amj)le, bi

altitude towards Sir Charles Bell, Marsiiall Hall, and .itlu is who have left an honored name and life work.

On .luly 23, 1831, Pattison was dismissed from Hie Chair of Anatomy at the I'niversity of London. The events preceding and following his dismissal are full of interest. Clarke, in his " Autobiographical Recollections of the Medical Pr<ifession," says :

No matter what a mans talents and acquirements might be. he had little or no chance of advancement at a Hospital, except through family or money influence. .•\11 the prizes in the Profession were monopolized by those who could pay for them, or who were fortunate enough to have friends at Court. The apprentice of the Hospital Surgeon paid a very large premium for his inden tures, and. as a rule, it was understood, that he was to be placed on the Hospital staff as part return for his money outlay. This gave rise to a system of nepotism of the most objectionable character: Hospital Surgeons were selected, not from the ma.ss of the Profession, but from the private pupils and relations of the " staff," ....

To add to the dis+++++ CONTENTS prevailing, there had been (1S27) an unseemly quarrel at the great Hospital of St. Uartholomew's. in

which .Mr. .-Vbernethy did not bear an enviable part At this

time, too, the establishment of what was then called the " University of London " attracted increased attention to the system

of nepotism The announcement of the names of Professors

of this Institution startled the Profession by the fact that most, if not all but one of them, were "outsiders"; were not. in fact, connected with any of the large endowed Hospitals, but were all of high and deserved distinction.

The first iiaiiie on tlic list given by Clarke is that of Pattison.

In the is.suc of the Lancet for March .">, 1831, tiiere is a communication signed " A Senior Student of the London University" in which an attempt is made to show that Patfison is unworthy of his professorship and that Bennett shotdd have the position. Much of " Senior Student's " compl.-iint and most of the student dissatisfaction is based on the fa<t that Pattison attcmpte<l to enforce discijdine in his cla.ssroom. That Wakley had jirevious knowledge of wlnit was taking place in Patti.son's lecture room is shown by the following quotation from the above-mentioned communicafioii :

You are already, Sir, aware of the proceedings which were Instituted during the last session by a part of the medical students against one ot the lecturers upon anatomy, Mr. Pattison.

This communication was replied to by another student, who signs himself " Veritas," under date of March 7, 1831, and throws considerable light on the case. One of the charges brought against Patti.son in the original complaint was "that the defect in his articulation rendered him unfit for the chair." This charge was afterwards erased. It is interesting to note that this is identically the same charge brought by Wakley against Sir Charles Bell. " Veritas " says " a more inikind and unfeeling imputation could not have been made." Toward the clo.«c of his reply " Veritas " says:

Picture to yourself. Sir, an assembly of mere youths, many of whom have Just commenced their studies, met together to decide upon the ability or inability of a professor who was engaged in teaching anatomy before many of them had an existence. The very idea is preposterous.

103

[No. 33b'

He goes ou to say that he has attended two sessions of Pattison's lectures and has always found them instructive and any one who pays attention to his lectures "cannot fail of reaping abundant store of anatomical knowledge."

As stated above, Pattison was dismissed July 23, 1831. Tlie resolutions passed by the Council show that they finally yielded to the student clamor ; but

In taking this step the Council feel it due to Professor Pattison to state, that nothing which has come to their knowledge, with respect to his conduct, has in any way tended to impeach either his general character, or professional skill and knowledge.

One member of the Cotmcil protested vigorously, but vainly, against Pattison's dismissal and enumerates eight reasons why he should not have been dismissed. In the seventh item the statement is made that the other professors testified to tlie excellency of Pattison's qualifications and that " many of them liad expressed their firm conviction to the Council, that the dissensions in the medical school did not ari.se out of any defect or misconduct of Professor Pattison." They evidently had in mind outside influences.

From this time mitil the end of the controversy in the Lancet the discussion was confined mainly to Wakley and Pattison, with now and then short communications from some of Wakley's friends. The final shot was fired by Pattison and his closing paragraph is exceedingly interesting reading:

In the letters of Drs. Turner and Thompson, and in your " strictures " on my Statement, the fact of my having been a successful teacher in the United States is treated with great contempt. " It does not follow " observes Dr. Turner, " that he could succeed in London because he was successful in America." The Americans, forsooth, are easily satisfied. It is very well for John Bull to say so. I should, however, have expected that you were too well informed as to the state of medical science in the United States, to have given currency to such a vulgar and unfounded prejudice. The Americans, I assert, are as far advanced and as enlightened in their medical opinions as any country in Europe: and I would further assert, without the fear of contradiction, that there may be numbered amongst the medical profession of that country, gentlemen who, tor extent and profundity of knowledge, and for capacity of conveying instruction, have no reason to fear comparison with the most eminent teachers in Europe. Let the improvements in medical and chirurgical science be reviewed for the last thirty years, and it will be found that America has furnished her full quota.

This defence of American medicine and American nuHJical men by one who had good reason for resentment shows Pattison to have been a man of more character than is generally acknowledged.

Shortly before Pattison was dismissed from the Chair of Anatomy Bennett died and the Committee of Education cif the University of Loudon looked about for a new jjrofesscir. They were fortunate in their selection, for they recummendcil Mr. Jonas Quain lur the |)rofessorshi|i and his In-nthei'. Mr. Eichard Quain. inr (lenioustrator, and ]ieace reigned fur the time being.

Pattison was not long withottt a professorship, for in lcS3v! he took up his duties as Professor of Anatomy in the Jefl'erson Medical College, in Philadelphia, where he met with innnediate success. He held advanced ideas as to the best wav in

which anatomy should be studied, as the following abstract from the annual announcement of the Jefferson ^ledieal College for the year 1832 shows :

Anatomy, the basis of all medical reasoning, can only be studied practicoUy during the term of the student's attendance on lectures. Should he neglect his opportunities for acquiring a complete knowledge of the science during the term passed by him at college, he must be +++++ CONTENTS to continue forever afterwards a mere driveller in his profession. Now, anatomy is not to be learnt by an attendance on lectures. Dissection, and dissection alone, can make a man an anatomist. The Professor of Anatomy, it is true, may, by animated and masterly demonstrations, do much to guide and assist the anatomical student in true prosecution of his studies, but it is in the dissecting room, with the dead body before him. by patient and assiduous dissections, that the student can alone acquire a knowledge of anatomy.

Pattison remained in Philadelphia tmtil 1841, when he joined in founding the iledical Department of the University of New York. Here he held for the remainder of his life the Professorship of General Descriptive and Surgical Anatomy.

With his return to this country, the strife and turmoil of his life very largely disappeared. He married a Scotch lady by the name of Sharp, who was possessed of some fortune. I have been ttnable to ascertain the date of their marriage, but it proved to be a very happy one, for Gross gives a pleasing pirtnre of their domestic life. He was social, ever ready to do a kind act, a lover of the beautiful in nature and art. He took an active interest in establishing the Grand Opera House in New York. He also was an enthusiastic disciple of Izaak "Walton.

Pattison was the atithor of " The Register and Library of iledical and Chirurgical Science." He edited with notes Burns' Surgical Anatomy of the Arteries of the Head and Neck, !Masse's Anatomical Atlas, and Cruveilhier's Anatomy : he \\'as one of the editors of the American Medical Recorder, a journal which contains many of his contributions to medical literature.

NOTES

Pattison's Exoneration. — All the facts concerning the divorce obtained by Dr. Ure were laid before the managers of the Andersonian Institution by James Burn. " Writer of the Signet." and Pattison was completely exonerated by them.

Pattison's Museum. — Cordell states that this " was extensively advertised in the medical journals and newspapers of the country." After he went to the University of Maryland he exerted a considerable influence in the councils of the University and he eventually induced the University to purchase it for $8000, and in 1S21 a new building (Practice Hall) was erected for its accommodation. It consisted " of upwards of 1000 selected morbid and healthy specimens, and in variety, excellence and number was far superior to any other in America." For some time it constituted the chief attraction for visitors to the University. Many of the preparations are still extant, but in a somewhat neglected condition. Dr. Phj/sick's Transfer to Aiiatonu/. — Chapman made the statement to Pattison that he thought by transferring Dr. Physick to the Chair of Anatomy and by bringing Dr. Gibson from Baltimore to occupy the Chair of Surgery the changes " would operate beneficially in two ways. It would strengthen the University of Pennsylvania, and at the same time weaken that of Maryland." This was before Pattison received his call to Baltimore. Apkil. 1!M!)J io;i Position Offered at the University of Pennsylvania. — The position offered Pattison at thr University of Pennsylvania was to bo shared with another, and he did not care to accept such an arrangement. He therefore besan to sive independent lectures on anatomy and surgery and he says that he had " a class of above one hundred and ninety students. " The hour of Pattison's lecture was fixed after consultation with Chapman and was one which Chapman assured Pattison would not conflict with any of the professors. When, however, ("liapnian learned that Pattison's lectures were popular with the students he changed the hour of his own lecture to that used by Pattison and thus prevented the students from attending Pattison's lecture. Gibson-Putt ison Controversy. — Apparently no one in Philadelphia knew of the particular structure demonstrated by Pattison. Gibson, however, found in CoUes' Surgical Anatomy ' an unusually full and well-written account of those very parts, which Mr. Pattison had claimed as a discovery of his own." Like many another worker Pattison thought he had found something new. but as soon as he found he had been anticipated he withdrew all claims of discovery, only claiming that certain post-operative results were best explained by the presence of this structure (Colles' fascia). Gibson's Chnnirteri.'itics. — " He was very vain in his personal appearance, and more so of his reputation as a surgeon and teacher of surgery. His style of lecturing was easy, agreeable, and instructive, but he never omitted an opportunity to set forth his own merits and to depreciate the ability of surgeons whom he disliked. He was especially vindictive against his leading rival in Philadelphia." In 1847 Cibson was in Europe and returned late in the fall with a wardrobe of broadly striped waistcoats and trousers to match. These he displayed to his class until the lot was exhausted, causing much merriment in the class-room and prolonged rounds of applause which he received as evidence of his personal popularity (Busey. l". P.. 1848). Dr. S. D. Gross says. "Gibson was not an amiable man. His ill temper often betrayed him Into unkind expressions, even in the lecture room." During his last illness Gibson sent for Gross. " .\ly acquaintance with him was slight, and I was therefore not a little surprised when I received a message to visit him at his country residence. .\n old friend, to whom I mentioned the fact, exclaimed, ' Don't you know that lie has no friends in the medical profession of Philadelphia. " Pattison's Hroiiue. — " What added interest to the speaker was a slight lisp and a Scotch accent, which never entirely forsook him. despite his efforts to overcome them in early life " (Gross). Chnitmiin us n Teathrr. — " A cleft palate, with its consequent indistinct utterance, robbed him of every charm as a teacher, for which his vast experience, great learning, and qualities of heart and mind so well fitted him. The most careful attention, near and in front of him was necessary to catch the words as they were spoken, except by those who by long experience had become accustomed to his unfortunate and defective enunciation " (Busey. V. P.. 1848). He (Chapman) "has seen several cases of hydrocephalus in girls about the age of puberty, caused by metastasis of action from the uterus to the brain." Chapman believes " many cases that have a decided character of angina pectoris afterwards terminated in well-marked gout cases. -A gentleman long afflicted with this affection had gout induced In his extremities by the use of sinapisms, and the former affection was relieved: but. Improperly removing the sinapisms, the disease suddenly returned to Its place and Immediately killed him." Epilepsy. " usually assigned to a certain state of the nervous system — a peculiar sensibility or irritability — It Is the temperament of genius and intellect — Julius Cspsar, Mahomet, Napoleon, etc." (From bound volume of MS. notes taken by .lames C. Hall (U. P., 1827 » of Chapman's lectures delivered In 1826.) Pattison's Resignation from the University of .UuriiUind. — Pattison. in his " Statement of Facts in his connection with the I'niversity of London, " says that it was his intention to return to the States and deliver another course of lectures: instead of doing this he spent some time in Germany. I have tried to ascertain the date of nis resignation, but have been unsuccessful. This mlgtil help by showing that he resigned from the I'niversity of .Maryland to accept the position in the I'niversity of London. Putti-ioii's iKtsiiniutioii Jrum the I'nirrr.iilii u) London. — The only medical man who was a member of the Council of the University ol London (Dr. Birkheck) supported Pattison and opposed .Mr. Bennett and the way in which Bennett was appointed. I do not think that Pattison. at the time he wrote his " Statement of Facts." realized the extent of Wakley's opposition and influence. Later he understood it better and gave it proper consideration. Defense of Amrricuu .Mrdirim-. — Medicine in the I'nited States 1800 to 1830. Pattison, in the closing paragraph of his final communication made the statement that if the advances In medicine and surgery " be reviewed for the last thirty years, it will be found that America has furnished her full quota." 1 have had the curiosity to look up American medicine during this period and find abundant material to substantiate his aflirmation. In Boston, there was .lohn Warren and J. C. Warren, eminent as anatomists and surgeons — the latter founder of the Massachusetts General Hospital: James Jackson in internal medicine and Jacob Bigelow. who published in 1820 his " American .Medical Botany " — his essay " On Self-Limited Diseases " did not appear until 1835. In New York, Wright Post and Valentine .Motl were doing pioneer work in surgery. In Philadelphia, there was Casper Wistar and W. E. Horner in anatomy: Philip Syng Physick in surgery; John C. Otto in clinical medicine (he was the first to describe hemophilia): J. K. .Mitchell in neurology: W. P. Dewees in obstetrics: Nathaniel Chapman in the theory and practice of medl cine. In Connecticut. Elisha North was introducing vaccination, recommending the use of the thermometer in fevers and in 1S17 established the first eye infirmary in the United States. Nathan Smith was establishing medical schools in New England and furnishing the entire faculty: he was a pioneer operator for ovariotomy and. in 1824. published his essay on " Typhus Fever." now a medical classic. In the West there were four men who have made a name in American medicine. Ephraim McDowell, B. W. Dudley, Wllllani Beaumont and Daniel Drake. .McDowell Is known the world over as the father of ovariotomy (Nathan Smith did not know of his operation when he operated in 1821). Dudley was famous in his day for his success in lithotomy. Beaumont, in 182.';, began those studies on digestion which he gave to the world in 1833. Drake was estal)lishin,< medical schools and publishing essays on niedlcal education in the Wrslrm .loiirnul of the .Urdirnl und Phii.siiul Sciences: at the same time he was preparing for his great work. " Diseases of the Interior Valley of North America." Other names could be added to this list, but it is unnecessary. I consider the point raised by Pattison well proven. Has the lurotid (Uund Ihrr liec, h:.rtiri)uled.'— The Professor of Surgery at the University of Pennsylvania (Dr. t;ibson) In a cUnic at the Philadelphia Alms House, open to students of the Jefferson and the University, referred slightingly to the claim of the Professor of Surgery at Jefferson (Dr. McClellan) that he had performed the operation (under a general attack on Sir Charles Bell who had made the same claim). He refers to Bell as a Cunvu.ihuik </i(' t more worthy of his gun than the Dipper (Dr. McClellan). Pattison took up the challenge and made a reply which was brilliant for Its wit and sentiment and convincing with its weight of learning. In the same publication Pattison ridicules the story that he was so Ignorant of the subject that he mistook the omo hyofd muscle for the carotid artery and was about to llgate it 104 [Xo. 33S when one of his students called his attention to the mistake and, being set right by his pupil, found the artery and tied It. I have tried unsuccessfully to ascertain what were the relations between Chapman and Pattison after his return to Philadelphia as Professor of Anatomy at Jefferson. Dr. J. W. Holland, of Philadelphia, made Inquiries for me of a distant relative of Dr. Chapman and reported that " he does not know a living soul who could state what were Cliapman's relations to Pattison in later years." As nothing further appears in print, the animosities of earlier years seem to have died out and disappeared. BIBLIOGRAPHY Bell, John: Philip Syng Physick. Philadelphia, 1S61. Busey, Samuel C: Personal reminiscences and recollections. Washington. 1895. Chapman, Nathaniel: Correspondence between Mr. Granville Sharp Pattison and Dr. N. Chapman. Philadelphia, 1S20. Idem : Case of divorce of Andrew Lire. M. D., vs. Catherine L're Philadelphia. 1S21. Idejn : Correspondence between ilr. Granville Sharp Pattison and Dr. N. Chapman. 2d edition, with explanatory remarks. Philadelphia. 1821. Clark. J. F. : Autobiographical recollections of the medical profession. London, 1874. Cordell, E. F.: Historical sketch of the University of Maryland School of Medicine. Baltimore, 1891. Gibson. William: Strictures on Mr. Pattlson's reply to certain oral and written' criticisms. Philadelphia, 1820. Gross, Samuel D.: Autobiography, 2 vols. Philadelphia, 1887. Henry, F. P.: History of medicine In Philadelphia. Philadelphia. 1897. Lancet, The: London, 1830-31, 1831-32. Pattison. G. S.: Experimental observations on the operation of lithotomy, with the description of a fascia of the prostate gland, which appears to explain anatomically the cause of urinal infiltrations and consequent death. Am. Med. Recorder, 1820, III. Idem: An answer to a pamphlet entitled "Strictures on Mr. Pattlson's reply to certain oral and written criticisms, by W. Gibson. M. D." Philadelphia. 1820. Idem: A refutation of certain Calumnies published in a pamphlet, entitled Correspondence between Mi. Granville Sharp Pattison and Dr. Nathaniel Chapman. Baltimore, 1820. Idem : Final reply to the numerous slanders circulated by Nathaniel Chapman, M. D., Professor of the Institutes and Practice of Medicine in the University of Pennsylvania. Baltimore, 1821. Idem : Professor Pattlson's statement of the facts of his connection with the University of London. London. 1831. Idem: A lecture delivered in Jefferson Medical College, Philadelphia, on the evening of Tuesday, the 22d of January, 1833, on the question " Has the parotid gland ever been extirpated? " Published by the students of Jefferson Medical College. Philadelphia. 1833. COMMENTS ON THE PATHOLOGY AND BACTERIOLOGY OF FATAL INFLUENZA CASES, AS OBSERVED AT CAMP DEVENS, MASS. Bv S. BuKr WOLBACH, Bo.stou Death from influenza means death from Imig eomi)lieiitions — pneumonia in some form. The pathological picture ol' the Itmgs as seen in a series of postmortems is a kaleidoscopic one. At first it was most difficult to correlate the various gross findings, and it also has been difficult to correlate the microscopic findings, and this part of the work is not yet completed. I have had the advantage of comparing my observations with those of Dr. Goodpasture at the Xaval Hospital at Chelsea, Mass., and again with a study of the series of cases we have had at the Peter Bent Brigham Hospital in Boston, and it now is possible to give a fair account of tlie probalile sequence of events and to explain tlie apparent great diiferences in the ])athology. In a series sucli as is presented here two types of lungs staml out as strikingly characteristic findings in this disease. The first is encountered in those cases in which death has occurred within a few days after the onset of pulmonary signs. These cases yield lungs which are partially collap.sed, dark red, la.\. but meaty in consistency. Tlie pleural surfaces are often partly covered with a dusky red mottling, due to small extravasations of blood beneath the serous coat. There mav be a thin layer of dusky red fibrinous exudate u])on the pleural surfaces, particularly over the posterior borders. On sectimi these lungs are dark red and wet. They are dripping wet, and the fluid from some portions is a blood-tinged serous liquid and from others dark red and bloody. On close inspection the cut surfaces are usually found to be thickly sprinkled with air vesicles of considerable size. The lung tissue as a whole, after the liquid has drained from it, is brownish-red in color, and somewhat translucent and friable. The mucosa of the bronchi is usually very dark red in color, and the bronc'hial lymph nodc^ are enlarged and deep red in color. The other type of lung, which is found in patients that ha\ e lived for 10 days or more after the onset of the disease, whilr showing traces of the type of lesion just described, is characterized by a very extensive bronchitis, n'ith bronclio-pneumonia, discrete or confluent, and peri-bronchitis. These hmgs are more voluminous than the preceding, but they do not fill the chest cavity at postmortem. They are nodular, and the ]deural surfaces occasionally show a striking tracery, due ti> the injection of the stib-pleural lymphatics. Portions of the surfaces of the lungs may be covered with a thin layer of fibrinous exudate. On section the most prominent feature is the extensive injection of the bronchi, particularly the smaller imes, with a fibrino-purulent exudate. The injection of the lu'onchi may be so extensive and uniform as to produce geometrical patterns, which are very striking when the condition is accomijanied, as it usually is, by a marked infiltration of the inter-lobular septa. A casual inspection suffices to show that the smaller bronchi are distended, nsuallj' markedly dilated, and in eases of two weeks' duration spherical and cylindrical bruncliiectases are very common. The gross appearances of this type of lung are very much like those described by Dr. MacCallum in pneumonias after measles. The condition in fact Ai-KiL. 1919] 105 is one of pan-bronchitis; peri-bronchitis with extensive infiltration of thf interlobular sopta : and organization in alvi-oli and bronchioles. These two preduniinatiiig types on first consideration seem to represent ditTerent processes. 1 hope to show convincinglv that they simply represent difTeri'ut stages of the same process. Before I undertook tlie study of the Camp Devens cases I had .some experience with influenza pneumonias at the Peter Bent Brigham Hospital, and I have since quickly surveyed tlie material obtained there during the time I was at Camp Devens. The Brigham Hospital cases, on the whole, have been t|nit(' diflferent in their gross appearances. On the other hand, the cases at the Naval Hospital in Chelsea have been very similar to those at Camp Devens, and I think a cross-section of the study of one series of cases is very much like that of the other — to which Dr. Good|)asture agrees. There are many other interesting features of the i)athology of the lungs, such as tlic rapidity with which bronchiectasis occurs and the large number of case.s which develop interstitial emphysema, and of course the consequences of both of these conditions ; bronchieitatic abscesses and gangrene of lungs from the first, emjiiiysenia of the mediastinum and subcutaneous emphysema fnmi the second. Of this series of 2S postmortems, done between the 2d and 32d day of the disease, there were six that showed sulicutaneous emphysema: eleven showed emphysema of tlic mediastinum. In comparing notes with other pathologists one is struck by the dillerenees in gross appearances of the lungs in dilferent localities. The .same is true in regard to the bacteriology. The table which accompanies this report shows the very higii percentage of pure liarillus injUienza: jmeumonias at Camp Devens : again, a similarity with the series at the Chelsea Na\;il Hos|)ital as reporteil i)y Keegan. However, in the Camj) Dcveii> series there were a few cases in which the hemolytic strejitocoecus and the pneumococcus were found, and the.se hnigs presented different gross apj)earances. In a cursory analysis of the Brigham Hospital cases auto])sied (about 30), I find a predominance of hemolytic streptococcus and pneumoco((ii> lungs. Without going into corroborative details at this time, I nniy say that in the gro.ss appearance of the lungs I have laid tniphasis ujion, li. iujiuenzte was the only organism wliirli could be cultivated and I iniliesitatingly associate these distinctive conditions with tiiat organism. In lungs .showing other types of solidification, other organisms were responsililc for the exudation characttrizing the pneumonias. The iicniulytic streptococcus, the staj)hylococcus and the pncumncoccn~. each produces its distinctive picture, the last often that i>\ lobar jtneunionia. While the bacteriological evidence, based u|irin the assumption that B. iiiflttetizie is the cause of influenza, is very good in support of the stand that there is a distinctive lung lesion in these influenza [>neumonias, the histological sttiily has afforded very definite proof. Early in this study of tlic Camp Devens ca.ses. I recognized the fact, as have others, that a striking type of reaction was present, a condition of acute idveolar emphysema with the deposit of a hyaline fibrinoumaterial on the alveolar walls. The intervening alveoli af compressed and filled with exudate, which in the early cases is largely serous or bloody, containing but little fibrin. It is this acute alveolar emphy.<ema, with the .-icrous and hemorrhagic exudate, that gives the characteristic gross appearance to the lungs in the early stage of the disease. In order to determine how eounnon this lesion is, I have gone over all of the Brigham Hospital autopsies on influenza cases, and find it to be constant. It may be nuisked by a jjueumococcus or streptococciis exudation or bv extensive hemorrhage, but its presence can always be determineil by the finding of the hyaline fibrin outlining greatly distended air spaces in the lungs. It is the one di,stinctive feature in the ]iathology of influenza i)neumonias. and its constant occurrence is indicative of the entity of the initial lung infection. The interjn-etation of this lesion was not ca.sy. The hyaline fibrin, because of its prominence and the jiixta])osition of cellular exudate, often simulates the outlines of alveoli. As a matter of fact, it outlines cavities filled with air, which may or may not completely fill groups of alveoli. Although alveolar walls in contact with tliis fibrin may be necrotic, tissue elements ])lay no part in its formation. .\ similar hyaline fil)rin was found in two cases of emphysema of the mediastinum where the mediastinal areolar tissues weninfected by ])neumococcus, secondary to ])neumococcus peri<arditis. The jihysical characteristics of this fibrin are determined by its contact with air, and an imiiortant factor is probably the mechanical com|)ression of strands of fibrin i)y air. What is the source of the exudation in the alveoli in these early jmeumonias! The exudation may be ])re.sent in alveoli ^vith intact walls, or walls showing very slight reaction, mainly evidenced by activity of the resjiiratory e])itheliuni. In all cases severe lesions were found in the finest bronchioles, and in the alveolar ducts. The latter show an exudation eompo.-icd mainly of polymorphonuclear leucocytes and small (pnintities of fibrin. The walls are filled with leucocytes, and are often necrotic in places. The intralobular bronchioh's show severe lesions of the mucosa, and it is often po.ssible to demonstrate the source of hemorrhages from cajiillaries. The obvious explanation, and indeed the only possible one from the material at hand, is tliat the major injury is to the bronchial system. and nniinly in the finest bronchioles and alveolar ducts. To secure the degree of cniphysenni ])re,sent it is necessary to assume a valve action of the exudate in the bronchi. Tbe character of the hyaline fibrin de])osit annmd air vesicles and upon the alveolar walls suggests a jiouring of exudation into the alveoli from the bronchioles and alveolar ducts, at a time when air is able to pass. Thus the patient is virtually blowing bubbles in his own lungs, into a medium of exudation relatively poor in fibrin. The meibanism of interstitial eniiiby.senni formation is easily seen, where tbe greatly distended alveoli are in contact with the pleura of interlobular septa. In tlie.s' locations it is liossiblc to demonstrate ru])turc of the alveolar walls and the direct continuity of fibrinous strand.s, partially filling cleft* dis.sected by the air from alveoli to pleural or interlobular connective tissue. A series of gross .sections and microscopic sections from lungs with interstitial emphysema shows that the air finds the easiest route of exit from the lung in the con 106 [No. 338 iieetive tissue surrounding blood-vessels. It dissects altnig blood-vessels to the hylus of the luug and from there along the great vessels and bronchi into the mediastiuuni, over the j)ericardium into the anterior mediastinum, and upwards along tlie trachea into the tissues of the neck, whence it escapes into the subcutaneous tissues. This subcutaneous emphysema may appear very early, as will be seen by the accompanying chart. The earliest case was seven days from the first symptom, which means, of course, a shorter duration of the lung involvement. The majority of the cases were noted on or after the 10th day from the initial symptoms of the disease. It must be l)orne in mind in considering the i)atliology of these lungs, that the lesions are not imiformly distributed, and therefore very extensive injury in portions of one or several lobes are compatible with life for a considerable period of time. The bronchial lesions apparently progress, and may extend throughout tlie whole of one or both lungs, producing the anatomical picture of the more chronic cases, that of a panbronchitis with bronchiectases and peri-bronchitis. During this period of extension in bronchi, a number of things may happen to the portions of the lungs first involved. They may become secondarily infected with pneumococcus or stre])tiicoecus, or the Gram-negative diplococcus called by English workers "Diplococcus mucosus." In rare instances Staphylococcus and Friedlander's bacillus have been encountered. Tlie fate of the tissue depends on the nature of the infectingorganism; as, for example, fibrinous exudation with the pneumococcus and abscess formation with the staphylococcus. In a number of instances these portions of the lungs, severely damaged at the onset, did not become secondarily infected ; at least, these lungs have shown only the influenza bacillus at the autopsy, and have undergone extensive organization resulting in cicatrices of large sizes. If we take a series of lungs which have shown only the influenza bacillus in cultures and in sections, we may still have all the stages described exclusive of those with secondary infection, and accordingly we must conclude that the reaction to the influenza bacillus is less intense in the later stages of lung involvement than in the earlier. This is shown best in comparing two lungs from the same ease, where in one lung, iisually the right, we find the severe damage of the early lesion with bronchiectasis ami peri-bronchitis, and in the other kuig a much less intense bronchial reaction, with much less marked peri-bronchitis, or none at all. The involvement of the pleura in lungs infectetl solely with tlie influenza bacillus is very slight. There are hemorrhages into the pleura and perhaps a thin layer of fibrin upon the surface. The amount of fluid in the ])leural cavities was always small, though blood-tinged. Empyema was found in cases secondarily infected with the streptococcus or pneumococcus. The involvement of the pleura may result from the extension of the inflammatory process along the interlobular septa and lymphatics, or, and this I believe is more commonly the case, from bronchiectatic cavities situated close to the pleural surface. Gangrene of the lung was noted in one of the Camp Devens series in a case showing very extensive bronchiectases, witli bronchiectatic abscesses. Extensive necrosis of the hum- lias been observed in a number of eases in this same series and at the Brigham Hospital — necrosis due to organisms other than the influenza bacillus. Organization in the jiure B. infliienzce cases was a common end result. The organization of the exudate begins early, certainly before the 10th day of the disease, and a prominent factor in liringing about this result is, I believe, the plugging of the bronchi with exudation. In patients who had survived three weeks or more there Avere very complicated gross appearances, due to extensive cicatrization of large portions of the lung. The contraction of interlobular septa, due to the avascular organization of exudate, causes marked distortion of the lobules of the lung, and peculiar lines of retraction on the pleural surfaces. It is not the purpose of the present report to include the whole pathology of influenza. There are a few interesting features in other organs which are worthy of emphasis, howover. Eight of the Camp Devens series showed waxy degeneration of the rectus muscles, and subsequent experience at the Brigham Hospital indicates that it was probably overlooked in some of the earlier postmortems done at Camp Devens. A number of these cases showed rupture and extensive hemorrhage into the rectus muscle. This lesion has been noted in other muscles ; for instance, the transversalis, the internal and external oblique muscles, the latissimus dorsi, the pectoralis major and the intercostal muscles. The testes occasionallv showed minute petechia, but on the whole no striking gross change was observed. Microscopically very striking changes were encountered in nearly every case, nameh', the cessation of activity in the seminiferous tubules; actual degenerative changes were frequently noted, and in late cases beginning fibrous tissue replacement of the degenerated tubules. This lesion of the testes seems to be wholly a toxic one, as there is very little cellular reaction. It is difficult to imderstand why such severe toxic lesions of the muscle and testes should occur, in the absence of effects attributable to toxins in other organs. For instance, the reaction of the spleen is very slight, the heart muscle rarely has shown any gross or microscopic lesion, and in general seems to escape entirely the toxic effect of the disease. Lesions of the adrenal, when extensive, such as hemorrhage, can be attributed to secondary infection, usually tlie hemolytic streptococcus. Minor acute lesions are constantly found in the cortex in influenza cases, but these lesions are similar to those found in manj^ infectious diseases — the disappearance of lipoid +++++ CONTENTS, and focal necrosis with mononuclear phagocytic cell reaction. The head was opened in 20 of these cases. Infection of the middle ears was found in 13. Infection of the sphenoidal sinus in 20, frontal sinus in seven, and of the ethmoidal cells in eight cases. The bacteriology of the sinuses is given in tlie chart. Three cases showed punctate hemorrhages in the cereliral cortex. BACTERIOLOGY I do not intend to discuss at length the bacteriology of the epidemic. The table is a true account of the findings, and I prefer to have individuals draw their own conclusions. The opportunities for bacteriological work were particularly good. THE JOHNS HOPKINS HOSPITAL REPORTS VOLUME I. 423 pages. 99 plates. VOLUME II. 570 pages, with 28 plates and figures. VOLUME III. 766 pages, with 69 plates and figures. 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A Fatal Case of Multiple I'rimary Carcinomata. By E. D. Plass. M. D. Congenital Obliteration of the Bile-ducts. By James B. Holmes. M. D. Multiple Abscesses of the Brain in Infancy. By James B. Holmes, M. D. Gastric Carcinoma in a Woman of Twenty-six Years. Bv R. G. HussEY, .I. D. Subdiaphragmatic Abscess with Rupture Into the Peritoneal Cavity Following Iniliiii'd Pneumothorax for Pulmonary Hsemorrhage. By' R. G. IlrssKv. M. II. Heart Block Caused by Gumma of the Septum. Bv E. W. Bridge.man. -M. D.. and H. C. Schmeisser. M. D. Analysis of Autopsy Records. A. The .Johns Hopkins Hospital. I Table Showing Percentage of Autopsies. I B. Th.. City Hospitals. Bay View. iTable Showing Percentage of on the Staff of the Department of Pathology. "The .Mon.lay d (""linical Uepri'seii Donation. Fasciculus II. The ROIe of the Autopsy in the Medicine of To-day. Bv M. C. Winternitz. M. D. Exp.riin.-nt.il N.'i.liii.pathy in the Dog. 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The Effect of Diet on the Healing of Wounds. (Illustrated.) The Effect of Different Bloods on the Growth of //. Inftucn^n.

By Admoxt H. Clark. M. D 117 (Illustrated.)

Bv T. M. KivERS. M.D.. Haltimor.-. Md 129

The Relation of Spontaneous Nephritis of Rahbits to Experi- ".

^ , , ,1, » i J Observations on the Clinical Pharmacolofjv of DiKitalis. (Illus mental Lesions. (Illustrated. I •, fe. o v

„ . T T. 1.TI trated.)

By Artiiub L. Br-ooMFiELD 121 ' „ .. . . ..

' By Alfred M. \\ EDO, M. D., Pittsburgh, I'a l.U

A Sketch of Dr. Lyman Spalding. N'otes on New Books 1;16

By Henry M. Hurd, M. U 123 Books Received 139

THE EFFECT OF DIET ON THE HEALING OF WOUNDS

By Admoxt (From the Pathological Laboratory of

The work uf lluojur and Whipple' on blood regeneration after anseniia .-jIiow.* that .;pecifie diets produce a very markcil effect. The rate of blood regeneration on a meat diet is very rapid, a matter of ilays or a few weeks ; whereas, on a diet rich in carbohydrate it is very slow, months being .sometimes required for coni])lete regeneration. Tliese results suggested the possibility that specific diets mi;,'ht influence the rate of wound healing and the following experiment.-; were accordingly underUikcn.

Carrel '• ' has studied the process of wound healing in both men and animals and has found that the curve representing thediminution in size of an aseptic wound while it is cicatrizing is regular and geometric. From Carrel's curves Du Xoiiy " has derived mathematical formula?, by means of which the area of a wound at any given date can be predicted. Ilis formula; arc :

S-S'

(1)

(VI

• The experiments reporte<l in this paper were carried out b.v Dr. Clark during the spring of 1918. Owing to Dr. Clark's death the results which they show are of a preliminary nature and represent incomplete work. I thought tliem. however, of sufficient interest to publish, hoping that they might suggest further work along the same line. — Janet Howell Cl,\rk.

II. Clark. M. D.

Thr Johns Hopkins i'niversitj/. Baltimore)

S represents the original area of the wouml. S' — area i days later.

T = time from first observation and — I'm ( 1 ). <' = time from .S" to S" .

i=constant coefficient which is ciiaracteristic of the womid and which varies with the size of the wound and the age of the jiatient. After calculating i from (1) S" can lie jiredicted with a remarkable degree of accuracy, any deviation from the calculated curve showing the |)resence of an infection.

In his e.\i>erinicntal work on animals'-' (dogs, guinea-pigs and cats), where the wounds were kept as sterile as possible. Carrel found the process of cicatrization ta be divided into four part.s:

(1) Quiescent I'l-riml. — During this period tlicrc is no contraction and the main characteristic of tiie period is its variable length, I-.") days.

(2) Period of Granulotis Contraction. — During this jieriod the wound contracts at a rate wiiich is jiroportional to tiie size of the wouiul.

(3) Period of ICiiidermizalinn. — Tiie epithelium iicgins to form and the process of healing may now continue by epidermization alone or by epidcrmization and contraction together.

(4) Cicatricial Piriml. — .\<Ut thr wound is healed the scar enlarges.

118

[Xo. 339

No previous work on the effect of specific diets on wound healiug has been reported.

EXPERIMENTAL METHOD

Twelve dogs as nearlj' the same age, size and general condition as possible were cliosen and three were put on each of the following diets :

(1) Mixed Diet. — 41 gm. of fat (lard or butter) and 107 gm. of lean meat (beef or liver) were boiled together, then mixed with 354 gm. of bread and run through a meat chopper. This was divided among three dogs.

(8) Carbohydrate Diet. — 500 gm. of bread moistened with water were divided among three dogs.

(3) Protein Diet. — 500 gm. of lean meat, either round of beef or liver, were boiled and divided among three dogs.

(4) Fat Diet.— 300 gm. of fat (equal parts of butter and lard) were boiled and groimd with 100 gm. of bread.

The dogs were fed on these diets for three days before the wouuds were made. Throughout the experiments the dogs were weighed and the weight was found to remain practicallv constant.

Preliminary experiments with various types of dressings showed that the wounds healed better and showed less tendency to infection when left entirely open with no dressing of anv' kind. The dogs were given ether anaesthesia, the backs were shaved and two circular skin flaps (one large and one small) were removed from each side of the back. The wounds were placed where the dog could not lick them and were left open. As soon as they were made, the size of the wounds was traced on a piece of transparent celluloid with a wax pencil and similar tracings were made at intervals of three or four days throughout the experiment. These areas were copied on heavy tracing paper and measured in square centimeters by means of an Amsler polar planimeter. If a wound showed marked infection the results were discarded.

A second set of wounds was made after the first had healed and finally a third set in which the dogs were interchanged in diets.

I. Effect of Diet on }Yound Healing. — The results for Sets 1 and II are averaged in Fig. 1. The large and small wounds are averaged together; the area given being the total wouml area on one dog (i. e., the area of two large and two small wounds). As there were three dogs on each diet in each set, each curve shows the average result on six dogs. Tlie diet seems to aiiect the length of the quiescent period. The \m>tein-fed dogs have no quiescent period, the contraction beginning at once. The carbohydrate dogs have a quiescent period of three days, those on the mixed diet, of four days, and the fat-fed dogs, of six days. After the sixth day the curves run parallel and the dates of final healing differ by the same amount as the lengths of the respective quiescent periods.

The diet, therefore, is a factor in determining the date of the beginning of Period II, the period of granulous contraction.

In Set III, four dogs which had been on a fat diet in Sets I and II were put on a protein diet. The results sho^^n in Fig. 2

c

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Fig. 1.— Effect of Diet on Wound Healing.

Average results of Sets I and II.

C = carbohydrate diet.

P = protein diet.

M = mixed diet.

F = fat diet.

Abscissae = time in days; ordlnates :

wound area In sq. cm.

give the same result as Curve I, though not so markedly as might be washed. I believe that there should have been an

T P

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Fig. 2.— Effect of Change in Diet.

Curve F gives results for fat- fed dogs in Sets I and II.

Curve P gives results for same dogs fed on protein diet in Set III.

Abscissae = time in days: ordinates = wound area in sq. cm.

interval between the two sets of experiments during which tli dogs could be fed on the new diet. In this experiment Set 1 1 i

Mav, 1919]

119

was begun as soon as Set II was finished and the change in diet was simultaneous with tlie making of new wounds.

c

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AMD

WOUND MOUND

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Fig. 3. — Curve Showing Formation of Epithelium.

area of wound and scar.

area of wound.

Abscisss — time in da.vs: ordinates = wound area in sq. cm.

Ill Fig. 3, the pmgri-s.s of Period III. the period of epidermization, is shown, the dotted line indicating the area of the wound and the scar, the heavy line the wound area.

It is evident that the formation of the epithelium starts on the same day, irrespective of the diet and the size of the wound.

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i

\

T^ *

1

X \

VL

XT

r.

1

V X

/

.-ATo;;

\

"

/

S

S

\ »A^a

-♦

"

lo

IT

Fio. 4. — Average Curve for Sets I ami II (all Diets).

area of wound and scar.

area of wound.

Abscissa- = lime in days: ordinates = wound area In sq. cm.

Contraction continues throughout Period III and tlie closing of the wound is due to a combination of the two factors, contraction and epidermization. The dotted curves giving tinarea of wound and .<car are parallel, showing that diet has no

effect on either the date of beginning of Period III or the course of epidermization. The difference between the two curves gives the area of the epithelium.

In Fig. 4 an average curve is given for all four diets (Sets I and II), showing the course of all four periods of wound healing. It shows that contraction continues all through the period of epidermization and even for live days after the wound is completely healed. At this point the formation of jiigment begins at the outside edge of the scar and as the pigmentation moves inward the scar rapidly enlarges until the pigmentation is complete, when it reaches a stationary state.

It would be interesting to compare this fourth period in animals with different degrees of pigmentation and determine the exact relationship l)etween the formation of pigment and the scar area. Carrel ' says that the expansion of the cicatrix after the wound is healed is less marked in man than in the

^


N \

n

\

^

F

\

.V

C"

\

^s^

^

p

N^

Q

r.

\

r

^1

nJ

\

v.

• <

1

s^,

"^

<o

DATS

Ir 1-^

It

l>

°

10

i;. 5. — Results of Sets I and II Averaged Separately for Large and Small Wounds.

Curve if = mixed diet.

Curve C = carbohydrate diet.

Curve P — protein diet.

Curve F = fat diet

Abscissa* = time in day.s; ordinates = wound area In sq. cm.

(log. If the expansion is conditioned by the formation of the ])igment this would naturally result.

II. Effect of Size of Wounds on Ckatriznlion. — Carrel' has already shown that tlie rate of contraction is proportional to the size of tlie wound, but tliat tbe rate decreases le.ss rapidly than the area, .«o that large and small wounds tend to become equal. Fig. 5 shows the results in Sets I and II averaged for large and small wounds separately for all four diets. In every case the curves siiow tiiat the rate of healing in large wounds is greater, so that tbe wounds heal in the .same length of time. The rate of healing as measured by the change in area per day is not, however, proportional to the size of the wound on any one day. For example, take

120

[No. 339

Fig. 5 (C). The area of the small wound is 2 sq. cm. on the fifth clay. At this time the rate of healing is .10 sq. cm. i)ev day. The area of the large wound is 2 sq. cm. on the teutli day when the rate of healing is .35 sq. cm. a day. However, if tlie rates throughout each set of curves are compared it will lie found that the ratio

rate of healing of large wounds rate of healing of small wounds on any given day is approximately equal to the ratio

original size of large wounds original size of small wounds

if the quiescent period is neglected (see Table I). So that, knowing the rate of healing of a wound of any given size, the rate of healing of a womid of any other size can be calculated. However, this probably would hold true only within certain limits of the original size. In these experiments the wounds are all relatively small.

TABLE I

Bo

Day

S, _ or

ginal size large wounds

Rate healing

Bi 1 , Rate healing ;i„x V='^i large wounds ^=

Sj original size small wounds

in square cm.

per day

M

.3-6

1.7

.04

.11

.07

fi-9

.16

.30

.27

9-12

.20

•33

.34

12-15

.13

.23

.22

P

3-6

1.7

.08

.13

.14

6-9

.16

.23

.27

9-12

.20

.40

.34

12-1.')

.l.T

.23

.25

C

3-6

1.8

.07

.12

.12

6-9

.20

.30

.36

9-12

.17

.32

.31

12-1.5

.17

.23

.31

F

3-6

1.7

.08

6-9

.36

.52

.61

9-12

.26

.33

.44

12-15

.10

.17

.17

The results for F are poor, but for the others are fairly good. If this fact has any general application and can be extended to the interpretation of womids of any size it would mean that the rate of contraction is governed by a variable factor depending on its age and a constant factor depending on the original size.

In comparing the curves for different diets in Fig. 5 it is seen that the effect of the diet on the length of the quiescent period is greater in the small than in the large wounds.

Xejtlier the diet nor the size of wounds has any effect on the time of beginning of Period III. The formation of the epithelium starts about the ninth or tenth day in every case. The amoimt of contraction subsequent to this depends on the size of the wound when the epidermization begins. The contraction and epidermization complete the healing together. The size of the sear when complete healing has taken jilace is about ihe same in every case, and equals approximately onequarter the size of the original wound.

DISCUSSION

In connection with these results it is interesting to consider the well-known fact that the ingestion of proteins produces a much greater increase in body metabolism than that of any other foodstuff's. In a recent monograph on the subject of the stimulating effects of nutrients, Benedict and Carpenter " have given a very complete report of this question. They find that while carbohydrates give a maximum increment to the metabolism of 25 per cent and fats 12 per cent, this increment occurs within two hours and the metabolism then returns rapidly to the base line. With proteins the increment reached a maximum of 25 per cent to 45 per cent and persisted for as long as 8 to 12 hours. This increase in metabolism, or excess energy given off by the body as a result of the ingestion of food, may be regarded as waste energy, but Benedict suggests that we may consider the extra heat developed under these conditions as a normal physiological stimulus to cellular activity. Practical experience with heavy muscular work on protein and carbohydrate diets points to this conclusion and the results reported here would certainly support the idea that proteins have a specific influence in stimulating the whole cellular system to greater activity.

CONCLUSIONS

The length of the quiescent period of wound healing is affected by the diet. It varies from zero in protein-fed dogs to six days in the fat-fed animals. This variation in the quiescent period is more marked in smaller wounds. As a consequence, the date of final healing differs by about five days for the protein- and fat-fed dogs.

When the second period, or period of contraction, has set in the rate of contraction is not affected by the diet. It is governed by a variable factor depending on the age of the wound and by a constant factor proportional to the original size —

^ = -^when Rj and /?„ = rates

if healing of large and small

wounds and S^ and .S\ = original areas of these wounds.

The beginning of Period III, the period of epidermization, is independent of the size of the wound and the diet. It is determined by the age of the wound. Contraction and epidermization continue together until the wovnid is entirely healed.

After the wound is healed the scar continues to contract until pigmentation sets in. During this latter process it enlarges and reaches a stationary state after pigmentation is complete.

REFERENCES

1. Hooper, C. W.. and G. H. Whipple; Amer. Jour. Physiol., 1918, XLV, 573, 576.

2. Carrel, A.: Jour. A. M. A., 1910, LV, 214S.

3. Carrel, A., and A. Hartman: Jour. Exp. Med., 1916, XXIV, 429.

4. Du Noiiy. P. L.: Jour. Exp. Med., 1916. XXIV, 451: 1917, XXV, 721.

5. Benedict, P. G., and T. M. Carpenter: Food Ingestion and Energy Transformation. Carnegie Inst., Wash., 1918.

May. I'Jlii]

121

THE RELATION OF SPONTANEOUS NEPHRITIS OF RABBITS TO

EXPERIMENTAL LESIONS*

By AuTiiiu L. Bloomkield {,From the Medical Clinic. The Johns Hopkins University and Hospital)

into the renal nrterv tliroujrh a fine needle. During the injection tlie kidney became mottled or blanched, but the normal color ])roni|)tly returned. Bleeding from the punctured artery was slight, and stopix-d when the kidney \va.< put back into the abdominal cavity. The wounds were closed with catgut and healed by first intention. In a few instances total or partial infarction of the kidney resulted from an arterial thrombus, but in most cases at autopsy the vessels were jiatent and there were no gross signs of circulatory disturbance.

After, two weeks a series of intravenous injections was begun with the organism previously used. The size of the dose and the interval between injections varied with the animal's reaction. The injections were regulated in such a way that the animals lost weight and seemed ill. In diilerent experiments from 1 to 19 re-inoculations were made over periods varying up to 15 months. Frequent urine examinations were made throughout the experiment, and in a few cases 'thallein tests were done.

Most of the animals died of cachexia and toxemia ; the remainder were sacrificed. Gross specimens were preserved, and blocks were fixed in formalin, embedded in paraffin, cut, and stained with hematoxylin and eosin.

Si.x strains of strejitococci were used : strains Q and Y were avirulent, long-chained green streptococci isolated from urine: strains T and S were hemolytic varieties obtained from septic infections and were highly virulent for rabbits; strains A and R, isolated from tiie throats of scarlet fever patients, were markedly hemolytic and virulent for rabbits. In the initial injections into the renal artery from 0.5 to 1.0 c. c. of a thick .saline suspension of organisms grown for 24 hours in meat infusion broth and killed by heating for half an hour at 60 to 70° was used. The charat'ter of the emulsion was such that most of the bacteria were filtered out by tiie kidney. This was controlled by microscopic examination of a few kidneys removed shortly after the injection. Living 24-hour cultures were employed in the intravenous reinjections.

EXPERIMENTS A single protocol of a typical experiment is givin m detail I in Table I ; the remainder are summarized in Table II.

Taiii.k I. — DhrTAii.Ki) Photocol of a Complete Exi-kkimknt No. 51. White male rabbit

March 1. 1916. Weight 1580 Km. Trine clear.

March 2. Left kidney exposed llirouKh lumbar Incision. It Is of normal size an'l consistency, but there are many shallow depressions on the surface, varying In size up to 2 mm. In diameter. Growth from 0.5 c. c. broth (24hour) of strain S (killed) Injected into renal artery. During injection, yellowish blotches appeared over entire kidney, except the lower pole and anterior surface.

During the past few years an extensive literature has accumulated, dealing with the experimental production of renal lesions. A variety of injurious agents has been employed, among which may be mentioneil cytotoxic sera,' cantliaridin,' foreign proteins,' uranium nitrate,' bichloride of mercury,' tartrates,' diphtheria toxin,' anesthetics," and a variety of bacteria, such as streptococci,' staphylococci," colon bacilli," Friedliinder bacilli," and others. Although lesions of various types have been obtained, many of them specific of the particular poison employed, it has not been possible adequately to reproduce a condition corresponding clinically or anatomically with advanced types of chronic nephritis in man. The work of Faber," who was able to produce arthritis in rabbits with great constancy by injecting streptococci intravenously .some time after a preliminary intra-articular sensitizing inoculation with the same organism, suggested the employment of a similar procedure in the attempt to produce experimental nephritis. It was thought that a preliminary injection of bacteria in relatively high concentration directly into the renal artery might sensitize the kidney in such a way that subsequent small repeated intravenous injections might result in renal lesions of a chronic type. Coulter and Pappenheimer" employed a somewhat similar method. Working with rabbits, they gave a series of intravenous injections of an extract of typhoid bacilli, and two weeks later injected the same material directly into the renal artery. To avoid possible confusion with " spontaneous lesions," attention was confined to the acute lesions, and the animals were killed after 48 hours. Scattered focal glomerular lesions, similar to tho.se described in bacterial endocarditis, were found. In the unsensitizcd animals these changes were either very slight or absent.

The following experiments are re|)orted because they represent an attempt to produce chronic renal disease by a method different from those previously used, and because it was possible accurately to control the significance of " spontaneous lesions " by direct inspection of the kidney at the beginning of the experiment, as well as by later examination at autopsy.

Healthy rabbits weighing from 1000 to 2500 gm. were used. After a preliminary urine examination,! the animal was anesthetized with ether and the left kiilney delivered through a lumbar incision. The vessels were stripped free of fat and connective ti.«suc and the bacterial suspension wa,< injected

• These experiments were carried out during the winter of 19151916, at the suggestion of and in collaboration w^lth Dr. Theodore Janeway. Publication has been unavoidably delayed.

f The urine was obtained by massaging the abdomen over the bladder.

122

[No. 339

March 3. Animal in good condition. Urine contains albumin, granular casts and a few R. B. C.

March 4. Urine clear.

March 6. Urine clear. Weight 1550 gm.

March 16. Growth from 1/20 c. c. 24-hour broth culture strain S (living) intravenously.

March 17. Urine clear. 1/20 c. c. (S) intravenously.

March 18. Looks sick. 1/10 c. c. (S) intravenously.

March 20. Urine clear. 1/10 c. c. (S) intravenously. 1490 gm,

March 22. Urine clear. 1/10 c. c. (S) intravenously. 1450 gm.

March 27. 1430 gm.

March 2S. 1/20 c. c. (S) intravenously.

March 30. 1350 gm.

April 5. Urine clear. 1390 gm.

April 8. Urine clear. 1/100 c. c. (S) intravenously. 1470 gm.

April 10. Urine clear. 1/100 c. c. (S) intravenously. 1490 gm.

April 11. 1450 gm.

April 12. 1/lOQ c. c. ( S ) intravenously.

April 17. 1/100 c. c. (S) intravenously.

April 19. 1400 gm.

April 22. 1/100 c. c. (S) intravenously.

April 24. 1350 gm.

April 25. 1/lOOc.c. (S) intravenously.

April 28. 1/lOOc.c. (S) intravenously. 1300 gm.

May 2. Urine clear. 1/100 c. c. (S) intravenously.

May 3. Urine clear.

May 6. 1/100 c. c. (S) intravenously. 1360 gm.

May 9. 1/100 e.c.(S) intravenously. 1320 gm.

May 11. 1/lOOc.c. (S) intravenously.

May 14. Urine clear. 1/100 c. c. (S) intravenously. 1300 gm.

May 15. Animal killed. Autopsy: General condition good. A few parasitic cysts of omentum. Heart and lungs normal.

Left kidney: Weight 5.0 gm. It is loosely adherent to region of scar without new formation of vessels. Capsule moderately thickened (post-operative), but strips freely. Same degree of surface pitting as seen at operation. Consistency seems normal. Cortex of normal width, markings distinct. Glomeruli appear as red dots. Intermediate zone separated from cortex by an irregular, grayish-yellow line about 1 mm. in thickness. Medulla rather pale. Microscopicallp: A good many small scattered areas of round-cell infiltration are seen. In some places there is a beginning fibrosis which causes the cortical depressions. The lesions are focal and interstitial. The glomeruli look normal. The vessels and tubules are normal except where Involved in the scars.

Right kidney: Weight 5.0 gm. Gross and histological examination similar to that of left; same degree of scarring. Renal vessels patent on both sides.

, RESULTS Apart from the " spontaneous nephritis " described below, no definite lesions were found. The glomerular, tubular, vascular and interstitial structures differed in no way from those of untreated controls. This result was unexpected in view of the direct and intensive injury, the constitutional reaction of the animals and the e\idence of at least transient renal irritation furnished by the appearance of albumin, casts or blood in the urine after some of the injections. Pappenheimer, Hyman and Zedman " studied rabbits' kidnej's removed at short intervals after the injection of streptococci into the renal artery. They found that the organisms were rapidly disposed of by leucocytic and fixed cell phagocytosis, with return of the glomerulus to normal. An overwhelming bacterial injury, on the other hand, led to immediate partial or complete disorgani

zation of the glomerulus by thrombotic or suppurative processes. This is possibly the explanation of the difficulty of producing experimentally a gradually progressive process such as that seen in the subacute or chronic glomerulonephritis of man. In our animals, despite repeated injections, the immediate injury was apparently promptly repaired without the initiation of an advancing lesion.

SPONTANEOUS NEPHRITIS

In connection with attempts to produce experimental nephritis, many writers refer to the difficulty of interpreting lesions which occur spontaneously in the kidneys of various animals, such as the rat," dog " and rabbit. Spontaneous rabbit nephritis has been recently described by Le Count and Jackson," who summarize the literature on the subject. Such lesions were found in many of our animals and correspond with those pictured in previous reports (Figs. 1-10).

Every grade of change from accumtilations of a few round cells between the tubules to extensive scars was seen in one or another of the specimens. On gross examination, the earliest forms of lesion appear on section as streaks about 1 mm. wide, slightly more yellowish than the normal kidney substance running from the base of the intermediate zone to the surface. At this stage there is no corresponding depression on the cortical surface, but the lesion is shown by a mottling of the kidney over it. With more advanced disease there are very slight depressions, and in extreme cases a coarse pitting which may affect the entire renal surface. These depressions vary in size from minute dents up to pits 2 or 3 mm. in diameter.

Microscopically, the earliest lesions appear as collections of a few round cells in the interstitial tissues between the tubules. The latter show granular degenerations and the cell boundaries and the nuclei become indistinct. Later the remains of the tubules may be seen between dense collections of round cells. The next stages show the presence of new connective tissue, wMch finally may take the form of scars which contract and distort the tissues. The tubules may be greatly dilated and contain detritus or casts. The glomeruli, as a rule, show relatively little apparent change, even when the intervening tissue has been largely destroyed. In some eases there is marked fibrosis about the capsule, htit the glomerular structure shows no definite alteration. Finally, the glomeruli may also disappear in the scar. The individual lesions may be large or small, they may be abundant or widely scattered, and they are located in cortex or in medulla. They are always distinctly focal, however, with normal intervening tissue, and are never diffuse, as in the contracted kidney of human nephritis. It seems probable that the lesion is a reaction to an injury which is not primarily interstitial.

In reviewing the reports on experimental rabbit nephritis, it is striking that many of the lesions described correspond in detail with these spontaneous lesions, thus raising the question of possible misinterpretation of the findings. An attempt was made in these experiments to control the significance of these lesions by careful inspection of the kidney for scars at

May, 1919]

123

the beginning of the experiment when the renal artery wa:injected, comparing its appearance with the later autopsy findings. It was also possible to compare the left kidney, which was directly treated with a large dose of bacteria, with the right, which was affected only by the smaller intravenous reinjections. These findings are summarized in Table III.

In all but four of the 16 animals the appearance of the kidney at the end of tlic experiment was exactly like that seen

at the preliminary operation. In these four animals, periods of 161, 25T, 352 and 4C0 days had elapsed since the beginning of the experiment, so that it is probable that the sliglit focal lesions which were similar to those seen in mitreated controls had developed spontaneously. The duration of the other 12 experiments varied from 8 to 74 days. In all of these animals in which tlic kidney had been smootli at the start no lesions were found later at autops}-, and where the kidney had

TABLE II.— SUMMARY OF RESULTS OF EXPERIMENTS

Brown (emile..

Brown male. Weight 251(

While mile. Weight 1420

Black male. Weight 1600

Brown hare. Weight 1990 gm.

Brown hare. Weight MM gm.

Dec. 8, 1915. Injection into left renal arter>' of growth from 5 c. c. of broth in 0.5 c. c. salt sol. of strain Y (killed).

Dec. 30, 1915-Mar. 13. 1917. Six intravenous injections of strain Y (living).

Dec. 13, 1915. Injection into left renal artery of growth from 5 c. c broth in 0.5 c. c. salt sol. of strain Y (killed). •

Dec. 24. 1915-Feb. 8, 1916. Six intravenous injections of strain Y (living).

Occasional trace of albumin in urine after injections. Condition goud except for lo^s of weight after injections.

.\ 1 b u m i n ir urine at times after the injections. Moderate loss of weight.

into left renal artery of growth from 1 c. c. broth in 0.5 c. c. salt sol. of strain Y (killed). Dec. 27, 1915-Jan, 28, 1916. Five intravenous injections of strain Y (living)

Dec. 14. 1915. Injection into left renal artery of growth from 5 c. c. broth in 0.5 c. c. salt sol. of strain Y (killed).

Dec. 27, 1915-.\ug. 29. 1916. Seven intravenous injections of strain V (living).

Dec. 22. 1915. Injection into left renal artery of growth frt)in 3 c. c. broth in 0.5 c. c. sail sol. of strain T (killed).

Jan. 5, 1916-Jan. 22 1916. Three intravcn ous injections o strain T (living).

Killed Mar. 13, 1917, 460 days from beginning of experiment. Both kidneys look normal except for few slight surface depress i o n s. Microscopi

call]/: Glomeruli


normal; moderate spontaneous lesions iq. v.).

Killed Feb. 8. 1916, 61 days from beginning of experiment. Right kidney normal. Infarct of left except for lower pole. Microscopically: No lesions except the infarct.

Dec. 14. 1915. Injection [Steady loss of Died Jan. 20, 1916, 44 days from beginning of experiment. Both kidneya normal in g' r o 8 8 and microscopically.

Loss of weight Killed .\ug. 29, 1916.

after each ii jection. .\ftei sixth injcc tion, albumin and R. B. C, in urine (oi two days.

Steady loss of weight, bumin and casts in urine for five days after last injection.

Dec. 22. 1915. Injection into left renal artery of growth from 3 c. c. broth in 0.5 c.c. salt iol. of strain T

i (killed^

tJan. 5. 1919-Jan. 20.

I 1916. Four intravenous injections of strain T (living).

lUar. 2, 1916. Injection into left renal artery of growth from 0.5 c. c. broth culture in 0.5 c. c. Halt ftol. of Rtrain S (killed).

Mar. 16. 1916-May 14. 1916. 17 intravenouA injections of strain S (Hiring).

I

.Mar. 2. 1916. Injection into left renal arterv of .25 c. c. culture S (killed) in 0.5 c. c. •lalt sol. lar. 16. 1916~May 14. 1916. 17 intravenous intertions of strain S (living).

Stead;r loss ofloied Jan. 23. 1916. 32

weight, bumin after first Injection. Albumin, casts and R. B. C. for one day after fourth injection.

k-eight. Tran sicnt albuminu r i a following some Injections.

days from begin of experiment. IV-th kidneys show markr<l grade of sponlanpnu' Interstitial lc<<{on<^. Otherwise normal.

257 days from begi ning of experiment. Both kidneys normal in gross and microscopically, except for a very few lesions of spontaneous nephritis.

Died Jan, 22. 1916. 31 days from beginning of experiment. Both kidneys normal in

days from beginning of experiment. Both kidneys show marked h[Nintiineous interstitial lesions. Otherwise normal in grotis and microscopically.

Killed .May 15. 1916. days from beginni of experiment. B* kidneys show mo<l ate grsde of upontji ous inten«litinl sions. Otherwise n nial.

Steady Iom of Killed May 16. 1916. ~\

DescriptioD

Brown female. Mar. 20, 1916. Injection Steady loss of Weight 1250 I into left renal artery weight, gm. I of growth from .25

I c. c. broth in 0.5 c. c. [ , salt i^ol. of strain S

(killed). Apr. 4, 1916-May 4, 1916. 13 intravenous I injections of strain S I (living).

Brown female. Mar. 20. 1916. Injection Steady loss Weight 1020 into left renal artery weight, gm. of growth from .""

c. c. broth in 0.5 c. ' salt sol. of strain I (killed). I

I Apr. 4, 1916-Aug. 29, 1916. 15 intravenousj iivjcctions of strain SJ (living).

Brown female. Mar. 20, 1916. Injection Loss of weight Weight 1260 into left renal arter>- after injecgrn. uf growth from .25

' c. c. broth in 0.6 c.c. salt sol. of strain S t (killed).

Apr. 4, 1916-Mar. 7, I 1917. 16 intravenous injections of strain S (living).

JIale. Weight Mar. 25. 1916. Injection

1080 gm. into left renal artery

I of growth from 0.6

c. o. broth in 0.6 c. c.

salt sol. of strain R

(killed).

Apr. 8, 1916-June 15.

1916. 14 intravenous

' injections of strain R

(living).

Male. Weight Apr. 1, 1916. Injection 1090 gni. I into left renal artery

of growth from 0.6 c. c. broth in 0,5 c. c. salt sol. of strain R (killed). Apr. 15. 1916-May 19. 1916. 10 intravenous injections of strain H (living).

Apr. 1. 1916. Injection into left renal artery of growth from 0.5 c. c. broth in 0.5 c. c. salt sol. of strain R (killed).

Apr. 15. 1916-.Iunc 1. 1916. 12 IntravenouH injections of strain R

I (living).

Brown female. Dec. 9, 1916. Injection Weight 1550 into left rcnnl artery of growth from 6 c. c. broth in 0.5 c. c. salt sol. of strain (j (killed). Dec. 2*1. 1916. One intravenous injection of train () (living).

Male. Weight Apr. 27. 1916. Injection

1270 gro. i Into left rma! artery

of \ an agar fiUnt of

I hronchxAtptiruM in 0.5

I c. c. Hit sol.

lions.

i t h occasional albuminuria.

Steady loss of weight Developed a r tliritis of left hind leg.

Rapid emaeiatinn. Albumin and casta

'zr.

Killed May 15. 1916. 55 days from beginning of experiment. Both kidneys normal in every way.

Died Aug. 24. 1916, 161 days from beginning of experiment. Slight spontaneous lesions in both kidneys.

Died Mar. 7, 1917, 352 days fnmi beginning of experiment. Minimal degree of spontaneous lesion. Kid* neys otherwise normal

Died June 15, 1916, 71 days from beginning of experiment. Kidneys normal in every way.

Died May 19. 1916, 49 days from beginning of " experiment. Kidneys normal in gross and microscopically.

Died June 5. 1916, 66 days from beginning of experiment. Kldnej-s normal except for a few early spontaneous lewiuns.

Died Dec. 23. 1916. 14 days from beginning of experiment. Both kidneys normal in gross and microscopically.

Died Mav 5, 1916. eight days from beginning of experiment.

Extreme spontaneous Icitions.

124

[No. 339

been pitted at the start, focal interstitial lesions were found. Furthermore, in spite of the intensive direct treatment of the left kidney, in every case in which changes were present they were of equal extent in the two kidneys. It seems impossible to interpret these findings in any other way than that all these lesions were spontaneous and independent of the experimental procedure. The great frequency and variety of the changes, their apparent independence of any constant factor in the animal's condition, such as age, weight, etc., suggest that possibly many of the chronic interstitial lesions ascribed in the literature to experimental infection are really the effects of spontaneous nephritis.

CONCLUSIONS

1. An attemjjt was made to produce chronic nephritis in rabbits by intraveiaous injections of streptococci, following a direct injection into the renal artery.

2. Failure to produce chronic glomerular lesions was thought to be due to the means used by the kidney to dispose of injected organisms, which resulted in complete healing if the glomerulus survived the acute injury.

3. Chronic focal lesions were found in many animals.

4. Control examinations of the kidney at the beginning of the experiment, and comparison of differently treated right

TABLE I IL— SPONTANEOUS LESIONS

COMPARISON OF APPEARANCE OF LEFT KIDNEY AT OPERATION WITH LESIONS FOUND LATER AT AUTOPSV

Description

Appearance of left kidney at beginning

of experiment at operation

No.

days to autopsy

Lesions at autopsy

No

Description

Appearance of left kidney at beginning of experiment at operation

No.

days to autopsy

Lesions at autopsy

No

Right kidney

Left kidney

Right kidney

Left kidney

11

Normal size

460

Weight 8 gm. Looks

Weight 8 gm. Looks

63

White male.

Numerous mark

74

Weight 5 gm. Very

Weight 5 gm. Post

, ,

and appear

normal except for few

normal except f o r

Weight

edly depressed

many marked cortical

operative capsular

Weight 1560 gm.

ance ; surface

slight cortical depres

some thickening of

1450 gm.

scars over sur

depressions. Capsule

thickening. Similar

smooth.

sions. Capsule not

capsule (post-opera

face.

strips freely. Micro

lesions to those on

tive). Capsule strips

scopically: Man y

right and of same

scopically : Moderate

freely. A few slight

degree.

number of linear in

cortit-al depressions

with fibrosis, con

terstitial lesions, mod

(less than on right).

tracted scars, com

Microscopically:

pression and atrophy

few small, scatter

Same as right.

of glomeruli and tu

ed, round-cell infiltrations.

bules. Apart from these focal interstitial lesions, kidney is

14

Brown

X r m a 1 size

61

Weight 8.5 gm. Looks

Total infarct of kidney

normal.

male.

and appear

perfectly normal.

except for lower pole.

56

Brown

Nonnal.

55

Weight 4 gm. Normal

Weight 4 gm. Like

Weight

ance; surface

Microscopic sections

female.

in gross and micro

right except for post

25 lU gm.

smooth.

Microscopically : No

of lower pole show normal kidney.

W^eight 1250 gm.

scopically.

operative capsular thickening.

15

White male. Weight 1420 gm.

and appearance; surface smooth.

44

Weight 4.-1- gm.. Looks normal ; surface smooth. Capsule not adherent. Micro

Weight 4.-h gm. Some post-operative thickening o f capsule; strips freely. Micro

57

Brown female. Weight 1020 gm.

Surface perfectly- smooth.

161

Weight 5 gm. A very few very slight depresions on surface. Capsule strips freely. Microscopically : A few round-cell infil

Weight 5 gm. Same as right except for postoperative capsular thickening.

scopically: No lesions

scopically: No le

seen.

trations with beginning fibrosis.

16

Black male.

N o r m a 1 size

257

Weight 5.5 gm. Capsule

Weight 6.-r gm. Post Weight

and appear

strips freelv. A verv

operative capsular

59

Brown

.Surface perfect

352

Weight 5 gm. A very

Weight 5 gm. Same as

1660 gm.

ance; surface

few small '"' pits " on

thickening; strips

female.

ly smooth.

few scattered slight

right except for post

smooth.

surface; in general, is a smooth kidney. Microscopically: Two small round-cell accumulations with be

freely. No " pits " seen. Microscopically: One lesion seen in entire section, similar to right.

M" eight 1-360 gm.

beginning surface depressions. Microscopically : No abnor sections.

operative capsular thickening.

ginning fibrosis in entire section of the

63

Male.

Surface perfect

71

Weight 4.5 gm. Nor

Weight 5.5 gm. Like

cortex.

Weight 1030 gm.

ly smooth.

mal in gross and microscopically.

right except for postoperative capsular adhesions.

17

Brown hare.

Normal size

31

Weight 5.0 gm. Capsule

Weight 5.5 gm. Post Weight

and appear

strips freely. Surface

operative thickening

65

Male.

Surface perfect

49

Weight 5 gm. Normal

Weight 5.+ gm. Like

199U gm.

ance ; surface

smooth. Normal in

of capsule; strips free

Weight

ly smooth.

in gross and micro

right except for post

smooth.

gross and microscopically.

ly. Normal in gi-oss and microscopically.

1090 gm.

scopically.

66

Male.

Surface perfect

66

Weight 5 gm. Surface

Weight 5 gm. Like

19

Srown hare.

Kidnev showa

32

Weight 6.5 gm. Multi

Weight 7.5 gm. Post

Weight

ly smootli.

smooth and normal.

right except for post

Weight

multiple de

ple small depressions

operative thickening

1100 gm.

Microscopically : A

operative capsular

1650 gm.

pressed areas an surface. 1 to 1.6 mm. in diameter.

on surface, but capsule strips freely. Microscopically : Abundant, well -advanced.

of capsule; strips freely. Similar lesions to those on right and of same degree.

very few small, scattered, roimd-cell infiltrations

thickening.

scattered interstitial

12

Brown

Surface perfect

14

Weight 4.5 gm. Normal

Weight 4.5 -i- gm. Like

lesions, both in cortex

female.

ly smooth.

in gross and mici-o

right except for post

and medulla, with ex

Weight

scopically.

operative capsular

tensive round-cell in

1550 gm.

thickening.

filtration, fibrosis, and

compression and atro

77

Male.

Extreme pitting

S

Weight 6.0 gm. Ex

Weight 4.5 gm. Same

phy of tubules.

Weight 1270 gm.

of kidney surface.

treme pitting of kidney surface, but capsule strips freely.

kind and degree of lesions as on right.

51

White male. Weight

1580 gm.

Many small, depressed scars over kidney surface.

73

Weight 5 gm. Multiple small depressions on surface, but capsule strips freely. Microscopically : A good many small accumulations of round cells with beginning fibrosis. Kidney otherwise normal.

Weight 5 gm. Postoperative tli.kening of capsule; strips freely. Similar lesions to those on right and of same degree.

Microscopically : Tlie sections are shot with numerous contracted scars which distort the kidney structure. Areas of compressed o r dilated tubules containing casts. The most extreme grade of spontaneous lesion.

THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919

V

^:^^<'*'^* '--•-•

^<|V^

Fig. 1. — Earliest typ<' oi l. sum Shows beginning accumulation of round cells between the tubules.

Fig. 2. — Earliest type "l l. sum aii|» arini; :is ;i linear streak of round-cell infiltration.

Fig. 3. — Portion of Fig. 2. Higii pun^r. Siiuws round-cell Infiltration with beginning tubular changes.

Fig. 4. — Moderately advanced lesion.

THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919

.1. ' '^ ,

— Portion of Fig. 4. Higli power. Beginning scar witli slirunken and distorted tubules.

"t .' -SJ^^"^^,;^:^

Fig. 6. — Multiple small areas of scarring with normal intervening tissue. Well-advanced lesion.

.<?fiWH5«?^,

Fig. 7. — Same as Fig. 6. High power. Shows area of fibrosis with atrophied dilated tubules and fibrosis around a glomerulus.

Fig. S. — Very advanced lesion showing a linear scar with destruction of normal elements.

THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919

PLATE XIII

FiQ. 9. — Low power. Most advanced type of lesion, resulting in a scar.

m

Fio. 10.— Portion of KIg. 9. High power.

May, 1919]

135

and left kidneys sufr^est that all these lesions represented the " spontaneous nephritis of rahhits."

REFERENCES

1. Pearce, Richard M., and Elsenbrey, A. B.: A physiological study of experimental nephritis due to bacterial poisons and cytotoxic sera. Jour. Exp. Med., 1911, XIV, 306.

2. Opie. E. L.: Lymph formation and edema of the liver with experimental nephritis produced by cantharidin. Jour. Exp. Med., 1912, XVI, 831.

3. Longcope, Warficld T.: The production, of experimental nephritis by repeated proteld intoxication. Jour. Exp. Med., 1913, XVIII, 678.

4. Oliver, Jean: The histogenesis of chronic uranium nephritis, with especial reference to epithelial regeneration. Jour. Exp. Med., 1915. XXI, 42.5.

5. MacN'ider, William de B.: A study of acute mercuric chlorid intoxications in the dog, with especial reference to the kidney injury. Jour. Exp. Med.. 1918, XXVII. 413.

6. Underbill, Frank P.. Wells, H. Gideon, and Goldschmidt, Samuel: Tartrate nephritis. Jour. Exp. Med., 1913, XVIII, 322.

7. Frothinghani, Channing, Jr.: A glomerular and arterial lesion produced in rabbits' kidneys by diphtheria toxin. Jour. Med. Res.. 1914, XXX, 365.

8. MacNlder, Wm. de B.: A study of the naturally nephropathlc kidney of the dog rendered acutely nephropathic by uranium or by an anesthetic. Part 2. Jour. Med. Res., 1916, XXXIV, 199.

9. Le Count, E. R., and Jackson, Leila: The renal changes in rabbits inoculated with streptococci. Jour. Infec. Dis., 1914, XV. 389.

10. Major, Ralph H.: The production of kidney lesions with staphylococcus aureus toxins. Jour. Med. Res.. 1917, XXXV. 349.

11. Bailey. C. H : Chronic nephritis in rabbits by repeated intravenous injections of living colon bacilli. Jour. Exp. Med.,

1916. XXIII. 773.

12. Major, Ralph H.: The production of acute and chronic kidney lesions with bacillus mucosus capsulatus. Jour. Med. Res.,

1917, XXXII, 125.

13. Faber, Harold K.: Experimental arthritis in the rabbit. Jour. Exp. Med.. 1915, XXII, 615.

14. Coulter. C. B., and Pappenheimer, A. M.: Proc. New York Path. Soc. 1916, XVI, 80.

15. Pappenheimer, A. M., H>Tiian, H. T., and Zedman. F. D.: Proc. New York Path. Soc., 1916, XVI, 73.

16. Ophiils, W., and McCoy, George W.: Spontaneous nephritis in wild rats. Jour. Med. Res., 1912, XXVI, 249.

17. Winternitz, M. C, and Quinby, Wm. C: Experimental nephropathy in the dog. Jour. Urology, 1917, I, 139.

A SKpyrCH OF DR. LYMAN SPALDING '

By Henry M. IIukd, M. D.

Dr. Lyman Siial(lin<r wa.s iwrn at Cornish, X. 11., in 177"). His early education was ohtained at the Charlestown Academy, and later he was a student in the office of Dr. Nathan Smith, the eminent founder of medical schools, and the first of the name of the Smiths who later hecame distinguished in New England and Maryland. He afterwards visited the Harvard Medical School in 1794 ami attended two courses of lectures there, hut clid not receive his degree of M. D. until 1797. He returned to Cornish, N. H., the residence of Dr. Smith, an<l took charge of his jiractice during the hitter's ahsence in Euro|)e. He suK-iequently tauglit chemistry and materia medica witii Dr. Sniitli at the newly estahlished medical .school at Dartmouth College. N. H. He also hecame demonstrator of anatomy.

He soon removed to \Val|Mile, N. H., where he practised for a few months also. His residence there is mainly interesting hecauseof the fact that he purchased a set of Perkins Tractors, then much u.^cil ami highly prai.^ed for the treatment of disea.xes. These tractors were sold for -$30,00, with the c.xclnsivc right to u.«e them in |)ractice hoth in this country and in Europe. It was one of the common medical frauds which arc perpetrated on all nations ahout once in so often, Dr, Spalding removed to Port.'^mouth, N. H., in 1797, and there had a succe.<sful career. He hecame a contract army surgeon, and had .«o much to do that ho relinquished his connection with Dartmouth College. He was a diligent student, and active in all matters i-onnected with medical co-o|)erHtioii. 'Read before The Johns Hopkins Hospital Historical Clvib, February 10. 1919. He established a medical society, an anatomical museum, and originated and distributed .'Jo-called " Bills of Mortality," giving the causes of death of persons who died in Portsmouth from the years 1800-1 SI 3. He al.so essayed the growing of opium and lettuce in his garden for medicinal purposes. In the "Life of Dr. Lyman Spalding " several interesting chapters are given on the introduction of vaccination into this country. Dr. Spalding, who was living at Portsmouth, wrote to Dr. Waterhouse, of Cambridge, who had received the Kiiie Po.x from Jenner in England and seems to have had the monopoly of the introduction of vaccination into this country. Waterhou.se was undoubtedly a man of ability and energy, but proi>ably lackwl money and felt the need of •.\|)Ioiting the new discovery for his own benefit. He, accordingly, writes to Dr. Sj)alding, in reply to his letter, asking for one-quarter of the amount received from Dr. Spalding's va<'ciinitions during the succeeding 14 months, insists that " the small sum of five dollars" be charged for each vaccimition, and ginirantees that the e.xclusive privilege will be granted upon these terms. He also nnikes carefid mention of the fact that he has .Tenner's matter direct from England. A long i-orrespondence took |)lace between Spalding and Waterhouse. Both parties seem to have been an.vious to make money from the introduction of vaccination, but Waterhouse appears in the most unfavorable light. After acceding to Spalding's proposition that he have e.xclusive control of vaccination in Portsmouth, ho shows great an.xiety that he, Spalding, should associate with him a Dr. Cutter and, later, Dr, Cutter's son, on the ground that the activity of these men would increase the number of vaccinations and thereby increase the profits to be 126 [No. 33"J derived from the exclusive privilege of managing them. In one letter Spalding asks for the privilege for 12 months, and later suggests that he will pay 10 per cent of all the sinus which he receives for vaccination until such time as vaccination becomes public property. All that he received from Dr. Waterhouse seems to have been the exclusive privilege of vaccinating persons within the limits of Portsmouth, and a small piece of thread which had been dipped in the vaccine lymph. Later it seems that Spalding was to pay$130.00 for this piece of thread, and a certain proportion of the money which he received for the vaccinations. Owing to the fact that it soon became apparent that one patient could be vaccinated directly from the arm of another, the exclusive privilege of using the vaccine lymph was soon broken up.

This destruction of the monopoly was undoubtedly much hastened by the unsatisfactory character of the vaccination when the thread impregnated with lymph was used, and the great inferiority of this method to tlie method of vaccinating from arm to arm. The physicians had many failures. It is also interesting to note that Dr. Spalding, on two separate occasions, made observations upon patients who had been vaccinated and afterwards placed in smallpox hospitals, and freely exposed to the disease for a number of days without acquiring smallpox. Spalding also received a letter from Edward Jenner, the discoverer of vaccination, and subsequently a specimen of vaccine lymph directly from him.

Spalding issued at Portsmouth during the following 12 years bills of mortality— so-called— beginning in the year 1801. Copies of these bills were sent to John Adams, then President of the United States, and subsequently to Thomas Jefferson, Benjamin Waterhouse and Benjamin Bush. Waterhouse, with his usual critical spirit, made reply in the following letter :

Cambridge, March 18, 1802. Dear Sir: Your letter of the 11th mst. came duly to hand and I have endeavored to comply with your request, so far as to send you some matter on the point of a quill. As to the thread, it is full a month old, but was from a very perfect case and has been kept in a proper degree of temperature ever since. I am now so in the habit of taking the vaccine fluid from arm to arm, that I am not so constant in preserving it on the thread or otherwise. Considerable attention and patience are required in the first use of an old thread. It ought always to be moistened with the vapor of hot water.

You mention my not having answered your last letter. I have received no letter from you since you wrote to me in answer to one of mine. I received a printed bill of mortality, 5 or 6 weeks ago, but no written line whatever with it and I have had no letter from' you for 4, 5 or perhaps 6 months past.

I have just received "Observations on the Cow Pox" from Dr. Lettsom. I shall probably publish a second pamphlet in a month or so. being practical observations, etc. In the meantime I sent a few to the Medical " Repository " for their next number.

I am glad to find that you attend to the occurrences of Mortality. Excuse me for making a few remarks on the one you were so obliging to send to me. 1. Did APHTHAE kill the infant, or was it a symptom of another disorder, or in other words: was it sympathetic or IDIOPATHIC?

2dly. We very rarely see consumption in patients above 50 years of age, more rarely above sixty and very rarely indeed at 70.

There is a chronic cough and emaciation, and great expectoration in old people, but it is not the true Phthisis Pulmonalis.

3dly. Is not DEBAUCHERY rather a VAGUE term for a general Head? Does it mean Drunkeness exclusively?

4thly. I never yet saw a very young child with Epilepsy. There is a wide space indeed, between the convulsions of infants, and that truly wonderful disease, EPILEPSY.

5thly. Mortification: Was it in the bowels or the feet? As they are widely different in their cause. See Pott in the LATTER.

6thly. Death from SCROFULA is very uncommon. It predisposes to fatal diseases.

7thly. PAREGORIC: Does it mean that the Child was poisoned by that composition? If so, had it not better been by Opium as Paregoric means a Mitigator?

You will excuse these hasty observations that occurred on the perusal. They have not originated from a disposition to criticise but from a desire to have them free from every exception. Yours Steadily, B. WATERHOUSE.

In 1802 Spalding invented a galvanic battery, which gave rise to considerable corresjiondence, and which unquestionably was used extensively among his brother physicians. He had letters asking how to make similar batteries and also their exact therapeutic itses. He further devised a process for manufacturing oxygen for inhalation, and later invented a soda water fountain, which seems to have been quite extensively used. As he neglected to protect his invention by patents, as it appears in his biography some years later, patents were secured by other persons, and he was forbidden to use it without paying a royalty for his own invention. He was an active writer, especially upon anatomical and surgical subjects. His practice also extended in surgical line.s, and he performed operations for hernia, extraction of cataract and removal of necrosed bone. He continued his interest in vaccination, and received a second letter from Jenner, who acknowledged the reception of some interesting details concerning vaccination and the bills of mortality, for which he thanked him. In Jenner's letter an interesting detail is given concerning the good effect of vaccination in controlling cases of smallpox in Vienna. Prior to vaccination the annual average of such cases was 800. Four years subsequent to the introduction of vaccination, but two cases of smallpox occurred iii the city.

Dr. Spalding seems to have had a remarkable facility for friendship, and made warm friends in many parts of the country. One of his friends and subsequent correspondents was Bishop Philander Chase, a boyhood acquaintance, who subsequently became Bishop of Ohio, and later of Illinois and founder of Kenyon and Jubilee Colleges. Dr. Luther Jewett was another friend, a Vermont worthy who liad excelled in the practice of medicine, the practice of law. the gospel ministry and the editorship of an influential news])aper; four distinct branches of effort, in each of which he achieved marked success. He was also a warm friend of Dr. John C. Warren, of Boston; Dr. Alexander Eamsay, the famous anatomist from Scotland, and Dr. George Shattuck, of Boston. He wrote letters to John Bell, the distinguished Edinburgh surgeon, and also to Charles Bell, and as his thoughts turned very much to medicine abroad, he made every effort to get an opportunity to visit England and the continent to bettur fit

May. 1919J

12i

liimself to teach medicine. He sent a petition to the Secretary of State of the United States Government, asking that he be made a .«j)ec-ial messongcr to t-arry (li.<|mtehes to France, and received a courteous message to the elTcct that the services of no such messengers were nec(k'(l at that tinu'. He visited PhihHh'l|)liia in order to lit liinisidf hotter for his profession, and tlieri' saw tlie eminent Dr. I'liysick, and Drs. Wistar, Hush, Slii|)|)fii and Harton. lie writes tliat the school in Philadelphia had 3.")0 medical students and later, when in Xew York, he contrasts the ])o|)uhirity of I'iiiladelphia and tlie large nund)er of students witli tiie fact that New York had only about 100 medical students.

There is an interesting chapter in Spalding's life wiiich has been detailed at considerable length i)y his biograplier and deserves mention. In 1809 he became connected with the Fairfield .\cademy, located at Fairlield, aiwut 10 miles from Little Falls, N. Y. Fairfield .\cademy was one of a chain of academies whieli had been establisheil to promote edmation in tile state under the charge of the Board of Regents. The great demand for medical men to provide for the needs of an ever increasing emigration to the west at tliis time gave rise to many medical sdiools. In addition to the Xew England .schools founded by Ur. Xathan .Smith, there were schools at Pittsfield, Mass., and t'astleton, Vt., in addition to Harvard anil the schools in Philadelphia and Xew York. He was appointed lecturer at Fairfield .Academy in 1809, and lectured there for several years. The journey to Fairfield from Hoston wa.s a matter of three days and nights. He was made lecturer on chemistry and surgery during his first appointment, while Dr. George t". Shattuck, of Harvard, was made lecturer on medicine. The courses .seem to have been not simultaneous, but t-tindeni, as it were, Dr. Spalding lecturing on chemistry and surgery for si.\ weeks, and being followed by Dr. Shattuck, who lectured for tlie .same period on medicine, this making a term of three months. The success of tlie school was so great that it became nei-cssary to erect a new building, and ])ermi.ssion was aske<l of the legislature to establish a lottery to raise $.")000. Ix)tteries, it may i)e remarked, were at this time a popular method of raising money for educational and religious purposes. The Washington Monument in Baltiniori' was startetl ity a lottery, as also the University of Maryland, the First Presbyterian Church and St. Paul's Church. JIany <letails are given in the iiiography of S|ial<ling in reference to the lottery plan, and new light is thrown upon it by the suggestion in one of the letters that, if the Icg^islature granted the authority, the privilege of the lottery might lie disposed of to .xonie other parties at a discount. The success of the .school at Fairfield became .-io great as to e.xcite the cupidity of persons who were interested in the development of Hamilton .\cademy. at Clinton, X. Y.. into Hamilton ('(diege, and an effort to establish a siinilar medical school at Hamilton. The agitation finally brought an appropriation of$100,000 to Hamilton -Academy, and it l)ecanie Hamilton College, wiiile Fairfield was obliged to Im" satisfied with receiving $10,000 for the construction of a building and a <-harter giving the privilege to grant ilegrees, and thus to become an established medical .<chool. The following letter, sent by Dr. S))alding to Dr. George Shattuck, of Boston, gives a very interesting idea of his conleption of the infiuencc of medical teaching, and its benefit to I he medical teacher: Dear Sir: I can only say that I regret exceedingly the opinion of yourself and friends, that your avocations will not sulTer you to Wsit Fairfield once more. I acknowledge that, at present, the compensation is not adeqiiale lo the output and the loss of business, but. Sir. 1 do really believe that this school may be made second to none but Philadelphia. If not. I will join with you in resignation. What eflect has the Professorship already had on you? It has compelled you to pay close attention to your profession, to pass the wliole of CuUeu's " Nosology " in review, before you annually, and llureby qualifying yon for the practice of your profession more than any other way in which you could have spent your time. It is the high road to fame, and usefulness. I know that my sacrifices have been great. I know that yours must be. But, show mc the man who has risen to be a Prince of Physicians, while slumbering on the couch of idleness. Soon after I came to Portsmouth. I resigned my office of Professor of Chemistry in Dartmouth, no doubt from the same motives that now influence you, with this addition, that my lectures there had to continue three months. I soon found myself slumbering on my oars and relaxing my pursuits. In fact, so far from Improving, I hardly kept pace with the others. A kind of indifference for science pervaded nie: Indignant I aroused. I went lo Hanover to see Ramsay, I went to Philadelphia, and I planned a voyage to Europe. This change, Sir, I consider the most happy circumstance in my wliole Professional career. Admit tliat you resign your office. Man is an indolent animal. What inducement have you then, to labor incessantly? None! Your reputation is as liigh as that of your contemporaries. Then, wrapped in the lap of affluence and ease, you will slumber and sleep till old age creeps upon you. when you will find yourself outstripped in the race of usefulness and fame, your opinions so antiquated as to be regarded not, and yourself a mere old Granny! Look at the Priaces, or rather. Fathers of Physic. Who have they been or who are they now? So far as my memory serves me; Teachers of Physic. Boerhaave, CuUen, Desault. lx>ok at Hush, Warren and Smitli. What has put them at the head of the profession? Notliing but their being compelled to labor, and annually to review their profession, and incorporate with their old slock all the new improvements. Show me a man in private practice who does this, annually. He is not to be found. But. your friends say that you can do this, yet stay at home. I acknowli'dge (his, but tell me honorably. Will you do it? No, Sir, you have no inducement. For a man to be pre-eminently great, there must be a great occasion. What made Washington Great? Opportunily. You are now on the same high road lo reputation that every Prince of Physicians has travelled. If you turn aside, you are lost forever. These in conjunction with those in my last letter are the reasons which ought lo inMuence you. You can have no doubt of my wishes on the sul)jecl. The time for the commencement of the lectures Is so near at hand, that no successor can be appointed in season for the next course. I therefore beseech you, on my account, if neither honor nor fame will move you, to deliver This One Course, and I will consent to any arrangement that you may then choose to make If nothing farther, as a mere matter of policy. I wish you to withhold your resignation till the meeting of the Trustees of tlie New Medical College and let us see what they win do for us. Dr. Mann I knew had be<'n appointed a Hospital Surgeon, but 1 did not know that he had been made Surgeon General. He must be with the Army by this time, ami cannot be prepared for the ensuing course. 1 have no objection to this man, but must for want of room decline saying anything about your successor until I hear from you again. Your friend, Lyman Spalding. 128 [No. 339 Sliattuck, after serving two terms as professor of medicine, relinquished the position, but Spalding, in 1813, was made president of the Fairfield College, and filled most of the chairs in 1814-1815 and 1816. The number of students seems to have varied between 50 and 70. Spalding seems to have done very faithful, conscientious work, for which he received somewhat irregular paj-, and often more pay in promises than in actual money. The school remained in active operation until 1839, when it went to pieces in consequence of squabbles among the faculties as to the division of fees from medical students. The fees seem to have been very small. In 1814, Spalding went to New York to reside, and had an office on Broadway, for which he was to pay about$200 per year. His fees from his patients during the first year amounted to a little more than $1000. At this time, Spalding seems to have attempted to write a book entitled the " Institutes of Medicine " which, as far as I can learn, was never published in book fomi, but was circulated in pamphlets, each chapter furnishing a pamphlet. It was praised by Shattuck and Waterhouse, and the reception of a sample pamphlet was certainly acknowledged even by Dr. Caldwell, but the book seems to have made little impression. The following letter is from Governor Plunier, of New Hampshire, a friend of Spalding's : Epping, N. H., Oct. 24, 1818. Dear Sir: This weelc I received your letter with your "Reflections on Fever," and Report of the Trustees of the Free Schools, for which you will please accept my grateful acknowledgments. I have read your pamphlet with attention and pleasure, but it is on a subject with which I am not sufiiciently acquainted to decide with precision. You know the low state of the Faculty in New Hampshire. We have scarcely any who write on the subject of medicine, and of the great body of our country physicians but few who have any books to read. and what is worse they have little inclination to purchase books, to read those few that they have, or to investigate the complex and intricate subjects of their profession. These facts have long induced me to believe that, in many cases, the patient has more to apprehend from the ignorance of the physician, than from the disease, and that it is safer to trust to nature for a cure than to rely on the prescriptions of those whose knowledge is limited to a few hard technical terms. With us. the Gentlemen of the Faculty have made less progress than those of law and divinity: the latter, indeed, have much to do before they can attain real eminence. In your profession I have long considered it a desideratum to have an able but simple work, accurately describing the nature and functions of the several parts of man in a state of health, the effect or changes diseases produce on each of those parts and of the remedies for those diseases. I would purchase and read such a work with pleasure, and that pleasure would be enhanced if it was simple, plain and free, so far as the nature of the subject would admit, from abstruse technical terms, and of attachment to existing theories. Mystery is the enemy of improvement, and it is better suited to prolong the reign of ignorance and of error than to promote that of truth and science. And, the knowledge of things is vastly more important than that of words. I really wish we had an accurate Journal kept in different sections of our Country of the actual state of the weather, the crops, the general diet and regimen of our citizens, the diseases most prevalent in each, their type, character and mode of treatment, etc., so as to exhibit the means by which health was preserved and lost and how far they depended on climate and modes of living. Such a Society, I think, might be formed of Gentlemen living in various parts of our Country, with little expense and from whose reports much information could be obtained which would be useful to all, and particularly to Medical Characters. I would freely contribute to such an establishment. But, I am wandering from the object of this letter, which was to thank you for your Pamphlets and to say, that if you or the Historical Society of N. Y., should need any of the few pamphlets we publish here, it will afford me pleasure to procure and transmit them. I remain with much esteem and respect. Yours, etc., William Plumer. About 1817 Spalding began to agitate the preparation of a national pharmacopceia, notwithstanding the fact that several local pharmacopoeias already existed, the most extensive and authoritative one being that of Massachusetts. His motive in urging a national pharmacopoeia was due to his desire to secure uniformity, and also to discard local remedies which seem to have been used in different parts of the United States without any sufficient scientific authority. As an example of such local favorites may be mentioned Scutellaria or skullca]) as a remedy for hydrophobia. It was shown by Spalding that the authority for the use of this remedy was weUnigh universal. Numerous cures through its employment were reported, and in the literature its claims were overwhelming. We now know that it is worthless, and its elimination from the pharmacopceia was promptly made. The plan proposed by Spalding for the preparation of the pharmacopoeia was an excellent one, and has practically been followed for the last 100 years. The pharmacopoeia was originated in a paper by Dr. Spalding, read before the medical society in the city of New York, in wliich he pointed out the difficulties attendant upon the present lack of uniformity in the preparation of drugs in the different states. As a result of the discussion which followed the reading of his paper, a committee was appointed, of which Dr. Spalding was chairman, to suggest measures for the preparation of a national pharmacopoeia. The country was divided into four districts, known as the nortliern, middle, southern and western. Through the medical societies of these regions, delegates were cliosen to meet at some central jioint in the district to discuss matters pertaining to the drugs to go into the pharmacopoeia, and to elect two delegates, each to go to Washington later to prepare the book for publication. The only two district conventions were those of New England, at Boston, and of the Middle States at Philadelphia, which met on June 1, 1819. The meeting in Philadelphia, although attended only by delegates from the middle district, had done valuable work in the discussion of remedies aud methods. The delegates chosen at the two district meetings met in a general convention in Washington on January 1, 1830, Dr. Spaldiii'jbeing one of the delegates. The two rough drafts from tlic district meetings were examined and discussed, and the prej):!ration of the pharmacopoeia was outliaied and plans made for its completion and adoption. A Committee of Publication was chosen, with Dr. Sjialding as chairman, which met in New York in June, 1820. The pharmacopoeia wa.s printed in English and Latin, and was immediately adopted as autlmritative throughout the covuitrv. Mat, 1919] 129 About the same time Dr. Spalding also had, in addition to the pharmacopceia, a jdan for the establishment of what he ternieil a medical police to liave charge of all sanitary matters. The latter scheme, however, seems to have faded from public sight. Dr. S])alding did not live long after the publication of the pharmacopoeia. In 1821, while walking in the city of New York, he was struck down by some building material whicli fell upon his head, and rendered him unconscious. Although he recovered apparently, he never enjoyed good health, and gradually went into a state of physical and mental decline. He gave up practice, sent his family to New England, and later rejoined them there. He died on October 31, 1831, a few days after he reached them. It is evident that he was a man of unusual ability, being industrious, efficient, and with large powers of initiative. Imperfectly educated as he was, he had made himself an excellent physician, a remarkable surgeon and anatomist, an interesting and ins])iring medical teacher, and a member of the profession full of enthusiasm for its advancement and perfection. He wa.s denied the great desire of his life, the privilege of studying aiiroad, and doubtless liad lie been able to do so, and had returned to .\merica with tlie new ideas, his subsequent lal)ors might iiave resulted in great additions to the medical knowledge and resources of the country. The story of his life is a most inspiring one. N(>T>:. — Since the above sketch was written and presented to the Historical Club, Dr. Kelly has placed in my hands a copy of tlie first edition of the Pharmacopoeia of the United States of America. It bears the following title page: The PH.\R.MACOPOEIA of the rXlTEn STATES OF AMERICA. 1820. By the Authority of tlie Medical Societies and Colleges. Printed by Wells and Lilly. For Charles Ewer. No. 51, Cornhill. Dec. 1820. It is bound in leather and is in excellent state of preservation. The name on the fly leaf cannot be deciphered definitely. It is in pencil and is dim in places. The inscription seems to be James Burbeck. 1827. It has undoubtedly belonged to a druggist or apothecary as it contains many recipes neatly interleaved In various portions of the book. There are also prescriptions for various diseases. The book contains an interesting Historical introduction explaining the object of the preparation of the National Pharmacopeia. There is also a Preface which gives full details as to the movements which led up to the preparation of the work. In the list of delegates orisinally selected to attend district conventions to prepare lists of medicines and to select local committees are to be found names eminent in the profession one hundred years ago, many of whom figured in medical literature. A good many of tlicm also were meiubers of the linal committee which prepared tlie National I'liarmacopeia. From New York there were; llavid Ilosack, Samuel L. Mitchell. T. Romeyn 13eck. Lyman Spalding, John W. Francis and Valentine Mott. From Massachusetts; Jolin C. Warren. Jacob Uigelow, James Thaclier and George C. Sliattuck. From New Haven; Eli Ives and Nathan Smith. From Philadelphia; T. T. Hewson and Joseph Parrish. From Maryland; Nathaniel Potter, Elisha DeButts, Samuel Baker and Ennals Martin. THE EFFECT OF DIFFERENT BLOODS ON THE GROWTH OF B. INFLUENZAL' P.y T. M. liivos. M.I)., Ballimorc :Md. The growth of B. infiwnzx has been described as small dewdrop colonies invisible by direct light, but becoming larger when near colonies of other bacteria, as staphylococci, pneumocoeci and streptococci, this latter phenomenon being called obligate symbiosis. This is a correct description of the colonies as they appear on human blood agar. In making routine throat cultures it was noticed that on certain days the colonies of B. influenzcB were large and easy to isolate, whereas on other days they were very small and often overlooked. The results from day to day differed so much tluit an explanation was sought. It was found that on tiie ilays when the colonies were large either cat or rabbit blood luid been used and human blood when thev were small or over ' From the Departments of Pediatrics and Patholog>', Johns Hopkins I'niversity. looked. Tiiis led to the comparison of the effects of different bloods and sera on the growth of B. influenza:. In three petri dishes respectively was placed 0.5 c. c. human. 0.5 c. c. cat and 0.5 c. c. rabbit blood. Then 10 c. c. of meat infusion agar were added at 40° C. from the same llask to each of the dislies. After liic agar had solidified, each plate was streaked with a broth siuspension of two strains of B. influenzcE. The growth on the raiiliit blood (Fig. 1) and cat blood agar was lu.vuriant. The colonies which were well separated became very large and slightly opaque, and when they were 48 hours old some were umbilicatod or checker-sluiiied. The growth on the human blood agar (Fig. 2) appeared very slowly and at the end of 48 hours was still seen with difTiculty. Three other plates were made lus above and streaked wilii a broth suspension of B. influcnzw. In the center of ea<li plate there was also streaked a broth suspension of piicunio 130 [No. 339 cocci. On the rabbit blood and the cat blood agar the colonies of B. influenza grew best at the edges where they were well separated. There was no tendency to be large.'it near colonies of pneumocoeci (Fig. 3). On the human blood agar the colonies of B. inftuenzm were just visible at the edges but grew large near pneumococcus colonies (Fig. 4). This has been repeated with six lots of meat infusion agar and each time the difference has been observe<;l. B. influenzcE grows well on rabbit blood agar, cat blood agar and Averj' medium when 1 per cent of washed cells is added to the agar at 95° C. There is also no difficulty in growing the bacillus on " chocolate blood agar " even when human blood is used. If the " chocolate agar " is good there is no obligate symbiosis, but at times, when the medium is improperly made, this occurs. Very rarely does the symbiotic relationship appear on rabbit or cat blood agar. It would seem that fresh human blood either has an inhibitory effect on the growth of B. inflii^nzce which pneumocoeci or other bacteria remove by their growth, or else it lacks something which is supplied in the neighborhood of other bacteria by the products of their metabolism. The fact that it grows well on Avery medium and on " chocolate human blood agar " makes it seem most likely that there is an inhibitory factor which is removed by heating or by the growth of other bacteria. Two tubes each containing 0.5 c. c. of defibrinated human blood were inoculated respectively with api)roximately 100,000 influenza bacilli and "pneumocoeci. Two tubes of 0.5 c. c. defibrinated rabbit blood were likewise inoculated. A loopful from each was streaked on a separate rabbit blood agar plate 20 minutes later. There was a heavy growth (400-500 colonies) on all the plates except the one streaked from human blood and influenza bacilli which had only several colonies. After four hours' incubation a good growth was obtained from all except hiunan blood and influenza bacilli which was sterile. To be certain it was sterile an extra plate was streaked with one-tenth of the +++++ CONTENTSs of the tube. Still no growth was olitained. This precaution was taken because it had been observed that influenza bacilli' occur in chains and clmnps in liuman blood and serum whereas in smears from rabbit blood and serum they are found diffusely scattered. Clumping could account for a marked difl'erence in the number of colonies from a loopful, but not for a sterile plate from one-tenth the +++++ CONTENTSs of a tube. Approximately 100,000 influenza bacilli were added to 0.5 c. c. meat infusion broth, 0.5 c. c. normal human serum, and 0.5 e. c. rabbit serum. The broth was used as a control. The tubes were incubated for two hours and a loopful from each was streaked on a blood agar plate. A heavy growth was obtained from the broth, less from the rabbit serum, and only a few colonies from the human serum. After 18 hours' incubation, the human serum was sterile while there was a heavy growth from the rabbit serum (Figs. 5, 6, 7, 8, 9). - Uniformity of growth has been sought by using rabbit blood agar for plating and for each experiment the plates were all poured at the same time from one large flask of meat infusion agar. Sera from four adults and one infant, some of whom had had influenza, others not, have been tried with several strains of influenza bacilli and all have shown a bactericidal effect. Sterile plates cease to be obtained at different points in the dilutions of the various sera when a constant number of bacilli are used for an inoculation. The same is true when one serum is used and the number of bacilli inoculated is varied. Normal human serum kills influenza bacilli rapidly, in many instances causing the death of thousands of bacteria in 20 minutes at room temperature. This bactericidal property is lost very rapidly upon dilution. Rabbit serum, also, is slightly bactericidal and, if a light inoculation is used, the midiluted normal serum may yield a sterile plate. There is no comparison, however, between the two sera. Guine'a-pig serum, too, is not very bactericidal for B. inflxienzce. Inactivating himian serum at 54° C. for one-half hour markedly decreases its bactericidal properties for B. influenza. Normal rabbit and guinea-pig sera were tested at the same time with normal and inactivated human serum. Rabbit serum decreased the number of colonies at first, but this effect soon disappeared and at the end of 18 hours a heavy growth was obtained from the rabbit and guinea-pig sera. Even inactivated human serum kills in 12 to 18 hours. Experiment Showing the Difference Between Normal and Inactivated Human Serum. The Count.s are Reported in Round Numbers for Convenience Dilutions of normal and inactivated Approximate inoculation of each tube with B. in fiuenza: Number of colonies obtained at different times by streaking a loopful from each tube on a blood agar plate liuman aerum 20 minutes 4 hours 18 hours Serum Locke's Solution Normal Inactivated Normal Inactivated Normal Inactivated 1.00 c.c. 0.75 c. c. 0.50 c.c. 0.25 c. c. 0.00 c. c. 0.25 c. c. 0.50 c.c. 0.75 c. c. 100,000 100,000 100,000 100,000 35 20 40 150 300 300 200 250 300 300 300 300 10 200 400 Attempts have been made to reactivate the inactivated human serum with rabbit and guinea-pig serum as they do not inhibit the growth of influenza bacilli to any great extent. This has been accomplished a number of times. It has been accomplished also with normal human serum. An objection might be raised to the use of normal human serum because it is in itself bactericidal. The experiment as shown in the table on page 131 .seems to show that it can be done. During the epidemic of influenza last fall thousands of antemortem and post-mortem blood cultures were taken and very few positive results were reported for B. influenza, de.spite the fact that at autopsy they were as numerous in many of the lungs as pneumocoeci and hemolytic streptococci which were easily obtained in a large percentage of the post-mortem blood cultures. Positive blood cultures are at times obtained from patients with influenza endocarditis and from children with PLATE XIV F|... :.. -i.r.,.,;i, r.«.,ii,i,K ;. .u. .li.akinlfa rabbit blood Hg^r pUK »illi • loofiful of meat Infuaion broth which hxl been inoculateil with ft .v»l-fr^--r n"-? nrihflf<»d 'wo hour". THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919 •/ v.- • .#• V '.:•.•* . • Fin. 8.— Growth obtniniil aa in KiK. R i-xccpt that incubation was for eJKhtccn houra iiiatcail oltwo. Kiii.li.-firowth obialniMl iia in hit. 7 i-xep|.t that incubation una (or <'l([litcen houra inatcad of two (plate iaatiTik-). May, 1919] 131 influenza meningitis, but these are the exception when compared with the patients who died during the epidemic and had influenza bacilli in the lungs at autopsy. B. infiuenza eitlu-r does not invade the blood stream, is promptly killed when it does, or, if alive, is not recovered by the present cultunil EXfBRI.MK.NT Til SilOW Rl--\rTIVATl<).N OF THE I.VAITIVATEU HlMA.N SERf.M AMI Resix)RATION OK ITS Baotkkiciuai, Pkoperties. Thb Counts ark Rkpokted in Rocnd Nimbers for Convkniencb Number of colonies obtained in streaking blood agar plates witli a loopful from each tube at different times Smin. ,hr. 2 bra. 4bri. 7 hrs. U brs. 0.5 c. c. normal 100,000 human serum. 0.5 c. c. inacti- 100,000 vated human Derum. 0.4 c. c. inatti- lOO.OOO vated human serum +0.1 c. c. norma! human serum. 0.4 c. c. Locke's 100,000 solution 4- 0.1 c. c. normal human serum. 400 400 400 400 400 50 300 400 25 200 200 300 125 400 methods. As shown above, human serum and defibrinated blood are very bactericidal for the influenza bacillus in vitro as compared with other bloods used and also as compared with the pneumococcus. This bactericidal property is lost rapidly upon dilution, and laboratory strains have been grown in 100 c. c. of meat infusion broth with 10 c. c. human blood added even when very light inoculations have been made (le.>;s than 100 bacteria). Although conclusions cannot be drawn concerning hai>i)cnings in vivo by what occurs in vitro, may it not be possible that a combination of such factors accounts for so many negative blood cultures for H. inftuciiztp when they arc so abunilant in many lungs at autopsv? CONCLUSIONS 1. B. infiuenzcE grows well and produces large, often o|)aquc, colonies, upon the projjcr medium. 2. B. infiuemm grows better on rabbit blood and cat blood agar than on human blood agar. Some of the discrepancies between the findings of various laboratories during the i'\ndemic may be explained possibly by the difference in the media used. 3. Obligate .symbiosis occurs more conmionly on liunum blood agar than on rabbit or cat blood agar and in part, at least, is due to the inhibitory effect of the blood which is removed by heating or by the growth of other bacteria. 4. Defibrinated hmiian blood and normal hujuan serum arc very bactericidal for the strains of influenza bacilli studied as compared with defibrinated rabbit blood, normal rabbit .serum and normal guinea-pig serum. 5. Inactivated human serum, although less bactericidal than normal serum, also kills in from 12 to 24 hours. 6. There is evidence that the marked bactericidal properties can be restored to inactivated human serum by a quantity of normal human serum which by itself is not bactericidal in the same lengtli of time. Keactivation can be accomplished by other normal sera. OBSERVATIONS ON THE CLINICAL PHARMACOLOGY OF DIGITALIS By Ai.FRKD M. Wedd, {From the Medical Clinic nf the Clcvelniitl Although introduced into therapeutics by Withering in 1T85, digitalis received but little consideration from medical scientists until comparatively recent years, and the modem clinical knowledge of the drug may be said to date from the work of Jlackcnzie," reported in 1911. The present communication is comjjiled from data on un.selected cardiac and caniiorenal patients admitted to the I'ity Hospital during the past year to whom digitalis was given, including 29 in who.se ca.ses electrocardiographic records were taken every 24 hours, or more frequently, during the period of administration of a standardized preparation of the drug. I'rkparation and Dosaor The preparation was the tincture, two different lots being u.sed, each of which had been standardized by Prof. R. .\. M. D., rittsburgh, Ta. I'ity Hospital. Scrvi( e of Dr. K. P. Carter) Hatcher, of ("ornell University. Digitalis dosage, referring to the tincture, in clinical practice is subject to rather wide variation; from a ihiily dose of 1 c. c. or less, used by some practitioners, tlirough the dose of from 4 to 6 c. c. recommended by ilackenzie, up to the massive doses of 15 to 25 c. c. in 2-1 hours (usually O.lKi c. c. \wt |)ound of body weight), advocated by Kggleston ' and recently studied ami indorsed by White and Morris.' In this work it was desired to give enough of the drug to bring the ])atient pmnijitly under its influence, but to avoid such amounts as might by the early producti<in of toxic symptoms prevent us from following its jirogressive action. The daily dose us«'d was from 8 to 12 c. c, usually 10 c. r\, and this was continued until definite evidence of digitalis action was 'Mackenzie: Heart, 1911, XI, 273. 'Eggleston: Arch. Int. Med., 1915, XVI, 1. ' White and Morris: Arch. Int. Med., 1918, XXI, 740. 133 [No. 339 noted. The indications to discontinue the drug were alimentary disturbances, derangements of the cardiac mechanism or slowing of the pulse rate to a level beyond which it was deemed inadvisable to continue. The cat unit of Tincture A was 1.11 c. c. and it was, acccjrdiiig to Professor Hatcher, a fairly good specimen. This ])re]iaration was given to five patients. The following are lirief details of these cases: No. 320. Diagnosis, clironic myocarditis. Age, 16 years: body weiglit, 125 pounds. Total dose, 72 c. c. Rate wliile in bed slowed to 60. No. 299. Diagnosis, chronic myocarditis. Age, 44 years; body weight, 140 pounds. Total dose, 115 c. c. No clinical effect. No. 321. Diagnosis, chronic myocarditis and nephritis. Age, 48 years; body weight, 135 pounds. Total dose, 101 c. c. Rate, when up, reduced from 120 to 110. No toxic symptoms appeared. No. 323. Diagnosis, chronic myocarditis and nephritis. Age, 52 years; body weight, 140 pounds. Total dose, 137 c. c. Pulse slowed from 120 to 60 after 119 c. c, then increased to 84 and remained at that rate. No toxic symptoms. No. 332. Diagnosis, chronic myocarditis with atrial fibrillation, nephritis. Age, 45 years; body weight, 140 pounds. Total dose, 149 c. c. Fulse rate slowed to 56. No toxic symptoms. These were the first cases studied and in tliree of them the drug was discontinued because it was feared that some unex])ected result might occur, since the dosage then far exceeded that usually given. In the remaining work a second tincture was used, the cat unit of which was 0.85 c. c. The total dosage with this preparation showed considerable individual variation. In No. 368 nausea and vomiting occurred after 20 c. c, while in No. 374, 100 c. c. were given without the development of any toxic symptoms. Because of an oversight No. 304, a case of complete dissociation, received 280 c. c. during a period of 10 weeks without showing any clinical symptoms. In nine cases toxic sym])toms were produced by 40 c. c. or less; in seven lascs, by 40 to 60 c. c. ; six patients took from 95 td 100 c. c. The average total dose required for the production i>r toxic symptoms in 22 patients was 52 c. c. No. 321 entered the hospital a second time six months after the first admission, with moderate decompensation, presenting a clinical picture similar to that when first seen. Digitalis was again given and nausea and vomiting occurred after 35 c. c. of the second tincture, whereas 100 c. c. of the first produced no clinical effect. The inefficiency of the first tincture was undoubtedly due to delayed absorption from tlic alimentary tract, as will be shown when the effect of digitalis on the T-wave is considered, but the cause of this is not known. It is evident, however, that biological standardization showiim' approximation to theoretical strength is no guarantee of the clinical efficiency of a given preparation of the drug. Individual power of absorption for a given tincture appeared to Iw quite uniform, so variation in toxic dosage is due to variatido in individual tolerance for the drug. No constant relation between the amount of digitalis that could be given and the age or body weight of the patient or the condition cil' the nivocardium could be discovered. Effect on Edema, Dyspnea and Cyanosis That digitalis has no specific diuretic effect is now generally recognized. The decrease in edema depends on improvement in the circulation, and rest in bed alone is an important factor in bringing this about. In three purely cardiac cases the edema had almost entirely disappeared before any digitalis action was recorded. Its removal in cardio-renal cases was much more slowly accomplished. The value of determining the output of phenosulphonaphthalein before and after the administration of digitalis may be pointed out as a means of determining the relative cardiac and renal elements in the original clinical picture. The alleviation of dyspnea was also seen to be an indirect digitalis effect, depending on improved pulmonary circulation, the rest, morphin and venesection, when used, affording the immediate relief, while more permanent removal of this distressing symptom came with improvement in the myocardium. Cyanosis was a characteristic and persistent sign of myocardial involvement. In those cases in which true myocarditis was believed to be present, and especially in those whose electrocardiograms showed intraventricular or bundle branch block, even though free from edema and dyspnea on moderate exertion, the cyanosis was not influenced by any treatment. The Effect on the Heart E.\te It was formerly maintained that the function and the prinpipal action of digitalis was to slow the pulse. However, excessive slowing with the ordinary use of the drug usually occurs only in atrial fibrillation, and according to Cohn * reduction in rate is not constant, and to produce slowing is not a function of digitalis in therapeutic doses. In five cases of fibrillation the pulse rate was reduced to 55 or lower before or without the onset of toxic symptoms ; in one case it fell from 130 to 84 when nausea and vomiting occurred. Eighteen cases with normal mechanism were studied ; in five the rate fell to 60 or lower ; in three there was no change : ill the remainder the reduction of the initial rate varied between 8 jier cent and 33 per cent, the average fall being about 20 per cent. Contrary to the statement of Sollman ' that fairly normal hearts are slowed by large doses, but that this is due to blocking of impulses from the atrium, the rate in six cases was reduced to 65 or lower before the onset of tdxic symptoms with an increase in the P-R interval varj'ing from 0.02 to 0.05 sec. as the only sign of block. In one case the rate after 10 c. c. had increased from 89 to 96 and after 20 I', c. nausea and vomiting occurred, the rate remaining at 96. In a number of cases after reaching a low level the rate increased as the point of toxicity was approached, c. g.. No. 323 ; rate after 119 c. c, 60, after 137 c. c, 84. This is comparable to the ex])erimental findings of Robinson and Wilson ° in which slowing continued until about three-fourths of the • Cohn: Jour. Amer. Med. Assn., 1915, LXIV. 463. '^Sollman: Manual of Pharmacology, 1917, Philadelphia. "Robinson and Wilson; Jour. Pharni. and Exp. Therap., 191S, X, 491. May, 191!) J 133 U'thal dose had been injected when acceleration set in and continued until fibrillation replaced the normal beat. Tiiis acceleration is due, accordinj; to Cushny, to increased irritability of the heart muiide rather than to any nerve influence. It d(x\< not seem jKissiblc to form any definite conclu.«i(in alx)Ut the time factor in the slowinfr of the initial rate. Usually there was a jrradual fall of from four to ten beat.^^ daily. Other ajjents than difritalis, the rest in bed and the sedatives given, certainly contribute to the first sudilen lowering which occurs before there has been time for any specitic digitalis action. Thus, in Xo. 329, a case of fibrillation, an initial rate of HiS fell to 108 in 12 hours, during which 10 c. c. of the tincture had been given. Comparing this with other eases it does not seem reasonable to attribute this prompt reduction of 60 beats solely to digitalis. In general, there seemed to be a gradual ilecline in rate, which in the fil>rillation cases nearly always progres.<ed to a much lower level. In each of 13 csises of atrial fibrillation examined while under the influence of digitalis, an increase in rate occurred following the administration of atropin (the dose usually given was 2 mg.). In all of these ca.<es in which the effect of atropin was studied both before antl after digitalis, the ma.ximuni rate after atropin in the digitalized heart was not equal to tiiat obtained before any digitalis was given ; in five of six eases this decrea.«e was exactly GO beats, and in one 72 beats. Atroj)in was given to 13 ca.ses witli normal mechanism lieforc and after the course of digitalis; in seven tliere was a decrease in the maximum e.<cape ranging from 4 to 32 beats; in Hiree there was an incrca.<e in the maximum of 3, 4 and 17 beats, res|)ectively ; three cases showed no escape after digitalis. TllK KfFE( T (IN THK Hl.iiOl) rHKSSlKK .Altiiough the digitalis ixidies profluce a characteristic rise of bifiod pressure in animals, the effect on the pressure in man is very variaiile. The subject has been recently reviewed and studied by Eggleston.' In 1(5 cases the blood pre.«sure was carefully followed: in 10 there was no appreciable change; in three the systolic increa.^ed without change in the diastolic: in two casi-s with high pressure the .systolic fell 3.") mm. and 30 mm., respectively, with a corresponding reduction in the diastolic of 10 mm. an<l 2.> mm.; in one the diastolic fell 2.J mm. while the systolic renniined unchanged. The conclusion is that the alteration in blood pressure is again an indirect digitalis effect which depends on the improvement in thi' circulation and is always in the direction of the optinuini pressure for the individual. ToxK Kkkkcts The manifest-atir)ns regarded as evidences of digitalis toxicity were all included in the alimentary disturbances nr cardiac irregidarities. From 24 tf> 3(5 hours In-fore actual nausea and vomiting <wcurred, many |)atients complained "f general malaise, often headache or of some indefinite and indescribable sensation of discomfort and usuallv refused food. Eggleston: Jour. Amor. Med. Assn.. 1917. LXIX. 951. Considering 20 cases, nausea occurred in 12 and vomiting in six of these; diarrlnea was encountere<l five times. In nearly all eases these disturbances disai)])eare(i promptly after discontinuance of the drug. In Xo. 355 miu.<ea aiul diarrhum persisted for fo.ir days. This was the only instance of anything that might be regarded as evidence of the so-called cumulative action if digitalis. The central origin of the nausea and vomiting i>.-oduced by digitalis has been established by the work of Ilatchar and Eggleston." In six cases it was necessary to discontinuo the digitalis becau.se of the onset of serious cardiac irregularities unaccompanied by alimentarv symptoms. DiGIT.VUS Irregil-vrities Digitalis " coui)ling," a familiar sign of excessive digitalis dosage, appeared twice in the series. The occurrence of premature beat^ at irregular int^-rvals was frequently seen, usually at the time of otlier evidences of toxicity. These ])rcnniture beats, an expression of heightened irritai)ility of the ventricular muscle, always disa|)peared after atropin. Sinus arrhytlunia <lue to digitalis occurred in two cases. In Xo. 334 (see Fig. ID) it disappeared |iromptIy after atropin, but returned and persisted, though gradually decreasing, for 10 days. In Xo. 37.J the arrhytlunia was not removed by atropin, although there was an escape of the pacennikcr (Fig. oD). Production of " jiuisus altcrnans," dcscrilicil by Mackenzie and others was not encountered. In one ca.se in which that condition was originally present the alternation disappcareii under digitalis (Fig. 2). ."Similar results have been reported by Wimlle.* In Xo. 342 after 25 c. c. of digitalis atrial tachycardia with irregular ventricular response and varying conduction time was present. .N'ornuii nirchanism was rcstoreij bv atropin (Fig. 3). That com|)lcte atrioventricular dissociation may occur iluring the administration of digitalis is well known. Christian '" has reviewed some of the literature and reported ca.ses. Hoi)inson and Wilson ' have shown that in cats with the vagi intact complete dissociation constantly occurs when 7.") per cent of the mininnim lethal ilose has liecn given ;.with the vagi cut. the effect on conduction is not constant. In two cases transient complete di.ssociation occurred, beside the case of atrial tachycardia with high-gradi- block previously mentioned. The production of dissociation by action on the iidiibitory mechanism is illustrated in Fig. 4, which shows in sequence, prolongation of the I'-R interval, dropped beats and dissociation. In these cases of di.ssociation atrr>|iin restored the normal mechanisu) and this persisted during the hour under examination in the laboratory and was still present at examination 12 hours later. That "e.sca[)e" from vagus a<'tion on the con<luction system may occur is illustrated in Fig. 5; tlu- I'-H interval had •Hatcher and Egglfston: Jour. I'harm. and Exp. Tlierap.. 1912. IV. 113. •Windle: Quart. Jour. Med., 1917, X. 274. "Christian: Arch. Int. Med.. 1915. XVI. 341. 134 [No. 339 lengthened from 0.12 to 0.22 sec, dropped beats were present and complete block was anticipated ; however, a record taken eight hours later showed the mechanism to be normal and the P-K interval 0.16 sec. Changes in the Electrocabdijgram Modification of the T-wave of the e^ jctrocardiogram by digitalis has been carefully studied 'jy Cohn and his coworkers." The following changes in tlie T-wave were observed in this study: Any degree of flattening of an upright or inverted wave until the isoelectric line was reached ; inversion of an upright wave ; reversion of an inverted wave ; the formation of a diphasic wave, either alone or in conjunction with any other change. The change in the wave continues throughout the administration of the drug so that its conformation varies from day to day with the amount given. Compare the T-waves in Figs. 1 and 3. These changes are attributed by Cohn to an alteration in the muscle balance, resulting in turn in an alteration of the relation of apex to base negativity. This action is for the most part on the myocardium itself. That the true digitalis effect may be masked by vagus stimulation is seen in the changes that frequently occur after atropin. The height or depth of a wave may be affected or reversal may occur, as in Fig. 3. These changes disappear with the action of atropin and the specific digitalis effect is again evident. In every case the first definite digitalis effect was a change in the T-wave. This was found by Cohn in his cases and Robinson and Wilson ' in their experimental study observed the first change to be a flattening or inversion of T, which occurred with 25 per cent of the lethal dose. A comparison of the T-wave changes produced by each of the tinctures used is interesting and points clearly to slow absorption of the first as the cause of its inefficiency. In No. 320 lowering of T, was observed after 16 c. c, definite inversion after 84: c. c. In the four remaining cases in which the first tincture was used an average of 34 c. c. was given before any definite change could be recognized. With the second tincture definite changes were recorded in most cases after 10 c. c. or less. In No. 371 Tj was lower after 5 c. c. ; in No. 368 Tj was definitely inverted after 10 c. c. Eecords were seldom taken between 10 and 20 c. c. and no attempt was made to establish the minimum amount that would produce a change. From this small series in which large doses were used so that changes in more than one wave were recorded simultaneously it is not possible to say which T usually changed first, but it did appear that T. is most frequently affected and undergoes the greatest change. The disappearance of the digitalis action may likewise be followed by changes in the T-wave which begin soon after the drug has been discontinued. The duration of the digitalis effect, as might be estimated by these changes, was not determined. The alteration in tlic P-wave seen in some of these cases has been considered elsewhere." In nine cases, 30 per cent of "Cohn, Fraser and Jamison: Jour. Exp. Med., 1915, XXI, 593. "Carter and Wedd: Arch. Int. Med., 1919, XXIII, 1. the series, the P-wave was affected; in eight of these the change occurred only in the third lead, and in one in both the second and third leads (Figs. 1 and 5). In five cases an originally inverted P was rendered upright by digitalis and in three of these the return to the original form was followed after the drug was discontinued. In four of the cases of this group a temporary reversion occurred after atropin. In four cases an originally upright wave was inverted by digitalis and in three of these the wave was reversed by atropin and remained upright, whereas in the fourth the inverted wave was upright 12 hours after the discontinuance of digitalis. Satisfactory explanations for these observations are wanting. There may be a rearrangement of atrial muscle fibers, but the response to atropin in both groups indicates greater vagus influence than in the case of the T-wave. Concerning the limiting of the effect to the third lead, it may be noted that this lead represents primarily the left side of the heart, and all but two of these cases clinically showed marked enlargement to the left, and in six the electrocardiogram was of the type characteristic of left ventricular preponderance. The occurrence of tlie U-wave as a component of tlie ventricular complex in the normal electrocardiogram is recognized. According to Lewis," it is not uncommon and is related to the early events of diastole. In the records of this laboratory it has seldom been seen. In one case (Fig. 6) a U summit appeared after 30 c. c. of digitalis had been given and continued throughout the remaining observations. It was not due to the appearance of a latent wave with a slower rate, for the rate when it was first seen was faster than the original, and it did not seem to be influenced by atropin. As the patient left the hospital, changes occurring after digitalis was discontinued could not be followed. In his text Sollman states that, in man, a-v conduction is constantly impaired and that this is an early and positive sign of digitalis action, and Cohn and Fraser " found changes ' in 12 patients studied by them, including four who had no heart lesion. According to AVhite and Sattler " " this impairment of conduction is practically entirely due to increased vagus tone " and they report that in every instance after digitalis in which delay in conduction amounted to more than 0.05 sec. atropin reduced the P-R interval to less than its original value. In six of 21 cases in this series there was no appreciable change in the P-R interval. Measurements were made with calipers and a hand lens, but are believed to be sufficiently accurate for clinical purposes. In not one of five cases in which the conduction time was prolonged 0.05 sec. or more did atropin restore the original, and in two cases in which complete dissociation occurred the P-R interval in the normal mechanism after atropin was longer than in the original (Fig. 4). In the case with atrial tachycardia and high-grade block the P-E interval after atropin was the same as the original. "Lewis: Clinical Electrocardiography, 1913, London. "Cohn and Fraser: Jour. Pharm. and Exp. Therap., 1913-14, V. 512. » White and Sattler: Jour. Exp. Med., 1916, XXIII, 613. THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919 r 1 1 t I R f [ [ [ I i > Ui V f THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY, 1919 PLATE XVII Fiii. 2 (Case 321). — A. on admission; B, after 102 c. c. of digitalis. HBn^iji^^i*^iiP^N*jii^i'^i*iFVfci^*'*^wMi^^^ IKWl^lll i:^ ^ -^ -a ^ ' ^ ' ^ mwii'liii mimitmiWjiMrmi] i owji^n "i -- "f vv;- ::" / V - ^".f'--= -f immm - ' -H:5E-i y^-mmAj'jm>^ Fig. 3 (Case 342). — A, on admission; B, after 12 c. c. of digitalis; C, after 25 c. c, atrial rate 216, ventricular rate 80; D. 30 min. after atropin; E. 1 hr. after atropin; F. 12 hrs. later. Fig. 4 (Case 351). Lead II.— A. on admission; B, after 24 c. c. of digitalis; C, after 72 c. c. ; D, after 96 c. c. ; E, after atropin. THE JOHNS HOPKINS HOSPITAL BULLETIN, MAY. 1919 PLATE XVIII rAiN>/VvV^'^i'N*s^/ /9 U¥«'w*'^*'^'w**^' " '***^* ^ ^ ^ W' * ***^ *» «>ii n »»»i^ '«M,^-^\V-*-**/-- s,,^^ TC 3> A. an. HMMM V«y^MHMMM«<MMMM« -rff Fig. 5 (Case 375).— .4. on admission; /}. aft. r nn c c of diK'iialis; C. 8 hrs. later: D. after 100 c. c. (a) ; after airopiu (b). 2)o. I I ^t^mmmi p^^^ ^^^-^^-A. S,0m^*m^-Si I I ^^,^,i0^f/m^Jf^^0^^ Kic. 7 (Case 354). Lead II.— .1. on admission: «, after 22 c. c. of digitalis: C. 19 lirs. later, after 29 c. c. (a) ; after atropin (b); /J. after 39 c. c. (a): after atropin (b). fl a. tr y'*S/*V Xy*-V S,,r^V H.V<-v atropin. di»!iUiM.> 1 .1 p . .111. I HI II. 1. 1 later. I May, 101!) I JOHNS HOPKINS HOSPITAL lULLETIN 135 Direct action on the conducting; tissue may be illustrated i)y Xo. 323: orijrinal P-R, 0.120; after digitalis, 0.213; altor atro])in, 0.163, and there was no escape of the pacemaker. In Xo. 27!) in which a lenirthening of 0.02 sec. occurred there was no shortening of conduction and no sinus escape after atropin. Also consider the I'-R intervals in Fig. 7. In otiior cases there was partial or complete reduction of the conduction time. The data ohtaincd tend to show that impairment of conduction by digitalis nuiy be due to either increased vagu-^ tone or to direct action on the conducting system, or to a combination of both, which is the usual mechanism in cases of pronounced action. Definite ini|)airmcnt of conduction was certainly not an early evidence of digitalis action, but a gradually progressive one, and an appreciable change in it* time relation .seemed comparable to the finding of Robinson and Wilson, that prolongation of conduction time occurred after 50 per cent of the lethal dose had been given. But few cases with an original conduction time of more than 0.18 sec. were studied. In Xo. 364, a referred patient, an original conduction time of 0.25 which had been increased to 0.29 by 12 c. c. of digitalis was restored completely by atropin. The possibility of escape from digitalis action on the conduction system has been mentioned (Fig. 5). Xo criterion was apparent by which a marked effect on conduction might be predicted and the conclusion reached is that of Cohn.* that any effect on conduction is a specific effect of the drug, a])art from any pre-e.xisting damage in the .system. Action ix Fibrill.\tiox .vxd Flutter There is sufficient satisfactory experimental evidence that digitalis produces its characteristic effects by acting centrallv in the medulla and locally on the heart muscle. The usual test for differentiating central and local action is the behavior after removal of vagus intluence, by section of the nerve or the use of atropin. That the various digitalis effects may l)e pro<luced in man through either mechanism alone or througli both simultaneously has been jiointed out when considerin": the specific digitalis actions. In 1871 Traube showed that digitalis slowing was due to (itimulation of the vagus center and this has been confirmed by many experimenters since that time. Cushny " has demonstrated that in the perfused mannnalian heart, in certain rare cases with normal mechanism in man and specially in atrial fibrillation in man, digitalis may slow the pul.<e inde|)endently of the inhibitory mechanism. Robinson and Draper" have shown in atrial fibrillation in man that mechanical stimulation of the right vagus nerve usually cau.i^ed marke<l slowing or stoppage of the ventricular rhythm and state that the ventricular pauses were apparently due to blocking of .stimuli from the atria. Ilirshfelder" found that in dogs with artificially induced fibrillation the heart could be markedly slowed "Cushny; Jour. Pharm. and Exp. Therap., 1918. XI, lO.S. "Robinson and Draper: Jour. Exp. Med.. 1911, XIV, 217. " Hirshfelder: Jour. Pharm. and Exp. Tlierap.. 1915, VI. 597 by digitalis and that tlie rapid arrhythmia promptly returned after paralysis of the vagi with atropin, and also that further .^lowing and com|)lete block could be i)roduced after the vagi liad been paralyzed, although the fibrillation continued. Commenting on this work, Cushny says: "But this is not the characteristic reaction in clinical fibrillation as he seems to suppose; the slowing in these cases is independent of tiie iidiibitory mechanism." In all cases of fibrillation under the inllucnce of digitalis to which atro|)in was given an increase in ventricular rate occurred. Similar results have been reported by Cushny " and by Mackenzie. The atria are seen to continue in fibrillation, so there is no functioning pacemaker. Hence the increased ventricular rate must result from an increase in the number of impulses ])ermitted to pass through the conducting tissues, and such an increase brought about by atropin implies a former depression of conduction by vagus tone. Tinit digitalis produces more marked slowing by the direct action on the mu,«cle of the fibri Hating heart no one would attempt to deny, but that the vagus center in the medulla, the usual site of action of the drug, should be ignored because of an altered condition of the mycx-ardium which is less obvious. That the decrease in the ma.ximum rate under atropin of the digitalized heart which was observed in 100 per cent of the fibrillating hearts and in 76 per cent of those with normal mcchaiiisni nniy be tjiken as a measure of the local action of the drug is seemingly a possible interpretation. From a compari.son of the reaction of the perfu.sed heart tfi digitalis with that of clinical fibrillation, Cushny concludes that the reaction so characteristic of fibrillation is due not to the fibrillation itself but to a more fundamental factor, malnutrition. Furthermore, it is conceivai)le that i)ecau.«e of the faulty circulation of the fibrillating heart an accumulation of cellular metal)olites may result, by virtue of an increased H-ion concentration in the jiroduction of a more highly glucosidolytic medium, and that because of increased destruction, there may result an increa.sed capacity for digitalis bodies. Similar action may jm.ssibly occur in other tissues also and may constitute the mechanism by which many individuals with .severe myocardial lesions can take large amounts nf digitalis before toxic symptoms a])])ear. The action of digitalis in atrial fiulter, a condition similar to fibrillation, is both central and local (Figs. 7 and 8). In four cases of flutter examined the administration of atropin reduced the block to 2:1. Unfortunately atropin was not given after the change to fibrillation, but in Xo. 354 the normal mechanism jircsent after the last flutter record shows sinus cscajK' and partial n'ductidn of the conduction time. .SUMMAKY Careful observations on the action of tincture of digitalis have been made in many j)atients. It wa.s soon apparent that successive tinctures supplied to the hospital wards showed marked variation in their efficiency. Two biologically stand " Cushny. Marrls and Silberg: Heart. 1912, IV, 33. 136 [No. 339 ardized tinctures of approximately theoretical strength were studied and it appeared that the ineificiency of one was due to failure of prompt absorption from the alimentary canal, as was indicated by the larger amount necessary to produce a change in the T-wave, the earliest demonstrable digitalis effect. Daily doses averaging 10 c. c. were given and continued imtil alimentary disturbances or abnormalities in the cardiac mechanism appeared. In no case was there any ill effect attributable to digitalis and there were no evidences of the so-called cumulative action. The toxic dosage showed marked individiial variation, from 20 c. c. to 100 c. c. The earliest signs of toxicity were slight nausea and premature beats. It is believed to be a perfectly safe procedure and one which will promptly bring about the expected benefits of digitalis to begin with an initial dose of 5 c. c. of tincture and to continue with 8 or 10 c. c. daily until signs of toxicity appear or until clinical improvement warrants discontinuing the drug. The various changes in the electrocardiogram have been considered. Of these alteration in the T-wave was the earliest and most constant. Modifications of the P-wave in the third lead in about one-third of the cases is noteworthy. In one case digitalis appeared to be responsible for the appearance of a U summit. Definite prolongation of the P-E interval, indicating increased conduction time, was seen in 80 per cent of the cases. In two cases complete dissociation occurred and in one atrial tachycardia with high-grade block, and in all these normal mechanism was promptly restored by atropin. From a consideration of the effect of atropin on the pacemaker, the ventricular response and the conduction time, it is believed that in all cases the action of digitalis is both central, in the medulla, and local, in the myocardium, with relatively greater local action in atrial fibrillation. Exception is taken to the statement of Cushny that in fibrillation there is no digitalis action through the inhibitory mechanism, and it is suggested that the decrease of maximum rate after atropin of the digitalized heart may be taken as a measure of the local action of digitalis on the myocardium. In the series studied were cases with all possible valvular defects, all grades of decompensation, renal lesions of varying degrees of soveritv', systolic blood pressures ranging from 90 mm. to 230 mm. and almost all of the recognized types of myocardial involvement, including cases of intraventricular block, bimdle branch block and complete dissociation, and there was not found any clinical entity which might be said to constitute a contraindication to the use of digitalis. NOTES ON NEW BOOKS The Principles of Acidosis and Clitiical Methods for Its Study. By Andrew Watsox Sellards, Associate In Harvard Medical School. {Harvard University Press. 1917.) This work of some 111 pages exclusive of the bibliography deals with acidosis with a terseness of style and elimination of unnecessary detail which make it very interesting as well as valuable to the physician and student. There is careful consideration of the various theories concerning acidosis and the evidence in favor of each is thoroughly discussed. The first three chapters are given to the consideration of the chemistry of acids &nd bases, their metabolism in the human body, and methods of diagnosing pathological alterations in the mechanism. Particular attention is paid to the exact importance of change in the alkalinity of the blood and the physiology of the kidney in adjusting its excretion to these changes. In the next chapter the reaction of the body to sodium bicarbonate in health and disease is taken up. The value of observing this reaction is brought out. In this chapter also a very valuable test for the changes in the alkalinity of the blood is described in full. . Succeeding sections deal with the occurrence of acidosis and a definition of the condition. The determination of a definition is most timely, since there is considerable variance among writers as to the exact meaning of the term " acidosis." The part dealing with therapy is very suggestive, although no definite working guide is given. Nevertheless, from a discussion of cases and results sufficient data are given to enable the practitioner to make immediate use of the method described by the author. By no means the least important part of the work is that contained in the appendix, in which necessary laboratory methods are described fully and clearly. Definite instructions for carrying out the author's test for acidosis are given explicitly. There is also a very helpful method described for determining the patient's tolerance for sodium bicarbonate. A very important feature of the book is the discussion of the pathological processes in the acidosis of diabetes, nephritis, and Asiatic cholera, with a differentiation of the steps in each. It is perhaps to be regretted that the writer did not take up the more intricate problems of protein, carbohydrate, and fat metabolism with the relation of each to acidosis, or that other acetonurias were not considered in the same thorough manner. But what the book may lack in tliis respect it gains in being concise, containing no confusing details, and being available for any one wltn a rudimentary knowledge of biochemistry and physiology. It is an important contribution both from the standpoint of information contained and also from the suggestions made concerning other problems in tlie same field which offer rich opportunity for study. H. M. W. Trench Fever: Report of Commission Medical Research Committee, American Red Cross. Prepared for publication by Richard P. Strong. (Printed for the American Red Cross Society at the Oxford University Press ty Frederick Hall, Printer to the University, 191S.) Members of Commission: Richard P. Strong, Major, M. R. C, Assistant Director Division Laboratories and Infectious Diseases. In charge Subdivision Infectious Diseases, A. E. F. Homer F. Swift, Major, M. R. C, Senior Medical Officer, No. 1 United States Army General Hospital. B. E. F. Eugene L. Opie, Major. M. R. C, Pathologist, United States Army Base Hospital No. 21, B. E. F. Ward J. Macneal, Captain, M. R. C. Head Department Bacteriology, Central Medical Department Laboratory, A. E. F. Walter Baetjer, Captain. M. R. C, in charge Clinical Laboratory, United States Army Base Hospital No. 18, A. E. F. A. M. Pappenheimer. Captain, M. R. C, Pathologist, No. 1. United States Army General Hospital. B. E. F. A. D. Peacock, Captain, R. A. M, C. (T.). 2d London Sanitary Co. (Entomologist). (Subsequently attached.) May, IDli)] 137 David Rapport, first Lieutenant, M. C, National Guard, A. E. F. Major Richard P. Strong, M. R. C, In liis report on trench fever, has given another proof of the brilliant work which the public is now learning to expect from the army medical corps: and the investigations he reports in regard to trench fever should rank with their model, the classic studies of Reed and his colleagues on the method of transmission of yellow fever. The fact that during 1916 and 1917 no other infectious disease caused so much sickness among the soldiers in France as did trench fever, and its great prevalence at Salonica, in Italy and in Mesopotamia, made it of primary importance. To ascertain the method of its transmission would enable the authorities to take proper preventive measures, and thus much could be done to minimize an enormous wastage among the fighting forces. Accordingly. Dr. Strong, in October, 1917, was selected by the Medical Research Committee of the American Red Cross to take charge of the work ot a special Trench Fever Committee. From that time the committee conferred with the British Army and medical authorities, who were also studying the problem, with the result that in February, 1918, experiments on a group of 82 selected volunteers from the United States Army were commence<i. The work was carried on at a stationary hospital of the I3ritish Expeditionary Force in France, sufficiently near to the front line to insure the study of trench fever cases early in their course. As the spring offensive was expected in two months' time, Uie workers had only this short period to investigate the problem before them. There resulted a marvel of coordinated research, which required simultaneous experimentation along many closely associated lines, each modifying the others as the work proceeded. The clinical, bacteriological, serological, louse investigation, blood inoculation and other studies all contributed their part in completing the work, which was reported as it developed to the British Army medical officers, who were also at work on trench fever. In all a total of 103 different human experiments were carried on in the study of trench fever and its cause, and in these the disease itself was produced experimentally 62 times in different ways. Too much cannot be said in praise of the soldiers of the United States Army who offered themselves so heroically in order to make possible this splendid medical study. The results of this masterly piece of work are best summarized in Dr. Strong's own words: "The most Important facts which have been demonstrated by our investigations are: "1. That trench fever is a specific, infectious disease: that it is not a modified form of typhoid or paratyphoid fever, and is not related, from an etiological standpoint, to these diseases. "2. That the organism causing the disease is a resistant, filterable virus. " 3. That the virus causing trench fever is present particularly in the plasma of the blood of trench fever cases, and that such plasma will produce the disease on inoculation Into healthy individuals. " 4. That the disease Is transmitted naturally by the louse Prdivulus humanus. Linn., var. rorpohs. and that this Is the important and common means of transmission. That the louse may transmit the dieease by its bite alone, the usual manner of infection, or the disease may be produced artificially by scarifying the skin and rubbing in a small amount of the infected louse excrement. " 5. That a man may be entirely free from lice at the time he develops trench fever, the louse that Infected him having left him some time previously as his host, and that the louse neea only remain upon the Individual for a short period of time In order to infect him. " 6. That the virus of trench fever is also sometimes present in the urine of trench fever cases, and occasionally In the sputum. and that the disease may be produced in man by the introduction of the virus in the urine or sputum through the scarified or otherwise abraded skin. "7. That since the urine and sometimes the sputum of trench lever patients are infective, these should be sterilized in order to avoid the possibility of accidental infection from them. " 8. That in order to prevent trench fever or limit its spread, and thus save manpower for the armies, greater efforts must be made to keep soldiers in general from infestation with lice. "On account of the great importance of the matter, the following sanitary regulations are advised: " Exceedingly great care should be taken to disinfect completely all patients as soon as practicable, and particularly upon their entering the hospital. Patients on entrance should be carefully bathed, and subsequently sponged with alcohol. Their clothing and blankets should be removed, and. whether or not lice or ova are found upon them, should be carefully sterilized by moist heat at a temperature not below 70° Centigrade for half an hour, since it is possible for the virus to be still present on the clothing. It should be borne in mind that a man with trench fever may be entirely free from lice at the time that he develops symptoms of the disease. Trench fever patients should at all times be carefully protected from louse Infestation, and inspection of them for lice should be made daily. They should be treated in separate wards. As the urine contains the virus and is infective, It should be sterilized durins the active stages of the disease. Sputum cups should be provided for patients, and any expectorated sputum and saliva from tliom sterilized. Officers should regard the systematic destruction of lice as one of the most urgent of their duties, and shotild exercise every effort to prevent louse infestation among soldiers and to see that any of them Infested with lice are promptly disinfected and their clothing sterilized." He further discusses in some detail the nature of the experiments above referred to, with special reference to tlie transmission of the disease, and points out that tlie incubation period of trench fever, when studied experimentally, was shown to be from 14 to 38 days, depending on the dosage and other factors. No reliance, however, can be placed on a study of the apparent incubation period in uncontrolled cases, naturally produced anions the troops. The practical value of these incubation period studies lies In the fact that it may be from 10 to 23 days after the last bite by an infected louse before a man will develop trench fever. A man may be quite free from lice at the time of the outset of the symptoms of the disease, and. although a sufferer himself, he is of no danger to others, unless he is in a louse-infected community, so long as his urine and sputum are carefully sterilize<l. The remainder of the book contains a careful and systematic detail of the numerous experiments which were the foundation of these conclusions. They enable the writer to examine the evidence and to decide upon the justice of tfie conclusions formulated by the commission. The work is most creditable to scientific medicine, and is a fresh example of what can be done by the association of a number of observers under the leadership of a competent and experienced head. Similar problems are existing throughout the world, and the need of equally coordinated investigations Is pressing. G. H. W. The Third Orrat Plague. By John H. Stokj^, M. D. Cloth$1.50. (Philadelphia: W. II. Saunders Company, 1!>1~.)

Stokes' essay Is a most timely one. This book is Intended primarily to enlighten the lay mind on the ever-Important topic of syphilis. It fulfills more than the author's purpose, for we believe any individual with medical training can profit by a thorough study of it.

The history, nature and course of syphilis; the blood test and treatment; the cure, hereditary aspects, transmission and hygiene

338

[No. 339

of this ever-Increasing plague — so aptly termed — are sketched in a lively, virile, and Intelligible style, and best of all In a most understandable manner.

In the chapter on " Mental Attitudes in Their Relation to Syphilis," the moral and personal prophylaxis and the public effort against syphilis are approached and handled with a fairminded conception of what they entail. A very brief and unprejudiced expose of the pros and cons of this ever-burning problem are given with a circumspection and Judgment which entitle the author to a most respectful hearing.

The book, therefore, is decidedly illuminating; it answers so satisfactorily many of the every-day questions regarding the handling of this, one of our greatest and most serious medical liabilities. It is attractively presented; the style is easy and clear, and the author's attitude on the various moral, social and economic aspects of syphilis are very sane and commendable.

I. R. P.

Syphilis and Public Health. By Edvvabd B. Veddab, M. D. Cloth $2.25. (Philadelphia and New York: Lea and Febiger, lOlS.) Following an introduction on the " Importance of Syphilis in Relation to Public Health," together with statistics of mortality, and after a discussion of syphilis as a sanitary problem, the book is divided into four chapters: 1. Prevalence. 2. Sources of Infection and Method of Transmission. 3. Personal Prophylaxis. 4. Public Health Measures. An appendix is included describing the technic of the Wassermann test of the blood serum; and. In addition, several sections, including the " Control of Syphilis in the Army." " Methods Employed In Some Cities," etc. This book is a real contribution to the literature of syphilis. Statistics are frequently a " necessary evil " and always open to criticism, but the value of figures in a book of this scope is essential, and therefore beyond the domain of a critical review. Veddar's discussion of facts and of figures is supplemented by a splendid bibliography, especially on the methods of transmission. This latter chapter is worthy of careful reading. The presentation of the pros and cons of prophylaxis, as well as the discussion on the value of chemical methods of prevention, together with a history of the use of calomel ointment, are splendid features. The author's views on notification, treatment, and especially on the sociological aspects, are rational and worthy of commendation. This handy volume is well written and well typed. We would recommend it most warmly to the notice of all individuals interested in the medical and (consequently) sociological field of syphilology. I. R. P. Diseases of the Skin., By Mllton B. Haktzell, M. D. Cloth$7.00. (Philadelphia: J. B. Lippincott Company, 1917.)

With the appearance of another text-book on dermatology, the reviewer naturally looks, among other things, for something new or for a different presentation of facts already known. Dr. Hartzell's book is, in this connection, both satisfying and disappointing.

The subject is handled by the author in the manner usually followed by the every-day text-book. Nothing new is suggested or proposed. One finds the invariable divisions of anatomy, symptomatology, general etiology, etc., followed by the customary division of the dermatoses, according to anatomic characters, hyperaemias, inflammations, hjemorrhages, new growths, neuroses, etc.

The size of the book is adequate, but it is neither a short resume for the student nor an encyclopedic reference treatise tor the specialist. Nevertheless, it should prove to be very profitable read

ing for the general practitioner who is not too deeply concerned with the finer distinctions of diagnosis, pathology and treatment. If considered in this light one finds the book sufficient, and although it presents nothing startling or new in the consideration of general etiology and treatment, it deserves credit for voicing the author's personal views on many subjects. It is unfortunate that the author, after attributing so much well-deserved credit to X-ray therapy, has not incorporated a brief section on this ever-increasing and important therapeutic agent, and also on radium therapy.

With the exception of several worthless colored plates, the photographs and plates are notably splendid; and the photomicrographs in particular — a genuine relief from the almost diagrammatic sketches in the older treatises — brook no criticism. The remarks on etiology and pathology are eminently concise, rational and clear; they are adequately stressed.

There are other outstanding features: the author has avoided much needless discussion; in tact, his somewhat didactic method of presentation is a real advantage; but it is questionable whether the omission of at least a selected bibliography enhances the value of the book. He has certainly done a service in clarifying our knowledge of some dermatoses usually relegated to an obscure grouping. The other brief chapter on sarcoids is ample proof.

It would lead too far to take up the various chapters in critical review. Although the discussion of syphilis appears to be rather scanty, and the pathology somewhat briefiy discussed, there are excellent chapters on ringworm and on carcinoma.

The few typographical errors will surely be remedied, together with correction of the spelling of some proper names. The book, therefore, should appeal primarily to the general practitioner; next, to the specialist for a brief review; and lastly, only to the student who, without delving too far, wishes to read and to learn.

I. R. P.

Radio Diagnosis of Pleuro-Pulmonary Affections. By F. Baejon, Medicin des Hopitaux de Lyon. Translated by James A. HoNEij, M. D., Assistant Professor of Medicine in charge of Radiography, Yale Medical School. (Yale University Press.)

This volume Is the second work published by the Yale University Press on the Williams Memorial Publication Fund — a gift made to Yale University by George C. F. Williams, M. D., a member of the class of 1S7S, Yale School of Medicine.

Although this translation is a little late in appearing, it arrives at a time when it is most needed. Nothing concerning the X-ray examination of the thorax as yet published has been so thorough as this book. The fluoroscopic examination at the expense of the plate method of study of lesions of the thorax might be mentioned as one of its few weak points.

Frequent reference to other French Investigators exclusive of all other nationalities is made and. although the book may have been intended only tor use by our French colleagues, it nevertheless must create a little embarrassment to other notables who have so earnestly tried — and, it may be added, not in vain — to elaborate this valuable asset to clinical diagnosis.

The book is divided into five parts with many chapters subdividing each part:

Part I. The Fluoroscopic Appearance of the Normal Chest Shadows when Viewed from All Different Angles.

Part II. The Study of the Pleur».

All the different pathological states of the pleurte are taken up somewhat in detail. Especially interesting is the dissertation on the influences in the production of the curve of Damoiseau. The second chapter deals with circumscribed and encysted pleurisy and is especially clear and well illustrated. The paragraphs dealing with pleurisy of the hilus region with case reports and illus

May, 1919]

139

trations is a genuine addition to tlie chapter. The pages devoted to pneumothorax are well illustrated, interesting and instructive.

Part III. Foreign Bodies in the Bronchi.

The metallic foreign bodies and foodstuffs are discussed in detail and the possibility of late and serious pulmonary complications resulting from failure to diagnose them is worthy of mention. The X-ray findings in acute and chronic bronchitis, bronchial stenosis and bronchial dilatation are also instructive. Tracheobronchial adenopathy is next studied and a very acceptable and descriptive explanation is given. The various groups of glands are discussed and the best means for observing them on the screen are pointed out. Emphasis is laid upon the fact that too litile attention is paid to the study of adenopathy. Illustrations and diaphragmatic drawings also help to complete this part of the work.

Part IV. The Lungs.

The first chapter deals with the fluoroscopic appearances in acute primary and secondary congestion, passive congestion and oedemas. Infarction, its appearance and differentiation from other pulmonary sliadows, is particularly clear.

The remaining chapters of Part IV, which are the longest of any, are given over to the study of acute infectious pulmonary processes, chronic pulmonary processes, pulmonary tuberculosis and lung tumors.

Pulmonary tuberculosis is considered under three distinct groups; (1. Pulmonary tuberculosis without clinical or stethoscopic signs. ( Latent forms. ) b. Pulmonary tuberculosis with positive clinical but negative, doubtful or very limited stethoscopic signs. (Early Forms. Period of incubation. Miliary.) c. Advanced pulmonary tuberculosis with evident clinical and stethoscopic signs. ( Chronic pulmonary tuberculosis with its many forms. )

Nothing new in the way of diagnosis is offered, but the appearance, development of complications and their appearance fluoroscoplcally is well pointed out and the total absence of fanaticism certainly adds materially to tliis greatly discussed topic, the X-ray diagnosis of pulmonary tuberculosis.

Lung tumors complete this part of the book and, aside from mentioning the good illustrations, little need be said.

Part V ends the l)ook and deals with the penetrating wounds of the thorax by war projectiles. A brief clinical and radiologic

entity Is given which proves interesting, but certainly not comprehensive enough from a clinical standpoint to be of any material aid to the surgeon or internist in determining the course of procedure in these grave cases. The points discussed in diagnosis and complications are interesting and instructive, but the problems in the localization and extraction of these projectiles are still unanswered. c. A. W.

liointgen Tahnic (Diaffiiostic). By Noknian C. Prime, M. D. St. Louis: C. T. ilosby i( Co.. UU7.)

This book of 140 pages deals principally with the technic employed In making X-ray plates of different parts of the body.

The descriptive technic is mainly good, but one cannot help feeling that some of the manufacturers of X-ray accessories have used undue influence in advocating their particular products.

In view of the increasing popularity of technicians for the performance of technical duties in an X-ray laboratory the book might have some usefulness in this phase of the work, but when this has been said, no further need for it can be found.

C. A. W.

ll'or Neuroses. By John T. M.mCihkv, M. D. With a preface by W. H. R. Ri\TERs, M. D. (Lond.). 132 pages. (Camhrirlgr: At The Universit)/ Press. H'lS.)

This book consists of observations originally published in the P.ii/chintrie BuUctiii of the New York State Hospitals, and records the author's conclusions after a brief visit to Great Britain in 1917.

The point of view adopted, with the emphasis on the conflict between the different instincts, that of self-preservation and that of loyalty to the group, and on the adaptive role played by the symptoms in the neuroses, is now so widely accepted as not to require special elaboration. The different groups of neuroses, those with predominance of anxiety symptoms, those with predominance of physical synii)toms, those where cardiac symptoms are specially in evidence, etc., are discussed in a clear and interesting manner. In special chapters the questions of etiolog>' and of treatment are succinctly dealt with.

C. M. C.

.Veir Jersey. Forty-First Annual Report of the Department of Health of the State of New Jersey, 1917. 1918. 8'. 381 pages. State Gazette Publishing Company. Printers. Trenton, N. J.

Persei-uiions of th'- <;riil;s in Turk-ii t<inrr the Beginning of the European ^\^nr. Translated from official Greek documents by Carroll N. Brown, Ph. D., and Theodore P. Ion. D. C. L. 1918. %'. 72 pages. Published for the American Hellenic Society by Oxford University Press, American Branch. New York City.

Miehigan State Board of Health. Forty-Fourth and Forty-Fifth Annual Reports of the Secretary of the State Board of Health of the State of Michigan for the years ending June 30, 1916. and June 30, 1917. 1917. 8 . 243 pages. Wynkoop Hallenbeck Crawford Company, Lansing, Mich.

Amputation Slumps. Their Care and After Treatment. By G. Martin Huggins, F. R. C. S. Oxford War Primers. 1918. 16 . 228 pages. Henry Frowde and Hodder & Stoughton, Oxford University Press. London.

Bipp Treatment of War Wounds. By Rutherford Morison. Oxford War Primers. 1918. 16°. 72 pages. Henry Frowde and Hodder & Stoughton, Oxford University Press, London.

Xursing Terhnir. By Mary C. Wheeler, R. N. 32 specially prepared illustrations under personal supervision of the author. 11918.] 16°. 265 pages. J. B. Lippincott Company, Philadelphia and London.

The Essentials of Materia Mediea and Therapeutiea for Xurses. By John Foote, M. D. Third edition, revised, enlarged and reset. Llppincotfs Nursing Manuals. 11918.] 8°. 310 pages. J. B. Lippincott Company, Philadelphia and London.

I nited States. Department of Commcree, Bureau of the Census. Sam L. Rogers Director. Deaf-mutes in the United States. Analysis of the Census of 1910, with Summary of State Laws Relative to the Deaf as of January 1, 1918. 4°. 221 pages. Government Printing Office. Washington.

The Indian Opi ration of Couehing for Catarart. Incorporating the Hunterian Lectures delivered l)efore the Royal College of Surgeons of England on February 19 and 21, 1917. By Robert Henry Elliot, M. D., B. S. (Lond.), Sc. D. (Edin.), F. R. C. S. (Eng. ). etc.. Lieut. Colonel I. M. S. (retired). With 4.1 illustrations. 1918. 8°. 94 pages. Paul B. Hoeber, New York.

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Diseases of the Male Urethra, Incluciing Impotence and Sterility. By Irvin S. Koll, B. S., M. D., F. A. C. S. Illustrated. 1918. 8°. 151 pages. W. B. Saunders Company, Philadelphia and London.

Clinical Diagnosis. A Manual of Laboratory Methods. By James Campbell Todd, Ph. B., M. D. Illustrated. Fourth edition, revised and reset. 191S. 12°. 687 pages. W. B. Saunders Company, Philadelphia and London.

International Clinics. A Quarterly of Illustrated Clinical Lectures and Especiplly Prepared Original Articles. By leading members of the medical profession throughout the world. Edited by H. R. M. Landis, M. D. Volume II. Twenty-eighth series, 1918. 8°. 286 pages. J. B. Lippincott Company, Philadelphia and London.

The Harvey Lectures. Delivered under the Auspices of the Harvey Society of New York, 1916-1917. By Prof. J. S. Haldane, Dr.

F. M. Allen, Dr. Paul A. Lewis, Prof. H. H. Donaldson, Prof.

E. V. McCollum, Prof. J. W. Jobling, Prof. John R. Murlin, Prof. F. W. Peabody, Prof. W. H. Howell. Series XII. 1918. 8°. 323 pages. J. B. Lippincott Company, Philadelphia and London.

The Hodgen Wire Cradle Extension Suspension Splint. The Exemplification of this Splint with Other Helpful Appliances in the Treatment of Fractures and Wounds of the Extremities and Its Application in Both Civil and War practice. By Frank

G. Nifong, M. D., F. A. C. S. With an Introduction by Harvey G. Mudd, M. D., F. A. C. S. With 124 illustrations. 1918. 8°. 162 pages. C. V. Mosby Company, St. Louis.

A Treatise on Cystoscopy and Urethroscopy. By Dr. Georges Luys. Translated and edited with additions by Abr. L. Wolbarst, M. D. With 217 figures in the text and 24 chromotypographic plates outside the text, including 76 drawings from original water colors. 1918. S°. 386 pages. C V. Mosby Company, St. Louis.

A Manual of Otology. By Gorham Bacon, A. B., F. A. C. S., assisted by Truman Laurance Saunders, A. B., M. D. Seventh edition, revised and enlarged. With 204 illustrations and two plates. 1918. 12°. 583 pages. Lea & Febiger, New York and Philadelphia.

Botulism. A clinical and Experimental Study. By Ernest C. Dickson, M. D. Monograph No. 8. 1918. 4°. 117 pages. Rockefeller Institute for Medical Research, New York.

University of Michigan. Transactions of the Clinical Society, October, 1916-October, 1917. Volume VIII. Edited by the Secretary-Treasurer. 1917. 8°. 146 pages. University Hospital, Ann Arbor, Michigan.

University of Michigan. Contributions from the Department of Obstetrics and Gynecology. Volume IV, 1915-1918. 4°. Ann Arbor, Michigan.

Neurological Clinics. Exercises in the Diagnosis of Diseases of the Nervous System Given at the Neurological Institute, New York, by the Staff of the First Division. Edited by Joseph Collins, M. D. 1918. 8°. 271 pages. Paul-B. Hoeber, New Y'ork.

Food Primer for the Home. Compiled by Lucy H. Glllett. 1918. 8°. 19 pages. Bureau of Food Supply, Association for Improving the Condition of the Poor, New York.

Clinical Disoj-ders of the Heart Beat. By Thomas Lewis. M. D.,

F. R. S., D. Sc, F. R. C. P. [Fourth edition.] 1918. 8\ 120 pages. Paul B. Hoeber, New York.

The Medical Clinics of Xorth America. Vol. 1. No. 6. May. 1918. 8°. W. B. Saunders Company, Philadelphia and London.

The Action of Muscles. Including Muscle Rest and Muscle Reeducation. By William Colin Mackenzie M. D., F. R. C. S., P. R. S. (Edin.). With 99 illustrations. 1918. S\ 267 pages. Paul B. Hoeber, New York.

Symptoms and Their Interpretation. By James Mackenzie, M. D., LL. D. [Aber. and Edin.] Third edition. 1918. 8°. 318 pages. Paul B. Hoeber, New York.

Naval Hygiene. By James Chambers Pryor, A. M., M. D. Published with approval of the Surgeon General, United States Navy and by permission of the Navy Department. With 153 illustrations. 1918. 12°. 507 pages. P. Blakiston's Son & Co., Philadelphia.

The Wassermann Test. By Charles F. Craig, A. M. (Hon.), M. D. (Yale). Published with authority of the Surgeon General, United States Army. Illustrated with colored plates, halftone plates, and 57 tables. 1918. 8°. 239 pages. C. V. Mosby Company, St. Louis.

Essentials of Dietetics. A Text-Book for Nurses. By Maude A. Perry, B. S. 1918. 12°. 159 pages. C. V. Mosby Company, St. Louis.

Concerning Some Headaches and Eye Disorders of Nasal Origin. By Greenfield Sluder, M. D. With 115 illustrations. 1918. 8°. 272 pages. C. V. Mosby Company, St. Louis.

War Surgery of the Abdomen. By Cuthbert Wallace, C. M. G., F. R. C. S. (Eng.), M. B., B. S. (Lond.). With 26 illustrations. 1918. 8°. 152 pages. P. Blakiston's Son & Co., Philadelphia.

La Suspension dans le Traitement des Fractures. Par P. Desfosses et Charles Robert. Preface de M. Pierre Duval. 1918. 12°. 172 pages. Masson et Cie, Paris.

Surgical Applied Anatomy. By Sir Frederick Treves, Bart., G. C. V. O., C. B., LL. D., F. R. C. S. (Eng.). Seventh edition, revised by Arthur Keith, M. D., LL. D. (Aber.), F. R. C. S. (Eng.), F. R. S., and W. Colin Mackenzie, M. D. (Melb.), F. R. C. S. (Edin.), F. R. S. E. Illustrated with 153 figures, including 74 in color. [1917.] 16°. 702 pages. Lea & Febiger. Philadelphia and New York.

A Text-Book of Physiology For Nurses. By William Gay Christian, M. D., and Charles C. Haskell, M. D. Illustrated. 1918. 12°. 168 pages. C. V. Mosby Company, St. Louis.

Surgical and War Nursing. By A. H. Barkley, M. D. (Hon.), M. C, P. A. C. S. With 79 illustrations. 1918. 12°. 208 pages. C. V. Mosby Company, St. Louis.

Hygiene for Nurses. By Nolie Mumey, M. D. With 75 illustrations. 1918. 12°. 160 pages. C. V. Mosby Company, St. Louis.

Nursing in Diseases of Children. By Carl G. Leo-Wolf. M. D. With 72 illustrations. 1918. 12°. 314 pages. C. V. Mosby Company, St. Louis.

Gymnastic Treatment for Joint and Muscle Disabilities. By Brevet Col. H. E. Deane, R. A. M. C. With preface by Temp. Colonel A. Carless, Army Medical Service, and by Brevet Lieut. Col. F. W. Mott, P. R. A. M. (T.). 1918. 12°. 146 pages. Henry Frowde and Hodder & Stoughton, London. (Oxford University Press, American Branch, New Y'ork.)

Contribution to the Pharmacology of Opium. 1915-1918. By Dr. David I Macht, Baltimore, 1918.

Metropolitan Asylums Board. Annual Report for the Y'ear 1917. (20th year of issue.) 1918. 8°. 57 pages. London.

Hygiene of the Eye. By Wm. Campbell Posey, A. B., M. D. 120 illustrations. 1918. 8°. 344 pages. J. B. Lippincott Company, Philadelphia and London.

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Neuropsychiatry and the War. A Bibliography with Abstracts, Prepared by Mabel Webster Brown, Edited by Frankwood E. Williams. M. D. 1918. S". 292 pages. War Work Conmiittee, The National Committee for Mental Hygiene, Inc., New York City.

The Medical Association of the Isthmian Canal Zone. Proceedings of the Medical Association of the Isthmian Canal Zone. Vol. X, Part I, January to June. 1917. 1918, 8'. 149 pages. Published by the Health Department, The Panama Canal. Panama Canal Press, Mount Hope, C. Z.

Public Health Reports. Issued weekly by the United States Public Health Service, containing information of the current prevalence of disease, the occurrence of epidemics, sanitary legislation, and related subjects. Vol. 32, Part I, January-June,

1917. 1918. S'. 1074 pages. Government Printing Office, Washington.

The Surgery of Oral Diseases and ilalformations. Their Diagnosis and Treatment. By George Van Ingen Brown, D. D. S., M. D., C. M.. F. A. C. S. Third edition, with 570 engravings and 20 plates, and a selected list of examination questions.

1918. 8°. 734 pages. Lea & Febiger, Philadelphia- and New York.

Anatomy of the Human Body. By Henry Gray. F. R. S. Twentieth edition, thoroughly revised and re-edited by Warren H. Lewis, B. S., M. D. Illustrated with 1247 engravings. 1918. 4°. 1396 pages. Lea & Febiger, Philadelphia and New York.

Oenilo-Urinary Diseases and Syphilis. By Henry H. Morton, M. D.. P. A. C. S. Fourth edition, revised and enlarged, with 330 illustrations and 36 full-page colored plates. 1918. 8'. S07 pages. C. V. Mosby Company, St. Louis.

Ah Introduction to the Mammalian Dentition. By T. Wingate Todd, M. B., Ch. B. (Mane), F. R. C. S. (Eng.), Captain, Canadian Army Medical Corps. With 100 illustrations. 191S. 8°. 290 pages. C. V. Mosby Company, St. Louis.

Radio-Diagnosis of Pleuro-Pulmonary .Iffertions. By F. Barjon. Translated by Jam&s A. Honeij, M. D. 1918. 8°. 183 paws. Yale University Press, New Haven; Humphrey Milford. London.

Dispensaries. Their Management and Development. A book for Administrators, Public Health Workers, and All Interested In Better Medical Service for the People. By Michael M. Davis, Jr., Ph. D., and Andrew R. Warner, M. D. 1918. 8'. 438 pages. Macmillan Company. New York.

The Diseases of Infaney and Childhood. Designed for the use of Students and Practitioners of Medicine. By Henry Koplik. M. D. Fourth edition, revised and enlarged, Illustrated with 239 engravings and 2.t plates in color and monochrome. 1918. 8'. 928 pages. Loa & Febiger, Philadelphia and New York.

Roentgen Diagnosis of Diseases of the Head. By Dr. Arthur Schiiller. Authorized translation by Fred F. Stocking, M. D., M. R. C. With a foreword by Ernest Sachs, M. D. Approved for publication by the Surgeon General of the United States Army. 1918. 8'. 305 pages. C. V. Mosby Company. St. Louis.

The Human Skeleton. An Interpretation. By Herbert Eugene Walter. With 175 Illustrations. 1918. 12'. 214 pages. Mac millan Company, New York.

Abstracts of War Surgery. An Abstract of the War Literature of General Surgery that has been Published since the Declaration of War in 1914. Prepared by the Division of Surgery. Surgeon General'.s Office. 1918. 8'. 434 pages, c V .Mn.-^hy Company, St. Louis.

Engliah, French, Italian. Medical Vocabulary. By Joseph Marie. 1918. 24." 112 pages. P. Blakiston's Son & Co., Philadelphia.

Text-Book of .Anatomy and Physiology for Nurses. By Diana Clifford Kimber and Carolyn E. Gray, B. So. (Columbia University), U. N. Fifth edition, revised. 1918. 8°. 527 pages. Macmillan Company, New York.

Vaccines and Sera, Their Clinical Value in Military and Civilian Practice. By A. Geoffrey Shera, B. A., M. D., B. C. (Cantab.). With an introduction by Sir Clifford Allbutt, K. C. B., M. D., F. R. S. 1918. 16'. 226 pages. Henry Frowde and Hodder & Stoughton, London.

Tumours. Innocent and Malignant. Their Clinical Characters and Appropriate Treatment. By Sir John Bland-Sutton LL. D., F. R. C. S. With 383 illustrations. Sixth edition. [1917.] 8'. 790 pages. Paul B. Hoeber, New York.

Stanford University. Medical Bulletin No. 5, 1917-1918.

The Newer Knowledge of Nutrition. The Use of Food for the

Preservation of Vitality and Health. By E. V. McCoUum.

Illustrated. 1918. 12'. 199 pages. Macmillan Company,

New York. College of Physicians. Transactions of the College of Physicians

of Philadelphia. Third series. Volume the Thirty-Ninth.

War Neuroses. By John T. MacCurdy, M. D. With a preface by W. H. R. Rivers, M. D. (London.) 1918. 8°. 132 pages. University Press, Cambridge.

lioyal College of Surgeons of England. Calendar of the Royal College of Surgeons of England. August 1, 1918. 407 pages. 8'. Taylor and Francis. London, England.

The Effect of Diet on Endurance. By Irving Fisher. 1918. 12°. , 55 pages. Yale University Press, New Haven; Humphrey Milford, Oxford University Press, London.

.1 Text-Book of Home Nursing. Modern Scientific Methods for the Care of the Sick. By Eveleen Harrison. Second edition, revised. 1918. 12°. 193 pages. Macmillan Company, New York.

Dietetics for Nurses. By Fairfax T. Proudflt. 1918. 8". 444 pages. Macmillan Company, New York.

Compendium of Histo-Pathologieal Teehnie. By Emma H. Adler.

1918. 12°. 92 pages. Paul B. Hoeber, New York.

Mental Diseases. A Handbook Dealing with Diagnosis and Classification. By Walter Vose Gulick, M. D. Illustrated. 1918. 8'. 142 pages. C. V. Mosby Company. St. Louis.

Equilibrium and Vertigo. By Isaac H. Jones, M. A., M. D. With an Analysis of Pathological Cases. By Lewis Fisher, M. D. Adopted as Standard for Medical Division, Signal Corps, Aviation Section, by Surgeon General and Chief Signal Ofllcer. United States Army. With 130 Illustrations. 1918. 8°. 444 pages. J. B. Llppincott Company, Philadelphia and London.

Physiology and Rioehemistry i7i Modern Medicine. By J. B. Macleod, M. B. Assisted by Roy G. Pearce. B. A., M. D., and by others. With 233 illustrations, including 11 plates In colors. 1918. 8'. 903 pages. C. V. Mosby Company, St. Louis.

The Rockefeller Foundation. International Health Board. Fourth Annual Report. January 1, 1917-December 31, 1917. (Publication No. 7.) January, 1918. 8\ 160 pages. New York.

Information for the Tuberculous. By F. W. WIttlch, A. M., M. D. 1918. 12°. 150 pages. C. V. Mosby Company. St. Louis.

Inited States. Department of Commerce. Bureau of the Census. Mortality Statistics, 1916. Seventeenth annual report. 1918. 4°. 543 pages. Government Printing Office, Washington.

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THE JOHNS HOPKINS HOSPITAL REPORTS

VOLUME I. 423 pages, 99 plates.

VOLUME II. 570 pages, witli 28 plates and figures.

VOLUME III. "66 pages, with 69 plates and figures.

VOLUME IV. 604 pages, 33 charts and illustrations.

VOLUME V. 480 pages, with 32 charts and illustrations.

The Mal.nri.ll Fevers ot B.iltimore. By W. S. Thayer, M. D.. and

J. Hewetson. Jl. D. A Study of some Fatal Cases of Malaria. By Lewellys F. Barker, M. B.

Studies in Typhoid Fever.

D.. Walter Keed, .M. IL. ai

VOLUME VI. 414 pages, with 79 plates and figures.

VOLUME VII. 637 pages with illustrations.

VOLUME VIII. 552 pages with illustrations.

VOLUME IX. 1060 pages, 66 plates and 210 other illustrations. Contributions to the Science of Medicine.

Dedicated by his Pupils to William Henky Welch, on the twenty fifth anniversary ol his Doctorate. This volume contains 38 separate papers.

VOLUME X. 616 pages, 12 plates and 25 charts.

VOLUME XI. 555 pages, with 38 charts and illustrations,

VOLUME XII. 548 pages. 12 plates and other illustrations.

VOLUME XIII. 605 pages, with 6 plates, 201 figures, and 1 colored chart.

VOLUME XIV. 632 pages, with 97 figures.

Studies in Genito-Urinary Surgery.

The Treatment of Prostatic Hypertrophy by Conservative Perineal Prostatectomy. An analysis of cases and results based on a detailed report of 145 cases. By Hugh H. Young, M. D.

Recto-Urethral Fistula. Description of New Procedures for their Prevention and Cure. By Hugh H. Young. M. D.

The Early Diagnosis and Radical Cure of Carcinoma of the Prostate, being a study of 40 c:ises and presentation of a radical operation which was carried out in four cases. By Hugh H. Young, M. D.

VOLUME XV. 542 pages, with 87 illustrations.

Twelve papers on pneumonia By Drs. Chatard, Fabyan, Emefson,

Marshall, McCrae, Steiner, Howard and Hanes. A Study of Diarrhoea in Children. J. H. Mason Knox, Jr., M. D., and

Edwin H. Schorek. M. D. Skin Transplantation. By John Staige Davis. M. D. Epidemic Cerebrospinal Meningitis and Serum Therapy at The Ji.hns

Hopkins Hospital. By Frank J. Sladen. M. D.

VOLUME XVI. 670 pages with 151 figures.

Studies in the Experimental Production of Tuberculosis in the GenitoVrinary Organs. By Ceorge Walker. M. D.

The Effect on Breeding of the Removal of the Prostate Gland or ot the Vesicute Seminales. or of Both ; together with Observations on the Condition of the Testes after such Operations on White Rats. By George Walker. M. D.

Scalping Accidents. By John Staige Davis, M. D.

Obstruction of the Inferior Vena Cava with a Report of Eighteen Cases. By J. Hall Pleasants. M. D.

Physiological and Pharmacological Studies on Cardiac Tonicity in Mammals. By Percival Douglas Cameron. M. D.

VOLUME XVII. 586 pages with 21 plates and 136 figures.

Free Thrombi and Ball Thrombi in the Heart. By Joseph H. Hewitt.

M. D. Benzol as n Leucotoxin. By Lawrence Selling. M. D. Primary Carcinoma of the Liver. By Milton C. Winternitz, M. D The Statistical Experience Data of The Johns Hopkins Hospital, Baltimore,

Md.. 1802-1(111. By Frederick L. Hoffman. LL. D., F. S. S. The Origin and Development of the Lymphatic System. By Floreni:e R.

Sarin. M. D. The Nuclei Tuberis Laterales and the So-called Ganglion Opticum Hasale.

By Edward F. Malone. M. D. Venous Thrombosis During Myocardial Insufficiency. By Frank J. Sladen.

M. D.. and Milton C. Winternitz. M. D. Leuk.Tmia of the Fowl : Spontaneous and Experimental. By Harry C.

SCH5IEISSER. M. D.

VOLUME XVIII. 445 pages with 124 figures.

Fasciculus I. A Studv of a Toxic Substance of the Pancreas. By E. W. Goodpasture,

M."D.. and George Clark. M. D. Old Age in Relation to Cell-overgrowth and Cancer. By E. W. Goodpasture. M. D., and G. B. Wislocki. M. D. The Effect of Removal of the Spleen Upon Metabolism in Dogs : Pre liminarv Report. By J. H. King. M. D. The Effect ot Removal of the Spleen Upon Blood Transfusion. By J. H.

King. M. D.. B. M. Bernheim. M. D.. and A. T. Jones. M. D. Studies on Parathyroid Tetany. By D. Wright Wilson. M, D.. Thornton

Stearns, M. D., J. H. Jannet, Jr., M. D.. and Madge DeG. THCRrx)w,

M. D. Some Observations on the Effect of Feeding Glands of Internal Secretion

to Chicks. By M. C. Winternitz, M. D.

Spontaneous and Experimental Leukemia in the Fowl. By H. C.

Schmeisser. M. D. Studies on the Relation of Fowl Typhoid to Leukaemia of the Fowl. By

M. C. Winternitz. M. D.. and H. C. Schmeisser, M. D. Hyaline Degeneration of the Islands of Langerhans in Pancreatic Diabetes.

By M. C. Winternitz. M. D. Generalized Miliary Tuberculosis Resulting from Extension of a Tubercular

Pericarditis Into the Right Auricle. By M. C. Winternitz. M. D. Acute Suppurative Hypophysitis as a Complication of Purulent Sphenoidal

Sinusitis. By T. R. Boggs. M. D.. and M. C. Winternitz. M. D. A Case of Pulmonary Moniliasis in the United States. By T. R. BoGGS,

M. D.. and M. C. Pincoffs, M. D. Gaucher's Disease (A Report of Two Cases in Infancy). By J. H. M.

Knox. M. D.. H. R. Wahl. M. D.. and H. C. Schmeisser. M. D. A Fatal Case of Multiple Primary Carcinomata. By E. D. Plass. M. D. Congenital Obliteration of the Bile-ducts. By .Iames B. Holmes. M. D. Multiple Abscesses of the Brain in Infancy. By James B. Holmes. M. D. Gastric Carcinoma in a Woman of Twenty-six Years. By R. G. Hussey,

M. D. Subdiaphragmatic Abscess with Rupture Into the Peritoneal Cavity Following Induced Pneumothorax for Pulmonary Haemorrhage. By R. G.

Hussey. M. H. Heart Block Caused by Gumma of the Septum. By E. W. Bridgeman,

M. D.. and H. C. Schmeisser, M. D. Analysis of Autopsy Records.

A. The Johns Hopkins Hospital. (Table Showing Percentage of

Autopsies.)

B. The City Hospitals. Bay View. (Table Showing Percentage of

Autopsies. ) " The Monday Conferences."

Clinical Representatives on the Staff of the Department of Pathology. Donation.

Fasciculus II. The Role ot the Autopsy in the Medicine of To-day. By M. C. Winternitz.

M. D. Experimental Nephropathy in the Dog. Lesions Produced by Injection

of B. bronchisepticus into the Renal Artery. By M. C. Winternitz,

M. D.. and William C. Quiney. M. D. Mesarteritis of the Pulmonary Artery. By M. C. Winternitz, M. D.. and

H. C. Schmeisser, M. D. A Clinical and Pathological Study of Two Cases of Miliary Tuberculosis of

the Choroid. By Robert L. Randolph, M. D., and H. C. Schmeisser,

M. D. The Blood-vessels of the Heart Valves. By Stanhope Bayne-Jones. M. D. Equilibria in Precipitin Reactions. By Stanhope Bayne-Jones. M. D. Carcinoma of the Pleura with Hypertrophic Osteoarthropathy. Report of

a Case with a Description of the Histology of the Bone Lesion. By

Stanhope Batne-Jones. M. D. ,

The Interrelation ot the Surviving Heart and Pancreas of the Dog in Sugar

Metabolism. By .\dmont H. Clark. M. D. Congenital Atresia of the Esophagus with Tracheo-Esophageal Fistula

Associated with Fused Kidney. A Case Report and A Summary of the

Literature on Congenital Anomalies of the Esophagus. By E. D.

Plass. M. D. Ectopia Cordis, with a Report of a Case in a Fifteen-Month-Old Infant.

By James B. Holmes, M. D. Studies in the Mechanism of Absorption from the Colon. By Samuel,

Goldschmidt. M. D., and A. B. Dayton. M. D. Report of Two Fatal Cases Following Percy's Low Heat Treatment of

Carcinoma of the Utenis. Bv V. N. Leonard, M. D., and A. B. Dayton,

M. D. The Relationship in Tvphoid Between Splenic Infarcts and Peritonitis

Unassociated with Intestinal Perforation. By A. B. Dayton. M. D. Left Duodenal Hernia. By A. B. Dayton. M. D.

Histological as Related to Physiological and Chemical Differences in Certain Muscles of the Cat. By H. Hays Bullard, M. D. A Method of Clearing Frozen Sections. By H. Hays Bullard. M. D. On the Occurrence and Significance of Fat in the Muscle Fibers of the

Atrio-Ventricular System. By H. Hays Bullard. M. D. Studies on the Metabolism of Cells in vitro. 1. The Toxicity of o-Amino Acids for Embyonic Chicken Cells. By Montrose T. Burrows, M. p.,

and Clarence A. Neymann, M. D. The Significance of the Lunula of the Nail. By Montrose T. Burrows.

M. D. The Oxygen Pressure Necessary for Tissue Activity. By Montrose T.

Burrows. M. D. The Functional Relation of Intercellular Substances in the Body to Certain Structures in the Egg Cell and Unicellular Organisms. By

Montrose T. Burrows. M. D. Studies on the Growth of Cells in vitro. The Cultivation of Bladder and

Prostate Tumors Outside the Body. By Montrose T. Burrows. M. D..

J. Edward Burns. M. D.. and Yoshio Suzukl. M. D. The Studv of a Small Outbreak of Poliomyelitis in an .\partment House,

Occurring in the Course of an Epidemic in a Large City. By Montrose

T. Burrows. M. D.. and Edwards A. Park. M. D. Papilloma of the Larynx. Report of a Case Treated with Radium with

Resultant Chronic Diffuse Thyroiditis. By William C. Duffy. M. D. Analysis of .Autopsy Records. Auto'psv Statistics.

(n) Bay View.

(hi Johns Hopkins Hospital. Report of the Photographic Department. General Improvements.

## Contents

The Occurrence of Gastric Mucosa in a Case of Meckel's Diver- Tlie Development of CroasStriations in the Heart Muscle of ticulum Producing Intestinal Obstruction. (Illustrated.) the Chick Kinbryo. (Illustrated.)

By Emu. Goetsch 143 By Margabkt Reed Lewis 176

A Graphic .Application of the Principle of the Equilateral

Triangle for Determining the Direction of the Electrical Spina Bitida with Associated Disturbances in a Human Axis of the Heart in the Human Electrocardiogram. Embryo 17 mm. Long. (Illustrated.)

(Illustrated.l p^. g j \Valli.s Ccll 181

By Edward Perkins Carter. Curt P. Richteb and

Carl H. Greexe I(!2

_, . . , . , i- . ^1 f . i T 1 The Manus Meditationis. (Illustrated.)

Phaeocytosis and Agglutination in the Serum in Acute Lulmr . „ „ ,_.

„ ' .If -c •. c Tu ij . J 41 By Charles Si.noer ... 184

Pneumonia: the Specificity of lhe.«e Reactions and the "

Regularity of Their Occurrence. By Paul \V. Clough 107 , Books Received 183

THE OCCURRENCE OF GASTRIC MUCOSA IN A CASE OF Mi:CKEL'S DIVERTICULUM PRODUCING INTESTINAL OBSTRUCTION

By K.Mii> (ioETScii (From thi- Departments of ffurgrry of The Peter Bent Brigham Hospital and The Harvard and Johns Hopkins Mrdiial Sihooli)

The occurrence in the human liody of ahcrrant glandular tissue, at times in place,* far removed from the motlier tis,«uo, is a subject not only of general medical interest and of special interest to the embrj-ologist, but also attract'* the attention of the pathologist and surgeon, who frequently meet with alinormalities arising from such aberrant tissue. The purpose of this report is to record such an in.«tance occurring in an interesting case of partial obstruction caused by Meckel's diverticulum in which, at operation, a striking variation was discovered in the mucous membrane of the distal half of the diverticulum. This area of mucous membrane at the tip of Meckel's diverticulum was differentiated strikingly from the pro.ximal mucosa by a sharp line of demarcation and by a difference in color, surface character and in thickness. On subsequent sectioning, this area of muco.sa proved to be of the preci.«e character of gastric (fundus) mucosa, containing the typical gastric glands (foveol.T gastricaj) composed of the two distinctive types of cells, the parietal and chief, each of which presented their characteristics of morphology and of staining reaction. It is desired further to explain the probable embryological origin of

tiiis ga.stric ti.ssue in Meckel's diverticulum with a view to throwing further light upon the occurrence of aberrant glandular tissue at the umbilicus and in the renuiins of the omphalomesenteric duct, as reported in the literature.

The ca-fe, Hospital No. (123, is that of a well-developed, single young man, lit years of age, and caterer by occupation. lie was born in Ireland and came to America four years previous to bis entrance into the Peter Bent Brigham Hospital on August 26, 191.3. He was admitted into the surgical clinic of Prof. Harvey Gushing, to whom I am indebted for the privilege of reporting this case. The young man complained of pain in the abdomen and vomiting. No information was obtained in regard to his family or past history which had any licaring on his present trouble except for the fact that six years previously, while he was in Ireland, he was operated upon for what he called a stomach abscess. The details of the condition for which he was operated upon he was unable to give. At that time the abdomen was explored at a point just below the umbilicus and drainage in.-^tituted. The abscess healed in a few weeks and the patient made a complete recov

144

[No. 340

ery. Except for this experience he had enjoyed exceptionally good health.

Without going into the details of his present illness suffice it to say that his symptoms began with headache 48 hours before admission to the hospital and were followed in about 36 hours by severe cramps in the abdomen, especially in the lower half and toward the right side. The day before coming to the hospital he suffered severely with vomiting and retching, the vomitus containing large quantities of bile. These symptoms persisted up to the time he came into the hospital. His appetite was poor during the two days of his illness, and his bowels moved once on the day previous to admission. During this same day the patient had a definite fever.

On admission to the hospital he appeared very ill. As a consequence of his excessive vomiting and retching his mouth was exceedingly dry, his tongue red and " beefy " and there was some bleeding of the gums. His temperature was 101.2°, pulse 92 to the minute and his leucocytes numbered 15,000 per c. mm. Examination of the abdomen showed no discernible irregularities, nor were any peristaltic waves seen. There was some fullness present, especially in the lower half. Eespiration was entirely costal in type. There was no marked general muscular rigidity, although there was increased tension of the abdominal muscles over the lower half of the abdomen. On deep palpation over McBurney's point slight tenderness could be elicited. Elsewhere there was no abnormal tenderness. On percussion, dulness could be demonstrated in the right lower abdomen and in the flanks. This dulness shifted with change of position of tlie patient and gave a splashing sound when the overlying abdominal wall was tapped while pressure was made in the flanks. There was evidence, then, of free fluid in the peritoneal cavity. The upper abdomen was markedly tympanitic. The evidence of former operation was present in an irregular scar just below the umbilicus, measuring about 1.5 cm. in transverse and 2 cm. in vertical diameter. Rectal examination revealed nothing abnormal. Without entering into further details of the examination it may be stated simply that the diagnosis appeared to be either intestinal obstruction or acute appendicitis with perforation. As the patient's general condition demanded immediate operation, abdominal exploration was advised and readily consented to.

The operation, done about one hour after the patient entered the hospital, was carried out through a right rectus incision. In the peritoneal cavity there was present a fairly large amount of free, serous fluid. Several moderately distended reddishlooking loops of small bowel were seen and also some collapsed grayish loops. Exploration was first made in the region of the appendix. Numerous adhesions resulting from the former abscess and operation had to be carefully separated. After considerable difficulty the appendix, which was coiled back on itself in U-shaped fashion and firmly adherent in the right iliac fossa, was freed and brought into view. It was unusually long, measuring 17-18 cm. in length, of uniform thickness and of fibrous consistency. There was evidence of a moderate chronic inflammation in this region ; the appendix, however, was not acutely inflamed. Appendectomy was done. The

condition of the appendix, I felt, could not be held responsible for the patient's present condition and furtlier exploration was made. At once a collapsed small intestine was seen low in the abdomen and pelvis, while numerous overlying, reddish, distended loops of small bowel were seen coming from above. After further seardi it was found that the division between distended and collapsed bowel was sharply demarcated by a thick, firm, pinkish-white cord, measuring 1.5 cm. in thickness and 6-7 cm. in length, attached at the distal end to the abdominal wall by means of adherent omentum at a point just below the imibilicus and connected at the proximal end with the terminal ileum at a distance proximal to the ileocecal valve, common for Meckel's diverticulum (cf. scliematic drawing. Fig. 1). Over this cord the loops of small intestine were draped like clothes on a line and had become obstructed. The distal end or tip of the diverticulum was attached to the abdominal wall at the site of the former abscess and operation. Without great difficulty, the distal end together with the adherent omentum was dissected free from the abdominal wall and the base of the diverticulum at its attachment to the ileum amputated and treated in the manner of an appendectomy. Further rapid search revealed no other abnormal findings, such as infection or seriously damaged loops of small intestine, whereupon closure of the abdominal wound was made without drainage. There were no disturbing symptoms following tlie operation and the patient made a rapid, complete recovery.

In view of the findings at operation it seems likely that the abdominal abscess for which the patient was operated uj>ou six years previously had its origin in a perforation at the tip of Meckel's diverticulum and that simple drainage of the abscess was done through a small incision just below the umbilicus, following wliich the abscess healed. The possible cause of the perforation will be considered later.

Upon further examination it was found that the diverticulum had a large lumen which at the point of attachment to the ileum measured about three-fourths of a centimeter in diameter. It did not have the appearance of acute inflammation. The diverticulum was then slit open in a longitudinal direction, whereupon a striking appearance was presented by the mucous membrane. The proximal three-fourths of the mucosa had a rather smooth, rolling, slightly folded surface. It was pale-pinkish in color and resembled in this respect the mucosa of the terminal ileum or first portion of the large bowel. The distal one-fourth of the mucosa was considerably thicker and was elevated above the surface of the proximal mucosa from which it was separated by a sharp line of transition. It had, furthermore, a sharp differentiation in color, in that it was of a deep red, cherry hue and its surface was thrown up into large folds, the surface of which again was irregular and granular in appearance. {Cf. drawing, Fig. 2, g. m.) There was a marked difference also in the thickness of the diverticular wall which, in its proximal portion, was of the thickness of the terminal ileum, while at the tip it was three to four times as thick as the latter. The muscular coat, on the whole, was rather thin, and externally there was a

THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE, 1919

PLATE XIX

Fill. 1- Meckel's <livrrti<'uluni, with adherent oiiieiituni.* iittjchetl to the anterior alMliiniinal vtall at a point just below the unibilii'us. ( Sehemal ir. ) The chn>ni<- Hbrous adhesions resulted from old abs<^?>s (urniation and jjubsequent operation.

Ki<

-Meokel>

inc Ihe thinner pnixinial inuttis;! t i. n appearance, and the thicker tlislal jp|H?arinK Kastrif nuiros.1 [ff. m.). V -harp line of transition (T.). At O "riientuin. (Natural size.)

'.I {..neilndinallv : ) rt'scniblinu' iUun lie of irntrnlar.

- A

f^^;^

-*V

tofirraph -.ho\v^ tho strikinic «li(It left in the drawing (KifC. H. fflands in (he gastric niiic<>«a a

•e in thi< knew. U-twe*-!! tli' y a ^mall portion .*r the alM shown.

ftf

^'A

^y

^jf'-^.^ak^miM

the TiKht and the pi

, . • M,, Im.I.- I,.. Ill

Mill in -lain I The J

mal iiitesliniil niiicnsa on the lortuojily and depth of the

June, 1919]

145

serous peritoneal covering continuous with the serosa of the small bowel itself. At the tip there was a mass of adherent, corrugated-looking omentum which had probably become adherent tliere at the time of the former abscess and operation. Further examination at the time revealed no perforation nor evident defect in the mucosji at the tip of the diverticulum. The whole specimen was j)laced in 10 per cent formalin for subsequent study.

Frozen sections were made of the wall of tlie diverticulum BO as to include the transition line (cf. photomicrograph, Fig. 3) between the two types of mucous membrane and were then stained in lia.'mato.xylin and eosin. The proximal, thinner, mucosa (similar to that seen on the left in Fig. 3) resembled in structure that of the duodenum, or in many respects also tlie ascending and transverse colon ; whereas in the thicker. more irrt>gular. distal mucosa (on the right in Fig. 3), at the tip there were si^n deep glands which resembled in structure the fundus glands of tlie stomach and which were composed of two types of cells — the larger, less numerous, bright-red-staining eosinophilic parietal cells and the more numerous, smaller, indifferent-staining chief cells. In order to study in greater detail the two types of mucosa, paraffin sections were prepared. Several additional staining methods were used, namely, cresylecht-violett, the iron-ha-matoxylin method, the acid fuchsiii and the neutral gentian methods as recommended by Bensley and the mucicarmine method for the demonstration of mucus in the goblet cells and in the distal goblet zone in the surface columnar cells of the gastric mucosa.

I. Stkvctlre of the MrcosA Proxim.\l to the Transition Point (T) (cf. Fios. 2 and 3)

Sections were made at the line of demarcation or transition between the two adjoining types of mucosa. Fig. 3 represents a low-power photograph of an ordinary section stained in hsematoxylin and eosin and magnified 24 diameters. The photograph shows the sudden transition from the thinner proximal mucosa, on the left in the piiotograph, to the thicker, more irregular, distal mucosa on the right. The striking difference in the relative thickness of the two mucous membranes is well shofrn. A section of the proximal mucosa on the left when observed under the higher power and after staining in cresylecht-violett is seen to consist of a propria containing simple, unbranched, comparatively shallow tubular glands (cf. drawing. Fig. 4, of a similar section after iron-hiematoxylin). The mucous membrane has an irregular surface and forms papillar}- outgrowths between the openings or crypts of the glands. The lining epithelium is almost uniformly of the tall columnar variety, containing numerous goblet, mucous cells throughout the extent of the mucous membrane. These goblet cells in the neck and depth of the glands are so numerous as to form in places the majority of the cells lining the tubules. Here and there between the swollen goblet cells are seen thin, tall, irregularly compressed, columnar cells — probably discharged goblet cells. Their protoplasm is compact, non-granular and more deeply stained. The cells on the surface are of a low columnar, in places almost

cubical, type, with fewer goblet mucous cells tlian elsewhere in the glands. In sections doubly stained in iron-alum-hiematoxylin followed by mucicarmine (the strong stock solution of Mayer), as recommended by Bensley,* the goblet cells contrast strikingly on accomit of tiie brigiit red stiiin which their irregular, stringy or spongy +++++ CONTENTSs take, showing tlius tiie mucous character of the secretion of these cells. Afte'r staining in cresylecht-violett the mucous takes on a faintly purple tint as compared witii the remainder of the cell. Near the center of the cell is a denser, more deeply bluish stained zone of c}'toplasm separating the mucous section of the cell from the basal protoplasmic portion. The nuclei are large, rounded or oval, fairly clear and basally placed. They contain a moderate amount of chromatin and have each a densely stained purple nucleolus. Many of the nuclei, however, are elongated and flattened, due to pressure from adjoining cells; in tlie smaller cells they are basally placed, while in the discharged cells tliey have a more central location. The protoplasm of those cells lying between the goblet cells does not contain secretion granules.

Many of these appearances are seen as well in the sections stained after the iron-alum-ha»matoxylin method. Thus in the drawing (Fig. 4) the goblet cells appear unstained, being represented as clear spaces. There are no true villi of the small intestine type. In studying the section further in the oil immersion we find that the cells on the surface have a kind of striated cuticular Iwrder. The nuclei of the cells, which apparently rest upon a definite basement membrane, have the same character as those just described in the preceding paragraph. The protoplasm of the UM columnar cells between the goblet cells fails to show any granules which one would consider as the antecedents of fennent secretion.

The propria (Fig. 4) is a loose tissue, containing numerous .small blood-vessels and lymphatics, lymphoid cells and connective-tissue cells. In it are also a few smooth muscle fibers from the L. muscularis nuiscosce running upwards into the mucous membrane prolongations. In one area there is a definite aggregation of lymphoid ti-ssue with a germinating center; in fact, a lymphoid follicle with an outer denser. zone of small round cells in the center of which appears a clearer zone with larger cells and richer reticulum. Lymphoid tissue of this kind is seen also in the sections taken from this proximal portion of the mucosa.

The submuco.sa consists of a layer of loose connective tissue which contains blood-vessels and above which lies the L. muscvlaris mucosa (Fig. 4). Externally to this again there appears a thick tunica muscularis, consisting of a thick inner circular and an outer longitudinal layer, between which there lies a plexus of nerve tissue. A small portion only of this muscle coat appears in the lower right-hand comer of the drawing (Fig. 4).

Additional sections including both types of mucosa were made of the transition zone (T, Fig. 2) and .stained in hapmatoxylin and eosin, cresylecht-violett, iron-aluni-ha-matoxylin and in mucicarmine. In tlie mucosa just distal to the transition line (on the right in Fig. 3) the following changes

146

[No. 340

occur: The proximal duodenal or perhaps transverse-colon type of mucosa rather suddenly changes into a kind of transitional surface epithelium, consisting of two or more irregular cell rows and two different types of cells. The majority of these cells are of a taller t}'pe than those lining the intestinal mucosa, and the nuclei, which are irregularly oval or rounded, are more centrally placed and stain in ha?matoxylin a diffuse bluish-purple in which a darker pifrple centrosome is usually evident. These cells are often flattened and compressed, cylindrical, fusiform or dumb-bell shaped. Each surface cell has a marginal cuticular border and a distal clearer zone separated from the more proximal protoplasmic portion of the cell by a transverse denser cytoplasmic band. In the eresylecht-violett stain the distal clearer zone just described has a rather homogeneous structure and stains a very pale blue, as distinct from the denser blue proximal protoplasm. The nuclei stain a pale violet. In the mueicarmine the distal zone in many instances is stained bright red, showing the presence of mucus. In neither the eresylecht-violett nor in the iron-alum-hsematoxylin stained sections are any secretion granules apparent in these surface cells.

The cells of the second type in the surface mucosa are usually more deeply situated. These cells are rounded or hexagonal in shape and have a comparatively clear protoplasm. The nuclei are irregularly rounded or oval and deeply stained.

The propria is rich in lymphoid cells, blood capillaries and connective-tissue cells. Numerous mast-cells, so frequently seen in the normal stomach mucosa, are seen here also, and in their cytoplasm the characteristic large red granules, after staining in eresylecht-violett, can be recognized.

Numerous crypts or tubular prolongations are seen dipping down from the surface into the propria. These glands are highly tortuous, especially in their depths, and are lined by two kinds of cells. The majority of them, the chief cells, to use the terminology as applied to the gastric fundus mucosa, are low columnar or cuboidal in shape, with a darker-staining basal zone of protoplasm which has a slightly granular appearance. The lumen border of each cell is relatively clearer and the nucleus is rather large, irregularly rounded or oval, and basally placed. These cells after staining in eresylechtviolett are pale blue, with violet nuclei and bluish nucleoli. Secretion granules do not appear in this stain, but after the iron-alum-hajmatoxylin method, great numbers of black-stained zymogen secretion granules are seen, such as one finds typically in the chief cells of the gastric mucous membrane. A more detailed description of these cells is given later.

The cells of the second type found in these glands are considerably larger than the chief cell just mentioned. They do not, as a rule, touch the lumen of the tubule, as they have a parietal situation and f reqiiently lie between or upon the chief cells just mentioned. In the hfematoxylin-eosin preparation a cell of this type stains light red or pink in the eosin, as distinct from the chief cell. It has, further, a distinct cell definition and a round, usually centrally placed nucleus, rich in chromatin. Uniformly distributed in its protoplasm can be seen rather large, highly retractile, practically unstained

granules, suggesting in every way the appearance in the typical parietal cell of the stomach. In the cresylechi^violett these parietal cells contrast clearly with the chief cells by staining a faint pinkish-blue, while the latter are darker especially in their basal portions, which are dark blue. The secretion granules in such a preparation are of a violet color. The nuclei are well defined, large and vesicular, and contain relatively little chromatin. Many of the parietal cells are seen to communicate with the lumina of the tubules by a cleft between the neighboring chief cells. In the iron-alum-haematoxylin the parietal cells are clearly shown, and in their cytoplasm the secretion granules are seen to be uniformly distributed and stained black. Except for the columnar cells on or near the surface, the mueicarmine fails to show the presence of any mucussecreting cells in the neck, body or depths of the tubules. A further description of tliese glands as they occur in a section just beyond the transition line is given below (c/. Fig. 5). In the neck and body of a gland tubule the parietal cells are almost as numerous as the chief cells, while in the depths of the glands the smaller chief cells become more abundant. The appearance throughout in fact is that of gastric fundus mucosa, except perhaps for the greater tortuosity in the tubules than in the glands of the gastric fundus region (c/. Fig. 5).

Just below the mucosa there is a well-developed L. muscularis mucosce, which at one point just beyond the transition line runs upwards, as a papilla or indentation, into the mucous membrane and thereby suggests, together with the thickening in the outer muscle coat, the formation of a sphincter. Just beyond this point, furthermore, the mucous membrane assumes the exact appearance of the fundus mucous membrane and will be described in greater detail later.

The submucosa consists of a loose connective-tissue framework containing blood-vessels in great abundance.

The outer muscle coat is thick, and composed of muscle bundles, not in two definite layers as in the proximal intestinal portion of the section, but running in all directions and intertwining with one another. Numerous nerve fibers can be seen in the outer connective-tissue coat below the parietal covering and also between the muscle bundles. Here also scattered ganglion cells are seen.

II. Typical Gastric Fundus Mucosa From a Point Just

Distal to the Transition Line Described

Above (Fig. 5)

At a short distance beyond the transition line between the two types of mucosa the glands of a typical gastric fundus type just described for the transition zone are seen in great numbers. A more detailed description may here be given of the glands as revealed after staining with hematoxylin, eresylecht-violett, iron-aluni-h£ematoxylin, mu^picarmine, neutral gentian and acid fuchsin-niethyl-green. The appearance as revealed in the high-power magnification and in oil immersion need only be given here. Many of the findings in repetition of those described as occurring at the transition point are either omitted or only briefly mentioned. The drawing (Fig.

THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE. 1919

A

^®»,.

^l« — ItiMttiiiic lit intNJfnitelv inan niA.-<l «lion ( • 7S) (5 niiira Ihirktma, ironlu-niatox.vllii nirlhiHl) taken from the ilJMtjil niiKfKii iit ii point ju*t l>ry<>nfl the lnin>.it>on iniic. X.ite the tvpif-al fhiiniitrr. of ira>lri<' funilti'. niwoia. the lull airfare ooliimnar relU at (.4), an<l the too charnrterislir t>Te< of rell». the . hief an<l parietal, in the ne.-k III), Ik.Iv (f| and Iwse (11) of the dee|> tortuou.i gland.

Km. Ii- Jlr;mnii[« "r m|Uuii'.I aTOw (.4, //. C, /(. Kilt. .'.I afliT hiKh.|>ower uil-innnerNion niaKniltnition, to Khiiw the rjiol.iKiiiil .luirarlerK of the i-<'llt. .. .iiipri.ini: the Klanil tnliiile. .V.>lr llie tall irfai-e. i-olunuiar. non 7.>tniHt<-riir -.•IIk. (.1) the larite r.lill ively i le:ir purli'l4il cHIh i-oiiliilnhiK nioilerale nuMilx'iv of liirve, Mark MalllinK. iii-iil<iphili<' (granule., a(i<l the ntorr nnlnenm.. 'nialhr. .lurkrr •hief r-ellv coiitajiiiiiir Iitrt;e ininilierM of

hiai'k otaininK. /> iteiiir Kranulea

airtrr<ifate<l aloiiie the lumen bor.ler> lit the ..lU III. <. /').

(FiK. 2. n (: • of llru thi» nertion with the simple tvi>e of rellii. the lymph foil de\eiope«l L, mu*rula

• diKMlenuni. .Note the n. the nunterfiuo jfohlet Kland., and the well

June, 1919]

147

5) illustrates the appearance of a tvpieal gland in moderate maguifit-ation, after irou-alum-ha>matox_vlin staining. Four areas squared in this lower power drawing (Fig. 5, A, B,C,D) are represented as seen in high-power oil iuiniersiou magnitication (Fig. 6, A, B, C,D).

Surface Epithelium. — Numerous crypts or depressions found in the mucous membrane resembling the typical gastric crypts represent the openings or communications through which the more deeply situated glands discharge their secretion into the lumen of the diverticulum. These crypts are lined by epithelium of the surface type, composed of tall, cylindrical cells in a single row or layer (Figs. 5 and 6, .4). The large nucleus of each cell witii a well-marked nucleolus is round or oval in shape and is usually centrally placed, but often is found above or below the center of the cell. It stains fairly densely by all methods, due to a fair abundance of chromatin. The protoplasm of these cells takes a pale blue stain in the cresylecht-violett and a gray in the luvmatoxylin and has a spongj" structure. Secretion fjranules are not seen in the protoplasm. In the distal one-fourth of many of the cells there is a clearer zone, in places grossly granular in appearance, having a cup shape and separated from the remainder of the cell protoplasm by a transverse cytoplasmic band. This is the mucuscontaining end or zone of the cell, which is not, however, a true goblet cell. True types of the latter were not seen at all in sections from this area. In the cresylecht-violett this mucus stains a pale blue and after mucicarmine a few of the cells on the surface showed this cup-shaped end, or theca, red stained and cither grossly granular or string}- in structure. Just below the surface in the cr}-pts the mucus-containing cells are more numerous than on the surface where they are very few in number. Many of the cells have, furthermore, an outer cuticular border.

Glands of the Gastric Fundus Type. — (Figs. 5 and 6, B, C, D.) Into the depths of the crypts empty the secreting glands, one or two, occasionally more, tubules to each cr}7)t. These glands are of the simple tubular variety and occasionally branched. The necks of the glands arc quite straight, but in the depths the glands are usually tortuous or convoluted, as indicated by the numerous tubules seen in cross-section in the deeper zone of the mucosa. The glands are in close contact with one another, with almost no intervening tissue of any kind. The propria forms the groundwork or supporting tissue for the glands, surrounds them evervTvhere and extends upward to the surface epithelium. Under the surface epithelium the propria contains a great many lymphoid cells uniformly and ditTusely scattered and fairly abundant. These lymphoid cells, together with numbers of mast-cells, a blood capillar}' network and some slips from the L. mu-scularis mucosa are also seen extending from the level of the latter upwards between the glands to the surface epithelium. A typical gland may be divided into three portions: the neck (Fig. 5, B), the body (Fig. 5, C) and the depth or base of the gland (Fig. 5, D). The neck of the gland consists of a rather straight tube with a ven- narrow lumen, lined by two types of cells. The first tj-pe is smaller, low columnar or almost cubi

cal in shape and stains bluish in hsvmatoxylin, with a darker basal zone and a clearer zone bordering on the lumen and containing numerous rather large, black-stiiining secretion granules. After the neutral gentian technique (Fig. T) these same cells are stained a violet, especially in the basal portion, and the secretion granules along the lumen border of tlie cell now stain a dark violet. In the acid fuchsin-methyl-green method (Fig. 8) these granules are faintly green or unstained. These are the characteristic chief cells as seen tyi)ically in the gastric fundus mucosa.

The second type of cell is larger, is irregularly rounded or oval, borders on the lumen or is slightly removed from it and covered in part by the neighboring chief cells. This cell is clearer, the protoplasm is stained uniformly pinkish in eosin, pale blue in cresylecht-violett, grayish in iron-htematoxylin, faintly orange in neutral gentian ( Fig. 7 ) and red in the acid fuchsin-methyl-green method (Fig. 8). Scattered uniformly through tlie protoplasm are definite, large, discrete secretion granules, black in the iron-h»matoxylin (Fig. 6, B, C, D), faintly orange in the neutral gentian (Fig. t) and red in the acid fuchsin methods (Fig. 8). The nuclei are large and vesicular, with relatively little chromatin, are centrally placed and contain a well-marked nucleolus. The cell outlines are sharp. These are the parietal cells, the second characteristic cell of the fundus mucosa of the stomach. The neutral gentian (a neutral combination of the acid orange G and the basic gentian violet) and the acid fuchsin-methyl-green methods were employed to demonstrate the specific staining affinities of the cells and granules of these fundus glands, to add additional evidence to that obtained from the iron-ha.'matoxylin method, that we are dealing with specific secreting gland cells of the true gastric fundus type. The zymogenic secretion granules of the chief cells, having a peculiar affinity for the gentian violet in the neutral gentian stain, are seen colored a dark violet, while the acidophilic granules of the parietal cells have a relatively slight iiftinity for the orange G and hence appear faintly orange. In the acid fuchsin-methyl-green method, the conditions are just reversed, for which rea.son this method was employed. We now find that the acidophilic granules of the parietal cells stain a brilliant red in the acid fuchsin, whereas the zymogenic secretion granules of the chief cells are faintly or not at all stained in the methyl-green. The absence of mitochondria, so well demonstrateil after osmic-bichromate fixation of the tissue and staining after the acid fuchsinmethyl-green method, is doubtless exi)lainable by the fact that the tissue in this case had remained for a long period of time in 10 per cent fonnalin. It would have been interesting to study the mitochondria in this tissue as well as the secretion granules, had it been possible to fix some of the original fresh tissue in some other fixing fluids, such as the well-known acetic-osmic-bichromate mixture. The findings described above are well illustrated in the beautiful drawings in color (Figs. 7 and 8) by Miss E. Norris.

Body aiul Depth of the Gland. — As one observes the gland tubules at greater depths one finds that the same two types of cells are found as described in the neck of the gland tubule.

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Here, however, the larger or parietal cell has a truly parietal situation, that it lies removed from the lumen at the periphery of the tubules and communicates with the lumen of the tubules by a cleft between the chief cells. It also occurs oftener. The chief cells show the same characteristics described above. At the base of the cells and forming a kind of basement membrane, the membrana propria is evident. Secretion canaliculi in the parietal cells were not definitely seen, due probably to faulty fixation. We have here, then, a type of mucous membrane resembling in every particular, both as to structure and staining affinities, the characteristics of the fundus mucous membrane of the stomach.

A well-developed L. muscxdaris mucosce is seen, which here and there sends off small, thin prolongations into the overlying propria and between the glands. The submucosa has the usual structure of this layer in the intestinal tract.

The tunica muscuJaris is thick and composed of smooth muscle fibers intertwining with one another in various directions and not definitely demarcated into an outer and inner layer of longitudinal and circular direction. No definite nerve plexuses were recognized.

III. Section Taken From Proximal Part of Meckel's Diverticulum

The structure of the mucous membrane and wall of the diverticulum near to its intestinal attachment does not differ in any important detail from that described above as occurring just proximal to the line of transition (Fig. 4). It was thought that possibly the principal type of mucous membrane, that resembling transverse colon in structure, would assume at the proximal end of the diverticulum the character of ileal mucosa. This is not the case however, for the mucous membrane still resembles that of the transverse colon as described above. There is this difference, however: the mucous membrane is slightly thinner, the folds or plicae are lower and there is less IjTiiphoid tissue, both diffuse and in the form of follicles. There are more nerve fibers occurring in the submucosa, the tunica muscularis is thicker and more sharply demarcated into an inner circular and an outer longitudinal muscle coat, between which there are more nerve fibers recognizable. Inasmuch as the other findings are similar to those occurring more distally (Fig. 4), a further description need not be given here.

Thus, positive evidence has been advanced by the methods of finer cytological study, that the zone of aberrant glandular tissue in the tip of Meckel's diverticulum is identical in every respect with gastric fundus mucosa. It was thouglit desirable to make this detailed study of the histological character of this anomalous Meckel's diverticulum for three reasons: In the first place, to establish definitely the fact that we are dealing with a zone of aberrant, but typical, gastric mucosa. This was necessary in view of several reported cases of a somewhat similar nature in which the anomalous or aberrant tissue occurred at the umbilicus and was said to give the appearance of pyloric or simply gastric mucosa, although no histological

examination is reported. For purposes of argument in the explanation of these anomalies it was first of all necessary to advance definite proof that we were dealing with real gastric mucosa. This having been done I feel I have advanced good reasons for believing that the anomalous and aberrant glandular tissues occurring at the umbilicus, in obliterated vitelline cords, and, as in my own case, in Meckel's diverticulum, have a common origin, namely, from the remains of the omphalomesenteric duct. Cases in which pancreatic acini and Lieberkiihn's and Brunner's glands have occurred in Meckel's diverticulum have been reported and are given below. Undoubted cases of gastric mucosa, of pancreas and of Lieberkiihn's and Brunner's glandular tissue, occurring at the umbilicus in the form of polyps, depressions or fistulas, have been reported. Several cases are reviewed below in which such aberrant glandular tissue occurred in instances of umbilical fistulse which were connected with Meckel's diverticulum by a strand or cord. In one or two instances a patent Meckel's diverticulum connected with the umbilicus at which such glandular tissue was found. If we are forced to believe that certain fistulaj at the umbilicus, fibrous cords connecting with Meckel's diverticulum, and the latter itself represent the remains of the vitelline or omphalomesenteric duct, then it would naturally follow that all these anomalous glandular tissues have a common origin. With the discovery of gastric mucosa in Meckel's diverticulum, the chain of evidence of the common origin of these tissues is complete. Additional evidence is then afforded for believing that the umbilical anomalies arise from the omphalomesenteric duct, inasmuch as we know that Meckel's diverticuhmi represents the remains of the latter structure. A plausible explanation of the embryonic origin of these umbilical anomalies is thus afforded, a fact which is highly desirable in view of the many conflicting explanations with regard to the latter which have been advanced by authors writing on this subject. In the second place, it is interesting to speculate upon the manner in which true gastric mucosa comes to lie in Meckel's diverticulum, so far removed from the mother organ ; and in the third place, inflammations, ulcerations, and certain pathological new growths occurring at the umbilicus and in Meckel's diverticulum receive a rational explanation on an embryological basis.

In reviewing the literature in search for accounts of the occurrence of gastric mucosa elsewhere than in its normal location, I have found Chapter VII, pp. 144-158, of Dr. T. S. Cullen's ' excellent book on " The Umbilicus and Its Diseases " most helpful. A complete review is given in this chapter of the reported cases of gastric mucosa occurring at the umbilicus.* In the brief accoimt here to be given I have dra'mi f reelv from

• The occurrence of intestinal mucosa at the umbilicus, in the

form of polypoid growths, with or without depressions or fistulfe, is relatively common as compared with the frequency with which gastric mucosa has been found in the same region. For a good review of the cases of umbilical polyps composed of intestinal mucosa the reader is referred to Cullen: "The Umbilicus and Its Diseases," Chapter VI, pp. 120-143. A complete bibliography on this subject is also given at the end of the chapter.

THE JOHNS HOPKINS HOSPITAL BULLETIN, JUNE. 1919

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Fiii. 7. — DrawinfT of a Klaii'l tuhule (.'i niicra, neutral Ci'iitijii ttiiiii. uil iMiiiHToioiit fr.iiii ihc lip "f Mrckel's div<*rtit-itliim. rfim-spondink: tn tin- :iii>a ri*)ires<-n(i>(] in Kiff**. 5 aiKl fi. r anj D, I" wIm.w ihe rompItU' similarity in ttnirtntt' i)n<l Mainjni; atflnilv with the appi-annces tvpirally s*-«n in ffantrit- fumltiH iinuovi. Noti- (1) the rhiff o'IIh with ilicir zvni<>t.'i'ni< "M-rrclifn trriinnli's iili.nff thi- Iniiipn hor<)(-r «f tlif r^-IK ^.tainiil in the vi^lot: ;in<l (2) Ih.' pari.'tal (ills, Y.-.thvt and (l.artr and with larne. fjinily oranKP-fltained ffraniilf» MiitiercHl difTiiscly thn>iiKliout Ihe cyl'^plasm.

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Fin. 8. — Prawine of \hv Kliind lubiilcs in cross-wrtion (formalin, h niicra thickness, acid-fuclliln-niethvl-ifreen sliiiii. oil iinnursiolil from Ihe B-iini- ar.M as r.|)ri«,nliil in V\s. 7. The .hiif (ills iirc now scfii slain..! a taint Ki-c.'ii nnd the /.iiloKeni.- s.'.Ti'tion (rniniilfs ar.- Iiar.ll.v visible. The l.arietal .ells. liow. v.r, show their trial afflnilv for Ihe aii.1 fiichsin. and the laru-e irranules which the.v eonlain ar.> slain.sl a l.lilliani red. Note al-o an occii-si.iiial inast-eell in the inter-tubiilar conne.'tive tisnue.

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this review. Cullen (p. 145) classifies the lunbilical abnormalities in wliifh gastric mucosa was found into three tvpes, thus, for example :

I. An umbilical polyp attached to the umliilical depression by a short pedicle.

II. An umbilical polyp with a cystic cavity opening on the surface of the polyp.

III. An umbilical listula with or without a small projection. Fig. 9 will serve to illustrate the second type.

I. A most interesting example of the first type was described by Tillmanns" in 1882. In a boy, 13 years of age, there was found at the umbilicus a pedunculated tumor, the size of a walnut, bright red in color, without a central opening and covered with mucosa. After a meal had been eaten, the tumor would swell perceptibly, while the mucosa became redder and thicker. The secretion on the surface of the polyp had a tenacious mucoid character. Whenever the tumor was irritated the flow of secretion was increased so that at such times

Flo. 9. — A long umbilical polyp with a central fistulous opening, a remnant of the omptulomesenteric duct, (Schematic, after Cullen, p. 156.) This is an unusual t>-pe. the pol>-p being shorter and more KMile. A feu- instances are reported in which the lining mucofta was shown to be of gastric character. There is no connection between the umbilical polyp and the email inte.stine in this t^-pe of polyp.

2 to 3 c. c. of fluid could be collected in 15 minutes. The secretion was acid in reaction, digested albumen, and upon chemical examination was found to reseml)le normal gastric juice. Upon microscopic examination by Weigert the mucosa was found to have a structure similar to that of the pyloric region of the stomach. On account of its digestive action the secretion of the tumor had caused a maceration of the skin in the vicinity of the umbilicus. Histological examination of the mucosa of the tumor showed this to be similar in structure to pyloric mucous membrane. Tillmanns then explains the condition by showing schematically how a diverticulum of the stomach may be included in the umbilical cord as a prolapse of stomach wall through the umbilicus just as the ileum may do. This explanation will be considered again. No connection with the stomach or other organs was found.

Although the literature upon this subject is scanty, a few subsequent reports of ga.«tric mucosa occurring at the umbilicus were found. Thus, umbilical polypi with a covering of gastric mucosa have been desc-ribed by van Heukelom " (1888), Keichard" (1898), Strada " (1903), and Minelli" (1905).

In van Ileukolom's case, a child two and one-half years of age, a tumor the size of a hickory-nut was found in the umbilical depression. It was red in color and had a granular.

moist surface and was attached by a thin pedicle. The latter was divided and the tumor removed. On microscopic examination the tumor was seen to consist of an inner portion composed of muscle, connective tissue and vessels, luid an outer portion or cortex 2 mm. in thickness and consisting of a mucous membrane with long gland tubules, some interstitial connective tissue and some lymphoid tissue at the base of tlie glands. The latter resembled intestinal glands of tlie Lieberkiihn type. (Van Heukclom's explanation for tliis finding is given below.) Van Heukelom refers to 12 cases of this kind reported in the literature, his own being the 13th case. He feels that there doubtless are many more which have been reported under the diagnosis of " umbilical granuloma " and have not been examined further. Most of tliese granulomata when examined have been found to contain epithelium and glands of intestinal type. In these cases there is no mention made of gastric mucosa.

In a further study of the occurrence of gastric mucosa at the umbilicus and with particular reference to Tillmanns' case and his explanation of it, namely, that the gastric mucosa is derived from a gastric diverticulum, van Heukelom examined a number of human fetuses with this point in view. In one of his fetus cases he foimd a nodule of mucous membrane at the tip of Meckel's diverticulum constricted otf from the lumen of the latter. On microscopic examination this nodule was found to resemble the pyloric mucous menibriuic of this same fetus. The epithelium was very regular, composed of long cylindrical cells with refractile protoplasm and basally situated nuclei. There were no goblet cells. The mucous membrane of the diverticulum, on the other hand, and of the ileum itself was of an entirely different character, namely, intestinal in type. Van Heukelom att^Mupts to explain the origin of this heterotopic mucous membrane, a matter which we shall again consider. It is to be emphasized here that this piece of gastric mucosa was constricted off from the cavity of the diverticulum and in no way communicated with it.

Eeichard reports the case of a boy five years old who presented a tumor, the size of a hickory-nut, in the umbilical region, which had a small fistulous opening and from which a clear fluid escaped. There had been a " weeping navel " since birth. At operation the umbilicus was circum.scribed, the jjeritoneum was opened and a cystic, bluish, demarcated tumor was seen, from which a thin stalk ran upwards into the abdominal cavity. The stalk, which was very delicate and could not be followed, was divided. The tumor with the surrounding area of macerated skin was excised. Closure was made of the peritoBcum and abdominal wall and the patient made a good recovery.

The cavity of the tumor was lined with a mucous membrane which, when microscopically examined, was seen to resemble the gastric type. No further histological description 18 given and no statement is made as to whether it was clearly of pyloric or fundus character. Reichard is reminded of the case of Tillmanns, except that in his own case the condition had not gone on to evagination and prolapse of the tumor. He was inclined to believe in the theory of Tillmanns, namely.

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that this mucous ruembrane is derived from a diverticulum of the stomach, and that due to the rotation and further development of the stomach there is a twisting and later obliteration of the cord of communication with the stomach. Siegenbeek van Heukelom, as we shall see, is opposed to this view.

Strada reports the case of a young woman of 20 who had a tumor at the umbilicus covered with mucosa. On microscopic examination this mucosa was seen to consist of cylindrical epithelium and glands of the pyloric type.

Minelli describes an adenoma occurring at the umbilicus presenting a picture of gastric adenoma.

II. A case of the second type, namely, an umbilical polyp with a cystic cavity opening on the surface of the polyp, ha.s been described by Eoser" (1887) in a boy one and one-half years old. A bright red swelling was found at the umbilicus. Opening on the surface of this swelling, which, as stated, belongs to the second type, was a cystic cavity 1 cm. in diameter. The case was very much like that reported by Tillmanns. The secretion from the umbilicus digested the surrounding skin area, was acid in reaction and was responsible for a considerable induration and a red granulation-formation around the opening. The walls and mucous membrane of this cavity were excised. A secondary cauterization had to be done three weeks later on account of incomplete removal. A detailed description of the structure of the mucosa is not given, mention being simply made that the closely aggregated tubular glands, between which there was a good deal of muscle tissue, resembled in every way gastric mucosa. There is no mention made of a serosa nor as to whether the glands were of the fundus or the pyloric type. Eoser was inclined to accept the explanation of Tillmanns for this occurrence, namely, that a portion of gastric mucosa had been constricted off from the pyloric region at a time when the stomach had a vertical position and the pylorus was supposed to be nearer the umbilicus. It is hardly necessary to state, as will be explained in further detail below, that this assumption does not suffice, for it is well known that the pylorus in infants and very young children is in no such proximity to the umbilicus, inasmuch as the large liver sepalates the pylorus and the stomach from the anterior abdominal wall.

III. Fistulous tracts occurring at the umbilicus and containing gastric mucosa have been described by von Eosthorn " (1889), Weber (1898), Lindner"" (1898), Lexer" (1899) and Denuce' (1908). These belong to the third type of cases mentioned above.

Von Eosthorn reports the case of a boy seven years old who had an umbilical fistula. Its presence was first recognized when the cord dropped off. After this a red papule formed which secreted watery fluid and into which a sound could be introduced for a distance of 2 cm. There was a continuous flow of this secretion which amounted to 5 c. c. in 24 hours. It was acid in reaction, slowly digested albumen and did not positively contain free hydrochloric acid. The fistula was excised and the patient was wall in 10 days.

On microscopic examination of the tissues from the depths of the tmnor, gland lobules were found which reminded one of parotid gland, whereas the branched tubules resembled pyloric glands of the stomach. Von Eosthorn assumed that the acid reaction of the secretion was due to zymotic external influence which had altered the original alkaline reaction. Lieberkiilm's glands were also found in the fistula, von Eosthorn ofliers and accepts the explanation of Siegenbeek van Heukelom for the occurrence of his findings.

In Weber's case there was found in a boy three years old a small red tumor at the umbilicus from which a fistula led downwards for a short distance. From this fistula flowed a watery secretion which contained mucous shreds, but never intestinal or gastric +++++ CONTENTSs. The secretion amounted to half a wineglassful in 24 hours. At meal times the secretion was increased and then often accompanied by a colicky pain. A digestion ulcer had formed around the fistulous opening at the umbilicus which was one-half of a centimeter in diameter. This secretion was alkaline to litmus. Weber felt that the secretion of the tumor was increased during digestion probably by a reflex action through its nerve supply which he thought was doubtless the same as for the normal stomach, for, as we shall see, he felt that the tumor was derived from the stomach by a process of diverticulum-formation. This is iu keeping with Tillmanns' view.

The fistulous tract with the surrounding macerated skin was excised. After the peritoneum was opened a thin cord was found leading from the inner end of the tract to the under surface of the liver, but without attachment to either stomacii or intestine. A cystic bluish tumor was found at the umbilicus. The stalk was divided, the tumor extirpated as mentioned and closure was made, followed by recovery of the patient.

The cavity of the tumor was lined with a thick mucosa which was of the pyloric type. The columnar surface epithelium was seen to dip down to form glands which were made up of only one kind of cells. There were no chief and parietal cells as in the fundus region and no goblet cells, no villi and no glands or follicles of the Lieberkiihn type. There was an L. niuscularis mucosce and outside of this a longitudinal and circular muscle coat and a thick serosa. Weber felt that from the gross and microscopic appearances it was safe to assume that he was dealing with normal stomach mucosa from the pyloric region. He felt, also, that the cord passing to the under surface of the liver represented the remains of the umbilical vein. Weber was inclined to the view of Tillmanns, that this fistula and tumor represented a portion of the diverticular stalk from the pyloric region and had become constricted off at the umbilicus.

Lindner, iu the discussion of a case of extirpation of a persistent ductus omphalomesentericus reported by Korte in 1898, reports a ca.se of his own in which there was a small, reddish papule at the umbilicus in a boy three years old. For some weeks or even months there was a secretion from this fistula and around it there was a large area of digestion of the abdominal wall. A sound could be introduced into this fistula

JiXE. 1919]

IT) I

for a short distance. At operation a tumor was found, the size of a walnut, behind the umbilicus, wliich connected in no way witii tlie intestine. From the upper pole of the tumor there was a fine connective-tissue strand running to the under surface of the liver in the re>;ion of the incisura. There were no vessels palpable in tliis cord, which seemed to have no importance whatever. The tumor was excised and was found to be lined by mucous membrane of the pyloric type. Lindner states that ca.ses of this kind are extremely rare and dillicult of explanation. He refers to the cases reported by Tillmanns, but does not ajrree with Tillmanns' explanation of their occurrence. He states that there was no evidence in his case that the tumor had any connection with a diverticulum or former prolapse of the .<tomach. Lindner did not attempt to explain the oc-currence further.

Lexer's patient was a child one year old with a congenital umbilical fistula around which the skin was macerated. The fluid secreted bv the fistula was clear, tenacious and iicid in

Flo. 10. Persist*nre of the out«r end of the omphalomesenteric duct in the form of an umbilical flKtula attached to the small bowel by a (Ibroun cord. (Schematic, after CuUen, p. l.'>6.) This is the tj-pe of remnant of the omphalomesenteric duct described by Lexer. In the latter's rase, however, there was a blind fistula at the umbilicus leadinir downwanls a short distance and also a fistulous tract leadinf? from the small intestine through the fibrous cord or obliterated Meckel's diverticulum. The two fistulous tracts, however, did not communicate. The outer umbilical fistula was lineal by (gastric mucosa and the inner or proximal fistula by intestinal mucos;i.

reaction and chemically resemliled gastric juice, in that it readily digested egg albumen and fibrin. At operation the fistulous tract was found to have a cord of attachment, as thick as a lead pencil, to the convexity of the small bowel. The cord was amputated from the intestine and the fistulous tract excised. The child made a rapid recovery. The proximal or inner end of the cord, which was attached to the intestine, evidently represented Meckel's diverticulum (Fig. 10). The extirpated fistulous tract had a rather wide opening at the umbilicus and al.so at the intestinal end, although it was not completely patent throughout it.« whole extent. The external fistula was one and one-half centimeters in depth. The specimen was thus divided into two i)art.«. The proximal larger section, which communicat<'d freely with the bowel, had a mucous membrane very similar to that of the intestine and of the type generally found in Meckel's diverticulum. Lieberkiihn's glands with numerous goblet cells and individual lymph follicles characterized this mucosa. In the original, a plate of a low-power drawing is shown of the histological appearance which resembles my own case, the mucous membrane appearing very much like transverse colon in many respects. The appearance, as shown by section, of the external or umbili

cal portion of tliis fistula was very different. The mucous membrane was of tJie pyloric type, as similarly described by von Kosthorn and Lindner. The epithelium was tall and cylindrical and the protoplasm highly refractile. The nuclei were basally situated and there were no goblet cells. In the deptli there was to be seen a riclily developed zone of tubular glimds connected by numerous crypts with the lumen of the fistula. In general, then, the wliole structure of the mucous membrane resembled that of the pyloric region of the stomach. This structure was not as regular, however, as in the normal structure. In the original, a second plate is showi to illustrate this mucosa. External to the mucous membrane there are the usual muscular layers. For a short disUmce the luniina of the two segments overlapped one another, so that in a single section taken at this point one could see both types of mucous membrane: the intestinal, belonging to the proximal fistula or cavity, and the pyloric type, corresponding to the external or distal fistula. In the deptli there was only an imperfect cellular connection between these two types of mucous membrane. At this point tliere was a mixture of the two types of mucous membraJie and Ix'.xer believed that the outer fistula was formed originally, by a constricting process, from the original diverticulum of Meckel. The findiiig.s, as a whole, Lexer believes, allow of no other explanation than that there is a complete persistence of the ductus ompluilome.sentericus, whose outer portion, probably as a result of very early separation, is subjected to a different evolution of its mucous membrane than that portion of the fistulous tract which connected with the intestine, namely, Jlcckel's diverticulum.

In explanation of the similarity of the secretion from the outer portion with that of gjistric juice. Lexer was unable to give any satisfactory facts and referred to the rather unsatisfactory attempts at explanation by van Hcukelom and von Rosthorn. Lexer was more inclined to believe tliat tlu^se formations arose from rest* of the original omphalomesenteric duct and Meckel's diverticulum rather than from gastric diverticula, even though there was lacking the anatomical connection between the umbilicus and Meckel's diverticulum.

In order to feel that the gastric mucosa at the umbilicus was derived from the same mucosa or from the same structure* from which Meckel's diverticulum develops. Lexer said he would like to see a case in which there was a preservation of the connection between the gastric mucous memiirane at the umbilicus and a Meckel's diverticulum. My own case shows that even without such an anatx)niical connection gastric mucosa is found in Meckel's diverticulum and thus affords additional proof that the cases of gastric mucosa at the umbilicus have an origin similar to that of Meckel's diverticulum.

Denuce described in a boy 21 months old a congenital fistula at the umi)ilicus from which there was an abundant flow of secretion which was ordinarily colorless, sometimes slightly hemorrhagic, and which gave an acid reaction and upon chemical examination was found to be practically identical with gastric juice. There was digestive action on the skin around the umbilicus. The microscopic examination of the fluid revealed nothing of imjiortancc. Free hydrochloric acid was

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present. By means of a sterile pipette 3 c. c. of secretion were collected and examined chemically. The principal findings included demonstration of the presence of albumen, peptone and free hydrochloric acid. The fluid digested coagulated albumen. He concluded, then, that the secretion must be considered a kind of gastric juice. At the operation the fistulous tract was removed without necessitating the opening of the peritoneal cavity. The peritoneum was transparent and it was possible to see, a little to the left of the deeper attachments of the fistula, a cylindrical cord which, at its proximal or inner extremity, was connected with one of the intestinal loops (Fig. 11). It was at once recognized that this cord represented Meckel's diverticulum and connected at its distal extremity with the umbilicus. The diverticulum was then exposed and amputated at its base. The child made a good recovery.

Fig. 11. — An umbilical polj-p connected with Meckel's diverticulum by a fibrous cord. (Schematic, after Cullen, p. 121.) This is the type of remnant of the omphalomesenteric duct which was described in IJenuce's case. In the latter, however, the umbilical polyp had a central fistula which was lined by mucosa of the fundus tj-p'e. Remnants of practically the whole of the omphalomesenteric duct are present here. The outer end is represented by the umbilical polyp, the centrai portion by a fibrous cord and the inner end by Meckel's diverticulum. The latter had the usual intestinal type of mucosa.

The tissue removed was preserved in formalin. The specimen consisted of two parts : the outer fistulous part attached to the external surface of the peritoneum and the inner part or segment consisting of Meckel's diverticulum attached at its distal extremity to the inner peritoneal surface. A section from the outer fistulous part showed the mucous membrane to liave the characteristic structure of gastric mucosa of the fundus type. The surface cells were tall, cylindrical in type, and filled with mucus. In the connective tissue there were some fibroblasts, mast-cells and eosinophilic cells. The superficial tubules were continuous below with the true peptic glands. The latter were lined with clear cells containing zjaiiogen granules and a second type of cell, the parietal cells. These were very numerous in the depth of the culde-sacs, but less abundant in the deeper portions of the gland tubules. The eosinophilic cells and the mast-cells were also found in the deeper portions of the glandular zone. In the corium true lymphoid nodules with germinating centers were present. The muscular layer on the outside was very thick.

In brief, then, Denuce felt that he was deahng with a gastric heterotopy in the form of an isolated small cul-de-sac or fistula at the umbilicus, plainly and fully functioning. Before discussing further his own case he then refers to some previous observations on the development of our understanding of the

peculiar histology of congenital umbilical fistula of the socalled pseudo-pyloric type, which is extremely rare.

Finally, it may be well to refer briefly to the case described by Salzer "' (1904) of a patent diverticulum (Fig. 12), which in the free abdominal portion showed normal characters of the intestinal mucosa. In the prolapsed portion at the umbilicus, however, there were found glands resembling in structure the cardiac glands of the stomach. In the histological description of these glands he says the cells of the gland tubules are clear, finely granular, polygonal in shape and have a basal nucleus and some affinity for eosin.

In explanation thereof he suggests that, in the closure of the abdominal cavity, for some reason or other, there is a partial or complete cessation in the evolution of the vitelline duct and that thereby the entoderm is irritated or stimulated to

Fig. 12. — .\ patent omphalomesenteric duct with a polj-poid formation at the umbilicus. (.Schematic, after Cullen. p. 190.) This represents the type of case described by Salzer. The lumen is continuous through the umbilical polyp, through the persistent omphalomesenteric duct, and communicates with the small intestine.

a variable difl'erentiation, so that there is a development at one time of intestinal mucosa, at another time of gastric; again, there may be produced parotid gland or even pancreas. He says, furthermore, that these pathological pictures are always to be found at the distal end of the remnants of the \'itelline duct, in fact, just at that point where the incomplete involution of the vitelline duct is so apt to be found. There have been many different views in explanation of the origin of these aberrant tissues at the umbilicus, with particular reference to the occurrence of gastric mucosa. Before entering upon these, however, it will be helpful to review briefly the embryological evolution of the omphalomesenteric duct. In this way a clear conception can be had of the probable origin of a large number of anomalous conditions which one finds at times at the umbilicus and in its neighborhood.

The vitelline or omphalomesenteric duct represents in fetal life the communication between the intestine (ileum) and the yolk sac. The yolk sac in time develops into the umbilical vesicle. Ordinarily, at about the seventh week to the tenth week the yolk stalk, which connects between the ileum and the umbilical vesicle, separates from the intestine. The latter, which at first lies in part in the umbilical cord, retracts into the abdominal cavity and thereafter there is no further indication of the original connection between the intestine and the yolk sac. If the separation of the intestine from the yolk stalk is delayed or fails to

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occur at all, then various resultiug anomalies are found in the region of the umbilicus at the time of birth or even later in life. The slightest persistence of the vitelline duct is represented by a thin connective-tissue strand extending from the umbilicus to the ileum. This strand is of little interest aside from the fact that occasionally intestinal obstruction may be produced by it. The fullest degree of persistence of this structure is represented by complete patency of the duct, thus establishing a free communication between the umbilicus and the intestine. From a condition of this kind there develops the well-known type of congenital umbilical fecal listula, numerous cases of which liave been reported. Through such a listula a portion of the bowel wall or even a loop or more of small bowel may prolapse. Between these two extremes there are all possible transitions. The most common partial persistence of the vitelline duct is that of the well-known finger-like diverticulum of Meckel, which is usually entirely separated but may be connected with the umbilicus by a few fine strands of connective tissue. Such cases are also numerous. A diverticulum thus attached to the umbilicus may cause various types of fetal strangulations, torsions and obstruction. At other times, this duct connecting between the umbilicus and the intestine becomes obliterated at both the umbilical and the intestinal extremities with an intervening lumen lined by a cylindrical epithelium and containing more or less secretion. From a remnant of this kind arise the well-known cysts or entcrocystomata. Again, the duct may remain open at the umbilicus and become obliterated within the abdominal cavity. This type of persistence gives rise to umbilical fistulas, tumors and cysts. These may be opened externally at the time of the ligature of the umbilical cord or through umbilical inflammation. Again, there may be a nodule of mucous membrane with or without a lumen and constricted off from the tip of Meckel's diverticulum with which it thus has no communication. Both structures, however, evidently arise from a partial persistence of the original vitelline duct.

We might consider now the theories and views which liave been advanced to explain the occurrence of aberrant glandular tissue at the umbilicus and which concern particularly those cases of gastric mucosa reported above.

The first view was that of Tillmanns (1882), namely, that in the cases exhibiting gastric mucosa at the umbilicus in the form of a tumor or fistula we are dealing with remnants of gastric diverticula which have been preserved at the umbilicus, but which have severed their former connections with the motlier organ. This view was accepted by Reichard, Roser and Weber. The last, particularly, was a firm believer in this probable origin of the aberrant gastric tissue, and in his report in 1898 explains in detail the mechanism of this formation. As it was impossible for me to get Tillmanns' original article I have quoted largely from Weber's article which follows in general the views of Tillmanns. According to this view, then, there occurred in early fetal life a herniation of the stomach at the umbilicus, which herniation was still connected with the stomach by a kind of diverticulum and that this diverticulum was opened at the time of birth. The question which Weber

now puts to himself is this : How does a gastric diverticulum or herniation come to lie in the first portion of the umbilical cord? His explanation is as follows: In the youngest human embryos which had been examined up to his time, and which were from 14 to 18 days old, the intestine has not yet become a more or less closed tube, but communicates by a rather wide stalk with the yolk sac. Gradually the yolk sac develops into the umbilical vesicle, which is connected by means of the vitelline duct with the sub.sequent tubular intestine. The vitelline duct becomes a portion of the umbilical cord and later obliterates. The bowel retracts into the abdominal cavity and all connection with the umbilical cord disappears. Up to this point the presence of a portion of the intestine in the beginning of the umbilical cord is a physiological occurrence. If separation of the vitelline duct from the intestine is delayed, then traction within the umbilical cord is exerted upon the intestinal tract and the intestine remains as a normal +++++ CONTENTS of the first portion of the cord, thus producing an umbilical herniation with small intestine as its +++++ CONTENTSs. If this herniation remains it can be readily overlooked by the physician or the midwife, and at the time of ligature of the cord it may be opened so that a fistula may rise from which the child generally dies as a result of complicating peritonitis. On the other hand, such a hernia may be only a temporary occurrence and subsequently, after separation of the vitelline duct, the bowel may retract into the abdominal cavity. In a case of this kind a dilated ring persists at the umbilical opening and thus predisposes to a potential hernia. In this manner a diverticulum of the stomach might enter the umbilical opening, or even without assuming a delayed separation of the vitelline duct such a herniation is conceivable if one imagines the stomach held in application against the umbilical opening by the presence of adhesions.

The second question which Weber asks himself is this: Why is it that there is no tract or strand connecting with the stomach ; in other words, why is it that the prolapsed piece of mucous membrane appears as an anlage entirely separated from its point of origin ? He believes that there are processes of con.striction during the period of development which play a role if Tillmanns' theory is at all correct. Thus, if we assume that in an early developmental period there is an attachment between the first portion of the umbilical cord and the stomach, then, as a result of this, traction is exerted upon the stomach as against the traction of the mesentery. The stomach is drawn out into a diverticulum and the connection between the adherent portion and the stonuich proper is narrowed down to a very small duct. In addition to this, there are the subsequent changes of position to which the intestinal tract and the stomach are subjected in their further embryological development. Originally the stomach is formed as a fusiform dilatation of the otherwise uniform intestinal tract and has a vertical position. Its long axis becomes transverse and the pyloru.s comes to lie high on the right and the cardia moves to the left. The portion to the left then develops as the fundus. In addition there is also a torsion of the long axis, so that the left surface becomes anterior and the right

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posterior. The mesentery also makes these twists and must therefore alter its length and form, thus creating the bursa omentalis. If we now assume that abnormal adhesions have held tlie stomach wall in apposition with the region of the umbilicus, then this change in position can readily cause a narrowing of the duct-like connection between the umbilical herniation and the stomach, resulting in the formation of a twisted cord which in time obliterates and finally disappears entirely. Assuming these facts as a plausible hypothesis, Tillmanns and his adherents endeavor to explain the occurrence of gastric mucosa at the umbilicus as a form of ectopia ventriculi. Against this view van Heukelom takes a decided stand.

Van Heukelom, whose view was accepted by von Eosthorn, believes that these aberrant growths at the umbilicus represent remains of the vitelline duct and arise in a manner which he explains as follows : In the second month of fetal life the intestine still forms a loop which is to be found in the umbilical cord. The tip of this loop represents the point from which the ductus omphalomesentericus is constricted off. In the third month this intestinal loop retracts and then the intestine lies free in the abdominal cavity. If we now assume that this diverticulum or loop, for some reason or other, does not retract at its proper time on account of the tension of an unobliterated vitelhne duet, then the portion of the diverticuhim connecting with the intestine may be pulled away, and being thus entirely separated from the latter comes to lie isolated at the umbilicus. In this manner we have the beginning of our ectopia. If now this mucous membrane and musculature of the open diverticulum at the umbilicus continue to grow while the surrounding umbilical structures retract, then the former will evaginate and in this fashion, in time, a tumor forms, which is covered with mucous membrane. Van Heukelom refers to 12 cases of this kind which he has collected and gives reference to them, his own being the 13th. There are probably many more which have escaped notice because they are classified under umbilical granulomata without further report as to their histology. Many of these aberrant tumors at the umbilicus have been shown to contain intestinal glands and epithelium. In these 13 cases there is no mention made of gastric mucosa.

As already mentioned, van Heukelom described a case of his own of gastric mucosa occurring at the tip of Meckel's diverticulum and feels that there is a uniform origin for all the various aberrant tissues found at the umbilicus. There is a general consensus of opinion that these tissues are derived from the tractus intestinalis, but as to what part of the tract represents the mother organ there is a great difference of opinion. Van Heukelom, in the first place, answers what he considers the erroneous explanation of Tillmanns and Roser, namely, that umbilical gastric mucosa represents a portion constricted off from the early fetal stomach at a time when the stomach is supposed to lie in the vertical position, in close proximity to the umbilicus. Van Heukelom examined a series of fetuses with the purpose of determining the probability of such an occurrence. He concludes that it is impossible to

believe that gastric diverticula can thus be formed, for the reasons that the enormous liver occupies the space between the imibilicus and the deeper lying pylorus and relatively takes up more and more room, the younger the embryo. There is no connection between the pylorus and the umbilicus, but on the contrary there is always a wide separation between them. On the basis of his findings in one of his fetus cases, namely, of a portion of gastric mucous membrane at the tip of Meckel's diverticulum and separated from it, and the finding in Meckel's diverticulum itself of the usual intestinal epithelium, he constructs his theory for the explanation of these variations in histological differentiation.

Two questions, he says, now arise : Firstly, how can one explain the great difference between the epithelium of the distal portion separated from the diverticulum and that of the proximal portion of Meckel's diverticulum? And secondly, is it possible upon the basis of this observation to explain the origin of aberrant gastric ectopia at the umbilicus without resorting to the dangerous assumptions, such as those of Tillmanns and Roser ? In answer to the first question there are the f ollo%ving facts which are helpful : In very young embrj'os the intestinal tract is lined by a single layer of entodermal epithelium which is everywhere of uniform character. Later differentiation into gastric and intestinal epithelium appears and at the same time one recognizes folds and crypts which later become glands. Van Heukelom states further that the difference between stomach and intestinal epithelium occurs first at the time when the meconium or better when bile-stained material is found in the intestinal tube. Then for the first time one can differentiate the tall, regular epithelium from the intestinal epithelium, which is granular, low, shows a different kind of nuclei and contains many goblet cells. If we now remember that the portion of mucous membrane constricted off from Meckel's diverticulum was not in connection with the cavity of the diverticulum and therefore not in contact with the +++++ CONTENTSs of the intestinal tract and that this separated portion of mucous membrane corresponded in histological structure to that of the stomach, the thought arises that this differentiation in the types of mucous membrane is brought about by the influence of the intestinal +++++ CONTENTSs. It was van Heukelom's opinion that it is the influence of the bile which causes the differentiation into intestinal epithelium, and that the gastric mucosa and also this portion of mucosa separated from the diverticulum of Meckel, which do not come into contact with it, take on a different course of histological evolution. This explanation of van Heukelom can at once be considered as quite erroneous, for in the first place it is well known that the fetus swallows certain materials which must contain intestinal +++++ CONTENTSs and therefore bile. Van Heukelom assumes, however, that this swallowed portion is without the agent, which he feels acts upon the intestine differently than upon the stomach. In the second place, in my own case, the area of gastric mucosa occupied the distal third or fourth of Meckel's diverticulum, had a perfectly free communication with it and therefore the intestine and hence was subjected to the same influences as the intestinal mucosa. There could be no doubt about this point.

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One, therefore, need not assume, as van Heukelom did, that it was tlie total separation from the intestinal tract which caused this peculiar development of gastric mucosa.

Now as to the second question van Heukelom asks : Can the facts thus derived give a reasonable explanation for the ori^'in of aberrant tumors of gastric mucosa, such as Tillnianns, Roser and van Heukelom himself described? The latter felt that tliey could. He felt that Meckel's diverticulum might of course give origin to ectopia at the navel. The difficulty in the cases of Tillmaniis, Koser and van Heukelom lay in the fact that, whereas previous observers had derived the inti'stinal epithelium from Lieberkiilin's crypts, in the latter three cases the epithelium showed the character of pylorus. Van Heukelom e-xplains this variation by assuming that the ectopia at the umbilicus originated from the intestinal tract, inasmuch as in his own case the gastric mucous membrane was still attached to Meckel's diverticulum, which, as everyone grants, arises from intestine. The reason, then, for the variations in the initial ditferentiation into gastric and intestinal types of mucous membrane he explains by assuming that if the nmcous membrane preserved its communication with the intestinal tract up to and beyond the period of bile formation and was thus subjected to the influences of the latter, then intestinal epithelium developed; if, however, this aberrant epithelium became separated off from the intestinal tract before the secretion of bile appeared, it developed into gastric mucosa, and thus became morphologically identical with pyloric epithelium. Van Heukelom prefers this view to accepting the hypothesis of Tillmanns and Koser as to the origin of these tissues from gastric diverticula, which view has no anatomical basis and which a priori is doubtful. Here again my findings refute this view, for in my own case the gastric mucosa was developed in full connection and communication with Meckel's diverticulum and therefore in the presence of bile and its influences. Van Heukelom thus derives the intestinal ectopia at the navel from portions separated off from a true Meckel's diverticulum and as a consequence divides this umbilical ectopia into two groups: the first group which separated by constriction and became isolated very early, that is, before bile formation, and thus developed into gastric mucosa ; and the second group which became separated off at a later time. The former will thus contain pseudo-pyloric epithelium and later secrete an acid juice, the latter will show Lieberkiihn's crypts with goblet cells and secrete an alkaline fluid.

The third explanation for the origin of this aberrant tissue is that of Salzer (1901) and Kirnii.sson. According to this view, the following a.ssumption is made: At the time of the closure of the abdominal cavity, for some reason or other, there is a partial or complete cessation in evolution of the vitelline duct. As a result, the entoderm at the umbilicus is stimulated to manifold differentiation and, consequently, at one time we find a diverticulum of intestinal epithelium and at another time of gastric epithelium, and then again we may have the formation of parotid gland or pancreatic tissue. These pathological formations, according to Salzer, are always to be foum! at the distal end of the vitelline duct, at that point particularly

where the predisposing cause of the incomplete involution of the vitelline duct seems to be located. This cause may be in part local irritation or inflammation. In favor of the irritation or inflammatory view, these men pointed to the presence of lymphocytes, mast-cells and eosinophile cells in the mucosa. One need merely state, however, in refutation of this assumption that the finding of such cells is very common in the normal mucosa of the stomach and intestinal tract. There is the statement further that aberrant tissues are always to be found at the distal end of the vitelline duct, never at the proximal. With this assumption it would not be possible in my own case to explain the occurrence of gastric mucosa in Meckel's diverticulum, in a position certainly not subjected to irritative influences such as are supposed to be present at the umbilicus.

The fourth theory was that advanced by Albrecht and Fischl. According to this view these aberrant tissues arose from fetal inclusions or rests occurring at the time of the closure of the abdominal wall. This view is similar to that offered for the explanation of the occurrence of atypical tissues in various parts of the body. The misplaced rests from the junction points of the blastodermic layers are assumed to be the points of origin of these new tissues. It is thus assumed that these misplaced cells may retain their original powers of differentiation. This is the old teratological view for the origin of tumors and aberrant new growths. Here again one need not assume this view, for, in van Ileukelom's case in the fetus and in my own, the aberrant tissue was found in the former attached to Meckel's and in the latter within Jleckel's diverticulum, and thus probably was not the result of misplaced tissues at the umbilicus. In fact, in my own case the gastric mucosa was in direct continuity with the intestinal mucosa of the diverticulum. Salzer, however, admitted that in many cases in the closure of the umbilical ring there was a complete or partial persistence of the omphalomesenteric duct. Fischl felt that his theory explained more satisfactorily the fact that the abnormal formations of gastric, duodenal and pancreatic tissues are most often to be found in the distal extremity of the diverticulum than did those of Tillmanns and Salzer.

The fifth explanation offered by Lexer (18'.)9) and Denuce (1908), whose view is doubtless most nearly the correct one, assumes that these umbilical abnormalities represent the remains of the omphalomesenteric or vitelline duct. Lexer gives no real explanation for his peculiar finding of pseudopyloric glands in the case of the umbilical fistula which was attached to but did not communicate with .Me<'kcl's diverticulum ; but he leans toward the views of van Heukelom, that these tissues represent rests of Meckel's diverticulum rather than of gastric diverticula even in tiiose cases in which we find a mucous membrane with gastric structure and secretion, and in which there is no anatomical connection between the umbilicus and Meckel's diverticulum. He would like to see a specimen in which there is a connection between the umbilical gastric mucosa and Meckel's diverticulum in order to afford anatomical proof for his belief. Such a case is that described by Denuce, in which case the fistula at the umbilicus did not

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communicate with but was attached to Meckel's diverticulum. My own case completes the evidence, for in this case gastric mucosa is found at the tip of Meckel's diverticulum. Denuce, in spite of this latter view, cites the following facts : Originally the intestinal tract is lined throughout by a simple uniform entoderm. The differentiation into gastric and intestinal types is a later development. The cause of this differentiation in the epithelium is not clear. He suggests that isolation and occlusion of segments of a diverticulum from the intestinal tract are essential to the formation of gastric epithelium, and that there might be very early displacement in the original vitelline duct which gives rise to variations in subsequent differentiation. He is inclined to agree with van Heukelom that the occlusion of the segment is the initial cause for this variable differentiation, but he does not accept van Heukelom's view that the differentiation depends at all upon the action of the bile. He says this leads us into the domain of pure hypothesis. In other words, Denuce and Lexer lean to the view that these tissues arise from remains of the omphalomesenteric duct, namely, the intestinal tract, but offer no further explanation for the variations in subsequent differentiation. Denuce thinks that while occlusion and separation are probably responsible, the action of bile is not a factor. He gives no further explanation. Here again tliis view can be answered in a word, namely, that occlusion and separation are not necessary, for they surely were not present and could not be responsible for the variation in my own case. In a review of the cases reported in the literature of aberrant glandular tissue occurring in Meckel's diverticulum itself, I have been unable to find mention of the occurrence of gastric mucosa. In the search it became apparent, however, how often, relatively, pancreatic tissue has been found in the intestinal tract; in fact, cases were found in which pancreatic nodules occurred in the stomach, duodenum, jejunum, ileum and even in Meckel's diverticulum. There were no cases found in which pancreas was discovered below Meckel's diverticulum, a fact which will be considered again. Because of the relative frequency with which aberrant pancreas has been found in the intestinal tract, a brief review is given of these cases and finally a few others are also reported in which Lieberkiihn's* and Brunner s glands and pancreatic tissue were found in Meckel's diverticulum. There is one case also reported in which pancreas was found at the umbilicus. These cases are reviewed with the hope that they may throw some light upon our own case and in general upon the occurrence of gastric mucosa at the umbilicus and in Meckel's diverticulum. The case reports are reviewed in groups according to the location of the aberrant pancreatic tissue ; the first cases being those in which pancreatic tissue occurred in the stomach wall, then in the duodeum, jejunum, ileum, Meckel's diverticulum and at the umbilicus. In only a few instances are the histological descriptions complete and in many instances not really convincing enough to make one feel that the author was really dealing with true pancreatic tissue. On the whole, the explanations offered for these abnormal findings are rather unsatisfactory. Eeference, however, will be made to them in order to

complete our review of tlie theories which have been offered to explain these occurrences.

Klob " (1859) found a flat, circular swelling, of glandular appearance, inserted between the peritoneal and muscle coats, in the middle of the greater curvature of the stomach. Upon microscopic examination this glandular mass showed pancreatic structure throughout. No further description or measurements are given. Klob called this tissue " pancreas accessorium." In substantiation of the belief that he was dealing with an accessory pancreas, he refers to Leydig," who claims that in the land salamander in the wall of the jejunum and in pelobates in the wall of the stomach one can find isolated portions of the pancreas with excretory ducts.

Gegenbauer " (1863) similarly described an accessory pancreas occurring in the wall of the stomach, 2 cm. from the pyloric sphincter and near the lesser curvature. It consisted of a rounded, somewhat elevated, tumor mass 14 mm. in width and 6 mm. in thickness and covered everywhere by stomach mucous membrane. Upon microscopical examination the mass was found to he an acinous gland, resembling pancreas in structure. No further description is given. He found a small duct opening upon the surface.

Merkel " (1905) described two cases of pancreatic rests occurring in the submucosa of the stomach.

Wagner" (1863) described two cases of aberrant tissue occurring elsewhere than in the normal location. In one of these cases, which was very similar to Gegenbauer's case described above, the pancreatic tissue occurred in the wall of the stomach.

Hyrtl " (1860) mentions a rare occurrence of accessory pancreatic tissue behind the arteria and vena mesenterica superior and surrounding these vessels at their roots.

Bernard" (1858) described a second, smaller, pancreatic duct communicating with the main duct, oftentimes, however, emptying independently just below the main duct, in man, dog, cat and rabbit. Bernard has also described tubuloacinous glands in the wall of the duodenum, which are supposed to have the same physiological properties as the pancreas.

Klob" (1859), in a second case similar to the one he described above, found a mass in the posterior wall of the first portion of the jejunum, 4 cm. beyond the duodeno-jejunal turn. No duct was found. Upon microscopical examination the mass was found to consist of pancreatic tissue.

Merkl" (1905) described a pancreatic rest in the subserosa of the jejunum.

Zenker °' (1861) described a frequent variation called the "pancreas minus," a lobe of pancreatic tissue possessing a kind of attachment to the caput pancreatis and emptying usually into the ductus wirsungiajius:, often, however, 1 cm.1.5 cm. below the normal duct. Zenker records five eases, in three of which the accessory pancreas occurred in the wall of the small intestine. In the fourth case there were two accessory pancreases, one 16 cm. the other 48 cm. below the duodenum. The most curious was the fifth case : in this one there occurred, 54 cm. above the cecal valve, a finger-like, true diverticulum 5.5 cm. long, with a narrow, fatty mesentery, in the fat

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of which the accessory pancreas was found situated near tlic tip of the diverticulum. In a foot-note Zenker says:

Vielleicht bezleht sich eine alte von Meckel (Patholog. Anat. I Bd. S., 590) citirte Beobachtung von Schulze auf elnen gleichen Fall. Dieser (Acta, natur. curios. Tom. T. Obs. 226, p. 504, Ao. 1727) fand bei elneni Neugebornen an der Spitze eines wahren Darmdivertikels "cine driisenahnliche Warze." (Im oriprinal beisst es, cuius apicem glandulosa papilla quaedam quasi roronabat. ) Da dieselbe nicht welter beschrieben ist. lasst sich freilich dariiber nicht entscheiden. Vielleicht ist damit auch nur eine jener Ausstiilpungen gemeint, die sich bisweilen an der Spitze des Divertikels finden.

The location of the accessory pancreas in the bowel wall varies. It may be in the submucosa or between the serosa and muscularis. Zenker gives a general histological description, makes no mention of the zymogen granules or islands of Langerhans and states simply that the general structure was that of true pancreas. He was able to find a duct in all his cases. The largest accessory pancreas of this series had a diameter of 3.5 cm. The true pancreas in all cases was normal. He regards the occurrence of accessory pancreas as a developmental anomaly originating in the earliest anlage of the pancreas.

Zenker thinks these anomalies can be explained as follows: The usual pancreatic evagination is single, sometimes double. occasionally triple for the first anlage. These evaginations when multiple then develop into separate glandular bodies. In the further course of development, one becomes the main. true pancreas ; the remaining evagination, either above or below the pancreatic duct, is carried upwards or downwards by the further growth and elongation of the original straight intestine. If above, it comes to lie in the wall of the stomach; if below, it may occur either in the duodenum, jejunum, small intestine or even in Meckel's diverticulum. The last would be the lowest possibility, as Meckel's diverticulum lies at the transition line between the upper and the lower intestine. It is difficult to understand how the gastric anlage in our case could get below the embryologically possible position of the pancreas or how gastric mucosa normally above could get below the level of the pancreatic duct according to this explanation. Zenker could find no evidence of an effect of the accessory pancreas upon the digestion in these individuals.

Several cases are reported further of the occurrence of pancreatic rests in Meckel's diverticulum. Thus ilerkel (1905) demonstrated a pancreatic rest or anlage in the tip of Meckel's diverticulum.

Neumann" (18T0) found, in a child 10 months of age. a swelling the size of a ."mall bean attached to the tip of Meckel's diverticulum by a short pedicle. In its center was a lumen connected by a kind of duct with the lumen of the diverticulum. Upon histological examination, this body was said by Neumann to have gland alveoli resembling in appearance those of the pancreas. No further description is given. This case in many respects resembles the one of the hiunan fetus reported by van Heukelom. except that in this instance the nodule was completely con.stricted off from Meckel's diverticulum at its tip, .separated entirely from the lumen and Wii<

composed of gastric nmcosa. It is interesting to have two cases in many respects simulating one another, one case composed of pancreatic tissue, the other of gastric tissue.

Regarding this anomaly as a Meckel's diverticulum, and this in turn as coming from the ductus omphalomcsentericus, Neumann finds it difficult to see an association between tlie presence of the diverticulum and the occurrence of pancreas. Neumann suggests that the former may not have been a true Meckel's diverticulum, but rather a secondary formation due to mechanical pull of the evaginating glandular mass on the bowel wall. The location of the diverticulum and the subsequent report of a number of similar findings in true Meckel's diverticula would indicate th.it this evagination was probably also a true Meckel's diverticulum.

A good description, together with illustrations of a case in which an accessory pancreas was found at the tip of a Meckel's diverticulum, was given by Bize ' in 1904.

Albrecht' (1901) foiuid in the tip of Meckel's diverticulum a yellowish nodule, about the size of a pea, which resembled microscopically typical pancreatic tissue. In this case, contrary to many other cases described, the author fakes pains really to identify the new tissue formation. He mentions the occurrence of abundant zymogen granules in the cells, centroacinous cells, islands of Langerhans, ducts emptying into the lumen of the intestine, nerves and blood-vessels occurring in normal fashion. Five, possibly six, ca.«es of similar nature are reported in the literature, but without further discussion or description.

In regard to the origin and development of the.fe structures this author suggests that they are possibly :

1. Aberrant Pancreas. — He thinks this pos,<ibi]ify cannot be denied, for on the basis of comparative anatomy it has been shown by v. Kupffer that in the sturgeon pancreatic tissue has been found in the ductus cholcdochus. Others have demonstrated the occurrence of pancreas in the pajiilla minor. These probably represent isolated portions of the original anlage. It is questionable, however, according to this author, whether such rests would lie found as low down as the umbilicus. Furthermore, this conception does not explain why these rests, when found in the region of the lower ileum, occur regularly in the tip of Meckel's diverticulum.

2. Hestx of Glandular Formations Orii/itiatint/ from the Yolk Stalh- or Sac. — That such an origin might be possible is perhaps indicated by the findings of Graf Spec, who described in the yolk sac in the case of the human embryo numerous tubular glands with prismatic epithelium. Opposed to this view, however, is the fact that an analogy of the normal pancreas is impcssible, and furthermore that one would have to imagine that a comple metaplasia of an embryonic organ had taken place.

3. The Alaii.stic Formation. — There is no evidence for this view.

4. " Cdrro(ieneti^." — By exchwion, f.liis conception seems to be more probable as compared with those just mentioned. Whichever view one prefers, a number of interesting thoughts arise. In the first place, the same general developmental fac

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tors or influences must have been present which determined the formation of the normal pancreas, except for the causes of tlie greater growth and the topographical relationship of the normal pancreas. Thus at once we are forced to dismiss the belief that pancreas develops as a result of factors which are present only in the region of the duodenum, such as certain mechanical combinations or strictly localized hormones or similar tissue-stimulating substances. It would seem that, according to this author, the influences which can give rise to these aberrant pancreatic formations are not specific for the duodenum. In fact, the specific reasons for the occurrence of this aberrant pancreas must be sought for in the potentiality for pancreatic formation in the whole small intestinal portion of the original intestinal anlage, namely, the entoderm, certainly in that portion extending from the normal pancreas anlage down to the ductus omphalomesentericus. Perhaps the frequent location of the heterotopic pancreas in the tip of Meckel's diverticulum is consequent upon causative factors similar to those responsible for the formation of pancreas in both instances and sharply localized in the immediately contiguous bowel. These factors may be of a mechanical character.

In conclusion this author speculates upon the possible benefit this type of pancreas can have for its possessor. Since, at least in this present instance, the aberrant pancreas was capable of active normal secretion, it would seem to all appearances that there was a lessening of the danger to the patient of stagnation of the intestinal +++++ CONTENTSs with its consequent possible mechanical and infectious complications, Meckel's diverticulum in this instance being 25 cm. long.

Brunner,' as cited by Tschiknawerow, found in a case of invagination, in a child four and a half years old, a Meckel's diverticulum, 37 cm. above the ileocecal valve, which had at its blind tip a tumor measuring, in its various dimensions, 25 X 22 X 19 mm. Microscopic examination of the tumor showed it to be composed of two parts : one consisting of adipose tissue; the other composed of gland lobules, ducts and lymphoid nodules and resembling pancreas in structure.

Hedinger " (1906) demonstrated in the body of a 30-yearold man, dead of cardiac disease, a Meckel's diverticulum 5 cm. in length. In the wall at the tip of the diverticulum a granular, light yellow nodule of tissue was found measuring 2.5 cm. in length and .5 cm. in width. Microscopical examination showed this nodule to consist of typical pancreatic tissue with an occasional duct and with a second lobule resembling Brunner's glands in structure. He adds a review of the literature bearing upon similar findings and discusses the significance of them.

Nazari " (1909) reports the occurrence of aberrant pancreas in the tip of Meckel's diverticulum.

Tschiknawerow " described three cases of Meckel's diverticulum in which pathological tissue formation was found.

In Case I he described a spindle-celled sarcoma occurring in the diverticulum.

Case II was that of a man 25 years of age who had died of pneumonia. At the tip of and extending into the lumen of the diverticulum, which was 3 cm. long, there was found a small

body, 1 cm. in length. Near the surface of this enlargement glands of the Lieberkiihn type were found, while those in the depths resembled Brunner's glands both as to structure and as to position. The remaining mucosa of the diverticulum had the structure of intestine. The villi were well marked, lymph follicles occurred in areas, and everywhere typical Lieberkiihn's glands were present.

Case III was that of a woman of 55 years of age. At the tip of Meckel's diverticulum, which measured 7 cm. in length, there occurred a rather hard swelling which was found to consist of atypical Lieberkiihn's glands and to resemble pancreas to a certain extent.

Lecene " described an adenoma developing at the level of the free end of a Meckel's diverticulum.

A number of additional instances are reported of aberrant pancreas occurring in intestinal diverticula other than in the true diverticulum of Meckel. The aberrant tissue in the bowel wall is supposed by many to be the primary factor in the subsequent formation of these diverticula, which then enlarge by a secondary evagination of the bowel wall due to pressure within its lumen at a point probably weakened by the glandular mass. Whether this conception is correct or not remains an open question.

Nauwerk ™ ( 1893) reports the occurrence of a diverticulum 9 cm. in length, occurring 2-3 mm. above the ileocecal valve in which an accessory pancreas was found, covered on the outside by serosa and having an excretory duct. He explains the formation of the diverticulum by the mechanical pull of the accessory pancreas on the bowel wall. In addition to pancreatic acini a hyperplastic overgrowth of Lieberkiihn's glands was also found, and the impression was gained that numerous transitions occurred between these overgrown Lieberkiihn's glands and the true pancreatic lobules. Besides this diverticulum a true Meckel's diverticulum was also found, measuring 3 cm. in length and situated 80 cm. above the ileocecal valve.

Further examples of this condition are reported by Thompson,'" Hulst " and Albrecht and Arzt.

A case of pancreas occurring at the umbilicus was described by Wright." In a girl 12 years of age there was found a congenital umbilical fistula which, after breaking down twice following operation, healed as a result of complete extirpation of the fistulous tract in which a pancreas nodule was found.

Franchomme* (1893) has described in greater detail the anomalies which are apt to occur in the remains of the vitelline canal.

Discussion

It is seen, then, that the occurrence of aberrant glandular tissue, particularly gastric and pancreatic, may occur in the stomach, intestine, Meckel's diverticulum, in the obliterated cord connecting the latter with the umbilicus and at the umbilicus itself. These aberrant tissues have a great interest for embryologists in view of their possible explanation and to pathologists for this reason also, and furthermore for the reason that new growths and other pathological processes may rise from these aberrant tissues. To the surgeon, furthermore,

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because they may be the seat of inflammation, perforation, abscess formation and even subsequently of intestinal obstrui'tion. In jreneral. very few complete histological studies with the idea of absolutely determining the nature of these tissues under consideration have been reported. As a consequence, there has been considerable confusion in the past in certain instances as to the exact type of glandular tissue witii which one was dealing. The case reported in this present ])ublication offered, therefore, a good opportunity for positively identifying in the tip of Meckel's diverticulum an area of gastric mucosa of the fundus type. This was done beyond question, and therefore the facts can he used in clearing up or in refuting a number of theories wiiich have been offered in the past to explain the origin of these aberrant tissues and to furnish certain facts for a more probable theory as to tiieir origin.

Speaking in the first place of aberrant mucosa it may be recalled that several cases of gastric mucosa occurring at the umbilicus, in the form of polyps, depressions or fistulae, were reported by Tillmanns, Reichard, Roser, Weber, Lexer, Denuw and a few others. In one or two instances such a fistula was blind and was attached at its inner extremity to a librous cord or to Meckel's diverticulum itself. The latter in these instances had the structure of intestinal epitliclium. In one instance, namely, that of van Ileukelom, there was found in a human fetus a small nodule of gastric mucosa at tiie tip of Meckel's diverticulum which had become com})letely constricted off and separated from tiie lumen of the divertiiuluni, but was still attached to the latter.

In many of these cases the reports, in which histological examination was more or less incomplete or not made at all, are rather unsatisfactory. In only one instance, I may say, was there a very careful histological examination made, namely, by Denuce, who reported mucosa of the gastric fundus type occurring at the umbilicus. Aside from this there were no other cases in which gastric fundus mucosa was found or described. My own ca.<e, then, represents the only one in the literature in wliich a consideral)le area of mucosa at the tip of Meckel's diverticulum, communicating freely with it and in continuity with tiie remaining muco.sa of the diverticulum, was found to be of the gastric fundus type or even gastric at all.

In this manner, then, the link in the chain of evidence which goes to show that this aberrant gastric tissue arises from remnants of the omphalomesenteric duct is complete.

Several of the theories which have been advanced to explain the origin of this tissue are thus effectively answered in the negative. Thus. Tillmanns' theory, which had few adherents and which supposed that gastric mucosa occurring at the umbilicus is derived from gastric diverticula, becomes quite improbable. Van Heukelom had already quite effectivelv answered this theory.

The second theory is that of Siegenlieck van Heukelom, who believes that these aberrant growths at the umbilicus and at the tip of Meckel's diverticulum represent tiie remains of the vitelline duct. He, however, felt that the differentiation into gastric or intestinal epithelium depended upon whether or

not the mucosa in early fetal life had become differentiated before or after the influence of bile had become effective. This view is doubtless in part correct, but not altogether, for again my findings show that gastric mucosa may differentiate from the intestinal epithelium even under the same influences so far as concerns the action of the intestinal +++++ CONTENTSs. In other words, isolation of the mucosa very early in fetal life is not essential for the development of gastric mucosa.

The third explanation, namely, that of Salzer, that misplaced entoderm at the umbilicus is stimulated to a variable differentiation by irritation or inflammation and consequently may give rise to gastric, intestinal, or even pancreatic tissue, similarly does not fully explain, for again, as my case shows, gastric mucosa may develop in the absence of such irritative or inflammatory conditions.

The fourth theory, tiiat of Albrecht and Fischl, that these aberrant tissues arise from fetal inclusions or rests occurring at the umbilicus at the time of the closure of the abdominal wall, similarly does not suffice, for the occurrence of these tissues in the tip of Meckel's diverticulum can certainly occur without these factors being present.

The fifth explanation, which is doubtle-^s the most nearly correct, was practically accepted by Lexer and by Denuce. These authors assumed that these umbilical aijuormalities represent the remains of the omphalomesenteric or vitelline duct, although no very detailed facts have been offered to support this view. My own case would complete the evidence so far as gastric mucosa is concerned, for it shows in the first place that gastric mucosa can and does arise from the remains of the vitelline duct if one assumes, which is doubtless correct, that Meckel's diverticulum itself is the representative of such remains. One need assume no further factors nor circumstances, such as improi)able constrictions in tiie stomach or misplacements and irritations affcK-ting the entoderm, which are thus caused to undergo this peculiar differentiation. It becomes evident then how important this finding has been, because it has allowed us to answer effectively the previous views and to furnish indisputable evidence that the gastric mucosa as reported in previous cases occurring at the umliilicus has doubtless arisen from the omphalomesenteric duct. .\s to the ultimate influences which iiave caused this differentiation one cannot state definitely in the present condition of our knowledge concerning these processes.

The sixth and last explanation, practically that of Albrecht, is, so far as present evidence goes, the most nearly correct, and this holds for pancreatic tissue or gastric or in fact any of the glandular tissues of the intestinal tract, such as Brunner'a glands. According to this view the original entodemial lining of the intestinal tube and omphalomesenteric duct pos.sesse8 potentialities of development into any of the glandular structures in the adult intestine or of its acces-sory glands, and under the influence of certain circumstances, which we do not understand, groups of cells may retain one or the other potentiality and develop into a glandular tissue or organ very different from the surrounding glandular tissue and rescm

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bling the adult organ, such as stomach or pancreas, which may be far removed.

In view of his findings of aberrant pancreatic tissue at various points in the intestinal tract, Zenker felt that these anomalies represented pancreatic anlages, which in the further course of development were carried upwards or downwards by the further growth and elongation of the original straight intestine and which might come to lie hence in the stomach or in any part of the intestinal tract down to and including Meckel's diverticulum. If this assumption is made in the case of the pancreas, then one should assume the same, I think, in the case of the stomach, in which instance it seems quite impossible to believe that a gastric anlage could by such mechanism become displaced so far as to lie below the possible embryological position of the pancreas. One certainly could not apply this view to the occurrence of gastric mucosa at tlie umbilicus or in Meckel's diverticulum.

Finally, Albrecht's view as stated above is probably tlie correct one. If we accept this view of the imiform potentiality of the entoderm to develop into any of these glandular tissues, we can readily understand how cases of aberrant stomach, pancreas, Lieberkiihn's glands and Brunner's glands can occur anywhere in the intestinal tract as far down as Meckel's diverticulum. The intestine below Meckel's diverticulum which represents the hindgut doubtless has not these potentialities, as a consequence of which these aberrant structures have never been found below the level of Meckel's diverticulum.

To summarize then, I have reported a case of a young man, 19 years of age, who presented before operation symptoms and signs suggestive either of acute appendicitis or partial intestinal obstruction. On examination, among other things there was found just below the umbilicus a scar which had been produced by a former operation for an abscess. The nature of the abscess was not determinable. Upon subsequent operation it was found that the small bowel had become strangulated over a thick, fleshy cord consisting of Meckel's diverticulum and some adherent omentum which fastened the former to a point on the anterior abdominal wall just below the umbilicus. Excision of Meckel's diverticulum with the adherent omentum was done and the patient made an uneventful recovery.

Upon examination of the open diverticulum there was found in the distal third or fourth of the diverticulum an area of thickened, irregular, granular, dark red mucosa which was demarcated sharply from the proximal pale finer mucosa, which in turn was of intestinal character. Furthermore, upon careful histological examination this distal segment was found to consist of a mucosa definitely resembling in every particular that of the gastric fundus region. The glands were precisely of the fundus type and showed the characteristic zymogen granules of the chief cells and the eosinophilic granules of the parietal cells as characteristic in the glands of the stomach.

Upon a careful search of the literature it is found that a number of cases have been reported of the occurrence of gastric mucosa at the umbilicus in the form of polyps or fistula?.

Other aberrant tissues, such as pancreas, have been described along the intestinal tract and even in one instance in a nodule at the tip of Meckel's diverticulum and connected with its lumen. Another interesting case reported is that of van Heukelom in which a nodule of mucosa was foimd at the tip of Meckel's diverticulum, constricted off from it, not connected with the lumen, but attached by a fibrous cord. This mucosa proved to be of pyloric nature. My own case is the only one of which I am aware of gastric mucosa occurring in the wall of Meckel's diverticulum and in free communication with its lumen. Careful histological examination was made necessary because of the rather uncertain findings reported by previous authors and of the various theories which have been constructed to explain the occurrence of these aberrant tissues at the umbilicus.

The finding in my own case of gastric mucosa in Meckel's diverticulum, which it is agreed quite generally is a definite remains or persistence of the vitelline or omphalomesenteric duet, makes it appear certain that these al>errant tissues occurring at the umbilicus, in fibrous cords and in Meckel's diverticulum, have a uniform origin, namely, from the entoderm of the original intestinal tube or yolk stalk. It was very important to complete the evidence that these aberrant tissues may arise anywhere along the tract of the original omphalomesenteric duct in order to answer the various hypotheses which were previously advanced.

After a review of these hypotheses and in view of the evidence that I have brought forward, the best explanation for the occurrence of these structures is, that the original entodermal lining of the intestinal tube and omphalomesenteric duet possesses potentialities of development into any of the glandular structures of the adult intestinal tract or of its accessory glands, and under the influence of certain circumstances, which we do not understand, groups of cells may retain one or the other potentiality and develop into a glandular tissue very different from the surrounding glandular tissues and resembling the adult organ, such as stomach or pancreas, which may be far removed. The finding in my case of gastric mucosa in Meckel's diverticulum effectively answers the various theories that the gastric growths at the umbilicus may have arisen by constriction or separation from gastric diverticula in the early fetus, or that a differentiation in the mucosa or in these aberrant tissues is brought about by the presence or non-presence of the bile, or that irritations, inflammations or fetal inclusions at the point of union of the blastodermic layers are necessary. In fact, there is good evidence now, with the findings in my own case, for believing that these aberrant tissues arise from remains of the omphalomesenteric duct ; but as to the ultimate factors which cause this differentiation we cannot state in the present condition of our knowledge.

The finding of this gastric mucosa explains well the reasons for the finding of acid secretion with digestion at the umbilicus, in cases of umbilical polyps and fistula as reported in the literature, although cases in which gastric mucosa oc

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curred at the umbilicus had been reported before. Again, we have a good embryological basis for understanding certain adenomatous tumors and growths of an intestinal glandular nature occurring at the umbilicus, in oblitenxted intraabdominal umbilical cords and in Mecicers diverticulimi. In fact, in the caj?e reported it is interesting to speculate as to the condition for which the patient had been operated upon several years previously. It seems probable that there was at that time a perforation at the tip of Meckel's diverticulum, though none was found at the operation. As a consequence of this an abdominal abscess formed which was simply drained and whicli healed with the formation of adhesions between the tip of Meckel's diverticulum and the anterior abdominal wall. It is interesting to think also that this perforation at the tip of Meckel's diverticulum might well have been a perforative gastric ulcer, for so far as the structure of the mucosa went we were certainly dealing with the fundus type of mucous membrane. This perforation evidently healed subsequently. The case further illustrates the desirability of examining carefully all cases of Meckel's diverticulum for the possibility of occurrence of aberrant glandular tissues in the mucosa, both for embryological reasons imd also because of the importance of these structures in pathology and certain surgical conditions.

In conclusion, I wish to acknowledge my indebtedness to Mr. H. F. Aitken for the drawings in black and white, to Miss Ethel Norris for the two figures in colors, and to Dr. T. S. CuUen for the use of the drawings of the umbilical anomalies as illustrated by Mr. Max Brocdcl.

BIBLIOGRAPHY

1. Albrecht, E.: Ein Fall von Pankreasbildung In einem Meekel'schen Dlvertikel (Abstr. ). Munchen. med. Wchnschr., 1901, XLVIII, 2061; also. Sitzungsb. d. Gesellsch. f. Morphol. u. Physiol, in Munchen (1901), 1902, XVII. 52, cited by Tschikna.

2. Albrecht, H.. and Arzt. L.: Beltrage zur Frage der Gewebsverlrrung. (2) Ueber die Bildung von Darmdivertikeln mit dyatopischem Pankreas. Frankf. Ztschr. f. Path.. Wleb., 1910, IV, 167186.

3. Bize: Etude anatomo-cllnlque des pancreas accessolres situfis & I'eztr^mitg d'un dlvertlcule intestinal. Revue d'orthop., Paris, 1904, 2 b., V, 149159.

4. Bensley. R. R.: The structure of the glands of Brunner, The Decennial Publications. The University of Chicago Press, 1903. X.

5. Bernard, C: Legons de phys. exp^rim. Tome II, Schmidt's Jahrb., 1858, XCVII. 21.

6. Brunner, C: Ein Beitrag zur Chirurgle und pathologlschen Anatomie der Darmlnvaglnatlon. Beitr. z. kiln. Chir., 1895, XXV, 345.

7. Cullen, T. S.: The umbilicus and its diseases. W.B.Saunders Company, Philadelphia and London, 1916.

8. Denuc^. M.: FIstules pseudopylorlques cong6nitales de I'ombillc. Revue d'orthop«die. 1908, l.\. 1-29.

9. Franchomme. H.: Anomalies de r^-gresslon du canal vitellin; dlvertlcule de Meckel, flstules ombllicales. 4', Paris, ISg.!.

10. Gegenbauer, C: Ein Fall von Nebenpankreaa In der Magenwand. Arch. f. Anat., Physiol, u. wissensch. Med., Leipzig, 1863, 163-165.

11. Hedinger: (Fall von Mekelschem Dlvertikel mit Pankreasgewebe und Brunnerschen Driisen an der Spltze desselben.) Corr.-BI. f. schweiz. Aerzte. Basel. 1986, XXXVI, 395. 1. WIntersitzung DIenstag, den 3 Okt., 1905.

12. Hulst, J. P. L.; Ueber elnen in einem Darmdivertikel gelagerten Pankreaskelm mit sekundarer Invagination. Centralbl. f. allg. Path. u. path. Anat., Jena, 1909. XX. 12-15.

13. Hyrtl, J.; Handbuch der topograph ischen Anatomie und ihrer praktisch niediclnisch-cliirurgischen Anwendungen, 46, 1860, L, 667.

14. Klob, J.: Pancreas-Anomalien. Ztschr. d. k. k. Gesellsch. d. Aerzte zu Wien, 1S59, XV, 732.

15. Lecene, P.: Ad6nome d6velop6 au niveau de rextr6mlt6 libre d'un dlvertlcule de Meckel. Bull, et m#m. Soc. anat. de Par., 1912, LXXXVII, 63.

16. Lexer, E. : Magenschleimhaut im persistlrenden Dottergang. Arch. f. klin. Chir., 1899, LIX, 859-865.

17. Leydig, F. : Lchrhuch der Hlstologle des Menschen und der Thlere, 1857, 352, cited by Zenker.

17*. Lindner. M. H.: Discussion: Ein Fall von Extirpation des persistlrenden Ductus omphalo-mesentericus. Deutsche med. Wchnschr., 1S98. XXIV, 172v.

18. Merkel: Discussion: Abgesprengte Pankreasanlagen. Munchen. med. Wchnschr., 1905, LII, 337.

19. Minelli, S.: Adenoma Ombellicale a Struttura gastrlca. Gazz. med. ital., Torlna, 1905, LVI, 101-105.

20. Nauwerck, C: Ein Nebenpankreas. Beitr. z. path. Anat. u. z. allg. Path., Jena, 1892, XII, 29-32.

21. Nazari. A.: Pancreas aberrato in un diverticolo di Meckel. Bull. d. r. Accad. mod. di Roma, 1909, XXXV, 245-250.

22. Neumann. E.: Nebonpancreas und Darmdivertikel. Arch. d. Hellk., Leipzig, 1870, XI, 200.

23. Reichard, V. M.: Demonstratlonen zur Magen-Darmchirurgle. Zentralbl. f. Chir., 1898, XXV, 587-588.

24. Roser, W.: Zur Lehre von der umbilikalen Magencystenfistel. Zentralbl. f. Chir., 1887, XIV, 260.

24'. Salzer, H.: Ueber das offene Meckelsche Dlvertikel. WIen. klin. Wchnschr.. 1904. XVII. 614-617.

25. Strada, F. ; Adenoma congenlto ombelicale a tlpo gastrlco (Contributo alio studio dei tumor! congenitl dell 'ombelico). Sperimentale Archlv. dl Biol., 1903, LVII, 637-658, I pi.

26. Thomson, A.: Diverticula of the alimentary tract, with particular reference to those met with In the ileum resulting from an accessory pancreas and from tuberculosis. Tr. Med.-Chlr. Soc. Edinburgh, 1908, n. s. XXVII, 118-129, 2 pi.

27. TlUmanns, H.: Ueber angeborenen Prolaps von Magenschleimhaut durch don Nabelring (Ectopia ventricull) und iiber sonstige Geschwiilste und P'isleln des Nabels. Deutsche Ztschr. f. Chir., Leipzig, 1882-3, XVIII, 161-202.

28. Tschlknawerow, L.: Zur Kenntnis dor pathologlschen Gewebsbildungen In Meckel'schen Dlvertikel. Berl. kiln. Wchnschr., 1911. XLVIII, 1676-1679.

29. van Heukelom, S.: Die Genese der Ectopia ventricull am Nabel. Vlrchow's Arch., 1888, CXI, 475.

30. von Rosthorn, A.: Ein Beitrag zur Kenntnis der angeborenen Nabelflsteln, Wlen. kiln. Wchnschr., 1S89, II, 125; 154.

31. Wagner, E.; Accessorrlsches Pankreas In dor Magenwand. Arch. d. Hellk.. Leipzig, 1862, III, 283.

32. Weber, W.: Zur Kaaulstik der Ectopia Ventricull. Beltrftge z. klin. Chir.. 1898, XXII. 371-385.

33. Wright. J. H.: Aberrant pancreas in the region of the umbilicus. J. Boston Soc. Med. Sc, 1900-1, V, 497-498. 1 pi.

34. Zenker, F. A.: Nebenpancreas In der Darmwand. Arch. t. path. Anat. (etc.), Berlin, 1861, XXI, 369-376.

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A GRAPHIC APPLICATION OF THE PRINCIPLE OF THE EQUILATERAL TRIANGLE FOR DETERMINING THE DIRECTION OF THE ELECTRICAL AXIS OF THE HEART IN THE HUMAN ELECTROCARDIOGRAM

By Edward Perkins Carter, Cdrt P. Eichter and Carl H. Greene (From the Cardiographic Department of The Johns Hopkins Hospital and University)

In 1908 Einthoven ' first called attention to the fact that a definite relationship exists between the amplitude of the deflections of the electrocardiogram obtained from the three leads — right arm, left arm and left leg — and that when the amplitude of any two such derivations is known the third can be determined ; formulating his law, based upon this relationship, that

A year later, in a joint paper with Fahr and De Waart,' he expanded more fully the principle of the equilateral triangle and published tables, based upon trigonometrical formulae, which made it possible to determine, within a negligible factor of error, the direction of the electrical axis of the heart, the relative preponderance of either the right or the left ven

L.R.

Fig. 1. — After Einthoven. Illustrating the fundamental principle of the equilateral triangle. P^Q - E, p, — g, = c„ p, — 9, = e„ P, — a, = e« e, = c, + e,. The angle = + 55°.

under like conditions of electrical resistance and tension Lead III must equal Lead II minus Lead I.

In 1912, in an address before the Chelsea Clinical Society of London,' he furtlier developed his fundamental conception of the course of the excitation wave in the heart, based upon the analogy of the three leads employed to the sides of an equilateral triangle in which the direction of the axial current bears a definite and determinable relationship to the parallel plane of Lead I (E. A. and L. A.).

tricle and the shifting alteration of tlie axis of potential difference in the more bizarre forms of electrocardiograms so frequently met with.

The fundamental principles involved are briefly as follows: Assuming that the tliree leads usually employed — the right arm, the left arm and the left leg — represent the three sides of an equilateral triangle (see Fig. 1), we draw a line parallel to the line uniting the two ann leads at a level corresponding to the center of a circle enclosing tlie triangle, the right-hand

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end representing 0° and the left-hand ond 180°. At the center of this line is placed the point // representin<r the heart, the electrical axis of which is diagTanimatically illustrated by the arrow p-q. Rotation, then, counter-clockwise of the axis above this horizontal line represents a negative angle, whereajs rotation clockwise below tlie horizontal represents a positive anjrle. The normal electrical axis is illustrated by the direction of the arrow in the figure in which the angle a, tlie angle of deflection between the arrow p-q and the horizontal line corresponding to the plane of Lead I, measures in our figure +55°.

If upon this arrow indicating the direction of the axial current we mark off two points p and q, Einthoven has shown that the distjince between lines projected from these points: at right angles to any one of the three sides of the triangle, which correspond to the three leads, will represent the amplitude of the deflections for that lead, and that under all normal conditions the amplitude of i?,-f i?3 = 7?j. Furthermore, from the amplitude of these deflections we may determine the direction of the axis of potential difference in the heart and may calculate the angle a, thus determining in degrees the rotation of the electrical axis in the sagittiil plane and the accurate measurement of the angle formed in relation with the horizontal plane representing Lead I (R. A.-L. A.).

It should be clearly understood that the amplitude of any given deflection represents the difference in potential in the electrical axis existing in the heart at a given instant of time in relation to the lead employed, and that this amplitude will vary as the electrical axis alters its position in relation to this lead. Hence, it is evident that the amplitude of any given deflection may not represent the greatest difference of potential possible in that lead, and Einthoven insists that we must distinguish between what we may call the recorded difference of potential and the maximal possible deflection, which he designates as the " manifest potential difference " or the " manifest value.'"

This manifest value depends upon the maximal distance separating the two points between which the potential difference is developed and is only met with when the electrical axis and the lead employed lie in parallel planes. It can be calculated from the height of the recorded curves and can be expressed in absolute measure in millivolts by multiplying the deflection measured in millimeters by lO"* when the galvanometer string ha,s been standardized for the usual deflection. In determining the angle a, however, for all clinical purposes we may disregard this manifest value, though a tat)le giving the various determinations of this potential differeni c is incorporated in the last paper referred to above.

Einthoven's formulae are as follows: If we let p-q = E, representing the manifest value, Pi — 7i = ^i, Pz — <Ii'=^i e, =f^eo6a. (1)

f5 = £cos (a-60). (2)

«', = i?cos (120-O). (3)

e, = e,-e,. (4)

It is evident that under these conditions the potential difference present between the angles of the triangle must bear the following relationship e, : f, : e,. From these data when the angle a is unknown it can be determined from the relationship of any two of these potential differences from the following formula? :

ie —e

Losing r, and c. /fl. a = ' ^'•

Using c, and e., tg. a = Using Co and e, tg. a =

(5) (6) (7)

2e^ + c^ f,V3

We have stated above that under normal conditions this law that 62 = 6,-1-63 holds true. That clinically, however, we constantly meet with apparent exceptions to this statement is a matter of common observation. It must be kci)t in mind that while we are dealing theoretically with a fiat i)lanc we have actually to do with a very complicated muscle mass and it is the more remarkable that this seeming exception to this fundamcntjil law is apparent rather than real, and that it is due, as Einthoven has shown, to the phasic variation between similar peaks of the electrocardiogram.

In order to determine exactly the proportional amplitude of a given deflection in the three leads, especially in all instances showing conspicuous pliasic variation, we must know the exact time relationship of the deflection to the cardiac cycle in each of the three leads, ilanifestly, this can only be determined by simultaneous records of the heart sounds and the electrocardiogram, such as have been made by Falir,* or by the use of two galvanometers as employed by Williams.' Fortunately, this apparent exception to the simplicity of the fundamental principle involved does not invalidate the application of the formulae given above in all normal instances and may be corrected for as Einthoven has shown in the more obscure forms.

Using two galvanometers Williams (I. r.) has shown by the projection of vectors determined from the manifest value e, in conformity with the different leads, the essential nature of this phasic variation in homonymous peaks of the electrocardiogram, and has further demonstrated that the bizarre curves met with are due entirely to the manner in which the direction of potential difference is shifting within the heart, and that, although the peaks arc absolutely in phase in only a few instances, such absolute accuracy in the calculated values is not essential for. the majority of clinical records.

Based upon the principle of the equilateral triangle Pardee' has published a graphic method by which the negativity of the initial ventricular deflections determines within the limits of 60° the direction of tlie axis of potential difference. This i.s accomplished by dividing tlie circumference of the circle into six quadrants, into any one of which it can be shown, by the positivity or negativity of the recorded deflections, that the axis of potential difference must fall.

It is interesting to note how closely the angle, determined by means of the tables published by Einthoven, Fahr and De Waart, coincides with the results calculated bv the use of

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their formulas 5, 6 and 7 given above. These observers have further demonstrated that the angle varies with inspiration and expiration in different individuals from 12° to 36°, being always greater in inspiration than in expiration, the normal angle falling between +40° and + 90°.

In a true left ventricular preponderance the angle a has a value approaching —20°, falling between 0° and —40°, while with a right ventricular preponderance it has a value approximating +120°, falling between +90° and +150°. If we assimie that the electrical axis in these cases originally had a normal value, we must postulate a rotation of the direction of potential difference through an arc of from 70° to 140°. That this, however, implies a rotation of the anatomical axis of the heart throughout anything like the same extent is manifestly absurd, and the explanation for the rotation of the axis of potential difference must be sought in the shifting balance of the muscle mass and the ensuing relationship of the plane of the electrical axis to the Derivations I and III.

Figs. 2, 3 and 4 may serve to make this point clear. Fig. 2 illustrates the normal direction of the axis of potential difference. In this figure the excitation wave passes from base to apex within the heart and from apex to basal structures through the galvanometer, the deflections being upright in all three leads. In Fig. 3, the deflections are upright in Leads I and II, though the predominant deflection may be do'miward in Lead II, and downward in Lead III ; while in Fig. 4, the deflections are downward in Lead I, and upright in Leads II and III. The direction of the course of the difference in potential is indicated in each instance by the direction df the arrow.

In a paper upon the localization of the origin of the excitation wave in the human heart, Fahr and Weber ' have demonstrated the soundness of the principle involved in the use of the geometric figure and the facility with which one can graphically determine the measurement of the angle a and the direction of the axis of potential difference by plotting upon an angle of 60° the values, in tenths of a millivolt, of the two leads and projection from these values of right angle lines.

In the graphic method of plotting the angle a, illustrated by Fig. 5, we have made use of the principle of the equilateral triangle inscribed wdthin the circumference of a circle upon which are marked the degrees from 0° at the right to ± 180° at the left-hand end of the axis of the circle. Following Einthoven's original description rotation of the angle downwards and to the left, clockwise, constitutes a plus angle, whereas rotation upwards and to the left, counter-clockwise, constitutes a negative angle.*

The point marked by the intersection of the ordinate from the middle of the line representing Lead I and the horizontal axis of the circle represents the heart, and may further be regarded as the point p of the axis of potential difference, as illustrated in Ficr. 1.

• This method of reading a positive or negative angle is at

variance with the accepted custom in vogue as given by Wentworth and Smith, " Plane Trigonometry," Chap. V, p. 77, 1914.

If from each side of our equilateral triangle we project ordinates, at a distance of 1 mm. apart, assigning to those on either side of the center of each base line, corresponding to the Leads I, II and III, their proper positive or negative sign determined by the projection of our arrow p-q, then the point of intersection of any two of these ordinates, representing the value of «!, e^ and e^ under their proper sign, must coincide with the point q in our diagram Fig. 1. A line from the center H to this point of intersection corresponds to the manifest potential difference E, and will give us the direction of- the axis of potential difference. By projection of this line to the circumference of the circle the angle a may be read off in degrees with its corresponding positive or negative value.

Utilizing the measurements of all three derivations in the terms of e^, e„ and e^, tmder their proper sign, we shall find that with the physiological electrocardiogram our point of intersection for all three leads coincides very closely, and that in those instances with a conspicuous phasic difference the point of intersection will vary slightly, depending upon the ordinates employed, thus suggesting in a graphic way the extent of this phasic variation.

In the instances suggesting a ventricular preponderance, the values e^ and e^ should be used, and whenever the initial ventricular deflections are definitely diphasic in character, their corrected value should be determined by deducting the lesser amplitude from the greater.

Figs. 6, 7 and 8 may serve to illustrate the method of application of the principles stated above for determining the axis of potential difference in the heart.

In Fig. 6, which represents a physiological electrocardiogram, i?i measures 9 mm., R^ 16 mm. and ^3 7 mm. in height. We may express these values in the terms of e, as e^=-\-9, e«=+16, and 63= +7, then ej^ej + fij. If we follow the ordinate +9 from the side corresponding to Lead I to the point where it meets the ordinate +16 from the side representing Lead II, we shall find that the ordinate +7 representing Lead III intersects this point (see the small circle in Fig. 5 in the lower right-hand quadrant) and a line from the center H projected through this point of intersection to the circumference of the circle gives the direction of the axis of potential difference and the value of the angle a as + 55° and approximately 30'. Determining the value of a for this electrocardiogram by Einthoven's formula 5 we get a value of + 55° and 53'.

In Fig. 7, the initial ventricular deflections have the following values: i?i=15 mm., jSi=— 1.5 mm., i?, = 4 mm., jSj = — 9 mm., i?3 = 1 mm., Sj = — 16 mm. We may ignore the values of S-^ and R^ as they approach each other so closely, and utilizing i?i and S^ (e, and 63) we repeat the steps outlined above and follow the ordinate + 15 representing the Lead I to the point intersected by the ordinate — 16 representing Lead III. A line from the center H through this point of intersection and projected to the circumference of our circle gives the value of the angle a as —34°. Determined by formula 6 the value is found to be —33° and 12' — an

June, 1919]

165

•K.A

X.A

•U.A

X.V..

Flo. 2. — lllutitmtin? the normal physiological dirrction of the axis of potentui difference in the heart. The arrows indicate the dirertiKii of the initial ventricular dellectlona in the three leads. See Fig. 6 and description in text.

Fio. 3.— IIlustratiiiK the direction of the axis of potential (Jiffercnce in left ventricular preponderance. See Fig. 7 and description in text.

Flo. 4. — IllustnitinK the direction of the axis of potential difference in ri(fht ventricular preponderance. See Via. 8 and description in text. Fiffs. 2, 3 and 4, modified after Pardee.

-i : : .

ii

m:

-L

1

• •!

r^'

1

! 1

1

electro. ar.liugrain. Tl.e iJ.Kli- a in..,..urM + .55" and approiimalel.r 30' bv plotting, and + i.i* and SS' by formula i.'

punilcmiiL-e. I lir titiKJi- a iii««Burcii — AA and i>nnie niinut>'< I'.t plotttlv, nd — 33' and 12' by fomiiilu ti.

Ittr prepondrmnce. The nnKJe a meiuiure« approximulciv -» 1'20" bv pliittInK, and exurllv -r I'JO by formula 0.

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[No. 340

^^o_j:3o

Fig. 5.— Illustrating the graphic determination of the angle a by means of ordinatcs projected from each side, or base, of the triangle representing the three leads. The ordinates are drawn to scale 1 mm. apart. The small circles in the figure represent the points of intersection of the e values determined from Figs. 6, 7 and 8. The arrows projected to the circumference point to the plotted measurement of the angle a in degrees of these figures. Se3 description in text.

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angle known to be associated with left ventricular preponderance.

In a similar way we may plot the values of Fig. 8, which after correction for tiie slightly dipliasic curves in Leads I and III are found to be as follows in the terms of e: e,= — 5 mm., «j= + 10 mm. Projecting our line from the center 11 through tliis point of intcrs:ection (see point in lower left-hand quadrant of Fig. 5) we find that the value of a falls between + 120° and +121°. Determined by formula 6 the value of the angle a for this figure is exactly +120°, an angle known to be associated with right ventricular preponderance.

The points of intersection of the ordinates as given above are marked by the small circles in Fig. 5, and the arrows indicate the projection of the axis p-q from the center H through these points of intersection to the circumference of the circle giving tlie direction of the axis of potential difference and the value of the angle o in degrees.

In addition we may determine graphically the true manifest value of the potential dilTerence. As Einthoven has shown {loc. cit., 1913), if the angle a = t)0° the manifest value E is equal to the deflection in Lead II, for this lead is then parallel to the electrical axis. If the angle a is equal to 0° or to ± 180°, E = e^. If the angle a=+120° or -60°, E = e,. Referring

again to the examples given above, in Fig. 6, £=16.2. In Fig. 7, J5:= i:.8. In Fig. 8, A'= 10.

It is then plain that this diagrammatic usage of the equilateral triangle is available for accurate det<>rminations of the direction of the axis of })otential dilTerence, the angle a and the manifest value H.

SU,M.\L\RY We have emphasized the value of the fundamental principle of the equilateral triangle as applied in the interpretation of clinical electrocardiograms, and have illustrated graphically a simple method of procedure by which the value of the angle a may be quickly found.

BIBLIOGRAPHY

1. Einthoven, W.: Pflug. Arch. f. die ges. Phys., 1908, CXXII, 55S.

2. Mem .• The Lancet, London, 1912, March 30, 853.

3. Einthoven, W.. Fahr, G., and De Waart, A.: Pflug. Arch. f. die ges. Phys., 1913, CL, 275.

4. Fahr, G.: Heart, 1912-13, IV, 147.

5. Williams, H. B.: Am. Jour. Phys., 1914, XXXV, 292.

6. Pardee, H. E. B.: Jour. Am. Med. Assoc., 1914, LXXII. No. 17, 1311.

7. Fahr. G., and Weber, A.: Deut Arch. f. klin. Med., 1915, CXVII. 361.

PHAGOCYTOSIS AND AGGLUTINATION IN THE SERUM IN ACUTE

LOBAR PNEUMONIA: THE SPECIFICITY OF THESE REACTIONS

AND THE REGULARITY OF THEIR OCCURRENCE

By Paul W. Clovoh (From the Medical Clinic of The Johns Hopkiyis Honpital)

In a previous article ' the writer reported the results of some observations in a .small series of cases on the activity of the serum developing, after crisis or lysis, in patients with acute lobar pneumonia. In agreement with the results obtained by most previous observers, it was found that the serum at this time usually developed a definite, though often feeble, protective power for mice, provided the test was made with the homologous strain of pneumococcus, isolated from the patient whose .scrum was being tested. This activity was not demonstrable in .«erum obtained during the active stage of the disease, either from patients who subsequently recovered or from those who died. It was further shown that, in a considerable percentage of the cases (six of 11 ca.ses), a definite phagocytic activity could be demonstrated in the serum from convalescent patients. It was especially emphasized that this phagocytic activity has a significance quite different from that of an increa.se in opsonic index, as determined by the Wright method. In the latter, one uses heterologous stock strains of pneumoi'wci of low virulence, which are at least moderately phagocytable in fresh normal serum. The strains studied by the writer, on the contrary, were (with one exception) of high virulence, and absolutely resistant to phagocytosis in fresh normal serum.

This phagocytic activity ran clo.«ely parallel with the protective power of the serum. It was entirely absent during the acute stage of the di.sea.se, and appeared only at or near crisis or lysis. It was not present in the serum of a fatal case. Like protective power it was manifested (with one exception) only toward the homologous strain of pneumococcus, and not toward those heterologous strains which were tested. It wa-s further siiown that in the two cases ti-sted as to this point, phagocytosis in riro ran ])arallcl to that in the testtube. In the peritoneal exudate of the protected mice, the pneumococci were ingested and dissolved within the leucocytes; whereas in the control mice receiving normal serum the organisms multiplied rapidly and remained exclusively extra-cellular.

In view of these facts, and of tiie ]mrt that jibagocytosis has been shown to play in the activity of jyotent immune serum,' the writer felt justified in concluding that jihagocytosis probably plays an imirortant role in the immunity developed in man at crisis.

The series of cases was too small, however, to demonstrate the regularity with which phagocytic activity develops. Furthermore, the strict limitation of the activity of each serum tested to the homologous strain of pneumococcus was sur

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prising, in view of the findings of Cole and Dochez that most strains can be classified in a small number of groups. It, therefore, seemed desirable to extend these observations over a larger series of cases, and to determine more definitely the exact specificity of the reaction.

The results previously reported by the writer ' were shortly confirmed by the independent observations of Lister ' in South Africa. Using a similar method, he also demonstrated in most of his cases definite phagocytic and agglutinative activity in the serum after crisis, when tested with the homologous organism. When these sera were tested with heterologous strains, pliagocytosis and agglutination occurred in some instances, but in others they did not. By trying crossed reactions with the cultures and (convalescent) serum obtained from 20 cases of pneumonia, he was able to classify the organisms into five definite groups. The individual strains in each group he found to be serologically identical; while strains in different groups had no serological relationship to each other. In a subsequent article," he reported further similar observations confirming the regularity and absolute specificity of the reaction, and added several new groups to his classification.*

The development of agglutinins in the serum of patients with lobar pneumonia has been noted by numerous observers. Bensangon and Griffon,' in 1900, reported positive findings in all but six of a series of 64 cases of pneumococcus infections of various types, of which 39 were lobar pneumonia. They obtained these results only by cultivation of the pneumococcus in concentrated serum from the patients, and failed to demonstrate any agglutinating activity when the serum was added to a broth culture of the organism. They found the activity most marked at crisis, and more effective toward the homologous strain than toward stock strains of pneumococci. Huber," using a similar method, obtained positive results in all of 10 cases of lobar pneumonia examined at or near crisis. Neufeld,' in connection with a study of the agglutinating action of immune serum, mentions the fact that in five out of about 15 cases of lobar pneumonia examined, the serum at crisis, when added to a culture of the pneumococcus, caused marked agglutination of the organisms. This occurred with serum dilutions of 1 in 4, or 1 in 8, but not in higher dilutions. Gargano and Fattori," in a series of 63 cases, reported that the development of agglutinating activity in the serum was " an almost constant phenomenon." The sera were all active in a dilution of 1 in 2, but none in a dilution over 1 in 10. They also found the homologous organism more readily agglutinable than heterologous strains. Jehle " also reported positive results in all of six cases examined. However, his findings differ radically from those of other observers, in that he found the seriun active in relatively high dilutions (1 in 20 to 1 in 80 and even 1 in 160) ; that the activity was well marked as early as the second or third day of the disease ; that it showed no tendency to increase as crisis approached ;

• As the earlier literature dealing with the subject of phagocytosis is summarized in my former article,' it will not be discussed

here.

and that it disappeared entirely within from two to four days after crisis. More recently Chickering" has reported the demonstration of agglutinins in a 1 to 2 dilution of serum in 73.8 per cent of a series of 40 cases of lobar pneumonia. Most of the negative reactions were with serum from fatal cases. He found that the agglutinative activity developed only at or near crisis, and that it might be present only for a single day, or persist {in vivo) for several weeks. The agglutinating activity of the serum was strictly limited to organisms of the same type as that with which the patient was infected, but sometimes was more marked for the homologous strain than for a heterologous strain of the same type.

The method used by the writer was described in detail in the previous article,' hence only the essential points will be repeated here.

The cultures used were, with a few exceptions, those isolated in the routine study of the cases in the medical bacteriological laboratory of The Johns Hopkins Hospital, which have been reported by Mildred C. Clough," and by Sydenstricker and Sutton," and I am indebted to them for transfers of most of the strains.

Through the courtesy of Dr. E. I. Cole of the the Eockefeller Hospital, New York, who kindly furnished us immune serum for the purpose, it was possible to determine the type of each of the organisms isolated. The phagocytic activity of the Type I and Type II immune sera has been tested with most of the organisms studied, and in some of the later cases observations have also been made with Type III serum, and with serum corresponding to Avery's Subgroups 2A and 2B."'

The leucocyte suspension was obtained by adding a few

cubic centimeters of normal human blood to 1,5 per cent

sodium citrate solution, washing three times in 0.85 per cent

• salt solution, and pipetting off the leucocytic cream after the

last washing.

The bacterial suspension was prepared by carefully emulsifying a loop of growth in one or two drops of physiological salt solution. The suspension must be fairly dense to give the most clear-cut results.

Fresh serum obtained from the patient by any convenient method, usually venapuncture, was used in a majority of the cases, though it was found that in nearly all cases the activity of the serum persisted in vitro for several days at least. In some cases inactivated serum was also used.

Equal volumes of undiluted serum, bacterial suspension and leucocyte suspension were mixed and incubated in capillary pipettes at 37° C. The actual concentration of serum in the final mixture was, therefore, 1 in 3. The time of incubation varied from 15 minutes to two hours, depending on the strain of pneumococcus in question.

When a negative result was obtained, if possible, the test was modified by making the culture suspension directly in the serum to be tested, and by using defibrinated blood from the patient instead of a salt solution suspension of washed normal leucocytes. In this way the organisms were exposed to concentrated serum, instead of to a 1 in 3 dilution of serum. Corresponding control preparations were made, consisting of a

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suspension of the organism in normal serum and defibrinated normal blood. Five cases which gave negative reactions by the first method were tested by this method; tliree gave positive results.

Smears from the mi.vtures after incubation were made on slides and stained with Hastings' stain (polychrome methylene blue). Suitably prepared films are free from sediment, and both the bacteria and the protoplasm of the leucocytes are clearly stained. As a rule, the margins of the capsules are sharply outlined and the capsular material is diffusely stained a bright pink, in contrast with the bluish-black color of the organisms.

As in the previous work, counts of the ingested organisms were not made. Only gross differences were regarded as significant. The degree of phagocytosis was recorded as (0) absent (or not to exceed five pair in 50 cells) ; ( + ) definite (about 100 or more pair in 50 cells) ; ( + + ) strong ; and ( -F -f- -(- ) maximal. Degrees of phagocytosis less than ( -|- ) in the test preparations were regarded as inconclusive.

In practically every case the tests were subsequently repeated, different specimens of normal serum and leucocytes being used to guard against possible errors.

This metliod is very simple, but in order to obtain reliable results certain precautions must be observed :

(1) The leucocyte suspension must be active. Tliis can usually be determined by simple inspection of a fresh preparation under the high power. As pointed out by Xeufeld," if the majority of the leucocytes show numerous filiform pseudopodia, one can be fairly sure that they are active. It is advisable also to set up a preliminary test with a strain phagocytable in fresh normal serum (not one spontaneously phagocytable). If a very marked phagocytosis has occurred after 15 minutes' incubation, the leucocytes are suitable for use. Attempts to compensate for an inactive leucocyte suspension by prolonging the period of incut)ation give unreliable results. The best results are obtained with fresh leucocytes. Phagocytosis is usually less active in older suspensions.

(2) The bacterial suspension should be fairly dense, and must be homogeneous and free from clumps.

(3) In every case controls must he made with normal serum, of the same age and condition as the serum under investigation, and all tests without exception be discarded if any appreciable degree of phagocytosis is present in the controls.

(4) The time of incubation should, if necessari-, be adjusted for each individual strain, so that the test preparation will show as marked a degree of phagocytosis as possible without permitting any phagocytosis in the controls. For organisms of Types I, II and III, one hour is usually the optimum, though clear-cut positive results are often obtained after I'l to 30 minutes. If the results are negative or inconclusive bfcause the degree of phagocytosis in the test preparations is slight, convincingly positive results may sometimes be obtained by prolonging the period of incubation to two hours. Rarely is anything to be gained by a longer period of incubation.

For organisms of Type IV and .\typiral Type II. the period

of incubation should, as a rule, be shortened to 30 minutes, and in some cases to 15 minutes. If the incubation is too prolonged, there may be sufficient phagocytosis in the control preparation with normal serum to obscure the difference between these and the test preparations, a difference which would have been clear-cut after a shorter period of incubation. Too prolonged incubation may also obscure results, because it gives sufficient time for intracellular digestion of the ingested organisms, and because prolonged contiict with the organisms seems to injure the staining properties of the leucocytes.

(5) TJie films must be properly spread and stained. The leucocytes and the larger bacterial clumps, if agglutination has occurred, will be found along the margins of the film, at and near the terminal portion. If the film is too thick, so that the leucocytes are heaped up or not well flattened out, observations are difficult. The presence in a serum of isoagglutinins active on the red cells present in the leucocyte suspension does not interfere with phagocytosis, but it makes it difficult to secure even films.

Before considering the result« obtained with serum from convalescent patients, the behavior of the organisms in normal human scrum should be discussed. In no instance were strains of Types I, II (typical) or III, on isolation, phagocytable in fresh normal human serum under the conditions outlined above. They also rcmainwl rcsistjint to jthagocytosis for at least several months while under cultivation on artificial media. The medium used was 5 to 10 per cent human blood agar; transfers being made at intervals of a week or 10 days. One Type II strain became very slightly phagocytable after two months' cultivation, and a second after cultivation for about a year. Type I strains seemed more resistant Of three Type I strains followed for a long period, one became phagocytable in fresh nonnal scrum during tlie third year of cultivation on artificial media ; a second, during the fourth year; while a third, after four years' cultivation without intervening animal passage, is still not phagocyt«l)lc.

The behavior of Atypical Type II and Type IV strains was variable, but most of those observed were less resistant to phagocytosis than were organisms of the fixed types. The majority of the Atypical Type II strains, and some of the Type IV strains, on isolation (from patient* with pneumonia). were not phagocytable in fresh normal human scrum after an incubation of half an hour, though after longer periods a slight degree of phagocytosis was occasionally observed. This resistance to phagocytosis was frequently reduced after one to three weeks' cultivation, so that the organism became phagocytable in fresh normal serum. In some cases the original resistance could be restored by animal pa.ssage. Such strains, after Ix-coming phagocytable in frcsli normal serum, were not phagocytable in normal scnim which had been inactivated cither by heating or by preservation for several days in the ice "best, and they usually retained this degree of resistance to phagocytosis after many weeks, and several even after two to three years of cultivation on artificial media.

Other strains, even immediately after isolation, were phagocytable in fresh normal serum, though resistant to phagocy

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tosis in inactivated normal serum, even after considerable periods of cultivation. It was found that the phagocytic reaction of these organisms in inactivated homologous serum, either from an immune animal or from a convalescent patient, were nearly as clear-cut and just as specific as were those of the more resistant strains when tested in active serum. Two such cases (Nos. 40 and 41) are included in Table I. Such strains may possess a moderate virulence for rabbits and mice, and, as a rule, were not phagocytable in fresh normal rabbit serum.

In examining (in inactivated serum) these strains which are phagocytable in fresh normal human serum, it is, of course, imperative that the leucocyte suspension be very thoroughly washed in salt solution (at least three times) to remove as far as possible all traces of fresh serum. Absolutely complete removal is probably not possible, and, as might be expected, there was frequently a very slight degree of phagocytosis of these strains in the control preparations. This must be allowed for in interpreting the final results of tests made with these strains.

Finally, there is a group of Type IV organisms which are spontaneously phagocytable, i. e., they are phagocytable in inactivated normal serum or in salt solution. They are, of course, entirely unsuitable for use in phagocytic tests, although, since some of them show no agglutination in normal serum, the demonstration of agglutinative activity in the homologous serum might be possible. In the course of this work I have examined 13 such strains, all isolated from the sputum or blood of patients with lobar pneumonia. In four of the 13 strains, all isolated from sputum cultures, it was definitely shown that the organism isolated from the sputum was not the etiological agent in the disease, but was probably an ordinary saprophytic inhabitant of the mouth, since the serum of these patients in convalescence acquired the power of causing phagocytosis and agglutination of stock strains of a fixed type (in two cases typical Type II and in two cases Atypical Type II strains). In one case a second attempt was successful in isolating from the sputum the Atypical Type II strain for which the serum had developed phagocytic activity.

Of the remaining nine, five were obtained only from the sputum (four by culture, one by mouse inoculation). The patients all recovered, and no further evidence was obtained confirming or disproving the relationship of the organism in question to the pneumonia.

In four cases, however, the strains were obtained by blood culture from patients subsequently dying of the disease. In three of the cases there were 2000 or more colonies per cubic centimeter of blood. The pathogenicity of the organisms in these cases can scarcely be questioned.

Although the primary object of this study was to determine the phagocytic activity of the serum, note was also made as to the occurrence of agglutination in the preparations, and a rough estimate recorded of the degree of agglutination present. With ordinary care in emulsifying the growth, it was easy to obtain homogeneous suspensions entirely free from clumps, with virulent organisms of the fixed types. In a large number

of tests no agglutination of these organisms was ever observed in normal human serum even when undiluted. In the active (convalescent) sera, however, clumping was usually a striking feature of the preparations. The clumps varied in size from groups of a dozen pair up to masses occupying a large part of an oil-immersion field. Of course, no clumping was regarded as significant unless the suspension was perfectly homogeneous, and unless the control preparations with normal serum were entirely free from clumps. The agglutinated masses of pneumococci, however, differed strikingly in appearance from the masses occasionally met with in poorly prepared suspensions. In the former, the individual organisms were more widely separated, and presented an appearance such as might be produced if the capsular substance between the organisms had been greatly swollen in the process of agglutination. This appearance has been described by Neufeld,' Huber ' and others.

Equally clear-cut results were obtained with a majority of the Atypical Type II and with many of the Type IV organisms studied. With a number of cultures, however, which showed a sparse dry growth on blood agar, and in which the capsules either were small or were not demonstrable, it was difficult or impossible to secure satisfactory suspensions free from clumps. Some other strains acquired this characteristic after prolonged cultivation on artificial media. Such strains also occasionally showed some tendency to agglutinate non-specifically in normal or in heterologous serum, and they were, without exception, discarded. The majority of these organisms were spontaneously phagocytable, and probably were saprophytic inhabitants of the mouth.

The results of the tests made with the serum of patients with acute lobar pneumonia are tabulated individually in Table I and summarized in Table II. With a few exceptions noted in the table, the homologous strain of pneumococcus was used in the test : Of 33 cases in which serum obtained at or shortly after crisis or lysis was tested with the homologous strain, isolated from the same patient, 28, or 85 per cent, showed definite phagocytic activity, while five, or 15 per cent, were negative. Of these five negative cases, in three only a single specimen of serum was examined, and only in a 1 to 3 dilution. Tests in concentrated serimi (if tried) might have yielded postive results. Of five cases which gave a negative reaction on the first test in a 1 to 3 dilution of serum, three gave positive results when tried a second time in concentrated serum. To these 28 positive cases may be added six others (included in Table I) in which the infecting organism was not isolated, but in which the serum after recovery caused phagocytosis and agglutination of a stock strain of one of the fixed types (Type I, two cases; Type II, three cases; Type Atypical IIA, one case). Only three patients in the series (Nos. 13, 14 and 21) received serum treatment with Type I serum, and in the two cases (Nos. 13 and 14) giving positive reactions there did not seem to be any immediate association between the administration of the serum and the appearance of phagocytic activity in the patient's serum.

Of the 33 eases tested with the homologous strain of pneumococcus, 26, or 79 per cent, gave definitely positive agglu

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171

tination reactions. The two sera which showed phagocytic but no agglutinative activity were among the three relatively feeble sera which were active only in full concentration. These figures correspond quite closely with those reported by Chickering" and obtained by a different method.

This phagocytic and agglutinative activity appeared with equal constancy after infection with pncumococci of Types I,

II and IV, and also in the only patient in the series with Type

III infection who recovered.*

Serum was also e.xamined from seven patients who later died of the disease, and the result was negative in six. The one case in which death occurred after serum activity developed will be discussed later.

In 18 of the 34 patients whose serum in convalescence was active in stimulating phagocytosis, tests were also made with serum obtained during the active stage of the disease. All were negative with three exceptions, and these three specimens were all obtained one day (or less) before the crisis. Of nine cases (eventually positive) tested 2-1 hours or less before the crisis, four were positive and five negative. Of nine cases tested about 24: hours after the crisis all were positive.

Very scanty data were obtained to indicate how long tlic activity of the scrum persists in the body. In one case it disappeared within 11 days, but it was usually present on discharge, from 10 days to three weeks after the crisis. In one case (No. 27) serum obtained two years later still showed slight phagocytic activity and fairly marked agglutinative activity for a stock Type II strain.

We may, therefore, conclude that the serum is inactive during the acute stage of the disease, and that phagocytic and agglutinative activity develop only at or near the crisis, occasionally appearing shortly before it, but often demonstrable only after recovery has definitely set in.

The only instance met with which seems to constitute an exception to this rule is No. 44, Table I. This patient was a man aged 61, alcoholic, with arteriosclerosis and hypertension. He was admitted to the hospital on the fifth day of the disease with signs of consolidation in the right upper lobe. On admission (fifth day), a Type IV pneumococcus was isolated from the sputum and also from the blood ( 1 colony per cubic centimenter of blood). On the 13th and 14th days the temperature fell by lysis, and it seemed probable that the patient would recover. However, the temperature did not reach normal. On the 16th day it again became markedly elevated, and a high remittent fever of the " septic " type persisted till death on the 21st day. A Type IV pneumococcus was again cultivated from the blood on the 18th day (2 colonies per cubic centimeter). All three strains were found to be serologically identical. On the 19th day the heart was found to be dilated, and a systolic murmur appeared

•The sera from two recent patients recovering rrom Type III empyema, not included in this series, showed well-marked phagocytic activity, but no agglutinative activity. This activity was present only In the fresh serum, and was limited to the homologous strain of pneumococcus.

at the apex. On this day the patient suffered a left hemiplegia. Nothing definite could be made out in the lungs or pleurae to explain the recrudescence of fever. No autopsy was obtained. While it was not certain tiiat the hemiplegia was not the result of a coincident cerebral hemorrhage, it was thought probable that a sepsis had developed, with an acute bacterial mitral endocarditis and a cerebral embolism.

The pneumococcus isolated from this patient was slightly phagocytable in fresh normal serum, but not in inactivated serum. The inactivated serum of the patient obtained on the fifth day caused no phagocytosis or agglutination of his organism, but a specimen obtained on the 13th day (during the remission), both in the fresh state and after inactivation, caused very marked phagocytosis and agglutination of this organism. A third specimen of serum obtained on tiie 18th day was equally active. This was two days after the recurrence of fever, and was after the reappearance of the organisms in the circulating blood. In this case, therefore, sepsis ai>parently ensued, despite the presence of phagocytic and agglutinative activity in the serum.

To determine the specificity of tlic reaction, a large number of crossed tests were made with the active post-critical .-ierum of each case, heterologous strains belonging to the same type and also strains of different types being employed. Table III shows results obtained with sera from patients recovering from Type I infections, and Table IV from infection with other types. In general, these data may be summarized as follows: A scrum which is active on the homologous strain, will, as a rule, cause phagocytosis and agglutination of any other strain of the same type, but is entirely inactive toward strains of any other type. This differs from the tentative conclusions previously reported by the writer. In the former series of cases, phagocytic activity, in the six sera in which it was demonstrable, was strictly limited to the homologous strain of pneumococcus, with the single exception of one serum, which was also active on one only of several lieterologous strains with which it wa.^ tested. In view of the findings in this present series the ex])lanation for the previous results probably is that only two of the organisms examined happened to belong to the same type.

The serum from patients recovering from Tyjic II iiifictidn showed no activity toward Atypical Type II strains (with the exception, possibly, of Xo. 27: Los., S.; Table IV). Serum from cases of Atypical Type II infwtions acted only on members of the corresponding suiigroup.

Case No. 14, Table I, illustrates well the sjjccificity of these reactions. This patient was admitted with a lobar pneumonia which was proven by si)utum and blood cultures to be due to an Atypical IIA infection. The serum shortly before crisis was inactive toward this organism, but shortly after crisis caused active phagocytosis and agglutination of it. Four days after crisis a second attack of pneumonia developed, a different lobe being involved, and a Type 1 strain was isolated from both blood and sputum. His serum at this time was inactive toward the Type I strain, though active toward the IIA strain. He had a second crisis on the eighth day, and after this crisis

172

[No. 340

phagocytic and agglutinative activity for the Type I strain had also developed.

Serum from one of the three patients infected with a Type IV pneumococcus was active only on the homologous strain. That from a second case was equally active on the homologous strain and on one other Type IV strain from another case of pneumonia, serum from whicli could not be obtained for study. The third case also furnished a serum which was active in promoting phagocytosis, not only of the homologous strain, but also of one other Type IV strain, isolated from the spinal fluid of a case of pneumococcus meningitis. The demonstration, among a comparatively small number of Type IV strains examined, of two pair of serologically identical strains, is in conformity with the recent findings of Olmstead," and indicates the probability that further study will reveal new types among the pneumoeocci now included in Type IV.

The serum of this last case (No. 27; Los., S.; Table IV) also caused phagocytosis of typical Type II strains and, less actively, of several Atypical II strains as well. This patient's serum four days before lysis was inactive toward the homologous Type IV strain, but was not tested at this time as to its activity toward a Type II strain, as this anomalous behavior of the serum was not anticipated. This is the only instance in the series in which a serum showed phagocytic activity toward a strain of a type different from that which was isolated from the sputum (except for four cases in which spontaneously phagocytable mouth saprophytes were isolated from plate cultures). This might be explained either on the assumption that the patient had a double infection with a Type II and a Type IV organism, or that he had previously had a Type II infection, with persistence of the antibodies for Type II strains. The possibility of such a persistence of antibodies for a long period is demonstrated by the fact that a specimen of serum obtained from this patient two years later still showed slight phagocytic and well-marked agglutinative activity for Type II strains. The activity of this specimen of serum for the homologous Type IV strain could not be tested, as the strain had been lost.

The agglutinative activity of this serum was less specific than its phagocytic activity, in that it not only agglutinated those strains which it caused to be phagocyted, but several other Type IV strains as well. The agglutinative reactions of the Type IV strains, and of some of the Atypical II strains, as observed in these tests, were not as specific as were the phagocytic reactions.

A special effort was made to detect any possible quantitative serological differences between different strains belonging to Type I. In two sera (Nos. 1, T. A., and 5, M. M., Tables I and III), both of which were but feebly active, the homologous strain was somewhat more actively phagocyted than were the heterologous strains tested.* This is in accordance with the observations of Chickering " on agsrlutination in the serum

• In two recent patients recovering from Type III empyema,

not included in this series, tlie piiagocytic activity of the serum was strictly limited to the homologous strain.

of convalescents. He reported that in several instances " the first organism to be agglutinated was the homologous strain, and only later was the stock strain agglutinated." Different strains may differ considerably in their phagocytability in the same serum. Thus, in one series of tests with stock Type I immune serum, strains S and R were phagocyted in 1 to 48 dilution ; strains V and B in 1 to 24 dilution ; while T and F were phagocyted only in a 1 to 12 dilution. When an active human serum was titrated in increasing dilutions with several different Type I strains, the highest titre was usually obtained with those strains which were most readily phagocytable in any Type I serum rather than with the homologous strain. Although such specific strain differences undoubtedly exist, they must be relatively slight, and it is not always possible to demonstrate them conclusively.

The activity of immune serum of the various types on most of the strains studied was also observed, and some of the results are recorded in Tables IV and V. The same complete specificity is observed here, except in the agglutinative action of Type II serimi on Atypical Type II strains. Type II serum in a concentration of 1 in 3 and with an incubation period of about 30 minutes caused agglutination of all the 25 Atj'pical II strains tested. However, Type II serum was much more specific in its phagocytic reactions toward these strains. With only two strains was any definite phagocytosis observed ; and this was much less active than was the phagocytosis of typical Type II strains.*

The Atypical Type II strains were actively phagocyted and agglutinated by an immune serum corresponding to the particular subgroup to which they belong, but were not affected by serum corresponding to the other subgroup or to any strain not belonging to their subgroup.

This test, therefore, offers an additional simple method for the differentiation of typical Type II and the various Atypical II strains, and has proved to be of practical value in the case of certain Atypical II strains, which were agglutinated macroscopically in Type II serum in dilutions of 1 in 32,- and even in 1 in 64, though somewhat more slowly that Tj-pical II strains.

The existence of other undescribed subgroups among the Atypical II strains is indicated by the fact that an immune serum prepared with a strain from a case of empyema, which did not fall into either Subgroup A or B, caused phagocytosis and agglutination of one other Atypical II strain.

As to the properties of the active substance which stimulates phagocytosis in these human sera, the observations previously reported by the writer have been confirmed. They are in the main thermostabile. In eight of nine cases tested, serum inactivated for 20 to 30 minutes at 56° C. retained its activity. When the lieating materially exceeded this, either in duration

• Several other Atypical II strains, after their resistance to phagocytosis had been lowered by cultivation on artificial media for a considerable period, also acquired a slight degree of phagocytability in T>-pe II serum. With the two exceptions noted, however, all strains when tested shortly after isolation were not phagocytable in Type II serum.

June, 1919]

173

TABLE I

PHAGOCYTIC AND AGGLUTINATIVE REACTIONS IN THE SERIM OF PATIENTS WITH LOBAR PNEUMONIA. TESTED WITH THE

HOMOLOGOUS STRAIN OF PNEUMOCOCCUS

Reault

Testa during meute itase

Tests during convalescence

Titre of

phagocytic

activity of

serum

No.

Name

Hospital number

Source of •train

Type

Ccri.18 L-lysis D-deatb

Day of

disease

Result

Daya before crisis, lyala.or death

Reault

Days

after

crisis or

lysis

Remarks

Phag.

Agren.

Phag.

Aggn.

1

T.. A.

3SS80

Sputum

I

L

21 !1 ..

+

,

4

1-1. -I

18

t

v.. J.

3S430

Sputum

I

C

16

+'

+'

1

+

1 8

1-3,-11-6,0

3

R., C.

35482

Sputum

I

L

13

7 4

1 19

1-6, -^

1-12.0

4

S., J.

35517

Sputum

I

C

9

D

3

+'

+'

2

4

11

l-12,-(

Serum had become inactive 11 days after lysis.

s

M.. M.

35828

Sputum

I

L

6

c

4

+'

1

1-1, -t1-3,0

«

P.. P.

35582

Sputum

I

C

6

1

+ '

+'

2

1-1. + 1-8,0

7

P., C.

35082

Sputum

I

L

11

8

+'

+*

1-3, -t1-6,0

8

li.,W.

35901

Sputum

I

L

10

8

+'

4

1-3,-1

8

McK., C.

39702

Empyema

I

L

f

+*

-I-'

80(f)

1-3,+

10

R., J.

35902

Sputum

I

11

4

+

+•

1-3, -h

11

a., N.

35274

None obtained

(I)

C

6

+

+'

12

1-3,-1

Tested with stock Type I strain.

U

B..C.

35681

None obtained

(I)

L

12

6

+'

+*

1

1-3,-11-6,0

TestedwithstockTypel strain.

18

W., H.

37334

Blood, Sputum

I

C

7

+'

10

l-S.-t

It

W., 0.

37&S0

Blood, Sputum

I

C

8

12

+'

+*

1-3, -h

1 1 A pneumonia. See No. S3.

<

IS

T.,C.

38870

Sputum

I

C

8

+

+'

1

1-3, -^

This (ollowcd 3 davs after a

Type 11 pneumonia. Not tested till 11 days after

1«

B.,U.

35028

Sputum

I

L

6 11

1-1,0

16

Ivsis.

17

W., M.

35082

Sputum

I

L

7

2

2

1-1,0

Clinicallv broncho-pneumonia.

18

M., 8.

35594

Blood, Sputum

D

19

14

Pneumothorax following aspi

18

F., J.

35588

Blood

I

D

?

f

ration.

to

J. W.

35308

Sputum

I

D

9

B

21

J.

37409

Sputum

I

U

3

3

n

8.. F.

353 IS

Sputum

11

L

10

3

1

+'

+'

4

1-12,0

a

M.. T.

37419

Sputum

II

Lf

f

+'

+•

f

1-3,-1

u

D.,H.

39040

Ulood, Sputum

II

C

7

+'

-I-'

u

C, J.

35311

None obtained

(11)

C

9

+'

+'

11

1-3, -h

Tvpe IV from sputum 8 days after crisis. Tested with stock Tvpe [1.

M

T.. J.

35871

Sputum (IV)

(11)

L

9

+•

+'

1

1-3,-f

Phajfocvtiiole IV from sputum. Tested with stock Type 11.

17

L..S.

35681

Sputum (IV)

(II)

L

18

+'

1

1-S,-I

Tvpe IV from sputum. Tested with stock 11. See No. 41.

»

0.. E.

37279

Sputum

II

L

9

+

4

1-8,0

Not tested in concentrated serum.

18

W.. H.

39103

Sputum

III

C

3

+'

+

1-3, -h

30

C.,C.

35596

Sputum

III

D

7

4

31

H.,0.

37200

Sputum

IIA

C

7

+'

-I-'

S

i^,+

32

B, W.

37328

Sputum Blood, Sputum

IIA

C

7

+'

+'

33

W.. (;.

37556

IIA

C

7

+'

+'

6

See No. 14.

34

H., B.

37354

niood. Sputum

IIA

L

7

+*

+*

35

8..T.

37298

IIA

C

9

+'

+'

6

1-3,+

3«

McC.. 0.

37468

(See remarlia)

IIA

C

8

+*

+'

3

1-3,+

Phagocytahle IV from sputum. Testeil with stock IIA.

37

J., H.

37074

Blood, Sputum

IIA

D

8

2

38

E.. R.

35806

Blood, Sputum

Atyp.II

C

10

7

1

+'

+'

6

1-6,0

88

D.. W.

37433

Sputum

Atyp.II

C

8 3

1-3,0

Not tested in concentrated

40

B..J.

35679

Sputum

IV

L

8

3

+'

-I-"

2

1-3,+

41

L.. 8.

35660

Sputum

IV

L

13

4

+'

-I-'

1

1-3,+

See No. 27.

41

W..H.

374U0

Sputum

IV

C

7

+'

+'

8

1-3,+

43

N.. A.

37810

Sputum

IV

L

8

+'

1

44

W.. J.

35627

Blood, Sputum

IV

D

21

18

8

1-3,+

4S

B.. W.

37335

Sputum

IV

L

8

+"

3

6

1-3,0

Not tested in concentrated

4<

N.. H.

37285

Sputum

IV

D

8

'

"

TABLE II

SUMMARY OF PHAGOCYTIC REACTIONS IN THE

SERU

MOP

PATIENTS

WITH LOBAI

IPNE

UMONIA

Reacttona with serum from convalescent patients (lobar pneumonia). Cases tested with the homologous strain

cases tested

with stock

strains

Total positive

No.

Reactions of serum d

from patients whose

gave positive

ring acute stage, serum eventually reactions

Reactions of scrum from patients who subsequently died

Ko.

Poaltire

Negative

Pofitive

No.

PoaitiTt

1 NegatlTO

No.

PoaitlTC

Nagitir*

Type 1 1 IS

Type II 4

13

8 1 6

«

2

2

i

IS S

s

8

U

3

8 2

1 '^

4

t

1

4

Type III 1 1

Type IV 6

Type Atyp. II 7

28-88%

6-lS%

6

34

IS

•8-17%

1 16-83' .

^

1-124%

7-874%

• TheM thrM fpccfmena were obtsineU on the da/ before criiii.

174

[No. 340

or height of temperature, the activity was lessened or destroyed. The serum usually remained active in vitro for several weeks, though it gradually weakened in activity. In two cases, serum, which in the fresh state was feebly active, lost its activity after from two to four days. Nearly all the sera, however, remained active throughout the period during which they were under observation, which varied from a few days to four months.

If the serum had become inactive or feeble as a result of overheating, long preservation or dilution, the phagocytic activity could not be restored or increased by the addition of complement. The substance is, therefore, quite different from the active substances (opsonins) of fresli normal serum, and corresponds to the bacteriotropins as defined by Neufeld."

The active substance was present in the serum in relatively small amount. In a majority of the sera tested as to this point, no phagocytosis occurred if the concentration of serum in the mixture was less than 1 in 3. In a few cases it was active in a 1 in 6 dilution, and in one case in a 1 in 12 dilution.

These bacteriotropins, as well as the agglutinins, were precipitated from immune serum with the euglobulin, on the addition of 36 volumes per cent of saturated ammonium sulphate solution. The euglobulin fraction of the precipitate, redissolved in salt solution and freed from an excess of ammonium sulphate by dialysis, caused marked phagocytosis and agglutination. The pseudoglobulin fraction of the precipitate, obtained by the further addition of saturated ammonium sulphate solution to give a concentration of 44 volumes per cent, was likewise redissolved and diah'zed, and was found to be inactive, as was the dialyzed supernatant serum from which the globulins had been removed. In this respect, therefore, the bacteriotropins resemble most other antibodies which have been similarly studied.

These bacteriotropins are probably not identical with the agglutinins. In two sera in which definite phagocytic activity was demonstrable, no agglutination whatever occurred. As a rule, however, the agglutinative activity of the serum was

more marked, was usually present in higher dilution, and persisted longer in vitro than did the phagocytic activitj' of the serum. In one case agglutinative activity was observed to precede the development of phagocytic activity. However, the observations with reference to this point were not sufficient to determine which type of activity is usually the first to appear.

Of 33 cases of acute lobar pneumonia in which the phagocytic activity of the serum after crisis or lysis was tested with the homologous strain of pneumococcus, 28, or 85 per cent, gave definitely positive results. These results confirm and extend those previously reported by the writer.

In 26, or 79 per cent, of these cases agglutinative activity was also demonstrable.

In 18 cases in which definite phagocytic activity was demonstrable in the serum after recovery either for the homologous strain or for a stock strain of known type, tests were also made with serum obtained during the acute stage of the disease, and negative results were obtained in 15. The three sera which showed phagocytic activity were obtained 24 hours or less before crisis.

Serum was also examined from seven patients who subsequently died of the disease, and negative reactions were obtained in six. A positive reaction was obtained in one patient, who, after a short remission, died apparently of sepsis and endocarditis.

This phagocytic and agglutinative activity of the serum developed after the recovery from infection with pneumococci of all the recognized types. It was strictly limited to organisms of the same type as that with which the patient was infected, but, as a rule, was exerted equally well on the homologous strain and on heterologous strains of the same type. It is, therefore, specific as to type, but not specific as to strain, as the writer originally believed.

The agglutinative activity of the serum as observed in these tests paralleled closely the phagocytic activity. In the case

TABLE III PHAGOCYTIC AND AGGLUTINATIVE REACTIONS IN THE SERUM OF PATIENTS RECOVERING FROM TYPE I INFECTION,

TESTED WITH

HOMOLOGOUS AND HETEROLOGOUS

TYPE I STRAINS Strain of pneumococcus-Typc I

Serum

Type I (stock)

Type II (stock)

T., A.

v., J.

R., C.

S., J.

M., M.

p., p.

P., c.

M.,W.

McK.

R., J.

B.,H.

W.,M.

So.

Joh.

Fen.

McC.

Mt.

For.

Scrum, Type I (immune). Serum, Type Iliimmune)

+' +'

+

+ ! +3

+' +> +3 +>

+

+" +' +» += + +"

+» +'

U

+ S +3

+'

+= +'

+s +3 +3 +3

+ += + +

+ 3 +3

+ 3 +3

+ 3 +3

+ 3 +3

+3 +3

+3 +3

+3 +3

+3 +3

+3 +3 u

+3 +3

+2 +3

±

+ += +» +'

+2 +3

+3 +3

±

+ +'

+2 +3

+2 +3

+

+ = +3

+= +»

+3 +3

+ S +3

+

+ 3 +3 + ' +'

+' +'

+ 3 +3

Serum, V., J

+ 3 +3 + 3 +3 + 1 +3

+

43 +3 +S +3

+: +' += +' +'

+ 3 +3

+ ' + =

'+="6'

+» +' +"

-r' +» + 11 + 2 +3 +3 +3 +3 +3 +! +8

+3

+ +=

+ 3 +3

+ +'

+ 2 +3 + 3 +3

+ 3 +3 + 3 43 + 3 +3

+=

+ 2 +3

+3 +3 +

+s + +' +1 +3

+2 + 2 +3 + » +»

+ 2 +3 +3 +3

Serum, S., J

+> +'

+ 3 +3

+ 2 +3

+3 +3

+ 3 +3 + 3 +3 + 3 +3

+2 +2 +3 +3 + +»

+1 +3

+3 +3 + 3 +3 + 3 +3 + +»

+ += + 2 +3

+ +'

+ +'

+ +'

+ +'

+ +»

+ +"

+ +=

+ +=

+ +'

+=

+s +»

+2

+"

+'

ach column represents phagocytosis, ami the second a^'g^lutination.

G

1

e

1

'5

B

s

•oqD

a, <

=•+ :

oo •

joo 1

•00 •

000 • •

• • 'O

•Jia

d

<

0+ .

0+ :

.0 .0

'e


J < O

< o

>

•IAS

d

<

®+ : o+ i

000

•000

00 .4. * • * 000 • • •

i i :®

•"in

•<

®+ ;

oo •

+® :
• oo '

°°+ : : : 00+ I : :

oiM.

a, <

04.0004.eo ooooeooo

OO.f.O • •

00+0 : :

•*a 'la

d •<

00 •

• 000

• 000

0=+::: 00+ •; : :

: : +
: : +

d

PJM

a

04.004.00 • 00004.00 '

°°+ : : : 000 • • •

• • ;0

^03

^5

•"H H •"If

•<

«+»+» : : : 0004-0 '• \ •

+::
+::

<

0+ i-t In

00 ;4

• • :

: :+++
: :+++

U '1*8

<

04.04.0 . . . 0004-0 J J j

:+ :
:+ :

HO hoo

•A-W

<

+ :-f

•0 j-f

• • •

: :+ : :i
+:."

• : : : . : : :

••<>H

<

00 :"

® : : : ^ • *

: :+++
: :++ +

TABLE IV

P PATIENTS UECOVERINQ FROM IN AND WITH HETEROLOGOUS STRA

'•"«.*

2

0+ : +

00 j"

• ' t

: :++ +
: :+++

a "^H

<

04.04.0 : : :

0004-0 • • '•

: : + + +
: :++ +

•iia

<

04.04.00000004.4.4.4.4.4.4.!;. 0004-000000004.4-4-4.4.4-0

•'I'M

S;

00 • 00 :

.00 . •00 •

==+ : : : 000 ' • •

• 1 Jo

: lo

•«)

>

00 '•

00

lo *

="=+ : : : 000 •. r :

: :°
: lo

•*J1H

>

00 .

00 '•

;0 ;

=>°+ : : : 00+ : : I

' • "o

•*tn

>

00 •

00 '•

'. jo •

+++ : : : +00 : I :

• '0

oz

B-»oa

>

oo : 00 •

'.oo 1 •00 i

00+ . . .

- r I c

00+ : . .

• '0

OSH

60 00

•f -JM

>

00 1 1 00 - •

joe j loo j

"++ : : :

M ', * ',

°++ : : :

= g Hg

T "q^a

>

00 ] J 00 ' •

. .0 .

+++ : : :

•< * Z I

+00 • . .

• *o

pa

fi '••pjtt

=

004.

00 -f

: : : +
: : :*

IPN

=

"+ : : 0+ I :

++ :
+ + :

=<='+ : : i 00+ J 1 ]

• -o

•J '8

=

0+ : ;

+ + + .

i + + + '

°°'+ : : :

"III

004- :: :

•  :®

• -0

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176

[No. 340

of Atypical II and of Type IV strains it was not so sharply specific as was the phagocytic activity.

This phagocytic activity is entirely different from a possible rise in opsonic index, in that it brings about active phagocytosis of a virulent pneuniococcus, not at all phagocytable in normal human serum.

The active substances in the serum also differ from tlie opsonins of normal serum in that they are usually thermostabile ; they usually remain active for several weeks in serum preserved in vitro; and when their activity is lost, they cannot be reactivated by fresh normal serum (complement). Tliey are therefore qualitatively comparable with the bacteriotropins of potent immune serum.

In view of the facts: (1) That this activity of the serum develops in nearly all patients who recover, but only appears, as a rule, at or near crisis; (2) that it is limited to organisms of the same type as that with which the patient is infected; (3) that, as previously reported, the "phagocytic activity of the serum ran closely parallel with the protective power for mice, both in incidence, in time of appearance and in strict specificity as to the type of pneumococcus concerned"; and (4) that phagocytosis in the peritoneum of the protected mouse closely paralleled phagocytosis in the testtube; it seems probable that this factor plays an important part in bringing about recovery in man.

The part played by agglutination in immunity to the pneumococcus in animals has been emphasized by Bull, and in all probability it is also an important factor in human immunity.

That other factors are also concerned is indicated by the death of one patient from sepsis, despite the previous development of phagocytic and agglutinative activity in his serum ; and by the fact that in several instances pneumococci, which had been cultivated from the blood of patients dying of pneumonia, were phagocytable in normal serum or even spontaneously phagocytable in salt solution.

The clinical value of the test will not be great as a method either of diagnosis or of prognosis, since the reaction develops only when recovery sets in. In cases in which as a matter of scientific interest it is desirable to determine the type of organism concerned in a recent infection, the development of a positive reaction either with a stock pneumococcus of known type or with an homologous isolation, would furnish practically conclusive evidence that this organism was the etiological agent concerned in the disease.

REFERENCES

1. Clough, P. W. : The development of antibodies in the serum of patients recovering from acute lobar pneumonia. Bull. Johns Hopkins Hosp., Baltimore. 1913, XXIV, 295-306.

2. Neufeld, F., and Rimpau, W.: Weitere Mittheilungen iiber die Immunitat gegen Streptokokken und Pneumokokken. Ztschr. f. Hyg. u. Infectionskrankh., Leipzig, 1905, LI, 283-299.

3. Cole. R. I., and Dochez, A. R.: Report of studies on pneumonia. Trans. Assn. Am. Physicians, Philadelphia, 1913, XXVIII, 606-616.

4. Dochez, A. R., and Gillespie, L. J.: A biologic classification of pneumococci by means of Immunity reactions. J. Am. M. Ass., Chicago, 1913, LXI, 727-732.

5. Lister, F. S.: Specific serological reactions with pneumococci from different sources. Johannesb., 1914, W. E. Horter & Co. S. African Inst. Med. Research., Pub. No. 2.

6. Lister, F. S.: An experimental study of prophylactic inoculations against pneumococcal infection in the rabbit and in man. S. African Inst. Med. Research., Johannesb., 1916, No. 8, 1-57.

7. Bensangon, P., and Griffon, V.: Etude de la reaction agglutinante du serum dans les Infections exp^rimentales et humaines a pneumocoques. Ann. de I'lnst. Pasteur, Par., 1900, XIV, 449.

8. Huber, F. 0.: Ueber Agglutination der Pneumokokken. Centralbl. f. innere Med., Leipzig, 1902, XXJII, 417-421.

9. Neufeld, F. : Ueber die Agglutination der Pneumokokken und viber die Theorien der Agglutination. Ztschr. f. Hyg. u. Infectionskrankh., Leipzig, 1902, XL, 68.

10. Gargano, C. and Fattori, C: SuU' agglutinazione del dlplo cocco; contributo di fatti e di osservazioni. Riv. crit. di clin. med Firenze, 1903, IV, 177, 193, 209, 225.

11. Jehle, L. : Ueber Pneumokokken-Agglutination mit dem Blut serum pneumoniekranker Kinder. Wlen. kiln. Wchnschr., 1903 XVI, 917-919.

12. Chickering, H. T. : Agglutination phenomena in lobar pneumonia. J. Exper. M., Lancaster, Pa., 1914, XX, 599-613.

13. Clough, M. C: A study of the incidence of the types of pneumococci isolated from acute lobar pneumonia and other infections, and an analysis of the cases classified by types in regard to mortality, complications, associated diseases, bacteriemla, and leucocytosis. Bull. Johns Hopkins Hosp., Baltimore, 1917, XXVIII, 306-311.

14. Sydenstricker, V. P., and Sutton, A. C: An epidemiological study of lobar pneumonia. Bull. Johns Hopkins Hosp., Baltimore, 1917, XXVIII, 312-315.

15. Avery, O. T.: A further study of the biologic classification of pneumococci. J. Exper. M., Lancaster, Pa., 1915, XXII, 804.

16. Neufeld, F.: Bakteriotropine und Opsonine. In Handb. d. pathogen. Mikroorg. (Kolle and Wassermann), 2. Aufl., Jena, 1912, II. 401.

17. Olmstead (Miriam): A preliminary report on the classification of pneumococcus IV. Proc. Soc. Exper. Biol, and Med., New York, 1916, XIV, 29-31.

18. Bull, C. G.: The mechanism of the curative action of antipneumococcus serum. J. Exper. M., Lancaster, Pa., 1915, XXII, 457-464.

THE DEVELOPMENT OF CROSS-STRIATIONS IN THE HEART MUSCLE

OF THE CHICK EMBRYO

Bv Margaret Reed Lewis

The results obtained by different observers in regard to the development of the cross-striations in muscle-fibers differ so decidedly that one is forced to question whether any one of the views presents the entire story. Even though the discus

sion be confined to the development of this structure in one organ and to one form, as, for instance, the histogenesis of the myofibrils in the heart muscle of the chick embryo, it is found that, although the papers published are few in number.

JrxE. 1919]

177

they nevertheless differ fundamentally from each other. In an effort to determine, if possible, the reason for these differences, a careful cytological study of the development of the heart of the chick embryo was undertaken. For this purpose preparations of embryos varyinlnKi:i|>li "I H ' hi. K :mi.'i 48 lioiirs ini'iiliation. Tlii embo'O had 22 iti.vuluiiio. The lieiirl iiiu.*.i-le wu?. full of 4-niv.-striiitoil llbrils.

i 1 1 » il

II i\ J I

Km. S. — A niiiiiTu ilrauiiiK from Ihe heart of an eiiibivo in wliiili the tcneli M.mili' was just Kiii. fi.— Ciliiieni ilrawiliif "f a »nnill |.iirliim iif a few nliril« tn .hmv

i^Hii|ilFtr<l. The riuik-i mi-ii- lielow the kiirlarv uikI their pre~eri(e i. only ^liKhtl.v indicated. the different wiillh iif «liril» found in u given region •>! Ilie li.ad

Z.nker without aiili. uri.l pins a few ilr.ip, .,( i prr twit o»mic aiid. I'nstaiiied. Z^l^» No. S oc. nniM-le ..f a dii.k i-nil.ryo ..f 1.', wmiiU-s. and 2 mm. lelu.

Kl... 4.- A laii.rra .|ra»init nf a (.« •! in. ii.... were more fibriU pro*«nt lliaii are Khown m the dr. oc. and i mm. Ien>.

..i oi II,. M...,i .,1 the «mbr>o ..1 1 ..; J There

dliuji « 4ibove. MrtinefJ with lron-heniatuA>hu. jCciu No.

June, 1919]

179

fibrils upon fixation. Whether these fibrils became crossstriated, varicose, or smooth, or whether they were broad or narrow, depended entirely upon the treatment to which they had been subjected.

Stained preparations were much more ditticult to control. Many of tlie stains ditfused across the cross-striation ; in other eases, much of the substance of the cross-striation, but not of the fibril, was dissolved out in the process of dehydrating and staining. The unstained preparations were so satisfactory that little experimenting was done with stains. Fig. 4, however, is drawn from a preparation successfully stained with iron hematoxylin.

The embryo was occasionally mounted in a drop of Locke's solution and the fixing solution permitted to penetrate under the edge of the coverslip. By this means the formation of the fibril eould be observed under the microscope. In this way it was found possible to control the phenomenon and to produce various types of fibrils at will, thus showing that the form assumed is due to factors present during the fixation of some substance in the muscle tissue.

From the above it may be seen that by tlie use of Zenker's solution (without acid, and with the addition of a little osmic acid) and fixing with the muscle slightly extended, completely cross-striated fibrils are formed in the heart of the chick embryo at the early age of 10 myotomes. Many of the discrepancies of opinion shown by the above-mentioned writers were evidently due entirely to the lack of extension of the heart muscle, while others depended upon the fixing solution selected.

CROSS-STRIATIOXS

The simplest method of designating these cross-striations seemed to be the dark band, the light band and the gray band. When the wing muscle of the house fly was fixed side by side with the embryo heart, there was a marked resemblance between the pattern of the cross-striations of the two tissues. Text Fig. 1

Dark

LioKt

Dark

z J Q Q J z

m KroLvjLsels (nemurcLn.e. ^= ^arcou-c, SubstQ.rv.ce.

tvijool irx.e_

Tkxt Fio. 1. — A diaj^ammjitir re|)re^entAtion o( the pattern of the crowi-iitriati«ii» found In the heart mu«-le of the rhirk embrj'o of 10 domlten. The temis used to indicate the different partjt of the rross-striationa are placed opposite the part.

shows the manner in which the various terms used by other observers may be applied in these observations. The most pronounced part of the cross-striated pattern was the light band. This band was lighter than the cytoplasm and probably was composed of some substance which upon fixation did not become as dense as that of other portions of the cell. The dark band was much darker than any other structure of the cell and was probably quite dense. The gray band was practically the same as the cytoplasm. The dark band was never seen without the adjoining light band on each side. In certain rather round cells the fibrils could not be found, but the dark and light

bands wefe present and sometimes appeared to be scattered dark granules of uniform size, surrounded by a light area. From Congdou's figures it might be supposed that what was present in his material were not hexahedral compartments, but some such appearance as this. In his Fig. 2 the dark band, or granule, and the adjoining light bands are so spaced as to require little imagination to form them into such cross-striated fibrils.

Occasionally the cross-striations extended entirely across a cell without the presence of fibrils. These cross-striations were meager in depth and difficult to focus. The gray band was not noticeable as a special structure, but the regular space between the two light bands indicated its presence. The dark and light bands, however, were striking contrasts to other parts of the cell. Their appearance remained practically the same wherever found. The whole cross-striated fibril retained its characteristic appearance, whether widely spread out or only a narrow thread (Fig. 4).

The observations described above are based entirely upon fixed material. They show that the completely cross-striated fibrils can be demonstrated to be present at an age younger than that found by any other observer and also that they are already present at the time when these observers describe the presence of certain granules, threads, etc., from which tlie cross-striations are supposed to be derived later.

The presence of some substance which coagulates to form fibrils has been shown by Lewis (1919) to be characteristic of the smooth muscle, the heart muscle and the skeletal muscle. The same phenomenon is exhibited by these young embryos; t. e., fibrils form upon fixation in the smooth muscle of the amnion, in the heart muscle and in the skeletal muscle.

In all probability the cross-striations are laid down in the heart muscle-cell coiucidently with the diiferentiation of these cells to form the muscle layer around the heart. This substance coagulates to form fibrils. It increases in amount in the cells during the development of the heart, with the result that the cross-striations become clearer and clearer, and the number of fibrils which can be caused to fonu becomes greater. With the increase in depth of tliis material along the surface of the miscle-cell the pattern of the cross-striations becomes less readily distorted upon the formation of the fibrils. Since it can be demonstrated by one procedure that the fibrils are completely cross-striated from their first appearance it is logical to assume that other methods fail to preserve these structures in their early form. For this reason, it is not necessary to discuss which theory so far advocated as to the origin of these interesting bodies is correct.

LIVING HEART MUSCLE TISSUE Needless to state, the various aspects presented by the heart tissue as descril)ed above, including those observed by the several investigators mentioned, do not correspond to the appearance of the living tissue. This might readily be surmised if for no other rea.son than that one is dead and the other living. When preparations are made by the same method as that specified herein, except that in place of a fixing solution

180

[No. 340

a drop of Locke's solution is used, very thin living hearts are obtained and these continue to contract for an hour or longer. The most noticeable feature of such tissue is the complete lack of fibrils of any type.

The muscle-cells are not spread out into a flat layer as in the fixed preparations, but remain rather round or spindleshaped, and because of this it is very difficult to determine whether there are processes between the cells or not. Certainly, the cells do not appear to form a marked syncytium.

In these observations on the living heart several embryos with 11 myotomes were studied, and as many as six of each of the different ages of older embryos (12, 15, 18, 20 and 22 myotomes). The muscular tissue of the hearts of embryos of from 12 to 15 myotomes appeared to be essentially the same. In that of older embryos trabeculse began to appear. The cell walls were distinguishable in places. Sometimes only a single cell in a given field showed contraction. Again, all the cells of a given region took part in the same contraction. The continued movement of the cells made it difficult to trace their individual boundaries. The tissue of the heart of older embryos (from 15 to 22 myotomes) appears to be more syncytial in nature. No preparation of a living heart was obtained in which contraction did not occur. The movement of these muscle-cells takes place so rapidly that it is almost impossible to be certain of the actual occurrences during the phenomena. In none of .the hearts observed (about 50) was there any evidence of a slowing of the actual contraction. The rest periods became longer and longer, the number of contractions fewer and feebler, but the last contraction that took place was as rapid as any of the previous ones and in every case relaxation occurred after each contraction, even the last one. Rigor mortis was not observed.

MYOFIBRILS

No structure resembling the fibrils of the fixed preparation was present in the living heart muscle at any of the ages studied. In fact there were no long threads of any kind, not excepting the mitochondria. The latter did not extend farther than past the region of the nucleus, and were never seen to extend from one end of a cell to the other, or to pass from one cell to an adjoining cell. Certain preparations of pieces of the heart of four- to six-day embrj'os were used for comparison. No fibrils could be found even in this older heart muscle.

MITOCHONDRIA

The mitochondria were very abundant in the heart-muscle tissue of embryos of all stages up to four days' incubation. They exhibited active movement, bending, twisting and traveling in the cytoplasm. The most frequent forms were those of threads and rods. The longest filament, however, never extended the length of the cell. The long axis of a mitochondrium usually coincided with that of the cell. In round or only slightly spindle-shaped cells, the mitochondria seemed to lie in almost any direction. The outer cytoplasm of the cell was not invaded by these bodies.

When the heart of a 30- to 48-hour chick embryo was injected with Locke's solution, to which janus green has been added, and the preparation then mounted in a drop of the same solution, the mitochondria in the muscle-cells became stained. In such stained preparations the mitochondria appeared as bright blue threads, rods and granules. Certain portions of a mitochondrium occasionally stained more deeply than the remainder. There were no elongated blue threads, either smooth or varicose, extending the length of the cell.

NEUTRAL RED GRANULES

Preparations stained with neutral red in the same manner as that described above for janus green contained few small, red granules. When such a preparation was sealed with vaseline and kept under observation many red-stained bodies appeared in the cytoplasm. Similar bodies were observed in a few unstained preparations which had been kept under observation for a long time. The stained bodies were mostly in the form of round vacuoles, with one or more deeply stained granules; a few active pink filaments, with darker granules, were sometimes observed. Owing to their accumulation in such sealed preparations these neutral red vacuoles appear to resemble the neutral red bodies supposed by W. H. Lewis (1919) to represent waste products of the cell.

CROSS-STRIATIONS

The cross-striations are difficult to observe, either in the hearts of young embryos (11 to 18 myotomes), or in those of older ones (two days), without the most careful search. The most active cells contain the cross-striations as parallel bands of light and dark material. They extend only so far as the surface of the cell is in the plane of focus, becoming lost as soon as the vision penetrates below the surface. They may consist of only five or six parallel bands, or of as many as 10 or 12, again depending upon the plane of the surface. This is quite different from the fixed material, in which the cross-striated fibrils extend for long distances within the field of vision. In a few regions, such as along the side of the trabeculaj, the cross-striations can be readily distinguished. Here they are arranged in the characteristic pattern, i. e., dark band, light band, gray band, light band and dark band.

The cross-striations were most readily observed in the living heart by the aid of janus green. In such muscle tissue they appear frequently as a blue band with an adjoining light band. These were either close together or separated by a space where the gray band was indicated. The blue band was undoubtedly the dark band stained with janus green. In preparations which had been stained for some time the material between the two light bands (the gray band) also became slightly blue. In no instances were the cross-striations of the living material as marked as in the fixed preparations. This was largely due to the fact that they were never drawn into thicker bundles, i. e., fibrils, but remained spread out over the surface of the cell.

Jl NE, 1919]

181

SUMMARY

Thus it is st-eii that in the liviii-r irll cross-striations an |)rest'iit. hut not filirils. The cross-striations art- very tliin l)an<ls on tlie surface of the cell. They extend across the cell and are never in the narrow threads or lihrils. The fixation of the cell causes the formation of the surface layer into fihrils in which the cross-striations are drawn toj;ether into dee]ier bundles and thus hei-oine evident as shar])ly marked structures. In places where the pull on the surface of the cell is such that the latter is not coajrulated into (ihrils, the cro.ss-striations remain spread out as thin hands across the cell (Figs. 2 and 4).

The comjjlete cross-striations are present in the muscle of the heart of very younjr emhryos (10 myotomes) much earlier than was su|)posed hy other ob.servers.

The physifdojrists have endeavored without success to formulate a theory, based upon the myofibrils, to account for the contraction of the muscle-<'ells. It is not surprising that such a theory has not proved satisfactory, at least in regard to the heart muscle, since the structure u|)on which it was ba.sed is not a part of the living heart-muscle cell, hut only of the dead cell. In other words, a cell containing the structure upon which it was attempted to huihl the theory is not capable of undergoing contraction.

LITERATI-RE

Bruno. G. : 1918. La struttura del miocardio dell 'embrione di polio air inizio della sua funzione contrattile. Monitore Zool. Ital.. XXIX. 53.

Congdon, E. D.: 1918. The embryonic structure of avian heart muscle with some considerations regarding its earliest contraction. Anat. Rec. XV, 135.

Duesberg, J.: 1909. Ueber Chondriosomen und ihre Verwendung zu Myofibrillen beim Hiihnerembryo. Anat. Anz.. XXX IV. 123.

Idem: 1910. Les chondriosomes des cellules embryonnaires du poulet, et leur role dans la gen^se des myoflbrilles. .Arch. f. Zellforsch.. IV, 602.

Godlewski. E.: 1902. Die Entwickelung des Skelett- und Herzmuskelgewebes der Saugethiere. Arch. f. mikr. Anat.. LX, 111.

Heidenhain. M.: 1899. Beitriige zur .\ufklarung der wahren Wesens der faserformigen Differenzirungcn. .\nat. .Anz., XVI, 97.

Jordan, H. E., and Ferguson. J. S.: 1916. Textbook of Histology. New York, p. 95.

Kurkiewicz, T.: 1909. Zur Kenntnis der Histogenese der Herzmuskels der Wirbelthiere. Bull, intern, de I'acad. des sciences de Cracovie, p. 148.

Levi, G.: 1916. Migrazione di element! specifici dlfferenziati in colture di miocardio e di muscoli scheletricl. Arch, per le Scienze .Mediche. XL. 1.

Lewis. M. R.: 1919. .Muscular contraction in tissue cultures. Contributions to Embryology 35. Pub. 272. Carnegie Instit. Wash

Lewis, \V. H., and Lewis. .M. R.: 1917. Behavior of cross striated muscle in tissue cultures. .Amer. .lour, of Anat.. XXII. 169

Luna, E. : 1913. Sulla importanze dei condriosomi nella gene!-i delle mioflbrille. Arch. Zellforsch.. IX. 458.

Meves, F.: 1908. Die Chondriosomen als Trager erblichcr Anlagen. Arch. mikr. Anat., LXXII, 816.

Mlodowska. J.: 1908. Zur Histogenese der Skelcltniuskcln. Bull, intern, de I'acad. des sciences de Cracovie. p. 145.

Rouget. C. : 1863. .Memoire sur le d^veloppement embryonnaire des fibres musciilaires de la vie animale et du cii>ur. Jour, de la Physiol, de Brown Sequard. t. 6, p. 459.

Schlater, G.: 1907. Die Myofibrillen des embryonalen Hiihnerherzens. Arch. f. mikr. Anat., LXIX. 100.

Wieraan, H. L.: 1907. The relation between the cytoreticulum and the fibril bundles in the heart muscle of the chick. .Amer. Jour. Anat., VI, 191.

SPINA HIl IDA WITH ASSOCIATI

EMBRYO 17

Hy S. T. W TlieJoln,.^lIoi,l.-i

Human monsters at full term or in late fetal stages are .seen, sooner or later, hy almost every i)hysician. Similar anomalies in very young embryos, such as the one described herein, arc, however, not so well known. Dr. Mall ' estimates the frequency of full-tenu monsters as ."JO to every 5000 pregmmcics and gives a resume of the ])rotocols of 7."> specimens showing localiw*! anomalies (which he regards as the forerunners of monstx'r formation) found among 1000 specimens in the Carnegie Colle<'tion of Human Kmbryos. This particular embryo (N'o. 1961, Carnegie Collection) is, however, of especial interest in view of the fact that, although having a nu-nstrual age of only 79 days, it pn-sents ahnornuilities of brain, spinal cord, viscera and skeleton, generally suppo.sed to be characteristic

' Mall, F. P.: On the frequency of localized anomalies in human embryos and Infants at birth. Amer. Jour. Anat.. 1917. XXII. 49-72.

i) DISTruHANCES IN A HUMAN

MM. LONG

M.I.IS C'l 1,1,.

)/v Miilirnl Schoul

only of much oldir monsters. The cliiiiial history is hrielly asf.dlows:

Parents white. Mother 42 years of age; has had five pregnancies, two of which ended at term, one child living ( 14 years), the other dying of "inanition." The third, fourth and fifth pregnancies terminati'd In abortion, the last furnishing the specimen under discussion. The last menstrual period began on August 19, 1917, and lasted four days; abortion look place on Novemlier 6. As both parents were very anxious for another child the possibility of mechanical interference may be excluded. There Is no history o[ venereal disease. The only clinical symptoms which the woman presented were severe nausea and vomiting Immediately before and during the abortion.

The gross appearance of the specimen is shown in the figure on p. 182. reference to which will emibic the reader to under-tand better the following description. This is based upon ^1 i)reliminary c.vaniination with a binocular microscope, supple

182

[No. 340

iiieiiti'd by exaniiiiatiini under liiiiiuM- powers of serial sections tlirougli the cinbryo.

As seen in the \eiitral view, the enihryo is normal above the level of the eyes. The latter are synmietrieal, except that the left eye is placed slightly higher than the right. Microscopically, the lens of each eye is found to be hollow, the retina and choroid nuicb macerated, and pigment is scattin-ed throughout the vitreous. The e.xternal nares are represented by two pin-point depressions asymmetrically placed, and the lateral nasal processes are but feebly evidenced. The mouth is of normal width and in correct proportional position. It is gaping, however, and an enlarged tongue can be seen. The medial and lateral palatine processes are likewise visible. The ears show a well-marked helix, with no evidence of the original tubercles. There is a Tuint antitragus, and the primordium of the crus helicis can lie distinctly made out. Microscopically, the external auditory meatus and the Eustachian tube were

Spi.na Bii IDA wrrn A.s

!)CIATED DlSTUKHANCES I.X A HU.MAX EmiiKYO 17 .MM. Lo.NG.

traced in section, but nothing could be made of the labyrinth. Taken as a whole, the face represents a development considerably in advance of that noted in the oldest of the human embryos described by Rabl in his " Entwicklung des Geschichtes," which measured 14 mm. vertex-ljreech. and was estimated to be 36 or 37 daj's old. The face aaid ears, in comparison with other embryos in the Carnegie Collection, represent rather closely a stage of development corresponding to that of a normal embryo of the same length. Such embryos, according to the Mall curve, are about seven weeks old. From the degree of development of the head we may safely assume that 49 days is the maximum develofimental age of this specimen. The discrepancy between this and the menstrual age, namely, 30 days, undoubtedly represents the length of time the embryo remained in the uterus after its death.

The arm buds .show the transverse lines of division, and the contour lines of arm, forearm and hand. The hand pad .shows the rays for five fingers, but progress toward digitation is not marked. Except for this, the arms correspond to the normal. The legs are disproportionately .short for the general stage of development of the embryo, the foot pad showing practically no indi(ation of beginning digitation. Study of the sections

shows that the cartilaginous sbouldcr and pelvic girdle are normal, but there is some stunting of the tarsals, metatarsals and phalanges of the foot pads.

There is a small genital tubercle behind which the clt^acal membrane has disappeared, leaving the sinus patent. The tail bud has been absorbed until only a blunt coccygeal eminence remains. There is some slight indication of a urethral furrow, whereas, according to the tables of Keibel atid Elze, this should be *' fairly deep " in an embryo of 17 mm.

Practically the whole ventral wall of the abdomen has undergone pathological changes, sloughed or been torn away, leaving the abdominal +++++ CONTENTSs exposed. The viscera of thorax and abdomen show extreme maceration and histolysis, but their main outlines are well in evidence. In sections the alimentary canal may l)e readily made out : the mouth, pharynx, cesopliagus, stomach, duodenum and coils of gut can he followed throughout their length. The larynx, trachea, main bronchi and macerated portions of the lungs could also be followed through the sections. The heart has suffered in the general maceration, but one chamber for auricles and one for ventricles can be clearly made out. The bulbus and first part of the aorta were traced, iiut no vessel was found leading from the latter. The liver was in a state of extreme maceration, but masses of liver tissue could be traced in sections, and also some vascular attachments connected with them.

The mesonephros is fairly well preserved, and there are discrete masses of badly macerated tissue occupying the positions where the suprarenals should lie. No evidence of a liladder or any of the urogenital ducts can i)e found. The same is true of the spleen and pancreas. There is widespread destruction of . the vascular system; not even the main vessels can be traced with any sort of continuity.

From the dorsal aspect the most striking feature is the apparent failure of the medullary plate to close, a fact whicli was confirmed by microscopical examination. Caudad to the upper cervical region, and extending throughout the thoracic, luntbar and sacral regions, are two parallel rows of spinal ganglia on either side of the mid-sagittal plane, with discrete, scattered masses of nervous tissue between. Contrary to gross appearances, none of this tissue is naked, but all of it is covered by loose cellular tissue, undifferentiated and of irregular thickness. There is no trace of closure to form a cord. In the cephalic region as far back as the level of the eyes, closure seems to have taken place, and sections prove tliis to be the case, as the macerated remains of two cerebral hemispheres and a brain stem, covered with the same loose cellular tissue, are to be made out. The whole region, however, presents an irregular, bulging appearance indicative of an embryonic encephalocele. Meninges could not be found for the brain or other tissue of the central nervous system. In the region of the vertex there is a breach of continuity in tlie cranial vault, giving rise to an opening into the cranial cavity. This o])ening, upon a study of the sections, ajipears to be traumalic or the result of sloughing.

Twelve ribs and 30 verteVira' could be counted in sections, the latter with ditlicnltv, owint;- to the fusion and twisting

June, 1919]

183

of various centra. As determined from the sections, the vertebral axis shows the following points of interest : In the upper two-thirds of the back tliere is a deep cuneiform cavity, and exactly corresponding to this region is a very pronounced lordosis of the column. The middle of this region of lordosis marks a pivot point about which the posterior half of the vertebral column is twisted sharply to the right. In this way the ribs on the right side and the spinal ganglia are crowded together and appear in successive sections at the bottom of the depression. They are covered with loose cellular tissue. Tiic cavity is due to the lordosis. In the region of the sj-mmetrical depressions there is likewise a lordosis, and between these and the cavity the column is bent in the opposite sense — t. e., there is a slight kyphosis. The vertebra? show little or no evidence of neural processes, and of course no mcmbrana reuniens. Technically speaking, therefore, we have an eml)ryonic rachischisis and partial aniyelia. Owing to the maceration and poor staining, the details of the chondrocraniimi could not 1)C made out.

If due allowance is made for the extensive maceration, most of which probably occurred in xdero after the death of the embryo, we arc perhaps justified in asserting that the chief point of patliological attack lay in the axial skeleton and central nervous system below the brain. At any rate, it is here that we find its most important result*. There is some stunting of the arms and legs, but not sufficient to be of any great significance, except that, had the viscera been early and seriou.sly attacked, it is difTicuIt to see why greater nutritional damage did not effect the extremities; for in spite of the fart that its aliment is furnished by the mother, the embryo must of necessity possess a correlated metabolism of its own. There is nothing to indicate that the viscera did not develop in a fairly normal way: at least the state of maceration docs not suggest the contrary.

From the menstrual histories found among the records of the Carnegie Collection of embryos, it is more than probable that most of the pathological specimens are aborted witliin the first half of pregnancy, and, Uierefore, particularly if very young, their significance frequently escapes the notice of the j)ractitioner. It follows that, in those cases in which the pathological involvement is not sufficient to cause the death and expulsion of the embrj'o, the latter will sur\ive until the term or near term, and it is upon this limited group that tlie popular idea of the frequency of monsters is based. In the " Manual of Human Embryologj'," Dr. Mall has tabulated the comparative frequency of various types of monster formation at term and in aborted material, and finds a close parallelism between the two. The percentage of frequency of spina bifida is greater in the embr}o, however, than at birth, indicating that the mortality is greatest in this variety of monster. A more careful examination of abortion material in the future will probably reveal numerous specimens like the one here reported.

That the cause of such conditions exists early in pregnancy is splendidly shown in tlie specimen above described. As pointed out by Dr. JIall, the popular conception that mechanical influences have an important bearing upon the formation of monsters has been ovcrthrowni by recent chemical experiment*. The specific action of dilute salt solutions upon amphibian eggs, for instance, will produce spina bifida in a large proportion of the embryos. The trouble would seem to lie, therefore, not in the ovum iteelf. nor in the external mechanical influences acting upon it at a later date, such as amniotic bands which compress the imibilical cord, but rather in the impairment of nutrition associated with faulty implantation, or in the toxic influences arising from a diseased uterus.

United Statrs Army Xray Manual. Authorized by the Surgeon General of the Army. Prepared Under the Direction of the DivlBlon of Roentgenolog>-. 219 Illustrations, 1918. 12°. 506 pages. Paul B. Hoeber, New York.

United Btatet. Department of Commerce. Bureau of the Census. Financial Statistics of cities having a population of over 30,000. 1917. 4°. 373 pages. 1918. Government Printing Office, Waahlngton.

United (Stairs. Department of Commerce, Bureau of the Census. Birth Statistics for the registration area of the United States. 1916. Second annual report. 1918. 4'. 96 pages. Government Printing Offlce, Washington.

United States. Department of Commerce, Bureau of the Census. Financial Statistics of States. 1917. 4°. 129 pages. 1918. Government Printing Offlce, Washington.

Oxford Loose-Leaf Surgery. By Various Authors. Edited by F. F. Burghard, and Alien B. Kanavel. In Ave volumes. Over 1800 illustrations. Vol. I. 1918. 8'. 971 pages. Oxford University Press. London; American Branch, New York.

Practical Physiological Chemistry. A Book Designed for Use in Courses In Practical Physiological Chemistry in Schools of Medicine and of Science. By Philip B. Hawk, M. S.. Ph. D. Sixth edition, revised and enlarged. With two full-page plates of absorption spectra in colors, four additional full-page color plates and 18.S figures, of which 12 are in colors. 1918. 8°. 661 paRPs. P. Blaklston's Son & Co., Philadelphia.

The Hearts of Man. By R. M. Wilson, M. B. 1918. 12°. 182 pages. Henry Frowde and Hodder & Stoughton, London. Oxford Uni. verslty Press.

I nited Stales. War Department. Annual Report of the Surgeon General, U. S. Army, to the Secretary of War. For the Fiscal Year 1918. 8°. 735 pages. Government Printing Offlce, Washington.

fnited States. Treasury Department. Annual Report of the Surgeon General of the Public Health Service of the United States. For the Fiscal Year 1918. 8°. 373 pages. Government Printing Offlce, Washington.

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[No. 340

THE MANUS MEDITATIONIS

By Charles Singer, Oxford

Man alone among animals knows that he must die, and civilized man alone among the races of men. Yet we moderns, with all the discoveries of science, all the complexity of our social system and all the wonders of past history crowding thick upon us, certainly ponder far less than our forefathers

upon our inevitable end. With the men of the Middle Ages it was far otherwise. Their present world was a small thing compared to ours and but a vestibule of the life to come. Mors jamia vita. It was upon the life after death that their thoughts were fixed and upon death as its portal. Death was their obsession, and there were whole classes of men whose current thoughts were of little but death and thereafter.

Every possible device was invoked to keep death ever before the mind.

But the physician spends his life in a contest which he must always lose at last and for which life is the forfeit. He, at least, hardly needs to be reminded of the temporary character of this life. Yet not so, thought our ancestors. They did not hesitate to insert a memento mori even in a medical work.

Among the means adopted to keep mortality before men's eyes was the manus meditationis, a method of illustrating, by a tale of the fingers, the thinness of the partition that separates the living from the dead. The manus meditationis that we here reproduce was inserted by some fourteenth century scribe in a very valuable and interesting collection of illustrated medical tracts now in the Bodleian Library. The phrases are written along the five fingers of the hand, a phrase for each phalanx and a terminal one for the nail. The phrases form rough but not unmusical verse.

TEXT Manus MEDrrAcioNES (sic!)

(1) Nescis quantum | Nescis quotiens | Quod deum offendisti

(2) Finis tuus amarus est | Uita tua breuis est | Uenisti in hunc

mundum cum peccato | Quod status tuus est miserabilis

(3) Nichil tecum afferes nisi quod fecisti | Uitam tuam non potes

prolongare | Mortem non potes evadere | Quod morieris

(4) Nescis quo deuenies | Nescis qualiter morieris | Nescis ubi

morieris | Quod hora mortis incerta est

(5) Cite obliuesceris | Quos relinquis parum facient pro te | Raro

facient pro te | Quod post banc uitam non est penetencia fructuosa

Meditari debes.

TRANSLATION In rendering a translation of this simple text we would call attention to the use of the word facient in line 5. Facere has sometimes in mediseval Latin the special sense of " to make a prayer," " to say a mass," or simply " to pray " — Orare est laborare.

The Hand of Meditation

(1) For that thou Itnowest not how greatly or how oft thou hast

offended God,

(2) For that thy end is bitter and thy life short, for that thou

earnest with sin into this world and thy condition is miserable,

(3) For that thy deeds alone thou canst take with thee, for that

thou canst nor prolong thy life nor escape death, for die thou must,

(4) For that thou knowest not whither thou goest nor place nor

time of thy deatli, for the hour of death is uncertain,

(5) For that soon forgotten thou wilt be, for that it is but little

and seldom that thy relicts will pray for thee, and for that after this life repentance availeth nought, Therefore meditate.

The Johns Hopkins Hospital Bulletins are issued monthly. They are printed by the LORD BALTIMORE PRESS, Baltimore. Subscriptions. ?3.00 a vear (foreign postage, 50 cents), may be addressed to the pubUsherg, THE JOHNS HOPKIKS PRESS, BALTIMORE; single copies will be tent b» moil for flfty cents each. Single copies may also be procured from the BALTIMORE NEWS CO., Baltimore.

BULLETIN

OF

THE JOHNS HOPKINS HOSPITAL

Entered ma Second-Class Matter it the Baltimore, Maryland, PostolHee Acceptanee (or mailing at special rate a( postage provided (or in Section 1103, Act o( October 3, 1917. Authorized on July 3, 1918.

Vol. XXX— No. 341]

BALTIMORE. JULY, I9I9

[Price, 50 Ce nts

CON

PAGE

Some Memories of t!ie Development of the Medical Scliool ami of Osier's .Ailvint. By Henky .M. Thomas ISo

Osier as Chief of a Medical Clinic.

By Lewellys F. Barker ISO

.Some of the Karly Medical Work of Sir William Osier.

By W. T. CoU.ncilman 103

Osier as a Pathologist.

By William (i. MacCali.tm 1!'7

Osier, the Teacher.

By W. S. Thayer lliS

Osier and the Student.

By Thomas R. Brow.n 200

Osier and Patient.

By Thomas McCbae 201

Osier and the Tuberculosis Work of the Hospital.

By Louis Hamman 202

Influence on the Relation of Medicine in Canada and the United States. By Thomas B. FrTciiEn 204

TENTS

PAGE

Dslcr as a Citizen and His Relation to the Tuberculosis Crusade ' in Maryland.

I By Henry Barton .Iacods 205

J Osier's Influence on Other Medical Schools in Baltimore. His 1 Relation to the Medical Profession.

By Edward X. Brush , 208

Inlluence in Building up the Medical and Cliirurgical Faculty.

' By Hiram Woods 200

Osier and the Book and .lournal Club.

' By J. A. Chatard 211

Osier's Influence on the Library of the Medical and Cliirurgical Faculty of the State of ilaryland.

By Marcia C. Xoves, Librarian 212

I Some Early Reminiscences of William Osier.

[ By He.nry M. Hurd 213

I Osier as I Knew Him in Philadelphia and in the Hopkins.

By Howard A. Kelly 21,">

Osier ns a Bibliophile.

By Thomas R. Boogs 210

Osier's Literary Style.

I By Edward X. Brush 217

Bibliography 210

SOME MEMORIES OF THE DEVELOPMENT OF THE MEDICAL SCHOOL AND OF OSLER'S ADVENT

By IIenuy M. Thomas

In thinking of tlic early days of The Jolins Hopkins University and IIosj)ital and the development of the nicdital school, my memories begin with the founder — Johns Hopkins. As a small boy lietween 10 and I'i I sat on the same beiu h with Johns Hopkins many Sunday mornings at the Friends' Meeting on P^utaw and Monument streets. I cannot remember that he ever spoke to me, and I remember him merely as a rather unkempt old gintlcninn. At that time he liad announced his intentions for his double bequest, had, in 186t^, incorporated the two institutions that were to Ijear his name, had niijiointed his trustees, and had lujught the site for the hospital. Calloway Cheston. the president of the university board : Francis T. King, president of the hospital board ; Francis White, James Carey Thooias. James Carey, and other trustees, were also

constant attendants at tiie meeting, and it is pleasjint now to think that in the congregation there were represented tlie founder, his trustees, and the rising generation which was to be benefited by tho bequest.*.

Johns Hopkins believed that his wealth had been given to him for a purpo.-^-, and, to use a Friendly form of speech, that he would bo " given to see how to dispose of it. He had asked atlvice freely and much had lieen volunteered, and many of his advisers have claimed that they suggested the objcct-s of his Ix-quests and the forms which they should take, but 1 like to think that the wise instructions that he gave to his trustees were finally determined in meeting. The most important of these for the development of the medical school was his direction in a letter to the hospital board, dated March 10, 1873,

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that iu all your arrangements in relation to this hospital you will bear constantly in mind that it is my wish and purpose that the institution shall ultimately form a part of the medical school of that university for which I have made ample provision by my will," so uniting forever the two bequests for the , furtherance of medical education.

Johus Hopkins died on December 24, 1873, and iu the early part of 1875 the trustees received the bequests and entered into active administration of the trusts. The first important decision of the university board was the wise and fortunate choice of Daniel C. Oilman as president of the university. He came to Baltimore May 1, 1875, and I can remember well the expectation and interest his coming aroused. He and his two daughters took apartments at the old ilt. Yernon Hotel, and for me a delightful friendship began.

Johns Hopkins chose his trustees well and left them untranuneled, and they in their turn gave President Oilman a free hand. They had already determined upon the establishment of a real university, which, as Oilman once said, was to supplement and not supplant existing institutions. In speaking of his first instructions which he received from the trustees, he says:

Often in private conversations and in official interviews, I was charged to hold up the highest standards, to think of nothing but the best which was possible under the limitations of the new establishment in a country where the idea of a university had not been generally understood.

Iu furtherance of these objects. President Oilman, in the summer of 1875, went abroad to visit the variotxs universities and to consult with the leaders in education. Medical education was much in his mind, particularly the establishment of the laboratories and courses of instruction in the fundamental sciences which would be best fitted for the preliminary training of medical students. The field was almost entirely unbroken, and young men not yet 30 were selected for its cultivation — Eowland in physics, Martin in biology, and Eemsen in chemistry. Rowland, although not then appointed to the chair of physics, had accompanied Oilman to Europe to aid him in the selection of physical apparatus and books. While on this journey he found time to publish some articles in the Philosophical Magazine which Oilman, with characteristic promptness and prophetic vision, dated from The Johns Hopkins University — the first university publications.

Oilman was inaugurated on February 22, 1876, and the university received students and began instruction in the fall of that year. Professor Huxley, who had taken much interest in the proposed biological department, and who had recommended a favorite pupil of his — H. Newell Martin — as its director, was in America and was asked to give an opening lecture. In this lecture he spoke of the importance of biological studies, and particularly their relation to a properly organized medical course. My father, who had selected me as the son most available upon whom to experiment with this new method of medical education, saw to it that I attended Oilman's inauguration and Huxley's opening lecture. I have no recollection of the inaugural exercises, but I do remember

hearing Huxley at the Academy of Music, principally, I think, on account of the storm of protest that followed. This protest was directed against the emi^hasis which the new university appeared to be giving to scientific research, especially in biology, even the study of which was thought at that time to be little less than impious, and was focused on the fact that Huxley, the great champion of science, had been asked to speak and that the lecture had not been ushered iu by prayer. I believe that Mr. King and my father, both devoted religious workers, were resi^onsible for this last circumstance. They certainly were astounded by the public reaction to this entirely consistent Quaker procedure.

Following the advice of Huxley and others the chemicalbiological course was designed, and was recommended to those students who intended to take up the study of medicine; indeed, it was also called the preliminary medical course. It was from the first the design of the university to establish the full medical course as soon as the hospital should be completed, and much thought was given to it. Martin and Eemsen were recognized as forming the nucleus of the medical faculty.

At the opening of the fourth academic year, September, 1879, Professor Acland,then Begins Professor of Medicine at Oxford, was expected- to give a- lecture embodying his advice as to the proper co-ordination between the university and hospital in the organization of an advanced medical school. Unfortunately, on account of illness, he was unable to deliver the address. His views, however, have been preserved in a letter to the university and hospital authorities. How surprised he would have- been had he been told that it was from this unborn medical school that his successor at Oxford was to be chosen !

In the early days the university was a small, compact body, made up, for the most part, of a young, active faculty, surI'ouuded by a group of advanced workers, called fellows, and other post-graduate students, and a few rather over-powered undergraduates. Every encouragement and opportunity was given to research and to prompt publication of work accomplished. There was the closest sympathy among all the departments, and everyone knew and sympathized with the work of the others. It was naturally around Martin that the idea of the medical school germinated, and a more inspiring teacher it would be hard to imagine. Besides the regular biological courses, he gave lectures to medical students and practitioners of the city, and graduates in medicine entered his laboratory for special work.

The emphasis which the university had put upon men in contrast to buildings had permitted it to function at once, and to strike a remarkable pace in a very short time. With the hospital it was different ; buildings were absolutely essential, and even though Johns Hopkins before his death had instructed his hospital trustees to begin work, time was necessarily consumed in the formation of plans, so that it was not until June of 1877 that these were adopted and the excavations were begim.

The choice by the hospital board, in 1876, of Dr. John S. Billings, surgeon of the United States Army, and librarian

I

THE JOHNS HOPKINS HOSPITAL BULLETIN, JULY, 1919

PLATE XXIII

/;^

WILLIAM OSLER IN 1906.

I'.lliili'il li) S.i.|;iil.

1

I

JlLY. 1919]

JOHXS HOPKINS HOSPITAL BULLETIN

187

of the surgeon-general's office, as their medical adviser was most fortunate, both as to the construction of the liospital buildings and as to the future of tlie medical school. Dr. Billings was much in Baltimore, and his encyclopedic knowledge of things medical was always at the service of the university as well as the hospital. He supplemented Oilman, and made with him a remarkable team. He was attached to the university academic staff as a lecturer on the history of medicine and nmnicipal hygiene, although I do not think he gjue many lectures until after the opening of the hospital.

Among the physicians who were attracted to Martin's laboratory was Wni. T. Councilman, who began work in 1878, just after iiaving received his medical degree from the University of Maryland, and who, after his return from Europe in 1882. was made a fellow by courtesy, and was appointed associate in patiiology in 1884. He busied himself about medical problems, gave some courses in special subjects, and lectured at the University of Maryland on pathology.

In 18T9. Wm. H. Howell came from the Baltimore City College and entered the chemical-biological cour.«e and began a career which was to mean much to the university and medical School. He soon became a favorite pupil of ilartin's. and after receiving his bachelor's degree, he was made in quick succession a fellow, an assistant, and then, in 1885, an associate in biology, having received his Ph. D. the year before. He resigned from the university in 1889, to return again as professor of physiology at the opening of the medical school.

I. in my capacity as experimental animal, was entered in the university the same year, and I can well remember Howell as the model student and also on the football field where be made up for his light weight by the accuracy and neatness of his tackling.

I look back ujion my course at the university witli tlie greatest pleasure. To have been under such men as Martin, Renisen, and Hastings in physics, to have read Shakespeare with Sydney I^anier, and to have heard the lectures from the noted men who were constantly coming to the university, could not help being stimulating to a youth even though overoccupied with many athletic pursuits. It had been hoped by tho.se of us who took the preliminary medical course that at its completion the university would have started its medical school, but this was not to be. The buildings of the hospital were going up very slowly, and as there seemed no immediate prospect of their comiiletion, we were forced to go elsewhere for our medical in.Ktruction.

While at the University of Maryland. I attended Dr. Couik ilman's first lectures on pathologA'. and also took a course with him in the biological laboratory in the histology of the nervous system. We had excellent professors at the University of Maryland, but it was the old lecture system, the only laboratories being the dis.«ecting room and a newly established chemical laboratory. The students had practically no chance of getting close to patients, and I was graduated without ever having been instructed in physical diagnosis, and I received the prize in obstetrics without ever having seen a woman in labor I I took my medical degree in 188.5. By this time the

university was on the point of establishing its medical department. In the register for 1883-1884 it is announced that The medical department of the university is soon to be organized. Its plan is receiving the constant attention of the trustees, and it will be made known before the completion of The Johns Hopkins Hospital. The nucleus of a medical faculty has been instituted as follows: The president of the university: J. S. Billings, M. D., lecturer on hygiene: W. H. Welch, M. D., professor of pathology; Ira Itemsen, M. D., professor of chemistry; H. Newell Martin. M. D., professor of physiology."

In this somewhat casual way, the university announced the epoch-making facts that it had recognized pathology as a full university sul)ject, and had appointed Dr. Welch to fill the chair. The first was the natural development of the university idea in medicine, and the credit of the second has been claimed, in a friendly rivalry between the university and the hospital, both by Oilman and by Billings. However that may be, no other choice now seems conceivable.

Dr. Welch's appointment was the first one that had to do with practical medicine, and I remember my father's enthusiasm over it, for with it he felt that the university had made a wonderful beginning in medical teaching. What a wonderful beginning it was he was to learn later!

Welch gave his first course of lectures in Hopkins Hall in February and ilarcii, 188G, on microorganisms in disease. The hospital trustees allowed the university to furnish the autopsy house as a pathological laboratory, and so the first of the hospital buildings to be used was dedicated to the common purpose of the two trusts. Dr. Councilman had been appointed an a.ssociate in ])atlK)logy, and courses of instruction were started on November 1, 188(i. Halstead came from New York to work in the laboratory and Mall was apjiointed the first fellow. Other students gathered, most of them graduates in medicine, and when 1 returned from Europe at the end of the year I joined the grou]). Those early days have often been described, and it was, indeed, a rare privilege to have taken part in them. As the hospital was not yet opened, the institution had to depend ujwn other sources for its autopsy material. This was obtained for the most part from the City Hospital at Bay View. In the reorganization of this charity, The .Tohns Hopkins University had assumed the care of the insane, and my father. Dr. Councilman and I were appointed visiting physicians. Dr. Ct)uncilnian was also pathologist.

.\t this time everything seemed to point to the early opening of the full medical school. The buildings of the hospital were practically finislied, and there seemed to be no reason wliy they should not be shortly opened. The university authorities were completing their plans and Welch was on the spot. It was just at this time that financial calamity overtook the university. The Baltimore and Ohio lonmion stock, of which the university had nearly l.'j.OOO shares, dropped its dividend from 10 to 8 per cent in 188(i, to 4 per cent in 1887, and ceased paying the next year; the university was struggling for life and could not take on new obligations, so that the plans of the medical schocd were indefinitely suspended. The hospital income had not been affected as it was derived almost entirely

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from real estate, and there had been no inroads on the capital bj' the erection of the hospital buildings. It had, indeed, increased, and the hospital had now become the rich member of these organically joined twin bequests.

The appointment was made in the fall of 1888, and he was to begin his service at the opening of the hospital, which was announced for May, 1889. It soon became evident tliat although it was easy to announce the opening day, it was quite another thing to get the complicated mechanism of the hospital organized and ready to function. In this emergency the hospital appealed to the university and induced Oilman to assume the task. The work was colossal and the time was short, and it speaks volumes for the estimation in which Oilman's organizing ability was held that no one doubted the result.

The formal opening occurred on May 7, 1889, and Osier, with liis satellites, took his place as our guiding star. He brought Lafleur from ]\Iontreal, Scott and Toulmin from Philadelphia, and those of us who were able to do so joined the ever-increasing group.

The hospital annexed Welch with his already organized department of pathology-. Halsted was given charge of the surgical department and the organization of the dispensary, Kelly was brought in June from Philadelphia to take charge of gynaecology, and in August Dr. Hurd, as superintendent, took over from President Oilman the direction of the hospital.

The opening of the hospital was for the trustees, the faculty, and above all for us expectant, impatient medical novices, the beginning of the fulfillment of long-suppressed desires. For me the reality far surpassed the fantasy of my dreams. In the association that was to follow, which for my part was as close

as I could make it, Osier as a physician, teacher and friend, constantly raised my preconceived ideal. Memories of this time overwhelm me.

The dispensary was opened first and patients were admitted to the wards from it, and Osier, surrounded by a few of us, himself wrote the first dispensary history. Until the wards were full he was constantly in the dispensary, organizing the various subdepartments of medicine, for it was an unique feature of the system that the services were continuous, and that the various special departments were grouped under either medicine or surgery. As it was in the early days of the university, so it was with the hospital at the beginning. Workers formed a closely united body. All that happened was of interest to each of us. On the medical side Osier radiated by his example and personality constant stimuli to careful clinical work and investigation along all sorts of lines. He pointed out problems, encouraged everj-one in what he desired to do, and was more than liberal in his commendation of work done. His absolute generosity threw open his whole clinical material to the use of any one who had a problem. He urged and assisted in the publication of the results, and saw to it that the young men got the whole credit of the work when often it should have gone to himself. Is it to be wondered at that such a chief has such devoted followers ?

The Medical Society, t