REPOiiT CIF TXE

DIRFCTOR OF TX2 I-iOS?ITk.L

OF

THE ROCI(EFELB INSTITUTE FOR KEDICAL RESEARCH

April, 1916.

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April, 1916.

To the Board of Scientific Directors
of the Rockefeller Institute.

Gentlemen: -

     Yre Director of the Hospital has the honor to submit the following

.r,ugzeations in regard to future developDsnt of the hospital, and report of

scientific worb: carried on during the past quarter.

      NEED FOR INCREASED LABORATORY SPACE : Since its

activities of the hospital have gradually increased, both

number of patients studied and the amount of work carried

cians in the laboratories of the hospital.  This increase

organization, the

as regards the

on by the physi-

in activity has

made manifest certain limitations in the facilities of the hospital and

hau [made evident that, for further increase, or even for the most &v&n-

tageous continuation of the work at its present extent, certain changes

are advisable.  The most evident requirement which has appeared during

the past year has been the need for extension of the space devoted to

laboratories. The work carried on in the chemical laboratories has in-

creased very materially and as a result, the space originally devoted to

this work has been nuch overcrowded, fourandfive persons working in a

space originally intended for two or three.  The bacteriological laborator-

ies have also been much overcrowded.  It has been impossible to provide

Dr. Allen with proper laboratory space for carrying on his work on diabetes,

and he has had to use several single rooms, widely separated.

     The Director is of the opinion that in order that those who are

engaged in xr&ing clinical studies and caring for patients m&y also carry


on e-xperimental ressarches relating to the liseases being investigated, it

is very is:gortant that the laboratories in which these men work shall be in

as clcsa proximity to the warAs as possible.  He drew attention to this

matter in his first outline of the prOFOGed organization of the hospital,

and his subsequent experience has confirmed this view.  Koreover, owing

to the sdvizsble limitation in the number of patients, it is important that

t:.esa Fltients be studied from different st&ndFoints, that is, that fre-

Quently chemical, bacteriological, or biological and physiological studies

be carried out simultaneously on the same patients, To s&e this possible

it is important that the men working along different lines work in harmony

and in cooperation.  If the laboratories are widely separated, this is in,-

possible.  For this reason it is better that the men work in somewhat crowd-

ed quarters than that they carry on their work in separate buildings, or in

laborstories widely separated one from another.  It is to be hoped, however,

that it may be possible to make some extensions in the space provided for

the chemical and bacteriological laboratories.  To do this, I have suggested

that certain of the rooms now used for bacteriology be equipped for use as

an addition to the chemical laboratory, and that temporary changes be made

on the west end of the sixth floor 'to provide for some of the bacteriological

work. ' It is suggested that the changes made on the sixth floor involve as

slight structural changes as possible, so that if later it is decided to

use this floor for patients, it can be restored to its present condition

with comparatively little expense.  Sketches of the changes proposed will

be presented at the meeting of the Board.

It is expected that Dr. Allen's work for the first part of next year,

at least, will consist nainly in experimental irk on dogs, and it is there-


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fore suggested that suitable arrangenlents be made for bin; on the second floor
of the present laboratory building, which will bs mde vacant by the removal
of tha chsn,ical 13bomtory to the new building.  It is hoped, also, that on
this flcor an operstin;S roofi cm be provided for Dr. Cohn and also one for

other workers in the hospital, whose work n&y require op%-ative procedures

on dogs.

     ADDITIONAL ROOti FOR PATIENTS :  The growth of the work on cancer
v.411 probably increase slightly the rnmber of petients cared for in the

hospital.  It is hoped that next year it will be possible to cam for this
slight increase by aoderate crowding of the space now available on the 3rd,
4th and 5th floors, and also pOS8ibly by using the isolation building for

convalescent patients, when necessary.

    Xt is k;.portant, however,  that at this time the Board consider

possible methods for futura increase of tha mmber of beds available.  The

past expariance suggests that the need will best be mat by providing addi-

tional single rooms.  In a mixed service as we have, consisting of both

men and mena it has been found difficult to separate patients suffering
from various disesses without overcrowding certain mrds and leaving other
Wrds containing comparatively few patients.  Such sewration in certain

cases sdems very important.  For instance, certain experiences we have had
have inlicated that it is very important not to treat pzmmonia patients in
the warAs containing Fatients with heart disease.  It has not bean wise to
place dial;etic patients, who ara not acutely ill, and whose mental state is
of considerable importance, in wards containing acutely si2k pneumonia

patients.


It has 51~0 been found advisable to keep patients on whom very

accurate chenlical or metabolic studies are being made in single rooms.

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Moreov;)r, the dcrrand on the part of persons of the better classes for ad-            i

mission to the hospital has grown, and it is found that in many ways these

are the bost patients for study, as they ara mom ready to cooperate in the

studies being n&e.  These patients also require separate rooms.

    It would seem, then, that the first axtsnsion of tb hospital facil-

ities should provide for additional single rooms.  This can probably best

be done by using the soconl floor, now occupied by nurses, for this purpose.

In th> original planning and construction of the hospital this floor was

built with this possibility in mind, and thfs floor could be used for this

purpose with compsrativaly slight change.

     NURSES HadE :  Such a use of this floor would, of cours3, ntmssitate

mkin; Frovlsion fcr ths rmrs~s alsewhare.  Tha nursas quarters are already


overcrowiel.  In very accursts work ana complax studiee, such as are -de

in the hospital, the numbar of nurses require2 is large, xruch larger than

nay be thought nacessary by those who have only had experianca in the

ordinary ganaral hospital.  Ths nurses ard naa3ed, not only in caring for

the imna9iate neais of the patients, but they are employed very largely

in assisting innakin observations and in assisting in the technical pro-

cedures trrrried out.   It seems.  therefore.  that sooner or later a ILu1SeS

home should be provided.  Then this is done, provision should probably be    I

made 5n this building for providing quarters for the doctors, a8 wall.

Vben this is lona, the second floor should bo available for patients.

    REOFGANIZATION OF THE X-RAY LABORATORY :   It has been well

r8co~Wzed by all those familiar with the work in the hospital that the

':-ray work has not been carried out in a manner commensurate with the other
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work dolce.  'Pie equirJrient ar.3 service have not been even so good asthat of
the average general hospital.  It is hoped that provision can now be rrade

for greatly irr,proving this service.  The work on cancer which it is pro-
posed to do sakes such a development very important. Moreover, it is hoped
to 1~k8 certain studies concerning the changes in the size and shape of the
heart that will give information as to output of theoretical and practical

irr.portance.

   To provide space it is proposed to enclose the open space on the
eighth floor, jnd to use all the space on this floor not occupied by the
operating suita. Plans of tL proposed changes will be presented. Addi-

tional equipment will ba required,  the estimated cost of which will also

ba presented.  It is also hoped that one man can be obtained V&O will give

all his time to this work.  pith th3 oxoption of this man, the changes

in ths hospital arrangomsnts which will be suggestad involve very little

change in tha size of the staff.  The changes will rmke such fiture increase

possible, but are not for the purpose of providing for any mediate ch3n@S
They will relieve the prosent crowding, and provide proper facilities for

carrying on the work as at pr2sant planned.

Rsport of the Scientific York carried on during
    -A---.-__                   the Past marter.

    AWTE LCIjR PN!ZJMONIA :  lhring the present winter (up to April
let) 70 cases of acute lobar pneumonia have been treated in tha hospital.

Of these, 14 die& a mortality rate of 20$, which is a distinct lowering

of total aortnlitg ir, a very bad pnaurronia year.  Tha cases dua to


pneumococcus 'spa I were treated with serum, unless they were very slightly
ill or were a&rAttsi vary late in the disease, whan senm treatmnt did not


seem indicatad.  Of the cases due to type II pneumococci, a few were tre&ted

with the extract of serum precipitate.  Many of the other cases were treated

with OptOCkiin.  Cur purpose is to treat cases of type II with a combination

of optochin and serum, or optochin and extract of serum precipitate.  It hKs

been inportant, however, to study first the action of each of these agents

alone.  The following table aives a surnrary of the cases and the results

as regards a.ortality.

Cases of Acute Lobar Pneumonia 1915-16 to April 1st.

Type No.Cases Mortal- $
          ity

I     22      1      4.5

  Treated Cases.      Untreated Cases
No .          Mortal- No.   Mortal-
          itY          itY

17   serum       1        5      0

II     23      5     21.7      g w;o~~~   8        9      3
                                3  optochin  +   0
                                   extract

III 12

6    50.         6 optochin 3       6      3

IQ   13    2     15.4           2                           2
                         optochin     0       11          1-I

70     14   20 $

The danger of drawing conclusions from mortality statistics in pnelmkonia rrplst

constantly be borne in mind, but as they stand the results seem interesting

and instructive,

   The results of serum treatment in the type I cases add further

evidence for the value of the ixrmune serum in this type of case.   Cur

conclusions as .to the value of the serum, however, are based on the study of

'the cases, rather than on the mortality statistics.

    The statistics give little information as te the value of optochin

in the traetment af pneumonia.  However, the studies of the cases have given

us vsluabla irdondtion in re13ardM the UBB of the drug. Seventeen cases


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have been treated with optochin, 9 of tme IX, 6 of type III, ind 2 of type IV.

of these seveRteen cases, twelve bve been very carefully studied.  These

studies have yielded inportmt results as m3ards the size snd spchg of the

doses.  Fran. these studies it seen: that careful attention should be hiven

tc tile size ol the body in 3ecidins the size of dose required.  It is now

ti.o?lght that bt least .024 gm. per Kg. per 24 hours should be given. In the

z:rlier studies it ~3s thought thEit in certain cases the drus wjs not con.-
plett3:y abscrbed, but it seem now that these spparent jifferences have been

due to insufficient snd improper dosage.  It is apparently best to give
3 gco3. sizsl lose at, th3 beginning and to follow this by snail doses fre-

quently r3poated.  Thesa results have been obtained by naking studies of the
bsctxricidal power of the blood very frequently during the period of a&in-

isbration.  By this biological test th3 mount of optochin in the blood

at any givan tin.3 rray bs estimatad.  with the sxcaption of tha casd of ax+
blyopia which was observed earlier in the year, no further bad effects of the

drug have been seen.  In the case rrentioned, recovery was CoWJlet3.
   It is too seen to speclk of clinical results in the c8sea trected with

oFtochin, but th;i Lprassiona obtained hava been vary dacidedly favorable.

Thj clinical rssults obtaine$ together with the expertiental evidence, IEke
it irzportant that the atuAy of this drug be continued further.  It is hoped
t&t 5~ combining the drug with serum mch better results cm be obtained
in csses of type II sn3 type 111 than with either aercLm or optochin alone.

   Studies hzva bean rr.a:?.; by Dr. Moors concaming the &cquireIl;ent by

bacteria of I1 fastness II to optochin.  This is undoubtedly an *port-t

question in rslstion to trebtm3nt.  Ths vsry interaating obsenmtim has been

n;ads tkit wh3n pnaurrjococci are grown in semm to which optochin has been added,


either by atiinistration zluring life or addition in vitro, the pneumococci

acquire very large capsules, much larger thin thosa seen when the bacteri;.

are grown in senm. alone.  By rapeated transfers in ogtochin-containing

medium, the bacteria are able to grow in very much higher concentration

of the drug than was originally the case.  After only a few transfers

slight powera of resistance become evident, but several weeks or months

kre require9 before the changes boccn.e of extreme Fade.  It is of interest

t;st when the organisms become very resistant to optochin, they 51~0 becoms

bile insoluble.

TA supply of optochin in this country is very limited, but per-

mission has now been obtained from the Gemzn government for a sn.sll amount

to be exported and also from the i?nglish government to allow it to cm

thrqh, so it is hoped that we shall now soon have enou& for our purposes.

Dr. Chickeriq is continuing his study of dissolved precipitate. In

his irk v;ith Dr. Gay last swmer obsarvations were made which suggested

that such precipit;tas acted not only by sup9lyin3 inmuna bodies, but also

stimulated leucocytosis and caused mobilization of the normal sntibodies.

Tha Fresant studies ar3 being made to determine whether or not the Fngu-

IT~COCCUS precipitatesS%vs any such s&ion.  The work has not yet progressed

far enough to permit conclusions to be drawn.

   PnJuLococcus INCOSU - Typa III. As previously rzentiomd, pneu-
mococci of this type h3ve been very frequently found in no-1 mouths.  On

t!;e other hand, pneumococci of types I and II are never found in ~-1

mouths except in the case of contacts.  Since the pneumonia caused by
pn~UZOcoccu3 3~osus is relstively infrequent and is of Very s-t SeWritY,
these restits aith pneumoccccus l~~lcosus are very surprisix and m&B diffi-
2ul.t the interpretation which has been placed on the findings Of type I and


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1    II as relates to epidemiolog;r.  It is conceivable, however, that the pneu-

   nococci of type III found in normal mouths differ in some way from the

1    i:'nCWLOCOCci of t,ypr3 III found in disease,

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i        To test whether iumunological differences could be found, Dr. Avery
   has collected about 70 strains of this t;.ye of organism from normal mouths,

   xnd from patients with pneumonia.  He has studied with much care, but no

i::ltural or other differences could be detected.  Rabbits were immunized to

vxious strains and cross reactions with the vsrious strains studied.   The

results, however, were negative;  no differences between the strains could

be made out.

    It will be rscslleci thet in our esrlier studies of this organism it

YJas never possible to obtnin an inzrune serum which would agglutinate these

organisms unless the latter were first treated with acid to remove the

capsules.  In our work rabbits, sheep ani goats were used in the attempt

to produce an immune senq but on account of the results obtained,

horses were never employed.  The immune serum from smsller animals had

slight protective power for rats, but it had absolutely no effect when

tested with mice.

    The State Board of Health under Dr. %dsworth's direction, however,

proceeded to inmunize a horse, and after several months Mnunization Sent US

SOme serum for testing.  To our great surprise it was found that this serum
had well rr.arLad agglutinating power for l&xxr.ococci of type III, and alSO

some protsctive pcwer for mice, 0.2.~~. serum protecting against doses as

high as 0.001 cc o? culture.  The agglutination reaction is very short and

cGrr;l?leta ir: 13. ;'-l;lti~,ns, bat does not occur in high dilutions.  The degree

,~i protect-its F;vqcr does not suggest thet the serum can be of much effect


in treatment, but the demonstration has been made that 3-n immune serum can

be obtained from horses and it is not impossible that methods may be found

for increasing -its potency.  This serum was tested by Dr. Avery against all

of the strains which he had collected, and vx+s found to be active against

all but 3 cf them.  These 3 strains were non-virulent and W8re from no-1

mouths.  However, it was active aeinst other non-virulent strains froffi

normal mcuths, so that it has not been pssible by this sem to distinguish

between the parasitic and non-parasitic stmins.  In general, the strains

from normal mouths are less virulent for mice thm are the strains from

cases with pnmmonia, but this is not constant. The

of pneumococcus mucosus in normal mouths, therefore,

Further studies are being u&e on this problem. Ths

frequent occurrence

is still obscure.


imnune semm had no

effect on four strains of cocci with large capsules and forming ~UOOUS,

which, however, were bile insoluble, were haeaolytic and did not ferment

irkrlin,  znd have therefore been called strettococcus uucosus.  The serum,

therefore, offers a reedy mans of distinguishing batween Pn3uuo~o~~u~

mucosus snd Sterptococcus mxosus.

    Dr. Avery h3.s also studied the effect of growing pneumcocci in

dilute solutions of bile.  It has been fcund that by prolonged growth in

this medium, gmkally increasing the concentration of bile, the bacteria

become accustomed to concentntions'of bile, which with the untreated

strains cause tiediste solution.  This property, however, is lost after

one or two transfers on non-bile containing medium.

Ernest Stillman has, during the past winter,

of pnemococci present in the mouths of a large

contacts and convalescents.  This material, in


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additicn tc tklst already obtained by Dr. Rchez and Avery, gives considerable

information in regard to epidemiology,  though there are still many obscure

r,uestions.  Dr. Stillnan has skdied 270 specimens of sputum from 246 nonral

nouths.  In 132, or about 505 of the instances, pneurrococci were present.

There has been no difference found in the percentage of persons harborina

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Fr~eumococcus as studied in the different mouths.  This study, however, has
been entirely carried out during the so-called pneumonia nokths.  Continua-

tion of tile study through the surxner nay show differences.   In 2 instxices

the pneun;ococci found were of type I, 4 type II, 14 atypical II's (a,b,or x),

29 tyj% III and E3 type IV.  In 511 cases but one in which type I or II

were found, the prsons harboring than. v.ere closely associsted with persons

suffering from ths disease.  The epidemiological significance of the

carriers of stypical type II and of typo III is more obscure.   It sems

that in this respect the organisms more closely resemble the type IV

pn3ukococci.  The extrerx virulence of the organisms of type III, however,

makes this difficult to understand.  In this connection a surprising obser-

vaticn has been mad=.  Pneurr.ococci of type III very quickly dis=pFear from

the mouth and sputum after an attack of pneumonia due to this organism.  On

the othx hand, they may persist for months and even years in normal mouths.

   It is hoped and expected that other interesting and valuable infor=-

tion will be obtained from this statistical data after the work has been

complcsto :.

    Production of Immune Serum.  The two most important practical points

to be solved in the study of immune sem are improvements in the methods of

Froducing serum so as to produce a more active senuk and, second3 methods of

de ten-dning proper dosage.


   Consis3erable work has alrearly been done on the first of these prob-

lens.  Last Year the study of immunization of rabbits showed that better

results could be obtained by the use of small doses of dead organisms,

frequently rereated, than could be obtained by 1 iving cultures.   This

!r.ethod i-as now been sppl ied in two horses, one being immunized to type I


puulococcus, one to type II.  In both cases,  after tinization over a

Geriod of 6 to 8 teelrs by the method mentioned, sera have been obtained

vkich are as active both as regards agglutination and protective power

as sny serum we have previously had, using other methods.  Attempts Err3

now Seing male to drive the immunity higher in these horses by employing

liva cultures, according to the method used by Dr. Flexner and Dr. Amoss.

It is hoped that in this way the effectiveness of the senxn can be increased,

but in any case a method for economizing time and horses has been secured.

   Dr. Avery has also conducted sorry experiments to study the haem+

lytic action of pneumococci in the hops of using this reaction as a delicat

test for irrmme bodies.  The experiments bearing on this problem are not yet

far mough advanced to report, but he has brought confimaticn of the con-

clusions dram from our previous studies, that the haemolytic action is dus

to mbstances contaiasd in the bacterial cells, and set free on their

solution.  Dr. Chesney~s studies enabled him to test the haeimlytio effect

of cultures at various stages of growth.  The cultures began to have

haeWlytic power only at a period whem Dr. Chesney was able to show that

dissolution of part of the orgsnisms in the culture was occurring. This

haemlytic power persists for four or five days, then gmdually dissppetis

and after eight days is entirely absent.

   Dr. Chesney has continued his studies concerning rate of grcwth

of pneuuiococc i.  By means of observations carried out on the supernatant


fluids obtained by centrifuging portions of a culture st varying intervals

during the period cf maximum rate of growth,  it has been derr.onstrated that

to:*rd the on3 of the period of rspid growth substances or factors are

present which bring about the death of a large proportion of the pneurr,ococci,

v$hich substsnces rurain in the eupemstant fluid after centrifugalization.

It has further been shown that the process of destruction or killing of the

yneun;ococci follows or is identical in its rate with that of a so-called

nonorf,olecular reaction of physical-chemistry, and in this respect the effect

of the fluid constituents of the aedis upon the bacteria is analogous to the

effect ( observed by other workers ) of bactericidal agents such as Phenol

2nd bichloride of xzercury upon anthrax spores and upon cultures of bacillus

FLratyFhosus. Fktheru.ore,  some evidence has bean sccumulzted to show

that these bactericidal substences in the culture medim disappear in part      '


when the culture is allowed to stand in the incubator for sevarel tiys, for

E filtrate obtained frm a culture at the end of 24 hours incubation show

decidedly n;ore bsctericidal activity for sctively growing pneumococci than a

filtrate from tha ssme culture 48 hours old, and at the end of 6 days incu-

bation, when there are no longer any living pneun~~occi present in the

culture, the filtrate fran thst culture shows decidedly less bactericidal

action for actively grtwdng

the 24 hour filtrate or the

    It has been possible

eqosing then, to the action

pneuniococci introduced into it than did either

48

to'


CiT

hour filtrate.

cause pneumooacci to grow less rapidly by

filtrats or supematant fluid obtained from

24 hour broth cultures of the sake strain, if, after exposure to such an

enviroment at ice-box ttxnperstur~s, th3 pneu~eccoci be reruwed and ra inoou-

lated inte umsed broth.  Attempts have been made to follew tbs behavior of

pneum~coccl from actively growing cultures (duriry the period of WX~ERD


rate oi growth) when injected into rabbits intravenously, and to contrast,

under these conditions, the behavior of these actively growing pneumococci

with the behavior of pneurrococci which would show a definite lag in the test

tube.  The study is not complete, but the preliminary experiments suggest

t&t prhaps there u.ay be a difference in the behsvior of "young" and "old"

cultures of the sane strain of pneumococcus, when they are injected int=ven-

ously into rabbits, the individuals from a

czxlrrunI rate of growth tending to increase

of the r=,bbit sometint more rapidly during

ing injection than lo the individuals from

culture during the period of

in rumber in the blood stream

the period inmediately follow-

aculture which ie nolonger

jrowing rapidly.  It is proposed to carry out this study at greater length.

   Dr. Dochez has continued his studies relating to the enzymatic

activity of pnemococci.   In a

antipneunococcus serum possess

u~ococcus in vitro.  After this

previoue report it was shown that

the capacity to inhibit the growth of pneu-

phenomenon had been definitely confimd,

an explanation of its nzchsnim was sought.  In the course of the investi-

gation it developed that antipneumococcus serum ha5 the capacity to inhibit

more or less completely the peptolytic and glycolytic functions of the


pneumococcus.  From this it has been as-d that inhibition of g&h is

in part at least dependent upon the entianzymotio properties of W.m.am

SO1VIZ1. This quality of inh$bition of mtabolic A;mction is possessed in

varying degree by the sera of normal anjmale and may have mm relationstip

to their nstural resistance.  Human sex-a during lobar pneumnia exhibit

the capacity of inhibition, and the degree &f inhibition reaches its maxirmm

grade during the period of recovery from the disease,  It is tharght that

for tke sniin31 kady tc rid itself of infection the growth of the infecting

sicroorganism mist f:`imr, Sa z;rx*dsted, and that only after this ha5 occurred


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do the aore specific substances have an opportunity to exert their full

effect.

   An ktterq!t lms been rr.ade by use of the methods previously described

to throw ;on.e 1 if;ht upon the phenomnon of parasitism,  It is obvious that,
in order ior a nicroorganisai to develop a parasitic phsse, it mst be able
to grow in the snixml body, which implies the development of a rrechanism
for resistance to the antigrowth influences of animal sera. A study of the

pnemococcus shows that the mtabolic function s of organism recetitly

isolated froffi the knxm body are K.ORI resistant to the inhibiting factors
of both nomal and immne sera than are those of organisms which have led

a saprophytic existence for considerable

    A study has also been nade of the

stances of the inmum aera.  It has been

Feriods of time .

nature of the antienzyaotic sub-

possible to obtain specific irumms

bodies in a fraction of the serum which does not exhibit antlenzymotic activ-

ity, but no light has been shed, so far, upon the actual nature of the sub-

stances themselves, or upon their source. They

in character, and their efficiency Is believed

the presence of specific me bodies. Up to

are thought to be non-specific

to he n;arkedlyenhanced by

the present time, work has

been carried on entirely with living organism, a difficult pro-tire *in
work sf this kind because of the low virility on artificial cultivation Of
pnWmococci recxmtly rerrioved. from 8 parasitic state. For example, it t&s8
M weeks for a strain of pnewococcue recently isolated from the hum
body to acquira a capacity of uniform growth on artificial media.  A consid-

erable si~@if-L-at;~.o~;~ hcwever, has recently been made in the fact that a

pepto1ytic $6:-r-.e:iZ h4s heen ::repared which is sotive in the absence of the

li-ziiy .:ell ~  ,_`i:iz !tath:xl shmld render the lnOerpr&atian of comp%rstive

+;;>;wz I;i.3ilTY ;&;;iJi- i;;rr;j ;-z:; i;';le .


    DIAi3ETES. Dr. Allen :  The principal effort is now being directed

toward publication of the data 2t hand.  The work still in progress centers

a-ound the acidosis problem.  All diabetic: patients are now cared for by

Dr. Fitz.  Practically no pstients are sdrr,itted except those with nzrked
acidosis,and Dr. Fitz is studying especially the concentration of acetone

bodies in the blood and urine.  There are two current theories of diabetic
intoxication; one, that it is a pure acidosis; the other, that it is a
sj-ecific poisoning with acetone bodies.  Acidosis is being zeasured by the
carbon dioxide of the blood and alveolar air, and by the total acidity of

the urine.  The concentration of acetone bodies is being determined by a

nodif iCatiOn of l&rriottt8 rr,icro-nathod.  Obviously the typical patient
apFroaching cma shows high acidosis with high concentration of acetone bodies,
but in special cases it say perhaps be possible to separate the tm factors
and learn whether one or both my be chiefly responsible for the entire
condition or for individual symptans, or &ether there may possibly be

another factor, viz., intoxication by yet unknown intermediary products,
especially those arising during fat rrLetabolism.  AS is known, the treatllient
eniployed in this hospital aims especially to prevent this intoxication and
to renove it when present by means of fasting and suitable diet, rather
than to attempt to neutralize it.  tit in patients bordering on ohs, the

question of alkaJi. therapy inevitably presents itself, and evidence iS
accUulatlng that intelligent use of sodium bicarbonate is beneficial at

a certain stage in some cases.  The foses used. are, however, relatively

sITall, and the alkali is employed as a temporary adjuvant, and not as the

print ipal t rea&ent .

   It is believed that the reproduction ef human diabetes in experimental

animals, and the experimental foundation of the fasting treatrrent, are now


fair12 acm-plete, with the exception of the feature of acidosis.  A few

animals have been caused to devalop what appears to be the

icaticn found in !:uman diabetes.  Hitherto no satisfactory
of diabetic acidosis in animals has been achieved, and the

sam3 fatal intox-

reproduction

present study

is therefcre believed to be important, to conplete the experimental counter-
Fart of the clinical disease, and slso to afford a basis for a more funda-

:r.er4tsl study of the condition than is possible in human patients.

   Five patients of this Hospital have been studied in the Ruse1 age
Calorimeter, under Dr. Eugene Du Bois and staff. From the same standpoint,

a few diabetics from other hospitals have also been studied by Dr. III Bois.
A paper (Allen & DJ Bois) now in press embodied the results with all the

Rockefeller Hospital patients except one.  The results are essentially as

follows:  (1) The existence of the Lusk dextrose-nitrogen ratio of 3.65 : 1

in cartsin case3 is confirmed, but this is not necessarily a "fatal" ratio

and such patients may recover considerable tolerance.  (2) The respiratory

quotient under these circurnstsnces is

showed very low Guotients, indic8ting

about 0.69.  All the severe czises

that they were actually of greater

severity than most cases called 1'8evere'f in the literaturs.  (3) The metabol-

isrr. of severe diabetics is increased when coqared on an accurate baai with
that of similarly emaciated non-diabetics, or when the s8me patient with
active diabetes is compared with himself when free from active symptOmse
These results are believed to be important in this disputed field. (4) The

metabolism is greatly reduced by the fasting treatment.  One pstient showed
a fall of 255 in the basal metabolism during the initial fast.  The lowest

metabolism ebserved in these pstients is 36s below normal.  (5) The raspir-

atory quotients prove that restorstian of the carbohydrate-burning function

occurs uader the fast&g treatment,  (6) Respiratory quotients h8ve been


:Our;d c;3ite ireqmr.tl;l wiAc!l are puzzling, because higher than can be

zccountod ior by knr,xn facts.

    Ci"!ICAL L:Wit"TORY, Dr. Van Sl,yke: 13th Mr. Cullen and Dr. McLean,

!:crk 0:: the fata 01 Frotein digestion products is being continued. Up tc the

present, it has been shown that as,ino acids increase in the blood during
                                   --

ril&estion, but that the intern.ediste ccmpounds, or peptones, do not. The

:L~c~Y is mw bein, extended to discover the eifect of digestion OA the

mixins of the blood plasm.

     It was found dec c lx-able to tiprove the nsthods for marititative

lrjtem.inztion of the fibrin, globulins, and albumin in the plasuz, and


..l`. Cullsn has succeeded in making thess oethods sufficiently accurate and

conveinent tc Fexxit their use in experimentation on a considerable scale.

Thefibrin is precirital jd fron. th; orclst> plasma by addition of calcim

chlcrid3 undsr d3finit.o conditions, end Is d3txminod by Kj3ldahl. Tha

al?nur.ins and glob& ins ar3 soFarated by th3 usual asmonlurr` sulfat3 method.

Tla difficulty hara was to find 5 sstisfactory nsans of razr.oving tb an-nia

in ordsr that ths nitrogen of the protsins might ba dataminad.  Boiling

with jvan dilate alkali deccmposes the protains.  It was finally found that

if magnesia oxide were used as alkali and alcohol added in ascartairwd pro-

portions, the ammonia could bs boiled off completely in 20 minutes without

decomposing the proteins.

   Miss Vinograd has bean engaged in a study of the protains of l-wan

n.ilk compared with those of COWS~ nilk, tha distribution of the nitrogen

?-r~~ong tke various types of amino acids baing daterr&ined by methods worked


out ?;reviously in out laborstories.  The problem was sugzastad by Dr. Halt

because of it.9 interest from the pediatrist's standpoint.  Tti results

indicate that the albumins from the two rrilks ars of definitely diffarent


mine Acid csqosition, but no diffsrdnce could be detenr.ined in the caseins.

Mis; Vinograd, cooparat ing with IJr . Losae oi tha Lying-In Hospital,


. 1

k;ts stldl3;1 tllj distribution batwsen rrztornal and plxantsl bloods of

351 xrsar. injec taZ into prsgn5nt  syphilitic wormn before dslivary.   Ths

arsclnic contsnt of the pliCfXlt3l blood o;m 2nd two hours sftor the injection
ms n~ch lass than that of tha riatJrn31, End, in soc.e cases, w&s nil.  From


t;!; r-sults obtrinod, it irmtirs, tk,arr3fore, that r.3lstively littie cf tha

z?lv:rsx-. ~ZS.SCG th3 placsnta ;n5 roaches the fcstus.  The E rser.ic detemin-

ztions wsro don3 by nathods previously levised by IKiss Vinogrod for use in

?Ir. Swift's salvnrsan work.

   Dr. Pallter, in axarr,ining urirus of pn;uc.onia pptiants, has noted in
s3vdr3 cases tha yrasanm of ccnsidarzble amounts of an apparently tinOWr.

organic acid.  Ho is st prasmt end3evoriq to isolst3 3~5 idai:tify this.
   Ha is also engsgad in FQrf3Ctin-J a rrjthod, Tre:irr.inary work 011
which had bean done at th3 Bsbias Hcspital, for detaI%.ination of the total
organic acids in the urine aftsr prmipitation of all the rrAnen1 acids,

axcapt H Cl, by mans of bariurr. hydrate.

   Drs. Still-n 2nd Fitz are continuing the study of tha blOod,alveolsr

air, and urine in diabstic acidosis.  The ralEtionships pf other factors t0
the bicarbonats content of tha blood plasma hava been studied, with the

following results.

   P&ants with B-oxybutyrats in tha blood show a lowerinlj of the
bicarbonate below nom& to 2lrr;ast ax2ctly the extant that is czhulhted
o!i the asmmptian that the B-oxybutyric acid displaces its chmiti 0&V'+

lam cf bicarbonsts,  This relationship is ten;porzrily lost after a&ilIiS-
?~z':x:I of soA-m bicarbonate, which nsy restore the blcod bicsrbonata t0

Xl-Id, and relieve th3 syacptezs of scidosi$ without causing the die2ppiir-

Exe of the B-cxybutyrate frm. the blocd.


/I                                                ._

     Tha alveolar carbon dioxide is not so roliabla an indicator of the

actual alkaline r3sorvJ of the bleed in diabetics, at least when undergoing

fastin& as it is in normal individuals.  h number of thz diabetics under
observation show habitually an alveolar C 0 2 tension 25 to 40 points below
nOr%al when tha plasma bicarbonate is nom.al and thar> ar3 no syal;toms Of

acidosis.  In such patients tho respiratory c3ntar appears to bs abnormally

asrsitiv3.

   For tha Fast yoar we have bean atta.pting to find a nun,srical factor
fJr the acid excretion in the urine which would bear soma dafinito ralation-

ship to the actual alkaline roserv3 of th3 blood.  The ordinary figures Of

anrronia excretion par day, ztc., vary so irrac@arly wh3n corqarad with
blocd conditions that the existanca of any definite ml;tionship betwedn

blood an9 urine seemel doubtful.  It now appears, howovor, that the Anbard
formula, h3r3 frankly 3n.pirica1, does indicsta a relationship.  Indicating
the daily excretion of auania + titratabla acid, in terms of cc. of N/lo,

by B , the excretion par liter by G, and the body

D    gives a value which varies indirectly as
v! c
i.e., it is nearly zero &en the parcant of CO2 ,
n&sin;~- of 80; it is about 25 when the p1asn.a CO2

waight by E, the formula

tha blood bicarbonata,

bound by plasrrk is at its

is 55, both figures ax-

pressink the oxtm.es of normal linlits on the bcrdor of acidosis; and it is

about 50 when the plasrra CC 2' also chmgin3 by 25, falls to 30 per cent,
the point at which acidcsis bscomss critical. Like the alveolar CO2 , the
urinary excretion is only an indirect m3asurs of blood conditions, and de-

pends upon the noms1 function of 2x-i ontira excretory mechanism, so that

urine analysis can not b2 so accurate an index of intamal conditions as

analysis of ths blood itself.  But tha ralstionship of acid axcretion to

int>mal alkalino rcmwva appears now so much mora definita that a new

significance znd vslur, can bs attached to tha excretion figures.


    A study of the zffect of bicsrbonste administration on the alkaline

reserve has yialdsd results of intaresf.  The bicerbonsts is not rat?ined in

ths blood, but arrears tc bz ir?nadistaly distributsd to 2 11 the body fluids.

Ths ris3 in F1asn.a bicarbonate followir,z ;in.inistration Far cs or intravan-

curly is a:-::roximtaly tha rise that wculd be o xpsctdd as th-, result of add-

in& thJ bic&rbocatJ to a solution qua1 in volum to 311 thj water in thd

toa, 23tir.ating th3 la ttjr at 0.7 of ti-;, body w,ight.  This f:Ct is Oi &s-

sistancs ir, calculating th3 dff*ct of 3 given dos; of bicarbonate.  Rouahl y

5 tat :d, for an inlividusl of 40 Xg. w3ight "ach grarr, of bicsrbonatti riisjs

thh plasna C O2  about 1 volum parc;;nt.


     &t systzatic study of th3 th3,rapmtic USJ of biczrbonat: in acidosis

is bsing tsk3n up by Drs. Sti::rran and Fitz, and thus far th3 Claim of

L!sgnus-L3vy for t::, indispms ibil ity cf slksl I thzrsry in crit icsl acidosis

appzar to b>  subetantiatod.  By studying simultsn~ously tb ~1am.a bicarbonate

and acid oxcr3tion it is hop3d th3t th-. + usa of alkali therapy my be put on a

u.ora axact basis.

    Mr. Cd.1 en is coop3rat ing ?ith Dr. Chasnjy in a study of tha davalop-

mnt of acidity tiring tha growth of pnmrr.ococci and th3 influmcs of the

reaction of th3 radium on growth,

    pi!TPHRITIS, Dr. McLean_:  Th3 study of th; mchanis~~ of urea sxcration

and Ursa rstantion by mans rf the nuxmrical laws govsming ths rata Of
excration of urea is bein; continued in patients with disturbed function dw

to nephritis, or secondary to disturbed circulation in heart failure. In

over 1000 observations rmde t;;ese laws have been found to be valid and to

give the m~ximm oi infomation regarding the particular function Of the

kidney which has to dc with the excretion of urea.  It has been possible

to follow the changes in.functicn during recovery frcm acute nephritis and

the downward tendency preceding urzen.is .  It has besn found th3t the so called


"retention" of urea in the blood is, in fact, a corqensatory mchaniem, in

order to provide the condition necessary for its excretion through a damaged

outlet.

    Study of the chlorid aatabolism is also being continued in a sinAlar


my.  This work has presented SOW interesting and compl icated problems.  A

sudden fall in the concentration of sodium chlorid in the blood plasma has

been observed in patients shortly before death from uraemia, the concentra-

tion cf chlorid in the plasma previously being high.  This fall has besn

shown to be due tc an increase in the H ion concentration in the blood,

which causes chlorid to increase in the cells snd to diminish in the plasma,

as had previously bean shown by Han-burger, both in experiments in vivo end

in vitro,

   We 513 attxqting to mplain certain fluctuations in the

concentration of sodium chlorid in the plasna, previously described, but not

unlxstood, such as the lowered concentration of chlorids in the plasma in

pmmonia,  ml in dlab&m.  Experimntal work is being carried out with

Dr. Van Slyks to test the effect of the introduction of salts, acids, bases

and non-olectrolytss into the circulation on the chlorid content of the

plasm , and it has been found, both in mn and dog6, th?t introdmtion of

certsin other sslta into the blood by muth or intrsvenously cause8 a dimin-

ution of the chlorid content, sppsrently. by replacing the chlorids by other

sslts.  Them westions sre being investigated particularly with reference

to ths mech?.nisr; snd intsr-relstionship of sslt retention 2nd edema.

   Rth Dr. Cohn the effect of verious diumtic drugs, espcielly

digitalis, diuretin snd theocin, on the specific ability of the kidneys

to excrsto water, urea and salt is being studied.


   The infl-ante of dietetic therapy in nephritis, on the vsrious

fUICtiOnS of the kidneys, 2nd on edem:, blood pressure, 2nd other symptoms,

Is being ccrried cut on the pztients under observ tion. SC fcr we hsve

not observed ?ny direct rel: tionship betwean diet, especially with regard

to its nitrogen content, 2nd tha systolic or diastolic blood pressure,
   HE?.BT-DISFASE, Dr. Cohn: Eerly in February, Dr. Jamieson left the
hospital to join the Csnsdisn L!ilit?ry Uedicsl Force for service, 2nd since
then the work in herrt disease has been csrried on by Dr. Cohn alone.
   The study of the action of digitalis in patients in pursuance of the

pl3n formed some tima ago hss been continued.  The study of the action Jf
digitslis in patients with pneumonia has, in pprt, been completed and

reported.  The rssults have shown, first thst digitalis is active in Patients
with fever. end second, that it may ba of benefit in certain cases Of

pnaumonin .

Ths question of the best way to give digitslis in pneumonia hss also

rjcjivod attention - for two reasons e~pecislly. First it is imPortsLt to
be abl3 to sul;,jsot pneurronie patients to its influence 1st rapidly 2s
                           Possible;
second, it k-s bean sqzestad that if the tot.21 amount of the PrePerstion
                                              --

cf known stren$h calculated for z patient

once, time will be ssvdd and more accurate
cation in administration accor~plished, V%

of a diven weight be given at
dosage instituted, and simplif i-
have thought it important to test

this second point,

zpproprio-te doses,
--ra comparing both

Ye have e,rrived c-t

and h%ve accordingly treated pneumonia patients with
given in 3 short period of tims, 2nd in certc-in patients
concentratad 2nd fsctionol mothods of administration.
no Isf inits conclusion as yet, but so fzr it =-ppears that,

in s tudyin, tho question of cdministrotion the rste'of excretion of the drug,
the optic. concentration in the circulation (Ffter absorption), ?nd the
stteib.:nt of its threshold value in the hesrt nslscles must be considered.


I: s.LW.3 t&t by 8 rapid concentrated SdnAnistrztion~f the dw, the heart
m-uscle my not be exposed a sufficiently long time, 2nd the threshold value
n?,y not be reSched before excretion of considemble Smounts t&es place.
The object of single large doses msy thwefom be defested.

   Exprirrsnts rra being mde on the subject of gsnersl 2nd spacisl

csrdisc hyl?ertrophy.  The plan of these experiments hss been reported befcra.
To produce gensrcl hypertrophy we sre ming dogs on s tread mill two or

three hours 5 dzy.  The effect on their hesrts is being ccntrolled by X-rw

snd by the electrocrrdiogram.  Ths poet mortem finding8 sre to ba a=-lyzed

and ccnp re 3.  Spxlzl hypertrophy we hope to 888 result from the expari-

mntnl


sm to

injury of sortie 2nd mitral -1~~8. The results of thoss injuriee

b3 studiad in th3 8f1r.3 ~%y as thosa occurring in running dogs.

Enrlljr axpsrimants on stfrrulue production in the auricles, 2nd on

tha vqzl md scalorstor control of the sinus sre'ii hsve slrezdy been re-

port3l.  Th> snetomiczl work is nosring completion and will ba xqorted

latsr.

    Cartzin clinical studios of mor3 thsn uSus int3rast hzva bean mzda.
First, two instances of vssomotor angine- pectoris ( Nothrsgal ) in the CaSe

Of young men having markad r^ortic insufficiency have basn studiod.  Both

Frtiants suffer from rspeated dsily sttacks.  In th3 cuss of both the

occurrsnc3 of such deily cltta*c is interrupted by the d8vezPGment of
febrile sttzcks of a f8W dSy8 duration, zccompsnied by abdoffiinzl pain.
In on2 ~2.53 the frbrilo period occurs with surprising regularity every

tW0 'vV03k8, l?aSts 4 - 5 dzys, is zccompsnied by 3 leW2OGytOSi8 ( 20000 ) I

,with c, relative increc-se in the polymorphonuclesr leucocytes. A Cau8e

for the recurring febrile zttzcks has not been found.  The tots1 cessation

of znginzl 5tt-cks during th febrile pried is 51~0 not explained.


   Second, a child has been observed during two ?,ttaCkS of acute
rh-tic fever with nn inter& of E year.  During the interval the tonsil8

hsve been removed.  In the first attack a green forming streptococcus was
isolated from the blood by Dr. Swift.  In the 88COnd attack, a similar or-
ganism ha8 been isolated and has been given to Dr. Swift for study. He
reports that the i-logical reactions which he ~1,s fortunately ible to
nake ( since he hzd pressrvud the origins1 culture snd also the sew of
animals inmunized to it ) failed to 8kOW the identity of the tW organi-.
   Finally, w were sble to observe rapid heart action (ventricular rate

2.30 - 240 ) in a chil3 of 12 over two long periods, shout 8 r-nd 36 hours.
The raFi;i action could be teminsted by left ocular pressure only. The
prOxysmR of techycardla were auriculsr in origin %d probebly depended for
their fomrtion on 3 site st a low level in the suricular n~3C18.  In inter-

v2nin; parioi8, the competition for dominsnce in stimulus production between
this site and the usual one cm apparently be observed. The heart of this
child 18 enlarged; the elves we sppwently nom~~l, There was no fever.
T~BXQ iu a history of vaaw transient cervical glandular involveasnt. A
pmgrmi8ing ltyoc~rsial lesion SMKIS to be the probable cause of the irrewar-

ity mi the hypertrophy.


   Cia3-n:  This ;vorl; is being carried on under the direction of

9r. YxqT!ly .   9r. :.:ontqrr,s-y came tc the hospital in the niddle cf February

to c5r2 for tIie 1-r ti2nts suffering f rem center,  and since then three such

T?tlants hsva barn :An;itted rr.,l sra beirq studled.  Several more bre cow

:,.Li;iw to recover from opentions in ether I-,o+tels before aAr.iasicn. It

1x8 so f-r not been necassrr; to cpen ths q:acizl ward on the sixth ilcor

tC C'-m for tliaSf3 F3tif3nts :Ed, as the n2ir,b6r of patients v;it:l pneumonis
*:A11 seen bet;in to diminish, the present available beds will probabiy ba

sulYici3nt unt.il n;xt e2tumn.

   T"> prJs>nt purposs of the study is to sscortsin whether by srisll
dosss of X-ray th-, s-a6 response on the pert of the lymphocytes csn be ob-

kined in mar. as hsd --lrer;w been observed in rr.imls.  In the second plsca,

if this lyzphocytosis csn be brought about, to observe whet effect this mW
have on an individusl~s rcsist-?3ca +A c%cer. Patients who have ha9 inCOLI+
L
Flat3 sur;icsl r3nlovsl of cancer,  p referably c&ncer of the breast, have

baen sA>ctsd for study,  I'; is hoped to obt~.Ln cssgs as soon as possible

after cpsration.  'l&o cases hsvs now bser. under observation over 2 mnth.

Tha first wss a breast carcinoma with the extensive involvement of the

axilla. As tha naw growth had invaded the lrrge vessels, it was impossible

to r2Kov3 it coqzletely.  Treztaent wzs started here about three weeks

2ftor operation.  This consisted of a snzll general exposure to X-my of the

whole body, with the axcaption of the involved area,  The second case was

one which had had the right breast reltoved for cancer five years agO, =nd
the loft breast removed shout one month ago, for a very extansive growth.
This woman rsc;ivad prsctlcslly the some trestment as tha first one, =nd
both hav3 r3actod in pr2cticnlly the ssme fsshian to the trentisent. Thaw%
was 5 slight fall in the circulzting lymphocytes, both in percents.33 znd


in actual nmbers, which reached its lowest level 48 hours after treatment.

Ti,is vi;`53 followed. by a percent rise w!;ich in one case want to 525, and in
xc Liar to 3%;.  In both cases there ttqs a secondary fall after shout one

x~;:, follomod by 4 sacond risa, which in both cases went higher than the

initisl one,  In the f-i rat case this went to SG$ and in the second to 50s.

Th, incraaso in sctual rnuribers of lytxphocytos in the first case was, ht its
ilf+3st, 505 ibove the initial level, and in the second casa ~9s 1005.  Both

33505 not.7 siter itOUt 1 1/z month  still rata-in a fsirly hi& level, but

*::ith s tanjency to ssg.  A second course of trestrcent is being given at the

?reser,t time,  A third case of n,uc;l the SCJITB type is under trestc.ent, but
it has not been fcllaved long enough to rzalce a report on it at present.

In sliitlon the blocd counts of two csses at the Vsnderbilt Clinic

vkich ars being trested with the destructive dose nethod of X-ray are being

followed, in order to

s mlicstions of X-rsy

     In addition to

nine the X-recy dosage

determine how much of a generd effect thess local

have.

the ciinicsl work, attempts are being trade to deter-
which is required to kill the cancer cell, using for     .

thia purpose transplantabla mouse tur~ors.  This is being estimted in.teme

of the possible ctase to ms,n.

  The experiments so far have damnstrateA that exposure to a dose sO$
above that which the hmen skin cm stand has' no appreciable effect on the
growth of these tuaiors when returned to the animal.  These experiniants are

being continued with both filtered and unfiltered rays.  The machine and

tubes have been s tandsrdized

continue the work a1or.g more

by Dr. Wtherbee, and it is now possible to

scientific lines.