I
. .   I

REPORT OF THE DIRECTOR OF THE HOSPITAL

October 21, 1921


l'iEPOEiT OF TEE DIRECTOR OF THE HOSPITAL

October 21, 1921.

&I the past year the Hospital has had the advantage of

heving the nost Prrrture and experienced staff in its history. llllhile

during the early yeare of the hospital the staff consisted chiefly

of young untrained mm, the oversight and direction of &ose work

was ahoot entirely in the hands of the Director, during the past

year there have been Included in the staff several rz#3n of mature

years &ose train5ng and experience have fitted them to carry on

independent research and to d5,rect the work cf others.   As a result

the work in the Hospital has gradually becoas uiore cr less separated

Into that of several divisions, more or lees analogous to the divi-

scOns of the Iaboratoriss of the Institute.   Ihe Director of tie...

Hospital now shares the responeibillties of tie work with several

aSSOCia't48, each of Tom is responsible for the work carried on in

his department.  It is well recognized that there are greater diffi-
c&ties 121 the develomnt of `this kind of organization in the Hospi-

tal than in the Laboratories, but it is hol;ed that with close

dooperat.lcn between .the different divislmq there will occur no loss

but 8 gnat gain ln ef f loiency .

During the years since Its organization the Hospital has

served as a training place not only for its own IpBn, those uho now

conat$tute its staff, but it has also dasrvad to train men to 0-H

acad!X&~~,.f$~~s )n Internal: lsedicine in the universities.  Espe c-

filly during the ,past year, on acceunt of the reorganization of the

depsrtwsnts of medicig#? izi several mdical schools, this de-d for

I

men trained here halp resulted in the departure of a nuzzber of the




mst valued members of the staff.  Doctor Blake, VLO has besn en-

gaged in important studies concerntig masles,Ws called to Yale

University to becorrs Professor of Internal Medicine in the mdical

cxhool v\hic;h has been undergoing reorganization.   Doctcr Stadi8,

V&IO has bean a r&x-bar cf the Hospital staff for three end a half

years, also left to go to the saw lnetltut ion as Assistant Profes-

sor of Medicine, and Doctor Peters likewise was called to the 6W

placd and accepted a si.mil8r position.   H"nile Doctor Peters occu-

pled only a voluntary position in this Hospital, being sent hem by

Vanderbilt University, of the faculty of which he was a mmber,

nevertheless, on account of his ability and industry, he had b8com

an iLport8nt memb8r of the staff and his d8partIZe Leant a very dis-

t lnct loss.


1      Doctor Blake aleo took with him Doctor Trask, VAIO had been

cooperating with hllr, and assisting him in the study of measles.  Doc-

tor Traek had been on thd Hospital staff for two and a half yaclrs

and had developed into a rdst capable worker.  Doctor Austin, 1410

has been resident @aysician in the Hospital, has been appointed pro-

feseor of Research Medicine at the University of Pennsylvania, and

Doctor Glenn Cullen has beea appointed Associate Professor cf Research

Medicine in the sac18 Institution.  The appointmts of these twc hien

becorae effective on Jarruary 1, 1922, and they will reflain at work in

our Hospital until $hat date,

     These changes make serious inroads upon the effective

staff of the Hospital but several new appointLent have already been

r,-&.e and it is hoped that the new organieation will soon become welded

into an effective force.


    Doctor Quisten Lundsgaard of Copetiagen has been given
an appointment on the staff of the Hospital, and it is expected

that he will erriva about Nover;iber first to take up his new duties.

For the present he will live in the Hospital ati will act as Resi-

dent Fhysician.  He ~evicusly mrked in this Hospital, in 1917,
car, lng on stuiiea of rmzh Lportance in the field of abnormali-

t it38 of reepiration.  lie had had a long experience in internal
I;sdicine ix the Rlkshosgital at Copen?xgan and has born the first

assistant in the Univeraity Clinic of Professor Faber,  Doctor Hugh
Morgan, of the Johns Hoptine University, ha8 been appointed an assiat-
ant resident &#ysicien,Mr. Je,mee Neil1 has been appointed assistant

in the checlical laboratory, and &. A. B. Hastings ha8 been as.ofiited
                                        

an aSSi6tkUlt, to carry on work along the lines of that now betig done

by Doctor Cullen.  Other appointments till be made as suitable uen

are found to fill the vacancies in tha staff.


t       With the arrival of Doctor Imndsgaard it is planned to ex-

tend the studies of nephrltie and to prosecute this work along new

and mu-e comprehensive lines.

hte hmiratom Disease.

    The study of acute respiratory disease. hae been uonti.nwJd

but along aoumihat different lines.  The treatuent of cases of `Type I
pnsumonia with specific iumne serz has been continued with &sults

agreeing with those previously reported,  !I?& is only an incidental

part of the study, however, since it is believed that the efficacy of

this 8erua has now been ml1 demonstrated and its further exqloyrznt,

as well as its mmfacture, Should be left to others.   The efforts

to produce serum effective against the other types of pnewnonia have


4

not proved successful or prodsing end it is believed t'nat tha

successful treatment of these other f omm will have to be attained

by so- other and new I;ethod of approa&:  Consequent ly during the

past year attent ion has been given to the study of certain funda-

rental properties of the bacteria concerned in the etiology of pneu-

mnia and to a more detailed investigation of the fun& ional

abnormlitles occurring in patients suffering from tinis disease.

        Doctor Avery and Doctor Cullen have cant irruad their studies

  on the ferments present in the bodies of pc~uc;ococcus, which were

  described at som length In the previous report,   These ,inves tiga-

  tions have shown that by r.eans of sterile solutions anti yxtrbcts of

  pn6u~ococc1, it Is possible to correlate any hf the functional ac-

  tivities of the living call with the enzymot lc processes of the intra-

  c6llular substances rermvad frorr, the growing organisa,

       Further study ha8 d6U%3nStrLited still other activities of

  these pnaumococcal substances.   These speclf ic intracellular agent 3



\  exhibit other proparties in the presence of different substrates.

For instauce, vhen allowed to act on blood, active solutions of pm%-
kiococci are strckgly heraolyt ic, causing corjplate di88OlUtion of the

red blood cells, and under proper conditions rs;ay affect i&portant

changes in the blood pigtint, transfamixq the her;oglobin into r;et-

heriioglobfn.  These substances partake of the nature of ,endohe:;otox-

ins and my prove to be concerned in certain blood changas clinically

associated with pmu.~ococcus infection in KZUI.

    &ring the past year it has been found that in addikion to
the anzymt$c and hemtoxic properties above referred tc, ih the

presence of bacterial substrates consistkqg of heat-killed pna~me-

cocci these active enzyr;e-containing solutions c-se coupleta and


Prompt lysis -of the dead batter ia.   This bacteriolytic enzyme

manifests extraordinary specificity, exerti?g its dissolving action

only on pnmococci and not on herolytic streptococci or stqhylo-

cocci.  On green-producing streptococci, &ich may bo Lore closely

related to $neumcocci than either of the other two oL~gmis~s, the

bacteriolytic enzyme of pneucoccus exerts a lytic action which,

however, is never so active or so corz,plato as in the case of the

homologous organism itself.   Investigation of the bacteriolytic

property of the intracellular substance of ~eumcoccus has shown

that this enzyme, flke those concerned in protein, fat and carbohy-

drat e cleavage, uanlfests its optimal activity over a hydrogen ion

concentration eimilar to the* sone optimal for the biological activi-

ties of the growing organism itself,

      In connection Wth tho investigation of these intracellular

enzyme 8, a study is being wde of autolysis oi' pneumococci.   It has

been found, vihon washed ~meuwcocci from actively growing cultxes

are suspended in solutions of various salts, that the extent end ra-

pidity of self dissolution of the organisms is dependent upon the
hydrogen ion concentration of the mix&e.  Autolysis is most rapid
Ad complete over the zone of pH 6.5 - 7.5; -Nithin vuhioh range lie

the optima of the protease, lipaze and invertase of $neumococcus. In

fact within this zone, all types of enzymes of pnewococci thus far

described can act siw.ltarmnsly.   This fact recalls the observation

of Dernby that autolysis of aniroal tissue proceeds furthest at a re-
action tier8 the various enzymes can function simultaneously.

      In the course of this study, observations have beon r..ade

on the effect of autolysis on the heat precipitability of pneu.~ocoo-

cus protein.  It has been found, that under the influence of heat,


precipitation of the autolypate occurs at a dtifinite raaction, and

moreovdr, that the point at which procipitaLion with pnJumococci,

Type III, occurs, is different from the point at which ;macipitation

of pnmmocccci of Tyws I and II occurs,  The reaction point of pra-

cipitation is also different frotc the zone of acid egglutixmtion of

these groups as detaminad by Gillespie,

     Doctor Avoq and Doctor Thjotta have besn undertaking

studies on bacterial nutrition, which have dealt a>ecSfically with

Certain accessory substances concornod with the growth of homophilic

bacilli.  Particular attsntionhaa born givtin thus far to the rrutri-

tional x#quirements of Bacillus influenzaa, since this orgenien bolongs

to a group of bacteria which heretoford have not boon grown except on

r;odla containing blood or blood &r ivatives.   The reason for the po-

culiar stsnsitivenass of those bacilli to the pescnco or absonco of

oven mirnxts traces of blood in culture rudia has baan the subject Gf

mx.h discussion and investigation.   Closer analysis of th.3 gxmth
requirexmnts of thljse organism, however, has shown that this so-callad
hemo@ilic property has bdsn based on a lack of knowltidge of t;hdir

    actual nutritional mods,


\         9.h~ substances in blood, upon vhlch @owth of Bacillus in-
   fluemae doper&is, have beJn traced by expertital wthcds and found

to bo depondant upon two separable and diettict factors, both of

*ioh are requisite for growth and aa& of dhich is separately inac-

tive.  Study of the growth stimulating action of these substances

and their ch~Aca1 and @ysical properties has brought out certain
fact a as to their biological sip$ificanae in the cultivaticn of
Bacillus influenzae in particular, and tieir relation to bacterial

rrutrition in genaral.   Both of these substances differ in character


one from the other in ways suggastive of their separate functions.

One of thdse, the so-called V factor,  is a vitamine-like substance

&ic.b car; be extractad frcL; red bleed cori;uscles, from. yeast and

vegetable celis; it is rabtivzb Zeat labile, reaiily absorbed

froc solution by charcoal, and similar in its growth promoting

action to the known vitamines.  The second substance, the so-called

X factor, in blood is heat stabile, present In greatest concentration

in red blood cells, absorbed from solution by charcoal, and effective

in such small amounts as to wg3st its catalytic nature.

     It has been found tither that these growth accessory eub-

st&ces v&ich occu 5.n blood are also prosent in Vlant as well as in

animal tissm.  The68 observations on the growth cf the so-called

hom@illc bacilli on blood-free madia have dewnatrated that sub-
stences of bacterial and vegetable origin (potato) can function in

the saw Kmer as tme growth inducing factors of blood.

     Fromtha results of this Investigation it hoema not un-

reasonable to asswie that nutritional deficiency in the cultivation

of other bacteria may be ov8rcomb by the addition to culture media

of the appopriate growth accessory substance.

Doctor E, G. Stillmn has completed and published his study

on the bfolo&ical classification of herno@ilic bacilli.   This work

has made possible the recognition of distinct variaties of organisma

Closely related biologically, y8t differing wit8 ahaQ)ly from one an-

other in their biochemical reactions,  Within this group of hemophil-
ic bacilli, Bacillus influenzae ie recognized as the type organism.
With the limits of this grOup more clearly defined bacteriologically,
Da&or Stillman has undertaken a study of the occurrence and distribu-
tion of l+8illus influenza8 in the noses and throats of ncm1


                                                                    ,I

                                                                     I  i 99 \
individuals and of patients suffering from acute respiratory dis-
                                      d

ease.  Rhile it is rocoenized that this bacillus may be of doubtful

significance in thd etioloa of clinical influensa, its importance

as a secondary crganism in respiratory infections in general is lit-

tl8 quest icned.   A study therefore OS the incidence of Bacillus in-

fluanzae, especially in asscciatibn with acute lobar pneumoniahas

b88Il Dade,  It has batin found that this organism occurs in the throats

of about 30 per cent of norm1 persons.   In 30 cas~)s of lokar pneu-

unia, on the other hand, Bacillus influenza8 was recovered from the

throats of 80 par cent of the patients.   The rarked increase in the

incidence of this organism In association with disease due to pleu~o-

coccus infection suggests that possibly Bacillus lnfluensae may b8 on8

of the contributing factcrs v,hlcb allowx the non-invasive pneumococcus

to penetrate the lower respiratory tract.


Doctor Blake and Doctor Trask.


     &ring the past year a most interesting and important inves-

tigation concerning the transmissibility of measles to monkeys has been

carried on by Doctors Blske and Trask.  Owing to the departure of

these men to take up their work in Yale University, mention of Which
'has been 418 elseaere, a study of measles will be discontinued in
\
this Hospital for the present.   Doctors Blake and Trask intend to

continue their studies at Yale University. !I& following is a some-

&at extensive report of the results of their work as far as completed.

      Although Anderson and Goldberger had reported the successful
tr&smission of measles to monkeys, and Hektoen had reported the arti-

ficial transuission of tsasles from man to man by subcutaneous injac-

tions of blood, others had failed to mske such successtil transmission


ex$eriWnts and t)e latest exiwrlments under the direction of Sclladn

had been entirely negative,  Therefore, at the time of undertaking

this work by Blake and Tzask, the quastion of tha transmissibility of

measles to animals was unsottlod.   In taking up this problem and in

devising wthods of attack, Doctor Blake was influanceci by the exper-

ianco gained in his studies concerning the production of pnBumOnia in

anim.lls.   Re decided that it would be advieabla to use comparatively

large amounts of raterial thought to contain the virus, and SCCO~,

'&at it would be advisable to inoculate this material in &at it ~36

thought to be the natural path of infection.   Clinical obsorvation

ha6 indicated beyond reasonable doubt that the virus of maaslee ie

abundantly present In the secretion6 of the rosyiratory tract during

the praeruptive and early eruptive stages of the disease and that the

respiratory tznmn.18 membrane ia the natural path of entry of the virus.

Iha mthod used in the preliminary experiments, therefore, consisted

in the inoculation of the mucous membrane6 of the respiratory tract of

umkeys with unfiltered nasopharyngeal secretions of patients in the

early stages of measles.  The secretions w-em collected by irrigation

of the nas0~aryn.x with 20 to 40 cc. of sterile 0.85 per cent salt 80-

lution.  The monkeys w8re inoculated with 5 to 10 cc. of these naso-

   aaryngeal washings by intratrachsal inJection in order to facilitate
.

retentionby the animal if as u~~ch of the material a6 possible.  &en

as much a6 5 to 10 cc. was inJected a sf~a11 sumnt was coauonly reps-

@tat ed and spread itself over the MUCOUS mmIimne8 of the buccal and

nasal cavities.

      By injecting in this way the unfiltered naso@aryngeal

washings from cases of measles in the proeruptive and early eruptive

s$agesdf the disease a relatively constant group of symptoms was

,


induced in the monkeys which closely resemble those of msaslas ia

me  Of seven monkeys Inoculated intratrachaally with unfiltered

nasopharyngeal ~shing6 from seven cases of.maaslas, five developed

tho sympt oma .  The same group of symptoms eras induced in one man-

k.ey by inoculation of thd zliucous membrane of the nose and mouth

with unfiltered naso&aryngdal mshings from a case of Icot;lsles,  In

these expriments a variety of organisms, largtily saproaytic inhab-

itants of the naso*arynx and rrwruth, were pesent in the material

inoculated.  There is sufficient evidence, howsvar, that thase orgen-

isms were in no my responsible for the reaction, since the sarm

group of symptoms was induced in two monkeys by the Untratracheal

injection of naso@laryngeal washings fromthrae cases of measles

after the washings had been freed from ordinary organisms of the

mouth flora by filtration through Barkefeld N filters.

     !lhe cheractori6tlc graup of symptom6 v-hi&i follows the in-

oculation of monkeya with the nasoaaryngeal washWgs from patients

with mJa816S has been successfully carried through six passagas by

intratradheal injection of saline emulsions of the 6kin and IYUCCa

mucou6 membrane6 of monkey6 kilbd from 2 to 6 days after the onset

of the r&Lction.   I;%om the fourth passaga monkey the reaction Was
also successfully induced in three monkeys by means of titrated dole

blood injected intravenously.  This experinwnt showed the blood to

be Capable of inciting the reaction from at least the 7th to 13th
days after ixA+ratrachei& inoculation of the donor monkey, but incapa-

ble of inducing it from the 2nd tp 4th days.   Cultures of the blood

showed no growth.

The grmp of symptoms Mducedwa been constant and definite

in character.  After an incubation period of 6 to 10 days the anti1


.

becomes listless and drowsy, the oonjunctivae become injected, and
~~11, discrete, hyperemic macules appear on the labial mucous mem-

braze.  These spots increase in numbar and way eventually coalesce

in the course of 2 to 4 days to form a diffuee, red, granular rash.

This rash is usually limited to the labial mucous membrane but may

extend to the inside of the cheeke.   %e individual macu166 my or

KIXLY not show the minute bluish white center dharacterlstlo of Kopllk

spate.  From one to several days after onset an eruption of amall,

discrete, red manulopapulee apjxmrs on thti skFn, usually coming out

f lrst on the face.  The rash progressively increases In the number

and size of the individual laslana and mqq in the couree of 2 to 3

days extend to the skin of the neck, 6hOuldOr6, upper arms, cheat;

abdomen, and thighs.   It is constant in character but varies con-

siderably in extent in different animals.  By the time the oxanthem

Id fully developed, the rash on the mucous membranss haa begun to

fade and soon disappears.  The exanthem In turn progressively fades,

sometimes witi a branny desquamation, sometkces without.   There may

be moderate pigmentat ion.  By the 6th to the 10th day after onset
all symptoms have disappeared and the animal again appears well.
Coincident with this g&p of symptoms there la a constant and defi-
nite reduction in the total leu&cyte count, frequent& canstitutixrg

a true leucoptrmia.  hther symptoms of irregular occurrence are ;pho-

to&obia, diarrhea, and fever.  Symptoms of rhinitis and bronchitis

have not been noted.'

Microecoplc examination of sections made from the skin of

the animala during the per fad of eruption have shown that the leeions

present reeemble exactly those seen in the lesions of the skin In

hmnn pat iont 0.  Numerous attempts were made to obtain cultures of


a Virus from the lesions and blood, but it has so far bnen j4Poy
sible to abtaizx cultuxs of any organism pihich seems to benr ;in,~

specific relationship to the disease.   The results of these exper-

imenta, therefore, have indicated that the disease, ap?arentl?

ldent ical with measles in ran, ray bo suocessfully transmttted f?om

man to monkey and from monkey to monkey.
    h order to bring still further evidence that the disease
produced in mnkeya can be truly termsd sxprtintal measles, DOC-
tors Blake and Trask have studied the immmity presdnt in the monkeys

followhg the disease produced by experlmntal inoculation.

        S3nce an apparently permanent imtn2nity against reinfection
    characteristically follows one attack of meaoles, the sax16 phenomenon
    6houldhold trUe with respect to the expertintal disease if the two

     conditions are to be regarded a6 similar.  Furthermore, an acquired
    ixnunity, If present, should theoretically be efficient against a vir-

     U6 of heterologous  source as wsll ae against that of hor;alogoU6 Origin,
   .

I   since there is little clinical evidence to show that one attack of

measles fail6 to confer an Wity that Is effective against all sub-

sequent exposures.  Autbentio roports of repeated attack6 of maa

in the sake individual are so few a6 to be nagli@ible In this COMIC?-

tian.  In order to test the validity of the foregoing assumptions a
series of reinoculation exsriments in Liol?kdys Hhioh had recovered

from a prevloU6 attack of e$perir;sntal measles mm carried out.

    Ihe result of the txperlmemts shows t&at one attack of ex-
perimental meaeles confer6 an apparentlQ coqlete immunity against
reinfection witi rasaslee for at least a considerable `period.   fn all

probability thL8 Wity is permanent.  Moreover, monkeys v&ich

have recovered from ex~eric~ental rzeaales are iuxne to reinfection '


I

with the virus of rmas:es j.rraspactlvo of whether tht, vinx is cf

homlogcrus or hetcrologous origin,   In this raspect experbental

rzeaslcs in the rconkey corresponds with zcasles a6 observed in human

beings, and thd result is the sam whether the virus is inoculated

on the roSpirat0~ UNCOU~ WL-brane or iS injectad htraVenOUSly.

       However, the exact nature of the irzmnity produced in ton-

boy; or thir lmunity dovcllo?lng in L;B~ following a natural infect ion,

  is still obscure.   The way, however , has now batin opened to a fur-

ther study of this probl& as well a6 to thd extremly important prac-

tical Ql66abn regarding xmtJ1od6 for producing artificial imm.nity in


   fmn.  Preliminary experiLsr&s by Doctors Blake end Trask indicate

that the production of artificial inmunity my be quite possible

though tk;J stiids have not yet reached a stage :vhich will justify

  drawing dof init e conclua ions.   The successful out cord of rmch an at-

teqt wodld undoubtedly be of vdry great valua, for althou& under

ordinary conditions masles itself is not a serious disease, yet the

cokplicatione following .saslas present one of the greatest hazards

4
  of childhood.  The dangers of this disease ar8 enomiously increased

&hen it occuru among groups of individuals living in unhygienic or

crowded GuFroundings, as in 2sylum~ or as occurred armng the soldiers

during the war.  Knowledge of a mthod of sro&ylactic Inoculation

at the beginning of tie late war would undoubtadly have saved riwny  1,.

  thousands of soldiars from death.

Doctor Van S1vk.e

     We have continued the work begun last fall with Doctor6

Bust in, Cullen, McLean and Peter6, in collaboration wi% the labora-

tory of L. J. Renderson, to a6certain the noxmal gas and electrolyte


composit.ion of tha jlood culls z& pl, and tho changes in thorn

resulting from changmg ~02 and 02 tensions.  `Ihe object of `the

work has been twofold, (1) to elucidate the blood changes that form

a part of the respiratory process, and (2) to obtain accurate norhal

blood pictures more complete than those hitherto available, tiich

may be used as a basis for comparison with the blood pictures in

patnologlcal cordi t ions, such a6 pneumonia and nephritis.

     It was found necessary to pay at tent ion to technique before

results of the degree of accwacy required for soie af the phases of

the probleL, could be obtained&  For f0zT.m purpo6e6, Such, .for 8X-

ample, as studies of acidosis, CO2 determination6 ti the blood were
mzfficiently accurate if the error did not exceed + 1 volume per cent,

For the present work it ha6 been necessary to reftie the techniqus

60 that the error was reduced to 2 0.2 volume per cent.   Similar re-

f inezente proved necessary in the current tbChnif&Ie for rapid satura-
tion of blood w+th atmos#eree cohtaining controlled tensions of CO2

end ojrygen, The necbsaitiee for; fir6t; unusual accuracy, end second,

  !
rapidity in order to complete operation6 before extra-vascular chqes
slter the bloodi have. required the developasnt oP new technique for

thia entir'e field of work.  like developn;snt of the becesstiy methods
                                                               

for this woblern has coned bn urkpected au#bbt dS time.   Baf tire

the &se of ths pe& yeer, howetier;, results dP a h&g& de@ee of conL

s&q' mere being obtained, and we hope to asaeable' thei desired d&a

before Doctor Cullen and Doctor Austin leave in January.

Doefor Stadie ha6 improved the details of his oxygen chati

her, so that the control is simplified and waste of oxygen ellminatdd.

During the pneumonia season a rmmber of severely ill patients were

treated In it.   !Ihe results confirmed those of preliminary exp3ri,,er,td


during the prcced.iw yhnr.  cyanosis disappeared when tie oxygen

cantent oi the air was raised to 40-50 per cent . .   In cases where

oxygen satxsation was low the oxygen conttent of the blood was

caused to t;pproach or regain a normal level.  Respire t ion becaua

slower and deeper, and tachycardia was markedly diminis;?ed.   Ir!

short, the syq~toms which mi&t be at trlbuted to oxygen want we): 3

diminished, and the comfort and clinical conditions of the patient

appear to have been unfdormly improved.   The courat3 of the Infection

doea not appear to have beep altered, however.  The temperature was

not brought down.  And if, vrhlle the temperature was still high, the

ptiente were removed from the oxygen chamber, tWy quickly relapsed

into about the condition in dish they would apparently have been

had oxygen not been administered..   In order to iqprove by oxygen ad-

ministration a patient's chataae of recovery, therefore, it seems

nscessary to maintain him csontkruously in t41e oxygen-enriched air
until he beckmas convalesoglt,  Rhen this is done, it b0e.s appear

that the oxygen treatment improves the chance of recovery in &&tents
     I

VI?+O a,re unable $I ordinary ais to Isew their blood normally oxygenated.?
                                     

The $a~orabls effect seems to result, not from lnfluenc$ng the course
                                              . .
of t$e Snfeotion, but by protecting the patient from the added inJury
                                 . . ._                         .'
of ID%J?~WI vmzkt , a& f corm .tho o&aust ion that results .frT ' the, .sposdk
                                        ,. .' ,(

ing -up af the reepiratory and ,circulatory apparatus &I the effort tp

wmpon6ate for incomplete oxygenation,   &oh protect ion .appareqtly
aida a ,csrtain pre.portion of p&ents, I&O would otherwise die, to

survive urati) the nakral factors of resistance overcome the infec-

tion.

Dootor Bina= has developed the luwg volume method tc ax!1

a point that it can be used quite without cooperation from patients,

. .                                                         I


and can be employed without .inconvenience even to those tie are ill.

As mentioned in the March report, this has been accomplished by

having the patient breathe from a spirometer a mixture of oxygen

and hydrogen, the hydrogen being accurately measured, the oxygen
merely approximately measured in amounts to affofd the patient a

sufficient supply for the 3 to 5 minute period of the experiment.

At the end of the latter, the ratio of nitrogen to hydrogen in the

gases is determined, and from it the nitrogen volume and hence the

air volurrs contained in the lungs at the start is calculated. The

method ha8 yielded results of interest with heart patients, although

the data are a8 yet not sufficiently complete to generalize.   Doctor

Binger will this year probably apply the method also to a study of

the lung changes in pneumonia, particularly during resolution.   The

latter problem was the one for ~&ich the lung volume work begun with

Doctor Iundsgaerd was first planned.

Miss Hiller has continued her work on the unidentified

    basic amino acid of gelatin.  ft ha8 proved possible to reCrystalliZe

   it Only a8 the @-lOS@lOtUlgStat8. . The free base ha8 been prepared,

    from the @osfiotungstate, and ha8 proved to be an amor@ous'solid.
    A                                              When the
  .   ke half ~.f the nitrogen i8 in the form of amino graups.

   \
!    substance is heated in vacua at 100o to dry it, it slowly decompases,
                              --

    Because.# the difficult properties of the substance, v&ich presuma-."

bly have prevented its former deteotion, the problem of determining

, the stlmcturs is not easy, and will probably requ$re a:considerable

amount of tirI+.

     Miss Biller at the same time has brought nearcornp~etion

her 8ystermXtic study of the protein precipitant8 applicable to analy-

88s of blood and of protein digestion products.   The nature and


                                                                  4
                                                                  I -%

purpose of this study were indicated in the report of last March.

      Doctor Edgar Stillman has carried the work on nephritis

through the year,  and has collected an amount of data an correlat-


ed functiaplal and clinical observat ions.   It is hoped that infor-

mation thus accumulated may ultimately afford us additional aid in

differentiating the types of ne&ritics and the corresponding types

of treatment that are Just if led.   The work is necessarily long, in-

volving as it does systeutic following-up and re-observation of

patients until sufficient data have been acculated either to con-

firm or to alter the present methods of classif ication and treatment

of the disease.



Doctor Swift



       Clinical Studies:   During the past year clinical studies

of patients with acute rheumatic fever have been continued.   lhir-

teen such patients have been studied.   Special at tent ion has been

paid to the effect of the administration of salicylates on the cause

of the disease, having in mind the question of the specificity of

this drug.

      In collaboration with Doctor Cohn definite evidence is

being collected of the presence of ngrocarditi8 and impairment of the

-1~8 .conduction ch;lring the course of the disease,   Electrocardio-

@EkKLS are Still being mad8 daily in the aCUt Stag8 of the disease

and at longer intervals in the subacUte and &ronic stages.   With

the assistance of Doctor Cullen, a study is be3ng completed of the

reaction of the joint exudates.  These have been found to range,

from fi 7.2 to pEI 7.4, showing that there is no appreciable acid pro-

duction in the involved joints.


  b

.

                              . 3%

     Bacteriological studies:   Joint exudates and blood of

patients have been cultured Lerobically and anaerobically, cultures

having been made during the year.   In no instance did the cultures

show growth.  Iiheuxratic nodules found subcutaneously and in the

tendon sheaths of ptients with acute rheumatic fever have been ex-
cised and cultured by the Nogucbl anaerobic method; thus far no
growth has been observed in these cultures, nor have organisms been
observed in sections of the nodules stained with eosin and methylene

blue and by the Giemsa rriethod.  The supply of such lesions has been
limited, owing to their infrequent occurrence in the pati&s stud-

                                                               .'

ied.  During the coming year it is hoped that a greater a'trundance
of material will permit us to exploit more elaborately this method
of attack, for these nodules, which are considered characteristic

of the disease, seem to offer the most hopeful method of approach

to the etiologic agent.

     Transmission experiments:   The attempt to transmit the

disease to animals has been continued.   Iaet year rabbits and

guinea pigs were inoculated with joint exxdateS and blood of patients.
We were unable to reproduce the `clJmical. picture of polyslbthrit is,
although several of the animals develapd a mnarthritis.   A histo-

logical study of the hearts of these a~?&cqls is being coqleted.
Certain of the hearta have 6hovm qyocardial lesions, the interpret&

tion Of v&i& is still unsettled.

    Fourteen monkeys have been injected witch blood and joint

sxudate. .;. Ihe results of this work have bean confused by s concur-

rent parasitic in$ection of the monkeys which mnifests itself clin-

ically by fever, leUCOCytOSis, eosinoailia, joint swellings, sub-

CUtaIIeoUS nodules 6nd blisters on the palm6 and 601eS; from these


latter lesions have been recovered the ova and the adult fam,sJe of

a worm which has baen identified by Dr. Stiles of the United States

Public Health Service as a membttr of the super-family trichinalloi-

dea.  Dr. Stiles reports that he can find no record of a s!milar

infarction in monkeys.

It is probable that this disease has boon srosent i1 the

monkey house for at least three years,   In order to cant irr~e trans-

mission experiments it seemed necessary to learn more of this dis-

ease which simulated in sovaral rospdcts rheumatic fever.  During

the last three months such a study has been undertaken.

     Ihe f'ully developed female worm, V&I&L mea6ures from. 1.3 -

1.5 cm. in length, and about 0.5 mm. in thickness, appears just be-

neath the skin of the palms and soles, giving rise tn a papule.   The

wornis recovered at this time are motile and contain many ova.   `l'ho

evidence indicates that the worm burrows beneath the skin, forming a

aerpiginous blister, aud the eggs are deposited.   !Cho blister rup-
tures and the ova are scattered OUtSid the body.)  Forty to 120 ova

have bean found in a single blister.  These ova are brownish in dol-

or, lemon k&aped, ?O-9OruLlong, and 25-40 )r, wide, with opercular plugs.

At the tlrm of mpture of the blaster the female worm se&~ to be
  b
part ially dielntegrated.'  NO male worms have been rauovored from the
.

  ekin lesiona.  The subcutaneous nodules have been' examined hiitolog-

icSll,y, SOXB of them showJng the prssence of a coiled 60rptl.  A few,

however, havo shorn no parae ite .  A few of the monkeya have bean

autop6ied recently to dotermine the visceral lesions.  Encysted adult

worms were found beneath the acosa of thb colon and in the omjntum

close to the transverse colon; these worm6 ware slightly thicker in

the body than the worm6 found in the Skin Zesione.   E:iost of them on


removal from the cysts were actively motii6; a few seemeh dead.

Some of the cysts contained only a brownish substance and no worm.

These worms are probably of the male sex.   Sylecimens of these have

been sent to Dr. Stiles Whose reply has not yet been received.

     Salicylate Investigation:   The non-hemolyt ic strept ococ-

cus is still believed by umy to be the etiologlcal agent of acute

rheumatic fever, and salicylic acid has been considered a specific

remedy.  If these views are correct, it muld seem that some pro-

tection could be afforded againat artificially produced etreptococ-

cus erthritia by the administration of the drug.   We have Just

completed such a study in rabbits.  Fifty-two rabbits were used,

one-half receiving salicylatee by mouth in dosage comparable to that

used In the treatment of acute rheuqat ic fever in man, the other half

act ing a8 control,   A11 the rabbits were injected with strains of

non-hemolytio streptococci recovered from cases of rheumatic fever.

Polyarthritie developed in both the rabbits receiving salicylates

and in the cant rol rabbits.  No difference in the frequency of oc-

currence or in the number or severity of the joints involved could

    be f omd in the two ser ice.                                  ;r

.         Dootor Swift has cant inued his investigation to determine

*ether or not the inranxle bodies famed by inJection of non-hemolytio
streptococoi into rabbit e could be enhanced by a simltane@as aclmin-

istratlon of salicylates.  His results have corroborated his prevl-

o-us ones, to wit, that no increase in antibody production followed

the administration of sallcylatea,


Doctor Cohn

     In the early part of the past year, the old laboratories

on the third floor of the administration building and on the sixth

floor of the Hospital were abandoned and the new ones on the eighth

floor of the Hospital building opened.   The Hospital 'building has

been re-wired and new wires have been run to the roof of the admin-

istration building to connect Doctor Carrel's laboratory with the

galvanometer room, as well as to the animal house.   !rheee changes

have proved to be eminently satisfactory in a technical sense and

have afforded the opportunity for considerable increase in the range

and volume of our activities.

     Ihe problem of the behavior of the heart in ante rheu-

matic fever has been studied in association wit21 Doctor Swift.   It

has long `been known that the endocardium and the pericardium of this

organ are frequently involved in rheumstism, and criteria for appre-

ciating disease of these structuree are available.   The disorders

of these structuree have long be& regarded as constituting heart

disease.  Bttt at least of equal 34nportance with t2mn is the Peso-
                     all

tion of the xnascle, wibich after represents the bulk of the heart.

cphis has until reoent times been relatively apeaking a silent area.

`Since the intro&a&ion of graghic, and mm eepcla1l.y of elpztric
methods, it haa beam poekble to study in oektain important details

the event 8 rihlch take plaae here.  We have taken advantage of this

technique.  It ms kxzo~ln before that the bundle of Bie, a thin ms-

culrv strand which conneote the ventricles to the',auricles, is in-

volved in the rheumatio procesg and mkum involved causes defects in

izqpu~se conduction.  The orderly, coordinated, beating of the cavi-

ties of the heart is thus seriously compromised; there are gross


disturbances .  We found ix addition to the gross changes that

alterations of a more subtIC: nsture were in point of fact tak?.ng

place from day to day, the degree increasing or decreasing, !&ese

gave UB an insight into the daily progress of the disease in so

far as it affects this structure and served as a valuable guide

in studying the state of the disease.   In a similar way, altw+

t ion in the great uass of the ventricular muscle has been inwsti-

gated.  !Ihls can be followed by studying the details of the

ventricular port ion (Q R S-complex) of the electracardiograaic


curve.  In the sams parson, such curves usually have a rernarkobly

constant form.  Changes of a striking nature were, however, actu-

ally found in the -es of at least one patient.   While the exact

significance of the observations requires further investigation, it

ia probable that advance in knowledge of the disease process can be

timI8 by thie method.  And not only knowledge of the disease pro-

cess, but also perhaps a guide to treatment mey be found.   so long

as alterations like these go on, no matter &at the other signs show,

the cowse of the infect ion cannot be regarded as having COILB to an

SSd.  The ordinary rhythmi@ irregularities in the mechanism of the

heart beat were ah found.  Although these are of interest, they

were not UIALIIU&1, except that by good fortune we vtere able to *oto-

gra* a transit ion from the ~dhanism of auricular fibrillation to

one of normal mf3chanism.

    Rsce+ly, in Oartmny, Frey, scting on a suggestion of
Wenckabach, m-introduced the use of a cinchona der ivat iv0 (quin i-
din su&hate) in the treatment of cardiac affections, notably fib-

rillation of the auricles, an affection in which the pulse is com-

pletely irregular, with the view to restoring the nor=1 cardiac


rrechanism. In LCI:~,;C,: IS!.: ng this he, as well as others, wiis

successful. in more than :I;:.: the cases treated.   Docto: L>\y

has given the drug t.o 1Z pat icnts in the Xospital of the lnsti-

tute and like the other o5serve2s has succeeded in restoring tie

normal rhythm in 3 cases.  The number of patients it ha? tee.1

possible to treat is insufficient. tu serv? as the bssis of 7, ~:a-

tlstical account of the d.zug's action, lxt he 5a~ Lzt>,l able fo

make very detailed studies both of the xx&hods of giving the dnrg,

and of the nature of the mechanisms tiich the drug induces and

through which the heart passes on the way back to its normal state.

     Concurrently we studied the action of quinidln In dogs.

It seemed important to us to do this for two reasons, f iret, In

order to study exactly the behavior of a drug which has so, pmfound

an effect in altering the mechanism of the human heart; and second,

because quinine has been regarded as having ir. depre6:smt action,

that is to say, an action tilch reduces the contractile function of

the heart muscle.   If thie mre a p$ominent feature of its activity,

its usef'ulzpma a8 a oardiqo remsdy might easily be lessened.   The

most striking alteration we $~und.was, contrary to uur expectation,

an increase in the power of contraction of the ventoiclea,   It IS

on this account that for clinical purpose we attach sieificance to

our experiments; for if the drug fe not a depressant, a residual

h&sitatfon to use it may be removed.  We have safeguarded. our con-

clusions by nwking a variety of tests, to exc+ude the possibility of

error due to the natu$w of the qXperiments, such as anesthesia and

the necsa may sprat i ye procedures .   We wish, howev8r, to be guard-

ed in draw'krg inis:enem from our work bearing on the use of quin-

idin for cliaioal admM%stsation because of the iqportance and


seriousness of the conditions in which the drug is employed.

     `she other actions of the drug in dogs, which we found,

yield no information of a striking mture except that a fall in

blood pressure takes place, at f iret great and tramient - later

moderate but ~rr&ment during the duration of the experiment.

This effect it was necessary to study in detail, bgcause it is

itself important and because it pry be Involved in bringing on the

increase in contract ion which has been described.   In patients,

however, a similar fall in pressure was never seen; the dmg has no

danger from this point of view.   Of its relation to the increase in

contraction, we can report that a mber of control experiments in

which the blood pressure was made to fall by other means, failed to

duplicate the result obtained with quinidin.   It 0 contractile action

then, is exerted apart from its action on blood pressure, and the lat-

ter is an effect which, as has fist been mentioned, we have not seen

inUH%l.

     Doctor Imy studied in animals, in a pelirninary way, the
act ion of a w stro&mthin coqwund, prepared by Doctors Jacobs

and Heidslberger ,  !Phls w appeared to be less toxic though ther-

ap3ut ically as effective as the mother substance.   In view of the

importance of the etro@anthb group of drqy in the treatment of
patients, it seema desirable to possess them in pure form and to *

study the action of varient forma with the view to finding ones serv-
ing the s]Fecific needs of clinical @~yaiology.
                                             `

Doctor Lmry is studying alterations of the size of the

heart in pumonia.  This study is important because of the doubt
vdhh still surrounds the occurrence of collapse in Ike course of'

this disease, and the relation of cardiac dilatation and failure to


its anset.  But it is i@ortant in addition to this because

apart from collapse, cbanges in the pulmonary circulation are be-
lieved to take place in this disease and to be attended by changes

In the size of the heart.  If) as experiments in our laboratory
show, digitalis acts on the heart during pneumonia, and if, as our

experimnts also show, this drug increases the contractile power

of Lhe hesrt, additional interest attaches to this study.   For

should a &snge in the size of the heart appear to be usual, we

have a means at hand, through ability to increase contraction, to

bring about relief of this. cmditicm.

?he method employed has been to make %-ray @otogra@s

with great care - all fiotographa being made as nearly as possible .

with en ident ical technique.   We are then assured of having plates

so nearly comparable that their measurements can be compared day by

w*  `Ihe plates are pllrced two meters from lhe target of the X-ray

tube; the target is elevated to the level of the substernal angle,

the tredian line of the front and of the back of the chest ere in

the 8aw line with the target; the exposure is made during norms1
inspiration.

    Doctor Iavy has found that if these conditions are ade-

quately met, the X-rays of normal persons do not diffrsr by more

than 1.0 cm. in the transverse dimension of the heart Is shadow nor

by more than 10-O sq. cm. *en the whole area of the shadow is meas-

ured.  A more accurate method than hitherto available has been de-

vised for outlining the cardiao si3houette.   When these re5dts are

compared with the situation in ten cases of lobar pneumonia, ft is

found in nine that there is a distinct Increase in both measurements,

in the transverse diameter as plllch as 19 per cent, and in the area


as much a8 37 per cent,   A similar increase is rare in broncho-

pneumonia, that is to say,  an increase was found in two of six



cases.   Tha size of the heart decreases with the fall in the tem-

perature and the pulse ratd, but usually it lags behind these and

doss not return to the base line until some time, perhaps a matter

of v.eeks,  afterwards.   Occasionally, during early convalescence,

the size falls below that finally attained.

      The observations, although still insufficient in number,

indicate that the management of convalescence has a bearing on car-

diac size - sitting up in bed, especially perhaps if permitted too

early, is attended by a return of increase in size.   Them is a

single observation in tiich It appears that giving digitalis ?re-

vented the anticipated de& In the return to normal size.   These

illustrations point out the practical bearing of this st;udy.

      Doctor Binger has worked on a method for measuring the

quantity of air in the lungs of patients suffering frorr shortness of

breatn , and has now perfected it.   The rathod determines not only

the so-called vital capacity or that volt of air which can be 8x1

    pelled from the lungs after rraxirnur, insgiration,
.
   `-- _

us3 sir which remains in the lungs and cannot be

f.oroed expiration.  Residual air is- masured by

to breathe to and from a spircmeter containing a

but also the resid-

expelled even on

allowing the subject

mixture of oxygen

and hydrrogen.  By a chemical ~lysis of the spirometer contents

before and after the Nt ient has breathed, the degree of dilution of

the oxygen and hydrogen mixtura with the lung air is estimzted and

thus the volur;le of the lung air is calculated.   By a similar tech-

nique the volume of air rek-aining in the lungs at the end of a usual

ex>iratory movement may be deterwined.  This r&hod has the advantage


of de-ding a miniuum of cooperat ion on the part of the subject

and heref ore is applicable to pat ient s with severe cardio-
z

respiratory embarrassment - the very type in &ich a study of

lung velures is needed.  Pravious methods have not proved satis-

factory in this type of case.   It has been applied to a series of

individuals suffering fromheart failure with the view to under-

standing further the mechanism of their circulatory and respiratory

incawcity.   A series of observations has been r;ada on normal indi-

viduals for control purposes,  The measuemnts obtained have been

correlated with certain *ysiological standards as a further contral.
It is planned to carry this work furthar with wtioular attention

to the volume of air content in the lungs in the expiratory *ase of

normal breathing, ar,d to study its value in relation to the so-called

tidal air, which is the mt inhaled and exhaled with each breath.

By these relative valces it is believed that a more or less quanti-
tative expression for dyqnea (shortness of breath) will ba obtained.
The method for measuring lung volumes in its present form, JVO be-
lieve, ie applicable to the study of pneumonia, in vuhich an investi-

gat ion of the sir content of the lung during stages of donsolidatfon
and resolution would be very inskuctive.  So far as we bnow, pre-

vious methods of studying lung volumes have not been practicable for

sue investigation.

     Ihe study of respiration in heart failure has pointed to
the intiru&e relation between oirculatory failure in the lung and

decreased lung capacity.  It has emphasized again a fact long ob-
served at the Rockefeller Hospital that patients suffering from

heart failure have a tendency to elevation of temperature.   An ex-

planation of this *enoIllenon has presented itself in a more or less


hypothetical form as being due to impairad heat excretion due to
the fact that the blood is stagnating in the internal organs and

not adequately brought to the surface of the body.   This inter-

pretation of the findings has suggestad a field for investigation.

Apparatus has been designed and is under construct ion for measuring

by an electrical therm0 couple the temperatue of the circulating

blood in msn as well as the teuperature of the body surface, and

LUIM accaXate determinations of rectal and mouth temperatures than

are possible with the ordinary clinical thermometer.

RUFUS COLE