.

.


Ger.tler;lon:

RXPOKT Or TE!? CIRZCX!R OF 33 HOSPITAL

oc to-00 r,  1923.

/    I

In th3 raprt of ths work of th3 Hospital for the pre-

codinc ;`o or mention was z&b of th3 chzng2s ir, plz of organizztiori 9e-

pendcnt u;?on tha greatar ass of the deFart..GnC, and incrccsed experionca

on t>s part of certain nonbars of the s tGf .   !?h3 separation of the

Hospital activities into several divisions :!DS taken place tithout any

serious loss in unity ~322 nitk: `az urAoubt:d gain ir, off3cticznss.s. It

is obvious t&t in alinlccll work thz rrut?~l assistance and coaperatior.

of the various members of the Staff is of v3ry great importance; indeed,

it is quite nocessarJ in order that ths grantest use be pade of the avail-

able Trw terial .  The spirit of coordinated effort and interest which is de-
nrtnded and which has been so evident' in the Hospital in the pait has not
diminished and each member df the' Staff has been Gilling to bring his.'

special bo>vledge to the $olution of any problem under investigation in any

part of the Xospital.  As a result of this, a review, such as the `present,

describing the activities of the individual poxqzeof wopkers, my not give'
,full credit 50 aa& i-idi-rid-z1 or gmup. For instance, in the study of

nephritis, or in t:le study of rcspira$oqT disease, studies tist b6 made

. .   not Only Of re-na1 fractions or of tha respiration but frequent and care-


                                                               r;. .,
                                                                * .' . * : -156,

2~1 studies must be nade of `;he state of' th,a heart as well,. Studies
                                   _
of this kind carried on by Dr. Cohn and his associates, not bearing di-

                               .
rectly on their own problems, r3ceiveS no sp3cial notice in Dr. G~III'S

report, though they may have dglnsnded much time and effort and have been
of much value in aiding in tho eolution of the problems under investi-

gation in ths Hospital.  This fact must be kept in mind when reviewing

                                                                           .

tho achievements of the various groups of worksrs.
      Compared with the previous year many changes have oc-
curred in the staff, but thsso have occurred without any serious effect
    w
on the work of the Eosyital.  Mention was mado in the last report Of
the appointment of a number of the m3n fo positions in other insti-

tutlons.  The appointmen, + of Dr. Austin, Resident Physician, a8 PrOf3SsOr
of Research Medicine at the University of Pennsylvania did not become

effective until J;uluary first, so that he was able to continue his duti3S

hors until that time. Upon his doparturo his duties as Resident Physi-

cian were taken ovar by 3r. Lu2dsg`aard.  ZJs long experience as resi-
dent physician at ths Hos~;it~l of the University of Copenhagen enabled
him to carry on this work her3 with great 3ffcctivencss. However, h3
d3sired to be relieved of his addnistratj.Vo duties and wished to reside

outside the Hospital, so Dr. Xugh Morgan has been appointed to the post,

of Resident Physician.  Dr. Lundsgaard remains a member of the staff
and Is engagedSzespeciaJly in,the, Study. of nephritis.. ..:    ~ . .    ,  Ye' : ; .: 1 ,,
                                                                           .,.

Dr. Edgar Stillman, who for rnw years hss been a nierhb& '
                                                             

of the Hospital sbaff and has assisted in the work carried on in relation

to diabetes, the stxdz: of ch3ro-therapy of sy-hilis an2 more recently

the stue of nephritis, has received an appointment as Associate in Medi-
cine in Columbia Univcrsit;r and Assistant Visiting Physician at the Pres-

byterian Hospital,  Dr. Levy, :vho has been associated with Dr. Oo@n in

^ .   - -.


rl

J,

t#llC s',ud;- of heart disease, also has left. to accept similar positions at

Columbia and ths Presbyterian HosPital.  These changes have necessitated

several new appointments.  It is a great satisfaction to note that the

mmber of well-trained CCT! aho desire to undertzke thn, kind of work for

which the Hospital rrr~kc3 Frovision is imch greater no:v than it WCS im-

mediately following the \':isr.  Xs a result, it has been possible to com-

plete the staff for noxt yea r vdth a group of well-trained, enthusias-
tic a&, apparently, capable young men.

       nvo new undertakings are nbv under way in tho Hospital ,

the results of which, however, will have to wait for a later report.
Tha two developznents may be nzmtioncd, however. First, the character

of th8 studies which are being conducted in relation to heart disease
is being modified, and this has necossitatcd a reorganization of the

group of men working under Dr. Cohn and a considerable change In the

labora tory equipment o  Dr. Hews A. !.lurray, who has received an ap-

pointznent on the Hospital staff, will undertake the culture of heart
tissue in vitro with the purpose of using this growing tissue in the
solution of. certain probl,ems relating to the physiology and @th010&~
of thi heart,.

The second important enterprise consists in undertaking

the study of chi &en-pox.  This study is not being conducted because      . .

of any very great social or economic importance of the disease itsslf,

but it is believed that further knowledge concerning its etiology and

.

nature may have wide application to our knowledge of other contagious

di seaqe s .  This work will. be czrried on directly by Dr. Thom%s Rivers,

who comes from the Pathological Department of Johns Hopkins University,

with the assistance of Dr. William S. Tille tt .

With these new projects well under way and with a prom-


L
.   islrz outlook .for prograss in the solution of problems previously under
  investigation great hopes are entertained for the success of the coming

year.

        Inquiry by visitors and others is frequently rade COP

cening the methods we employ for ob"%ining patients suitnblc for the

studies being carried on.  Very soon after the Uospital was opened it

became apparent that thsre wore pmctical difficulties in the way of

.

obtaining ptients .through other hospitals and it was found that it

would be necessary to dehend upon practicing physicians to refer to the

HOSpital the kind of patients desired. For the purpose of getting into
contact with these physicians and of informing them of the types of pa-
tients vie wish to admit, we began the practice of sending bulletins from

time to time to all the physicians in New York. I am attaching the
latest Bulletin which gives information concerning the diseases which

it is planned to investigate during ths coming winter. The response
on the part of physicians in the past has been most satisfactory, and
on the part of the public there has never been the least evidence of

fear or distrusgtrar.disincfination to come to this Hospital because one

of its functions ia, to aid in the investigation of disease.


?'

",                                                        169
                                                                         . ;--.
                                                                           ? ? o ??

FORM 80-1OM                                                                        NO. 1s

The Hospital of The Rockefeller Iwsfitute for Medical Research confines its work to selected cases that bear u)on
a limited number of mtbjrcts chosen for irlvesfigatiotr. It is the practice to issue Bullefins frown time to time, giving
notice of subjecfs thus chLsen, in order that suitable pafirnfs may be referred to the Hospital by physicians and
othirs ~~,ho are itrtercstcd and who are willing to co-operate in this way.  No chorgcs are made for freafmenf, room,
Do&d, or any other services.

HOSPITAL OF THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH
            46th Street and Avenue A. New York, N. Y.

BULLETIN OF DISEASES UNDER INVESTIGATION

September 30, 1922

  The following conditionr will be the subject of study in this Hospital during the coming winter; patients
suffering from there diueascr ~$1 be admitted to the extent of the Hospital facilities:

1. Acute Rheumatic Fever.

(I)  Patients with acute rheumatic polyarthritir.
(2) Children during the acute stages of recurring endocarditis, pericarditis, or myocarditis of supposed

   rheumatic origin.
(3)  Paticntr with chorca and arthritic or cardiac involvement.
(4)  Patients with rheumatic fever showing rubcutaneous nodules.

I I. Nephritis.

  Patients suffering from acute nephritis or from chronic nephritis of moderate severity, also a few casea with
arterial hypertension unassociated with evidence of kidney diaeaae, will be admitted.  Casa of nephritis in young
persons, particularly caru showing edema, are especially suitable.

I I I,  Chicken-Pox.
  Patienta with chicken-pox will be admitted to the Iaolation Ward of this Hospital for care and treatment.  It
is desired that patients be referred as early in the disease as possible.

IV. Acute Pulmonary Infections, including Acute Lobar Pneumonia.
It is desired to receive patienta n&ring from atypieal fours of acute infection of the respiratory tract as well'
as those with acute lobar pneumonia. Patienta with the latter condition should be referred as early in the disease as-
possible in order that suitable cases may receive the greatest benefit from serum treatment.  A chamber ir now avail-
able in which patients may be treated in atmospheres rich in oxygen.

b    V. * Cardiac Disease.

     .    In continuing the study of the treatment of chronic heart disease, it is planned to admit patients, either young
    or old. in the more advanced stages of heart failure. Such patients aa show completely irregular pulse and are s&ring
    from fibrillation of the auricles are especially desired.

  Physicians may communicate with the Hospital by telephone (Rhinelander 0900) or by pumml application to
the Resident Physician. An ambulance will be rent promptly when required.


8
.

.
;"b
      I

i
I

:`i:is study beg3n sovcral ysars ago 3ith an investigation

of lobar pneumonia, one of thz objcc ts bzing the dovclo~z~?;;: cf a speci-

This iZ;v?L?i,,~.tiOX resulted in the accumul~tior. of more

accuruto PmwloCg~ concorning the b:actoria concerned, ths dcvclosment

of IX Cods Tar ctot2minir.g `,hc bs:terial incitant in c=ch individual
case an> ths devsloprzn t of a me tkod of  se;yun trzntmcnt effective in

the cases associated with tho prasonco of one kini of bcrctzria. During

thJ Frogrcss of t;lzsa st-;di>s it Secnme increasingly evident that lobxr

pnoumcniz, of pnour,:ococcus origin, should not bc studied as an isolated

phenomenon but that it is related, certainly as regards p%thogenesis,

to a whole series of infections of the resr,ixatoT tract, some severe,

    others very mild in their oznifestations.  Moreover, during the years

   this study has bcln in ~ro3m3s the character of t'ne prevailing pncu-
.
   mania has varied greatly .   This has been dus to some extent to the un-

usual conditions brought about by the war, and also by the prevalence

of so-called influenza in epidemic fopA, but, in addition, other factore

have probably also been operating.  It was therefore thought necessary      ._
tq greatly broaden the score of this inquiry if a clear conception of the "
                                                                           ._

nature of this group of diseases was to be obtained.  This explains why

during the past year the studies which have been pursued have taken sev-

eral different directions.

        Although in the following description the studies may

appear somewhat xlrclatad, nevertheless they represent work necessary to

be done before progross may be made in the general problem under inveati-

gation.


         It has corn3 to ba generally held that in acute lobar

     .
pncuiionio infection takes place by xay of th> respiratory tract. There

is sorns ovidcnce t!zt in tho ca3s 0; p,;o*monia ~522 to Pmumococcus me

I an.l `Qpo II. infection 1s S-irly dircc:, that is, is spread i'-ror~ tha

sic'k to the ~rell `,hraugk fsir1; r?irsct contact.  T7-a chief b;,?sis for

the latter point of viz\-1, V;hizh i.2.s a -tar-- i:.Foi-tanf bearing on the pro-

blen of pnmmoni~, i3 the wcrk of Stillman., diskssod IL t >rcvious re-

port, by xhich 1 t ~733 shown t%t pnsumocoxi of thcso t>;)eo are found
                         t

nroly in the mouths of the healthy, and then chiefly in thz mouths of

parsons in ir.z*dic?te contxt with patioilts suffering from pneumonia

dw to t>e same tnc of pncumococcus.

Few, if pnau~ococci of these types do not have a wide

distribution apart from disease, the impor",ance of She mere presence Of

th ese organisas An the respiratory tract bccomss emphasized.

The eq23rin2ntil studie; of Blak and Cecil, however,

indicate ti%: ex-en ;vit> pneumococci of these fixed types, infection does
  .                                              
not occur uniess the cocci gain access to the lower' respiratory tract

and that this does not occur unless some accessory factor or factors
operate to b&k down a defensive mechanism which ordinarily prevents
bacteria reaching the lower re,spiratory tract, t'ie lung itself. The

following studies which have been Carried on .by Dr. E, G, Stillman in-

dicate that even this alone is not suffiadent,, ,but that probably still

other factors must be operating befox infccticn occurs,  The foIlowing

is a description of these experiments and the results obtained::
                                  

Nice and guinea pigs were placed in specially constructed

metal chambers and sprayed ~zith cultures of pneumococci, the virulese

of which for the test animals `had been previously proved by the &r&e


  .

b

~p~rl',onYLi in5cGitloc of 0 t&r ar_imrels.  Cf the 198 mice used in these

S,rLjiili exFeri.mezts a 3-4 were kilk:! and autopsied at intervals of from

    .
If `Y to 4% hour5 af tel- spraying.  Pneumococci of the same type wrs rd.-
covered from the 1%1&s of 19 nice autopsied w:thin 1 hour of so:a?inS-:.
titer th5.s period the incidence of recovery of ?neumococci from the

lung6 rapidly decreased.  Of the mmining 164 xicc viii&? cerc sprayed
and allowed to live, all. survived for 10 dzys wit.h :he exception of 5

which died with a pneumococcus soptlcemia.  These obsel*~:-~;io~le afford

evidence that viruleQt pneumococci following lnhalat,ior. :&W rear:- the
l-q-p and may be implanted in the lungs in appr2ci35lc numb~~rs but that

in all but a relatively fae instxxcs the. L3r.zncoco7ci ar3 effectively

disporad of without inj-3r-y to ths anirrzls.
       Of 40 mice sprayed with hemolytic streptococci 18 were

killed. Hamolytic streptococci y,vero rocovorsd from their lungs regularly

up to the 7th hour after exposure, in izlf the mice after the 8th and

12 th hour but not after 24 hours.  The heart's blood and spleen cultures

were nestive.  Of the 21 mica allowd to live, oniy 9 survived 14 days,

the remaining 57s dying of a hemolytic streptococcus septicemia on the

2nd to the 12th day.                                                      3'

        In the case of 33 mice sprayed with non-virulent B, .in-
fluenza the recovery of' the organisrils YI~S much more irregular,. B., in-
                

flwnzae was not recovered from either of -2 mice killed at.the end. of.

1, 2, 4, 6, and 24 3ours, respectively, after spraying, :but was present

in one animal after 70 hours. The heart 1 s ,b&ood ,and ,sp+ecn. cultures re-'

mained sterile.  All of the mice not, killed survived. the 10 day period

of observation,

       These experiments suggest that even in highly susceptible
animals (mice) virulent pneumococci are apparently unable to multiply in

.


their r6.si.d disposal when. introduced by ssr?,ylng.
.                                                                           3

        This esperimzntal work and also observation of the dis-

tributicn an2 spread of the dioease in imn ir,dicrrt,e ths naed for further

Study Of tke fZlCtOr6 conccrnod in pnoumococcus pLrnor!ry irfection other

thar. t2.e presence iz 20 1ur.g of the pnoumococcus itself. It is pos-

sible that those factors may ba sr entirely non-sgocific and m3y have

nc'Alng to do with a living virus.  Ths other possibility, however,
that even a&te lobar pneum0nin may be tho manifestation of a secondary
infection mat always be kept in mind,

       !Fhe discovery by Olitsky and Gates of a new variety of
0~11 bacteria, previouoly overlooked, in certain case6 of influenza
has 133. to thd suggestion that those or similar organisms might be
sressnt in oti:er t:Ges of acute respiratory diseases, even in lobar

Dneumcnia itself ,  Studio6 bearing on this problem have been carried

on by Dr. Avery acd Dr. &rg%n.  In this investigation they were for-

tunate in having t'nc; si;pport of Dr. Olitsky anil Dr. Gats6.
       Some time \vas first spent in becoming familiar with the
biologic characteristics of the strain of Bacterium pneumosintes ori-,
ginally isolated by Dr. O&it&y and Dr., Gates in the epidemic,of in-

fiuenza in 19i8-19.  The tec`hnique originally employed by them in iso-

l.atZng B, pneumosintes was used in naking cultures from G series of cases
of mild resptiratory infections occurring during t3e past ainter. Oui-
turoa were made both from filtered and unfiltered nasal secretions.
L'here have been isolated 14 strains of bacteria having characters which
serve to identify them with the group of organisms of which B. pneumo-
sintes may represent the type; 7 ware recovered from patients with
mild respiratory infections such a6 ltcolds, I1 tracheitis, bronchitis, etc< i


4 stzA-3 v;erz rcco-zrad :_`p?:n one p.ienk witk brsncSo-~~ne-~lonla, culture&
3ei:lg m.de at weekly intervals during the mozth of convalescence and the
three o thar strains were obtajned from patients in whom tha clinical di-

agnosis of influenza was rmxdo.  All the strains posSoss in commo?~ the

following characteristics: they are ~~11, Gram negative bacilli, are

strictly anaerobic, and were cultivated directly from th3 filtrates
of USC pharyngeal vmshings after passsga throu@ Berkfeld candles "VI' -
that la, they were filter-passing in the form in which they existed

baforo artificial cultivation.

Variations in morphology and seralogic reactions sug-

gest that these strains differ in certain characters from B. pru%mosintos.

Further study of the cultural and im;nulological properties of these
recently isolated organisms is necessaq, however, before any certain

opinions can be give.. q as to their identity with or similarity to the

strain of B. pneurmsintes originally isolated.  It is interesting that

in several instances the bacteria were isolated from cultures made di-
rzctly from filtered washings on blood agar plates.  The possibility of

chance conteunination from kidney tissue, ascitic fluid, or animal pas-
aage ,%yas thus e&i.+tsd.  Vbatever c&tion these strains , and others

                       `.,.

that my (iubseqwnti;y be isolated, may bear to one another or to the _' : -
Original E, $neumosintes, and whatever may eventually be proved as to
         ,                                            4
their causal relationship to acute respiratory disease, ,it has been
demnattited that ba$teri& of this hitherto unknown and'unrecognised

type are frequently present in the respiratory tract.

       ,SO far organisms of this type have hot been isolated from
patierlts suffering from acute lobar pneumonia. Nevertheless, the dis-

covery Of the incitants of the milder infections of the upper respiratory

tEUA, which SO often precede pneumonia, would undoubtedly go far in


Lol-Anz tLe i2ro-9lerfl 02 t'ne patilogenes* i of pneumonia.

       Studies alon. these 3pe ,$l..J,lar lines are in progress

i?rLj. vii!.1 be -srsued during t`ne coming wi:iter.

Gro.:th ~e?Arem:pts of 5,jnfluencae and other Bacteria.

      In tho last report, there YCIC dirczsscd certain studies
of Dr. Aver= an,?, 3r. T;jc:tr. +Lc'.= >a;- rosultei i:l tLe di~c~v~r~ that

ths grorvth stiumla',ir,- effe:+, of blo~?~ on 3. Influenza was dependent on

~JO se,unEblo RA?! LI scinz! factors, one in a vitamin-like substance, and

the ctiler a heat stablo subs*&nce a0tir.g in extre:.iely low concentntion.
Thqr furthemro stimci :hat both of these factors are found in certiin
plant tisaucs (Poe&to anl bara:*).

       3r. Lvaq~ and Dr. L1orgc.n during the p%st ysrr 2'klvS

grX+.tQ* extended theso observations.  mey have sholva that yellow and

white turnip, czrro t, beet, parsnip, nrxl z:ee t potato, when added to
fl-aid media possess the same growth stirxilating action as does white

potato.  Moreover, they have found that these vegetable tissues not
only permit `&e culti-Tation of the so-called hemoglobinophilic organisms,
                                  .

but t&at they aiso greatly favor the growtii of other entirely unrelated

or*ni sms . . For instance, in the case of pneumocoecus, not only is there
a marked kc&eration of growth in media contsinlng fresh vegetables, but  ( `,;,
                                                                           : ,
              5                                            \ -3' i. `.      "5 I
a seeding, too minute in itself to initiate growth in plain broth alone,      .;i.

will amply suffice `to Induce abundant multiplioa.tlon in the sake medium
to which small pieces of sterile, unheated vegetable &we been'added.
Moreover, in the slant tissue medium th3 zone of $,Jrogen ion concen-

tmtiozi ~1 tYi~ i-lhich grovrth can be initiatscl is conside:%bly extanded

begorxi t3e lirits of the range in ordinary 3oulllon. Ii1 a&lition cartair

ot`ner bacteria, Which ordinarily fail to grow: in cha presence of free

oxygen, nrultiply in a medixx containing fresh plant ti ssua even though,


no precautions are taken to exclude aif,  It :s evident, therefore,,     E
                                              J

.tbat the pk6enca `in media of certain substances contained in fresh

plant tissue not only sqplies the necessary factors for growth of

the hemcglobinophilic bcilli but furnishes the necessary require-

,. 1

ments for the cultitntion of other bacteria which ordinarily multiply

only under .certzin restricted conditions.

         The exact nature of the substances contained in plant

.tissue upon which these properties depend is not yet detedned, but

the studies so fzr node suggest that the growth inducing properties are

related to the presence of certain oxidizing and reducing enzymes in

fresh plant tissues ae well aa to the presence of so-called accessory

food substances .

Chemical Basis af Methemo~tlobin Formation b?? Pneumococci.

: Dr. Av6~ and Dr, Mor@n.

: On6 .of the most btriking and characteristic properties

of pneumococci is the effect which they produce on hemoglobin, chang-

ing it into methemoglobin,  This is made evident by the change in color
which the merJi~+ under&es when p~urno&eci .are .cultivated on blood

rosdium.  This ph6ncmk~n ha6 famed the ba6Zs of considerable study
in this.Hospital in the p@lt, as. ika6 thought pqsqIble that it had   .,
                                                  .* 
a.mch deeper ih.&ficbnce in connection with t&e'.problem of infection .
?h+ Ai lobvioue at first d&t.                                               .
                                                                           

                            I `_  In studying t+ pb3nomenon several~ '
            .                                                            
years a@ Dr. Idle -found that change .f rom hetig$?bin to methemoilobin   

                                                                           _
     ,.                   
' occurred only when livin& :organiams .were present, and it seemed that     @

the reaction was-clo$aly related to growth phenomena and could not be

induced .by extracts or filtrates of. the organisms.    

        Avery and Cullen during later studies on enzymes of tho

pneumococcus =de observations which indicated that under certain co-n-


ditions tho tnnsforzz,tion of hemoglobin into mzthemoglobin might be in-
duced by extracts of pneumococci or filtrates of the cultures, no living

organisms being present.  In other words, it sezmed that the reaction
Is probabi;r dw to a substai%ce, probably a ferment, which might be sepa-

rated from the bacteriai ~311s.

        During the past yccr Dr. Avo ry and Dr. Morgan have nude
still further observations which ar3 highly suggestive that this pheno-

menon nqr be &.IB to a simple inorganic substance formad in thG culture

medium during the growth of pncumococcus.

       On `testing certain pneumococ~us culture filtrates for
the power to prod;lce methesw,globin, it was four.1 that while these fil-
totes had little or no p wrer to produce the reaction on lalred blood,
they very rapidly acted on crystalline hemoglobin in watery solution.

!fhis discovery wae U only .?nde possible through the work of Dr. Heidsl-
berger who had prepai*ed a large amount of crystalline hemoglobin by a
ZXSJ method and primarily for another purpose.  They were nwv able to
study in detail the action of the filtrates of pneumococcus cultures
on P~~ococci and have found that frse access of air to the culture
during &with is esSentia1 for' the reacting substance to be formed.
%Y have found also that if reducing substances or titalase bo preselit

in-the rkiium the fowtion of the reacting substance is entirely in-
hibited, or mere likely is `destroyed as rapidly as it is formed.. Further.,
it has be&found that the `substance first rrakes its appearance during
I the period of maximum growth of the organisms, This indicrttes that it
is a product of cell metabolism rather than the resultant `of. autolys~s.
Th3 readting &&stance is thermolabile, being destroyed by exposure `to
the temperature,of boiling water for 15 minutes..  In a medium .in which
it has once formed It may persist for several daysi the exact time de-,


I
  I

  !
  I

0 .t

gandhg on %a kezct:c;l cf `;hz ~~lt-~`a fluid ;nd khs tempa*tura at

which it is prssefied, jcing less stabile in alkaline than acid SO-

lution and suffering progressive Loss in potency v;ith expostire to in-

crJasir,g tempe nature s .

            In 3d3ition to Al--c
                 k.SJc propertiea t'his substance gives

certain chemical reactions q.Trhick. ate indicative of Its nature.  For

instance, flltr:.tss of p;le~.~~occ-~s cultures containin this substance

give a positfve bonzidin reaction rlhich iwctive fil:rates foil to give,

This test is based on tho fact that in the presence of A cLc.talytic

i

agent, peroxidase, solutions of bonzidin give a blue color on tha nd-

di tion of bdrogon peroxide.  The benzidin test, therefore is recog-

nized as a delicate method for the detection of hydrogen pcroxido.

It seems justifiable, therefore, to regard tha benzidia reacting sub-

stmco In pm coccus filtrates as hydrogar? peroxide, and since only

filtrates giving this test ~rodzce methemoglobin it soems probable thus',

the substance on whi& the latter reaction depends is hydrogen poroxida.

This view is st=ngthensd b the f&t that a, solution of hydrogen    I

peroxide, even in great dilution, is capable of changing crystalline

hemoglobin into me themoglobin.

. .  ~Moreover, the sam? agents which tire found to Cause i-tic
                               _

-*ion of the culture filtm~es~slso render hydrogen peroxide inactive

as. regards me themoglobin, f om tion. . The fact that these agents are

destroyed by catalase explains why culture filtrates have no action on

whole blood since in whole blood c+taIf~~eis alv&ya present.

Growth Inhibition by Pneumud~ccus Filtstes,

       In a previous rqort it was pointed out that pneumeco.-.ci

fail to grow when reinoculated into filtrates of culture fluids in wili 5~.

they have previously grown.  !Fh$s phenomenon of growth inhibition V,ZLS


                        e 7) \ . ) `l&9.
                                             * , -5 .:

fourd to be depandent ir, gctrt at lxst upon the exhaustion of some IX-

tritive substcmcc in the medium.  Experimental evidence indicated that

the substance exhausted by th3 initial growth of the pneumococci and

in the absarxe of which secondar; growth can not be initiated, is

probably of c-mbohy3rato natura, since the addition of G readily fer-

mentabla sugar', evm in sz.11 amount, to exhausted filtxtes suffices

to rostore the growth szpporting property.

        The discovery that pneumococci produce pornxite during

gro-<rth and th+t this compound can be readily dzmonstnted in aLt;llre

fluids adds anothor factor which must be t&en into consideta+,ion ir.

dealing with thi3 complex phenomenon. Hydrogen percxic'a excrtd a marked

restraint upon growth of bacteria, and in sufficient concentntion is

def ini tely bacteriacidal.  The presoncs of this substance, therefore,

in culture fluids might itself ox-plain, in some instances at least, the

inability of organisms to grow in CJiture Ziltra';es.  It hs, indeed,

been found tlmt Staph.ylo~o~c~ s aureus cannot be mde to grcv in the

filtrates of pnmmococcus cultures which contain p!arouida.  Proof that

the peroxide is initself solely responsible for lack of growth under

these conditions, is found in the fact that Stap`hylococci will grow

in tirese same culture fluids after the peroxide has been destroyed by

heat or lost by deterioration thr.%ugh aze. Ertner! Stqhyloeocci grow
                               

abundantly in culture filtmtes of gtieumococci ii.1 ~Li31 tL3 fo~~~~tion

Of peroxide has baen prevented.

        In the case of pneurnococcus, however, growth inhititioz

Of this organism irk its' own culture fluids ,is conditioned prlmaril;; b;
the exhaustion of f6rmntable substance, and only secondarily by t?le

presence +f the peroxide, since in'oulture filtrates in which percAd;?

is not present a second growth of pnemococci cannot be initiated -.11-~1~ss


. .

                        . . .
addi timal czrbohydm te i s zddcd.

Producti.bn 9s` Peroxide b.v Bacteria Other thm Pneumococci.

The discovery of peroxide fomation by pneumococcus

b

has led to the study of the occurrence of this compound in the culture

fluids of other cocci. It has been fetid that under similar cor& tions

of growth Streptococcus viridans, an organism closely related biologi-
cally to pneurnococcue, produces peroxide actively and promptly, this

substance bein;: readily demonstrable in culture filtmtes within the

first 18 hours of growth.  The production of peroxide by hemolytic
                          . .

streptococci, ,however, is less constant dnd its form&tion nlways~ de-

layod.  Of 23 strains of S. hemolytlcus, 8 failed to give the peroxide

reaction at any time, while the remaining 15 strains gave a positive
reaction only after the cultures had be& incubated 86 to 110 hours.

Only 2 strains of Staphylococcus aureus havd been tested and both of

those failed to form peroxide.  It is interesting in this connection

to observe that Staphyloe~cous aureus possesses a marked oatalyase

which is capable of splitting hydrogen peroxide.  This fact may account
for the absence of peroxide in culture fluids of thie organism.

i@~~al-Nature of Soluble Specific Substance of ~neumococcus OriPin..
                               .
DF; Aver and Dr. Heidelbarzer.                                     .

      %e study of the soluble, -specifically preoipitable sub-
8tznCg which is excreted in the urine of' patients suffering from pney-
                                      .' .
mania is being continued, !Chis a&ivq substance. is `derived from the,

infecting organism and passes the kidney tichanged in specificity and
appears in `the urine in a for& which reacts only with ahtipneurnococcus
serum of the same type as that of the infecting pneumococcus. The
study of this specifically reacting substance has shown that it is not

protein in nature.  It iso stable $n boiling solutions; is not dialyzable


dilute trcotic acid. nlc ncutmlize d x,d concentrsted filtr:tc is now

pol;rsd into 10 volux~s of acotoxe, the aqueous solution of the result-

   ing procipit?.te is then dialyze1 until salt-free, and reprecipitated

   first with ace tone and then wit:? absolute alcohol.  !Fhe specific sub-

   stmce differs from rumy of the im_rxtrities accompnying it IT? not being
  precipitated by phosphatingstic acid or mercuric chloride and in being
  insdluble in hot glacical acetio acid.  The purified preparations have
  been found to retain calcium very stubbornly, but ara still highly
  specific aftor this is removed so that the presence of caloium doee not

   appear to be essential.  One purified sample which has been tested
  contains 65 nitrogen and practically no free amino nitrogen: but on
  hydroloeis yields about 50 per cent of the tot&l nitrogen as amino

,   nitrogen and 20 per cent as ammonia.  About 1.56: of sulphur was also
  found, and if this is an actual part of the molecule it would indicate
  that the specific substance has a moTecu$ar weight of at- least 2000; +'

       A product with practically identical properties'and an&
lytical figures is obtained by dissolving inshed pneumococci in anti&
formin and purifying as in the case of urine.  ft has recently been r"'
                                                                           .I._'

found that a further inactive fraction can be split off by precipita-

ting fractionally with acetone and it also appears that the active
substance is not a polypeptide or proteose, as it is not precipitated

bjt mercuric chloride in neutral solution.

       The serologic type specificity of the reacting substance
remains unimpaired by these chemical Brocedures.  This pen-d ts the em-
ployment of a delicate biologic test :to detect the presence of the active


                                                           I' * 1
                                                                 `.

substance throeghou t t'ne irar 1. ou; chemical manipulations incident to the

search fCr its StiTlCtUIYLl constitution.  The conditions seem excellent

far determining the chemical nature of this subst3nce with which the

type specificity of pneumococcus is so intinwtoly bound,

Oxsvcen The raw in Pneumonia.

        Brief attention was given in the last report to the

question of the administ;~tlon of oxygen to patients with pneumonia,

Snci tha construction of a special &amber to bo used for this purpose

was briefly comnontcd upon.  The designing and construction of this

chamber was undertaken two years ago by Dr. Stadio. With his departure
`for Now Haven the work was continued by Dr. Binger. Dr. Stadle's re-
port of his work appenrod in March, and although the problem is still

under investigation by Dr. Binger, who is acoutnulating further data

from the study of patients In the chamber, it may be appropriats now
to discuss with some greater dotail the questions involved and to de-

scribs a little mom accurately the apparatus employed.

The employment of oxygen as a therapeutic agent is not

new.  Shortly after the discovery of oxygen, and particularly foJlow-
.
ing the demonstration of ths role of ojtydation in life processes, the

inhalation of oxygen as a therapeutic measure began to be employed, . .:

Ever since then it has been employed to a greater or less extent, ,the

frequency atid ds&ee of its use tmrying in waves like that of fastion j

in dress.  The rational of its usa, however, has never been firmly    .:

established and the method of its employment has been a varied as would

be expected under the existing conditions.  It may fairly be said that

a very few years ago the general opinion of physiologists was that the

therapeutic use of oxygen was entirely irrational and unsupported by

experimental evidence,  Consequently, although oxygen continued to be


.
           .,,, 353

                                                                  I `,, , :I

cqlo,:lcd in cer'iain ci;ndl t.icn; , its use became c*nief ly a death-bed

assure and, utiortunztzly , in most cases a measure employed chiefly for

the purpose of creating an impression of great endeavor.

       During recent years, howwer, there has occurred a great
increase in knowledge concerning the phenomenrz of oxydation and reduction
in the tissues and concomiq the r&s played by hemoglobin in the

respiratory mechanism.  This advance is due largely to the accurate

quantitative work of Danish and English physiologists, and to the work
of Van Slyke In this Hospital as well as other American investigators.
These studios hove again supplied theoretical support to oxygen therapy;

evidence has beon accunrJlated to support the view that in cases where
the blood passing through the lungs is unsaturated with oxygen 1 t should
be possible to Increase the degree of saturation `bjr Increasing the per-

cent&-g Of oxygen in the alveolar air. `Whether this would be practically
possible in cases of infection of the lung could only be determined by
the direct detetiration in thee9 cases of the degree of saturation of
the arterial blood after it passes the lungs,

       Now, the work of Dr. Stadie has rmde the direct investi-
gation of the arterial blood possible, so that it has seemed important

that the question of oxygen therapy should again ba investigated, 5p the
hope of getting evidence, based both on theoore tical considerations. qnd _ ,. -...,
                                                                           : .
practical experience, to justify its employment, especially in the treat-

ment of -pneumonia, but also in the treatment of cardiac and other dQseases
in which there is apparently a deficient oxygenation of the blood in the

lungs.  To mke this study of any real and lasting value it was obvious

that the administntion of the oxygen should be made under conditions

where the amount could be aecu$ately Gontrolled, where the dis.comfort to
the patient should be reduced to a m$ainruzR; and where %he investigation
                               ,,i

.;


Of fhe patient as ragar2.s cnalysis of the blood gases, studies of the

respiratory movements, etc. should not be interfered with.

          The old0r :.lothods of adminis tcring oxygen were very un-

satisfactory.  When oxygen is allowed ?o fl0.~ through a funnel held

Over th,? paticnt'sfm and h,: t,i:us brzathos a mixture of air and oxygen

of unknown amount : it ?L-LS bczn found that diffusion of oxygen occurs

so rapidly that t&T ..b oxyi;cn content of air in the Pwlgs is but little

lnflucnccd, or influcncod in 2 very inconstant 2nd irregular manner.
The use of masks held tigh`,,Qovzr the patient's mou:h :.nd nose causes SO

much discomfort and is so disyrassing that it c-tn bo continued only over

very short periods oi^ tine.

         After d=rc cocsidontion it become evident that to solve
th0 problem whether cr not thz inhalation of oxygen is `beneficial and thur

to detert-iine the optimum amounts to employ, it ivoulh be best to construct

C chamber in which the atmosphere could be regulated at will, and large

enough to contzin the patient and the necessary apparatus for investi-

gation, and also suf2icientl.y large eg that the nursing within the chamber
could.be aa effectively done as though the patient were in the open ward.

A chamb~3~ of th$s kind has ~JCKT been built in one of the
                    `\

`Kurds bf the Hos'l)itai and after r--any changes and much effort on ihe part
Of Dr. F&die, and later Dr. Binger, it has been made very eati&actCjry so

that p%tients may be kept ;in it for days, or even c.veeks, in an'atmosphere
corrtaitirii 5074 of oxygen `or even more .

        A picture and diagram which give some idea of the construct

ion of this charn3er are shown on the following page:


, --. --_
I .. .--*   ---_ -_

  .
i     : .-._. AlA..Zlr) .m

:
I:

`i


            `ITi,e phi> L 3 ix xi. i- .i i zlieg;-2m indicates tie coastmction of

the ci-ccbe r ,  While the c'harnbsr is not absolutel; air tight, it has

baen so constructed by msans  o f fzlt gaskets on the doors, etc. that the

leakage is vary little. Thoro are tnro doors, one leading directly into

tha dambar for the adr.ission of the bed, and a second ona leading

from the vestibule or lock.  `E-B nurse or physician enters tha tightly
closing lock closet, quickly closes the door behind him and then through

a second tightly closing door entors the chamber.  In this way loss of

large amounts of oxygen is avoided.  A food lock is provided so that
food and othir small articles IYXL~ he taken in or removed without great

loss by diffusion.. !Phe oxygen is delivered from tanks to openings neati
the `floor of the chamber.  The air is dram out from the roof by means
of a fan and is then passed over rofrigention coils and readmitted nea2
tlhe floor,. a constant circulation of air being kept up.  The diagram chow:.:

the air passing through a scrubber, that Is a case containing soda If me,
inserted for the purpose of removing the excess of C 0~~ It has been
found, hoxevek, much`more eatisfacto.xy to have tke scrubber directly
in the chamber and to employ a se&d SIIEU fan for the purpose Of forc-

ing the air through it., A very satisfactoFJ variety of soda Iime has
now been obtained which is comparatively inexpensive and'with which the
C 02 content of the chamber can be kept under 55, even for very prolonged

periods.  While the aut3;;atic analyzsr devised by Dr. Stadie was a most
ingenious invention !t has been found to require much attintion, and a
vary simple met'nod of analyzing the air has been arranged by Dr.. Binger

so that t.he nurse can take samples of air as of ten as required and with-

in a fe!v minutes determin,e the 02 and C O2 content.. V?ith a vary little

attention and care i,t has been found possible for the nurse to control

the a&xi s s ion of oxygen so that the percent of oxygen in the air within


o ???
? ?
,. 1.

the chamber is kegt zt LII ?o???? uniform 1~~1.

        Whils In t>e first experiments that were rslde it was

found rwcessaq to use ltrgo amounts of oxygen, the loss by laakaga,efc.

has n0.v been so controllad ttut the chamber can be properly employed at
a cost of only $4.00 per da:, for oxygsn.

        Pith this chamber and with the methods previously

mentioned It is note possible to determine before the patient is placed

in the chamber emdtly the degree of oxygen saturation of his arterial

blOOa, and then, af'ter a patient has breathed an atmosphere of knoll

OOmposi tion for a given length Of time, to again determine the degree

of

of

oxygan,'~turation and so to know the effect produced by tho atmosphere

high concentration of known degree.

      A number of patients have now been treated in this cham-

ber for mrying Lengths of tirns, one patient was kept in ths chamber

almost continuously for thirteen days.  One conclusion can now be draw'n

from these studies Snd that is that in most cases tho anoxamia, that is,

the oltygen satulat3,on of the blood, may be relieved. Whether, however,
&Is is of aqy i&al importa& 'in the xmtkome of the disease only .myzh

tsora p2aOtical'.~e~rience will Tail.. ' The~dmpwssion so far gained,, how-.
ever, 4s th&:the &&d'FB of cfJlliea3;~.virlue;~t.patients treated    '

in.'thia Wy~&e%rprowd.'and their chances .for.293covery become greater.
fb 5eem5 off-II& that this &ould be ths, `cme and that the :vlief of
this condi~ion'of anoxemia, which is certainly abnormal;~.shOuld aia %h.e

patle'nt in recovering. The mechanism of xthis `relief, h&ever, is diffi-

cult to Iknow.  Certainly the patient'-with pneumonia is not

a deficient emaunt of oxygen eupply to the tissue. In the

suffering from

case of anemiL

of moderate grades, for instance, tbe'amount of oxygen sqplied to the
tissues may be much less than in ths case of pneumonia and still no


                                                o ?? ?
                                                                ? ?? ?? ?
                            ????

  symptoms be m2r.i ic s t ,  1s Starlie hhs polntcd out, however, the tension

at which the oxygen is delivered to the tissue mxy be very different

  in the two instances .  Those ar:d reiative rzttcrs must be studied bc-

fore a clear idea can be hzd 02 tha value of this forr,j of thempy. The

fZ.cilitics for study of thz problem in the Hospital are now excellent

  and it is pl2nncd to continue this work durlnz the coming winter. If

.  ?O??* therapy proves to be useful, in order to make tha method. gen-

erally available it will probably be necessary to devise some simpler

  arrangement than the chamber.  It rmy be possible to construct a rub-

ber tent, to be placed over the bed, which will be effective. Dr.

  Bingor i.s new at work dosigning an arrangement of this kind. For hos-

  pitals, however, a chamber such as built here will probably always be

  the meet satisfactory.

Expedition to the Andes to Study the Phvsiolop<c Effect of High Altitudes.

        In November, 1921, Dr. Binger was granted leave of

absence to join an expedition to the Andes, which had for its object

the study of problems closely related to those involved in the question

of oxygen thenpy. This expedition, financed by grants from the Royal
Society and other institutions and by a grant from the Rockefeller In-

stitute, was headed by Joseph Barcroft, F.R.S.  C.B.E.. the physiologist

at Kings College, Cambridge) who is known chiefly for his contributions

on the Respiratory Function of the Blood. The, four Americans besides

Dr. Binger were Drs. Bock, Forbes and Redfield of Rarvard UniversiQ

Meditz.1 School, and Dr. Harrop of the Presbyterian Hospital. These men

were joined in Lirnz, Peru, by Mr. Barcroft 2nd Dr. Doggart of Kings

College, and Professor Meakins of the University of Edinburgh.  Through

the courtesy of the Central Railroad of Peru, a British corporation, a

baggage car was obtained which with a little c-rpentry was converted


                                                                 ,\ .I

into a splendid phyjic;oqlc ;c?b3ratory, and a i"reight car which se,rved

a6 a store for supplias.

         After a little more than a week at sea level, while the

laboratory car was being equipYc. --d and prelimirary observations were being

mada, the partjr procecdcd upwcrd on ths famous Andean rsiiroad to an

altitude of from 14,OCT) to 15,030 feet.  The terminus of ona branch of

the railroad is at Corro do Pasco, an ancient Peruvian town of some

3,000 inhabitants,  fIere the expedition rado its headquarters and car-
\
riod out tho investigations planned at sea level.  Cerro de Pasco is

the sito of the great copper mines, originally worked by the Incas and

Spanish Colonials ani in recent timss chiefly by American interests.

The officers of the Cerro do Pasco Copper Company wore most hospitable

and cooperative and, indeed, took a great interest in the work of the

expedition which was not without its practical bearing. Throughout

their sojourn on the mountain top the personnel of the expedition lived

as guests of the Cerro de Pasco Copper Company in the Company Ho tel.

         Tha rapid transition from sea level to an elevation of

15,000 feet was not too well borne by the members of the party. Indeed

all of them in greater or less degree succumbed to the condition bown

locally as 1t8errcche~V , which is the Peruvian name for mountain sickness,

This is a rather distressing condition, characterized by intense head-.

ache, nausea and vomiting, sleeplessness, shortness of breath, r@id

heart rate and often fever and visual disturbances, Some of the party

WeI33 incapacitated for a day or two, others for a week. Mountain sick-

ness is now known to be due wholly to the low oxygen pressure in the

atmospheric air found at high altitudes.  It was the acclimitization

t0 this diminished oxygen supply which' the expedition undertook to study,

          The subject has been undar investigation for more than


half a century.  Physio!.ogists of many lands have made bailoon ascen-

sions, climbed to the tops of mountiins and lived in steel c&%bers

undar diminished atmospheric pressure to study the consequent bodily

c'hangc s .  One of the most noteworthy e,xpedl tions was that headod by

Prof. ila1dar.e of Oxford to the summit of Pikos PC&, in 1913. This

group of investigators fott?C wk3t Haldane bad proviously balieved,

that under conditions of oxygen want, the lungs had the ability to

socroto oxygen just as the mucou,, p membrane of tho sto;?ach secretes

hydrochloric acid, and in this mnor the nor.-al prsssure or concentm-

tion of 02 in the circulating blood is kept up, in spi te of the re-

duced pressure of 02 in the atmospheric air. Recently new methods of

investigation have been devised whit k have justified a reinvestigation

bf this problem.  It is no:7 possible to take samples of arterial blood

and analyze them for oxygen &nd thus ascertain to what extent the ar-

terial blood is saturated with oprgen. `Hnowing its capacity for' oxygen

and its oontent, we can express quantitatively the per cent of satura-

tion. Mr. Barcroft used this tech&&s on himself in 1920, when for
                                                                        

six days and under conditions .oP considerable `discomfort and, indeed,
i . . .                                              .' `.`, .,
hardship, he lived in a steel c&nber'&der greatly diminished at&d@

with oxygen and containing no more than could be accounted for by

simple diffusion of atmospheric oxygen tiwougd the

lung tissue into.

the blood stream.

Baldane did not accept these results as conclusive I

because of the relatively short exposure of the subject to low atmos-

pheric pressure.  And it was largely to settle .this very inrportant            i
                                                                           I .
                                                                           11,


controversy tkt Mr. krc:=of'; orga:lized the Peruvian Expedition and.sel-

ect$d for tk work a plxa x-hsrc hens h?d lived and had done hard

physic21 labor for many generations at much diminished oxygen pressure,

and ?t ',ho sa:ne L,imz a plscc accessible by rail and thus ideal from

th3 point of view of tnn;;Tort.inl: the ncczssnry equipment .

        FL czpciitlon di-;idGd L ts material for study into three

e;rou,7s (1) tha natives, (2) :ke Aqlo-Saxor. rcaid3nt engineers, 6ome of

vr:hom had been at Cerro de Rmco for five yc3r3, (3) its own personnel.

One of tt3 first obscrvatione which it made GVS tho mar&d and almost

u3lvcrs~l presence of cymosls,- bjr which we nznn a blue color of the
  I

skin, r)3rticularly of tho chocks, oars, nose, lips, finger mils.  This

we know to be due to an increase in the prescnce of reduced or unoxydized

Hemoglobin - the red pigment in tho blood that chemically binds and oar-

Bias oxysn.  Analysis of arterial blood taken from subjects of all.

three classes corroborated this observztion, and showed, in fact, tha

presence of oxygen unsaturation to an extent v&olly accountable for by

the diminished partial pressure of oxygen in the air.

       A great variety of other p'hysiologi~cal phenomena, deal-

ing with circulation and respiz%tion, were inquired into, These are too
numerous ani technical to include in this report.  One investigation '
Which Was of cbnside'$able practiml interest to the Cerro de &Co' CC&"~

per Company was `the study of the s&called lldiffusion constantI of oxygen.

A method of measuring the rate at which 02 passes through the walls of

                                          

the air sacs of the lung into the blood stream has been devised by.M.

Gogh. Employing this method it was found that those members of the

Expedition in whom 02 passed slowly were more seriously affected by high
altitude than those in vghom 02 passed rapidly. This offers the possi-

bility of detexmining 3.n advance whether a given individual is or is not

,


(3) Certain chsmical cbang~s in the blood xre obssmsd which
  could bu intcrpretcd as s0rvir.g fo incxaso the blood's af-
  finity for 02.

* (4) A variety of anthropological moasurements wore made, indics-
    ting that tha A~u =`cc;~ has pro?osfionat3ly a larzor chest th,az
    the Anglo-Saxon,                                                      11
                                                                           ,i

The results were presented by Mr. Barcroft at a series of

lectures given at the Lowell Institute, in Boston, in February, 1922,              :

and have since been presented by Dr. Bingcr and other members of the ex-

roport Is about to appaar in the Proceedings of ths Royal Society.

Studies of Lung Volume.

pedition before several medical and scientific societies. A complete

Dr. Binaer.

been stirmounted so"Wt it"is `now applicable to $atiente who are capable T,`..!&
                                            P .( ,~            
                                                ~I. .A _.          `b
  (-,.+`19~L,.v' iF."..i.,:`fiF c"*rq; yc?c:.*-.~y& :`cjtl"$ ;:: . . . _. _ "`.`: .-:IU*4<   `?a
of veryeIittSe co-operation.                  `.? `! $,;: ,yy$,f;,+ ;f, : :`&i
                                                                   . .          -,' *. I
                                                                           .;.
                                                                           /  .f ..J
                                  .
      By lung volume is meant, not the volume of lung tissue,

but the volume of air enclosed in the air sacs and respiratory passages.

The maximum amount of air which can be enclosed in the lungs on f arced

inspiration is known as the total capacity. Of this only a portion,- in
normals, roughly, 72$ - can be expired,  That portion which can be e?rpired


after forced inspiration is kxowx as the Vital capacity", and that

which cannot, but which rexains in the lungs, is known 2s the "residual

air".  In no-1 subjects the vital capacity bears a definite relation-

ship to certain other body measurements, such as height and weight and

surf ace area, and, knowing those measurements, the vital capacity in a

nonral individual can ba predicted to an accuacy of about 105.

Employing these normal standards it has been found that

,:

in patients with heart disease tho vital capacity Is diminishsd and

that the degree of reduction nnx quite closely parallel to the severity   I

of heart fzailure  Since this diminution in vital capacity is undoubtedly

.

closely related to the phenomenon of dyspnea or shortness of breath

80 comnonly seen in patients with heart disease it is of great lmport-

ance that more should be learned of the nature and cause of this m-

duction.  It is obvloualy important to learn whether the reduction in
vital capacity involves a reduction of the total capacity or whether

vital capacity alone is reduced.  If vital capcity alone Is reduced and
the total capacity remains no-1 a proportionate increase in "residual

aiP must be present.  Now, vital capacity can be measured with relative

ease.  The patient needs simply to take the deepest ,breath possible and.
then to blow into a movable tank, called a spirometer, , /
      To measure the air remaining in the lung after foroad.,,
expiration, or the residual air, is far more difficult.. To determine

this, indirect methods must be employed.  Such a method has been de-

vised by Dr. Binger and was described in some detail in the last annual:

report.  The method has now been improved upon so that it can be easily
applied in ill patients and it has now been eqloyad in studying a

number of patients suffering from pneumonia and heart disease.  These

studies have shown that in some cases of heart disease, apparently the


t-%:*iy oIl?L, the residual air may be slightly increased.  This lends

XJ!?O 1-t to th-=: theory prevalent in the lital%ture that the cardiac pa-
?imf keeps ?iis lungs in a more inflated position than the normal. In
the mo:3 sovarely ill cardiac pticnts, however, especially those suf-

fering from evidxce of ccxgcstion in the palmonary circulation, tha
rasid-al air as wzli as :ha vital capcity have been found to be dim-

inished.

       Bat there is a close relationship between the air space     .

in tha lung and the condition of tha pu.lmomry circulation is apparent.
fit prcSc?If Wc hrr~e no m'thode for rlakinq iimat observation 0x1 the

lessor or pulmonary circulation which plays 80 large a role in the ?stho-
logical-physiology of heart Giseaso. The onl:r azsro&ch me have to the

state of the pulmorary cinxlatlon, besides 'the ordinary methods of

';j
!

@yaical exUi%tion, is through a study of the air content of the lung

or lung volume.  It is very probable whera there is stagna,?ion in the

pul monar; ~irc~~la';ion tSere is encroa&mel?t on the air sacs of the lung
and diminution of the lung VO~UEE,  A vicious circle is thus established,
stagration of blood gives rise to'diminished air content and diminished
air content Sn turn is followed by imdequate ventilation and imperfect
gaseous diffusion from and into the blood. It is possible that forced
deep breathing in the cardiac subject may lead to increase in lung volume
and to decrease in the degree of etagnation in the pulmonary circulation.
       Ike study of lung volume in heart disease may give import-

an% inforkx3tion concerning:

;i;
!I
, :j
,;:

(j-1 the meahanism of cardiac dyspnca;
!2> the condition of the ptilmonary circdafion;
(3) the problem of gaseous diffusion in the lung.


         In ;?n.? XlGillf, LIZ. Oinpr has made a few preliminary obscru-

vations on the cp3s~i0~ of lung ~0h-f~.  Xere, as in the cardiac patient,

the sir Sacs of the lu;ig sro onzroachsd -,~IOII xd 3vcn obliterated by

congested C-a~ilkriec arxl by `Y-G deposition of fibrin and exudate. As

Yet we !ELVC no Tory satisfactory correlation between the extent of pul-

monary involv6mont and the cour39 of the disease, particularly the ap-

pearance of such untoward smtons as mpid and shallow breathing and

CplOSiS.  It is hoped that a quantitative study from day to day in a

pneumonia patient may help us find such correlation.  It is knowledge

of this sort that can give us the information necessary for rational

oxygen the rapt,  Eventually v/e will need infonmtion about the diffus-

ion of gases in the lung of the pneumonia patient and to got this in-

formation it Is necessary to measure lung volux-0.
       The method of measuring lung volt in prk%mOnia patients

differs somewhat from that employed in the cardkc patients. we tSnnc%
get a satisfactory determination of the total c@.ci,ty, because the in-
dividual sick with pneumonia is incapable of a forced- deep inspiiation

and expiration. ye must therefore measure the volume of the air in the

lung during quiet, no-l, breathing, For this purpose Dr. Binger has
                                                                          .' -:

cho'sen an arbitrary though, to be sure, fairly constant point in the

respiratory cycle, nameQr,the p osition at the end of quiet expiration..
Lung volumes are measured at this point. At present Dr, Binger is e2b

gaged in the study of the rest$ng eqiratory position in a series of nonml

individuals for the purpose of establishing, if gossible,, some empirical

constant whereby the measure can be related to some other physical factor,

just as vital capacity is related to surface area.
      It is hoped that having established this factor, we will

know what the porr&rl resting expirafory position should be, and then,


Low much the patient undar invsstigaticn deviates from it, and how he

agprO%heS it during conw.lescence .

       :The recant work of Xrogh on the respiration Of insects

`has shown at what point the respintory trrscts becomes sufficiently large

to nccessiL%tc the res>irztory mot;on.  In the srialler insects simple

diffusion of air into the tubules is sufficient to mintain the oxidative

processes necessary for lifa.  In large inset ts where the tubules are too

long to permit diffusion alone to maintain the necessary oxygen concen-
tration in the air sacs, respiratory motions are necessaq. We have no
way of measuring the size of the respiratory tract in man, except by

measuring the volume of its air content.  With this knowledge, and par-
                                               .
ticularly with a knowlsdga of Mriations in size during diseased states,
:qo m;iy have valuable infonration on tha facts controlling rate and depth

Of respiration,

mnosis.

?r. Lundsgaard and Dr. Van Slyke .

       Considerable attention has been given by Dr. Lundsgaard
and Dr. Van Slyke to a consideration of the theoretLca1 and practical

aspects of cyanosis, basing their st$y on a historical review of the
literature and on the recent quantitative blood gas estimations made here

and by Dr. Lundsgaard.in Copenhagen.

         L L Cyanosis is the name given to a peculiar bluish color of
the skin and: ~cous membranes saen in various abnormalities of the cird

mtory and respiratory systems,  It has- been known to be dependent on
@rigs@ $n the blood, particularly changes in the hemoglobin, and In most
          1.
asee $8 related to an increased amount of reduced hemoglobin in the cap-

illary blood.  Dr, Gundsgaard, through quantitative studies, has shown

that the occurrence of cyanosis is directly dependent on the absolute

i
, 2


amount of reduced hemoglobin Tresent in the capillary Slood, rather t-ban

On the ratio between it and tile amoilnt of oxyhemoglobin present. As a

result of a saries of estimations of the oxygen saturation of the ar-
terial and venous blood in nom-al persons and in sick persons showing

various degrees of cyanosis, he has determined that in general the pres-

ence of at least 5 grams of reduced hemoglobin per 100 c .c. of capillary
blood is necessary before the skin acquires the bluish tint called cya-

nosis.

        Now lack of normal saturation of the hemoglobin in the

capillary blood may depend on one of seven1 conditions, chiaf of which

are, first, failure of the blood to undergo complete oxydation on pas-

sage through the lungs and, second, mixing of oxygenated and unoxygenated
blood in the veeaels , duo to a shunting of part of the blood from the

arterial to the various side of the circulation, this part of the blood

being unexposed to aeration in the lungs.  Drs. VQII Slyke and Lundsgaard

have subjected the known facts concerning the latter condition to a

mathematical treatment and have deduced formulae by means of which in any

given case the fraction of blood which fails to pass through the lung

can be estimated, if the degrees af unsaturation of the venous and of

the arterial blood are known.  By means of these forcrulae they have es-

timated that for cyanosis to become evident at least une third of the

blood must ~8s through the shunt and be unexposed to aeration.  This

is much more than was previously thought to be necessary but the con-
clusions from the available data seem to be valid. In any case, their

treatment of the subject has brought much clearness into a very complex

and difficult problem and will undaribtedly be of great practical value

in the rational application of oxygen therapy. Their paper dealing with

the whole subject of cyanosis will shortly be published.


ILeuqa',i c Feve r .

Sinfx tHe last &IXG,\i report iA cllr2ice.l stiLdy of .rhcuF

matic fever b;t Drs. Wift, Boot6 and :11111;?1* has bser. facilitC.tel `Cy great-

er ease in securing slitable patients and by th? cooperation of those

prevj ously &clmi t ted.  It seems more and more probable that. the disease

often persists in these patients for years and that the rolqses so fre-

quently seen are due to a lighting up of latent infections, Thus rha9-

matic fever IELY be tbmpared with syphilis or tuberculosis; disease9 of

known etiology, in ivhich there are often long periods of -iatency, followed

by relapses.  The analogy may be' carried still further: :.n tuberculosis

we know th3t the-most effective treatmsnt is the building up of the pa-

tient N 8 general resistance, and keeping him always generally fit. The

same may be applied to the trcA&ent of rheumatic fever.  It is a disease

accompanied by severe anemia and loaa of weight: the rate of improvemerit

usually parallels the recovery in weight curve; relapses often accompany

a fall in this `ourve.

`...' .Ebmratib fever tiesembles s~hhf3 in its tendency to re-

' `l+p& &ii in the manner some cf. .tG cl3nical manifehatidns respond to

certkn. d-s.. The le.sions .6f _ $&A&+ syphilis usua$ly Ustzppear when
                                      ., .'                                         :
                                           s
' the pattent .%8 gr0en, rmff%cietit f&o&& af potassium iodid&,. even though
this drug; doe&.ra&tTd;eat&y, the Treptim pallidurn. LikewIse, doses of
                                          I :`_

merMlry' or saiva~eiiti'~~&~fi&3ni to eliniinate comletely the Treponema
                                ! _

from tk;e bodp .of, the, syphilitic @iWont oft& ar'rest and remove secondarjt

lesions.                               .                 
                                           `,

   The action of the s'o-called specific anti-rheumatic drugs -

compour& of salicylic and*ph&yl-&xh&inic acid - seem to us to be com-

parab$e t0 the remedies ment&r,ed above. For nearly fifty years the


I

salicylates -izve bsen used succsssfully in combatting the fever and joint
inflammation of patients ;;rith acute articulnr rheumatism, but the reason

for this peculiar action is unknown.  The lack of knowledge of the cause
Of this disease is partiy responsible for the ignorance of tha mode of
action of the anti-rheomtic drqs.  Our clinical studies have elicited

ovidonca t&t cvcn thoui;:? FJt; = &,nts under ths influence of salicylates fail
to show such signs of activity of the irfoction as fever, sweating, rapid
loss of weight, and inflammation of t.hc joints, thero may b-2 cv?dence of

acute wrdiac involvcm,xt, and tic :-~i tlkrawa.1 of the lt71g 1 s o?`i;zn pron-ptl y

followed by relapse.
I) 1

        !Ih pro:Jldrn imdiatoly presents itself 0~' de:e;T-inicg
which patients are still harboring a latent infcctior. li?oi.r: to beccme

active i.S so03 a; salicylates are wi thdlawn.  It has been found that most
of these patients continue to have leucocyte counts of 10000 to 12000 or

,more .  Those mcdcrate degrees of leucoaytosis at times persist for months,
and close clinical and electrocardiographic stx%Iy of the patients indicate
that they are proba3L.y still harboring the infectious agent. Practically
all of the patients who have shown a normal number of leucocytes for sev-
era1 weeks have remained. free from relapses,  We now regard the leucocyte

curve as a valuable guide in the administration of the anti-rheunatic drugs.

       During the past year we have been studying th6 effect of
treating rheumatic fever patients with coqounds of phenylcinchonic acid.
These drugs have the trade names of atophan, or cinchophen, and novatophan,

neocinchophen or tolysin.  They were originally used in the treatment of
gout as it was found that they increased the excretion of urates by the

kidneys.  Later, it was found that they diminished the fever and relieved
the arthritis of acute rheumatic fever patients in much the same manner as

did the salicylates.  It has been alaimed that they `are less toxic than


the s;licylcte;.  Cha L  s 1b.d ,e s  j r.rlj c3 t 3 that cinehophen isuseful in re-.

lieving the dist.ressir-g acute syrqtoms of rheumatic fever, but that it ,,

is too mrkedly a gastric irritant; however, neocinchophen does not Mve

this distressing effect, seems less toxic than the salicylates, and in

thersrpeutic doses is especicll; less irritating to the kidneys. This

compound will probably not replace the salicylntes, but is a valuable

substitute in those Cases where the patients show an icXos:ncrasy to

the older drug.

Drs, Boots' and Cullen have completed the-; r qtucly of the

reaction of joint fluids in the various forms of arthri',is, and `have

shown that the rcaztion of the exudate in r11cum1ti-c i'evt-r ia practically

the same as that of the blood; while j n those jrLln,a~atj 611s ef joints
due to in%sion with hemolytic streptococci or staphylococzi'the reaction

is acid.  They have also shown that rabbits having an acute inflammation

of the knees due to infection with non-hcmolytic streptococci also have

exudates in these joints oc'ld in reaction.  Those findings point to the

improbability of recovering streptococci from the joints of rhewmtic

fever patients, and also show that patients satumted with sodium sali-

cylate could not have free salicylic acid in their joints.

Dr. Boots has made a microscopic study of the joint fluids

of rhemtic fever ptients, and found cell counts varying between 1000

and 32000; the higher counts occurred in the first days of inflammation

when the predominating cells were po3jrz;orphunuclear leucocytes; later,

large mononuclear cells were more in evidence.

         He has also studied the nature of the joint involvement

in patients with serum disease, and shown that small amounts of turbid

fluid having from 5000 to 20000 cells per cubic millimeter can be as-

pirated from their joints.  Both grossly and microscopically it is dif-


                     .,, -L7L
                                                            .*`f
                                                                     I. *
                                                  i (8  t

ficult, if not im>os;ible, to distinguish this exudate from that found

in rheumatic fever.  !%e gross signs of joint involvomont in serum

d.isesc zrt, however, much less m&cd.  Thcsa findings show that a

distinct lnflEL;%:ation of the joints rmy be excited by a foreign pro-

teir..

         We *have studied the action of sodium salisylate on

the arthritis of rabbits infected with ;rcanstrcDtococr.i. It has been

claimed by some t,fvLt these streptococci, of low virujen&, are the

cause of rheumatic fever, and that the lesions in IcbbilS infected with

thorn am tha same as those of rheurratic favor Iz~tLop.:s. V!e hava been

able to show that rihon rabbits were inoculctcri n*.th gr?en streptococci,

aftor being put under tha influence of sodium salicylate, they de-

elo
P pe d arthritis in practically the same proportion as non-salicylated

rabbits; but that the non-aalicylated animals had a considerably higher

propotion of severely Inflamed joints.  Although the effect of sodium

salicylate &n these an$nmls was different from that seen in patients,

this is the first demonstratign that this drug has a definite anti-

bacterial action in the anir#J body,

Cardiac Disease.

lb. Cohn f&@, Dr. Dew.

       During the past year,  the work in this laboratory has

been &cted to a coptinuance of the study of the action of qtinidine

both in patients stifering from auricular fibrillation and experimentally
id dogs; to a continuance of the electrocardiographic study of the heart

in rheumatic fever and to certain problems connected with the behavior

of the normal electrocardiogram,

Last year we called attention to the discovery which had

beeti nmde in Gezfmny, that @-@J&US, a cinchona derivative, when given


to a certain sercen kg3 cf Fersons suffsrixg from auricular fibrillation,

I

possessed the power of restoring the normai cardiac mechanism. At that

time v4e uxamincd axpcrincntally in dogs, certain cf Its effects on the

heart and circulation, describing eqxcially an augxcntiq action on

the contractilo povizr of the ventricular muscle.  Sine-5 t&n w3 have

studied in detail thz prcciso mechanism by means of which tfi:: drug is

abla to bring about a tennimtion of the fitr'il?tory ;~:OXSS.

        t/e proceeded on thd ass-xqtior. t.Ta+. thi ;.l:~ory of cir-

cular CxAtation, as the basis of the fibri:.lator;- p.oc~-~s WCLO correct.

That a procsss suc3 as this could be mede to ~5s `, WE ,;h.m in this

    CO'mt.ry in 1308 by A. C-. Flayer.  lktor, !I, 13i:x, I". E. C;arrcy in Ameri-

     ca, and S. R. Mines in England cug;;ested this ;,r=,ccss a; the cause of

     fibrillation.  Iator still, in 1921, Lewis demonstrated the probable

d    coorectness of this view in elabonte eqcrimcnts in dogs.  In this

    theory, 1 t is supposed that an impulse can course in a circular fashion

    in a piece of muscle, provided it is sufficiently large, especially

    if the muscle Is in the form of a circle, The entrance of the great

   veins into the right auricle results in an arrangement of the muscle

   about them such that a cirdular strip of tissue is actually available,
  -.

she uld there arise a stimulus ready to utilize it.  Phe experimental

evidence indicates that stimuli do arise which behave in this way. Now,

in order that an irtqulse may travel round and round a circular strip of
kuscle, it is obvious that a given bit of tissue at a given point of

the circumference must be ready to receive it, must be ready to be re-

excited by it, when the impulse returns to its starting point,  Other
                          

things being equal, the only practicabl e way a circus movement such

as this can be stopped, is to place the muscle in a `state in'which; when

the stimulus returns, it cannot receive it. This might be done by length- I;,,!
                                                                           3 .l'
                                  b,i:
                                                                           $ /. `1


                                   bs
                                                                      ..I
                                                                        I '
                                                                     ;  j I

CliilS the refractcq p2;`ioL of tlie muscle, that period during which the

rrr~s~?-e cannot be excitsd by the returning stimulus, or by rendering the

fkLt3 or' p;sage of the impulse so rapid that the impulse rc turn before

the rcfxactcxy ps:io:: Y.d ;asced off. Whether thes;: assumptions were the

facts, we determine3 to put to the test of cxperimcnt.

       For this ~~rposo we emplcyed araonthe tized dogs and studied

with two galvanometers, the late of passage oi 5.e ic?ulse between two

FOirts on the auricular surface to whit h t3e gil.vanor,eters wer3 connected.

This WG cculd do easily since we knew the distance betzveen the two points,

an!, by photographing the shadows of the Wo galvanome ter 8 trings , knew

tk ti.x Interval bekeen the appearance of the action current at these

t-No poin$s.  The refractory period we learned by stimulating the auricle

with induction shocks at various instants during diastole, and photograph-

ing the cardiac action current during this procedure. The calculations

which were made of the time elapsing between the last contraction and

the stixmxlus were then arranged chronologically. It was apparent that

there resulted first a series of such periods in which no responses on the

part of the auricles took plaoe and then another series in which responses

were obtained.  The refractory period is the longest period in the first

group, the group o f the no-responses.  The experiments are laborious SO
that not many were performed.
      Our *results were of great interest. we found first that

the rate of conduction'was eather unchanged or made more rapid; it Was

never slower,  This is a result contrary to the one which is desizable

for this purpose.  ?a learned however that the increased spsed was not

SO great as to `render ineffectual the effect which was obtained on  the

refractory period.  The effect on this we found to vary, but there  were

cases in which the increase was SO to 100 per cent, quite enough to render


        % were able to shon then thAt w;: pbss~sscd J means for

altc-,-in; c tuctlon oi t:-.cr knrL* rmscle in 3 Liw :tidil, sr.z: tir.t the

cor,tir:z,rx C,, LiS circus i.:o$ crrznt which is 2.t ti`i) bF.sia of: the fib.-

rillatory nrocosa is rendorod impossibiz.  Tii ; f-..BTrL.b;2 1..su,t 19 not

unifc rm.  %a: it 15 not, dopcnJs it appsx~s C,I differcxcs-f'ror.: x.imzl

to animal in the tono of tti cardiac ncrvcs. This inCLr `iAc3 IV? ttl1n.k

is justified, for in a parallel series of expcrirrmts pedormed by Lewis,

the inf'luence of the MNOS was exc1uJor.I and in his eqeriments the

rocxit ; r3re uniform.  The two series of exporinents are complementary;

they indicate the essential nature of the action of quinidine; they

sl=ow why ix pticnts that action is some tirms Trevantod.

During the year we continued in cases of rheuratic fever

to collect information on tha behavior of the heart from day to day.

To the grosser forms of irregular heart action, such as heart block, we

have already called attention; they were well `known. We found also that

*nor changes in the coordinated contnxtion of the auricles and ventriclea
weke to be deteoted.  In `certain cases it was indeed possible to show that
          \

with each reck=ing bout' of fever, a dititurhence of minor grade took pi&e
In the heart, even when no &dating manifestation qould be demonstratei'""-

                                                                           1    .,A,
in the joints or elsewhere. ye believe we possess evidence of a more -

certain nature than hitherto, of the slight but continuous ravages of the

disease. Bow slight `t&e changes am which my be reckoned as mnifesta-

tions of disease we do not know.  We have for this as well as for other
reasons returned to a study of the no&b1 electrocardiogram.

        The nom1 electrocardiogram, we were taught, was a phy-

sical.measurement so esct and so constant that it was placed in a &ss
with tb 0 finger print method, as a means of identifying individuals. It


w% known that in certain persons, the positicn of the body and the phases

Of respiration influenced the form of the curves. In most instances the%3

dafhmces were unimportant, for curves could be nnde in a manner calcula-

ted to exclude their effect.  Althaugh these variations were sr-1~11, they

might be sufficient to render the interpretations we were putting on cur-

ves taken from rheumatic fever patients doubtful, Ve determined therefore

to take series of curves for ten nearly consecutive days from a number of

no-1 young individuals. The measurement of these curves is not yet com-

plete. They are being measured not only with respect to the h eight of the

wmes, but also with respect to their duration and the time intervals bet-

ween them. Great care was taken In. making these curves* The individuals

   were always in the same position. V?e took care to know the extent and rate

   of thei: breathing. We did this by asking them to breathe from a SpirometS
  and by having the spfrometer connected with a signal n@gnet in such a way

P    that each alteration of 100 CC, in the position of the spirometer was com-

   municated to the signal hung before the electrocardiographic camera; the

   motions of the signal were photographed; In addition the inspiratory and

e%?imtory motions of the spirometer were conveyed to a closed system of

piston recottders. The lever of one of these also hung before the camera

and was likewise photogmphed. The electrocardicgrams themselves were mde

simultaneously with`three @.lvancmeters  af the three usual leads,From cur-

ves like these,the direction of pctential could he calculated without fear
Of error by the method of Einthovan, `Berg&tisiub and BAjtel. Fe believe

that we have obtained sets of curves having an exactness not hitherto

attained. It is clear even from an inspection of them and without meas-

urement; that the curves vary from day to day to an extent not previously

belived to be 1ikeQ.  ye learn from this that during the course of di-

sease; alteration In form of a grade disclosed in these series of normal


I

Ones, arc not to 2e ;ivan too great significanca.  We learn also that
                                                      

in a no-1 series, the time relations bekveen the waves are constant

to such an extent as to pernit the inference to be dram that a patho-

,I'        lOgical process Is present whsz there aro varktions as great
c

as those

which we found in the curvea %kerr oT rheu,=tic fever patients. Vie have

a sound basic then for comidarin;: the belGvior of the curves of the

,

I

patients as evidence of a pathological process.

        Having gone so far iq 0220 elaboration of ox tecSnique

we determined to apply it in another direction.  It is well known that

when the heart enlarges, it gives riss to alterationeln the electro-
oardlogmn; the curve takes on one form whan the left ventricle is hype%
trophic, as in aortio insufficiency; ib takes on an oppoelhte form when
the right ventricle ie principally involved, as in mitral stenosis.
These electrical signs have been useful in the clinic, but they have in

our experience been on accasion misleading, for we have obtained CWV~S
resembling those found in erlbrged hearts, in young soldiers and in civi-

lians who, we were quite certain, were not the subject of disease. It
Occurred to us that the position Q# the heart in the chest might be an
                                     I.

iqportmt contributing facto+ `ih `producing the ,abnormal- eleotrocardiogrsms.
!Qst m+ .cImhges in' the cums are poefsibla es the result of respiratory
movement8 we Mre &ady mentioned.  An exeggexeted instance occure in   : ..
                                                                           

dexttotx%rdiS; here "the heart is' t&aed to the' right' rather than the. left
side of the body and the eleatrooardiogm assumes the appearance of a

rPirrored image of the usual curve.  ?Ia?ing these experiments to guide us
we plazined to discover In a systematic manner precisely what was the ef-    .
                            $

feet of the position of the heart in the chest. Obviously we could not

rotate'ihe heart in the chest, but we could rotate the chest about the
                                 .            .                iI,
heart, Our method was a$ foliovv~;  &stead of taking leads from the limbs  $
                                                          R
                                                        ;`f


the apicUo of tkie lar,7;e;`, equilatcml triangle which we could apply to

the c:?cs t , the *.XLSG 02 t:;e tri-lnglo s tru tchin;: bz tv:Gor, th3 shoulders,

tho a:ex below ths ste:mr:. Us assured oursolves t`=t L,hG curves taken

from those lords rossmblad accumtaly those from the lir.lb lesds. T/e

procezdcd then to route this tx&mgle throuzh successivs arcs of 400,

takin;: cun~s nt each new position frorr those.pdints of the chest wall

t0 which the apices of the trian@ pointed. By this mans, we did in

effect rotate the chest about the heart.  In noxnxxl individuals, by quite

smll chznges in tIm position of the triangle of leads, by ch&n,-OS quite

possible in an crllrrtomiml sense, vm obtcLined mnws which xt~lly resembled

curves found in disease 2nd resembled closely those often thought to be

abnonz~l found in the yoq soldiers ati civilians already mentioned.

These were curves like those seen when the left side of the heart is

large; in other positions, though uzntomiczlly quite improbable, we ob-

tained curves resembling enlargement of the right side of the heart.

         But this is not all.  We tuwd next to patients whose
                                          .

hearts were known beyond doubt to be diseased and whose curves were

characteristic ,of this condition.  In these patients just as in the nor-   
ml p&rsons we applJed't,& 'technique ju6t described. We found that at      
                                     * -

some position in the' co&e of rc+,t& `the leads, curve 8 ~6r0 `0btZsa . . .
                        s...                                                .

                                                                           

nthich resembled nomml carves. In these cases, that Curves Of ap&oximatel
Ly norm1 anearance can be &`tgLlnecl is of theoreticsrl i&rest, &t

that in obviously no-1 persons, yielding abnomal curves, honnal curves

can be obtained by a alight altention of the position of the heart in

the chest, is a nrrtter of getine pr;actical. importance. It does not sim-

plify the interpretation-f electrocardiograms3 but it does soothing


more iqor:an',; it shows bon- the normal individual may be saved from

bsing considered the subject of chronic heart disease because of an

abnonrality in the curve.  It need scarcely be pointed out that this

danger is not theoretical, \ye kuvo not by these aqeriments solved
th0 p roblem of the relation of hypertrophy 02 tile heart to patent

abnoxxality in the electrocardiogram, but we `have sho:vn syctorztic3lly
and clearly that, especially in doubtful cases, the position of the
normal heart in the chest must be t&On into account as a factor in
the production of abnormal curves as well as the position of the abnofina1
heart in the chest in the production of no-1 ones.

Clinical Studies of CMnidine.

        The importance of the 6tudy of quinidine is better un-
derstood when it is appreciated that fibrillation of the auricles is
present in about 43 per cent of the cardiac irrogularitieo.  In 6any
instances the presence of the disorder is in itself serious. A rrajor-
ity of these individuals complain of unpleasant symptoms which are di-
rectly related to the presence of the irregularity.  In about half of
the cases trerted with quinidin.6 (in our own series 44 per cent) it is
possible to restore the normal cardiac r'hythm.                           ;
     In May 1921, a preliminary rsgort was l&lished dealing
with the therapeutic effects of quinidins sulphate in cases of auricular

fibrillation.  This work has been continued during the past year; _ twe;:ty
five patients have been closely followed over relatively long ;?eriods

of time.

       Before attempting to alter the heart r*hythm, we have

found it better to combat heart failure, if this is present by rest in

bed and by giving digitalis.  A satisfactory plan of treatznent has been
Outlined in which, after preliminary small doses to test for the presenw

i


of SCiOcpi.ra-,y to meder;: ol the CSnc!lona gro~r, gradually increasing

amo-mts of the drq v;sre Elver. over a fix day period.  It is rarely

neCessJ?y t0 COntinw thezpy after the fifth d&y, for tf the rioma1

rhythm has no' c ensued after five days of trec?.k~er.`:, i+ 5~ill prytzbly not

result from further doses; or, if it should appear, w<ll last only a

short period of time.

?a have made a special effort to learn what alterations

in the cardiac mechanism r'cll~~ the administration of tks d.~lg by means
-

Of electrocardiograms rcde at frequent intervals.  The f i?St l?ffOCt W?bS

' `.7

&r

usually acceleration of the ventricular rate.  Occasional vsntricular

premature beats were also not uncorrmonly observed. Restoration of the

normal mechanism occurred for the mst part on the second, third or
fourth day of treat.ment.  !?ha avorcrge dose ;vas 2.6 gms. givon in a

three day period.  The usual order of Chi3ilp in rhythm from auricular
fibrillation to the noma% mechanism is: re'tardation of auricular rate,
that IS to day the rate of the circular stimulus, im?we auricular f lut-
tern flutter, and then the no,real rhythm. The actual transition from

flutter to the normal sknile metinism has once been photographed.
      Certaia untow&d effeots have been observed, both in this
hospital and elsewhere. !l!hese accidents may be grouped under six head&:
(1) u@easaslt,sgmptoms due to general effects of the drug, (2) `sudden,
though Mt f's+&1 collapseI' (3) embolism, (4) sudden death, (5) occurrence
Of heart rhythms indioating `that the heart muscle has besn intoxicated,
(6) induction of heart failure,

       Patients with large hearts in whom multiple valve lesions

exist have, in our experience, been unfavorable subjects for quinidine

the rapy .  In them, extensive disease of the heart muscle may be presumed

tg exist.  In these individuals unpleasant symptoms follow ingestion of


the drug, 9-w patient died suddenly shortlg after the resuIpption Of
the normA rhythm; autopsy failed to reveal the cause of death, nor is

the meck.nisn of death in cases like this at all clear.  If fibrillation

                       . . . .
of the auricles has b66n of'short duration a favorable issue of tha

treatment is mDre likely.  We are Inclined to reprd the difference in
result as dependent on the slightor extent of cardiac injury, as this

is indicated clinically by the size of the heart.
       Attention has been called to the occurrence of ventricular
        w

W~hycrrrdla after quinidine.  This abnonral mechanism ~SSWBS great
clinical significance' if it is borne in mind that in doss injected with
digitalis or strophanthin it is the lmdiate precursor of ventricular

fibrillation and death.  Vcntr-lcular' tachycardia has in point of fact
baen observed five times in our patients; but giving quinidine has been

promptly discontinued and all the patients have recovered.

The duration of the nom1 &q+nn after a single course

Of therapy is variable, ranging from a few hours to six months.  In a

number of patients, small daily or weekly doses have served to maintain
                                              

the normal rhythm for as long as & year, No &mUative effects need

be fared, as the,dnag is rapidly eiim&ated.~
                .

,.

kxd,les of `heart size* vital capacity, blood preesurd and
  

~a'unas pressure have also been m;tde.  Theai have as yet rot been$crifi-
.
ally arrrlyzed.                                                         '
Ir,

At present it 2s difficult t:, solest P>.-orn. the. .vazixs~

C&SBS of auricular fibrillatiok which present themselves those which

do well-with quinidine .  In view&f Ithe,possibility 6f the appearance
                                        .,., ..       
of toxic qymptoms, the tre&tmknt shotild"be carried out with the patient

            ,                       
in'ied,. pP&erabiy in a hospitals where` the           
                 beh&%cr of the heart an.y be
. : .     .
                   . .
iwied with the aid of g.raphic records.  `Carefully administered,. this


:
1 . . k31,.

d-7;: is a Y-.,2-.apsutIc ?.g,a.i1; x? ,-rcat value; indiscriminately given,

it %.~y on occasion, be eqected to cause disastrous effects.

4j 73 lqpQJt.enC pI"L-ph&c S tU&y G f
                               .-  *he Sire of `he Heart in Pneumonia. with
                               -I-,,& _-_- b -_--

Consideration of ths Fffocts of i.)ixifaiis Theraav.

        Observations nnda tist year `have been continued and

amplified.  In brief, it has bctsn shown that in a large percontige of

Cases of lobar pneumonia and in J somewhat smaller number of cases of

bronchopneumonia, there is, In the ccurse of the disease, a signifi-

cant dllatn2ion of the heart, with return to normal size during con-

valesccnce.  The increase in the cardiac ailhoue tte probably represents

an attempt on the part of the heart to nupent systolic output by in-

crew3 i:? the length of its muscle fibres.  According to the Vaw of the     .
                                                                           

heart", as stated by Stading, such an increase is favorcblo up to a

certain point.  gct@r that optimum is exceeded in pneumonia it is

not possiblo to say, though signs of circulctory failure are conspicuous       "

by their absence.  Digitalis administration, early and in sufficient

doses, apparehtly setied, in a number of instancss in which dilatation

tight have been anticipated, to prevent sAteration in heart size.

       It is now known, through our esrlier experiments that      ; :,b
digitalis, ia therapeutia doses;                                               ,x .'
                  augments myocardial contraction and      .
increases ventricular volume output. .FOF this reason it maJree no dif- y '
fexence whether the `increase in the size of the haart is compensatory or

hele te rious.  1% eithsr event the drq is of bansfit. In the first in-

stance ii, serves to aid the heart in its effort to maintain an adequate

circulation during A period of stress; izl the second ixxtaace it hslps,

at least in certain cases, in preven.ting diiatation of the cavities of

the heart which' in all probability is the result of severe toxemia.


3r. I.~un~?s,~:+sr~., Dr. Vaz-~ 31~2c, Dr. Stiilman and Dr. Linder.

        By thorough clinical investi@tion, blood analyses and

functional tests, the clinical histories cf patients have been folloned

with a view to obtaining as logical a classifiation of nephritis as

Cny ba possible crd of trzatmnt a:cordlng to classification. Among

the observations made in connoctlon with the blood chemistry have been

the repeated determination of the urea index employed in conjunction

with urea feedings tests.  This was done in the anticipation that a more

definite estimte of the reserve pav;ers of urea excretion may thus be

made IJerihle.  In connection with this work Miss Hiller has elaborated

a new m.th,d for the determination o$ urea in srrall quantititos of

blood. If 1s intended while these data are being accumulated by rela-

tively short observation periods on a fairly large number of neph&itics

of all :-,irlds, to attack, one at a time, certain specific problems that
arise in connection with the study. For example, the abnormally high
blood fat of patients of the so-called ?iephrosisl' type raises the

Westion 05 the nature of the metabolic' disturbanue which @uses   

lipemia. Alx~=?b ld `fat.is norm&y either burned or deposited in the

body's fat depots so `mpidly that it never' rises in the blood to' the A.
heights found `in these patients. k!i~e` question is' presented ds to whkthe'r
such patients fail to burn fat as rapidly' as do no-1 Individuals. qotal
me tabolism experiments following fat feeding have been rrAde, therefore,

on some normal persons and on patients v.4 th nephritis accompanied by

excessive lipemia.

Another specific question Is *:Jhether in so-called hydremia

there is really a dilutio n of the blood with increased

or whether the low protein content of the blood is due

total blood volume,

to decrease in the


tirtCL `.3lCod prots!.r, cc;!:`;*;`; I,< t:;c, >oQr wiLh3ut increase lr blood VO~JDI~.
i3r. Lindzr `has followed thti vzri;t.ions in plxxxt I;rotsir-s 2nd has mde
repeated observations upon the blood volume in seven1 of ths cases.  His

resUlt8 indicate a considerable degree of constancy In tho plas:ra volume,
in spit0 of rx%rkod changes in the plasm proteins, in tha amount of edmm

a;ld in the clinical stato.  It therefore appears probable that the "hy-

dremics" of nephritis is no y 4 a condition of dilution of the blood, but

depends upon a loss of protein f ram the plasm,  The nature and quantity

Of the protein found in the urine is thereforo engaging our attention.
SMdiee on Acid-Ease Equilibrium in th=c Blood Carried on in the C&mical
Iaborato@ndar the Direction of Dr. Van Slake.
Drs. Austin, Sullen, Hastings, Heldelberger and Xeill.
      The stbdy of diseases in which there is a disturbawe in
the acid-base equilibrium of the blood Is dependent upon a knowledge of
the quantitative relationships existing between the various substances
which contribute to the maintenance of this equilibrim and presupposes

fnfomdion regarding the Iimits of variation to be found in nomal in-

divid`ua2.s. It has been the pu-ose bf the tOrk done in this laboratory

to advance our knowladgo"`of \bs' quantiliative ketitionshipe involved,. $0 J

detemine the limits of vari&ti& tip be found in non-ml variations and. to
apply the results .&s obtained to the study of bphritis and pxmmonia.
Intirmtely concerned wit@ this,problem Is the etU&r of n-2 rospimtory
processes which is also under investigation.

lbe &actions involved `in the respiratory changes of the

blood my be qualitatively represented as follows:-


(I) 3:: co3 + k  +.:.
             ?rotein

I! Tro tein + ITa ECL    -
(2) H;! CO3 + 1. Cl ? 3
IbHC03 + HCl    --

       4    ?

4) Z!IcA f 2 K IIbo2   #
                 -

: 5) Hz CO3 + I$ pod Y

Incr~sfw the %? c 03 concentration in the tissuee causea

the forneLti.on of Ih fI C 03 in'the pl+mrm and K H C 03 in the cel&s. m
resulting acidification of hemglobfn causes the partial liberation of
oWFk-~-C~nyerW4, increasing the 02 conoentra tion in the lungs sends
the react%& n the
  L  opposite direction and aids in the freeing of 'C 02
        quantitative xmasurement of these reactions has re-

ceived our attent-on during the past year.
      &Z 9-r to clarify the conception of buffer substances
which play such an important role in biological fluids a theoretical


papor was writ&n on the s-abject of buffer measurement, and the buffer
values of neak acids, bases end amphoteric substances, of various disso-

ciation constants.  Despite the work that has been done with buffers,
theso relationships hxve not heretofore boen worked out; in fact, there
has not even been a unit for e-ressing buffer effect in qualitative

xlumrrial terms.  As such a unit we have used the amount of strong alkali

or acid required to cause unit chaxe of PH. On this basis, a solution
possossos a buffer value of 1 when the pH chan;;os at the nte of 1 unit
                                                   .
per gram equivalent of added strong acid or alkali. titheatically eX-
pressed, the buffer value of a solution is d B. when dB is the increment

d PH

of added strong base (%LCH or KOH), d pH the accomp anying increment of

PH.  From the quntitative known relationships, fonnulatod according
to the TILISS law, of hydrion concentmtion to the ratios buffer salt

free buffer acid

and buffer salt  (in the casesof weak acids and weak bases respectively
free buffer base

acting as buffers) it was possible to derive by means of the differential
calculus a genenl equation expressing the buffer value of any Wfer

solution, viz.

Buffer palus d B
     d

For weak acids as buffers, K = Ka, the acid dissociation COnStXh.
             $4
ForweakWses K= 1%   ,
          K     where 5 is the dissociation constant of the,

buffer base, FQrbsolutions near enough to neutrality SO that p+]    and

&)q are relatively negligible, viz. between PH 3 and pH 11. a zone

covering nearly all biologioal solutions, the equation simplifies to

               Buffer value = d B
                      d PH


A; is ed Lmt, tk 2ffzctivcaes.s of 3 giver, buffer is Ciffercnt for

3vcl-y \;`+`j   Tnc e?fccti-,-an:ss of cvcly buffe: at vclrying pH fol-

lows tt-2 s1riic CUTJT) v;hich rsxh;s 1 ts VLLXiXiU xhen R z []:j (or lo?*

FH) , 2111 b9cows insi@f iant v&m tha r;tio-Tc.  falls oatsido the
                      pit-j
lirr,its 100  r.AL,  t'k t i c , ;' .I-.;r. -log K differs from pi3 by xio:`e t&n

salt.  At this po?nt tk
the buffer is 2.3 K2
        (2K) 2

d-'i'3<ti*CCC~SS, v&z-. K - LI+J any `cruffer is

b-lf f 0 r acid or br;oe, h:lf in t33 f0m of its
value of an M/ 1 solutionkhere C = 1) of
- 243 = 0.57;.  The molecular concentration,

and hence the molecular weight, of a dissolvad buffer may be ascor-

tainad by dividing 0.575 by the observed r~~~~lmum d
                                     B value. The
                              d pIi

lirtter is experimentally dotemined by addi% known increments of
strong base (d B), or acid (-d B) to the solution and measuring the
pH change, (d pII) .

The @-I+] of ma-m buffer value also indicates the    .

.

dissociation constant of' t'ne buffer acid or base, since at this Point

$dr.`bxkfers containing more than 1 buffer group (poly-

vale'nt we& aci  s & bases, or emphot+ric substances) the buffer value
                il:

13 the sum of tke buffer values of the different groups.

These principles were

hemoglo'oin and to t5.e de tannillcttion

then applied to the study of

of th3 hitho rto unknown second

and

third dissociation consLants of citric acid.


        'l%e axpzrir;ler.>l work on these problems has been

c;;rricd on by Austin, Cullen, IQstings, Heidelberger and Ieill. For

Our experimcntil wor!r iL, vc+s first necessary to imljrove our methods

of ar3.1;`ais and technique of `handling blood and gases.  Ni th a new

cons&ant volume .bl.~od 30 a,-_mratus we wore able to obtain results

which h3d an LL verai; error of 1 prt in 500,  The modified Iialdane

appzatus for the anQyso s of gas mixtures has an error of similar

ml.gli tudo .

        It was further necessary to have at our disposal

relatively large quantities of pure oxyhemoglobin. A method for ob-

tcLinlng th$s has been paccessfully developed by Dr. Heidelberger.

Tha oxyhomoglobin Is procipit ated from water solution by saturation

with a mixture of C 02 and 02 in the ratio of 4 to 1.  It is then

recrysta11iz8d several times by dissolving in alkali and repeating

the precipitation process.  Separation from electrolytes is finally

effected by dialysis under pressure in collodion s&s.  The hemoglobin

thus obtained retains its full owgen combining power and is practi-

.

tally free from electroiytes and other foreign substances.       !

       V$th this +terial and tech&we we have obtained the

data whioh is given below:

  (1) Tns amount

o f oacyhemoglobfn is

  (2) The amount

of s3G.i  l#ound at pH 7.40 to a gram molecule

2.13 2 0.10 equivalenta.

of additional alkali which 1 molecule of reduced

hemoglobin takes up when it is converted tto oxyhemoglobin at pH 7.40

is 0.6 8 2 0.10 equivalents.
  (3) The ratio of alkali combined with hemoglobin to the change

in oxygenation, i.e. d B    is constant for all degress of oxygenation.
         d H b02

This bears out L. J. Henderson*8 assurgtion.


(4) 19~ mo!.c;ul.~.r b~$fcr clue of o;ryhemoClobin, p0 = 2.64

       The mu 1 3 a;ll:Lr 3'Lil- ,
            `fr r vslue of reduced hemoglobin, pR = 2.45.

(This lztttir ml-x is obtnimd indirectly 2nd is subject to revision.)

     T&se value; arc constant over the physiological range of pH.

    Usin; t:-,ese moloculnr b-ufror values and applyin;; the princ',ples

laid do-tin in the

be shown that at

reaction between

theoreticr.1 buffer paper written by Van Slyke it an

least 5 monovslcnt acid groups are involved in the

al&~11 and hemoglobin over the physiological range.

  (5) 38 relationships existing bet;Jeen oxyhemoglobin, reduced

hemoglobin, base bound by hemoglobin 3r.d pH are smrized In the

oqu3 tion

      B

   (6)

for horse

made with

= 2.64  [Hb02j (pH - 6.585) + 2.45 ffij   (pH - 6.80)

It is important that the above const;ints which ara those

hemoglobin are different for dog hemoglobin.

Performing expe&&nts on horse blood, similar to those

hemoglobin, we have obtained the following results:

The average buffer

7,5 yas.?ound to be T&3 and
  (2) Frdm pH 7,2 .+c 7.5

value of oxygenated blood from pH 7.2 to

for reduced blood 24.4.

the bffer klw of Wood was Constant,
   .'

the degree of oxygenation being constant..

  (3) The hemoglobin was foupd to be responsible for about 765
of the total buffer va&ue ,of. the oxygenated blood and abou$ 735 of

the buffer value of the reduced blood. The per cent of the buffer

value attributable to the bicarbonate was 6.9 and 9.0 respectively.

!Che loss in buffer value of hemoglobin when blood is reduced is thus

only partially compensated by the increase in BHC03,

(4)  `I"ae decrease in BHCO3 per molecular increase in oxygen, i .e.

the d B
Iis&  ratio varied from 0,50 to O-59 at pH 7.30 and were con-


(5) c'!ith increasing pi-I the dB     ratio increased at the rate of
              dEbOZ

0.02 per 0.1 pH over the range 7.2 - 7.5.  Assuming that only one acid

~rslp in the hemo@obin molecule is changed it will be possible ni th

this data to estimate the dissociation constants of this group when

reduced hemoglobin is changed to the oxygenated state,

A theoretical paper on Vl'he No-1 and Abnormal Vari-

ation of the Acid-Base Balance of the Blood" @s been published. In

it the demonstration Ixis been r&rde on the basis of facts f ound in this

and other labomtories, that associated with each condition of hich,

nom1 or low blood bicarbo%to my be a high, normal or low pH.  The re

are thus 9 possible and actally observed combinzfians of BXO;, and pH,
of which only 1 Is normal, viz. that in which both plI and i3HC33 are

no-l.  mch of the other 8 conditions indicates a specific abnorma-

1 ity either in the metabolic processes by which non-volatile acids

are formed and excreted, or in the respiratory processes by which the

CO2 tension in the ?jlaod is regulated,  For the general diagnosis of

an abponnal condition, determination of both the pH and bicarbonate ex-

isting in the circulating blood becomes obviously necessary, although

in special conditions abnormality is one factor is so characteristic,
                        
such as the low BBC03 in diabetic acidosis, that the other can be neg-

lected.

       Since, if two of the three variables pH, 3HCO3 and H2
CO3 "a% known, the other may be c;Llculated and the acid base condition
of the individual is determined, we have undertaken to determine the

first two in nor ml individuals, in nephritis and in pneumonia patients.

The method used for the total Co2 of the blood has already been described.


                                                                           !.
                                                                           1 \-I j
A colorim~tric mcthoci for the detenA.nation of the pH which is simpler
than e$ectTomztric and noye acc=zrate than Frevious colorime tric ones

`W;LS deviesd by Cullen,,  !Che pH of plasm diluted 20 times under oil
with nautrnl saline, without ioss of C02, de tenlined colorime trically at
room temperature nay by a;~ empirical correction, y,vhich is cono!:o.zt

for each species, be convezted tc tile pi! vrhich vlould have ob'aitied

at 38O.

       !Ele question imS recently raised by Evans, of England,
as to xhcthor electromtric pfI estimtions on CO2- containing solxt ions

are valid.  Evans claimed that some acid is formed by reduction of CO2
at the electrodes, a3xi c~.uses the gH to be rmrke'dtoo low.  Cullen

and .das flnrp I've chcclsii -,hz rzxtta: ~`1 carefully on ;?hosphate oolu-
tions with and wi that COdI 2nd foun? theoratirLxJ. rl;su!.fs in both cases.
They believe i3vsns coul1 n; t have hen s-ufficianslp accux.t.e in regu-
latirq the CO2  t ensions in his electrodes,

       In connzctios wit'n our nephritis service, tulle deter-

mination of the acid-base hslance by combined prZ and BEC03 estirations
has already prove,: of clinical ~$1~3.  V!e ara a2plyin,r tlhese principles
and me thqds to the study of the acid-base balance in pneumonia. An
experimental application has also been rsde to the acidosis produced

by anesthesia.

      Since the relation between the reaction, the CO2 ten-
sion and the bicarbonate content is conveniently exljrensed by the &as-
elbalch equation

pH = pK' + log   BHC03
        oc. co;!

it wag thought necessary- to redetermine the two conuY,$n&pK' and&
with accuracy in order. to make the equation clinically useful.  Ve
                                                                        ,


.- -_

wereable to confirm the value for W  , the soluhility coefficient for

CO2 in blood, as originally determined by Bohr. Ve found. the value for
pK' as originally determined by Hasselbach to be correct for plasn~t but

incorrect for the whole blood or hemoglobin solutions.

Studies of Protein Chemistr:.

Miss Hiller.

        The investigtfon of the behavior of the different pro-

tein precipi tats used in studying blood and protein dlzests have been

cough ted.  The precipitant8 studied include picriu, trichloxastic,

metaphosphoric, and tuqs tic acids, colloidal iron, mercury salts, and

olcb hoi.  The amino and peptide nitropns were detemined in the fil-

trates from blood with and without the addition of known amounts of amino

acid and pepetone nitrogen.  The action of* the precipitants on Wi tte

peptone solutions was also studied, in order to aecertain which ones

remove most completely the intermediate protein products, and which re-

move the protein with a minimum of the intermediate&I. The data obtained

Will enable future investigators to choose precipitant8 adapted t& their

e8PCial Object8 in a way that ha6 not heretofore been pO88ible.  The

ixnediate Object of this work was to ascertain condition8 for studying

the absorption Of intermediate products along with the amino acid8 during

protein dig;es tidn.  It i8 hoped to attack this problem, which i6 an ulb
fiai6hed pertion Of the otudy of the fate of protein dige6tion product8.

%JI?US COLE