To the Doard of Scier" '
            Ak3fic Directors of t!m
Rockefell?r fmtitute for Medical Research.

Gent ienlen:

   The Director of the Hospital has the honor to submit the following report
of t3a work carried on during the last quarter year.
  During the months which have paseed ainca the preceding report, the work has
cmsisted tiinly ic a continuation of the work previously reported a8 in progress,
~lt11 cm<ia2or, of a nmber of the studies which are note ready for publication,

   , c-c.53 ?lo*cx~ i%our2onia.
    `1            The type of pneumacoccus concerned has &W been
Je:mined in 231 cama of pnemoah admitted to thir, Hospital.  Xa addition,

YJr -.a .-
-..Y.?ardsor, has datemined the type of pneumococcus concerned in 195 cases of
:Lm!onia abitted to the P0M8yzPaXlia Hospital.  te have thus quite aati:factory
~P~3mstioae i23 432 caSe8.  The results are shown in the following tablee:
  Camt jr the Eospital of the Rockefeller Institute.
Xological Agent      PO. of   Percentage
                 Cases           Nortality In Case6 not
                       fndidehce     treated with Sanm
?r;ouxAlocoocus type I     78      335         25%

    r       " II     75      32s         29%

    a     Q $71    22      9%         45%


                                                                           1 .-\`,
                                                                           4 ' 5'. \
                                                                           : \,`(
                               -2-

         Cases in the denasylvania Hospitai.
Etiological Agent     No. of   Percentage   Mortality in Cases not
                 Cases     Incidanoe     treated with Serum.

Ptiautaozoccus type I    60      31%         30%


       II      " II 39      20%         25%


       n     " III 13      6%         so%


       n   "fv+-     43%         12%

T:le figums tidicating percentage of incidence in the two series are not exactly
cmparable since Dr. Richardson has not included in his list the cases due to or-

gznisns other thas pneum~~ccus~  The results indicate, however, the correctness
of the conclusions previously drawn from a small number of cases*
    At the last meeting of the Board Dr. Janeway,drew attention to oetiain
races of pneuroocooci ieolated at Daltimore, which, while agglutinating in undi-
luted serum of type II, nevertheless did not agglutinate when then diluted Benam
was added to them, and when protection tests were made with tham the results wee
sot &ear cut and unequivocal.  Dr. Bloomf ield kindly sent us these five races
mi these kave bean $horoughly studied by Dr. Avery.  They were all found to be
of 10~ itimlence and, as imp before been noted of the type &rains of low viruh~ce,

+`I bi&e :xotection afiorded by the sera of different types was irregular ad inconstant,
ia c6:"tafn instances even nomd. horse senon was able to proteot agaiast them,              ;
                                                                           I
                                                          I
,`,I: 4'3 u..ese strains were rendered highly +irulent by frequent passage through Jnicem            (
Z%ri on testing protection against these vimlena strak,. it was found that type II        ,
eea'ilm 3rotectad against all of thw in a typical manner, while type 5 sells &d
famal Hcme Sem had no srcttective power whatever.  The agglutlnabilitp of these
straim, honever, has in this m,mer not been increase+   It see.m evident there-
fore that these are tme type IX s*Yrakx~, but which have relatively slight agglu-
tinab ility.  T:li* is q--"*'
          L...~a mralogous with what ie known of B. fyphomae, cefiaiaa
strains 0 i viz!. 22 a?3 t X#L~ ag,<iilt i2Sl le.  It is not thought that these erper-

iumts af fer zn.y evidanze t:-at tke at-ypical strains are chmged into fixed types.


Tk9 ~~c-..:-z-at~3 of styli stratis, moreover, need not necessarily 6ause any confusion


-.I
f-,- t& Llgt)lod 02 dhgnosis af tppa employed by usb

  %:xn Treatxant of Cases due to Pneux~ocacci of type I. Forty-eight cases

`.. ^ A
.b.rO .C ymvmocaxf of type I hava now been treated with me resume   Of these,

r'cur 2285, contrasting with the mortality of 25 - 30 per cent. in the untreated
caoea 3 this t;?e.  Of the fouc fF%l qxses, however, one died suddenly during
corxdes~ence iron pulmonary embolism; two of the casea were only treated when
<11?eJ' ver0 akzostn:t extremism, a few hours before death.   This leaves only one

case that can be considered to have been treated with any hope of 8ucce86, and
Lis :11as treated only on the fifth and sixth days, the patient dying on the sixth.

hp.

EPidezioloRp.  Dr. Docher and Dr. Avery have completed their study

0 f carriers.  The types of pneutnococcS occurring in the mouths of 113 normal in-

riividuals have been studied.  lbmi~ococci of the fixed types were found It times,
z2d these were always preeent in the moutha of parsons in close contact with pneu-

3x-k ptL3ats, the type found ln eadh case being that present in the cam of prl0U-

xnia afti: nhict &' ~.~e*personstudisd was in contact.  In 55 other persons pneuaococci
~=a also present, but these were all of the atypical group, Group 37.  The per
sistence of fixed types in the mouths of pneumonia patients &ad of carrietie has ale0

Seen studied, the fiaai results agreeing .koughly with those previously rsporbd.

     Am&last ic immunity.  Dr. bochet and Dr. Avery have oomplsted theystudy
of anablastfc immunity, and the results are reads for publication.
     Extraction of Immune Bodies from Ssxum Precipitates.  Dr. Chickering has
continued the study comeaced by Dr. oay and Dr. Chickering and has so dweloped
the method as to obtain constant results,   The best method of extraction has been
found to consist in dihzte sociitllP Gsxbonate at 424 C;  One patient suffering frrrnr

ai k-.isction with a type II ~ne~ococcus has been treated with such az~ extract given
:;:I ~utarreot?sPJ~ In fre y.:sntly rapezted doses.   In this case the olinical result8

uei3 excsl\;an';, and El0 lasts of the r;a.tient*s blood seened to indicate that %his




treatme caused a greater ixrease ir, lrznane bodies than had previously been ob-

serl*ed.  Th9 work of Dr- Buil also suggests that this may possibly be the method

,P
il, Scliie a8 by this mathod the immuzs bodies may reach ths blood more slowly.

m-. .
r.*lS ;;;6.tl?OS y:11 20 t- .ied furthar in casas of type If infection.   In the study of

`.::v+ :jj3
      9 ::; " .zcts 8 juicer of observations of theoretical interest have been made.


n.., I -.
. :.> ,`;= ir hy 3r. C>ic:<aricg daeliog a~th~atboso points is ready for publication.
3;. c'. : +;.ing
     e-e**.    ha been granted leave of absence for six months.  He goes to work

*tth 2. f&~y and 172::. cooperate with him in treating a series of patient6 with

+. -
;y"?dO ii fairar by an analogous method.   He will return In November to continue hi6

::ork i19re on pu3tmonia.

    Effect of Combined Infection of dptochin and Immune Serum. Dr, Noore
Laa worked in the Hospital during the past mix necks and be extended hi.6 studies

c: optochi?., corzenced with Dr. Flexner, in an endeavor to learn whether the ef-
fsc:ivenese, of irarrure serum may be increased by the addition of this drug.   The
rdsulta have boar, quite clear cut and ehon that the maximum dose against which ~IZP
xane aem will proteot Is def initel;r increased when the animal6 are treated at the

E-3228 time 7iAh *., .5 gm. of optochin given slznultaneously, or better, when 0.5 &m, is

-"-?a:: the first
--.       day. 0.45 &n, the second day, and 0.4 &a the third day.   These

Ibsea, kmever, are raiatfvsly very much greater than the doses that can be safely

-~.kiizistx-ad tc man.  Experiments are now in progress with larger animals of other

q3cias to s9e :;thether it is possible that a relatively smaller dose may be effectltre

S.2 larssr animals.

    Methods of producinn Agtjitre and Passive Tmnunity.   Btudiee carried
xx% in large series of anfnals shorv that the development of Jmmnvle bodies In the
6Sxvm of inmnxnized animals fs inhibited if very large doses of dead culture or
.yltigen prepared in various way are employed.  Eighteen rabbits so treated failed

to SNOT an;? bmne bodies in the blood whatever.  They all showed 6ome active in-

3tait y* iiOTEW9i~, I;= csrSain izstances of considerable grade.  These experiments

::rizg furtke1- nrocf ",:-.at iL.sre are certain features ti active 3mmunitp besides the


                                                                           .: 1 l?
                           -5                                : 2 `,
                                                                           .*


prc mnca oi kzx.ne sf~stancas in the body fluids.  We have called the former type
of imm%Git;- ~xnz+,tc kxuni$y in contrast with humoral -unity.

   Sli 433 ;tuiles izdicate, bovever, `ihat pure humoral immunity may be effective

. .  -.-
;I ". -3 illf8CtiOl; -Jt3 liOt extrm.8, ant! if the concentration of the imxnane bodies im


;. --
be.: >LooB ba of df:icient degree.  The attempts to increase the effectiveness of

.L*.
"I,C :?C-L3iqZC fc:.:tcjrs 3y other methods of Immunization have shown that this may be

do;:3 y:.-
      a  Ire ;ue71t7 ..y repeated small doses of dead cultures or probably better by giv-
ing !rs?uantly reraated da11 doses of live culture, combined with innnune eer%an,
                   e
Fro?:, tha studies on rabbits and goats it seems that a very definite advance has
bem made in the practical. method of hnunitatio~;        .

          HWart Disease      Dr. Cohn and Dr. Jamdeson
  The records from cases of pneumonia have been collected and are being studied;
first, to see, ln properly sbmlardixed curves, such as these, what change0 occur
in the electrocardiogram as the result of the disease; second, to 888 whether
digitalis cauees changes in the curves from these patients slmllar to thoee seen In

LO. .AAJ CW'V~S from patients suf ferlng from heart disease.   The studies indicate that


     2 .-
CL;"": -.- -;:r\;y ;" ;' .`.a occur as the result of pneumonia, and these changes serve as a


-.
. . -!.z for ~aie~~iiii:1g t:le degree and nature of cardiac involvement due to pueumonie(-o

r::: ragard $0 the second point, It has been found that digitalis doee induce ln
~nfixo'ilia patients changes s&nilar to those seen in patients with non-febrile he&
dkease, as indicated by electrocardiographic curv~s~
  The problem of the reliability of the electrocardiogram aw an indicator of
cardiao hypertrophy la being etudle&  Comparlsoas are balag made with the X-ray

shadows, and also with the weight of heart muscle.  Dr. Jamlesoa le trying to
produce :?ypertrophy in dogs by work (on a treadmill).  Dr @oh23 Is making a sfmilar

effort in dog3 in rlhith srti+Oicial valve lesions have been produced.
  The stU3y of patients alth chronic heart dieeaee Is being contimed along the

Tfaes pravlously il;~!.ce.tsd,

   Studies coi:cer-,i-, :* - -*
         ..= m-rre:oxma of contraction and conduction are planned.   To


.~                                                         

                              -6.              1 ?I`
                                                                           . -

renier %usa stuiias possible it hss Seer, . . -scessery to install a second &.lvsnometer,

so that simultanaous recoi*ds from trro points on the surface of the heart or on other

zmtracting organ may be made.   This se zond &Llvanomete r was aodered last autumn

`Jut , Odng to delays incident to the war, has just been installed.   The installat ion

n2 fkis galvanomoter is oi
.I -             importance in the work, not only because these special

;lxliJ; are rendered possible, but also because the new instrument is of much great-

- L' ay'curs:~ 3~;; ,t:la old one, and so much more exact studies are rendered possible.

-.
_ .; r.Sw i,?Stmo;:t ::as main17 constmcted i?r this country according to design

:*.:yy.i &ad by Dr. V. B. Villisms, and the tests have shown that the instrument en-

5k-ly fulfills the expectations.

       Diabetes.  Dr. Allen is continuing experiments showing the effect Of
raising and lowering metabolism (food, temperature, exertion, thyroid, etc.) upon
oqer?nental diabetes, observations thus far supporting the idea that increased
netabollsn increases, and dimlnfshed meiabolism dimlnlshes the strain upon the

ir.tenal pancreatic function.  The coming of Dr. Palmer has made possible a series

of experiments to test the hypothesis of cwnblned sugar,  This series of experiments

leaIs nit'n ieeding and injection of sugar In normal and diabetic animals, with tests

of the blood for sugar, estimation of hemoglobin content, and eatimatioa of various
physical properties, (vlscosltp, surface tension, freezIng point, conduotAvity)

End parallel observations concerning the urine, lymph and tissues.

    Dr. Stillman is carrying on the treatment of patients on the lines p+

vlously laid down.  The number of patients at any one t3me averages from ten to

: i:t can.  He is studying particularly the question of acidosis and blood-sugar.
in wgard to acCdos3.8, the analyses made are for the three acetone bodies and EWXHP-
ia Ir; tke xi$a, and. C 02 tension An the alveolar air, in parallel with the blood

studies Of Drs. Van S>yke sad Cullen.  The C 02 detenainatlons in the alveolar air,

and blood seem to offer the most satisfactory index of acidosis.   Patients with

slight acidosis or no::9 na:j, during the inltlal fast, show the sezm slight acidosis

as a fasting normal ;?er30n*  Cs.ses with severe acidosis, however, invariably show


a iQO33Ss il; acidosis during the fasting.  All tests confirm the clearing up of

aclclosis under the treatment.  Sugar is determined in the whole blood and in the

,Ir?~a, with some idea o* + observing the permeability of the corpuscles, but chief-

l;- -lo learn wh3'lher the treatment reduces the sugar conteht to normal.   This has

~:-.?y.`~.J to `ca so in come very severe cases, but in some older patients it may per-
&pz not 30 necossarycto attempt this, and the question whether it is possible ip

tivory case cannot be answered at present.

          Studies carried on in the Chemical LaboraMry,

    5&h of the work reported in April Is still being continued, but some of

t& problems have boon brought to a sufficiently definite conclusion to prepare
                .

for publication:

   Studies of the Abderhalden Reaction by Dr. Van Slyke and Miss Vinonrad

Sufficient data have been collected with our quantitative method on the pro-

tanse zon:ent of normal and pregnant sera to justify considering the problem as

closed, and sha Abderhalden reaction for pregnancy as rrorthlees.

    ~Iiss Vinograd, with material furnished by flrr Isaac Leoin, has had simila.r

re sCts in attwptlng to apply the Abderhalden reaction to cancer diagnosis-   As

o--`~* one preparation of cancer tissue was used in the tests made, however, the
`-0.;                                                                           .,

uselessness of the reaction for cancer diagnosis c&mot be aff inned with the lsame    5

degree of finalftp that appears justified in reporting the results of the p=mCy

test.

   Pfabetdc Acidos&   Dr. Van Slgke, with Drs. Cullea and Still=% is
making an extended study and has obtained suf ffcient data for publioation OA the
first points of attack&  Data have been obtained covering, in 6ome cases, months,

with almost daily analyses of the urine and deterWnations of the alveolar carbOA

dioxide, with, for comparison, determinations of the actual reserve alkalinity of

the plasma by our i>%w :.&I?ods, viz, the determination of its carbon dioxide capa-

city, aA of 153 r.2X.it~  to maintain a neuba& hydrogen IOA corrcentration after

.?C; 3 Itlor. 2,I' z.ci.3 o    `P  ?&I taats aFo~ tire actual condition of the blood, and are


                               -a-                          r; ; '
                                                                           .4 h -,
                                                                           . .

cc -'3? 4 -.--
     r-b,. 46 ",h: iksp sewii:.y s:.lw even ths slightest physiological variations in

:`oserve alka:in+ty,  Tim alveolar carbon dioxide determinations run fairly parallel


. ..L*. A.*.
_ r_. --AS blood i'esults, and r;e have not yet observed a pathological change that Was

:;cL, :ho-~1; simultaneously by both.  After the direct blood tests, it appears that

-:.e ?.1-%o%- carbon dioxide tension is the most sensitive indication of a state of

  . -
.L"lLX3iS.  iJrii:o analyses pi any kind are much less reliable, although a gross

t ;?nnga in the direction of acidosis is usually accompanied by an increase in the

n:LIor~in crutput.  `3s acetone bodies, on the other hand, may give no warning, even

C2 the verge of co-

     One point in which the blood and alveolar air tests promise to be of aid

in the Allen Treatment of diabetes is in controlling the condft ion of fasting pa-

tients.  &me devalop no acidosis, or very little; but in other case8 acidosis

doss develop rapidly, becoming marked after a single day's fast .  A control by

Wick and sensitive methods for detecting the presence and dOgr88 of acidosis sO8ms


-. . `"?S%nt, for as yet there is no wuy of telling which caa8s will develop acidosfs

3:: %8 treatment, and which will not.,  The sensitlveaess of the methods developed

1.r.s zcovered a physiological problem as an offshoot of the acidoeis work.   It heI0



_ iF,z believed by some authors that during digestion acid products were ppured into
Xie blood, aad that these were responsible for the increased general metabolic and

:;az'c psoduction noted after a meal.  By othere it has beeA believed that, on the

co`ntrary, the alkalinity of the blood increases, because of the secretion of gastric
liydrochlorid acid.  EqSrimeAtS on men which w6 have already performed to test this

point have already shown that an ,appreclable increase  IA blood alkalinity usually

follows a meal.  The work will be continued on both'animals and men, the effect of

digestion of carbohydrates, fats, and prote$.ne being studied, and also the effeot of
stimulation of gastric secretion in the absence of digestible foods, so that the few
dative effects of H Cl. excretion and of absorbed digestive products of various

;:ature of the blood alkalinf5!7 can be d&barmfned.
     Tha -;jorlc of !`i3s Vinograd with Dr. Osborne of New Haven OA the ~i.nO


                               ;q
                             -9-                                        ; I'


acid xn3os~-;:=\rl cf
- .._ -A .__.__ A.-. ?Oti proteins is 3aiv iming prepared for publication.   &
b,n,SiC COZlstiblcxt6 d riGo protein, wheat gliadin, and milk dbdn have been
dAominod By entiraly differont methods in the two laboratories, so that errors

by acc?~ could he eliminated,  Consequently these determinations are probably &e
aost thorou&ly controlled that have eva been k& in amino acid determinations

c.p proL,ains.  The reslllts have a direct bearing on the interpretation of the AJX+
portant tvork of Xxzdel and Osborne in their nGrowth Studiosn, in which la&a-lb*
iiLS ?nd gll?Ain h-.vo been used 2s roprcsontative proteins.

       Nephritis.  Dr. UC Lei3n~s studif with the sensitive functional tests

Cz: '1:'oa end Edt exorotion, `are being continued, with a groduolly w@ating
rx-,:z of data ;vhich premises to be of definite Value in the di43nosis and prognosis
:2 d?s,'ferent t;rpes af nephritis.
    One case of postpnmania nephritis ~23 particularly interesting as

A.- -.X iICphAti5 VJZLS accaspanied by an exceptional type of acidosis.   Plasma tests

*Z?-GA-O2 a degree of acidosis which, at its height, was nearly equal to that seen
is 3inba"vim threatened with ccrm, but the onxnonln excrotim, instead af being
i:xzrmsed, was a,bnomd.ly low, being less than cm per cent of the total nitrogen*
%rz~~g convalescence the return cf blood alkalinity to normal has awconpanded the
restoration of kidney function, axI the exncmia excretion has risen gradually t0

normal.  IIenderson and Palmer, of Rarvard, have reported nephritic6 in wha a ,
low anznonia excreticm accaspsnied an acid urine, but could not demonstrate axi&-
ence of actual acidosis, as has been done by the plasma tests in this CaW3e