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REPORT OF THE
DIRECTOR OF THE HOSPITAL OF
THE ROCKEFELLER IMSTITUTE,
April 1915.

Acuts Lebar Prewnonia, During the quarter forty-three patients sufforing
iror. acute lobar pneumonia have been adiitted to the Hospital. This numbet 4s somew
saat larger thar. the number admitted during the same period last year. Of these ¢
vatients ten were dus to pneumococei of type I, All the pationts of this type were
treated and all rooovered, _ No observations have been made to change our former con=
clusions as to the efficacy of serum of type I. in cases due to type I infection.
Curin> the present winter only a part of the cases due to type II have been treated
with irrune seruz. The resukte have not been Satisfactory. There has been no evi~
sou.ca that the seri: has had any very marked effect, At the present time we are
0% treating cases 2ue to thie type of organism with immuno serum.

Small amounts of the serum of type I have been sent to tne Brigham Hospi-~
‘al in Boeton, the Presbyterian Hospital in New York, and to Dr Hanes of Richmond.
ports on the results obtainad have not yet been received. te the type I serum is
to ts sent out and to be used more or less indiscriminately, an important question
is as to the use of preservatives. No preservatives have been employed in any of
the serum so far used. It is obvious that the use of such serum is accompanied by
considerable danger, Considerable study will have to be made te determine whether
the use cf a preservative is practical, where such large amounts of serum are ade
tinistered, A practical method of concentration of the serum would, to some extent
overcone the difficulties. The study of methods of concentration by Dr Avery and by
Dr Gay and Dr Chickering has been of great theoretical interest ,but,so far, these
studies do not seem to be of practical applicatione The method employed by Dr Avery
requires vary exte:aive handling of the serun, with corresponding danger of contami-
cation, and a doncentration of only about four times is obtainede The concentration

cf serum by ths method deseribed by Dr Gay and Dr Chickering has demonstrated the
~2-

sbility of obtaining the inmune \odies in very small amounts of protein,but the
‘ts so far,owing to untnom factors, cannot be constantly obtained, and in many

.3 where such results are obtained there is considerable loss in the immune sub—
12, 86 that the method practically would be verz expensive. Important principles,
‘Ty, have been demonstrated by these investigations and it is quite possible that
--ical application Hay de mada of them. The important fact, however, has been de~
ined now beyond any aouht that the limit to the practical application of this form
-.2Tapy ds dependent upon the degree of infection. If the infection is of a certain
~s no amount of immune serum will protect, and concentration of immune bodies is
-< Practical advantages Observations which ve have made, however, indicate that,
-. tie concentration of imcune bodies in a given serum may not furnish better pro-
sn than ds obtained by the unconcentrated serum, it may be possible to produce

- of nigher grades of protection, possibly depending upon the so-called avidity of
«10 Dodies for the bacteria,

The therapeutic treatment of cases of type I now seems to have reached a

tical stage, while the treatnernt of pneumonia due to other types is still in a
-¥ experimental condition. The New York Board of Health is now preparingmserum of
‘3 IT and serum of type I is being prepared vy Dr Lewis at the Phipps Institute, Phila ©
-Falae Commercial houses have desired our compperation in the preparation of serum
- “6 have discouraged their taking up this matter at the present time. A more de~
-tsd account of the exact nature of the work on pneumonia follows.

Observations dealing with the occurrence of Pneumococc’d of various types in
-touths of healthy persons, and in those of persons sick and convalescent from pneu
a are being constantly carried on by Dr Dochez and Dr Avery. Twssty families in
sh one or more members have been sick of pneumonia have been quite thoroughly studied.
“: olght of these families one or more healthy members have been discovered to be
“ters of pneumococci of a fixad type. In all the so-called carriers so far de-

-néd the type cf organism has been the same as that responsible for the case of

 

 
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cieunonia in the family. These carriers nave been followed wherever possible until
the fixad virulert type of prnaumococcus Sisappeared from the sputum. The longest

rériod during which healthy persons have so far been found to carry the fixed type of
vrsanise has been forty days; the shortest twenty-one days; the average approximately
thvity dayse In none of these carriers that have been observed has pneumonia devel-
enede Three inetances of pneumonoccus infection occurring in individuals in contact
vith cases of vreuxopia, however, hhve been observed and studied. In each case the

tyne of organism isolated corresponded to the type found in the case considered as the
souree of infection. urther studies have oeen made concerning the length of time
during somvalsscence, during which patients with pneumonia harbour in their mouths the
ifgad virulent types of pneumocozcd. The longest period during which the patient has
savvied She pnaumocoscus of the fixed type has been ninety days, and the shortest period
nas de2n trelve dars;éhe average has teen about twenty-nine days.

Strdies concerning the mode of action of antipneumococcus serum are being
made. Dr Avery has shown that when a mixture of pneumococci and anti-pneumococcus
serun is made no dbacteriolytic or bactericidal action could be observed, When,however,
raites are made from the mixture at short intervals of time, there can be demonstrated
a weliedefined inhibition of growth during a period ef about six hours. This retarda~
tion of growth is not dependent upon agglutination, since it may occur in dilutions of
serum in which no agglutination of the organiem occurs, and it is not completely speci- “|
fic for the different types, while agglutination, on the other hand, is very epecific. 7
This phenomenon has suggested that part of the action of the serum may be due to ine
nibition of certain metabolic activities of the bacteria. We had previously found that
iovune serum when mixed with pnewmococci did not inhibit the power of the lattsar to
produce methemoglobin. Later observations, however, have shown that if the bacteria |
and serum are allowed to remainlin contact with one another at 37°C for two hours pefore
tne hewoglohin is added, no methemoglobin formation occurs, so that the serum apparently

doss possess tue power of inhibiting this functional activity of pneumococci.

 
neni ena

 

   

Dr Deenss and Dr Avery ars making observation to determine whether or not
the serum izhibits certain digestive and feruentative properties of the pneumococeus,
especialiy the formation of amino acid from protein, and the fermentation of various
carbohydrates. It has been found that when the normal curves of these types of acti-
vity have been determined, when immune serum is added to comparable mixtures there is
either complete or partial innibition. It is possible, therefore, that a part of the
action of ixmune serum may be due to the inhibition of fermentative processes, which
tacteria carry on in the medium immediately surrounding them, which processes are neces=
sary for the life of the bacteria. Experiments indicate,however, that the inhibition
of these activities of the pneumococci are not absolutely specific as regards sera of
the different types in relation to the corresponding orzanisms.

Dr Avery has made a study of the relationship of the fermentative reactions
of the differert types of pneumococci to the antigenic differences. A large number
of strains of the different types have been studied, but no welledefined differences
in tne fermentative activity of the members of the different groups could be determined.

Dr Chickering has continued the work comrenced by him and Dr Gay on the speci-
ile precipitation of antitodies from antipneumocoscus serum by tacterial extracts.Their
conjoint work has already been published. Various methods of producing the bacterial
extracts have been tried, but the use of large amounts of acetone as employed by Dr
Yan Slyke and others in the precipitation of ferments, has proved to be of the greatest
value. Dried acetone-precipitated bacterial substances go into solution much more
easily than the bacterial substances prepared in other ways. The fractional employ-
nent of bacterial extracts in the precipitation of irmune serum has been found to be
sfiective in completely removing the protective substances from the serum. To remove
the bacterial protein from the serum precipitate, the best method has been found to
consist in extracting the precipitate with normal saline, after the addition of weak
a.xalie, as sodium carbonate, heating and shaking. The supernaten’ fluid after cen-

trifugalization contains onlyia very small amount of protein and apparently protects
Stirals as well are ths wholg serum. fush extracts not only contain the protective

susstance, out alse acclutinin and précipivins, Studies nave been carried on to de-

vercine the toxicity of the extracts in various aninale, under various condations. No

Mcinistration of such extracts has yet been made to patients, but the experiments ine

-icnte that there ig little denger ef sheir Froducing toxic effects. Studies have also

seen made te detenning tne duration of the inmunity following the adainistration of

and also the possibility of produsin-~ 313

extracts, & Siigat active, as weil as passive, im

‘Unity, by means éf suck. extracts. Apparently passive irmunity, whether obtained by

vhole serum or precipitates, kas disarpeared at the end of about five dats, but aftor

“-& days when the extracts are used Blisht srades of active immunity are seen,

Studies are being sarried on by Dr Cole with the assistance of Miss Stryker

sith have for their objects first, the determination of the differance between active

“Ld passive pnsumoceccus immuhity, and Secondly, the production of mors effective ime

“be Serum. By careful qualitative studies 4: mice it has teen found that by the pro-

“sstlon of very slight grades of active inmrity the cegree of effect obtained from ine

tums serum is very markedly increased, mich more markedly tiian can be accounted for by

. Simple aidition of the two factots. Second, ty traating animals with @aily doses of

-iving bacteria, combining these doses of bacteria with an amount of immne serum suf-

zistent to protact tha animal, it has teen found possible to produce within three or

cur weeks such immunity in rabtits that the serum will protect mice against doses of

virulent culture as high as 1 to 1.5 c.e. » whereas horse serum, obtained by the ordinary

rethod of immnization, even after six months, or even after one year's treatment, is

able to protect against no mors tian sl or at most .2 ¢.c. of virulent culturo. A

reat is now in process of immunization, and if the serun of this animal proves sitfica~

cious, we shall proceed with the di:rmumization of horses by thic sew method.

Dr. Conn, Heart Disease,

It is seusrally Helisved that the form of the electrocardiogram remains con

‘taut in human beings for lonz periois of time. In experiments on animals it has been

 
=~ 6 =
found that its form can be altered by the application of heat to the apex or base of
“© ventricle, by the application of muscarin to tha surface of the heart, and by the
tinulation of the vagus nerve, In studying the curves of patients to whom digitalis
is given we have found that under the influence of this drug the form of the electro=
>réio-ran is also changed. The change takes place in that part of the curve in
cluddd between the R and the end of the T wave. The T wave flattens and later becomes
-nverted in the greater number of our patients. It is a general rule that inversion
c: the T wave depends on the fact that the apical portions of the ventricular muscle
ire, relatively, electrically more active than the base. Digitalis evidently has the
rover of bringing about this state. Ye have discovered this effect of digitalis in
2 day and a half to two days after beginning the administration by mouth. It outlasts
“32 adrinistration by five to twenty-tyvo days. If the presence of the electrical
hance actually means that the drug is still present in the heart muscle, it bacomes
‘lear why digitalis action in patients comes on so promptly when a second course of
treatment 4s ocegun ten days after the first ended, for after so long a period complete
:cinination ia usually believed to have taken place.

Ye have utilized this Sisn of change in T waves in studying the question of
sianlation of failing hearts in pneumonia. In pneumonia, especially among acute in= |
“ctions, the value of digitalis as a stimulant has been much debated. The first
0int we though, which should be decided, was whether there was a way of determining

~at digitalis was exerting an influence. It was clear, from our own and from the ex-
periences of others, that te judge by its effect on the rate of the heart was valueless.
“e found in the electrocardioprams of pneumonia patients what the T wave changed just
sit does in the non-febrile. The changs takes place in about the same length of tine,
and it requires about the same amount of the drug to produce it. Te have, therefore,
Aueans of telling that digitalis does produce an effect. Inthbe group of patients

42 avélop auricular flutter or fibrillation, a rhythm of the heart, which develops

-Oitaneously in pneumonia, digitalis is beneficial. The rate of the heart, when

 
an
saese rbthus occur, usually rises to a great heicht. Disitalis has the power of re#
icing the ventricular rate in them, by blocking the auricular impulses, just as it
is in non-febrile patients having these tyythms. Whether it is beneficial when
t.¢ chythms is normal, we are not yet able to say.

Dr Jamieson has attempted in another way to find whether there is a iiffer-
-see between the action of digitalis in pneumonia and the non-fetrile state. Hoe in-
‘ceted crystalline strophantin(ouabaine) intravenously into dogs and cats, to find the
-inimal lethal dose ger kilogram. In this he followed the method of Hatcher and Eg-
‘leston. Then he injected a number of dogs and cats with virulent cultures of pneu-
zeesd by the mthod of insufflation, hen the animals were at tho height of the di-
sease, he injected strophanthin into thom in the sare way as in the control. He found
that the minimal lethal dose per kilogram was the sane in the infected as in the non-
infected animals, 6.1 mgm. in cats and 0.12 mgm. in dogs. Post nortem the lungs ©
cf the animals were seen to be consolidated,

Tae conclusion ie dravn from the observations in patients and from the ex
rerimonts in infected anirals, that digitalis or strophanthin, may be expected to act
in the samé waye

Dr Cohn carried out experiments, sone time ago, in dogs which showed certain
quite definite differances between the action of the right and the left vagus nervese
Tae main difference was that stimilation of the right acted more especially on the
pace-naker, while stirmlation of the left acted nore especially on auriculo~ventri-
cular conduetion. Experiments were next carried out to see what influence the sino-
auricular node, usually accepted as the pace-maker of the heart, exerted on this dif-
ference. The sinus node was therefore destoryed in the jaws of a clamp. It was
found that stimulating the vagus nerve still showed about the same differences as
tefore, except that stirmlating the left vagus nerve caused a greater effect on the
vace-razing funetion than it did before destewying the node. This effect differed

, vefere clamping, the auricles continued to peat during stimilation, after

slanpins they ceased. It appeared, therefore, that an influetice which caused the

 

 
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“.534e8 to sontinue to contrast suring leit vagus stisulation had been destroyed. The
s.nnt vas therefore rade to discover whether the accelerators provided this stimulus.
os? 7308 accordingly sut ina number of experiments, sometimes the ri¢ht, sometimes
leit, and sometines toth, Cutting ther produced no influence on the usual differ
*; Eotuveen the vagus nerces. What mechanisr it is which is affected wen the S-A
-‘¢ ib destroved, has not ye. been ascertained,

The study of the action of digitalis in pationtsa suiforin;; from heart disease
csing continusd. Tne action of the drug is teing studies on rate of the beats,on
suction, blood pressurs, diuresis, and its effect on the electrocardiogram. Former

- [6.08 have dealt sith its astion in payients having simple forms of disease. Ye are
. 20llseting data in nore complicated forms in which abnormal rhytims, high blood
Ssure, o@dera, and dypsnosa are found. Experiments in aninals are going on, plane
- t@ correlates the chan326 which take plave in the size,shape and weicht of the heart
“r various conditions with the eiectrocardiographic curves. The shape and size are
"dled by X-ray observation = the weisht, post mortem. Those animals are to be

“ated under the conddtion of strain, as when dogs run on the tread-mill, and also in

Fvescnce of artifielal valvular lesions, The influence of digitalis on them is

-0 10 La studied,

Study of Diabetes. Up to the present time forty-one patients with diabetes
ve been treated. in this hospital. The results of treatment of patients, tp to the
:vesent, are as follows: Total nunber of patients treated, forty-one. Number of
xaths, five. Of these, two wers deaths in coma shortly after entering the hospital;

“<t patient with a sever cardia leston died of heart failure, shortly after entering

3 hospitals one boy died following a break in diet; one man recently died after

“sral months of declive in spite of traatnent, and autopsy showed caseous{ tubercular)
-"snnda. Two cther patients treated 4n coma were brought out of coma. Of several

#8 received sless +o coma, rene ent into coma. Two patients have left the hos-

 
ws EN
ee

~ vithout permission cr instructions, aitoar several months of treatment and improve-
. (One of these left because he imazined himself well.) Twanty patients have been
rz24 in satisfactorg$ condition, free from glycosuria and acidosis. Several of
“ere childrec, ranvinz from seven to seventeen years of ase. Two patients have
~-d eving to treaking diet, but have re-entared the hospital in better condition
1 first, and have teen cleared up more easily than at first. One other patient

as +

olisht relapse owing to the advice of another physician that he eat bread. Other-

J reports show continued freedom fror. glycosuria or symptor's. This includes

‘crotreet, the first patient, «hose case was one of the severest. The remaining

ml:
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PS

.-G in the hospital are kept sugar-free and apparently improving.
Tie reutine study of these patients, involvingas it does a very large number
. ical enaiyses of urine, requires mush tine and labour. Under the section |
' Go irom the Chemical Laboratory" is siven a description of the studies of aci-
:vhisn are being made.
Ds Stillman is alse studying the blood sugar in a series of cases, especialiy
lcrense to the relation between the concentration of sugar in the blood and rate
-ssreviox in the urine. |
As will be remembered, the theoretical. basis of the treatment employed is
. pancreatic function may be spared by diminishing body mass and metabolic activity.
‘s vas based on the changes observed ih depancreatized animals, under varying condi~ .
+8 The studies in animals are being continued, parralel to the studies in patients.
tially depancreatized animals are being subjected to conditions which alter body : oy
3s or metabolic activity. It is hoped by such observations to obtain evidence in
“ort of the theoretical deductions on which the treatment is based.
Dz Allen has previously brought experimental evidencx in favour of the view
. blood sugar exists in a differe:t physical state in diabetic and non-diabetic ani-
‘&. Experiments are now under vay and observations are being made having for their.

pose the demonstration of sush physical differences.

 
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Tne study of morphological changes in the Islands oi Langerhans occurring

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Liletie animals and in patients is being continued. The large amount of material

wdivals in all stazes of the disease, as well as o? fresh huuan material, affords

.settioual opportunity for the study of this problem.

ph roseiienrirreey

Pe et eI ge ne LR at a

% is nov planred during the sumer to publish the naterial sc far obtained

- 2orn of a “ienograph. This vill include (a)a report of the animal exverizrents .

  

_ Tort, the sasis for the propoesd modification in the treatment of diabetes; (bd)
s.irtior of the rthod of ‘traatmert and reports of clinical cases treated.
Studies concerning tie Nature of Acidosis and especially Acidosis ir Diabetes
rv Van Sly:e, Dr Stillman and Mr Cullen have undertaken a study of acidosis
1 UDTe6. Pralininary work by Dr Van Siyke and Dr Stillman has indicated that the

waiiuation of the carbon dicxied tension of the alveolar air is one of the most

 

vile wethods, if not the most vaiuaole method, of determining the actual condi~
.¢f the patient, as rezards acidosis. A very large number of observations of al~
as COg vension in the patients with diabetes has been made by Dr Stillman, by a

wrod thiol is quite sinple, but seems to yield accurate and comparaple results, at

-:$ in patiants not comatose, and who can be daught a very simple procedure. Dr Van
ze and Mr Cullen then wndertook the problem of determining the changes in the bloo#
ish corresponds to the changes in alveolar carbon dioxide, in order that the inter-
“tation of the latter determinations might be put on a firm scientific basis. Mr
“len has gone on with the work commenced by Dr Zacharias last year, the direct de-
-urdnation ef hydrogen ion concentration in the bloo by electrometric methods, and

. devaloped the wethod for the present purpose. It had already been shown dy

“saslia and ethers that in acidosis the actual hydrogen ion concentration of the biood
_l3xgoes little or no change and Mr Cullen nas confirmed these observations. It ther
3d that it might be possible +o determine by this method whether or not the reserve

+y of the blood in such cases was decrea@ed. To determine this two metaods

“3 beer employed and by. these methods i+ has been possible to determine that such de--

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wken normal plasma is treated in the same way. As an example of results,the hydrogen

1h ual

    
  
 
 
  
 
  
 
 
 
   

cle ae ne ee ee eee reg ae ee ee eee nem”

W~1ll-
rreaco in reserve alkalinity is actually prdsent. First, when a given amount of
4C1 is added to the plasma of a case of acidosds, the acidity developed, as measured —

“y the hydrogen ion concentration with the electronetric method, is mich greater than

ion concentration obtained after addddg one volume of “As H Cl to the plasma from a
severe case of acidosis wae one hundred and fifty times as great as the hydrogen jon

concentration of ‘normal Plagne similarly treated.
Second, Dr Van ‘Slyke ‘has béen able to show that the ability of the- placma --

to fix carbon dioxide which, of course, depends on the amount of reserve alkalie, in

Sa a ae a Fatt ee a Rr rer Pe pn ; ae

such torus ‘as s alkaline + pheno and ‘carbonate, ‘4s reduced in acidosis.” In order’ to

  
    

   

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a3 the result of which the COs gas iumediately leaves the solution. The mercury is .

shen let back into the pipette, and the volume of CO, read off on the upper stem,on. |

“nich a scale is etched. Duplicate resuits rarely vary by more than one per cent. .
Normal plasma binds 75 per cent of its volume of COo. In cases of acidosis

-2 fijure may be as lew es 20 per cent. This new and simple technique for determining

 

th3 co, capacity of the plasma provides a clinical method for the measurement of aci- x _

cosis direstly in the blood itself. Ina series of cases there are now being deter=

 

vined iitenecusiy, firet the alveolar * C035. second, the alkaline reserve of the plas :

sau 8 studies: arried ere the nemical taborate “under the

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resuits obtained have not indicated that through immunization, at least with pneuno~
socci,one or other of the protein fractions 4s increased over the normal, Whether a
sindlar erltical study of the effects obtained by immunization of horses to diphtheria
toxin will yield similar results,contrary to those now generally held true, cannot be
stated but these observations throw some doubt on present conceptions. i
The study of the ‘enino acid content of certain proteins, which Dr Van Slyke
and Miss Vinograd becan, over a year ago, in collaboration with Professor Osborne of |
New Haven, has reached a satisfactory conclusion. One point of interest which has
finally been settled concerns the content of cliadin, the principal wheat protein, in |
lysine, one of the amino. acids which the work of Osborne and Mendel has shown to de- : LA
absolutely escential for, srowth. , All work except that from this laboratory had “pros
viously indented that this wheat protein contains no lyeine. Nevertheless Osborne”
and Mendel found, that they, were, able to cat least maintain rate in quilibrivn with tne’

 

as their so16 protean, fot

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of the dying Tn Hospital, “has. boon. ¢ contimaed. ‘The nethod exployed, has ‘consisted. ‘ta

 

de termining the, Ancrease ta aminoen! ‘trogen in. the ‘mixtures as indicating degree’ of

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proteclysise - Piret, proteolytic ‘enzymes ocour, dn measurable amounts in every. normal -

BerUwie | ‘They are by no means characteristic of | prognant serae _ Second, such proteo~

 
~i4'~
tic enzymes digest not only placenta protein, but other proteins as well. Third,on

: average the enzymes in the sera of pregnant women are somewhat more activexx than
338 in the sera of noi -pregnant woren and of normal men. The individual variations,
-cvor, in the latter cover nearly, if not quite, as great a range as those of the

cicft precnant women. In certain pathological conditions,morsover, as in pneunonia,
- ar..tly the most active disestive actior is seen. No evidence, therefore, of the

c .to of a specific enzyme in the serun of prepnant women has veen obtained. The
coat quantitative variations observed in the amount of the non-specific ferment pre-

t in normal and pathelogical sera, as well as in the sera of pregnant women, indi-=-
vig that the Aoderhalden reaction is unreliable for the diagnosis of pregnancy.

4th the assistance of Dr Losee at the Lying In Hospital, studies on the tox
‘4a of pregnancy have veen carried out. The most concrete theory corcerning these
‘oxemias has been that of Eving,according to which the toxenias are due to liver insuf-
ficiency. The cherical evidence for this was the increase of non-determined nitrogen
in the urine, which Ewing attributed to excreted amino acids, which were supposed to
-ave escaped normal catabolism because of the inefficient liver. Direct determinations

' «he amino acids, aa well as the other nitrocenous constituents, not only in the urine
‘yt also in the blood, have teen made, and the amino acid content in both has been four
to be absolutely normal. The results make Ewing's hypothesis untenable. The abnormali
ties of the urinary nitrogen appear to be, as surmised several years ago by Underhill
of New Haveny the abnormalities of hunger, and nothing more.

Studies in Nephritis. Dr McLean has continued his etuay of kidney func=
tion, and has used for this purpose cases of cardiac disease admitted to the Hospital
‘or study and, in addition, a small number of cases suffering from nephritis of various
types have been admitted in order that studies may be carried out cn them. Dr McLean
has continued his study of the ratios between the concentration of chloride and urea
ir the blood and the rates of excretion of these subs* bances in the urine. The method

5: sstimating the excretory afficiercy of the kidne? in this manner has been reduced

 

 

 
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,

tu a yracticai basis Ly Dr IisLean, so that the resuits are expressed in per centage
of norral efficiency. The labour of calculation has been reduced to a minimum by
ivisiny a slide rule for the purpose, which enables one to perform the otherwise
-.ovhae prolonzed calculation in a few seconds. The rethod for determination of
calsriles in small a.ounts of plasma has teen further simplified by Dr McLean so that
results can readily te obteined within a half hour after the blcod has been drawn.
Tt is plaraed to continue this study of nephritis, employing this method in compari-

“vi 2th other methods for determining kidney function.