REPORT

OF THE

DIRECTOR OF THE HOSPITAL

TO THE

BOARD OF SCIENTIFIC DIRECTORS

OF

+

THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH

APRIL 21, 1917.

Pie

«
TEPORT ON THE WORK IN
THE HOSPITAL

Rufus Cole

As usual the midwinter quarter has been
the most activa of the year. Much of the work under way, however, has
not yet been completed and final reports of results can only be given
in the report for the succeeding quarter, No changes have occurred in
the staff, As usual, so far as possible, the work will be grouped undar
the headings of the diseases which are being studied,

PNEUMONIA, = During the present winter the mmber of per~-
sons suffering from this disease who have applied for admission has been
greater than ever before and it is evident that this year we shall treat
in the hospital at least 150 cases of this disease.. The relative mm-
ber of cases due to the different types of infection corresponds well
with that of the cases treated during previous years, About one third
of the cases have been dus to infection with Type I pneumonocci. Up to
the present we ldve "had''33 ‘such:.cases and‘ of ‘these’ 29"were’ treated with
_ serum.” . The:remaining 4 “cases were’ not’ treated ‘because they were admitted
late “in the ‘disease when“revovery Was’ épparéntly"inprogress* Of the!’!
_ treated 29 Casse\all irécovered but ore. Thia*patient Was’ admitted ‘Late
-in the diseage “'on the" seventh: day;* ‘suffering from ari: extremely ‘sévere
infection, ‘cultures’ fromthe ‘blood ‘showing 1600:.colonies ‘per’ co. This!
patient was very intensively treated, though perhaps not so actively on
the first days ag we should now consider advisable. Although a marked .
effect was obtained on: the septicaemia,.and no extension occurred in

the lesion, the patient ‘finally died on the 12th day. Before this time

fibrillation of the auricles occurred and it seems probable that in this

 
-¥ -
case the intoxication and injury were so great at the time treatment was
commenced that recovery could not occur, even though progress of the di-
sease were stopped. Adding the cases this year with those previously
treated makes a total of 101 cases with only eight deaths. The Brigham
and Presbyterian Hospitals which we have supplied with serum have also
continued to have very good results. The accumulating experience seems
to leave little doubt as to the efficacy of the serum treatment in this
type of cases. Determination of type by Board of Health and other labo-
ratories also seems to be practical, though at first there have been dif-
ficaltied owing to lack of experience of the men making the teste. In-
terest in this matter has become quite wide spread and considerable time
hag been spent in demonstrating the technique of determination of type
and serum treatment in persons coming here for the purpose, During the
pest year or two several commercial houses have been extensively adver-
tising and selling so-called antipneumococcus serum. ‘We have made tests
of all these sera and are also controlling from time to time the sera
prepared by Boards of Health. The sera prepared by commercial houses,
up to the past few months, have been worthless. Now one of these houses
is preparing a satisfactory serum, and to all of them we are supplying
proper cultures and samples of serum for making comparative teste, 20 one
that we hope that very. soon all. of them may be mamfacturing satisfactory
products. Of great. importance, we think, is that fact that most (of them
are agreeing to manafacture Type I sera and so label it, The determina- .
tion of a standard: of potency has now become important. Steps have been :
taken to have the Hygienic Laboratory of the United States Public Health
and Marine Hospital Service establish such a standard, It haa been ar-
ranged for us to furnish them with a nevus which may be considered of

standard strength and against this other sera can be titrated. There
oe
- 4 ot

are many problems to ba worked out in connection with the standardi-
zation of serum ani also in connection with the mamfacture and pre-
servation of serum, It seems however that this work more properly be-
longs to the Hygienic Laboratory than to us, provided they will under-
take the work,

Studies of the curves of agglutination titre of the blood
of all patients following the administration of immune serum have been
made and important knowledge concerning proper dosage and proper spacing
of doses has been obtained,

During @ considerable part of the quarter Dr Dochez has
been absent in France, but Dr Avery has continued the study of the soluble
bacterial substance which is present in the blood and urine of pneumonia
patients, concerning which mention was made in our last report. Further
studies seem to show that this substance is a product of the life pro-
cesses of the pneumococcus, and not due to its disintegration, This is
rendered probable from the fact that it is present in considerable
amounts in culture filtrates during the early stages of development of
the culture when the organisms are growing at their maximm rate and
undergoing’ little or‘ no cell destruction’ as indicated by growth ‘carves.

“Ie rabbits are infected ‘int raperitoneally with pneumo~
coosus this ‘substance’ whore ie specifically precipitable with ‘aatipneu-
mocooous' serum "can be" demonstrated ‘in’ their blood serum freed from bac~
teria by filtration; from within two. to six hours following ‘the time’ of

infection. | — pe |
Studies of the urine by precipitin reactions in 76 cases

of lobar pneumonia due to Type I,II or III show a specifically precipi-

table substance to be present in about 85 per scent of the cases during

some atage of the disease. A positive reaction has been found as early
“>
as 12 hours after the initial chill, and has been demonstrated in one
instance as late as six weeks in convalescence, The reaction in dif-
ferent urines may vary from a faint cloud to a heavy precipitate. In
certain instances the reaction may be negative when whole urine is used,
but be positive in the specimen of urine which has been concentrated by
certain chemical methods, A repid and accurate method of concentration
has been devised which is clinically applicable in testing the urine of
pneumonia patients for the presence or absence of this substance. Such
a method may be of value in facilitating the diagnosis of type in in-

focted cases.
A study of the chemical nature, toxicity, antigenic

properties and fate of the soluble substance in normal and infected animals
is still in progress. The preoipitinogen has been found to pass the
kidney of a normal animal end to appear in the urine in demonstrable quan-
tities. The determination of total nitrogen and nitrogen partitions made
on the active substance obtained by repeated precipitation with acetone
andi alcohol show that this substance is of protein nature or is associ-
ated with protein, .
A Large portion « of Dr Chesney's time during the past .
winter has been consumed in the routine clinical work associated with tabs
the care of the patente, The clinical wort has been greater this year, 7
owing to the increased munber of admissions and to the fact that ‘there |

s

were foner anteries available for the service. ‘However, he hes carried

Be sede &

t

on, with Dr Moore, an en extension of the study,, ‘begun lest your, of the use
of ethylhydrocuprein in lobar pnevuonia. . .
Further work has shown that the amount of the drug which
can be given safely, and which suffices to produce @ bactericidal action
of the patient's blood is not sufficient to prevent the death of some of

the patients so treated, indicrting that the dosage at present employed
-4-

is inadequate and that some way should be fcund to detoxify the drug,
Several opportunities have presented themselves for show-

ing that while the patient was under treatment with optochin the infect~

ing atrain of mMeumococcus became fast to the action of the drug. We

believe thia is the first instance where it has been conclusively shorm

that a parasite in the humen body became fast to the action of a destructive

agent.
At present studies of the growth of meumococci in bouillon

containing optochin are being pursued, in an attempt to verify some ideas
gleaned from the clinioal work, and designed to throw light on the reasons
why the drug is not more effective. Already it has been shown that the
behaviour of pneumococe’ in the presence of optochin in bouillon varies,
depending upon the size of the inoculum of bacteria. These studies, while
chiefly of theoretical intereat, should have practical siginificance also,
if they elucidate the shortcomings of optochin and emphasize the essential
requirements of an ideal chemo-therapeutic agent in lobar pneumonia, Ap-
parently there are at least two reasons why optochin is not effective, One
possible reason, as above noted, is that the bacteria present in the oir
culation absorb the drug, removing more then, is’ required for their destruc .

te bh Ui by oe) eee. Fitiyeorne specimens of dost fren oc heuses
tion. “Mother and possibly more Potent reason ad associated with the long

tT
o

Le Seine

»
€

ah Te a a

time required for the optochin to be in contact’ with ‘the becteria, in order

TE Fath.

to obtain bacterioidel action, “In test-tube experiment ae or 15 ‘hours.

oy whe Shivee,. ‘ 4 us iti a nas sR Ow wl h

are regired “in order that the bacteria be killed, If thia is also % trae “s

 

in the body, “ae is evident that the constant invasion of the blood by
bacteria from the local lesions mekes it possible that the blood may ‘con- .
tain even large numbers of organisms, even though such blood may have
bastericidal power,

During the last three months Dr Stillman has continued his
study of the epidemiology of meumonia. Sputum and specimens of dust
. ' /

are collected from all persons living in the houses from which Type I and
Type II pneumonia patients come. 96 individusl from 28 homes in which a
case of Type I pneumonia had occurred were studied, From the saliva of
16(16 per cent) of these individuals a Type I pneumococcus was isolated,
A Type II pneumococcus was isolated from only one individual, In 10 of
the 28 homes one or more positive contacts were found. 46 other types

of pneumococci, Type ITI and atypical organisms, were isolated from the
individuals studied, while from 57 persons no pneumococci could be isolated,
Specimens of dust were taken from all 28 hanes, In all, 69 specimens of
dust were studied, and from 25 pneumococed were isolated. In 16 instances
these pneumococol were of Type I (25 per cent) in one instance Type II X
and in 6 instances Type IV. From the dust of ons or more roans of ll of
these homes pneumococci of Type I were i1eolated,

Seventy-five individuals from 24 homes in Which a case of meu-
monia due to Type II pneumococous had occurred were aleo studied, Pnsu-
mococci were cultivated from 42 of these individuals, from 33 no pneumo~
coccus could be isolated, Six carriers of Type II pneumococci, one in
each of the six 7 the 24 houses, were found, No One was found carrying

‘jmeumscoce | of type’ ‘T,. . The other Peunococed Asolated belonged to Type III

- a se Sod e i
y Types bad. hes

 

and ¢ the atypical groups, Fifty-one specimens ‘of dust ‘from a housés
aia “ond aoe Bio see EU oe Was 8 . a
wore reused. In 18 specimens: ‘from 12 of “the houses neumecesot of , Type II"
bid Gemr TCE ‘he Ast Xoo. to vacedl, Foul ew bok tees pe godeh |
were found. "Ty only one instance were Pnetmooceot of Type I Present. In .
7 tak ‘ ar, BoE ky OL wee oie Cen oh ae ote, ete!
9 of ‘the other specimens al dust ‘Fomumoooces, of Type | ur or r atypical groups
oe Ske £2 Se oh de o

were present,

The posatbility of direct transfer ‘of ‘infection is suggested ‘by
the following two cases. (1) MK, who had just recovered from a Type I
pneumonia left the hospital on March 9th. The next day he went to see his

brother who had developed a Type II pneumonia on March,.8th, On March 12th
ye

U.K. developed a Type II pneumonia, (2) Miss H. 111 with pneumonia
(type not yet ascertained) was taken to a private hospital by Mrs. A,
who developed a Type II meumonia in a fow days. <A friend,Mr A., sat
at night nursing Mrs A. but in a few days himself developed a Type II
pneumonia,

Through the courtesy of the State Department of Health end
the local health officer of Rochester, we have had cpportunity to study
two epidemics of pneumonia in institutions. The first occurred in an
orphan asylum at Rochester, New York. In this asylum were about 200
boys, but the six cases of pneumonia were limited to the boys occupy-
ing two of the four dormitories. Three boys in each dormitory deve- —
loped pneumonia. From the sputum of three ef these six boys a Type I
Pneumococcus was recovered, fran two atypical pneumococci, while from
one no pmeumococcus was recovered. The absence of Type I pneumococci
from three cases may be due to the fact that this study was not made
until the cases were convalescent, The sputum of the other 56 boys
who slept in these two dormitories was studied. From the saliva of
six(l0 per cent) @ Type I pneumococcus was isolated. In 2? instances | .
other pneumococci* of" Type III and atypical organisms were isolated.

a

A Type 1 ‘organism was also recovered from specimens of ‘dust ‘taken from

Fee 4 cer p

each dormitory, The Gist, from the vacant room which had bem used .
as a ward failed to show a Type I poeumocoosus but a preumococous
of Type II ana” of ‘type’ “ay 3 were recovered.” "In ‘this epidemic 50
per cent of the cases of pneumonia wore * found to be dus to Type t
Pmeumococci, 10 per cent of healthy ‘contacts were found to harbor
this type and the same type of pneumococcus was recovered from the

dust. ,
The second epidemic occurred in the Rochester State Hospital
 

 

& ot
- = wo F

for the Insane, Here six cases of pneumonia occurred among the in«
mates of one ward of about 200 inmates, A Type I pneumococcus was
recovered from four of these patients but the other two patients died
vefore the type of infecting pneumococcus was determined, Each of the
patients who died had shared a double bed room with one of the patients
who showed a Type I pneumoccocus, A Type I pneumococcus was recovered
from the dust of ohe of these two bed rooms, From the saliva of one
hondwed' and forty-eight of the over 200 inmates of this ward where

the pneumonia cases ooourred, a Type I pmeumococcus was recovered in
three instances, a Type II in one instance, and in 45 instances pneu-
mococei of Types II X, IIT and IV, In this latter epidemic six cases
eof pneumonia occurred in the ward of an institution. A Type I pneu-
mococcus was recovered from 4 of the 6 patients, from 2 per cent of the

healthy contacts and from the dust, .

 

Type I
- Pneumococoi recovered
No, of No, of I - II ITA IIB IM III IV NoP,
Femilies Persons .

DE a ats hate dae 3 .
28 96 16 l- 4 11 8 23 57
Dust .
A ees Specimens: cies ssh Vheitte: Sanna nour. ”
28 69 16 = - - i - 8&8 %

In 6 houses both dust end individuals positive.

11 " aust ee eee ee ew " , (23 per cent )
10%  — ---e eee contacts" (16 per cent) —
16 * dust 0 <---- == negative |

17: * wenn ee contacts "

 
 

 

Type II
Pneumocoeci Recovered
No, of No, of I II IIA IIB IIx Iii IV No.P
Families Persens
24 75 - 6 - 6 9 6 24 33
22 Dust
51 i 18 - 1 - 2 6 24
In 3 houses both dust and individuals positive.
"1g 8 dust oo = -=--- " (35 per cent)
" 6 * woe individuals " (8 per cent)
"10 = =«* dust coeee= negative
"18 * onewe individuals «
Control Duste
Type
Number 40 I II Iya IIB IIX §#£MITI Iv. NoP,
¥ wae . le 0" 'O 35 1 ne oye 8 26
wit Thur tlata, Tie ordtpire udtlode tre ag, yore atta: ;
TM nN es yan 6% 36 pe Pr pent. Prewmococed, LPL wy veri dng Temes

ee
Q 4 *,

ge PRR a8 esr nt m
a ey

ik kzlown Type. I carrier was ‘qisiting in“this house, Os! #

 

Ee ae oy rane mek is sph eyer aye : wo sams wane eee . 4
wake ly OY ma. SYaaMe TED bag DASe Veber a a ete ca OE nee. oye
a mee ree . . ss oh dk
p waa Say Uyls oe fue wbwey ay wevoogse Pigave Eh Gt de

Dr Blake has given much assistance in the care of patients with
preunonis, He has finished his studies concerning methemoglobin formation,
. concerning which mention was made in the last report. In addition he hag
earried on studies to improve the methods of identification of pneumococod

for clinical purposes. This was made necessary by the difficulties arising

in certain laboratories, where strains of pneumococci’ which agglutinate in
 

doe

both Type I and II sera have been encountered. It was shown by means of
the precipitin reaction that there is a definite zones of non-specific im
minity reaction for all types of pneumococes. The limits of this non~-
specific zone for the agglutination reaction have been determined and the
optimum dilutions of type sera have been worked out that will surely
identify all type organisms ani fail to agglutinate “atypiocal" streins
which are properly classified in Group IV.

An improved method for the identification of pneumococcus types
directly from the mouse peritoneum has also been developed, It has been
shown that the clear supernatant peritoneal washings contain sufficient
amount of soluble precipitinogen to give an immediate specific precipitin
reaction with the homologous antipneumococcus serum, This method is of
particular value in cases where the presence of other organiems in the
peritoneal washings cams a delay of 18 to 24 hours in the determination

of the pneumococcus type.

HEART DISEASE, ~ Dr Cohn. We have been interested with ©

Dr Londegeard in the problem of the blood pressure in patients when the

auricles fibrillate:” ‘The ordinary methods are wholly unsatisfactory, ““*"*

VR aw

for the pressure valua of succeeding’ beats is ‘Sontinuously varyin ae “vanes”:

* Int eh re vee LHe
and Hart ‘have: “attempted very” ingeniously” to “gupbly ‘a’ means of overs ning’?

af r cury)

the difficulty by'mlt Siylng the pressure’ Yaike (in millemeters 62”

Cathe tp natieania, We pave cn ltad a me? precieesy Dies foe: Gechis
of the beats by their fomber, adding these producte’ abd dividing py the eh

total mamber of poate. “this of course ‘gives ‘an average figure | wot it is”
necessarily inaccurate." ves . ° os

Ye have proceeded from different point of view. The difficulty
in estimation of the brachial pressure is due to the constantly varying

pressure, If there were @ point at which the pulse pressure showed less

ree
N\ ~
y- (te

fluctuation, that would be a more satisfactory point at which to measure

the blood pressure. 4s the smaller arteries and capjllaries are reached
the pulse pressure diminishes and the flow tends to be constant and con-
timous; large fluctuations in pressure do not ocour, We have accord-
ingly made experiments in dozs under anaesthesia to examine the pressure
relations in one large and in one very small artery, One cama was in-
serted into the right femoral, and one in the left dorsalis pedis artery,
These were connected with either a Hirthle or with @ mercury manometer,
writing on long strips of smoked paper, Artificial respiration was given
the cheat opened by incising one intercostal space, and electrodes (pincetess)
fastened to the right auricular appendix. These were connected to the se-
condary coil of an inductorium, An interrupted current to the auricle could
then be provided and the gsuricles set into fibrillation. We could therefore
get records of pressure variations in the two arteries mentioned, both

when the beats ware regular and when the auricles were fibrillating, We
found of course that the pulse pressure in the small artery was very small
amounting to less aaa 5 nD. that this variation was not exceeded when the
auricles were made to fioriliate, and that in fresh dogs in which the level
of the blood pressure ws was normal there was no ‘fall in the blood pressure,
barring a siignt initial one, hen the surtoles Were made to fibrillate,

we

We: have bean able te put. ‘the remlts ‘of these experinaate 3 into

18h ys
be a ty whe S a con

practice ‘An patients. We have epplied a cuff ‘precisely i Like the prachial
one of v,. Recklinghausen ¢ to a finger arid then slowly releasing the pressure
in the cuff, have determined thet pressure ‘at which blood passed through |
the digital artery, this point being fixed as the ‘point at which color
returns to the finger previously planched by pressing out the blood with

a rubber ring rolled on the finger. This is the method of the tonometer,
devised by Girtner in. 1899. That the method is fairly ‘accurate is shown
~ he

by the results of readings made by each of us on the same patients. Averager
of ten readings on the saze patient by each one of us usually do not differ
by more than 2 - fam, The range in ten reading is usually not more than

4 om, though occasionally differences of as mich as 8 mm, occur. These
estimations have been made on both fibrillatore and non-fibrillators. The
usual difference between brachial and digital pressure is about 20 um.Hg.
We think that we have therefore found a olinical technique for applying

the results of our experiments to persons suffering from auricular fib-
rillation, the digitel artery corresponding to the dog's dorsalis pedis.
Technically the Gartner method is extremely simple, the experience very
easy to acquire; it requires no calculation and the reading represents

a fact.

The experiments on hypertrophy, the etudies on human anatomy, the
mode of action of digitalis, the action of strophanthine in pneumonia, all
referred to in previous reports, are still in progress.

Dr Levine has continued his studies to determine by experiment
whether the effect of digitalis depends upon the concentration of the drug
in the blood which bathes the heart or upon the quantity bound and held
by heart muscle, Both: positions are held by mmerous investigators.*~ The
problem ie not- without’ practical interest, for on its solution depend ~*~
certain therapeutic procedures, especially in infectious diseases, such’
as pneumonia, It was our plan to employ a less artificial: experimental
technique than has been used heretofore in the study of this problem and
one more nearly analogous to clinical conditions, Cats have been employed
because they are known to be susceptible to digitalis in certain know
amounts. Crystalline gratus-strophanthine was selected for injection on
account of its uniform minimal lethal dose. The reaction looked Zor was
the occurrence of extra systoles, these being detected by the electro-

cardiograrhic method. This reaction occurs almost regularly when about
~ he
‘ per cent of the minimal lethal dose has been injected. The animals uniformly
.<vive when no more than this amount is employed, The same cat can consequently
injected repeatedly at intervals of from 3 to 4 days. It was thought that if
18 reaction always occurred following the injection of 60 per cent of the mini«
1 lethal dose, no matter whether the injection ocoupied 1/4. 1.2 or even 4 hours,
.9 conclusion would be justified that the drug acts by virtue of the amount bound
. the heart macle. For this conclusion to be valid we must assume that unless
wore #0 bound, excretion of a part at least mst have occurred before the ex~
ivration of the 4 hour experiment. The experiments have shown that extrasystoles
, not cocur when about 60 per cent of the minimal lethal dose is injected, whether
12 injections sre made during @ period of 1/4,1,2, or 4 hours,
The criticism has been made, however, that even during the longest period
2 conaiderable amount of the drug may have been destroyed or excreted and that
onsequently the experiments do not yet show that 60 per cent of the minimal lethal
.c36 was bound. It is still possible that a sufficient concentration to pro~
iuce the effect was only obtained when the amount in the blood reached 60 per cent
of the minimal lethal dose, + - ee oo ae
. To anewer the oriticien two modifications of the experiment are’ eug~
gested; first, ‘the period ‘during which the! injections are made may be: lengthened “*
and second, cross trazsfision ‘experiments ‘uisy’'be perfomied,’: Experiments of both’
types are in progress ‘end the: ‘te eal te will: be: reported later,” The cress’ trans« |
fusion experiments ‘are performed ag follows,“ cat is taken, the tolerance: of <5;
which ig already nom; it is giveneither an effective dose (60 per cent of the
minimal lethal dose to cause extrasystoles) or one ‘just short of effective, Half
of ite blood is then taken from the carotid.or femoral artery and injected into an-
other cat(the tolerance of which is also known); if the strophanthin is in the

pleod(4f the action of etrophanthin depends apon concentration) as mich more

to Pn Mah aie gee ee
» av
will be required to cause effects in the second cat as the difference between the
total amount required by the second cat and the amount calculated to be present in
the firet cat's blood, If more than this is required, spproaching 60 per cent of
the minimal lethal dose, the conclusion may be dram that some of the strophanthin
injected into the first cat must have been bound by heart muscle. At the present
time it appears that the problem may be solved in this way.

In comparing electrocardiograms of a patient who hed .been bled, Dr,
Morigon found that the electrocardiogram taken after bleeding differed very dis-
tinctly from those taken before bleeding. The differences were present in the
terminal portion of the electrocardiogram,i.e. in the T wave. He has since bea
accumilating instances in which similar modifications occur under corresponding
conditions. We have thought that the reason for the change lies in an alteration
in blood volume which brings about a change in intraventricular pressure and this
produces an alteration in the tension af the ventricular miscle. The first step
in the investigation of this phenanenm has consisted in attempts to alter blood
volume and to correlate the electrocardiogrephio alterations with this alteration,
The estimation of the blood volume has been undertaken by Dr Palmer, He has re~
lied on haemoglobin estimation, estimation of cellular volume, using the hemato~
crit for the purpose, and conductivity and refraction ‘estimations. ‘The sodium
chloride and ‘urea in blood ‘and urine, acidity ‘and amount of the urine ‘and the ‘rate
of ite excretion, variation “in ‘Body weight and amount of water evaporation have
been ascertained. Electrocardiograms in. the 5 leads have been taken at very
frequent intervals and blood examinations have been made five or six times during
the experiments. . - Lowa ote ee re ee a

The measures by means of which it was attempted to alter the volume of
the blood were: the drinking of large quantities of water in a short space of

time ( 2 liters in 30 mimtes), the drinking of sodium chloride solution, the
Ng -

taking of magnesium sulphate(27 gms. in 600 co of water,) sweat baths, and cold

pecke,
So far it appears that the volume of the blood can be altered when

these measures are employed and that when such changes in volume occur modifi-
cations in the eleotrocardiogram take place. It appears, furthermore, that the
slectrocardiongarm is very sensitive to these changes. At the present time two
theories to explain the especial form assumed by the electrocariiogram exist,

the first held by Einthovan and Lewis that it depends on the distribution of the
iuscle of the heart by weight; and second, that recently advocated by Fahr, that
it depends in part at least on the relative lengths of the conduction paths in ths
two ventricles or on the relative rate of conduction in the two ventricles. ‘The
vbservationa and experiments performed here suggest still another possibility,
namely that the tension at which the mscle is held is a factor involved in the
<urve. A number of experiments designed to test these hypothese occur naturally,
‘hase we hope to undertake and to report upon later,

Dr Morison has also undertaken to study the reaction to digitalis of
peripheral blood vessels, using for this purpose a plethysmo-graph,. The difficulty .
consists in reproducing from time to time the ome conditions in the receiver, He
has expended mich time and Angemity on thie work, but until now the observations

are not in a state to render a report possible,

‘DIABETES, “- “ Dr Allen, ©The former report dealt chiefly with: ©
westions of fat metaboliem, Miss Wishart is continuing this work, using Bloor's ©
wethed of analysis for total fats, lecithin and cholesterol in the blood, Can-
patisons are made between normal, phloridzinized end mildly and severely diabetic
animals to ascertain something of the nature of diabetic lipemia, In addition te
the feeding experiments, a few intravenous injections are heing made. The ex~

,orimente seem to confirm the idea that in the diabetic organiem fate and lipoids
~~ pte

are less readily teken up by the cells from the blood, There is a primary and
specific impairment in the metabolism of fat as well as of carbohydrate.

Dr Perlzweig's principal work consists of analyses of amino-acids in
blood and urine, with the usual camparisons between normal, phloridzinized and
diabetic animals, He had previously been concerned chiefly with the acidosis
experiments and the amino-acids problem ia too new for a definite report, beyond
the fuct that an inorease of amino-acidsin the blood and urine of phloridzinized
and diabetic animals as compared with the normal is confirmed,

In the work concerning the influence of various organs on diabetic
symptoma, it is possible to mention sane results obtained with the thyroid.

Severe diabetes with continuous hyperglycaemia and ketonuria and glycosuria on
feding a very small quantity of meat, can be promptly and surprisingly transformed
by total thyroidectomy, It is apparently impossible to produce @ retum of any
appreciable acidosis, The blood sugar falls and the tolerance as judged by either
glycosuria or hyper glycaemia is miltiplied. The tendency also is changed so

that after excessive feeding the glycosuria and hyperglycaemia tend to clear up
pranptly instead of to contime. ‘This 4a @ cure of diabetes according to current
conceptions, but baie result is in ‘keeping with the hypothesis that diabetes con-
sista not in these eymptome ms in a specific tnability to use food normally for
either combustion or synthesis of tissue. The doge in question oat and digest

a diet ample to nourish normal dogs, but they slony canciate and finally die

in cachexia. There are sone possibilities of Considerable interest in the res-
piratory metaboliem emiDr Lusk’has premised to take these and some ‘other interest
ing animale of our series for calorimeter observations,

During the past three months things seem to have come to a focus in
the anatomical study, so that I believe we can affirm a definite and consistent

pathology of diabetes, Some confusion has heretofore resulted from attempted
~Y2- : i

‘Tisons of series of "diabetic" and "non-diabetic" autopsy findings, without
‘mu differences, But the majority of diabetics are old Persona, who, we now
» Bre generally capable of acquiring a rather high tolerance, and the possible
-once Of any degree of lowered tolerance in the "non-diabetic" cases has prac=
ily never been tested, Accordingly it is nothing surprising if more or less
-losclerosis or other senile changes should be found rather iniiscriminately
ch series, with no positive diagnostic distinctions, This is merely analogous
9 state of affairs with the kidney, for which an unquestioned though incom
9 pathology existe, and yet it camot always be told from the microscopic
ire whether there was albumin in the urine or how mich. In ediition, the new
tment has cleared up some clinical misconceptions, Death in cama does not
‘sp@rily mean sever diabetes, It has frequently been merely fat intoxication
4668 essentially mild, Also, when « young patient suddenly developed intense
-etes and died in a few weeks or months and the pathologiat found mmerous
nda of Langerhans present it seemed that such evidence was opposed to the
+ Of deficiency of these islands as the cause of diabetes, But, for exemple,
» case of Geylin and Du Bois was one of rare » intensity, more voilent and rapid
an the average in even the young, pationts. ‘Yet under treatment this patient i
“¥ quickly acquired & tolerance of sone +200 Grens of carbohydrate, therefore LL
is obvious thet considerable elena tome was present; any other finding -
ald contradict not support the Aslend theory. | We know that these cases ad
crt rapid course ordinarily acquire tolerance quickly under efficient treat«
ct. The following basis for pathology is indicated by our short series of
~88 and by the specimens sent me by a few Physiciens. We should start with
+ cases demonstrated as severe by the present treatment, namely the ones that
uve unable to acquire any satisfactory tolerance and perhaps finally die in
ite of the best treatment, I believe it is possible to diagnose diabetes
Se- "
diabetes with the microscope positively in every such case, by the extremes
deficiency in islands, Then, there are the cases of great intensity dying
Perhaps in coma without adequate treatment, I am inclined now to think that
411 such cases will show the specific exhaustion in all or ecne island cells,
as in experimental animals, The trouble is that most pathologists do not
know how to recognise these significant changes and the ordinary mutopsy
raterial is too old for them to be made out positively even by an experienced
observer. On the other hand, when the symptoms of even the severest case are
told in check and the patient even allowed to starve to death rather than de-
velop glycosuria, as in our care of the Sankey boy, the cells of the few re~
‘mining islands are free from exhaustion, just as in animals under similar
vonditiona. There is a further possibility that some of the supposed normal
islands in some of the reported human cases heretofore have consisted of A-cells,
remaining after disappearance of the B-cells, but this suggestion is based only
on anmlogy with animals end has not been investigated in patients,

In keeping with the above is the outcome of a new group of animal ex~
periments. In seeking a means of producing diabetes without removing so mich
pancreatic tissues, I last “year succeeded in leaving large remants end pinching
them between’ the fingers’ so as toset Up severe inflametion, then ovérmfeeding -
with carbohydrate’ to injure the islands. ‘The result was that the acinar tismue’
regenerated but the islands Were destroyed; so that there Was severe disbetes °°
with very large pancreas remiants, which ‘at ‘autopsy’ appleared’ fully normal .
except for the absence of islands; The method is uncertain and failures
are more numerous than successes, Therefore recently I tried asphyxia, and
found that by clamping the vessels for about 20 mimuites diabetes can be pro=
duced with a third or more of the pancreas in position, I am seeking to pro«
duce it with the whole pancreas present; this attempt will quite likely fail,

but there 1s no inherent reason againat it except that dogs are more resistant

to disbetes than human beings. Specimens obtained to date indicate that there
SQ fT.
ry - . fe.

is first an inflamation with degenerative and regenerative processes in both
islands and acini; the pancreas is hard but not fibrous, The acini are either
injured less or regererate better than the islands. The eni result seems to be
@ normal-appearing pancreas, grossly and microscopically, except for the scarcity
of ialands. The work ia incomplete as yet. ‘The most significant feature seens
to be the proof that a temporary acute inflammation, not greatly incapacitating
the individual or interfering mch with digestion, can destroy the islands
80 as to bring on diabetes yet leave no signs at subsequent autopsy except this
scarcity of islands as found in the human cases. The relation to possible mild
pancreatitis set up by accidental infections, injury of the pancreas by bile or
other agencies, eto. is still hypothetical, and the hereditary element in dia-

betes is still important in at least some groups of cases,

CHEMICAL LABORATORIES. = Dr Van Slyke. The method for rapid de~
termination of oxygen in the blood, which was mentioned as an object of work in

 

the last report, has been perfected, so that oxygen can be determined with the
sane apparatus used for COs, and with practically the same simple technique, The
blood, 1 to 3 ca, is introduced into the apparatus, laked with dilute anmonia
and saponin, and the oxygen sot free by addition of potassium ferricyanide. The
oxygen is extracted by shaking the evacuated apparatus for about a seconds, and
the volume of gas obtained is. read Ofte Duplicates usually Give volumes of ad
80 nearly equal. ‘thet, it i difricalt to detect | o difference in the readings, , me
results give an averaze oxygen capacity of about 20 volume per cent tor normal
blood, which is higher than the 18. 5 per cont’ ‘taken as an average by Haldane,
The method has been in constant use in two. ‘Problems by Dr Palmer and Dr Lundsegaard
described below, . -

The determination of hydroxybutyric and diacetic acids by oxidation of
the former to acetone in the presence of mercuric sulfate and weighing or titrating

the mercury~acetone precipitate formed, has been tested in some hundreds of
4

* :

ro

- Be. ‘

joterminations, chiefly by Dr Fits, in connection with the diabetic work, The
results, both with blood and urine, have been so uniformly satisfactory that the
wethod may be considered ready for publication,

Dy Fitz and Dr Stillman are well into the study of diabetic metabolism

which has as its object the ascertainment of the relation between the amounts of
-at, carbohydrate, and protein burned in the body and the formation of ooybutyric
uni diacetic acids. The COg formation and oxygen consumption are being followed
taily by Dr Stillman with the Tissot spirometer, For the extremely accurate ges
-alysea required a new apparatus has been devised with which we have obtained
-nusually consistent results, ‘From the gas exchange this determined and the
itrogen excretion, the amounts of fat, carbohydrate ani protein burnt in the
vty are calculated, Dr Fitz has been determining the diacetic end oxybutyria
»2ids in blood and urine by the new methods mentioned above, as well as the total
itrogen, urea, ammonia, free acid, sugar and chlorides, The problem is in its
sufancy, but interesting leads are being uncovered, It appears, for example,
“nat when carbohydrate is withdrawn sudienly from the diet of a moderately severe
iiabetic, the body requires ahout two days to get its defensive mechanism against
+cidosis in order, The first day there is little ammonia formation, the res-
piratory quotient falls to about 0,72, indicating no utilisation of stored glyco~
sen, and acidosis begins to develop, as shown by a sudden drop of 10 to 20 volume
ier cent in the plasma’ C02,’ The secona day the"acetone acids" are neutralized
with ammonia, the plasma COs rises towards normal, and the respiratory quotient
«lso may go up to 0.78 or 0.79, indicating utilization of glycogen, After «#:
‘ew days the glycogen is exhausted and the respiratory quotient falls, moderate
-aounts of acetons bodies are excreted daily, but the organiam hae adjusted itself
“0 their elimination, and the alkaline reserve of the blood stays normal,

Dr _lundsgaard is bringing two problems into a very satisfactory con~

‘ition, The chemical measurement of lung volume, by breathing several times
-2-

[0 @ bag containing a measured volume of pure oxygen and analyzing the gas
-ixture obtainad, has been thoroughly tested by comparison with the mechanical
-asurements Obtained with an ordinary spirometer. On all subjects the two
‘lois gave approximately the same values for the vital capacity. The accuracy
i the chemical method seems therefore assured. Its advantage over the spironeter
isa in the fact that it enables one to determine not only the eir that can be
<pired(vital capacity), but also the residual air that remains in the lungs and
.inot be forced out. Consequently while the vital capacity obtained with the
; irometer depends upon chest mobility, the chemical method enables one to de~
3ruine the total lung volume, indsperndent of variations in mobility. We also,
/ obtaining skeletal measurements on the chest in three dimensions of space
anterior-posterior, lateral at 6th rib, and length of stermm) are able to cal-
alate within 10 per cent what the lung volume is if conditions inside the chest
«re normal, Consequently we appear to have in our hands a fairly sensitive means
.t detecting and measuring the extent of decreased aerating volime such as my be
used by tuberculosis, tumor in the thorax, or unresolved pneymonia., A few pre~
liminary results have proven sufficiently interesting to justify an extension of
the work to pathological subjects, and: Dr: Lundsgaard is at the time of present “
writing taking advantage of-the' hospitality of the Ray Brook sanatorium'to study .”*
tubercular patients, *)'” te igten Tha Bi teee Bete oe hat 1 Sat Pw Cor Rt a
‘Dy Lundsgaard.is obtaining;” in“collaboration with Dr Cohn, results of
importance: in studying on‘heart patients and normal subjects the difference be-

tween the oxygen ‘contents of arterial’ and venous bloods,” The venous’ blood is.

drawn from the arm vein of the resting subject. ‘The arterial oxygen is estimated | ke

by either saturating a portion of the venous blood with air end determining its
oxygen content, or by determining the hemoglobin with Dr Palmer's new technique.
The oxygen consumption of resting miscle being fairly constant, the amount of

oxygen taken from 100 cc. of blood should be proportional to the time required
ge
vy the blood to pass through the tissue fran artery to vein, i.e. the slower the
flow the greater the proportion of oxygen absorbed and the greater the difference
vatween arterial and venous oxygen content One would consequently expect in
cart decompensation @ venous oxygen content lower than the arterial by an ab-
cntally wide margin. This is found to be the case, and the results are rather
striking. A normal individual, or one with a compensated cardiac condition, never
snows @& venous oxygen content more than about six volumes per cent lower than the
-xygen content of arterialized blood, the average figures being arterialized blood,
ajper cent, venous 16 per cent. In decompensation, arterialized blood being the
o4ing, venous oxygen usually falls to 4 to 7 per cent. Thus far all decompensated
-28e8 have shown this extreme change; no intermediary cases have been encountered,
slthough it seema that they mst be met when more cases are examined,

Mr Cullen has deen collaborating with Dr Avery in an attempt to isolate
10d determine the chemical nature of the antigen found in pneumonia urine. By
ulcohol and acetone precipitation, dialysis,etc. a highly active specific product
vas obtained containing 14 per cent of nitrogen, When completely hydrolyzed 42
per cent of the nitrogen was converted into free amino groups. The same figures
Were obtained from a product prepared from ® broth culture. The total nitrogen
content is that of a protein, but the low smino nitrogen obtained on hydrolysis
(all proteins thus far studied show .60 per cent or more of their nitrogen in amino
form when hydrolyzed) indicates that either a non-protein nitrogenous substance ae
accompanies the protein, or that the protein itself is of peculiar structure,
Further experiments are under way to settle the point. seh, by

Dr Palmer's comprehensive study of the different factors in edema, .
mentioned in the lest report as being prepared for, 1s now under way, the difficultie
of technique and routine necessary for the various physical and chemical deter

minations having been successfully disposed of. The work, because of the current
some
- 3 - .f
eG

-ck of knowledge concerning the causes of edema, mist pass through an exploratory
- age during which profitable avemes of attack ars sought. It is at present in
19 stage, and, althouzh results of some interest have already been obtained, they
i. ba reported more clearly when the work has Progressed further,
One outgrowth of the problem has been an improved method for the
lorimetric determination of hemoglobin, which Dr Palmer was led to devise fron
9 necessity of an accurate ani rapii means of estimation in the edem work, 0.2cc¢
- blood are diluted with water, saturated with carbon monoxide by passing illumi-
-ting gas through the mixture for a minute or leas, andi compsrad in a colorimeter
-th a standard solution of carbon monoxide hemoglobin, The standard is ke pt in
bottle, the gaa space of which is filled with illuminating gas and appears to
sit for months, The color can be read with great accuracy, and results obtained
ith those calculated from the oxygen capacity(determined as deacribed in first
‘ragraph of this report) with an error usually not exceeding 1 per cent of the
ount determined. The standard hemoglobin solutions thus far used have been made
.rom blood, the hemoglobin of which was eetimated trom a careful determination of
vig oxygen capacity. In order to base the entire work on as firm a standard as
,-O3gible, however, pure hemoglobin is being recrystallized, and further standard
solutions of pure hemoglobin will be ‘prepared and “standardized not a by the:
oxygen capacity but also by means. or the | srectrozhotonstor. nn
| The alkali ‘retention "test ‘for 1 acidosis of Palmer, Henderson eni ‘Seilards er
ig being further studied by Dr ‘Palmer; “the “amount ‘of ‘ploarbonate ‘required ‘to ‘tum
the urine alkaline being compared with the plasm COs capacity. Data on normal,
diabetic and nephritic individuals confirm the preliminary observations in whowing
that the alkali requirement is proportional to the fall of plasm C02 capacity be~
low the value of 70 to 75 volume per cent, For a subject of 40 kilos weight, ap-
proximately 1 gram of bicarbonate is required to raise the plasma COs by 1 volumes

per cent, and the amount required varies in proportion to body weight, The effect

Fan
SO ee
- >

.3 what would be calculated by assuming that tha body is 70 per cent fluid and

3a bicarbonate distributed evenly not only to the blood plasma but to all the
wining fluids, The results clarify the explanation of the retention test, as

titration of the body fluids, and also make it possible, on the one hand, to
stimate from the retention test the approximate level of the blood bicarbonate,

ci on the other to calculate from the plasma COs. capacity the amount of alkali

at mast be absorbed to raise the blood bicarbonate to the normal level,

Dr Palmer has shown that the hydroxybutyric acid in a diabetic urine can

.9 approximately estimated by bringing the hydrogen ion concentration to 107° and
{trating with N/10 alkali till the point 1077:“ is reached, the titration being
ontrolled at each eni by a solution of standard hydorgen ion concentration colored
‘ith alizarin, The titration gives 83 per cent of the phosphoric acid, 50 per

ent of the hydroxybutyric, and only traces of other acids. Consequently when

8a phosphoric acid is titrated separately with uranium nitrate ani subtracted
trom the first titration, the result indicates approximately the hydroxybutyric,

It does not indicate the diacetic acid, Comparison of the results with those
obtained by the accurate ‘gravimetric method on'a number of urines showed’ approxi-
nate agreeinent between the two methods. ‘The results calculated from the titrationa’’
are of course not 80 accurate as those of the direct: determination; but the agree-

nent 1s such that “the extremely ‘simple titration method inay well’ prove: usefui.**

heh a egy Gow Tees hy Muvopaled Cusabsea cn, tw iy nha ues ek ses eho,
CANCER, . Drs. Murphy and Morton. ‘The problems as outlined in the .
last report have progressed sonewhat. | The progress has been for the most, part a wad
in determining the proper X-ray dosage which would stimulate the lymphocytes.

We have certain indications from the laboratory side that changes brought about

in the lymphoid tissue are secondary to changes in the blood. The basis for this

is the fact that we have observed a depression in the blood lymphocytes following

exposure of the ear of a rabbit to X~ray, and this followed by a stimulation phase,
x

be

- BK-

In other worde much the same eftect is obtained by this method as when a
stall generalized dose is given to tha animal, Studies of the lymphoid
tissue, as tiie spleen ani glanis, show the same changes when ths ear alone
is exposei aus when the whole enimal is treated, With this as a basis, we
sre giving our treatments over the large vessels. This has given a vary
gharp ard more uniform stimulation than was obtained by the previous methods.

The first atudy was maie with three normal individuals treated as
parallels to three cancerous individuals, The chief trouble with the results
obtainei is that the reaction is not durable enough, If the treatment is
contimied, @ marked decrease in the lymphocytes finally results, The method
is being modified now by decreasing the penetration of the rays and incraas-
ing the tine ani area of exposure. Results so far from this dosage indi-
cate a distinct advance in the method,

Few new cases have beon admitted, as with the present staff it is
not possible to carry more than twenty-five patients at a time. Since the
last report, three of the cases with advanced cancer have died, two of these
directly from extension of the disease, and the third from the effects of
an operation, an attempt to remove @ lymphedematous arm, It is of interest
to note that as these cases advanced, the fluctuations in the lymphooytes
hed a more and more downward tendency, uhtil towards the end the counts .
reached & very low level. Autopsies obtained on two of these cases showed
particularly interesting changes in the spleens, The Malpighian bodies |
were greatly reduced in mumber and contained only e fraction of their normal
quota of so-called mother cells. Likewise there was a great reduction in
the number of emall round cells, which are usually eo abundant in the area
around the follicles, Tha sane condition was observed in another case

“utersiad a number of months azo.
~ B+ a4 ‘

A case of advanced sarcoma of the hip with » large lung metastasis
which had been held in a stationary condition for somewhat more than a year
has also shown some advance, With these exceptions, the cases which are be-
ing followed are practically in a stationary or slightly improved condition.

There are several incidental points of interest which have developed
in the course of the study of these cases. In about thirty individuals with
cancer of the breast, we have had six with both breasts involved; three of
these have had in addition benign tumors elsewhere, two of the uterus and
one @ lipoma of the shoulder, One patient has given an interesting family
history. There is @ larger cancer incidence in this family than any yet
reported in the literature, There have been nineteen individuals in three
generations who have died of this disease, both branches of the family being
involved. Records are available for further study of this group. In the
light of Slye's work, it seems of importance that such cases should be re-
corded,

A final opinion of the effect of the indirect X-ray treatment
must be reserved for the present, Certain cases have certainly responded

well, even with our as yet imperfect method of X-ray dosage.