RECENT ADVANCES IN NUTRITION

MICHAEL G. WOHL, M.D., F.A.C.P.*

Progress in the basic contributions to the science of nutrition has been

extensive. In this review we shall survey the most notable recent de·
velopments in nutrition of practical importance.

VITAMIN ANTAGONISTS
.,
The recognition of the existence of vitamin antagonists came largely
through the work of Woolley,1 Woods and Fildes. 2 A vitamin antagonist
is a structural analogue of a biologically active compound which induces
signs of specific deficiency disease. The signs of the induced deficiency
disease can be nullified by the administration of the biologic compound
in question. An example is provided by the following: a slight modifica-
tion in structure of nicotinic acid (S03 for COOH), results in an antago-
nistic compound, pyridine-3-sulfonic acid. This compound inhibits the
growth of certain bacteria. The addition of nicotinic acid nullifies the
inhibitory effect of the antagonist.
Vitamin antagonists have been found in natural occurring forms and
many may be synthetically prepared. Certain ferns contain antivitamin
BI 3; certain foods consumed by humans are known also to contain anti-
vitamins of a deleterious nature. For instance, raw clams and certain
kinds of fish such as carp contain an enzyme that has an antivitamin Bl
activity. Fortunately this enzyme is destroyed by heat.
Oxythiamine is a thiamine antagonist recently synthesized. 4 This com-
pound when given to thiamine-deficient animals may prove fataL
Oxythiamine has recently been used in experimental work with polio·
myelitis virus since the latter is known to develop less rapidly in thia-
mine-deficient ani.mals. It is interesting that mice infected with the
virus show less paralysis when they are deficient in tryptophane. The
possibility of using certain antagonists to modify certain viruses suggests
itself.5
The exact physiologic activity of antivitamin El is not known. It may
function in a manner similar to other antivitamins: (1) by inactivating
the specific vitamin (B I ) ; (2) by uniting with this vitamin forming an
irreversible compound and thus render it unavailable; (3) it may com-
petitively interfere with the action of thiamine. 6
Some synthetically prepared antivitamins have a chemotherapeutic
action. Among these are the folic acid antagonists, of whicA there are
From the Department of Medicine and the Nutrition Project, Philadelphia
General HospitaL The Nutrition Project is supported by grants-in-aid from
Swift & Co. an l National Livestock and Meat Institute.
* Associate Professor of Medicine, Temple University Medical School; Chief, Nu·
trition Institute, Philadelphia General HospitaL
1721
1722 MICHAEL G. WOHL

several synthetic preparations. 7 One that has aroused considerable in-

terest is aminopterin (4-amino-pteroylglutamic acid), which is reported
to bring about remission in some children with acute leukemia (see
Table 1).
It is interesting to know how the administration of aminopterin in
acute leukemia came about. Farber8 observed that the use of folic acid
conjugate in leukemia causes an acceleration of the leukemic process in
the bone marrow and viscera not seen to that degree in children treated
without folic acid. Farber felt that it would be worth while to employ
this acceleration phenomenon to advantage by irradiation, nitrogen

TABLE 1
4-AMINO-PTEROYLGLUTAMIC ACID AND DERIVATIVES

rNyNi-NH2

A--COONR-CHR1-"'N~;
NH2

A R Abbreviated Name Re fer-

RI e nee
._'". --- ---
Glutam ic acid. .. H H 4-amino pteroylglutamic acid
OH .... .... CH, H 4-amino-N,o-methyl pteroic acid 2
Glutam ic acid .... CH, H 4-amino-Nlo-methyl pteroylglutamic 2
acid
Glutam ic acid .. CH, CH, 4-amino-9, lO-dimethyl pteroylglu- 3
tamic acid
Asparti c acid .... H H 4-amino-pteroylaspartic acid 4

1. Seeger, Smith and Hultquist, J. Am. Chem. Soc. 69: 2567, 1947.
2. Seeger, Cosulich, Smith and Hultquist, J. Am. Chem. Soc., in press.
3. Hultquist, Smith, Seeger, Cosulich and Kuh, J. Am. Chem. Soc. in press.
4. Mowat and co-workers, in press.
(Courtesy of Dr. T. H. Jukes.)

mustard therapy or by administration of folic acid antagonists, after

pretreatment with folic acid conjugate. Indeed, when folic acid antago-
nist was used by the intramuscular route in fifteen infants and children
ill with acute leukemia, ten showed signs of hematologic and clinical
improvement. It was found at the Children's Hospital of Philadelphia
that the drug is superior to blood transfusions, urethane and all other
methods employed in the past in acute leukemia in children. The recom-
mended dese is 0.5 to 1.0 gm. per day intramuscularly. It is to be noted
that the improvement, although significant, is only temporary.8a Spon-
taneous remissions have been known to occur in acute leukemia. Aminop-
terin is toxic and may produce deleterious effects such as stomatitis,
spongy gums and gastrointestinal hemorrhages. A more potent and less
toxic folic acid antagonist, amino-an-fal, was recently described.
Since folic acid is synthesized in the intestinal tract by certain bac-
 RECENT ADVANCES IN NU'I'RITWN 1723

teria, it would appear logical to employ a poorly absorbed sulfonamide

such as succinylsulfathiozole during therapy with aminopterin. Inter-
ference with bacterial synthesis of folic acid may enhance the therapeutic
effect of aminopterin so that smaller doses may be required in acute
leukemia.
In recent years other antivitamins have been isolated or synthesized.
There is at least one antivitamin for each of the water-soluble vitamins
and for the fat-soluble vitamin K (Dicumarol and derivatives) and E
(a-tocopherol quinone). In many instances, there is not one but several
antagonists for each biologic compound 9 (Fig. 278).
It is interesting to note that antagonists to certain aminoacids have
also been described. It was shown for example that a compound, in-
doleacrylic acid, which structurally resembles tryptophane, interferes
with the growth of E. coli; this inhibitory effect is reversed by the addi.-
tion of tryptophane.1°
The concept of metaboli.te antagonism is being actively explored at
present by several investigators. It may lead to the development of
therapeutic agents of practical value.
From this brief review, it is apparent that there is a metabolic simi-
larity between all living cells and that biological processes may be
blocked by metabolic antagonists.
VITAMIN B12
The outstanding contribution in the past year has been the isolation
by Rickesl1 and associates from the liver of a crystalline compound, co-
balt in nature. This compound, B 12 , in microgram dosage is capable of
producing hematopoietic response in patients with pernicious anemia.
Animal Protein Factor.-The discovery of vitamin B12 is interwoven
with that of the "animal protein factor." In 1946, Cary and his co-
workers reported that rats require a new unidentified factor that is
essential for growth.1 2 This x factor was found in commercial liver ex-
tracts. Similar investigations were being carried out by numerous
workers. They found that the growth of chicks and normal hatchability
of hens' eggs require in their breeding rations some protein of animal
origin. Thus, a new nutritional factor designated "animal protein factor"
was discovered.
Mary Shorb,13 investigating the nature of the new animal protein
factor, found that the microorganism Lactobacillus lactis Dorner re-
quired for growth two factors; one of these was contained in crude and
refined liver extracts. She determined that there is an almost linear re-
altionship between the clinical activity of the liver extract in pernicious
anemia and the rate of growth of the lactobacillus under study. Thus,
she succeeded in using bacterial growth for assaying liver fractions for
antipernicious potency rather than patients, as had been the earlier
practice.
The crystalline substance B12 was found to possess growth-stimulating
activity in chicks and in Lactobacillus lactis Dorner. This suggests the
close relationship between B12 and the animal protein factor.
 VITAMINS AND ANTI-VITAMINS
VITAMIN 86
CHO

HOOCH2OH
Pyridoxol
H3 C
N 011 ~ave CHO
vitamin
B.
which Tryptophane
CH 20H HOOCH20P03H2 functions metabolism
activity.
When os 0
HOOCH20H Pyridoxine led, H3 C N --+ necessary Amino acid
>- they ~ port 01 decarboxylation
H3 C
certoin
~ N ore
partially
pyridoxal enzymes
-+ Transamination
phosphate in
converted,
CH 2NH 2
into
(co. decarboxylase )
~
HOOCH20H Pyridoxamine
CH 3
H3 C N
HOOCH20H .. -desoxypyridoxine
H3 C
N because 01 a structural
Some substances
such. as similarity to the vitamin
"- CH 2OCH3 may inhib~ these reactions

HO 0 CH 2 0H .. - methoxypyridoxine
H3 C
N
 SIMILAR RELATIONSHIPS HOLD FOR OTHER MEMBERS OF THE VITAMIN B GROUP
VITAMIN COENZYME FORM NECESSARY FOR THE ACTIVITY OF ANTI-VITAMINS
NIACIN Coenzyme I, (DPNI, coenzyme 11, (TPN) Several Dehydragena,e, Pyridine-3-.ul/onic acid
3 acelylpyridine, elc.

THIAMINE Thiamine Pyropho,phale Several Organic Acid Decarboxylase, Pyrilhiamine

2 bUlyl Ihiamine, elc.

RIBOFLAVIN Flavin Phosphale, FAD Several Oxidalive Enzymes Phenazine analog of riboRavin
.... isoriboflavin, etc.
~
PANTOTHENIC ACID Coenzyme A (unknown ,Irudure) Acetylaling Enzyme, Panloyltaurine
phenyl panlolhenone, elc.

BIOTIN Coenzyme form nol known Carboxyla,e" Some Deamina,es Desthiobiolin

biolin suI/one, elc.

FOLIC ACID Coenzyme form nol known Pleroyla.partic acid

melhyl/olic acid, elc.

Fig. 278.-Yitamin B complex, its functions and antagonists. (By courtesy of Wayne Umbreight and Gladys Emerson.)
172(i MICRAl'jI, G. WORL

It is noteworthy that vitamin B12 is synthesized by streptomyces

griseus. It was isolated from this mold III sufficient quantity to be used
successfully in patients with pernicious anemia. This may furnish a less
expensive source of vitamin B12 than the present method of extracting
it from liver.
Clinical Results.-Vitamin B12 is now considered to be the most effec-
tive antianemic agent. It also produces rapid regeneration of the lingual
mucosa. Favorable reports on the regression of neurologic manifestations
have been reported. This is clinically significant since folic acid may cor-
rect the blood findings in pernicious anemia in a relapse, but it is generally
recognized that the neurologic manifestations are not influenced. Indeed,
in some instances folic acid may hasten development of neurologic signs
and symptoms.l4 Patients with nutritional macrocytic anemia of infancy,
nontropical sprue and tropical sprue in relapse have shown good hema-
tologic improvement following the use of vitamin B 12 .15
At the Philadelphia General Hospital we studied the effects of vitamin
B12 in eight patients with pernicious anemia, four of whom had neuro-
logic complications. 15a In this paper we are reporting the effects of vita-
min B12 in three patients with severe forms of pernicious anemia follow-
ing the intramuscular administration of two doses, each of 25 micrograms
of B12 at twenty-five day intervals. The clinical response was striking. All
three patients on admission to the hospital were extremely ill, weak,
dehydrated, anorexic, and they were mentally depressed. Seven days
after the first injection, clinical improvement occurred. The appetite
returned, increasing muscular strength and alertness soon followed.
Good hemotologic response was obtained in all three patients as illus-
trated in Figures 279 and 280.*

REPORT OF CASE

E. R. was an 80 year old white woman admitted to the Philadelphia General

Hospital (Service of Dr. David N. Kremer) in January, 1949 because of weakness.
Past History: Pernicious anemia was first diagnosed in 1945 in this patient
at this hospital and treatment with liver extract followed. In 1946, she under-
went a cholecystectomy for chronic cholecystitis and cholelithiasis. In April
1948, one year before this present admission, she again complained of weakness,
dizziness, nausea and pain in both legs. At that time she was found to be mark-
edly anemic; the liver and spleen were enlarged and there was loss of vibratory
and position sense in the lower extremities. After a good response to liver, she
was again discharged to the Medical Clinic. However, she did not attend regu-
larly and had no treatment for about nine months.
Interval History: The interval history was difficult to obtain on admission
because of mental confusion, disorientation and marked deafness. She appar-
ently was becoming extremely weak and anorexic.
Physical Examination: She was an elderly, extremely pale woman with a blood
pressure of 120/60, temperature lOO°F., pulse 108, respiration 26. The tongue
margins were smooth and although some papillae were found on the dorsum, the

* We are indebted to Dr. Augustus Gibson, of Merck & Co., and C. H. Mann,
of E. R. Squibb & Sons, for the generous supply of B 12 •
 RECENT ADVANCES IN NUTRITION 1727

general appearance was that of moderate atrophy. There was a moderate tachy-
cardia and a faint apical systolic murmur. The liver was just palpable at the
costal margin. Minimal ankle edema was present. The physical examination was
otherwise unremarkable.
Neurological Consultation (Dr. A. M. Ornsteen): There are hyperactive deep
reflexes but no pathological reflexes. Sensation and vibratory senses are within

11

10

3 9 60

a
Z.S so
7

6 40

5
1.5 30
4 I
\
I
I

'"\ I
I
\
os 10
I
I
\
I I

• • ,..
-, •.-*' \to,
".--.----.--IIt-.--.-.---.--.--.--.
I "', •
o . ...••,
-'-'-y .

J 'v---",-~
IS ....,....

~% ':
o
Fig. 279.-Hematologic response of patient with pernicious anemia to vitamin
B12 • Note reticulocyte response and elevated uric acid levels.

the normal range. There was no clear evidence of peripheral neuritis or posterior
column lesions.
Laboratory Study: A bone marrow biopsy revealed hyperplastic and megalo-
blastic erythrocytopoiesis. The total plasma protein was 6.4 gm. and the albumin
was 4.5 gm. per 100 cc. The urine was negative and the patient had complete
histamine achlorhydria. Initial blood count revealed hemoglobin of 3.2 gm. and
a red cell count of 660,000 per cu. mm. Two days after the first dose of vitamin
B12 (25 micrograms) the hemoglobin was 2.95 gm. per 100 cc.
Course: On admission the patient had seemed moribund. She was too weak to
sit up or feed herself and she was deathly pale. By the end of the first week of
1728 MICHAEL G. WOHL

therapy, little change was noted. Her food intake had been negligible in spite of
strong nursing encouragement. However, by the second week she began to eat
with more interest; she was now able to sit up and there was a slight increase in
the papillae of the tongue. She progressively became stronger, mentally alert,
cheerful and cooperative. After two months she was clinically but not hemato-
logically cured. During her hospital stay, she received no treatment except fer-
rous sulfate and vitamin B 12•
The essential hematologic data are shown in Figure 279.
Commenl.-Several interesting features are to be stressed: (1) All
three of our cases showed no reticulocytosis upon the second injection of
B12 , although the red cell count was low enough for one to expect some
reticulocyte response. (2) The increase in red cells and hemoglobin began
to decline at about twenty-five days after the intramuscular injection of
25 micrograms of B12 • This would suggest that a single large dose of 25
micrograms may suffice in some patients with pernicious anemia for a
period of from three to four weeks; however, there is a wide variation
in the effective dose in different patients. (3) An extremely high uric acid
blood level (from 10 to 15 mg. per 100 cc.) was sustained for fourteen
days following the first intramuscular injection of B12 • This finding was
noted in the case cited, in which the patient showed pernicious anemia in
the most severe form (Fig. 279). (4) The second of our three patients de-
veloped hypochromic red blood cells as the maturation of erythrocytes
exceeded the available hemoglobin. Supplementary oral iron therapy
corrected the hypochromia (Fig. 280).

AMINO ACIDS
An important phase of protein research has been the development of
microbiological methods for the determination of individual amino-
acids. Such methods, first used for the determination of vitamins, have
recently been employed for the quantitative assay of ammo acids. The
"test" microorganisms used in these assays are the species of Lacto-
bacillus, such as Lactobacillus casei, arabinosis, Streptococcus faecalis,
and Leuconostoc mesenteroides.
We are coming to believe that just as there are vitamin deficiencies
of varying degrees, so too there may be amino acid deficiencies. It is
known that a deficiency of amino acids may develop much more rapidly
than a deficiency of vitamins. The difficulty has been to recognize specific
clinical patterns for amino acid deficiencies in man. A few pertinent ob-
servations are available. Holt and his associates1& have observed that a
few days after subjects are placed on a diet from which lysine has been
eliminated, they develop nausea, headache, dizziness, and abnormal
sensitivity to noise and excrete nonketogenic organic acids. When a
casein hydrolysate containing lysine is substituted for the deficient pro-
tein hydrolysate, the symptoms disappear, but recur when the deficient
hydrolysate is again taken. Three subjects on an arginine-deficient diet
showed, on the ninth day, alarmingly low figures for spermatozoa. When
supplementary arginine was supplied, a prompt rise in the sperm count
occurred, but only after many weeks of normal diet were normal figures
 RECENT ADVANCES IN NU'l'RlTION 1729

for spermatozoa restored. Holt has reported that, in growing rats put on
arginine-deficient diets, marked anatomic changes occurred in the testes
as early as the third week. The rats' testicular tissue became so dis-
~
rtr
N
It]

RBC Hb REliC
0/0
0 e • ~
~

I
~
1/1 r.n /0
4.0 12- N N
o. 0

~/~\
J\ lai°
~~\
\I e
3.5 •Ii:>'ct"i
f'-fII.V 'J ,/
/e
10 0-0

o/tI.
/./\o~/e'/ •
3.0 9 /./ \ {loo
?o1 ~_eo

8 ~/TJ
2.5 25 ~IJJ
IV! e
7

•" ~J
~
2.0 6 20 /'
'e, /'

1.5
s
15
n° J.\
VO , I
/
P
I

\\

4 , I \
\
, I \
\
oft.
,
I
1.0 3 10 I \ ,
•,,
..,
.
I
2. ,
I
I \

0.5 S
.,
I
I
lit,
'-
'*lit

•
I
/
e • \'*lIt",""'--"'", "'-Ift-_-liI- ... --"'--.,.
°
/

0 5 10 15 20 ZS 30 35 40 45 50 55 60
DAYS
Fig. 280.-Hematologic response of another patient with pernicious anemia to
vitamin B l2 •

organized after two months that it was hardly recognizable; there was
no evidence of spermatogenesis and the tubules were filled with cellular
debris.l 7
With improved methods for estimation of individual amino acids it
may be possible to determine whether certain disease states are asso-
ciated with a specific pattern of amino acid urinary excretion. For ex-
1730 MICHAEL G. WOHL

ample, it is claimed that tryptophane is excreted in greater quantities

by the tubercular than by nontubercular patIents.

IMMUNITY AND PROTEIN DEFICIENCY

Many diverse factors are involved in the mechanism of immune body
formation. However, the state of protein tissue reserves plays a signifi-
cant part in antibody formation.
Antibodies are modified plasma globulins. The production of anti-
bodies, therefore, in common with globulins, depends upon amino acids
in the food or in available tissue protein reserves. It would appear there-
fore that protein deficiency with depletion of protein tissue reserves
should lead to lowered capacity to manufacture globulin antibody.
Indeed, Cannon and his associates in a series of animals made hypo-
proteinemic, although well nourished otherwise, have shown that such
animals tend to fabricate antibodies less effectively than those whose
protein reserves are not depleted. Such animals are unusually susceptible
to intercurrent infections. Thus a simultaneous occurrence of hypopro-
teinemia and decreased resistance to infection suggests a mutual rela-
tionship.I8
Because of practical importance of these findings in human medicine,
my colleagues and I have conducted a similar investigation in humans.
We investigated two phases of this problem; first, antibody production
in hypoproteinemia in man, and secondly, the effect of an increased
dietary protein intake in hypoproteinemic patients on the formation of
antibodies and other plasma proteins.I9
The method used in this study is interesting. By careful survey, over
a period of time, a group of patients numbering over one hundred were
found on the wards of the Philadelphia General Hospital with hypo-
proteinemia (i.e., less than 4 gm. of serum albumin per 100 cc. of blood).
The hypoproteinemia in these patients was partly due to an inadequate
protein intake and was partly a result of their specific disease. The clini-
ca.! ability of the patient to produce antibodies was determined by in-
jecting intradermally 0.2 cc. of typhoid antigen and the antibody in
the circulating blood was then measured by standard methods.
The patients were divided into three groups. Group A received the
standard hospital diet plus protein supplementation in the form of a
protein hydrolysate; group B received a standard hospital diet without
supplementation, and group C instead of receiving hydrolysate to supple-
ment the protein intake received a modified casein concentrate prepara-
tion. Patients were selected in such a way as to keep them clinically
comparable to one another. The hospital diet provided about 75 gm. of
protein per day. In this connection it is interesting that, in the early period
of our studies, we observed that patients failed to respond to the supple-
mentation due to an inadequate protein and caloric intake. Thus it be-
came apparent that it was necessary to increase total food intake to
prevent weight loss and utilization of the supplemented protein for
energy requirements. This experience is in line with that of other in-
 RECENT ADVANCES IN NUTRITION 1731

vestigators who have observed that hospital patients are often on a low
intake not only of total calories but of protein.
What were the results? Where the patient was able to synthesize
protein and the protein reserves were restored upon adequate protein
supplementation, antibody formation increased significantly.
There was a group of patients in whom the synthesis of protein by the
body was markedly impaired (by disease), as, for example, cirrhosis of
the liver. In these patients the administration of additional protein did
not by itself correct the abnormal blood protein pattern. Clinical im-
provement may sometime occur, however, and interestingly enough
they showed an increased antibody titer upon supplementation.
Another interesting finding arose from this study. Supplementation
with lactalbumin hydrolysate or casein preparation enhanced antibody
formation and partially overcame the subnormal response. But the
improvement in antibody response failed to attain the high titer ob-
served in subjects with normal blood protein values receiving the same
antigenic stimulation. This indicates that, other factors being equal,
patients in normal nutritive balance have the best antibody-producing
capacity. This we believe is a very important point.
A relevant phase of our work is that of antibody response in diabetic
patients. In analyzing a large group of hypoproteinemic patients, we
observed, as others have in the past, that the diabetic patient has a
decreased capacity to form immune bodies as compared with normal
persons. We found that the hyperglycemia is apparently not related
to the decreased capacity to produce antibodies. We further found that,
as expected, diabetic patients with hypoproteinemia showed a lower
average typhoid agglutination titer than those diabetics with normal
blood protein values. Thus the lower antibody level in the circulating
blood may partly be responsible for the recognized susceptibility of
diabetics to infection. Supplementation of these hypoproteinemic di-
abetic patients with lactalbumin hydrolysate or casein concentrate, as
in our previously discussed groups, also enhanced antibody formation 2C
(Fig. 281).
Our work in patients tends to confirm the findings in animals that
protein depletion leads to a lessened capacity to form antibodies. Fur-
thermore, our experience with diabetics is in line with that of Schneider21
that patients with complications (hemorrhagic retinitis) show low plasma
albumin levels. In some patients in whom they succeeded in correcting
the plasma protein pattern by high protein diet, retinal hemorrhages
were either eliminated or lessened. Thus the treatment of diabetic
retinopathy by high protein diet seems to hold some promise. It is sur-
prising ho,' often in our routine laboratory work-up of the diabetic
patient with complications hypoproteinemia is uncovered.
It is now recognized that in time of stress larger quantities of amino
acids should be made available in order to counteract the catabolic loss
of nitrogen. 22 Surgeons have recognized this and are maintaining the
surgical patient on high protein levels.
In the management of diabetes this rule has been generally neglected.
1732 MICHAEL G. WOHL

5000
TVPHOID H AGGL.UTININ TITEF\
4800 IN DIABETES MELLITUS

4600

4400

4Z00
• NORMA~ CONTROL~
•
4000 o CLINIC. DIABETICS GROUP l:
Q C~INIC DIABETICS GROUP 11
... HOSPITAL.IZED DIABETIGS
3800 (PROTEIN SUPPI..EMENTED)
... HOSPITAL.IZ.ED DIA&ETICS
3600 (NON SUPPI..£MENTE.C»

3400

320
Z
0
§3000
.J
ii 2800
rL
bJ 2600
I-
j:
Z400
2
2 2200
j:
:>
~ 2000 0

.,..~
0

"
et 1800
0
%
Q.
>-
"..
I-:
:r ~ ~
J: J:
0 1600
0 d 0 <i
J: Cl.
Q. 1400 0
>-
I-
%
Q.

1200 ~
~
:t
III
1000 ci

SOO

600

o 4 8 10 12. 14 1(, la zo t2. U Z" 28

DAVS
Fig. 281.-Antibody response to typhoid H antigen in patients with diabetes
meJlitus. Note the difference between normal controls and hypoproteinemic hos-
pitalized diabetics. (Wohl, M. G., Proc. Soc. Exper. BioI. & Med., VoI. 70)
 nECENT ADVANCES lN NUTRITION 1133
The uncomplicated diabetic patient may do well on the usual food
allowance of 60 to 80 gm. of protein daily; however, we believe this
ration is far too small an amount for the diabetic patient in times of
stress due to surgical complications.
It is recommended that values of serum protein be determined in
every case of diabetes with complications and a high protein diet or
protein supplement be given on indication.

REFERENCES
1. WooIley, D. W.: Science 100: 579, 1944.
2. Woods, D. D. and Fields, P.: J. Soc. Chem. Ind. 59: 33, 1940.
3. Weswig, P. H., Freed, A. lVI. and Haag, J. R.: J. BioI. Chem. 165: 737, 1946.
4. Soodak, lVI. and Cerecedo, L. F.: J. Am. Chem. Soc. 66: 1988, 1944.
5. Elvejem, C. A.: J. A. M. A. 136: 14 (April 3) 1948.
6. Wright, L. D.: J. Am. Dietet. A. 23 (4) : 289 (April) 1947.
7. Smith, J. M. et aI.: Tr. New York Acad. Sc. Ser. Il, 10: 82, 1948.
8. Farber, S.: New England J. Med. 238: 787 (June 3), 1948.
8a. WoIlman, I. J. and Githens, J. H.: Pennsylvania M. J. 52: 474 (Feb.) 1949.
9. WooIley, D. W.: PhysioI. Rev. 27 (2): 308 (April) 1947.
10. Fildes, P.: Quoted by Welch, Arnold D.: PhysioI. Rev. 25 (4) : 696 (Oct.) 1945.
11. Rickes, E. L. et aI.: Science 107: 396 (April 16) 1948.
12. Cary, C. A. et aI.: Fed. Proc. 5: 128, 1946.
13. Shorb, Mary S.: Science 107: 397 (April 16) 1948.
14. Ross, J. F. et aI.: Blood 3: 68 (Jan.) 1948.
15. Spies, T. D. et aI.: J. A. M. A. 139: 521 (Feb. 19) 1949.
15a. Wohl, M. G. and Waife, S. 0.: To be published.
16. Albanese, A. A., Holt, L. E., Jr.: Proc. Exper. BioI. & Med. 52: 209, 1943.
17. Holt, L. E., Jr., et aI.: Tr. Am. CoIl. Phys. 58: 143, 1944.
18. Cannon, P. R.: Advances in Protein Chemistry. New York, Academic Press,
Inc., 1945, VoI. 2.
19. Wohl, M. G., Reinhold, J., Rose, S. B. et aI.: Arch. Int. Med. 83: 402 (April)
1949.
20. Wohl, M. G., Waife, S. 0., Green, S. and Clough, G. B.: Proc. Soc. Exper
BioI. & Med. 70: 305 (Feb.) 1949.
21. Schneider, R. W. et al.: Cleveland Clin. Quart. 14: 76 (April) 1947.
22. Cannon, P. R. : J. A. M. A. 135: 1043 (Dec. 20) 1947.