August 19641 NUTRITION REVIEWS 237

common in schizophrenia. It would appear that a dietary source of the extra creatinine excretion is unlikely.

During the periods of behavioral worsen- ing the expected increased motor activity, largely restlessness, was observed. This in- creased the caloric demand at a time when intake of food had decreased. The authors suggest that the body was required to call on its own tissues for a supply of energy, and that the increased creatinine excretion was a reflection of breakdown of muscle protein. The protein breakdown in addition would release tryptophan and methionine, and this was reflected in the increased tryp- tamine in the urine.

An interesting hypothesis is suggested which can be summarized briefly. An un- known initiating cause starts a chain of events (including loss of appetite). There then follows a release of tryptophan and methionine from an endogenous source, per-

haps muscle. The released amino acids in- tensify the behavioral disturbance through the formation of psychogenic methylated indoleamines.

The hypothesis has several points which are reasonable. The Kety group experiments cited earlier in this review would support the idea that in vivo metabolism of some indolic compound gives rise to specific hal- lucinogenic substances which can affect be- havioral shifts. It is also reasonable to ac- cept the possibility that the decreased food intake during these times would result in protein breakdown with release of some stores of the implicated amino acids.

It is possible that the hypothesis may stimulate research which would shed light on some secondary factors involved in schizophrenia. Unfortunately, it may not lead to elucidation of the fundamental ques- tion: what is the nature of the initiating cause which starts the chain of events?

VIGOROUS WEIGHT REDUCTION DURING PREGNANCY

A 76 kg. loss during 42 weeks prior to conception and a 38 kg. loss during 39 weeks of gestation were associated with positive nitrogen balances despite a diet of 900 cal- ories.

Although the never ending problem of obesity has received considerable attention in the past year (E. S. Gordon, M. Gold- berg, and G. J. Chosy, J . Am. Med. Assn. 186, 50 (1963); Editorial, J . Am. Med. Assn. 185, 65 (1963) ; L. C. Wood and A. N. Chremos, J. Am. Med. Assn. 186, 63 (1963); S . H . Blondheim, N. Kaufmann, and R. Poznanski, J. Am. Med. Assn. 186, 10.43 (1963); D. Berkowitz, J. Am. Med. A m . 187,399 (1964) ; E. J . Drenick, M. E. Swendseid, W. H. Blahd, and S. G. Tuttle, (J. Am. Med. Assn. 187, I00 (1964)) , one of the most unusual reports has been that of C. E. Allen, J. Q. Adams, I. F. Tullis, and R. R. Overman ( J . Am. Med. Assn.

1 188, 39.2 (1964)) who studied the weight reduction of an obese woman on a 900 calorie diet over a period of 81 weeks.

During this time the patient lost 113.5

kg., 37.9 of which were lost during the 39 week period immediately preceding the birth of a normal 3.2 kg. female infant. Since the patient was one of a group of obese individuals whose nitrogen balance was be- ing studied during vigorous weight reduc- tion programs, the authors availed them- selves of the unique opportunity to study nitrogen metabolism during pregnancy un- der circumstances which provided extensive preconception data as well as data on weight reduction during pregnancy itself.

While obesity brings its usual hazards to pregnant women, it also increases their risk of complications of pregnancy, including toxemia, prolonged labor, difficult delivery due to large infant size, and post partum hemorrhage. Nonetheless, strong opposition (W. T. Thompkins and D. G. Wiehl, Obstet. Gynec. 4,365 (1954)) to anything but mild

238 NUTRITION REVIEWS [Vol. 22, No. 8

calorie restriction in the diets of obese preg- nant women has been expressed. These cir- cumstances make the report of Allen and co-workers all the more unusual and suggest that i t may a t least open the door for an- other assessment of prevailing concepts.

Previous studies of nitrogen metabolism during pregnancy, all performed several decades ago (F. C. Hummel et al., J . Nutri- tion 13,263 (1937) ; C . M. Coons and G. B. Marshall, J. Nutrition 7 , 67 (1934) ; I. G. Macy and H. A. Hunscher, Am. J . Obstet. Gynec. 27, 878 (1934) ; Hunscher e t al., J . Nutrition 10, 579 (1935); and K. M. Wilson, Bull. Johns Hoplcins Hosp. 27, 121 (1916) ) , all indicated that positive nitrogen balance normally occurs in pregnancy. These investigations concluded that the ma- ternal body retains nitrogen considerably in excess of that required for the products of conception.

The patient whose course has been re- ported by Allen e t al. was a 35 year old white female with a history of obesity since the age of eight years who, on admission to the hospital, weighed 214.7 kg. Her obesity was generalized, and, with the exception of a slightly elcvated fasting blood sugar and a prolonged glucose tolerance curve, her history and physical examination, except for the obesity, were essentially negative.

After three weeks on a 3,600 calorie liquid diet designed to simulate her usual intake, the patient was shifted to a 900 calorie formula containing 70 g. of protein, 110 g. of carbohydrate, and 20 g. of fat, as well as sufficient vitamins and minerals to ensure adequate nutrition. Fluid intake was main- tained a t 3,400 ml. daily. Throughout the study, daily measurements were made of body weight, fluid intake, urine output, stool weight, urine and fecal nitrogen, and urine creatinine.

Forty-two weeks after beginning the 900 calorie formula, the patient weighed 139.2 kg. having lost an average of 1.7 kg. per week. During this time, with the exception of the first four weeks on the formula, the patient was in positive nitrogen balance,

and over the course of the 42 week period experienced an average positive nitrogen balance of 0.74 g. per day. The patient be- came pregnant a t the end of the forty- second week.

Although she had displayed normal he- matologic values at the onset of pregnancy, by the twentieth week her hematocrit wag reduced to 30 per cent, her hemoglobin w88

11.8 g. per cent, and her peripheral smear showed red cells which were norinochromic and normocytic in appearance. Serum iron was 83 pg. per 100 mI., unsaturated iron binding capacity was 247 pg., and total iron binding capacity was 330 pg per 100 ml. Al- though oral administration of ferrous sul- fate, 50 mg. three times daily, was begun in the twenty-second week and continued until delivery, and although 250 mg. pyri- doxine was administered intramuscularly starting with the twenty-eighth week of pregnancy over a five week period, no sig- nificant changes in reticulocyte count, he- moglobin, or hematocrit value occurred, leading the authors to the opinion that the low hematocrit and hemoglobin levels rep- resented the physiologicsl anemia of preg- nancy.

With the exception of the period extend- ing from the eight to the sixteenth week of pregnancy, the patient was in positive ni- trogen balance, which averaged 1.2 g. per day throughout the 39 weeks of gestation, Maximum positive nitrogen balance of 3.31 g. per day was achieved during the twenty- fifth week.

Although the membranes ruptured spon- taneously on the two hundred seventy. fourth day of gestation and the uterine contractions began, failure of the fetal head to progress beyond the pelvic inld led to the performance of a low cervical Caesarian section five hours after the onsel of labor. At operation, an apron of redun, dant skin and subcutaneous fat weighin! 1.6 kg. was excised. The 900 calorie formul was resumed on the first postoperative daj At the end of the sixth post partum weel the patient weighed 91.5 kg., a loss of 47.

August 19641 NUTRITION REVIEWS 239

kg. after becoining pregnant, but including Although the retention of 1,200 g. of the products of conception and the skin and protein exclusive of the products of con- subcutaneous fat removed surgically.

According to Wilson (loc. cit .) , the ni- trogen content of the products of concep- tion plus the maternal breast and uterine hypertrophy during pregnancy is approxi- mately 135 g. If this estimate is applied to the patient of Allen and co-workers, she would have retained approximately 193 g. of nitrogen in her own body during pregnancy.

ception and hypertrophy of the breasts and uterus in difficult to accept a t face value, i t is evident that this patient did not lose body protein, despite her weight loss of 38 kg. during gestation. Current concepts re- garding protein metabolism in man during caloric restriction obviously deserve reap- praisal.

HIGH FLUID INTAKES AND SERUM OSMOLALITY

T h e great variability in serum osmolality in normal persons does not appear to be related to differences in fluid intake.

In a recent study (A. M. Dashe et al., J. Am. Med. Assn. 185, 699 (1963)) i t was found that even under considerably dif- ferent fluid intakes an individual's serum osniolality remained constant. Individuals with polyuric syndromes were found to show some change in serum osmolality after six hours of water deprivation. A marked change in the ratio of urine to serum osmolality was also seen when an individual with diabetes insipidus was compared with normal groups during this water deprivation period, During the course of this study a group of a few individuals was given increasing amounts of water each day until their daily water intake after six weeks was 8,000 cc. above their usual intake, or ap- proximately 10,000 cc. of water per 24 hours.

Such intakes over the period tested did not affect serum osmolality during subse- quent six and one-half hour water depriva- tion tests. Significant changes did occur in urine osmolality during this period. Other reports had suggested that high fluid intake for extended periods of time did affect serum osmolality (D. Kunstnann, Arch. Exp. Path. Pharnaakol. 170, 701 (1933) ; A. Regnier, 2. Exp. Path. Therap. 18, 139 11916)). Further study of the response of normal individuals to high fluid intake in relation to changes in serum and urine

osmolality, particularly during water depri- vation tests, were undertaken.

J . F . Habencr, Dashe, and D. H. Solomon (J. Applied Physiol. 19, IS4 (1964)) ob- served four male volunteers in good health with no history of renal or metabolic dis- eases for a total period of six weeks. During the first two weeks normal water intake was allowed and no dietary restrictions were made. The daily fluid intake, fluid output, and body weight were measured. At the end of each week a six and one-half hour water deprivation test was undertaken, and urine volumes and serum and urine osmolalities determined a t one-half and six and one-half hours.

At the start of the third week water intake was increased 2 liters per week. A similar increase was made each additional week until in the sixth week approximately 8 additional liters per day had been added to the intake. During the control period water intakes between 1,300 and 2,500 ml. were attained. Some of the individuals were unable to increase their intake to the maxi- mum average, thus actual intakes during the sixth week ranged between 7,400 and 9,500 nil. per day.

Subjects complained of some distaste for the fluiis and in the fifth and sixth weeks suffered from mild nausea, diarrhea, and lightheadedness. The presence of a slight in-