tient in whom it was clear that the neoplasm had not been totally removed. Patients with benign tumors revealed no urinary pterin-6-aldehyde." It should be noted that the degradation in humans of folic acid to pterin-6-aldehyde is a process that is apparently not limited to malignant tissues. The authors state that in unpublished experiments they have found pterin6-aldehyde and other metabolites of folic acid in the urine of normal humans following consumption of 50 to 100 mg of folic acid. Whether the degradative pathway of folic acid under these circumstances is the same as in malignant tissues remains to be determined. In any case the pathway in malignant tissues would appear to be a much more active one and hence should be more amenable to study. Of interest in this connection is the occurrence in human red blood cells of a dormant enzyme system capable of degrading folic acid to pterin6-aldehyde and p-aminobenzoylglutamic acid.3 Activation of this enzyme may be achieved by making blood hemolysates 2 N in HCI. Activity of the enzyme may then be observed at physiological pH values upon the addition of Mn++, ATP and glutathione as co-factors. It would be of interest to know whether a folic acid cleavage system can be obtained from malignant tissues and whether it requires cofactors similar to

those needed in the red blood cell system. The authors are careful to point out that their observations on the occurrence of pterin-6aldehyde in the urine of patients bearing diagnosed cancer require further documentation. If confirmation of their results is forthcoming, then as the authors indicate, a worthwhile application of their findings could be made to the diagnosis and treatment of cancer. In addition their experiments should serve to focus more attention on the requirements for and the metabolism of folic acid in malignant tissues. 0 1. R. Halpern, B.C. Halpern, B. Stea, A. Dunlap,

K. Conklin, B. Clark, H. Ashe, L. Sperling, J.A. Halpern, D. Hardy and R. A. Smith: Pterin-6Aldehyde. A Cancer Cell Catabolite: Identification and Application in Diagnosis and Treatment of Human Cancer. Proc. Nat. Acad. Sci. USA 74: 587-591, 1977 2. O.H. Lowry, O.A. Bessey and E.J. Crawford: Photolytic and Enzymatic Transformations of Pteroylglutamic Acid. J. Biol. Chsm. 180: 389398, 1949 3. B.M. Braganca, I. Aravindakshan and D.S. Ghanekar: Enzymic Cleavage of Folic Acid by Extracts from Human Blood Cells. I . Preparation and Cofactor Requirements of the Enzyme System. Biochsm. Biophys. Acta 25: 623-634, 1957

ASCORBATE AND CHEDIAK-HIGASHI SYNDROME Oral administration of 200 m g ascorbic acid daily for two months restored normal chemotaxis, degranulation and bactericidal activity to leukocytes taken from a patient with Chediak-Higashi syndrome. Improved function was accompanied by a return of greatly elevated levels of cyclic AMP to near normal values. Key Words: ascorbate, cyclic nucleotides, ChediakHigashi syndrome, leukocytes

Chediak-Higashi syndrome is a rare inherited disorder of humans with homologues in the Aleutian mink, a strain of Hereford cattle and a beige mutant of the C 57 black mouse. It is characterized by pigmentary dilution, increased susceptibility to pyogenic infections and the presence of anomalous giant granules resembling lysosomes in leukocytes and other cell types. The increased susceptibility to infec170

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tion is caused by abnormal function of the polymorphonuclear leukocytes brought about by impaired chemotaxis and delayed delivery of lysosomal enzymes into phagosomes, events which may be dependent upon the normal assembly of microtubules. Improvement in leukocyte function has been achieved in vitro by incubation of a patient's leukocytes with cyclic 3',5'-guanosine monophosphate (cyclic GMP) or pharmacologic agents which can bring about an internal increase in cyclic GMP, but these agents have not provided a

useful therapeutic treatment. A recent report demonstrated that ascorbic acid was also capable of potentiating chemotaxis and increasing cyclic GMP concentration in vitro in normal leukocytes.’ Boxer et al. have now examined the potential benefits of ascorbate ingestion in a patient with Chediak-Higashi syndrome.2 The subject was hospitalized at the age of two months because of poor weight gain. Physical examination revealed the signs associated with the syndrome including ocular albinism, abnormal leukocyte morphology with the presence of giant lysosomes, and an absolute leukocyte count which ranged from 288 to 3439 cells per cubic millimeter (1410 ? 1150 mean ? S.D.). At the age of nine months the patient was begun on 200 mg daily of ascorbic acid. After two months of treatment, the abnormal leukocyte morphology persisted but the absolute leukocyte count had increased to a range of 2156 to 3848 cells per cubic millimeter for a mean t. S.D. of 3260 ? 957. The impact of this regimen was evaluated with regard to chemotaxis, degranulation, bacterial killing and cyclic nucleotide concentration within the polymorphonuclear leukocytes. These parameters were tested on multiple occasions including after discontinuation of the ascorbate for one month and following its reinstitution. Data were also obtained on two normal controls given 1000 mg ascorbate daily for an unstated period of time presumably equal to that of the clinical trial. Chemotaxis was determined by measuring leukocyte migration toward a chemotactic factor in a suitable chamber. Ascorbate treatment was followed by an increase in migration from 104 ? 16 cells per 10 full fields to 258 ? 44 (P< 0.001). Cessation of the therapy for one month resulted in a return to the previous low values. Ascorbate supplements also caused a slight but significant (P< 0.005) increase in normal controls from 182 ? 10 to 215 ? 8 cells per 10 fields. The capability for degranulation was estimated by measurement of the release of the enzyme beta-glucuronidase following exposure to opsinized zymosan. Total betaglucuronidase activity was low in the pa-

tient’s leukocytes (70 ? 12 nmoles p-nitrophenylglucuronide hydrolyzed per milligram of protein) as compared to controls (120 ? 5 nmoles) and the percent of total activity released into the medium after 5, 15 or 30 minutes was only from 40 to 64 percent as much as that observed with the control. These results were evaluated as significant (P< 0.001) based on three separate experiments. Treatment with oral ascorbic acid had no effect on total activity but restored the percent release to the normal range. As with the chemotaxic response, percent release of beta-glucuronidase was not maintained when the ascorbate supplement was withdrawn but returned to normal upon its renewal. The possibility of cell lysis as an explanation of these results was ruled out by the finding that the cytoplasmic enzyme catalase remained constant at less than 7 percent of total activity during degranulation. Oral ascorbate also improved the bactericidal capacity of the patient’s leukocytes. Before therapy, a 40-minute lag occurred before a population of Staphlycoccus aureus 502A showed a reduction in viability. The ascorbic acid treatment eliminated the delay in bactericidal response and the overall rate was comparable to that of the control with the pooled repetitions showing a highly significant difference (P< 0,001). Ascorbic acid administered either in vivo or in vitro was without effect on the leukocytes from control subjects but in vitro incubation with the patient’s leukocytes was effective in improving the killing defect. Analysis by radioimmunoassay of the levels of cyclic nucleotides in the polymorphonuclear leukocytes provided an interesting clue into a biochemical defect of these cells and the effect of ascorbate in improving function. Contrary to expectations, cyclic GMP concentrations were normal in the patient’s cells, were unaffected by incubation with 10 mM ascorbic acid and were reduced by about 50 percent in response to the oral ascorbate treatment. Cyclic AMP, on the other hand, was greatly elevated in the untreated patient’s leukocytes (24 to 45 pmoles per lo7 cells vs. 2 to 5 pmoles per l o 7cells in controls). Incubation with 10 mM ascorbic acid had no statistically significant effect on controls but reNUTRITION REVIEWS / VOL. 3 5 , NO. 7 / JULY 1977

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duced cyclic AMP in the patient’s leukocytes to 10 pmoles per 107 cells. Daily ingestion of 200 mg ascorbate for four weeks was associated with a reduction in cyclic AMP concentration to 6 pmoles per 107 cells. Cessation and renewal of the ascorbate supplement was followed respectively by a return to the pretreatment elevated levels and a restoration of almost normal values. The authors suggest that the elevated concentration of cyclic AMP may inhibit microtubular assembly which in turn may impair degranulation and thus bactericidal activity. Chemotaxis may also depend upon normal microtubules as well as microfilaments. Cell movement has been shown to diminish with increasing concentrations of cyclic AMP and to increase in response to added cyclic GMP.3 The biochemical mechanism by which ascorbate brought about the reduction in cyclic AMP is not known. Inhibition of adenylate cyclase would be a possibility worth investigating, especially since ascorbate has been shown to inhibit this enzyme in isolated

adrenal cells from vitamin E deficient rats but not in similar cells from control rats4 Thus this effect of ascorbate may only be manifested in certain restricted circumstances rather than being a genuine function in normal organisms. 0

1. J. A. Sandler, J. I. Gallin and M. Vaughan: Effects of Serotonin, Carbamylcholine and Ascorbic Acid on Leukocyte Cyclic GMP and Chemotaxis. J. Cell Biol. 67: 480-484, 1975 2. L. A. Boxer, A. M. Watanabe, M. Rister, H. R. Besch, Jr., J. Allen and R. L. Baehner: Correction of Leukocyte Function in ChediakHigashi Syndrome by Ascorbate. New Engl. J. Med. 295: 1041-1045, 1976 3. R. D. Estensen, H. R. Hill, P. G. Quie, N. Hogan and N.D. Goldberg: Cyclic GMP and Cell Movement. Nature 245: 458-460, 1973 4. A. H. Nathans and A. E. Kitabchi: Effect of Ascorbic Acid on ACTH-Induced Cyclic AMP Formation and Steroid Genesis in Isolated Adrenal Cells of Vitamin E-Deficient Rats. Biochem. Biophys. Acta 399: 244-253, 1975

USE OF INTESTINAL BYPASS TO TREAT MORBID OBESITY Follow-up data are reported on weight loss, medical complications and other changes in 75 obese patients who underwent jejunoileal bypass operations.

Key Words: obesity, jejunoileal bypass, hepatic dysfunction, electrolyte loss

An estimated 10,000 short-circuiting operations of the intestine for morbid obesity have been done by surgeons throughout the U.S. since 1956. Despite this, its use remains controversial and many institutions do not perform the operation at all. There is lack of follow-up data on weight loss, medical complications and weight changes of patients postoperatively. Data were recently reported concerning 75 obese patients who had undergone jejunoileal bypass since December, 1968’ which answer some of these questions. The obese patients were selected according to standard criteria, such as maximum lifetime weight in excess of 100 percent of ideal weight for at least one year, failure to sustain weight loss in response to usual dietary methods in172

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cluding anorectic agents and psychotherapy, absence of treatable metabolic disorders which cause obesity such as Cushing’s syndrome and hypothyroidism, absence of irreversible liver disease and alcoholism. Also, in a three month preoperative observation period, the patients had to show adequate motivation and ability to comply with measures required in the postoperative care. Most of the patients had complications of obesity which favored surgery such as the Pickwickian syndrome, venous thromboembolic disease, congestive heart failure, poorly controlled diabetes, muscular skeletal disorders and ventral hernia. Seventy-three of the bypasses were performed according to the procedure of Payne and DeWind which is an end-to-side anastomosis of the first 35 cm of jejunum distal to the ligament of Treitz to a point in the ileum 10 cm proximal to the ileocecal valve. Two by-

Ascorbate and Chediak-Higashi syndrome.

tient in whom it was clear that the neoplasm had not been totally removed. Patients with benign tumors revealed no urinary pterin-6-aldehyde." It shou...
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