Alfred E. Slonim

A preliminary study of growth hormone therapy for Crohn's disease.

BACKGROUND Crohns disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease. METHODS We randomly assigned 37 adults with moderate-to-severe active Crohns disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohns disease. The primary end point was the change in scores on the Crohns Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity. RESULTS At base line, the mean (+/-SD) score on the Crohns Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287+/-134 vs. 213+/-120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohns Disease Activity Index score had decreased by a mean of 143+/-144 points in the growth hormone group, as compared with a decrease of 19+/-63 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment. CONCLUSIONS Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohns disease.

Continuous Nocturnal Intragastric Feeding for Management of Type 1 Glycogen-Storage Disease

The clinical and biochemical abnormalities associated with Type 1 glycogen-storage disease can be reversed by avoidance of hypoglycemia and secondary hormonal flux. Three patients with Type 1 disease were treated with intragastric infusions of a high glucose formula at night with three-hour starch feedings during the day. This regimen stabilized blood glucose levels above 70 mg per deciliter and decreased serum uric acid, triglyceride, lactate and serum oxalacetic transaminase levels, as well as hepatic size, in all patients. Increased linear growth rate (mean 1 cm per month) was associated with a decrease in mean plasma glucagon (from 190 to 40 pg per milliliter) and an increase in mean plasma insulin (from 19 to 43 muU per milliliter, [two patients]). These changes occurred within four weeks of beginning of treatment and continued with home treatment for 13 months. No complications resulted from tube placement daily by the patients. Type 1 disease can be managed by nighttime intragastric feeding and frequent daytime high starch meals.

Protection against streptozotocin-induced diabetes by superoxide dismutase.

SummarySuperoxide dismutase was administered intravenously to rats 50 min prior to intravenous administration of a diabetogenic dose of streptozotocin. A dose of 45 mg/kg streptozotocin alone produced marked glucose intolerance and a decrease in pancreatic insulin content to less than 10% of control; both of these effects were abolished by prior administration of 105 u/g of superoxide dismutase. Superoxide dismutase (105 u/g) administered 50 min before 65 mg/kg intravenous streptozotocin did not prevent the development of diabetes. The fall in pancreatic insulin content seen with streptozotocin alone was, however, partially reversed by superoxide dismutase.

Diencephalic syndrome revisited

This report details the histories of five patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. A review of an additional 67 patients indicates that the observations are not unique. The anatomic variability combined with the fact that the course of those who are treated is infinitely better than those left untreated adds urgency to the establishment of precise anatomic diagnosis. These considerations led to a critical review of the histories of the 72 patients. From this it can be stated that anteriorly and posteriorly placed tumors do exhibit subtle but significant differences in their clinical course, and roentgenograms of the optic foramina and analysis of the CSF cell and protein content appear warranted early in the investigation of emaciation from unknown cause. Further, an evaluation is made of the role of various radiologic techniques and of endocrine studies in establishing the diagnosis. Similarly, the relative merits of radiotherapy and/or surgery in the treatment of the disease are defined. Finally, the adequacy of the term diencephalic syndrome is discussed.

Modification of chemically induced diabetes in rats by vitamin E. Supplementation minimizes and depletion enhances development of diabetes.

Administration of the antioxidant vitamin E to rats, prior to administration of either streptozotocin or alloxan, provided protection against the diabetogenic effect of both these agents. This was demonstrated by their response to a glucose load, their pancreatic insulin content and light microscopy findings. In addition, rats whose antioxidant state was depleted, by being maintained on a vitamin E and selenium-deficient diet, demonstrated increased diabetogenic susceptibility to normally nondiabetogenic doses of streptozotocin. These findings provide indirect support for the suggestion that the chemical agents streptozotocin and alloxan may exert their diabetogenic effect by acting as oxidants or free radical producers.

Improvement of muscle function in acid maltase deficiency by high‐protein therapy

Progressive muscle weakness in acid maltase deficiency (AMD) is associated with intralysosomal accumulation of glycogen and altered myofibrillar morphology. A rapid fall in circulating branched chain amino acids after protein ingestion in a child with AMD suggested that increased net muscle protein catabolism may play a part in the pathogenesis of this condition. To reduce this muscle catabolism, the patient was treated with a high-protein diet for 12 months. This has reversed the weakness and wasting, with improvement in muscle function, exercise tolerance, and growth.

Type I glycogen storage disease: Five years of management with nocturnal intragastric feeding

It has been five years since the original report indicating that intragastric feedings could reverse most of the clinical and metabolic abnormalities present in patients with type I glycogen storage disease. We have now treated seven patients with nocturnal intragastric feedings for five years. All patients have shown marked improvement in blood chemical values (urate, lactate, triglyceride, cholesterol) as well as linear growth. The only serious complication has been symptomatic hypoglycemia and acidosis resulting from acute gastroenteritis and vomiting. Results indicate that nocturnal intragastric feeding is a practical, safe, and effective form of long-term treatment for patients with type I glycogen storage disease.

Myopathy in McArdle's syndrome. Improvement with a high-protein diet.

IN normal muscle, the principal sources of energy during exercise are glucose and fatty acids. The proportion of energy derived from each of these substrates depends on the intensity and duration o...

ATP Depletion, a Possible Role in the Pathogenesis of Hyperuricemia in Glycogen Storage Disease Type I

Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and P(i) and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis. Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 +/- 0.09 to 0.73 +/- 0.06 mumol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 mumol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 +/- 21 to 311 +/- 17 mumol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 +/- 0.51 to 6.68 +/- 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 mumol/g liver), fructose-6-phosphate (from 0.17 to 0.45 mumol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 mumol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min. Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid. We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.

Chemiluminescence as an Index of Drug-induced Free Radical Production in Pancreatic Islets

Chemiluminescence induced in isolated islets from rat pancreas by the diabetogenic drugs, alloxan and streptozotocin, has been measured. The assay system consisted of 3 μM of luminol, 10 islets, and 100 μM of alloxan or 500 μM of streptozotocin in 5 ml Krebs-Ringer bicarbonate buffer containing 16 mM of Hepes (pH 7.4). Alloxan-induced chemiluminescence appeared very rapidly and lasted more than 5 min. On the other hand, streptozotocin failed to produce chemiluminescence over a period of 60 min after addition. The presence of Superoxide dismutase (1000 U/ml) and/or catalase (100 U/ml) markedly suppressed alloxan-induced chemiluminescence. These results suggest that alloxan acts as an exogenous free radical generator in pancreatic islets, but that streptozotocin does not. The involvement of Superoxide anion and hydrogen peroxide in production of chemiluminescence by alloxan suggests that the hydroxyl radical may mediate this chemiluminescence.