Intraperitoneal insulin administration produces a positive portal-systemic blood insulin gradient in unanesthetized, unrestrained swine.

The present study was performed to evaluate the porto-systemic insulin gradient in response to (1) glucose feeding (2) intramuscular insulin administration, and (3) peritoneal insulin administration in unanesthetized swine. The experiment was designed to verify the hypothesis that intraperitoneal insulin administered might lead to a more physiologic portal vein insulin concentration than systemic administration of a similar insulin dose. Studies were performed in 4 domestic swine with chronic, indwelling catheters in the inferior vena cava and portal vein. Unpaired studied of the absolute portal venous and systemic venous insulin concentrations were performed in response to glucose prn(n = 4), 1 unit regular insulin/kg i.m.(n = 4), and 1 unit regular insulin/kg i.p.(n = 5). Timed blood samples were obtained and serum insulin concentrations determined by RIA. Portal and caval serum insulin concentrations following intramuscular insulin injection showed no significant difference. A significant portal vein insulin excess (p less than 0.001) was demonstrated following both feeding and intraperitoneal insulin.

Effect of pregnancy on diabetic retinopathy.

The incidence of progression of diabetic retinopathy during pregnancy is unknown and its proper management uncertain. In this study, 55 insulin-dependent diabetic patients under strict glucose control were followed throughout pregnancy with serial retinal examinations by ophthalmoscopy and photographs. Nineteen patients had minimal or background retinopathy and 7 had untreated proliferative changes. Six patients had been treated before pregnancy with photocoagulation for proliferative retinopathy. A positive correlation was found between progressive proliferative diabetic retinopathy and the duration of diabetes mellitus independent of glucose control. During gestation 3 of 19 patients (16%) with minimal or background retinopathy and 6 of 7 patients (86%) with untreated proliferative retinopathy experienced deterioration of their eye disease. In 4 patients with proliferative retinopathy, progression of retinal disease was arrested with photocoagulation during pregnancy. Only 1 of 6 who had received laser treatment prior to pregnancy experienced progression of her retinopathy. These results suggest that photocoagulation prior to pregnancy may protect against rapidly progressive proliferative retinopathy and that aggressive treatment during pregnancy can prevent progression of proliferative retinopathy and visual impairment.

An aberrant adenylate kinase isoenzyme from the serum of patients with Duchenne muscular dystrophy.

The sera from patients with human Duchenne (X-linked) progressive muscular dystrophy contain elevated adenylate kinase (ATP: AMP phosphotransferase, EC 2.7.4.3) activities, in addition to their characteristically high creatine kinase (ATP; creatine N-phosphotransferase, EC 2.7.3.2) activities. By agarose gel electrophoresis of human Duchenne dystrophic serum, the presence of an apparently normal human serum adenylate kinase together with a variant species of adenylate kinase was detected. The latter enzyme species appeared, in its mobility, to be similar to that of the normal human liver-type adenylate kinase. The presence of this aberrant liver-type adenylate kinase could also be demonstrated by characteristic (for the liver type) inhibition patterns with P1,P5-di-(adenosine-5')pentaphosphate, 5,5'-dithiobis(2-nitrobenzoate) and phosphoenolpyruvate. On the other hand, by inhibition titrations with an anti-muscle-type adenylate kinase, hemolysates from the erythrocytes of several Duchenne and Becker's dystrophics were found to contain approx. 96% muscle-type adenylate kinase and their serum approx. 97% muscle-type adenylate kinase. These same patients contained approx. 89% M-M type creatine kinase in their serum (by inhibition against anti-human muscle-type creatine kinase) indicative of the presence also of M-B plus B-B type active isoenzymes. All of these data can best be explained by the presence of a variant or mutant adenylate kinase isoenzyme in the dystrophic serum. This isoenzyme appears to resemble the liver type in its inhibition patterns with P1,P5-di(adenosine-5')pentaphosphate, 5,5'-dithiobis(2-nitrobenzoate) and phosphoenolpyruvate, and in its heat stability (compare also the agarose gel electrophoresis pattern); but structurally, it is a muscle type, or derived from a muscle type, as shown immunologically by inhibition reactions with anti-muscle-type adenylate kinase. Whether this is a fetal-type isoenzyme of adenylate kinase will require further investigation.

Electron spin resonance studies of erythrocytes from patients with Duchenne muscular dystrophy.

The membrane organization of the erythrocytes from patients with Duchenne muscular dystrophy was studied by means of electron spin resonance. The fluidity of the membrane near the polar region of Duchenne muscular dystrophy erythrocytes was similar to that of normal erythrocytes. The membrane environment in the nonpolar region, however, was quite different from that of normal erythrocytes, judged by the spectra with 2-(14-carboxytetradecyl) - 2 - ethyl - 4,4 - dimethyl - 3 - oxazolidinyloxyl as probe. The temperature dependence of the ratio of the line height of central field to that at the low field showed two inflection points in normal erythrocytes at pH 7.4 (13.5 degrees -16.5 degrees and 37.5 degrees -40.5 degrees C, respectively) but the inflection point in the lower temperature range was not detected in Duchenne muscular dystrophy erythrocytes. When pH was varied, an abrupt decrease in the ratio was observed at pH 5.9-5.6 in normal erythrocytes whereas there was a gradual decrease over the range of pH from 6.6 to 5.0 in Duchenne muscular dystrophy erythrocytes. The rate of reduction of the radical 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl by ascorbate in normal erythrocytes was faster than that in Duchenne muscular dystrophy erythrocytes. Treatment of both erythrocytes with phloretin markedly reduced the rate of reduction by ascorbate and eliminated the difference in the two types of erythrocyte. These results indicate that in Duchenne muscular dystrophy the erythrocyte membrane is involved as well as the muscle cell.

Assessment of muscle strength in Duchenne muscular dystrophy.

Muscle strength in 23 patients with Duchenne dystrophy was tested against gravity and manual resistance during an 8-year period. The data show striking linearity in rate of loss of strength with age for any given patient. The tempo does not appear altered during growth spurts, bracing, or loss of ambulation. Variability in disease severity was documented clearly by 7 years of age and appears to be related to earlier age at onset of symptoms. This long ignored method of muscle strength assessment provides a precise measure of disease progression and, since the technique is widely used by physical therapists, it should be incorporated in clinical studies and therapeutic trials.

Infertility in patients with hyperprolactinemia from a pituitary adenoma. Effect of transsphenoidal pituitary adenectomy.

Four patients with infertility caused by a prolactin-secreting pituitary adenoma underwent transsphenoidal pituitary adenectomy. Preoperatively, in three patients prolactin level was elevated and gonadotropin levels were depressed. In one patient, prolactin level was elevated, and gonadotropin levels were normal, although no rise in gonadotropin levels was noted after clomiphene citrate therapy. In another patient growth hormone level was elevated. Pituitary function was otherwise normal in all patients. The patients underwent transsphenoidal pituitary adenectomy and postoperatively the first three showed normal prolactin and growth hormone levels. The fourth has not yet been reevaluated. Spontaneous pregnancy occurred in all four patients without manipulation shortly after surgery. We suggest that transsphenoidal pituitary adenectomy is a successful and low-risk approach to infertility secondary to prolactin-secreting pituitary adenomata.

Assessment of 11beta-hydroxylase activity with plasma corticosterone, deoxycorticosterone, cortisol, and deoxycortisol: role of ACTH and angiotensin.

UNLABELLED: In this study we evaluated the role of ACTH and angiotensin on regulation of activities of 11beta-hydroxylases of the adrenal cortex. The ratio of the plasma concentrations of 11 deoxycorticosterone (DOC) to plasma corticosterone (B) reflected the activity of the enzyme of the B and/or aldosterone pathways, and the ratio of plasma 11-deoxycortisol (S) to plasma cortisol (F) as the activity of the enzyme in the F pathway. In normal subjects, both ratios were significantly lower at 0800-0900 h (Doc to B, .01+/-.004, mean+/-SE, n=10; and S to F, .01+/-.003) than at 2000 h (DOC to B, .028+/-.024 and S to F, .015+/-.005). The plasma levels of DOC, B, S and F were all significantly lower at 2000-2100 h than at 0800-0900 h. In contrast 9 patients with Cushing's syndrome exhibited no diurnal change in the ratios. The ratios increased substantially following dexamethasone or metyrapone administration. A high or low salt diet and an angiotensin infusion produced no significant effect on the ratios. The plasma concentration of all four steroids was increased by more than 50% by an infusion of angiotensin. Four hours after administration of 80 mg of Lasix at 0800 h to 10 normal subjects, the ratios of DOC to B and S to F increased significantly (P less than .02), an effect possibly related to a decreased secretion of ACTH. CONCLUSIONS: 1) 11beta-hydroxylase activity of the B and/or aldosterone and F pathways appears to change in parallel with ACTH secretion, and 2) although angiotensin stimulates steroidogenesis of the pathways, it has no apparent effect on 11beta-hydroxylase activity.

Uric acid catabolism in the woolly monkey.

The degradation and excretion of 2-14C-uric acid were examined in three adult woolly monkeys (Lagothrix lagothrichia) to determine the basis for the relatively high serum and urinary uric acid concentrations previously reported in this species. Like man and the great apes which lack uricase, but in distinction to most other mammals, these animals converted very little urate to allantoin. Uric acid turnover, as has been reported for other New World monkeys, was several times that of normal man. Renal urate excretion as well as disposition by extrarenal mechanisms may protect Lagothrix vrom hyperuricemia. The capacity to convert urate to allantoin appears to have been lost late in the evolution of New World monkeys. The woolly monkey deserves further study as a primate model for investigations of enzyme replacement strategies.

Cushing's syndrome in a patient with an empty sella turcica and a microadenoma of the adenohypophysis.

A patient with Cushing's syndrome and an empty sella turcica is presented. A pituitary microadenoma was removed by the transsphenoidal approach. The Cushing's syndrome was alleviated, and the function of the other pituitary trophic hormones has remained normal eight months after surgery. It is emphasized that an empty sella turcica does not rule out a pituitary tumor. The therapeutic implications are discussed.

Kinetics and interconversion of prednisolone and prednisone studied with new radioimmunogassays.

To determine the kinetics of metabolism and interconversion of prednisolone and prednisone, the plasma levels of these synthetic glucocorticoids were measured by new radioimmunoassays (RIA) after intravenous (iv) or oral administration to normal humans. Following the iv injection of prednisolone phosphate in 8 normal subjects, the mean half-time of prednisolone was 240+/-20 min (mean+/-SE) and the metabolic clearance rate was 82+/-7.2 1/24 h/m2. Of 10 mg of prednisone given orally to 5 normal subjects, 69+/-5% was absorbed and converted to peripheral plasma prednisolone within 8 h. The data indicate that prednisone is extensively metabolized to prednisolone before it clears the splanchnic circulation and the formation prednisone by oxidation of the 11-hydorxyl group of prednisolone appears to occur mainly in peripheral tissues.

Thyroid nodularity in children.

Of 5,179 school children surveyed in Utah, Nevada, and Arizona for thyroid abnormalities because of possible exposure to radiation from fallout, nodularity of the thyroid was found in 98 (1.8%). In 34, the nodularity represented lobulation associated with adolescent goiter, and in 31, thyroiditis. Two malignant neoplasms were found. In a normal childhood population in which nodularity is incidentally discovered on physical examination, the risk of nodularity being malignant is approximately 2%. Factors that favor exploration of thyroid nodules in children are discreteness, growth of the mass, singleness, and absence of other thyroid disease.

Apparently normal pituitary-adrenal suppressibility in Cushing's syndrome: dexamethasone metabolism and plasma levels.

In this study, we evaluated the responses of the pituitary-adrenal axis to the suppressive action of dexamethasone by relating plasma dexamethasone (Dex) and cortisol (F) levels in normal subjects and patients with Cushing's syndrome. Various doses of Dex were ingested at midnight as a single dose or at 6-hour intervals for 2 days beginning at 8 A.M. A nomogram was prepared by plotting the 8 A.M. plasma F concentration as a function of the plasma Dex value. Two patients with Cushing's syndrome had normal responses to Dex suppression as assessed by conventional tests. With the nomogram, we found that all patients with Cushing's syndrome, including these two, exhibited abnormally high plasma F values at some time during our evaluation. A decreased metabolic clearance rate of Dex appears to explain why one showed normal suppression. Another patient with bilateral adrenal hyperplasia showed sequentially over 13 months abnormal, normal, and abnormal suppression, which could not be attributed to an abnormality of Dex metabolism. We conclude that relating plasma Dex and F provides the investigator with a reliable index for evaluating resistance of the pituitary-adrenal axis to the suppressive effect of Dex.