Testicular leydig cell hyperplasia as a cause of familial sexual precocity.

Testicular Leydig cell hyperplasia was observed in two brothers presenting with progressive sexual precocity at 2 yr of age. Virilization was shown to result from increased secretion rather than decreased clearance of gonadal testosterone. Testosterone hypersecretion appeared to be gonadotropin independent, as basal and gonadotropin-releasing hormone-induced serum LH concentrations were low by both RIA and bioassay. Adrenal steroidogenesis was demonstrated to be normal by ACTH stimulation, dexamethasone suppression, and split adrenal venous function tests. Testicular histology revealed immature reproductive structures in the 2 yr old, but advanced spermatogenesis in the 3 yr-old brother. The etiology of both Leydig cell hyperplasia and reproductive testicular maturation in the absence of significant gonadotropin secretion remains to be established.

Glucocorticoid effects on the embryonic chick heart. I. Glucocorticoid enlargement of the heart.

Cortisol increases the heart weight relative to body weight following injection of growth suppressing amounts of the hormone on incubation days 9, 10, 13, and 15. Hormone administration increases glycogen, glycosaminoglycan (GAG), and total lipid concentration in the embryonic myocardium. Deoxyribonucleic acid (DNA) and protein concentration are decreased proportionally. Glycogen synthetase and radiosulphate incorporation into GAG are increased by the glucocorticoid. Lack of growth inhibition of the embryonic myocardium by glucocorticoids is not due to absence of glucocorticoid receptors. [3H]-Dexamethasone was shown to bind to a cytoplasmic and nuclear fraction of the chick heart. Binding to a cytoplasmic protein could be demonstrated in the heart at nine days of embryonic development and increased with developmental age. The increase in cardiac mass appears to be specific for the glucocorticoid hormones when compared with epinephrine and deoxycorticosterone. The latter two hormones did not increase cardiac mass.

Endocrine-metabolic relationships in patients with leprechaunism.

Leprechaunism is a rare, heritable syndrome, associated with multiple dysmorphic and pathologic features, suggestive of an endocrine dysfunction. Few endocrine and metabolic studies have been obtained because of the rarity of the syndrome, and the small size and early demise of these infants. The authors present here the clinical, anatomic, and endocrine-metabolic studies of three patients, with a view toward careful delineation of the syndrome and further characterization of the metabolic defect.The most striking and consistent metabolic derangements present in all of these patients were fasting hypoglycemia (less than 20 mg/dL), postprandial hyperglycemia (more than 250 mg/dL), marked hyperinsulinemia (more than 2000 µU/mL), and severe insulin resistance (less than a 20 percent decrease in blood sugar with 0.3 to 1.0 U/kg of regular insulin IV). Hyperinsulinemia was observed in response to oral feedings and glucose infusion, and after tolbutamide. Insulin secretion was less marked with amino acid infusions. Normal increments in blood glucose occurred following alanine, galactose, and glycerol. Glucagon caused a rise in glucose 4 hours after a meal, but no response was seen after a 12-hour fast. Pituitary, gonadal, and adrenal hormone levels were normal, and there was a normal response pattern to GnRH and TRH. Hyperinsulinemia would appear to be the biochemical hallmark of this disease. Our previous studies were suggestive of a postreceptor defect in insulin action. The present endocrine-metabolic studies are compatible with this hypothesis. Interaction of supraphysiologic concentrations of plasma insulin with growth factor receptors, this may provide a partial explanation for some of the dysmorphic features seen in the disorder.

Apparent focal motor seizure with a jacksonian march induced by fentanyl: a case report and review of the literature.

This report describes an unusual presentation of focal motor activity resembling Jacksonian march, which developed during fentanyl induction of general anesthesia. Simultaneous spectral-edge activity recording of electroencephalography (EEG) failed to show evidence of an epileptic focus. A negative history of previous seizures, as well as failure to show postoperative postictal symptoms or seizure activity by 16-lead EEG, suggested a myoclonic rather than epileptic nature of the observed muscle activity. Pertinent literature and current theories regarding opioid-induced seizures are discussed.

Diabetes mellitus in a pig-tailed macaque (Macaca nemestrina).

An eight-year-old male pig-tailed macaque developed clinical signs of diabetes mellitus: constant glucosuria, uriposia, fasting hyperglycemia, hypertriglyceridemia, marked pre-beta-hyperlipoproteinemia, glucose intolerance, hypoinsulinemia and hyperglucagonemia during intravenous glucose tolerance tests (IVGTT). During a ten-month period of intensive surveillance, the monkey's body weight decreased, but ketonemia or ketonuria were never observed. Exocrine pancreatic functions remained normal.

Presynaptic modulation of ganglionic ACh release by muscarinic and nicotinic receptors.

The present experiments were undertaken to investigate the effects of atropine and d-tubocurarine on acetylcholine (ACh) release and ganglionic synaptic transmission in the isolated cat stellate ganglion. Ganglionic release of picomole amounts of ACh was measured by radioenzymatic assay, and ganglionic transmission was estimated on the basis of the compound action potential recorded from the postganglionic stellate cardiac nerve. Atropine (5 microM) produced a significant increase in both spontaneous and evoked ACh release from the ganglion while depressing synaptic transmission. d-Tubocurarine (20 microM) also caused a significant, though smaller, increase in spontaneous release of ACh but had little effect on evoked release of ACh. These results suggest that ACh release and synaptic transmission in the cat stellate ganglion are subject to cholinergic feedback regulation, which appears to be mediated predominantly via muscarinic presynaptic receptors.

Direct comparative effects of isoflurane and desflurane on sympathetic ganglionic transmission.

Although the sympathetic ganglion is an important site of peripheral regulation, few studies have examined the effect of anesthetics on synaptic transmission. In the present study we compared the actions of desflurane with those of isoflurane on synaptic transmission and neurotransmitter release in the stellate ganglion. In the electrophysiologic group, 14 stellate ganglia were isolated from adult mongrel dogs after halothane anesthesia, desheathed, and superfused with Krebs' solution. Compound action potentials (CAP) were induced by supramaximal stimulation of the preganglionic T3-ramus at a low frequency of 0.4 Hz and were recorded from the postganglionic ventral ansa subclaviae. Each ganglion was exposed to two levels of anesthetics (equivalent to 1 and 2 minimum alveolar anesthetic concentration [MAC]), followed by an anesthetic-free washout period. While equianesthetic concentrations of isoflurane and desflurane caused essentially equipotent suppression of ganglionic transmission, desflurane was more efficacious than isoflurane, both with respect to the onset of and recovery from the inhibition of synaptic activity. In the electrochemical group, 25 ganglia were exposed to both anesthetics at a high concentration (equivalent to between 1.82 and 1.95 MAC) during maximal and submaximal current stimulations, and the release of actylcholine (ACh) in the superfusate was measured with liquid chromatography. Although desflurane and isoflurane caused a significant depression of CAP, neither anesthetic inhibited the release of ACh in the superfusate at either maximal or submaximal current stimulations. These results indicate that the suppression of ganglionic activity is equipotent for both anesthetics based on equivalent MAC values, but that desflurane is more efficacious than isoflurane with respect to onset and recovery at the higher concentrations of anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased cyclic guanosine 3',5' monophosphate and guanylate cyclase activity in leprechaunism: evidence for a postreceptor defect.

Patients with leprechaunism have hyperinsulinemia and extreme insulin resistance. The mechanism of the insulin resistance has not been delineated. To examine postreceptor events in this unusual syndrome we have assayed the enzyme guanylate cyclase [E.C.4.6.12], which is modulated by insulin, and the concentration of the intracellular messenger cyclic GMP in liver from two children with leprechaunism and extreme insulin resistance. Both patients exhibited down regulation of the red blood cell insulin receptors, but normal insulin receptor binding to Ebstein-Barr transformed IM-9 lymphocytes and monocytes. There was no evidence of antireceptor or antiinsulin antibodies. Activity of liver guanylate cyclase expressed as pmol/mg protein/10 min incubation in the soluble and particulate fractions were, respectively, Ark-1 133 +/- 18, 25 +/- 6; Ark-2 129 +/- 17, 23 +/- 8; control children (six average) 287 +/- 16, 55 +/- 9. The concentration of cyclic GMP was also 50% lower (0.08 +/- 0.03 in Ark-1 and 0.07 +/- 0.04 in Ark-2), compared to 0.19 +/- 0.07 pmol/mg protein/min in the control livers. There was no change in adenylate cyclase activity in children with leprechaunism versus the control children. These data suggest an abnormality of a postreceptor event in this rare genetic disease. These data, however, do not rule out that in some cases of leprechaunism a receptor binding abnormality may be the primary defect. We speculate that a defect in insulin action distal to plasma membrane receptor binding may be etiological in this unusual syndrome.

Alterations in cartilage metabolism by neurostimulant drugs.

Suppression of growth without significant alterations in hormonal patterns has been demonstrated for the neurostimulant drug pemoline. Comparison of the in vitro effect of pemoline, methylphenidate, and methamphetamine on somatomedin-stimulated sulfate uptake by cartilage showed all three drugs to be inhibitory. Sulfate uptake by cartilage can be directly related to growth and glycosaminoglycan biosynthesis. Assay of two of the enzymes involved in the glycosaminoglycan biosynthetic pathway showed that methamphetamine and methylphenidate caused a marked depression of xylosyl- and galactosyltransferase enzyme activity. These data suggest an interference with cartilage metabolism as one possible mechanism for the growth retardation observed in children on neurostimulant drug therapy.

Impaired growth in hyperkinetic children receiving pemoline.

Decreased longitudinal growth was observed in 24 hyperkinetic children receiving pemoline therapy. Mean height velocity was 3.67 +/- 0.25 cm/year during therapy but 5.35 +/- 0.42 cm/year after treatment had been discontinued (P less than 0.01). There appeared to be an inverse relationship between growth velocity and drug dosage. All patients receiving less than the median dose of 3.72 mg/kg grew 4 cm/year or more, while seven of 12 patients receiving more than this dose grew at a slower rate. Body weight, basal and stimulated growth hormone values, and plasma somatomedin concentrations were not significantly altered by pemoline treatment, suggesting that this drug may have a direct effect on cartilage metabolism.

Parathormone and perinatal calcium homeostasis.

Plasma parathormone (PTH) and calcium concentrations were measured in 309 specimens collected from 190 newborns during the first 7 days of life. The patient material consisted of 51 preterm, 130 term, and 9 postterm infants, including 22 infants of diabetic mothers (IDM), 38 infants with hypocalcemia, and 25 asphyxiated infants. PTH was detectable, although in low concentrations, in cord blood samples despite the presence of elevated calcium concentrations. Postpartum, PTH concentrations in term, appropriate for gestational age (AGA) infants remained low during the first 2 days of life; a significant (P less than 0.05) and sustained increase in plasma hormone levels was noted starting on day 3. PTH concentrations in IDM and preterm infants remained low for 3 days and a significant hormone increase did not occur until day 4. Hypocalcemia was common in IDM and asphyxiated infants; these infants accounted for two-thirds of all hypocalcemic infants. The profile of plasma calcium in IDM during the first week of life was different than that of any other group of infants. Plasma calcium concentrations remained depressed over this period of time and exhibited a temporary drop on day 4 accompanied by an increase in plasma PTH levels. Asphyxiated infants exhibited low plasma calcium concentrations, despite PTH levels that were significantly (P less than 0.007) higher than those of age-matched term AGA newborns.

Hepatic ultrastructure in leprechaunism. Hepatic ultrastructural evidence suggesting a syndrome with defective hepatic glucose release.

Leprechaunism is a congenital syndrome with characteristic habitus and facies, with fasting hypoglycemia and hyperinsulinism. In response to a glucose challenge there is prolonged severe hyperglycemia with an increased hyperinsulinemia. Our studies on such a patient showed a normal response of the serum glucose to glucagon stimulation in the fed state but no response in the postabsorptive state. Ultrastructural studies on the hepatocytes demonstrated that a lack of hepatic glycogen was not responsible for the biochemical features, since there was abundant normal beta-glycogen in both the fed and fasting state, the granules being smaller in the fasted state. We speculate that carbohydrate intolerance in leprechaunism may be due to a relative insulin resistance of cell receptors in the fed state. Reactive hyperinsulinemia persisting into the postabsorptive phase appears to antagonize the usual glycogenolytic response to glucagon during fasting, resulting in hypoglycemia despite the presence of large hepatic glycogen stores.

Glycogenosis type IB: possible membrane transport defect.

We have described a 20-month-old child with type IB glycogen storage disease, based on clinical and biochemical manifestations. Functional testing data were similar to those found in glucose-6-phosphatase deficiency, but in vitro studies showed normal hepatic glucose-6-phosphatase activity. Disruption of membranes with deoxycholic acid was followed by an increase in enzyme activity compared to a control liver tissue, suggesting "latency" of enzyme. We suggest that this patient had glycogen storage type IB and that this disorder may represent a specific glucose-6-phosphate transport defect.