Heterozygous oim mice exhibit a mild form of osteogenesis imperfecta.

The oim strain of mice is one of several rodent models that exhibit an osteogenesis imperfecta (OI) phenotype. These mice have a mutation in the gene encoding alpha-2 chain of type I procollagen that prevents proper assembly of this propeptide with alpha-1 propeptides. Homozygous oim mice experience multiple bone fractures under standard laboratory animal housing conditions and are representative of moderate to severe forms of OI. Because fractures are not typically experienced by heterozygous oim mice, they have not been studied extensively. The present studies show that the organization of cortical bone is deficient in heterozygotes, exhibiting a morphology intermediate to specimens from homozygotes and wild-type mice. The biomechanical properties of femurs isolated from heterozygous oim mice are also intermediate to homozygotes and wild-type mice when tested in four-point bending. Although it is not possible to distinguish visually between heterozygous oim and wild-type mice, the quality and biomechanical properties of bone in heterozygotes is significantly reduced by twelve weeks of age. Heterozygous oim mice are useful as a model for a mild form of OI.

Erythroid-specific expression of human growth hormone affects bone morphology in transgenic mice.

The regulation of bone deposition and remodeling is highly complex. To further understand the influence of growth hormone on bone deposition, several lines of transgenic mice were generated that expressed the human growth hormone gene (hGH) driven by beta-globin regulatory elements. In situ hybridization confirmed that the hGH gene in these mice was expressed in an erythroid tissue-specific manner; in the fetus hGH was expressed in the liver and in the adult mice hGH was expressed in the bone marrow. The bones of mice in two lines were visualized radiographically by mammography, and relative bone densities were measured. The transgenic mice had detectably more bone density than nontransgenic littermate controls by approximately 3 weeks of age and the relative difference in density increased with age. Histological cross-sections of the tibia showed that adult transgenic mice had increased average cortical bone thickness when compared to their controls. The hypothesis is that the local effect of hGH release from differentiating erythroid cells in the bone marrow is a major contributor to the increased bone deposition in these transgenic mice.

Sequence of the sheep fetal beta globin gene and flanking region.

The sheep beta F globin gene has been sequenced completely, including 829 bases of 5' flanking region and 1368 bases 3' to the stop codon. In evolutionary terms, this gene is a homolog of the adult beta-like globin genes, including human beta. Over the course of evolution of Bovidae (comprised of sheep, goats, and cattle) the expression of beta F has become restricted to the fetal compartment of development. Comparisons between beta F and other closely related Bovidae beta globin genes indicate repetitive sequences that were inserted in these genes over the course of their divergence and a region which may be functionally significant to the developmentally regulated expression of beta F.

Porphyria cutanea tarda associated with autoimmune hypothyroidism, vitiligo and alopecia universalis.

The aetiology of porphyria cutanea tarda (PCT) has not been elucidated, but the possibility of an autoimmune mechanism has been proposed. We report a case of an unknown clinical combination of PCT with autoimmune hypothyroidism, alopecia universalis and vitiligo with thyroid and parietal cell circulating antibodies. This is highly suggestive of underlying autoimmune damage in this patient.

Sjögren-like pluriglandular exocrine insufficiency after drug-induced toxic epidermal necrolysis.

We present the case of a patient that progressively developed xerophthalmia, xerostomia, cutaneous xerosis and exocrine pancreatic insufficiency 3 months after metamizole-induced toxic epidermal necrolysis. Though the association of Sjögren's syndrome and exocrine pancreatic impairment is well established, the Sjögren-like syndrome after drug-induced toxic epidermal necrolysis in association with such a wide exocrine glandular insufficiency has not been previously described, to our knowledge.

Case report 674: Well-differentiated lymphocytic lymphoma with skeletal involvement.

We report the case of a man with generalized osteosclerosis secondary to well-differentiated lymphocytic lymphoma. This finding is considered to be exceptional in this type of lymphoma, especially when other organs were not found to be involved. A year after the diagnosis was established the patient appeared to be in relatively good health. The radiological pattern showed no change from the original studies, nor was there any evidence of neoplastic involvement in any other location.

Raynaud's phenomenon with digital necrosis as the first manifestation of undifferentiated connective tissue syndrome.

A patient with severe Raynaud's phenomenon (RP) associated with the presence of antibodies against extractable nuclear antigen (ribonucleoprotein) in the context of undifferentiated connective tissue syndrome is presented. The rapid course of digital necrosis in her case resulted in the surgical amputation of 9 of her fingers. We conclude that massive digital necrosis accompanied by severe RP could constitute the first manifestation of a connective tissue disease.

Nocturnal growth hormone surges in type 1 diabetes mellitus are both sleep- and glycemia-dependent: assessment under continuous sleep monitoring.

Our work has studied the relationship between nocturnal growth hormone (GH) surges, sleep and glycemia in seven conventionally treated type 1 diabetic patients under continuous sleep monitoring and the results were compared to those found in five age-matched healthy controls. On the experimental day, sleep was monitored from 24.00 to 07.00. Blood glucose levels and GH were assayed in both groups. As a group the diabetics had nocturnal GH responses higher than those in controls. However, the sleep-related GH release is not abnormally high in patients who maintain strict normoglycemia. Early-night hypoglycemia and/or rapidly decreasing blood glucose concentrations enhance sleep-related GH secretion in diabetics, whereas hypoglycemia not associated with slow-wave sleep (SWS) causes a moderate increase in GH. Late-onset nocturnal hypoglycemia is not potent enough to stimulate GH. It is proposed that in diabetics sleep-related GH production is probably not abnormally elevated within a wide range of stable glucose levels, but when these thresholds are crossed or when there is a rapid decrease in blood glucose, then GH secretion is inversely related to the changing blood glucose. Therefore, our study supports the conclusion that sleep-related GH secretion is finely modulated by the actual glycemic fluctuations in diabetic patients.

[A model of extreme insulin resistance with carbohydrate intolerance in a patient with Werner's syndrome]. / Modelo de insulinorresistencia extrema con intolerancia hidrocarbonada en un paciente con el síndrome de Werner.

We present the study of a patient suffering insulin resistance with Werner's syndrome which had abnormal glucose tolerance determined by euglycemic fixing ("Clamp") using an artificial pancreas (Biostator GCIIS, Miles Martin) and the binding of insulin to its receptor in erythrocytes. The results obtained show a dose-response curve of insulin serum levels to dextrose infusion rate, shifted significantly to the right and bottom which indicates a diminished insulin sensitivity; similarly a moderate decrease in receptor is obtained with no decrease in their affinity and absence of abnormalities in contraregulatory hormones. These results are compatible with a postreceptor alteration.

Dihydrotestosterone regulates plasma sex-hormone-binding globulin in prepubertal males.

Plasma levels of sex-hormone-binding globulin (SHBG) in man are known to be regulated up and down by oestradiol and testosterone, respectively. To determine whether testosterone reduces SHBG level directly or via its conversion into dihydrotestosterone before puberty, the changes of plasma SHBG, testosterone, oestradiol and dihydrotestosterone following human chorionic gonadotrophin stimulation are studied in ten 5 alpha-reductase-deficient and in six normal prepubertal boys. Three main observations provide evidence that dihydrotestosterone plays a major role in SHBG regulation. (1) Basal plasma SHBG in 5 alpha-reductase-deficient is higher than in normal boys (P less than 0.1). (2) Circulating SHBG fails to decrease (P greater than 0.1) after human chorionic gonadotrophin stimulation despite striking elevation of plasma testosterone in 5 alpha-reductase deficiency where negligible dihydrotestosterone response occurs. This is in contrast to normal boys where SHBG is significantly reduced (P less than 0.01) after stimulation. (3). In normal boys the magnitude of plasma dihydrotestosterone response to human chorionic gonadotrophin correlates with that of SHBG (r = 0.72) more than testosterone does versus SHBG (r = 0.36). It is concluded that dihydrotestosterone decreases SHBG concentration in plasma of prepubertal boys. At least part of the observed decrease in SHBG following testosterone administration in earlier reports must have occurred after its conversion to dihydrotestosterone.

Effect of two new alpha-glucosidase inhibitors in insulin-dependent diabetic patients.

The delay in glucose absorption at the intestinal level obtained with the administration of alpha-glucosidase inhibitors may contribute to an improved metabolic control in diabetic patients. We have examined the effects of two new compounds, BAY m 1099 (short acting) and BAY o 1248 (long acting), on the postprandial glycemic changes, the insulin requirements and the meal-induced hormone responses in nine insulin-dependent diabetics (IDD). The investigation was conducted according to a protocol in which medication and placebo were administered in a double-blind randomized manner. Twelve hours before each experimental day, the patients were connected to the Biostator GCIIS (Ames-Miles) to maintain stabilized normoglycemic levels for the whole period of study. The results showed that: (1) BAY m 1099 decreased the 4-h postprandial glycemic excursions compared to placebo both at dinner and breakfast (P less than 0.05), (2) BAY o 1248 when compared with placebo showed a significant lowering of the peak glycemic levels at breakfast (P less than 0.001) and at lunch (P less than 0.0025), (3) the 2-h and 4-h post-breakfast insulin requirements fell significantly after either drug (P less than 0.02), (4) the plasma levels of contrainsular hormones were not affected by drugs or placebo at any time during the period of study, and (5) no side effects with either drug could be detected. We conclude from our study that both drugs may be useful adjuncts to insulin therapy in insulin-dependent diabetics by reducing postprandial glycemic fluctuations as well as by decreasing insulin requirements with no modification of the meal-induced hormone responses.

Somatostatin analog SMS 201-995 and insulin needs in insulin-dependent diabetic patients studied by means of an artificial pancreas.

SMS 201-995 is a new somatostatin analog which is 10-60 times more potent and specific than somatostatin as an inhibitor of GH and insulin release. The aim of this study was to assess its value as an adjunct to insulin therapy in insulin-dependent diabetic- (IDD) patients. Six IDD patients were studied. Their average insulin doses ranged from 22-46 U/day, and hemoglobin A1c levels varied between 6.5-11.5%. Two patients had background retinopathy and mild sensorimotor neuropathy. After 12 h of glucemic stabilization, the patients were kept normoglycemic by connecting them to the Biostator-GCIIS. The study entailed two parts in random order, in which standardised mixed meals were administered at 0800, 1400, and 2000 h with or without sc bolus injections of 50 micrograms SMS 201-995 immediately before meal ingestion. Plasma free insulin, C-peptide, GH, and glucagon were measured by RIA. Postprandial hyperglycemia was significantly diminished by SMS 201-995 after breakfast, lunch, and dinner. Insulin requirements, both total and 2-h postprandially, decreased significantly with a parallel reduction in free insulin levels. Postprandial glucagon levels also significantly decreased, but GH profiles were similar. In conclusion, the somatostatin analog SMS 201-995 has a potential value as an adjunct to insulin in the management of IDD patients.

Long survival of diarrhea-associated hepatocarcinoma treated with Adriamycin and indomethacin. A case report.

The existence of tumors producing prostaglandins is well documented in the literature. At present, no case report of a prostaglandin-producing hepatocellular carcinoma has been published, to our knowledge. The authors report a patient with hepatocellular carcinoma associated with diarrhea mediated by prostaglandins, surviving 30 months after receiving treatment with indomethacin and Adriamycin. The authors will discuss the possible role played by indomethacin in the exceptional clinical course of the patient.