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Biomedical subjects

J R Weisinger

Publications and source records attributed to J R Weisinger.

35 records · Page 2Linked to original sources
PubMed1996

Possible role of cytokines on the bone mineral loss in idiopathic hypercalciuria.

Decreased bone mass has been reported in patients with idiopathic hypercalciuria. Previous studies, using bioassays, have suggested a role of interleukin-1 (IL-1), in the decreased bone mineral density (BMD) of fasting hypercalciuria. The present study was designed to determine which IL-1 fraction (alpha or beta) correlates with bone resorption and whether other known bone resorting cytokines like interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) may play a role in this process. Cytokines production was determined by quantitative and specific analysis, enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR). Dual-energy X-ray absorptiometry and cytokine production by unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) were determined in a group of 29 patients with recurrent nephrolithiasis (17 hypercalciurics and 12 normocalciurics), and 12 healthy controls. The hypercalciuric subjects showed lower vertebral BMD than the normocalciuric or normal controls. There was no difference in spinal or femoral BMD between absorptive or fasting hypercalciurics. A significant negative correlation existed between urinary calcium excretion and vertebral BMD (r = -0.55, P < 0.01). Basal IL-1 alpha production correlated with vertebral BMD (r = -0.45, P < 0.02). This correlation was not seen with IL-1 beta, IL-6 or TNF-alpha production. LPS-induced IL-6 and TNF-alpha production were enhanced in the hypercalciuric patients, when compared to normocalciurics or controls. Control and normocalciuric subjects showed minimal amounts of IL-1 alpha mRNA. In contrast, hypercalciuric patients showed a significant increase of spontaneous IL-1 alpha mRNA transcription. These results suggest that different cytokines could be involved in the bone resorption process observed in hypercalciuria.

Absorptiometry, Photon↗
PubMed1996

Changes in bone mineral density, growth velocity and renal function of prepubertal uremic children during growth hormone treatment.

Thirteen prepubertal children with a mean chronological age of 6.7 +/- 3.4 years and severe chronic renal failure (mean glomerular filtration rate of 20.8 +/- 17.7 ml/min/1.73 m2) were studied. Patients received recombinant human growth hormone (rhGH) at a dose of 1 IU/kg/week given subcutaneously on a daily basis for 12 months. Mean growth rates of our patients increased significantly from a baseline level of 4.3 +/- 2.1 to 9.1 +/- 2.0 cm/year at 12 months of rhGH therapy. Mean height SDS improved from -3.5 +/- 1.0 at initiation of therapy to -2.6 +/- 1.3 at 12 months. Mean serum creatinine and blood urea nitrogen levels remained stable during the study, while mean glomerular filtration rates decreased initially and then stabilized; however, 2 subjects had a significant deterioration of their renal function at 6 and 9 months of rhGH, requiring discontinuing treatment. Before rhGH treatment, total bone mineral content as well as bone mineral density in cortical and trabecular bone were significantly reduced in our patients when compared to healthy controls paired for chronological age and similar to those of a healthy control group paired for bone age and height. Both these parameters increased significantly during rhGH treatment so that at 12 months our patients had values similar to those seen in a healthy control population paired to our patients for chronological age. While trabecular bone mineral density did not change in a group of untreated uremic controls during 12 months of follow-up, the percent of bone mineral density change in trabecular bone in our uremic patients during 12 months of rhGH treatment was very significant (p < 0.001) and larger than that noted in a group of healthy controls paired for bone age and height during 12 months of follow-up. This study demonstrates how rhGH treatment in prepubertal uremic children increases their growth velocity and their bone mineral density significantly, with an improvement in height for age. Careful followup of the renal function of patients in needed as they improve their height and bone mineral status.

Blood Urea Nitrogen↗
PubMed1995

Bone mineral density of prepubertal age girls with Turner's syndrome while on growth hormone therapy.

Bone mineral densities and growth velocities of young girls with Turner's syndrome treated with recombinant human growth hormone at an age before the decreased levels of estrogens secondary to their ovarian failure could contribute to osteopenia were studied. Twelve patients with a mean chronological age of 8.9 +/- 0.9 years and a mean bone age of 6.9 +/- 0.8 years received growth hormone therapy for over 2 years (0.5 IU/kg/week s.c.) Mean growth velocities increased significantly from a baseline level of 3.5 +/- 0.4 cm/year to 6.4 +/- 0.3 and 5.7 +/- 0.4 cm/year at 12 and 24 months of therapy, while height SDS improved from -3.1 +/- 0.4 at baseline to -2.7 +/- 0.3 and -2.4 +/- 0.3 at 12 and 24 months, respectively. Total bone calcium as well as cortical bone mineral density of our density of our patients while on recombinant human growth hormone were similar to that of a control group of prepubertal healthy growth children paired for bone age and height; bone density of trabecular bone was however increased in our patients when compared to healthy controls (0.791 +/- 0.04 vs. 0.669 +/- 0.02 g/cm2; p < 0.025). We conclude from our study that the bone mineral status of young girls with Turner's syndrome on growth hormone therapy seems to be normal.

Age Determination by Skeleton↗
PubMed1992

In chronic uremia, insulin activates receptor kinase but not pyruvate dehydrogenase.

We studied in vivo biochemical effects of insulin in the skeletal muscle of chronically uremic and control rats. The rate of disappearance of blood glucose (determined with a short intravenous test) was reduced by 38% in uremia (p less than 0.05). Intraperitoneal treatment with insulin plus glucose for 30 min caused a 3-fold increase in the activity of insulin receptor tyrosine kinase in the skeletal muscle of both rat groups. Conversely, pyruvate dehydrogenase activity increased by 115% in controls but only by 26% in uremics (p less than 0.01). Exercise (swimming for 30 min) increased muscle pyruvate dehydrogenase activity approximately 2-fold in both groups of animals. These experiments show that in uremic rats, insulin binds normally to its muscle receptors and adequately activates receptor tyrosine kinase but fails to activate an otherwise responsive pyruvate dehydrogenase.

Animals↗
PubMed1989

Regulation of 1,25-dihydroxyvitamin D3 by calcium in the parathyroidectomized, parathyroid hormone-replete rat.

Parathyroid hormone (PTH) is a major stimulus for the renal production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Elevated arterial blood ionized calcium ([Ca2+]) depresses serum 1,25-(OH)2D3 in nonparathyroidectomized rats even when serum PTH is maintained at high levels by infusion. However, suppression by [Ca2+] of endogenous PTH, causing the fall in 1,25-(OH)2D, cannot be excluded. To determine whether [Ca2+] regulates 1,25-(OH)2D3 in the absence of a variation in PTH, we parathyroidectomized (PTX) rats (post-PTX calcium levels less than 7.0 mg/dl), inserted arterial and venous catheters, and then replaced PTH using an osmotic pump. We varied [Ca2+] by infusing either 75 mM sodium chloride (control), 0.61 mumol/min of EGTA (EGTA), or calcium chloride at 0.61 mumol/min (low calcium) or 1.22 mumol/min (high calcium) for 24 h 5 days after surgery. Blood was then drawn from the rat through the arterial catheter. Compared with the control, [Ca2+] fell with EGTA, remained constant with the low-calcium infusion, and rose with the high-calcium infusion. 1,25-(OH)2D3 was correlated inversely with [Ca2+] in all four groups together (r = -0.635, n = 34, p less than 0.001), within the control group alone (r = -0.769, n = 11, p less than 0.002), and within the EGTA group alone (r = -0.774, n = 10, p less than 0.003). Serum phosphorus, PTH, and arterial blood pH were not different in any group, and none correlated with serum 1,25-(OH)2D3. We conclude that 1,25-(OH)2D3 levels are regulated by [Ca2+] independently of serum PTH, phosphorus, and acid-base status, all of which support the hypothesis that [Ca2+] is a principal regulator of serum 1,25-(OH)2D3 in the rat.

Animals↗
PubMed1989

Effects of chronic metabolic alkalosis on Ca2+, PTH and 1,25(OH)2D3 in the rat.

The effect of chronic metabolic alkalosis on arterial blood ionized calcium concentration ([Ca2+]) and the levels of serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is difficult to predict. Although a fall in pH directly decreases [Ca2+], chronic alkalosis reduces urine calcium excretion, which could elevate [Ca2+]. [Ca2+] modulates the serum level of PTH and the level of 1,25(OH)2D3 directly and through PTH. To determine the effect of chronic metabolic alkalosis on [Ca2+], PTH, and 1,25(OH)2D3, rats were made alkalemic by feeding a chloride-deficient diet (LCl) or LCl with 75 mM NaHCO3 in the drinking water (LCl + HCO3-) and compared with controls fed a chloride-replete diet (NCl). Compared with NCl, after 8 days of LCl and LCl + HCO3- arterial pH and PTH rose and [Ca2+] fell. Serum 1,25(OH)2D3 tended to rise with LCl and rose with LCl + HCO3-. Serum 1,25(OH)2D3 was correlated inversely with [Ca2+] (r = -0.510, n = 54, P less than 0.001) and with pH (r = -0.291, n = 57, P less than 0.03) but not with PTH or phosphorus. Stepwise regression analysis indicated that [Ca2+] accounted for the majority of the variance of serum 1,25(OH)2D3. Chronic metabolic alkalosis induced by a low-chloride diet and HCO3- appears to increase serum PTH and 1,25(OH)2D3 through a fall in [Ca2+].

Alkalosis↗
PubMed1988

Insulin binding and glycolytic activity in erythrocytes from dialyzed and nondialyzed uremic patients.

Insulin resistance in uremia has been attributed to impaired hormone-receptor binding or to postbinding defects. Oral glucose tolerance tests, insulin binding, and in vitro glycolytic activity were studied in purified red blood cells from normal control subjects (C) and from uremic patients belonging to three groups: nondialyzed (U), on chronic hemodialysis (HD), and on continuous ambulatory peritoneal dialysis (CAPD). Glucose intolerance and hyperinsulinemia were demonstrated in all groups of patients. Maximal specific binding of 125I-insulin to erythrocytes, kinetically derived receptor numbers per cell, and affinity constants for insulin binding did not differ between control and patient groups. No correlation was found between the degree of glucose intolerance and insulin binding parameters. Basal lactate production by erythrocytes incubated in vitro was significantly higher in U and HD patients than in C, whereas CAPD patients did not differ from C in this respect. Addition of 1 mM dibutyryl-cAMP and 0.5 mM isobutyl-methyl-xanthine during incubation of erythrocytes caused an increase in the rate of lactate production that was similar in magnitude in the U, HD and C groups, whereas cells from CAPD subjects showed a significantly larger absolute response to these compounds after 1 h of incubation. There was no evidence of impairment of glycolytic capacity in red blood cells from uremic patients. In addition, no correlation was found between the degree of glucose intolerance and basal or stimulated lactate production by erythrocytes. Our results obtained in human erythrocytes suggest that the insulin resistance observed in uremia does not involve a defect in hormone binding or in the intracellular capacity to utilize glucose through glycolysis.

Adult↗
PubMed1987

Effects of cadmium on canine renal cortical adenylate cyclase.

The present studies examine the effects of cadmium (Cd2+) on adenylate cyclase activity in basolateral renal cortical membranes from normal dogs. Cd2+, in the dose range of 1 to 200 microM caused a dose-dependent inhibition of adenylate cyclase activity due to competitive inhibition with respect to the allosteric activator Mg2+ (increase in the Kact for Mg2+ from 13.8 to 37.2 mM). In addition, increasing Cd2+ concentrations from 0 to 25 microM resulted in a purely competitive inhibition with respect to ATP. The Km for ATP increased from 61 to 128 microM. When Mn2+ at a concentration of 20 mM was substituted for Mg2+, Cd2+ maintained its inhibitory effect at concentrations lower than 25 microM. At higher concentrations it stimulated enzyme activity in a dose-dependent fashion. In the absence of other divalent cations Cd2+ was a potent stimulator of basal adenylate cyclase activity, far more potent than the physiological activator of the system Mg2+. Kact for Cd2+ was 1.0 mM (Kact for Mg2+ 20 mM), whereas the Vmax showed a fourfold increase compared with the Mg2+-stimulated membranes. However, under these conditions, synthetic bovine parathyroid hormone (1-34) or 5'-guanylylimidodiphosphate did not stimulate adenylate cyclase. It is concluded that Cd2+ behaves as a partial agonist in this system, due to its ability to form a new enzymatic substrate complex: Cd-ATP, which competes with the physiological substrate Mg-ATP at the catalytic site of the enzyme. In addition, Cd2+ in the absence of other divalent cation stimulates basal enzyme activity, presumably through interaction at an additional site, closely related to the allosteric metal regulatory site of this enzyme system.

Adenylyl Cyclases↗
PubMed1986

Massive cerebral calcifications associated with increased renal phosphate reabsorption.

Extensive bilateral cerebral cortical calcifications were demonstrated in a young patient with a history of convulsions since the age of 4 years. Initial metabolic workup showed normal serum calcium levels, hyperphosphatemia, normal renal function, low urinary calcium excretion, and normal serum immunoreactive parathyroid hormone levels. The intravenous infusion of edetate disodium (disodium EDTA) showed a normal phosphaturic and cyclic adenosine monophosphate response, ruling out the diagnosis of pseudohypoparathyroidism. The infusion of acetazolamide produced a blunted phosphaturia with almost no change in the renal phosphorus threshold, suggesting a tubular defect that allows enhanced proximal tubular reabsorption of phosphorus. Although the exact mechanisms responsible for the localized calcifications remain obscure, we suggest that an enhanced proximal tubular reabsorption of phosphorus could be involved in the pathophysiologic basis of this abnormality.

Absorption↗
PubMed1985

Effect of metabolic acidosis on the PTH receptor-adenylate cyclase system of canine kidney.

The phosphaturic action of parathyroid hormone (PTH) is blunted during metabolic acidosis. Previous studies suggest that the activation of renal cortical adenylate cyclase by PTH is decreased under this condition. However, the mechanisms underlying the defect are not completely defined. The present studies were designed to examine the interaction of PTH with its receptor-adenylate cyclase system in basolateral cortical membranes from dogs with metabolic acidosis. Chronic metabolic acidosis was induced in seven normal dogs. Venous blood pH decreased to 7.21 +/- 0.01 and serum bicarbonate to 12.58 +/- 0.32 meq/liter. In seven control dogs blood pH was 7.38 +/- 0.002 and serum bicarbonate was 20.14 +/- 0.26 meq/liter. The kidneys were surgically removed and basolateral membranes were prepared by differential centrifugation and ultracentrifugation in discontinuous sucrose density gradients for studies of adenylate cyclase activity and hormone-receptor binding. Metabolic acidosis resulted in a significant decrease in PTH-dependent adenylate cyclase activity (Vmax 2,119 +/- 150 pmol cAMP X mg prot-1 .30 min-1 vs. 3,548 +/- 116 in the controls). The PTH concentration giving half-maximal activation of adenylate cyclase was unchanged. However, PTH-receptor binding showed similar affinity and binding capacity in both groups of membranes. Basal enzyme activity was also similar. In the presence of the GTP analogue 5'-guanylylimidodiphosphate, PTH-dependent adenylate cyclase activity remained markedly decreased in the acidotic dog membranes compared with the controls. The ability of NaF to stimulate enzyme activity was also depressed in the membrane of acidotic dogs. Enzyme activity in the presence of Mn2+ was similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1978

Clinical and histological kidney involvement in human kala-azar.

A 19-year-old women developed prolonged fever, weight loss, hepatosplenomegaly, anemia, leukopenia, and hyperglobulinemia. Appropriate tests indicated that she had visceral leishmaniasis (kala-azar). Urinalysis demonstrated significant proteinuria and microhematuria with the presence of red cell casts. A kidney biopsy was performed. Light microscopy showed a slight mesangial thickening and segmental mesangial proliferation. Immunofluorescence demonstrated deposits of immunoglobulins A and M, complement, and fibrinogen. Electron microscopy showed subendothelial and intramembranous deposits. After treatment with N-methylglucamine antimonate the proteinuria and microhematuria disappeared and the patient recovered uneventfully.

Adult↗
PubMed1975

Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure.

Varying degrees of renal failure were produced by surgical reduction of renal mass in normal dogs and in thyroparathyroidectomized dogs (TPTX) in whom serum calcium levels were maintained in the normal range by the administration of vitamin D. Both groups of dogs maintained normal serum phosphate levels in spite of progressive decreases in glomerular filtration rates (GFR). Furthermore, both groups of dogs were able to increase the fractional excretion of phosphate as GFR decreased. Thus the same renal response to loss of GFR was maintained in the complete absence of parathyroid tissue. Finally, stable serum phosphate levels and increased fractional excretion of phosphate in response to a decrease in GFR were also demonstrated in acutely TPTX dogs who were not receiving vitamin D. These results indicate that phosphate homeostasis can be maintained in renal failure in the total absence of parathyroid hormone secretion.

Acute Kidney Injury↗