Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis.

OBJECTIVES: Hypocitraturia is a risk factor for calcium nephrolithiasis. 1,25(OH)2D3 influences renal citrate handling and enhances citraturia. The aim of this study was to evaluate the relationship between vitamin D receptor (VDR) allelic variant and urinary citrate excretion in recurrent stone formers (SF) patients. DESIGN: Case-control study. SUBJECTS: A total of 220 recurrent calcium oxalate SF patients and 114 healthy control (C) subjects were enrolled for this study. Subjects with urinary tract infections, hyperparathyroidism, cystinuria >70 micromol/24 h, gouty diathesis, renal tubular acidosis, renal failure, chronic diarrhoeal states, intake of thiazide diuretics, angiotensin-converting enzyme (ACE)-inhibitors, glucocorticoids or oestrogens were excluded. A standard constant diet was given for 7 days. The 24-h urinary citrate excretion and the active tubular reabsorption of filtered citrate (Rcit) were evaluated. Hypocitraturia was defined as a urinary citrate excretion lower than 1.7 mmol day-1. Stone formers patients and C were genotyped for BsmI and TaqI VDR alleles. Contingency table chi-square tests were used to compare genotype frequencies in hypocitraturic SF patients, normocitraturic SF and C. RESULTS: The prevalence of hypocitraturia in SF patients was 32.7% (72 of 200). Hypocitraturia in these patients resulted from excessive Rcit of a normal load of citrate. We found a different distribution (P < 0.05) of BsmI and TaqI VDR genotypes in hypocitraturic SF patients compared with normocitraturic SF and C. In particular, the prevalence of bb and TT VDR genotypes in hypocitraturic SF was significantly higher than in normocitraturic SF and C. CONCLUSIONS: These results point to a genetic association between BsmI and TaqI VDR polymorphisms and idiopathic hypocitraturia in calcium-oxalate recurrent SF patients.

Clodronate treatment reduces serum levels of interleukin-6 soluble receptor in Paget's disease of bone.

OBJECTIVE: Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) stimulate osteoclast formation and activity. The primary cell abnormality in Paget's disease of bone (PDB) involves osteoclasts. Pagetic osteoclasts overproduce IL-6 and IL-6 receptor in vitro. In vivo, IL-6 serum levels are very high in the acute phase of PDB. The aim of this study was to evaluate the modification in the serum levels of IL-6, sIL-6R and osteotropic hormones (parathormone, 25OHD3 and 1,25(OH)2D3) as a in long-term response to clodronate treatment in patients with PDB. METHODS: 16 patients (8 females) with polyostotic PDB were studied. IL-6, sIL-6R and osteotropic hormones serum levels were evaluated in active PDB and after clodronate treatment (300 mg injected intravenously for 5 consecutive days). The sequential changes in total alkaline phosphatase (tALP) serum levels were used to assess the maximal pharmacological response to treatment. RESULTS: In untreated pagetic patients, mean serum levels of IL-6 (3.20+/-1.18 pg/ml) and sIL-6R (35.02+/-8.33 ng/ml) were significantly increased. Serum osteotropic hormone levels fell within the normal range. Eight weeks after treatment, the maximal pharmacological response to clodronate was associated with a significant reduction of sIL-6R serum levels in all patients, without a significant variation in serum IL-6 and osteotropic hormone levels. Moreover, we observed a correlation between lower sIL-6R serum levels before clodronate therapy and complete remission of PBD, defined as a decrease of tALP serum levels within the normal range. CONCLUSION: The decrease in serum sIL-6R levels could be one of the molecular mechanisms that play a role in the clinical response to clodronate treatment in PDB.

Past history of nephrolithiasis and incidence of hypertension in men: a reappraisal based on the results of the Olivetti Prospective Heart Study.

BACKGROUND: We have previously reported that in the Olivetti Prospective Heart Study cohort the incidence of nephrolithiasis was higher in hypertensive participants than in normotensive ones. As the time sequence and the mechanisms underlying the association between nephrolithiasis and hypertension remain controversial, we further tested the hypothesis that in a cohort of normotensive males a history of nephrolithiasis predicts the development of future hypertension. METHODS: The analysis was conducted in 381 male workers at Olivetti who were normotensive at the baseline examination and who were re-examined 8 years later. RESULTS: A past history of nephrolithiasis is associated with an increased risk of hypertension of 1.96 (95% CI=1.25-3.07) relative to subjects with a negative history, after adjusting for age. CONCLUSION: In this 8-year follow-up study, a history of nephrolithiasis resulted in an increased risk of developing hypertension in the future. As the reverse was also true, as previously reported, a clear-cut time sequence, as well as the mechanisms linking these two conditions, remain to be identified.

Relationships between salt sensitivity of blood pressure and sympathetic nervous system activity: a short review of evidence.

Experimental and clinical studies provided evidence in favor of complex relationships between sympathetic nervous system activity and salt-sensitivity of blood pressure. Genetic and acquired metabolic alterations associated with a tendency to retain salt and water may generate salt-sensitivity of blood pressure and shift the pressure-natriuresis curve to the right, promoting an increase in blood pressure. Sympathetic activation is a factor contributing to this result. Chronic high dietary salt intake is followed by a derangement in mechanisms of central sympathetic inhibition and then by an enhanced peripheral sympathetic tone. This, in turn, may generate salt-sensitivity of blood pressure by affecting renal hemodynamics, tubular sodium and water handling. Insulin resistance and sodium and water retention are prompted by high-fat (as well as high carbohydrate) diets, and by an increase in body fat mass. Also, aging is a condition of impaired interactions of the above factors. A gain in weight due to reduced physical activity, not followed by a parallel decrease in calorie intake, brings to a fall in insulin sensitivity. In many cases, the natural age-related decline of renal function is associated with a reduced physical exercise, hyperinsulinemia and sodium retention; sympathetic nervous system activity is enhanced and causes an increase in blood pressure.

Echistatin inhibits the adhesion of murine melanoma cells to extracellular matrix components.

Echistatin, an RGD containing peptide isolated from Echis carinatus snake venom, inhibited the in vitro attachment of B16-BL6 mouse melanoma cells to fibronectin, vitronectin and laminin. Its inhibitory activity on cell adhesion was non-cytotoxic, dose-dependent and fully reversible. Kinetic analysis showed a competitive type of inhibition for all the three substrates examined here. Chemical reduction and alkylation of echistatin almost abolished its effect on cell adhesion to extracellular matrix components. Native echistatin was also able to inhibit B16-BL6 cell attachment to IgG antihuman fibronectin receptor-coated wells, thus suggesting that the molecule binds to adhesive receptors on melanoma cell surface. Our results indicate that echistatin is an useful disintegrin for research on cell adhesion.

Glutathione depletion induced in rat liver fractions by seven pesticides.

Glutathione (GSH) plays a central role in the chemical detoxication. Xenobiotics which induce GSH depletion, either via GSH conjugation or via oxidation of GSH to glutathione disulfide (GSSG), alter the mechanism of natural cellular defence against toxicants. The aim of this study was to evaluate the ability of seven widely used pesticides (Alachlor, Atrazine, Benomyl, Captan, Linuron, Methyl Parathion and Propanil) and/or of their metabolites to deplete GSH in rat liver fractions. In our experimental conditions, Atrazine, Linuron and Propanil failed to interact with rat liver GSH. Conversely, Alachlor, Benomyl and Methyl Parthion were able to deplete GSH in rat liver, probably by forming GSH conjugates. The fungicide Captan rapidly reduced the rat liver concentration of GSH by converting it to the oxidized form GSSG. But a longer incubation of Captan with rat hepatic enzymes produced the formation of metabolites which depleted GSH via conjugation. Our results suggest that exposure to the pesticides Alachlor, Benomyl, Captan and Methyl Parathion may induce an alteration of natural mechanisms of defence against toxicants in mammals, including humans.