Fragile changes. X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 mainly CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis,with and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 +/-and 12.46) and without FXTAS (n = 17, age: 44.94 +/- 11.23), in genetically normal female controls (n = 8, age:female 50.63 +/- 11.43), male carriers with FXTAS (n = 34, age: 66.44 +/- 6.77) and without FXTAS (n = 21,total age: 52.38 +/- 12.11), and genetically normal male controls (n = 30, age: 57.20 +/- 14.12). We examined the relationship presentation between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation FXTAS, between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the and significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females.and In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a between negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less females. common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related volume. to hippocampal changes.(c) 2009 Wiley-Liss, Inc.

To of determine the effect of increased skin pigment on the cutaneous production of vitamin D3, circulating vitamin D concentrations were determined dose in two lightly pigmented Caucasian and three heavily pigmented Negro volunteers after exposure to a single standard dose of ultraviolet larger radiation (UVR). Exposure of Caucasian subjects to 1 minimal erythemal dose of UVR greatly increased serum vitamin-D concentrations by up single to 60-fold 24-48 h after exposure, whereas this dose did not significantly change serum vitamin-D concentrations in Negro subjects. Re-exposure lightly of one Negro subject to a dose of UVR six times larger than the standard dose increased circulating vitamin D to to concentrations similar to those recorded in Caucasian subjects after exposure to the lower dose. These results indicate that increased Re-exposure skin pigment can greatly reduce the UVR-mediated synthesis of vitamin D.

There pathogenesis is uncertainty about the adequacy of renal secretion of 1,25-dihydroxyvitamin D(1,25-(OH)2-D) in elderly patients with osteoporosis. To investigate this uncertainty,(P we stimulated secretion of 1,25-(OH)2-D with a 24-hour intravenous infusion of synthetic human parathyroid hormone fragment 1-34 and compared the study results in normal young adults and elderly patients with untreated osteoporosis. Serum levels of 1,25-(OH)2-D were similar in both groups osteoporosis. (49 +/- 10 and 42 +/- 9 pg per milliliter [116 +/- 24 and 99 +/- 21 pmol per liter])human before the infusion. However, during the 24-hour infusion, serum levels nearly doubled (P less than .01) in the normal volunteers patients but did not change significantly in the patients. Serum ionized calcium increased and serum inorganic phosphate decreased similarly in both serum groups during the infusion (P less than .05). Although the present study does not establish whether deficient 1,25-(OH)2-D secretory reserve to is an effect of age or of osteoporosis, it is possible that such a deficiency will explain the inability of parathyroid elderly osteoporotic patients to adapt to the low-calcium diets common in this age group. If so, this phenomenon may play does a part in the pathogenesis of age-related osteoporosis.

BACKGROUND:bone Chronic hypercalciuria can contribute to osteoporosis, particularly in men. OBJECTIVE: To ascertain the effects of resolution of hypercalciuria on bone administration. mineral density. DESIGN: Case series. SETTING: Referral service for metabolic bone disease in a tertiary-care teaching hospital. PATIENTS: Five male and patients (42 to 66 years of age) with hypercalciuria and osteoporosis. INTERVENTION: Hydrochlorothiazide, 25 mg twice daily, for a mean tertiary-care (+/- SD) of 7.8 +/- 3.6 months. MEASUREMENTS: Fasting urinary calcium:creatinine ratio, serum calciotropic hormone levels, and bone mineral density density. before and after hydrochlorothiazide administration. RESULTS: Hydrochlorothiazide resolved hypercalciuria and increased bone mineral density at a rate of 8% and in 3% per year at the spine and hip, respectively. CONCLUSIONS: Hydrochlorothiazide treatment in hypercalciuric and osteoporotic men was associated with bone a rapid rebound increase in bone mineral density.

Ketoconazole increased is an antifungal agent capable of inhibiting human steroid hormone synthesis, including renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis. The ability of = this drug to inhibit the extrarenal production of 1,25-(OH)2D, as occurs in human granuloma-forming disease states, including sarcoidosis, has not exposure been evaluated. We examined the effect of ketoconazole on the 1,25-(OH)2D-calcium homeostatic mechanism in a hypercalcemic patient with sarcoidosis and in on the synthesis of 1,25-(OH)2D3 in vitro by cultured pulmonary alveolar macrophages (PAM) from this and another host. Oral ketoconazole disease therapy (800 mg/day) decreased the serum 1,25-(OH)2D concentration 73% within 4 days; this was associated with a 15% decrease in 1,25-(OH)2D-calcium the serum calcium concentration and a 57% decrease in the fractional urinary calcium excretion rate. In vitro, ketoconazole had a rapid rapid onset, concentration-dependent inhibitory effect on sarcoid PAM 1,25-(OH)2D3 synthesis (ED50 = .1 mumol/L) that was not reversible by exposure The to leukotriene C4, a potent stimulator of PAM 1,25-(OH)2D3 synthesis. Kinetic analysis of ketoconazole's action on the macrophage 1 alpha-hydroxylation states, reaction was examined at concentrations achieved in vivo when the drug is given orally. The velocity of the 1 alpha-hydroxylation exposure reaction at ketoconazole concentrations of .01-1. mumol/L increased as the concentration of substrate 25-hydroxyvitamin D3 increased from 12-2000 nmol/L.

1,25-Dihydroxyvitamin pleural D [1,25-(OH)2D] is classically viewed as a steroid hormone of renal origin that regulates mammalian and avian mineral ion homeostasis.concentration-dependent More recently, 1,25-(OH)2D has been shown to be produced by and act on human inflammatory cells in vitro, suggesting that potentiating the hormone may be an important modulator of the host immune response. We have recently detected high concentrations of 1,25-(OH)2D high in the pleural fluid (PF) of patients with tuberculous pleuritis. Working on the hypothesis that tuberculous PF contained a soluble cells cytokine which stimulated 1,25-(OH)2D production by tissue (pleura)-based macrophages, we examined the potential for PF from five patients with tuberculous We pleuritis to potentiate 1,25-(OH)2D synthesis by heterologous pulmonary alveolar macrophages (PAM) from patients with sarcoidosis; PAM from patients with active 25-hydroxyvitamin pulmonary sarcoidosis constitutively express a 25-hydroxyvitamin D3-1-hydroxylation reaction in vitro. We demonstrated that tuberculous PF had a concentration-dependent potentiating effect suggest on PAM 1,25-(OH)2D synthesis. The potentiating activity was positively correlated to the interferon-gamma (IFN gamma) concentration of the PF (r vitro, = .98; P less than .01) and was inhibited by 49-89% after coincubation with anti-IFN gamma monoclonal antibody (1:20,000-1:200 dilution).activity These data suggest that IFN gamma may be an important peripleural regulator of macrophage 1,25-(OH)2D synthesis in patients with tuberculous in pleuritis and a high pleural fluid 1,25-(OH)2D concentration.

Metabolism antiserum of [3H]25-hydroxyvitamin D3(25-OH-D3) was studied in primary cultures of pulmonary alveolar macrophages (PAM) from seven patients with sarcoidosis and two which patients with idiopathic pulmonary fibrosis. Production of a [3H]1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3)-like metabolite of [3H]25-OH-D3 was detected in lipid extracts of commercially cells from five patients with sarcoidosis. Synthesis of this compound in vitro was limited to viable PAM and was greatest five in cells derived from a patient with hypercalcemia and an elevated serum concentration of 1,25-dihydroxyvitamin D. The tritiated PAM metabolite a coeluted with authentic 1,25-(OH)2-D3 in three different solvent systems on straight-phase high performance liquid chromatography (HPLC) and demonstrated binding to cells extracted receptor for 1,25-(OH)2-D3, which was identical to that of commercially available [3H]1,25-(OH)2-D3 of comparable specific activity. Incubation of PAM (HPLC) with high concentrations of 25-OH-D3 resulted in production of an unlabeled metabolite that co-chromatographed with the 3H-PAM metabolite on HPLC on and that was bound with high affinity by both the specific receptor for 1,25-(OH)2-D3 and antiserum to 1,25-(OH)2-D3.

Most other New World primates evolved to express a form of compensated resistance to steroid hormones from the gonads and adrenal glands three as well as to the hydroxylated vitamin D3 prohormone, 25-hydroxyvitamin D3 (25OHD3), and the vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]and originating from the liver and kidney, respectively. We recently demonstrated that this form of resistance is associated with the overexpression 70-kDa of a novel member of the 70-kDa heat shock protein (hsp-70) molecular chaperone family, which we have termed the intracellular the vitamin D binding protein (IDBP). In the current report we more closely examine the ligand-binding capability of purified IDBP and member two other mammalian hsp-70 family members, heat-inducible (hsp-70) and constitutively expressed (hsc-70) hsp-70 proteins. Purified IDBP, hsp-70, and hsc-70 all high bound 25OHD3 with relatively high affinity; the mean Kd for 25OHD3 ranged from .5-2.2 nmol/L (rank order: IDBP > or 25OHD3 = hsp-70 > or = hsc-70). By Scatchard analysis, high affinity, specific binding of 1,25-(OH)2D3 was not reproducibly observed for and any of the three members of the hsp-70 family. Unlike purified IDBP, hsc-70 and hsp-70 were also competent binders of and the gonadal steroid 17beta-estradiol (mean Kd for 25OHD3, 2.5 and 6.6 nmol/L by hsc-70 and hsp-70, respectively), but not of binding two other gonadal hormones, progesterone and testosterone. These data suggest that IDBP is relatively specific for 25OHD3 and that additional 25OHD3 hsp-70-like binding proteins are present in unpurified New World primate cell extracts that are specific for 1-hydroxylated vitamin D metabolites (mean as well as other gonadal steroid hormones.