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

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

There 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, 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 results in normal young adults and elderly patients with untreated osteoporosis. Serum levels of 1,25-(OH)2-D were similar in both groups (49 +/- 10 and 42 +/- 9 pg per milliliter [116 +/- 24 and 99 +/- 21 pmol per liter]) before the infusion. However, during the 24-hour infusion, serum levels nearly doubled (P less than 0.01) in the normal volunteers but did not change significantly in the patients. Serum ionized calcium increased and serum inorganic phosphate decreased similarly in both groups during the infusion (P less than 0.05). Although the present study does not establish whether deficient 1,25-(OH)2-D secretory reserve is an effect of age or of osteoporosis, it is possible that such a deficiency will explain the inability of elderly osteoporotic patients to adapt to the low-calcium diets common in this age group. If so, this phenomenon may play a part in the pathogenesis of age-related osteoporosis.

Hypercalcemia and hypercalciuria in sarcoidosis are thought to result from the endogenous overproduction of an active vitamin D metabolite. We employed primary cultures of pulmonary alveolar macrophages from two patients with biopsy-proven pulmonary sarcoidosis and a recent or current clinical abnormality in calcium metabolism to synthesize in vitro a 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-like metabolite from 25-hydroxyvitamin D3 (25OHD3). The macrophage metabolite cochromatographed with [3H]1,25-(OH)2D3 on normal phase and reverse phase high performance liquid chromatography and was bound with high affinity by the chick intestinal receptor for 1,25-(OH)2D3. On UV spectroscopy, the metabolite possessed the carbon-5,7,10 (19) cis-triene chromophore characteristic of a vitamin D sterol. Electron impact mass spectrometry of trimethylsilyl ether derivatives of the metabolite revealed a mass fragmentation pattern similar to that of the trimethylsilyl ether derivative of authentic 1,25-(OH)2D3. The incubation of cultured macrophages from two patients with idiopathic pulmonary fibrosis and two with scleroderma with [3H]25OHD3 did not result in production of a metabolite with the chromatographic identity of 1,25-(OH)2D3. These data indicate that the metabolite of 25OHD3 synthesized by sarcoid macrophages in vitro is 1,25-(OH)2D3 and that the macrophage is a synthetic source of the sterol metabolite in sarcoidosis.

Serum calcium and phosphorus levels, urinary excretion rates of calcium, phosphorus, and cyclic adenosine monophosphate (cAMP), and plasma parathyroid hormone (PTH) concentrations were determined in 11 normal subjects and in nine patients maintained on long-term prednisone therapy for chronic obstructive pulmonary disease. These same determinations were repeated in five of the prednisone-treated patients during the course of a seven-day calcium infusion. Prior to the infusion, the prednisone-treated patients demonstrated significantly elevated serum levels of PTH (P less than .005) and increased rates of urinary phosphate and cAMP excreation (P less than .005) when compared with normal subjects. After initiation of calcium infusion, the previous elevations in all of these determinations decreased to near normal levels. These data suggest that the effects of secondary hyperparathyroidism in patients maintained on long-term prednisone therapy may be overcome when calcium is administered intravenously.

Two hundred and twenty-nine consecutive subjects, 202 women and 27 men, referred for evaluation of osteoporosis or low bone mineral density (BMD) had serum measurements of immunoreactive PTH (iPTH) and 25-hydroxyvitamin D (25OHD) performed. Fifteen individuals (mean age +/- SE, 75+/-2.4 yr) had depressed serum 25OHD (<15 pg/mL) and concomitantly elevated (>65 pg/mL) iPTH levels. After successful treatment of vitamin D insufficiency in all subjects, iPTH remained inappropriately high or frankly elevated in 5, describing a 2.2% prevalence rate of coexistent primary hyperparathyroidism and vitamin D insufficiency in our population. Despite persistent primary hyperparathyroidism, normalization of serum 25OHD levels in these 5 subjects increased their BMD at an annual rate of 6.3% and 8.2% in spine and hip, respectively. Our results suggest that coexistent vitamin D insufficiency can obscure the diagnosis of primary hyperparathyroidism and, when treated effectively, can result in substantial short-terms gains in BMD despite persistence of the inappropriate production of PTH.

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

Ketoconazole 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 been evaluated. We examined the effect of ketoconazole on the 1,25-(OH)2D-calcium homeostatic mechanism in a hypercalcemic patient with sarcoidosis and on the synthesis of 1,25-(OH)2D3 in vitro by cultured pulmonary alveolar macrophages (PAM) from this and another host. Oral ketoconazole therapy (800 mg/day) decreased the serum 1,25-(OH)2D concentration 73% within 4 days; this was associated with a 15% decrease in the serum calcium concentration and a 57% decrease in the fractional urinary calcium excretion rate. In vitro, ketoconazole had a rapid onset, concentration-dependent inhibitory effect on sarcoid PAM 1,25-(OH)2D3 synthesis (ED50 = 0.1 mumol/L) that was not reversible by exposure 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 reaction was examined at concentrations achieved in vivo when the drug is given orally. The velocity of the 1 alpha-hydroxylation reaction at ketoconazole concentrations of 0.01-1.0 mumol/L increased as the concentration of substrate 25-hydroxyvitamin D3 increased from 12-2000 nmol/L.