Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage

DARWIN: towards the ultimate dark matter detector

DARk matter WImp search with liquid xenoN (DARWIN) will be an experiment forthe direct detection of dark matter using a multi-ton liquid xenon timeprojection chamber at its core. Its primary goal will be to explore theexperimentally accessible parameter space for Weakly Interacting MassiveParticles (WIMPs) in a wide mass-range, until neutrino interactions with thetarget become an irreducible background. The prompt scintillation light and thecharge signals induced by particle interactions in the xenon will be observedby VUV sensitive, ultra-low background photosensors. Besides its excellentsensitivity to WIMPs above a mass of 5 GeV/c2, such a detector with its largemass, low-energy threshold and ultra-low background level will also besensitive to other rare interactions. It will search for solar axions, galacticaxion-like particles and the neutrinoless double-beta decay of 136-Xe, as wellas measure the low-energy solar neutrino flux with <1% precision, observecoherent neutrino-nucleus interactions, and detect galactic supernovae. Wepresent the concept of the DARWIN detector and discuss its physics reach, themain sources of backgrounds and the ongoing detector design and R&D efforts

Pertussis toxin blocks the inhibitory effects of calcitonin on cyclic AMP accumulation in stimulated cultured human monocytes

Surface stimulation of fresh or cultured human mononuclear cells by latex particles causes an increase in the accumulation of cyclic AMP that is inhibited by preincubation with calcitonin (CT). Preincubation of cultured monocytes with 500 ng/ml pertussis toxin totally blocks the inhibitory effects of CT at low concentrations of this hormone. The effects of pertussis toxin are dose-related and eliminated by boiling the toxin. Similar preincubations with cholera toxin have no significant effects on subsequent inhibition of surface-stimulated cyclic AMP by CT. Membranes prepared from cultured human monocytes contain a 41,000-dalton protein that is ADP-ribosylated by pertussis toxin and may be the inhibitory guanine nucleotide regulatory protein (Ni) mediating this inhibition

Effects of human lymphocyte-conditioned medium on MG-63 human osteosarcoma cell function

Lymphocytes are implicated in the pathogenesis of bone disease in chronic inflammation, osteoporosis, transplantation and osteopetrosis. The effects of lymphocytes and lymphocyte-conditioned medium on bone-resorbing activity and osteoclast function have been well studied, but there are few studies of the effects of LCM on bone formation and osteoblast function. The effects of LCM on the function of the MG-63 human osteosarcoma cell line were studied, which, when stimulated with 1,25-(OH)2D3, demonstrates many of the properties of the mature human osteoblast. Lymphocytes contain oestrogen receptors and the model was also used to test the hypothesis that the effects of oestrogen on bone cells may be mediated indirectly via lymphokines. Lymphokines were measured by ELISA in human lymphocyte conditioned medium (LCM) collected following incubation of mixed lymphocytes with or without stimulation for 72 h. Unstimulated LCM increased proliferation of MG-63 cells and this increase was not affected by neutralization of interleukin 1 (IL-1), IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF), lymphotoxin alpha, or interferon gamma (IFN-gamma). Phytohaemagglutinin-stimulated LCM decreased proliferation of MG-63 cells, as well as induced expression of IL-6 mRNA, increased alkaline phosphatase production, and inhibited osteocalcin production. The decrease in proliferation was abolished by neutralization of IFN-gamma but was unaffected by neutralization of IL-1, IL-2, IL-3, IL-4, IL-6, GM-CSF, TNF, or lymphotoxin alpha. Neutralization of IFN-gamma in stimulated LCM also partially inhibited the increase in alkaline phosphatase production but had no effects on the decrease in osteocalcin production. Although oestrogen inhibited lymphocyte proliferation, the effects of LCM collected from lymphocytes in the presence of oestrogen on MG-63 cell proliferation and function was no different than the effects of LCM collected in the absence of oestrogen. LCM has multiple effects on MG-63 cell function and gene expression. Lymphocyte stimulation during the preparation of LCM further modulates these effects. Although partially mediated by IFN-gamma, the effects of LCM on these cells cannot be completely explained by individual component lymphokines. This may have implications for understanding the pathophysiology of bone loss in inflammatory disorders as well as possible feedback loops of locally generated cytokines in bone

Clinical reporting to primary care physicians leads to increased use and understanding of bone densitometry and affects the management of osteoporosis. A randomized trial

BACKGROUND: A major barrier to wider use of bone densitometry has been a lack of reports that are comprehensible to primary care physicians. OBJECTIVE: To compare the effect of short technical reports and longer clinical reports on use, understanding, and acceptance of bone densitometry by primary care physicians and on management of osteoporosis. DESIGN: Randomized trial. SETTING: Osteoporosis center of a community teaching hospital. SUBJECTS: 57 primary care physicians ordering bone mineral density tests with dual x-ray absorptiometry. INTERVENTION: Physicians were randomly assigned to receive short technical reports or long clinical reports written by endocrinologists with access to clinical information. MEASUREMENTS: Physicians were interviewed by telephone after receiving at least two reports. RESULTS: Before being interviewed, physicians receiving short reports ordered a mean +/- SD of 0.72 +/- 0.71 tests per month; those receiving long reports ordered 1.30 +/- 1.21 tests per month (P = 0.002). At the first interview, 30% of physicians receiving short reports and 86% of those receiving long reports understood the bone mineral density definition of osteoporosis (P \u3c 0.001). Receiving long reports led to more modifications in the pharmacologic treatment of osteoporosis by gynecologists (19% of patients whose reports were short and 61% of patients whose reports were long; P = 0.021) and less confusion about reports by all physicians (36% of physicians receiving short reports and 1% of those receiving long reports; P = 0.003). CONCLUSIONS: Clinical reporting of bone densitometry to primary care physicians increased use and understanding of bone densitometry, changed management of osteoporosis, and was well accepted. It may help achieve appropriate use of bone densitometry and may allow convenient dissemination of information on osteoporosis

A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors but not linked to the multiple endocrine neoplasia type 1 locus at chromosome region 11q13

Acromegaly is uncommon in kindreds with multiple endocrine neoplasia type 1 (MEN1), whereas primary hyperparathyroidism (PHP) has the highest penetrance of any endocrinopathy. We report an unusual MEN1 kindred with frequent expression of pituitary tumors and a low penetrance of PHP. Four members were found to have disease: PHP in generation I, acromegaly (2 cases) in generation II, and hyperprolactinemia associated with a pituitary tumor in generation III. There was no evidence for PHP in 1 patient with acromegaly (age 60 yr), the patient with hyperprolactinemia and the pituitary tumor (age 22 yr), and 1 asymptomatic obligate carrier (age 50 yr). Screening of 26 members revealed the possible diagnosis of PHP in 1 family member in generation II and possible early acromegaly in 2 members of generation III with elevated serum concentrations of insulin-like growth factor I and insulin-like growth factor-binding protein-3 but normal patterns of pulsatile GH release. Although the predisposing genetic defect in typical MEN1 families has previously been mapped to chromosome location 11q13 without evidence of heterogeneity among the 87 families analyzed, linkage of disease in this family to the MEN1 region is unlikely based on haplotype analysis. Localization of the gene(s) responsible for disease in such atypical families may aid in the understanding of the pathogenesis of MEN1. In addition, further study of the earliest changes in patterns of pulsatile GH release in familial acromegaly may allow more insight into the pathogenesis and natural history of this disease