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

Epstein-barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids

We report the diversity of latent membrane protein 1 (LMP1) gene founder sequences and the level of Epstein-Barr virus (EBV) genome variability over time and across anatomic compartments by using virus genomes amplified directly from oropharyngeal wash specimens and peripheral blood B cells during acute infection and convalescence. The intrahost nucleotide variability of the founder virus was 0.02% across the region sequences, and diversity increased significantly over time in the oropharyngeal compartment (P = 0.004). The LMP1 region showing the greatest level of variability in both compartments, and over time, was concentrated within the functional carboxyl-terminal activating regions 2 and 3 (CTAR2 and CTAR3). Interestingly, a deletion in a proline-rich repeat region (amino acids 274 to 289) of EBV commonly reported in EBV sequenced from cancer specimens was not observed in acute infectious mononucleosis (AIM) patients. Taken together, these data highlight the diversity in circulating EBV genomes and its potential importance in disease pathogenesis and vaccine design. IMPORTANCE: This study is among the first to leverage an improved high-throughput deep-sequencing methodology to investigate directly from patient samples the degree of diversity in Epstein-Barr virus (EBV) populations and the extent to which viral genome diversity develops over time in the infected host. Significant variability of circulating EBV latent membrane protein 1 (LMP1) gene sequences was observed between cellular and oral wash samples, and this variability increased over time in oral wash samples. The significance of EBV genetic diversity in transmission and disease pathogenesis are discussed

A Shot in the Dark: Failing to Recognize the Link Between Physical and Mental Illness

A 74-year-old widowed white man with chronic rheumatoid arthritis presented with nausea and weight loss. He was diagnosed with failure to thrive and admitted for hydration. Misoprostol was determined to be the etiology of his symptoms and he was discharged home. Three days later, he killed himself with a gunshot to the head. Clinicians often fail to recognize those at high risk for suicide. Suicidal risk is increased in both psychiatric and physical illness, and particularly when both are present. Psychiatric illness, particularly depression, often underlies chronic medical illness. The purpose of this case report is to remind health care providers of the strong association between depression and chronic medical illness, and to consider this in all patients, including those who present solely with physical symptoms. Recognizing this association and screening for it, as recommended by the U.S. Preventive Services Task Force, may prevent the unnecessary tragedy of suicide

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

Peripheral and central mechanisms of pain and hyperalgesia : effects of adrenergic and sensory neuron blockade on autotomy and pain sensitivity following injury

The mechanisms of pain and hyperalgesia were examined in rats following cutaneous-heat and peripheral-nerve injury. Central mechanisms of hyperalgesia were indicated since a heat injury produced a decrease in foot-withdrawal latencies in the paw contralateral to the injury and an increase in autotomy of the injured paw following section of the sciatic and saphenous nerves. The reduced contralateral foot-withdrawal latencies were reversed by spinal anesthesia and subcutaneous guanethidine, but were unaffected by local anesthetics and capsaicin at the site of injury. The enhancement of autotomy produced by an injury was reduced by spinal anesthesia and a combination of intrathecal capsaicin and subcutaneous guanethidine. Both intrathecal substance P and systemic noradrenaline produced an increase in autotomy following nerve lesions; guanethidine, but neither capsaicin nor procaine, produced a decrease in autotomy. A reduction in inflammation and hyperalgesia within an injured paw was produced by local capsaicin, but not by guanethidine. The results suggest that central mechanisms, such as spinal hyperactivity, combined with peripheral neurogenic mechanisms are involved in the production of hyperalgesia following heat injury. Pain and hyperalgesia following nerve injury are proposed to be due to spinal cord plasticity resulting from deafferentation and abnormal sympathetic activity

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