A novel mutation in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia in a family with two uncommon parathyroid hormone polymorphisms.
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A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described. (+info)
Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada.
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Although information on efficacy and adverse drug reactions is lacking, ribavirin has been used empirically for the treatment of severe acute respiratory syndrome (SARS). We report common adverse events in 110 patients with suspected or probable SARS who were treated with ribavirin. Sixty-one percent of the patients had evidence of hemolytic anemia, and hypocalcemia and hypomagnesmia were reported in 58% and 46% of patients, respectively. (+info)
TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption.
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Mg2+ is an essential ion involved in a multitude of physiological and biochemical processes and a major constituent of bone tissue. Mg2+ homeostasis in mammals depends on the equilibrium between intestinal Mg2+ absorption and renal Mg2+ excretion, but little is known about the molecular nature of the proteins involved in the transepithelial transport of Mg2+ in these organs. Recently, it was shown that patients with mutations in TRPM6, a member of the transient receptor potential family of cation channels, suffer from hypomagnesemia with secondary hypocalcemia (HSH) as a result of impaired renal and/or intestinal Mg2+ handling. Here, we show that TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and the brush-border membrane of the small intestine, epithelia particularly associated with active Mg2+ (re)absorption. In kidney, parvalbumin and calbindin-D28K, two divalent-binding proteins, are co-expressed with TRPM6 and might function as intracellular Mg2+ buffers in the distal convoluted tubule. Heterologous expression of wild-type TRPM6 but not TRPM6 mutants identified in HSH patients induces a Mg2+- and Ca2+-permeable cation channel tightly regulated by intracellular Mg2+ levels. The TRPM6-induced channel displays strong outward rectification, has a 5-fold higher affinity for Mg2+ than for Ca2+, and is blocked in a voltage-dependent manner by ruthenium red. Our data indicate that TRPM6 comprises all or part of the apical Mg2+ channel of Mg2+-absorbing epithelia. (+info)
Comparison of different thyroidectomy techniques for benign thyroid disease.
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Extent of thyroidectomy in the management of benign thyroid disease remains controversial. In this clinical study, three different thyroidectomy techniques were compared by means of the complication, short period recurrence and L-thyroxin requirement rates. Two hundred consecutive patients who had bilateral subtotal thyroidectomy (BST) (n = 71), unilateral total lobectomy + contralateral subtotal lobectomy (Dunhill Procedure (DP)) (n = 71), or total thyroidectomy (TT) (n = 58) for benign thyroid disorders were included in this study. One patient was re-operated due to bleeding in BST group. Wound infection was observed in 1 patient both in BST and DP group and 2 patients in TT group. Temporary hypocalcaemia was seen in 14 (19.7%) of BST group, in 19 (26.7%) of DP group, and in 14 (24.1%) patients of TT group (p>0.05). Transient recurrent laryngeal nerve palsy developed in 1 patient both in DP and TT group. One patient of DP group had secondary thyroidectomy due to postoperative diagnosis of papillary carcinoma. There was no significant difference in the mean durations of hospitalization between the groups. Mean postoperative follow-up periods were 27.7 months (6-56), 34.8 months (8-55), 26.5 months (6-54) in BST, DP and TT groups, respectively. While all patients were administered L-thyroxin in TT group, 26 (36.6%) patients in DP group and 34 (47.8%) patients in BST group needed no L-thyroxin supplementation and L-thyroxin requirement rates were not different in either group. We think that total thyroidectomy should be adopted for benign thyroidal diseases, because its complications are no different than those for BST and DP. If individual factors and patient's preference are not in favor of lifelong L-thyroxin supplementation, however, DP may be carried out for benign thyroidal diseases instead of BST. (+info)
Pseudohypocalcemia after magnetic resonance imaging with gadolinium in patients with cirrhosis.
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Hypocalcemia in patients with cirrhosis may be due to a number of causes. We noted a relationship between injection with gadodiamide, a particular gadolinium chelate, during magnetic resonance imaging of the liver and the development of a falsely low serum total calcium level in a patient with cirrhosis. A cross-reference and retrospective chart review identified 10 additional patients in whom this phenomenon was noted. We describe the temporal relationship and clinical characteristics of these patients. Pseudohypocalcemia following magnetic resonance imaging with gadodiamide contrast should be considered in the differential diagnosis of hypocalcemia in patients with cirrhosis. (+info)
Unexpected prolonged extreme hypocalcaemia and an inadequate PTH response in a patient with metastatic breast carcinoma.
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Although hypercalcaemia is often encountered during the course of malignant disease, hypocalcaemia appears to be rather rare. We describe a 37-year-old patient with metastatic carcinoma of the breast, who developed extreme hypocalcaemia (as low as 0.75 mmol calcium per litre) after chemotherapy. This is caused by a combination of hungry-bone syndrome and an insufficient parathyroid response. The latter may be the result of a direct toxic effect of chemotherapy on parathyroid hormone (PTH) synthesis possibly in combination with microscopic tumour infiltration in the parathyroid glands. Correction of the extreme hypocalcaemia over a period of 100 days by oral and intravenous calcium supplementation, corresponding to a total of 352 gram elemental calcium (1/3 of the total body calcium), resulted in gradual symptomatic relief. The possible mechanisms for these findings are discussed and the literature is briefly reviewed. (+info)
The burden of chronic kidney disease in renal transplant recipients.
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The National Kidney Foundation has developed guidelines for the diagnosis and classification of chronic kidney disease (CKD) but it is not known whether these are applicable to renal transplant recipients. This study determined the prevalence of CKD according to the stages defined in the guidelines, the complications related to CKD and whether the prevalence of complications was related to CKD stage in 459 renal transplant recipients. CKD was present in 412 patients (90%) and 60% were in CKD Stage 3 with a glomerular filtration rate (GFR) between 30 and 59 mL/min/1.73 m2. The prevalence of anemia increased from 0% in Stage 1 to 33% in Stage 5 (p<0.001). Hypertension was present in 86% and increased from 60% in Stage 1 to 100% in Stage 5 (p=0.02). The number of anti-hypertensives per patient increased from 0.7 in Stage 1 to 2.3 in Stage 5 (p<0.001). The number of CKD complications per patient increased from 1.1 in Stage 1 to 2.7 in Stage 5 (p<0.001). We conclude that CKD and the complications of CKD are highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians identify patients at increased risk and target appropriate therapy to improve outcomes. (+info)
Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia.
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Impaired magnesium reabsorption in patients with TRPM6 gene mutations stresses an important role of TRPM6 (melastatin-related TRP cation channel) in epithelial magnesium transport. While attempting to isolate full-length TRPM6, we found that the human TRPM6 gene encodes multiple mRNA isoforms. Full-length TRPM6 variants failed to form functional channel complexes because they were retained intracellularly on heterologous expression in HEK 293 cells and Xenopus oocytes. However, TRPM6 specifically interacted with its closest homolog, the Mg(2+)-permeable cation channel TRPM7, resulting in the assembly of functional TRPM6/TRPM7 complexes at the cell surface. The naturally occurring S141L TRPM6 missense mutation abrogated the oligomeric assembly of TRPM6, thus providing a cell biological explanation for the human disease. Together, our data suggest an important contribution of TRPM6/TRPM7 heterooligomerization for the biological role of TRPM6 in epithelial magnesium absorption. (+info)