Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced circulating concentrations of parathyroid hormone. The transcription factor GCMB is predominantly, if not exclusively, expressed in parathyroid cells and is critical for development of the parathyroid glands in mice. Thus, in the present study we examined the GCMB gene, mapped to 6p23–24, as a candidate for isolated hypoparathyroidism. We defined the boundaries of the five exons of the human GCMB gene and then identified a large intragenic mutation in the GCMB genes of the proband of an extensive kindred with isolated hypoparathyroidism. Her parents and several other unaffected relatives were heterozygous for the mutation. Despite an absence of any history of consanguinity, microsatellite analysis showed shared genotypes that flanked the GCMB gene over a span of 5 cM, suggesting that both of the proband's GCMB alleles had been derived from a single common ancestor. Analysis of additional, unrelated cases did not disclose the same mutation. We conclude that homozygous loss of function of the GCMB gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients with this disease.
Abstract Context Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. Objective To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. Design Open-label extension study; 5-year interim analysis. Setting 12 US centers. Patients Adults (N = 49) with chronic hypoparathyroidism. Intervention(s) rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. Main Outcome Measure(s) Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. Results Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. Conclusion Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.
Abstract Background: Hyperparathyroidism is uncommon in adolescence and is more likely to persist after parathyroidectomy than in adults. Cinacalcet HCl is a new calcimimetic that has been used successfully for the treatment of primary and secondary hyperparathyroidism in adults, but its use in adolescents has not been reported. Case: A 16 year-old male presented with hypercalcemia that had persisted for 1.5 years after parathyroidectomy for primary hyperparathyroidism. Parathyroid hormone (PTH) concentrations were nonsupressed despite a mean (SD) serum calcium concentration of 2.82 (0.06) mmol/L. Treatment with cinacalcet HCl was initiated and a pharmacodynamic profile was obtained for serum calcium, phosphorus, and PTH. Cinacalcet HCl normalized serum calcium. The changes in PTH were assay dependent. Issues: We use this case conference to review the evaluation of hypercalcemia in adolescents, examine the changes in relevant laboratory results during treatment with cinacalcet HCl, and discuss differences among assays for PTH. Conclusions: Interpretation of PTH results in patients treated with cinacalcet HCl requires consideration of the pharmacodynamic effects of the drug and the nature of the PTH assay.
Working between the Amos Gitai film One Day You’ll Understand (2008) and the 1987 Klaus Barbie trial against which it is set, the article explores how the trial marked a decisive turning point in France’s relationship to its wartime past. Of Barbie’s hundreds of crimes, including murder, torture, rape, and deportation, only those of the gravest nature, 41 separate counts of crimes against humanity, were pursued in the French court in Lyon. Not only did the trial raise crucial juridical questions involving the status of victims and the definition of crimes against humanity but, extending into the private sphere, it became the occasion for citizens to address heretofore silenced aspects of their own family histories and conduct trials of a more personal nature. Whereas the law in general seeks to contain historical trauma and to translate it into legal-conscious terminology, it is often the trauma that takes over, transforming the trial into “another scene” (Freud) in which an unmastered past is unwittingly repeated and unconsciously acted out. Such failures of translation, far from being simply legal shortcomings, open a space between grief and grievance, one through which it is possible to explore both how family secrets are disowned from one generation to the next, and how deeply flawed legal proceedings such as the Barbie trial may “release accumulated social toxins” (Kaplan) and thereby expose unaddressed dimensions of French postwar (and -colonial) history.
Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.
