Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and G384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP-WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred syndrome.
Background: Subclinical thyroid disease is common; however, screening recommendations using serum thyrotropin (TSH) level determinations are controversial.Methods: To study the use of serum TSH by primary care physicians and define populations at risk for having an abnormal TSH level at follow-up, based on initial TSH levels, we conducted an observational study of a large health care database in the setting of a health management organization. All outpatients without thyroid disease or pregnancy or taking medication that may alter thyroid function in whom the TSH level was measured in 2002 and during 5-year follow-up were included in this study. Repeated TSH level determinations were compared with the initial TSH level values.Results: In 422 242 patients included, 95% of the initial serum TSH concentrations were within normal limits (0.35-5.5 mIU/L), 1.2% were decreased (Ͻ0.35 mIU/L), 3.0% were
Denosumab (DMAB) efficacy for treatment of osteoporosis was demonstrated in a pivotal trial with a reduction in vertebral and hip fractures during 3 years, and fracture risk reduction was sustained up to 10 years in an extension study. DMAB causes potent yet reversible inhibition of bone resorption. Bone density declines rapidly upon discontinuation and bone turnover markers increase above baseline in a rebound fashion. Spontaneous multiple vertebral fractures after DMAB discontinuation were recently reported. Prior treatment with bisphosphonates (BP) was postulated to decrease the risk for this alarming phenomenon. We aimed to describe our experience of fractures following DMAB withdrawal with special attention to past history of osteoporosis treatment. A phone survey of physicians engaged in bone metabolism from nine hospitals in Israel was performed. Clinical data of the patients presenting with vertebral fractures upon DMAB discontinuation were summarized and compared to the previously published cases. Nine elderly (74.2 ± 5.3 years) female patients were identified. Most patients had a prolonged prior exposure to BP (7.4 ± 3.2 years). All but one sustained osteoporotic fractures prior to DMAB initiation and their FRAX scores were high. Thirty-six vertebral fractures were identified in nine patients. Eight patients presented with multiple fractures, and most fractures were spontaneous. In line with the previous reports, the timing and severity of the fractures raise concern of DMAB discontinuation effect. Prolonged BP exposure in most of our patients challenges the protective effect hypothesis. Care providers, patients, and regulatory authorities should be aware of the possible risk of DMAB treatment interruption.
An outcome of overloading of the endoplasmic reticulum (ER) folding machinery is a perturbation in ER function and the formation of intracellular aggregates. The latter is a key pathogenic factor in numerous diseases known as ER storage diseases. Here, we report that heterologous overexpression of the green fluorescent protein-tagged iodide transporter pendrin (GFP-PDS) perturbs folding and degradation processes in the ER. Pendrin (PDS) is a chloride-iodide transporter found in thyroid cells. Mutations in PDS can cause its retention in the ER and are associated with Pendred syndrome. Biochemical and live-cell analyses demonstrated that wild-type GFP-PDS is predominantly retained in perinuclear aggregates and in ER membranes, causing their collapse and vesiculation. Inhibition of protein synthesis by cycloheximide (CHX) or puromycin caused dissociation of the GFP-PDS aggregates and returned the ER to its normal reticular morphology. Blocking protein synthesis promoted folding and export of ER-retained GFP-PDS, as demonstrated by surface-biotinylation analysis and by CHX- or puromycin-induced accumulation of YFP-PDS in the Golgi apparatus during a 20°C temperature-block experiment. The chemical chaperone trimethylamine-N-oxide (TMAO) also reversed the GFP-PDS-mediated ER collapse and vesiculation, suggesting that exposed hydrophobic stretches of misfolded or aggregated GFP-PDS may contribute to ER retention. These data suggest that GFP-PDS is a slow-folding protein with a propensity to form aggregates when overexpressed. Thus, we describe a system for the reversible induction of ER stress that is based entirely on the heterologous overexpression of GFP-PDS.
Since the early 1980s, case reports and case series describe an association between silicon breast implants and the appearance of autoimmune diseases, particularly scleroderma. The publication of those cases led to a large number of studies to investigate this association. The conclusion of those studies is that most probably there has not been an increased incidence of autoimmune diseases in women with silicon breast implants. Nevertheless, the US Food and Drug Administration determined that silicone gel breast implants are not completely safe, only that they are 'reasonably safe.' The debate continues regarding this association. In this article we present new cases of silicon breast implant-induced scleroderma and review the literature on this subject.
The optimal treatment of metastatic thyroid cancer that produces high amounts of thyroid hormone has not been well defined. A 46-yr-old woman presented with a follicular thyroid carcinoma arising from a struma ovarii with hepatic metastases. After the removal of both the struma and the thyroid gland, the liver metastases showed evidence of a high degree of hormonogenesis. Brain, chest, abdomen, and bone imaging was negative for additional metastases. Because iodine uptake by most thyroid carcinomas is quite low in the absence of high levels of ambient TSH, we used recombinant human TSH (rhTSH) (Thyrogen) to achieve a concentration of 131I activity in the tumor high enough for a significant cytotoxic effect. After rhTSH administration (0.9 mg im daily for 2 consecutive days), a 131I diagnostic whole body scan confirmed the existence of 17 discrete hepatic foci of 131I uptake. To calculate the amount of 131I that would deliver an absorbed radiation dose that would be optimally cytotoxic to the metastases (>8000 rad/lesion) and not to the normal liver, we performed lesion dosimetry. Analysis of dosimetric data showed that 15 of 17 lesions would receive an adequate radiation dose following the administration of 65 mCi of 131I. Additionally, we performed whole body dosimetry to assure that this dose would not cause bone marrow toxicity. The patient was reevaluated 6 months after therapy; the liver metastases showed significant, but partial, response. In conclusion, we used the combination of rhTSH with lesional and whole body dosimetry for the treatment of highly functional metastases from follicular thyroid carcinoma arising within a struma ovarii. This strategy can be applied to determine a safe and effective dose of 131I for the treatment of any thyroid cancer metastases that produce enough TH to preclude stimulation of endogenous pituitary TSH secretion.
Parathyroidectomy success rate was similar in patients with primary HPT and MIBI-only or US-only positive localization studies compared to those with matched US/MIBI studies. The results support a clinical algorithm in which positive results from one imaging technique, either MIBI or US, are sufficient to refer a patient for parathyroid surgery.
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