Transient Thyrotoxicosis Following Minimally Invasive Radio-Guided Parathyroidectomy

ObjectiveWe report a case of thyrotoxicosis following minimally invasive parathyroidectomy.MethodsCase report with literature review.ResultsA 70-year-old woman with primary hyperparathyroidism developed thyrotoxicosis 2 weeks following minimally invasive radio-guided parathyroidectomy. A diagnosis of postparathyroidectomy transient thyrotoxicosis (PTT) was made after excluding other causes of thyrotoxicosis. The patient reverted back to a euthyroid state in 4 weeks with conservative management.ConclusionPTT should be considered in the differential diagnosis in patients developing features of thyrotoxicosis following parathyroidectomy. (Endocr Pract. 2014;20:e1-e3)     

Thyroid Function in Patients Treated with Radioactive Iodine for Thyrotoxicosis

A series of 105 patients treated at least two years earlier with radioactive iodine for thyrotoxicosis have been surveyed. Eighty-five patients (81%) were euthyroid clinically and on the basis of routine thyroid function tests. Of the euthyroid patients 46 (54%) had normal thyroid-stimulating hormone (TSH) levels and 39 (46%) had raised TSH levels. There was no difference in serum triiodothyronine levels between these two groups but the serum protein bound iodine and serum thyroxine, though still well within the normal range, were significantly lower in the group with raised TSH levels. The serum cholesterol was also significantly higher in this latter group.Most of the euthyroid patients were seen again a year later. None had become hypothyroid and neither those with normal nor those with raised TSH levels showed any evidence of a decline in the level of serum thyroxine.It is concluded that raised serum TSH levels in patients treated with iodine-131 are not necessarily indicative of hypothyroidism. There is no indication that patients who have this abnormality become overtly hypothyroid over a 12-month follow up.     

Effect of Pretreatment with Carbimazole in Patients with Thyrotoxicosis Subsequently Treated with Radioactive Iodine

Preliminary treatment with carbimazole in a series of 181 patients with thyrotoxicosis selected for treatment with radioactive iodine did not make any significant difference to the subsequent response to ¹³¹I therapy.     

Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor

The thyrotropin receptor (TSHR) is a G protein-coupled receptor (GPCR) that is member of the leucine-rich repeat subfamily (LGR). In the absence of crystal structure, the success of rational design of ligands targeting the receptor internal cavity depends on the quality of the TSHR models built. In this subfamily, transmembrane helices (TM) 2 and 5 are characterized by the absence of proline compared to most receptors, raising the question of the structural conformation of these helices. To gain insight into the structural properties of these helices, we carried out bioinformatics and experimental studies. Evolutionary analysis of the LGR family revealed a deletion in TM5 but provided no information on TM2. Wild type residues at positions 2.58, 2.59 or 2.60 in TM2 and/or at position 5.50 in TM5 were substituted to proline. Depending on the position of the proline substitution, different effects were observed on membrane expression, glycosylation, constitutive cAMP activity and responses to thyrotropin. Only proline substitution at position 2.59 maintained complex glycosylation and high membrane expression, supporting occurrence of a bulged TM2. The TSHR transmembrane domain was modeled by homology with the orexin 2 receptor, using a protocol that forced the deletion of one residue in the TM5 bulge of the template. The stability of the model was assessed by molecular dynamics simulations. TM5 straightened during the equilibration phase and was stable for the remainder of the simulations. Our data support a structural model of the TSHR transmembrane domain with a bulged TM2 and a straight TM5 that is specific of glycoprotein hormone receptors.     

Organ-specific Antibodies in Patients with Lichen Sclerosus

Organ-specific antibodies were looked for in 26 patients with lichen sclerosus. Ten of the 25 female patients (40%) had organ-specific antibodies to thyroid cytoplasm and 11 (44%) had organ-specific antibodies to gastric parietal cells. Both values were significantly greater than those obtained in age-matched controls. None of the sera from patients with lichen sclerosus contained antibodies to steroid-producing tissues. No organ-specific antibodies were found in the one male patient.The findings suggest that lichen sclerosus may be related to an autoimmune process.     

Thyrotropin Values in Patients with Micropapillary Thyroid Cancer Versus Benign Nodular Disease

ObjectivesStudies published in the last few years suggest that increased thyroid-stimulating hormone (TSH) values are associated with increased risk of thyroid cancer and/or a more advanced stage of malignancy. The aim of this study was to explore the hypothesis that TSH may be a risk factor for thyroid cancer initiation, which was tested by comparing TSH concentrations in patients with incidental micro papillary cancer (mPTC) and controls with a negative histologic exam.MethodsPatients were retrospectively selected from medical records from 3 district hospitals. Patients with biochemical/histologic evidence of autoimmunity, thyroid function-interfering drugs, and autonomously functioning areas, were excluded. TSH values of 41 patients with an incidental mPTC were then compared with a sex-and age-matched group of patients who had a negative histologic exam at a 4:1 ratio (164 patients).ResultsTSH was not significantly different in the mPTC group compared to the controls (1.1 ± 0.7 vs. 1.3 ± 1.0 mIU/L). After adjustment for age and gender, TSH levels were still not found to be significantly different between groups. In the mPTC group, TSH levels were not found to be a significant predictor of tumor size after adjusting for age and gender (β = 0.035, SE = 0.73, P = .844).ConclusionsOn the basis of these results, the hypothesis that TSH is involved in de novo oncogenesis of PTC is not supported. (Endocr Pract. 2013;19:651-655)     

A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease

ObjectiveAutoantibodies against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn).MethodsSerial measurements of TSH-R-Ab serum levels were performed using 3 different binding and cell-based assays in patients with GD either on medication or on placebo.ResultsIn contrast to the placebo group, in which no changes were observed, a 12-week mAb therapy led to an early and significant decrease (>60%) in the serum TSH-R-Ab levels in patients with thyroidal and extrathyroidal GD, as unanimously shown in all 3 assays. These marked changes were noted already at week 7 post baseline (P <.0001 for the binding immunoassay and for the luciferase (readout) bioassay). The 3 TSH-R-Ab binding and bioassays were highly correlated in the samples of both study groups (binding immunoassay vs luciferase bioassay, r =.91, P <.001, binding vs cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P <.001, and luciferase vs cAMP bioassay, r = 0.71, P =.006). The serological results correlated with the course of the extrathyroidal clinical parameters of GD, that is, clinical activity score and proptosis.ConclusionTargeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of patients with GD.     

Principles and Determinants of G-Protein Coupling by the Rhodopsin-Like Thyrotropin Receptor

In this study we wanted to gain insights into selectivity mechanisms between G-protein-coupled receptors (GPCR) and different subtypes of G-proteins. The thyrotropin receptor (TSHR) binds G-proteins promiscuously and activates both Gs (cAMP) and Gq (IP). Our goal was to dissect selectivity patterns for both pathways in the intracellular region of this receptor. We were particularly interested in the participation of poorly investigated receptor parts.We systematically investigated the amino acids of intracellular loop (ICL) 1 and helix 8 using site-directed mutagenesis alongside characterization of cAMP and IP accumulation. This approach was guided by a homology model of activated TSHR in complex with heterotrimeric Gq, using the X-ray structure of opsin with a bound G-protein peptide as a structural template.We provide evidence that ICL1 is significantly involved in G-protein activation and our model suggests potential interactions with subunits Gα as well as Gβγ. Several amino acid substitutions impaired both IP and cAMP accumulation. Moreover, we found a few residues in ICL1 (L440, T441, H443) and helix 8 (R687) that are sensitive for Gq but not for Gs activation. Conversely, not even one residue was found that selectively affects cAMP accumulation only.Together with our previous mutagenesis data on ICL2 and ICL3 we provide here the first systematically completed map of potential interfaces between TSHR and heterotrimeric G-protein. The TSHR/Gq-heterotrimer complex is characterized by more selective interactions than the TSHR/Gs complex. In fact the receptor interface for binding Gs is a subset of that for Gq and we postulate that this may be true for other GPCRs coupling these G-proteins. Our findings support that G-protein coupling and preference is dominated by specific structural features at the intracellular region of the activated GPCR but is completed by additional complementary recognition patterns between receptor and G-protein subtypes.     

Review of Transient Receptor Potential Channels

Transient Receptor Potential Channels; Islam, Md. Shahidul (Ed.); Series: Advances in Experimental Medicine and Biology, Vol. 704; 1095 pages; Hardcover; Publisher: Springer; 1st Edition (2011, XXIII); ISBN: 978-94-007-0264-6     

False-Positive Anti-Toxoplasma Fluorescent-Antibody Tests in Patients with Antinuclear Antibodies

The indirect fluorescent-antibody (IFA) method for diagnosis of toxoplasmosis is widely used and is considered to be as specific as the Sabin-Feldman dye test. After observing a patient with systemic lupus erythematosus (SLE) who had a positive toxoplasma IFA test but a negative dye test, we studied sera with high titers of antinuclear antibodies from 16 SLE patients and from 2 with rheumatoid arthritis for Toxoplasma antibodies in the immunoglobulin G and M (IgG and IgM) IFA tests and the dye test. Results of these tests were compared with titers of antinuclear antibodies, precipitating antibodies to single-strand deoxyribonucleic acid (DNA), and binding antibodies by use of DNA labeled with (3)H-actinomycin D. Of 18 patients, 11 had IgG and 4 had IgM IFA Toxoplasma antibodies; only 2 had antibodies detectable in the dye test. The immunofluorescence patterns in the Toxoplasma IFA test were indistinguishable from those obtained in patients with toxoplasmosis without antinuclear antibodies. Absorption of SLE sera with DNA did not result in a decrease in Toxoplasma IFA titers. When SLE sera were absorbed with live T. gondii, a marked drop in IgG IFA titer was observed as well as a decrease in titers of antinuclear antibodies and (3)H-DNA binding. Treatment of Toxoplasma cells with deoxyribonuclease and ribonuclease did not decrease their fluorescence. These results suggest that T. gondii nuclear antigens can absorb antinuclear antibodies but do not have exposed substrates for deoxyribonuclease. Tests in which organisms containing "nuclear" antigens for IFA detection of antibodies to these organisms are used may result in "false-positives" with sera containing antinuclear antibodies.     

瞬时感受器电位通道与疾病

哺乳动物瞬时感受器电位(transient receptor potential,TRP)通道超家族由TRPC、TRPM、TRPV、TRPA、TRPP和TRPML六个亚家族组成。这些亚家族的29个离子通道几乎表达于所有的组织和细胞。大多对单价和二价阳离子都有通透性。TRP通道与多种生物学功能有关,包括高血压、温度觉、血管炎症、刺激感、肿瘤增生、细胞内离子稳态及神经细胞信号转导。对这些通道的生理功能及其与人类疾病的关系的研究有助于开发具有潜在治疗价值的TRP通道调节剂。     

The G-Protein Coupled Estrogen Receptor (GPER/GPR30) is a Gonadotropin Receptor Dependent Positive Prognosticator in Ovarian Carcinoma Patients

Follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) were demonstrated to impact upon survival of patients suffering from epithelial ovarian cancer (EOC). Though structure wise the G-protein coupled estrogen receptor (GPER/GPR30) is related to FSHR/LHCGR, its prognostic impact in EOC remains controversial. We recently found that FSHR negative patients represent a specific EOC subgroup that may behave differently in respect to both treatment response and prognosis. Hence, the current study aimed to analyze how GPER may interact with the FSHR/LHCGR system in EOC and whether the prognostic significance of GPER in EOC cases (n = 151) may be dependent on the FSHR/LHCGR immunophenotype of the tumor. Ovarian cancer cell lines were used to study how FSH and LH regulate GPER and whether GPER activation differentially affects in vitro cell proliferation in presence/absence of activated FSHR/LHCGR. In EOC tissue, GPER correlated with FSHR/LHCGR and was related to prolonged overall survival only in FSHR/LHCGR negative patients. Although GPER was found to be specifically induced by LH/FSH, GPER agonists (4-Hydroxy-Tamoxifen, G1) reduced EOC cell proliferation only in case of LH/FSH unstimulated pathways. To the same direction, only patients characterized as LHCGR/FSHR negative seem to gain from GPER in terms of survival. Our combined tissue and in vitro results support thus the hypothesis that GPER activation could be of therapeutic benefit in LHCGR/FSHR negative EOC patients. Further studies are needed to evaluate the impact of GPER activation on a clinical scheme.     

Epitope Analysis of Anti-Myeloperoxidase Antibodies in Patients with ANCA-Associated Vasculitis

Objective

Increasing evidences have suggested the pathogenic role of anti-neutrophil cytoplasmic antibodies (ANCA) directing myeloperoxidase (MPO) in ANCA-associated vasculitis (AAV). The current study aimed to analyze the association between the linear epitopes of MPO-ANCA and clinicopathological features of patients with AAV.

Methods

Six recombinant linear fragments, covering the whole length amino acid sequence of a single chain of MPO, were produced from E.coli. Sera from 77 patients with AAV were collected at presentation. 13 out of the 77 patients had co-existence of serum anti-GBM antibodies. Ten patients also had sequential sera during follow up. The epitope specificities were detected by enzyme-linked immunosorbent assay using the recombinant fragments as solid phase ligands.

Results

Sera from 45 of the 77 (58.4%) patients with AAV showed a positive reaction to one or more linear fragments of the MPO chain. The Birmingham Vasculitis Activity Scores and the sera creatinine were significantly higher in patients with positive binding to the light chain fragment than that in patients without the binding. The epitopes recognized by MPO-ANCA from patients with co-existence of serum anti-GBM antibodies were mainly located in the N-terminus of the heavy chain. In 5 out of the 6 patients, whose sera in relapse recognize linear fragments, the reactivity to linear fragments in relapse was similar to that of initial onset.

Conclusion

The epitope specificities of MPO-ANCA were associated with disease activity and some clinicopathological features in patients with ANCA-associated vasculitis.