Thyrotropin receptor antibodies: advances and importance of detection techniques in thyroid diseases.

The study of autoimmune thyroid disorders (AITD) has greatly contributed to our knowledge of autoimmunity. Graves' disease and Hashimoto's thyroiditis represent two ends of the range of autoimmune responses seen in AITD. Autoantibodies reactive to cytoplasmic antigens are associated with cell damage, and thyrotropin (TSH)-receptor antibodies (TRAb) influence the function and growth of the gland and play a major role in pathogenesis. The heterogeneous nature of TRAb is well accepted. Besides their long-known thyroid stimulating activity, TRAb can act as blocking antibodies or growth-promoting antibodies and, thus, cause hypothyroidism (primary myxedema) or endemic and sporadic goiters, respectively. Advanced methodologies for detection of these antibodies with the TSH-receptor assay and thyroid cell bioassay allow various activities to be measured. Current data using these assays confirm the presence of heterogeneity of functional activities of TRAb(s) in vivo. The activity of predominating antibody may relate to clinical presentation. This indicates a need for paired determinations of both TSH-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI) for accurate clinical correlations. Cloning the TSH-receptor gene has clarified its structure and function. The future identification of its epitopes will further delineate the clinical role of these antibodies and may allow development of new diagnostic and therapeutic approaches.     

子宫内膜增生的治疗：对现行治疗方法的评价

目的:鉴定现行的治疗方法并评价其对子宫内膜增生妇女的治疗效果。研究设计:研究1998年10月至2000年9月期间所有在伯明翰妇女医院,经组织学诊断为子宫内膜增生的妇女。应用标准化资料提取表对每一位妇女进行回顾性病例研究,基线特征包括临床表现和治疗方案。应用治疗后子宫内膜组织的检查结果来评价治疗方法的组织学反应,用是否需要子宫切除术及其指征来评价临床反应。结果:在研究期间有351例妇女被诊断为子宫内膜增生,其中84%表现出异常子宫出血的症状且54%的患者已绝经。合并子宫内膜增生是最常见的诊断,占所有病例的60%。无细胞学非典型…     

Intracellular sodium in proximal tubules of diabetic rats. Role of glucose

Renal hypertrophy is a common consequence of diabetes mellitus that precedes and possibly accounts for the increased glomerular filtration rate. We have postulated that the glucose-mediated increase in the intracellular concentration of sodium [Na]i initiates the chain of events leading to the increase in cell size and eventually cell number. Experiments were conducted on Sprague-Dawley rats made diabetic by the intravenous injection of 45 mg/kg body wt of streptozotocin dissolved in a 5 mM citrate buffer solution. Control animals were injected with the vehicle alone. Ninety-six hours and 11 weeks later, measurements of [Na]i were done by NMR spectroscopy on suspensions of proximal tubules, using dysprosium tripolyphosphate as an extracellular shift reagent. At 96 hours after the induction of the diabetes, there was a 60% increase in [Na]i compared to control (P less than 0.01). No further increase in [Na]i was observed during the subsequent 11 weeks of observation. Addition of ouabain (1.0 mM) resulted in a fourfold increase in [Na]i in tubules from control animals, and a 2.5-fold increase in tubules from 96-hour diabetic rats. Ouabain-inhibitable Na+-K+-ATPase activity was substantially higher in the renal tubules of diabetic rats, the increase being proportional to that of [Na]i. In order to ascertain the effect of hyperglycemia on [Na]i, proximal tubules prepared from kidneys of normal and diabetic rats were exposed to low (5 mM) and high (25 mM) concentration of glucose in the media.(ABSTRACT TRUNCATED AT 250 WORDS)     

Concentration response relationships of amiodarone and desethylamiodarone

Twelve patients with frequent ventricular premature depolarizations (VPDs) received amiodarone, 600 mg/day, for up to 8 weeks. On days 0, 1, 4, 8, 15, 22, 36, and 57 of treatment, 24-hour ambulatory ECGs were obtained, and multiple blood samples were taken for determination of amiodarone and desethylamiodarone plasma concentrations. All patients had at least 75% suppression of VPDs. The mean duration of therapy before the onset of antiarrhythmic effect was 13.2 days (range 1 to 36 days). Trough amiodarone and desethylamiodarone plasma concentrations at the time of onset of antiarrhythmic effect were 0.86 +/- 0.48 mg/L and 0.23 +/- 0.15 mg/L, respectively. Sixty-seven percent of patients responded at amiodarone concentrations below 1.0 mg/L. For each patient there was a progressive decrease in frequency of VPDs as both amiodarone and desethylamiodarone concentrations increased. Regression modeling indicated that both amiodarone and desethylamiodarone plasma concentrations explained significant variability in the frequency of VPDs, and amiodarone and desethylamiodarone plasma concentrations were highly correlated with each other. There was a trend for desethylamiodarone to explain more variability in frequency of VPDs than amiodarone.     

Interactions of LDL and modified LDL with mesangial cells and matrix.

Hyperlipidemia may play a role in the progression of diabetic and other renal diseases. Low density lipoprotein (LDL) and other proteins including extracellular matrix components undergo nonenzymatic glycation in vivo. We examined the effects of glycation of LDL as occurs in diabetes (4 to 8%) on binding and uptake by mesangial cells and their proliferation. The glycation of LDL (g-LDL) significantly decreased its binding and uptake by mesangial cells by 15 to 20%, indicating that glycated LDL binds to the LDL receptor, but with lower affinity than LDL. Both LDL and g-LDL modestly stimulated [3H] thymidine incorporation into mesangial cells at 5 to 10 micrograms/ml. Native, oxidized (Ox-LDL) and glycated LDL all bound to the extracellular matrix generated by rat mesangial cells in culture. The binding of LDL, Ox-LDL and g-LDL to mesangial matrix was two to four times higher than to mesangial cells. Binding of LDL and g-LDL was significantly higher to glycolaldehyde modified matrix, which serves as an in vitro model for nonenzymatic glycation end-product cross-linking of matrix which occurs in long-standing diabetes. Based on these findings, we propose that glycation of LDL decreases its binding and uptake by the LDL receptor of mesangial cells and may slow its catabolism. Furthermore, LDL bound to extracellular mesangial matrix can undergo oxidation and generate cytotoxic LDL components. This process may be further enhanced by advanced glycation of the mesangial matrix in diabetes, contributing to glomerular pathology.     

Molecular mechanisms of apoptosis in the cells of the immune system in human aging

Summary: Aging is associated with progressive decline in immune functions and increased frequency of infections, autoimmunity, and cancer. Among immune functions, a decline in T‐cell functions during aging predominates. In this review, I discuss the molecular signaling of three distinct pathways of apoptosis, namely the death receptor pathway, the mitochondrial pathway, and the most recently described endoplasmic reticulum stress pathway, and the relative sensitivity of naïve, central memory, and effector memory CD8⁺ T‐cell subsets to apoptosis. In addition, I review apoptosis, especially via death receptor pathway, in naïve and various memory subsets of CD4⁺ and CD8⁺ T cells (with primary emphasis on CD8⁺ naïve and memory subsets) in human aging and discuss the role of apoptosis in immune senescence.     

Optimizing Cancer Radiotherapy with 2-Deoxy-D-Glucose Dose Escalation Studies in Patients with Glioblastoma Multiforme

Background and Purpose:  

Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of γ-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients.