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BackgroundThymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.MethodsWe compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.ResultsA total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P

Tuberous sclerosis (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs and is caused by mutations targeting either the TSC1 or TSC2 genes. TSC1 and TSC2 proteins form a functionally interdependent dimeric complex. Phosphorylation of either TSC subunit by different kinases regulates the function of TSC and represents a major mechanism to integrate various signals into a centralized cell growth pathway. The majority of disease-associated mutations targeting either TSC1 or TSC2 results in a substantial decrease in protein level, suggesting that protein turnover also plays a critical role in TSC regulation. Here we report that TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1–CUL4–ROC1 E3 ubiquitin ligase. Overexpression of FBW5 or CUL4A promotes TSC2 protein degradation, and this is abrogated by the coexpression of TSC1. Conversely, depletion of FBW5, DDB1, or CUL4A/B stabilizes TSC2. Ddb1 or Cul4 mutations in Drosophila result in Gigas/TSC2 protein accumulation and cause growth defects that can be partially rescued by Gigas/Tsc2 reduction. These results indicate that FBW5–DDB1–CUL4–ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover.

Copyright © 2001 D.A. Campbell et al. This is distributed under the Creative Commons Attribution License, which permits use provided the original work is properly cited. Peer reviewed., The king scallop, Pecten maximus, is a valuable economic resource in the UK. The industry relies on supplying premium "roe-on" processed scallops to the continental market. In July 1999, king scallops harboring the amnesic shellfish poisoning (ASP) toxin, domnic acid (DA), in gonadal tissue at levels above the regulatory limit (20 μg DA g-1) were detected across a wide area of northern and western Scotland. In response, a survey of the southern extent of the closed harvest areas was initiated to describe variability of ASP toxin levels over varying spatial scales (5 km); determine the anatomical distribution of the toxin, and identify, isolate, and culture causative Pseudo-nitzschia species. Toxin analysis was conducted using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) procedure. The DA content of tissues followed the predictable rank order: all other tissue -1 gonad -1 adductor. The toxin levels within all other tissue (95% Cl = 580-760 μg DA g-1, n = 170) consistently accounted for 99% of the total individual toxin burden. DA levels in the gonad (95% CI = 8.2-11.0 μg DA g- 1, n = 170) were an order of magnitude below levels in all other tissue and contributed to less than 0.5% of the total individual toxin burden, although levels above the regulatory limit were detected in individual gonad samples. Adductor muscle tissue contained the lowest concentration of DA (95% Cl = 0.38-0.82 μg DA g- 1, n = 170), and was typically within two to three orders of magnitude below levels in all other tissue. None of the scallops examined had DA toxicities in adductor muscle tissue exceeding the regulatory limit. Toxin variability among individuals and sites was high (range of coefficients of variation (CV) in all other tissue = 29&-l20% and gonadal = 45%-85%). The results do give an indication of the scale on which microhabitat differences may influence ASP toxicity in P. maximus populations, because significant differences were found in all other and gonadal tissue toxin levels between groups of individuals only 25-m apart. In total, seven species of Pseudo-nitzschia were identified from west coast waters. A suspected causative species, P. australis, was found to produce high levels of DA, in culture. The high individual variation in toxicities and the occurrence of DA in the gonad at levels above the regula1ory limit clearly demonstrate the complexity of managing the king scallop fishery during ASP events., The Scallop Association, the Highlands and Islands Enterprise, PESCA, and the Highland Council.