BACKGROUND Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon–ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, −10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon–ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, −2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.)

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To describe the clinical characteristics and define the indicators that best predict survival in patients with bone metastases from thyroid carcinomas. We collected data from medical records of 146 patients with documented bone metastases from thyroid carcinoma seen at our medical center over a 38-year period. Univariate and multivariate analyses of prognostic indicators for survival were performed. Bone metastases were present at the initial diagnosis in 47% of patients. Vertebrae (29%), pelvis (22%), ribs (17%), and femur (11%) were the most common sites of metastases. Multiple lesions were present in 53% of the cases. The overall 10-year survival rate from the time of diagnosis of thyroid cancer was 35%, and from diagnosis of initial bone metastasis was 13%. By univariate analysis from the time of the initial bone metastasis, radioiodine uptake by skeletal metastases, the absence of nonosseous metastases and treatment with radioiodine were significant prognostic factors. By multivariate analysis, radioiodine uptake by skeletal metastases and the absence of nonosseous metastases were independent favorable prognostic variables for survival. In a subgroup of patients in which histologic specimens were available and were reviewed, Hurthle cell carcinoma was the most favorable histologic subtype for survival with the undifferentiated subtype being the worst. The spread of thyroid carcinoma to bone is more common in patients over 45 years of age, is usually symptomatic, and is often multicentric. Overall survival is best in those whose lesions concentrate radioactive iodine and those who have no nonosseous metastases.

Single Ca2+-dependent K+-channel currents were recorded in intact and excised inside-out membrane patches of the anterior pituitary clone AtT-20/D16-16. The frequency of channel openings and lifetimes depends both on membrane potential and on the Ca2+ concentrations at the inner membrane surface. The curve of the open-state probability of the channel as a function of membrane potential appears to translate along the voltage axis with changes in internal Ca2+ concentration. For Ca2+ concentrations between 10(-7) and 10(-6) M, the shift is consistent with the hypothesis that three Ca2+ ions are required to open a Ca2+-dependent K+ channel. Single channel conductances are estimated to be 124 pS in patches with normal external K+ (5.4 mM) and 208 pS in excised patches with symmetrical K+ (145 mM) across the membrane. Tetraethylammonium (20 mM) added to the cytoplasmic surface reversibly blocks the Ca2+-dependent K+ channel.

Primary dissociated fetal mouse spinal cord cultures were used to study the mechanisms underlying the differences in persistence of botulinum neurotoxin A (BoNT/A) and botulinum neurotoxin/E (BoNT/E) activities. Spinal cord cultures were exposed to BoNT/A (0.4 pM) for 2^3 days, which converted approximately half of the SNAP-25 to an altered form lacking the final nine C-terminal residues. The distribution of toxindamaged to control SNAP-25 remained relatively unchanged for up to 80 days thereafter. Application of a high concentration of BoNT/E (250 pM) either 25 or 60 days following initial intoxication with BoNT/A converted both normal and BoNT/ A-truncated SNAP-25 into a single population lacking the final 26 C-terminal residues. Excess BoNT/E was removed by washout, and recovery of intact SNAP-25 was monitored by Western blot analysis. The BoNT/E-truncated species gradually diminished during the ensuing 18 days, accompanied by the reappearance of both normal and BoNT/A-truncated SNAP-25. Return of BoNT/A-truncated SNAP-25 was observed in spite of the absence of BoNT/A in the culture medium during all but the first 3 days of exposure. These results indicate that proteolytic activity associated with the BoNT/A light chain persists inside cells for s 11 weeks, while recovery from BoNT/E is complete in 6 3 weeks. This longer duration of enzymatic activity appears to account for the persistence of serotype A action.z 1999 Federation of European Biochemical Societies.

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.galantamine ͉ guinea pig ͉ pyridostigmine ͉ soman ͉ sarin T he organophosphorus (OP) compounds soman, sarin, VX, and tabun, referred to as nerve agents, are among the most lethal chemical weapons ever developed (1). Some of them were used with catastrophic results in wars and also in terrorist attacks in Japan in the 1990s (2). The majority of insecticides are also OPs, and intoxication with these compounds represents a major public-health concern worldwide (3, 4). The possibility of further terrorist attacks with nerve agents and the escalating use of OP insecticides underscore the urgent need to develop effective and safe antidotes against OP poisoning.The acute toxicity of OPs results primarily from their action as irreversible inhibitors of acetylcholinesterase (AChE) (5). In the periphery, acetylcholine accumulation leads to persistent muscarinic receptor stimulation that triggers a syndrome whose symptoms include miosis, profuse secretions, bradycardia, bronchoconstriction, hypotension, and diarrhea. It also leads to overstimulation followed by desensitization of nicotinic receptors, causing severe skeletal muscle fasciculations and subsequent weakness. Central nervous system-related effects include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.Current therapeutic strategies to decrease OP toxicity include atropine to reduce the muscarinic syndrome, oximes to reactivate OP-inhibited AChE, and benzodiazepines to control OPtriggered seizures (5). The limitations of these treatments are well recognized (4), and alternative therapies have been sought. Among these therapies are phosphotriesterases and butyrylcholinesterase (...

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