Fatigue is common in primary biliary cirrhosis (PBC). Altered central serotonergic neurotransmission may be involved in its pathogenesis. This multicenter, randomized, doubleblind, placebo-controlled, crossover trial evaluated the efficacy of ondansetron, a selective 5-HT3 receptor subtype antagonist, for treating fatigue in PBC. A crossover design was chosen, allowing subjects to serve as their own controls-appropriate to evaluate fatigue, a subjective symptom. Sixty patients with clinically stable PBC, a Fatigue Severity Score (FSS) > 4, and no other identifiable cause for fatigue were enrolled. Subjects were randomized to receive ondansetron (4 mg) or placebo orally 3 times daily for 4 weeks (period 1). Subjects then crossed over, after a minimum 1-week washout period, for a further 4 weeks of ondansetron or placebo (period 2). Fatigue was measured at the beginning and end of each period by using the FSS and Fatigue Impact Scale (FIS). Six patients withdrew; the remaining 54 subjects had a mean baseline FSS of 5.55 (؎0.1). Response to study medication in period 1 versus period 2 was not uniform; thus, it was necessary to analyze the trial periods separately. In period 1, there was no significant additional fatigue reduction on ondansetron over placebo. During period 2, FSS and FIS decreased significantly on ondansetron versus placebo (P ‫؍‬ .001). However, period 2 results were invalidated because drug side effects unblinded subjects (constipation affected 63.0% of patients taking ondansetron, versus 13.3% on placebo). In conclusion, ondansetron administration did not confer clinically significant fatigue reduction when compared with placebo in our study population. F atigue is common in primary biliary cirrhosis (PBC), affecting between 55% and 85% of patients. 1-3 It diminishes quality of life and interferes with many activities of daily living. 2,4 No known treatment exists for fatigue in PBC. Previously investigated drugs, including ursodeoxycholic acid, 5 cyclosporine, 6 thalidomide, 7 and antioxidants, 8 were not effective in ameliorating this debilitating symptom.The pathogenesis of fatigue in PBC is unclear. Fatigue in patients with PBC may be centrally mediated and not peripheral in origin. 9 The mechanisms proposed for this centrally mediated fatigue include abnormal neuroendocrine function and altered serotonergic neurotransmission. These mechanisms have been demonstrated in a bile duct-ligated rat model simulating acute cholestasis 10,11 as well as in humans. 12,13 In the rat model, repeated administration of a serotonin-1a receptor agonist relieved fatigue as measured by activity scores during a swim tank test. 11 In humans, administration of the serotonin reuptake inhibitor paroxetine resulted in decreased exercise endurance time in recreationally active young males. 13 Questionnaire studies conducted in individuals with PBC have consistently found an association of fatigue with depression. 1-3 Abnormalities in central serotonin transmission are thought to be key to the pathogenesis of

Hepatitis B virus (HBV) infection may be complicated by extrahepatic manifestations such as polyarteritis nodosa (PAN), glomerulonephritis, polymyositis, and dermatitis, but the etiology of these processes is not yet clear. HBV replication has been demonstrated in a variety of extrahepatic tissues and cell types, but the possible pathogenetic role of extrahepatic HBV replication has not been fully explored in patients with extrahepatic manifestations of HBV infection. In this case series, immunohistochemistry and in situ hybridization studies were performed on extrahepatic tissues from one HBsAg-positive patient with PAN and another HBsAg-positive patient with polymyositis, using HBsAg-seronegative control subjects with the same vasculitic disorders as controls. Tissue samples from the two study patients had detectable HBV RNA, replicative intermediates of HBV DNA, as well as HBsAg and HBcAg localized to vascular endothelium. In contrast, HBsAg-negative control patients had no tissue reactivity. Our results suggest that patients with HBV-related extrahepatic disease have evidence of viral replication in damaged extrahepatic endothelial tissues. While further studies would be required to support a hypothesis of causality, these findings suggest a role for both immune complex deposition and viral replication within diseased endothelial tissue in the pathogenesis of these poorly understood extrahepatic disorders.

No abstract

No abstract

We report on an experimental examination of a new powerful optical source with potential application in radiotherapy treatment simulation. The illuminance, effective source position, and source size have been measured for this new source and, for comparison, for conventional sources on a simulator and a linear accelerator. This new source is considerably brighter than those in common use in radiotherapy. Its effective optical source size is larger than that on the linear accelerator tested but comparable with that on a conventional simulator.