Objective To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis. Methods Adults with refractory polymyositis and adults and children with refractory dermatomyositis were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal core set measures (CSM) for adults. JDM patients required ≥ 3 abnormal CSM with or without muscle weakness. Patients were randomized to either ‘rituximab early’ or ‘rituximab late’ and glucocorticoid and immunosuppressive therapy were allowed at entry. The primary endpoint compared the time to achieve the preliminary International Myositis Assessment and Clinical Studies Group definition of improvement (DOI) between the 2 groups. The secondary endpoints were time to achieve ≥20% improvement in muscle strength, and the proportion of early and late rituximab patients achieving DOI at week 8. Results Among 200 randomized patients (76 PM/76 DM/48 JDM), 195 showed no difference in the time to DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74, log rank) with a median time to DOI of 20.2 weeks and 20.0 weeks respectively. The secondary endpoints also did not significantly differ between the two treatment groups. However, 161 (83%) of randomized patients met the DOI and individual CSM improved in both groups throughout the 44-week trial. Conclusion Although there were no significant differences in the two treatment arms for the primary and secondary endpoints, 83% of refractory adult and juvenile myositis patients met the DOI. The role of B cell depleting therapies in myositis warrants further study with consideration for a different trial design.

ER-associated degradation (ERAD) removes defective and mis-folded proteins from the eukaryotic secretory pathway, but mutations in the ER lumenal Hsp70, BiP/Kar2p, compromise ERAD efficiency in yeast. Because attenuation of ERAD activates the UPR, we screened for kar2 mutants in which the unfolded protein response (UPR) was induced in order to better define how BiP facilitates ERAD. Among the kar2 mutants isolated we identified the ERAD-specific kar2-1 allele (Brodsky et al. J. Biol. Chem. 274,(3453)(3454)(3455)(3456)(3457)(3458)(3459)(3460). The kar2-1 mutation resides in the peptide-binding domain of BiP and decreases BiP's affinity for a peptide substrate. Peptide-stimulated ATPase activity was also reduced, suggesting that the interdomain coupling in Kar2-1p is partially compromised. In contrast, Hsp40 cochaperone-activation of Kar2-1p's ATPase activity was unaffected. Consistent with UPR induction in kar2-1 yeast, an ERAD substrate aggregated in microsomes prepared from this strain but not from wild-type yeast. Overexpression of wild-type BiP increased substrate solubility in microsomes obtained from the mutant, but the ERAD defect was exacerbated, suggesting that simply retaining ERAD substrates in a soluble, retro-translocationcompetent conformation is insufficient to support polypeptide transit to the cytoplasm. INTRODUCTIONBefore being delivered to their ultimate locations, secreted proteins are monitored by a quality control "machine" associated with the endoplasmic reticulum (ER; reviewed by Ellgaard et al., 1999); aberrant polypeptides may be retrotranslocated from the ER to the cytoplasm and destroyed by the proteasome in a process termed ER-associated degradation (ERAD; McCracken and Brodsky, 1996). The importance of defining the molecular mechanism of ERAD is underscored by the fact that several human diseases arise from the accumulation or accelerated degradation of ERAD substrates and because some bacterial toxins and viruses coopt the ERAD pathway to exert their effects (reviewed in Thomas et al., 1995;Aridor and Hannan, 2000;Fewell et al., 2001).ERAD may result from inefficient protein folding, so it is not surprising that molecular chaperones are required for this process. Chaperones prevent the formation of off-pathway intermediates or directly catalyze folding and have been proposed to "judge" whether a nascent protein will ultimately fold or whether it should be targeted for degradation (reviewed by Hayes and Dice, 1996;Hartl, 1996;Horwich et al., 1999;Plemper and Wolf, 1999;Rö misch, 1999;Wickner et al., 1999;Fewell et al., 2001;Hö hfeld et al., 2001). Hsp70 (heat shock proteins with a molecular mass of ϳ70 kDa) molecular chaperones hydrolyze ATP concomitant with the binding of peptides with overall hydrophobic character (Flynn et al., 1991;Blond-Elguindi et al., 1993;Rü diger et al., 1997); therefore, Hsp70s might retain the solubility of unfolded, retro-translocating polypeptides during their voyage from the ER to the cytoplasm via the Sec61p translocation channel or might "gate" this c...

Background & Aims Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the US and Canada might be disproportionately affected. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. Methods The HBRN collected data on clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. Results Half of the subjects in the HBRN are male, and the mean age is 42 years; 72% are Asian, 15% are Black, and 11% are White, with 82% born outside of North America. The most common HBV genotype was B (39%); 745 of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and 67% of female subjects had levels of alanine aminotransferase above the normal range. Conclusions The HBRN cohort will be used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America.

Adherence to peginterferon and ribavirin decreased gradually during therapy but remained relatively high. Simple self-reported measures can be used to screen for nonadherence to HCV drug therapy, but should be considered as overestimation of the actual amounts taken.

Methamphetamine use has been characterized as a "rural" drug; however, little is known about rural methamphetamine use disorders (MUD). This study describes and compares characteristics of rural and urban patients with MUD. Rural study participants reported earlier first regular use of methamphetamine, more alcoholism, more intravenous use, and a greater number of cigarettes/day, and were more likely to report methamphetamine-related psychotic symptoms. Rural methamphetamine users report multiple factors that may contribute to medical and psychiatric complications and worsen their prognosis. This is of significant concern given the limited substance abuse, mental health, and specialty care available in most rural Midwestern communities.