Reaching the Unreachable: Strategies for HCV Eradication in Patients With Refractory Opioid Addiction-A Real-world Experience.

To achieve global hepatitis C virus (HCV) eradication, barriers prohibiting treatment access need to be overcome. We established a strategy to initiate antiviral therapy in patients with severe, refractory heroin addiction. All patients achieved sustained virological response. Outreach programs of hepatologists might be a reasonable way to overcome barriers to HCV treatment.

The 25 kDa HCN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity.

The extraordinarily potent clostridial neurotoxins (CNTs) comprise tetanus neurotoxin (TeNT) and the seven established botulinum neurotoxin serotypes (BoNT/A-G). They are composed of four structurally independent domains: the roles of the catalytically active light chain, the translocation domain HN, and the C-terminal receptor binding domain HCC are largely resolved, but that of the HCN domain sandwiched between HN and HCC has remained unclear. Here, mutants of BoNT/A, BoNT/B, and TeNT were generated by deleting their HCN domains or swapping HCN domains between each other. Both deletion and replacement of TeNT HCN domain by HCNA and HCNB reduced the biological activity similarly, by ~95%, whereas BoNT/A and B deletion mutants displayed >500-fold reduced activity in the mouse phrenic nerve hemidiaphragm assay. Swapping HCN domains between BoNT/A and B hardly impaired their biological activity, but substitution with HCNT did. Binding assays revealed that in the absence of HCN, not all receptor binding sites are equally well accessible. In conclusion, the presence of HCN is vital for CNTs to exert their neurotoxicity. Although structurally similar, the HCN domain of TeNT cannot equally substitute those of BoNT and vice versa, leaving the possibility that HCNT plays a different role in the intoxication mechanism of TeNT.

Severe CNS inflammation after discontinuation of natalizumab and start of daclizumab successfully treated with alemtuzumab.

Natalizumab is highly effective in the treatment of relapsing multiple sclerosis patients. Unfortunately, after stopping natalizumab, there is an increased risk of inflammation in the central nervous system and relapses. Switching from natalizumab to an alternative sufficient drug may prevent disease reactivation. Here we present a case of a patient who experienced a dramatic course with severe central nervous system inflammation after discontinuation of natalizumab and treatment initiation with daclizumab. During a treatment of 36 days, 20 g intravenous methylprednisolone in total and ten courses of plasmapheresis were not able to control the severe CNS inflammation. Alemtuzumab, which targets the whole lymphocyte population, was able to stabilize the devastating disease course in our case.