25-hydroxyvitamin D(3) suppresses hepatitis C virus production

Because the current interferon (IFN)-based treatment for hepatitis C virus (HCV) infection has a therapeutic limitation and side effects, a more efficient therapeutic strategy is desired. Recent studies show that supplementation of vitamin D significantly improves sustained viral response via IFN-based therapy. However, mechanisms and an active molecular form of vitamin D for its anti-HCV effects have not been fully clarified. To address these questions, we infected HuH-7 cells with cell culture-generated HCV in the presence or absence of vitamin D(3) or its metabolites. To our surprise, 25-hydroxyvitamin D(3) [25(OH)D(3) ], but not vitamin D(3) or 1,25-dihydroxyvitamin D(3) , reduced the extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. Single-cycle virus production assay with a CD81-negative cell line reveals that the inhibitory effect of 25(OH)D(3) is at the level of infectious virus assembly but not entry or replication. Long-term 25(OH)D(3) treatment generates a HCV mutant with acquired resistance to 25(OH)D(3) , and this mutation resulting in a N1279Y substitution in the nonstructural region 3 helicase domain is responsible for the resistance. Conclusion: 25(OH)D(3) is a novel anti-HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti-HCV treatment via the combination of vitamin D(3) and IFN. Our results also suggest that 25(OH)D(3) , not vitamin D(3) , is a better therapeutic option in patients with hepatic dysfunction and reduced enzymatic activity for generation of 25(OH)D(3) . (HEPATOLOGY 2012).     

Clinical evaluation of peginterferon α plus ribavirin for patients co-infected with HIV and HCV at Nagoya Medical Center

At Nagoya Medical Center, 10 patients co-infected with HIV and HCV received peginterferon α (PEG-IFNα) plus ribavirin therapy. Three of the cases were HCV genotype 1b, 2 cases were HCV 3b, and 1 case each were 2b, 2c, 3a, 4a and 6n. Nine patients received anti HIV therapy from the beginning. In 5 of these patients, anti HIV therapy was modified when PEG-IFNα plus ribavirin treatment was started. Of the above, 7 patients completed the protocol. No patients had severe adverse effects. Sustained virological response was achieved in 1 of 4 (25%) of the patients with genotypes 1 or 4, and in 5 of 6 (83%) of the patients with other genotypes. PEG-IFNα plus ribavirin therapy is considered a safe and efficacious treatment for patients co-infected with HIV and HCV.     

Mechanisms underlying the modulation of L-type Ca2+ channel by hydrogen peroxide in guinea pig ventricular myocytes

Although Cav1.2 Ca²⁺ channels are modulated by reactive oxygen species (ROS), the underlying mechanisms are not fully understood. In this study, we investigated effects of hydrogen peroxide (H₂O₂) on the Ca²⁺ channel using a patch-clamp technique in guinea pig ventricular myocytes. Externally applied H₂O₂ (1 mM) increased Ca²⁺ channel activity in the cell-attached mode. A specific inhibitor of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) KN-93 (10 μM) partially attenuated the H₂O₂-mediated facilitation of the channel, suggesting both CaMKII-dependent and -independent pathways. However, in the inside-out mode, 1 mM H₂O₂ increased channel activity in a KN-93-resistant manner. Since H₂O₂-pretreated calmodulin did not reproduce the H₂O₂ effect, the target of H₂O₂ was presumably assigned to the Ca²⁺ channel itself. A thiol-specific oxidizing agent mimicked and occluded the H₂O₂ effect. These results suggest that H₂O₂ facilitates the Ca²⁺ channel through oxidation of cysteine residue(s) in the channel as well as the CaMKII-dependent pathway.     

A recommendation on the basis of long-term follow-up resultsof our microvascular decompression operation for hemifacial spasm

Background

Microvascular decompression (MVD) for hemifacial spasm (HFS) has been popular, but it may take enough time to master this special operative technique and procedure. This may induce uneven distribution of the number of MVD operations in each institute, possibly resulting in an overall unsatisfactory quality of MVD surgeons. Nakanishi’s approach to MVD operations has the feature of using a, “supine, no retractor” technique, which would achieve various benefits for patients and medical professionals. We would like to recommend this approach for MVD surgeons on the basis of our follow-up outcomes.

Methods

A questionnaire, which was based on the method of evaluation for the long-term results of post-MVD operation as recommended by the Japanese Society of MVD, was sent by mail to the 154 HFS patients who had received Nakanishi’s approach at our hospital.

Results

Except for 42 patients who had changed their residences, 89 patients (79.5 % of 112) fully answered. The mean postoperative follow-up term was 13.0 years. The 76.4 % of the patients was estimated as excellent. Postoperative deafness was not present. The average value of satisfaction degree for the results of the MVD operation was 87.9 %.

Conclusions

This study revealed that Nakanishi’s approach produced good results equivalent of other approaches for HFS patients. This approach is considered to have many advantages comparing to the other approaches. Therefore, we would like to recommend that Nakanishi’s approach would contribute to overall advancement of the level of MVD surgeons.     

Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis

Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-α-induced adipose-related protein (TIARP), plays a role in tumor necrosis factor (TNF)-dependent arthritis models. However, its role in rheumatoid arthritis (RA) is still obscure. This study explored such a role for STEAP4. The expressions of STEAP4, TNFα, and IL-6 were compared in synovia of RA and osteoarthritis patients. STEAP4 induction was examined in TNFα-stimulated fibroblast-like synoviocytes (FLS) in vitro. FLS (with/without TNFα stimulation) were also analyzed for IL-6 expression after STEAP4 knockdown, using siRNA or transfection with STEAP4-plasmid DNA. IL-8, cell proliferation, and apoptosis were also evaluated in STEAP4-overexpressing FLS. The expression of STEAP4 in joints correlated with TNFα expression, specifically in RA synovium. In the cultured FLS, STEAP4 protein expression was augmented by TNFα activation, and localized in endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3. The results indicated that human STEAP4 is regulated by TNFα in synovium, where it controls IL-6 secretion and proliferation of FLS, suggesting that STEAP4 might potentially suppress the pathogenesis of TNFα-induced arthritis such as RA.     

Case with metastatic cutaneous malignant melanoma that developed Vogt–Koyanagi–Harada-like uveitis following pembrolizumab treatment

Documenta Ophthalmologica - The study reports a case with metastatic cutaneous malignant melanoma that developed Vogt–Koyanagi–Harada-like uveitis during pembrolizumab treatment. The...     

Elucidation of the electron energy structure of TiO2(B) and anatase photocatalysts through analysis of electron trap density

A clear understanding of the electron energy structure of TiO₂(B)/anatase is needed to study the related catalytic reactions and design new composite photocatalysts. In this study, the electron energy structures of TiO₂(B) and anatase were estimated by analyzing the energy-resolved distribution of electron traps measured by reversed double-beam photoacoustic spectroscopy. In the mixture of TiO₂(B) and anatase, interfacial charge-transfer excitation from anatase to electron traps of TiO₂(B) was suggested. By analyzing this for TiO₂(B), the electron level with a relatively high density of states was found to be located ∼0.07 eV deeper than that for anatase. Furthermore, a similar electron energy structure was suggested for a composite photocatalyst having a mixed phase of TiO₂(B) and anatase.

The electron energy structures of TiO₂(B) and anatase were estimated by analyzing the energy-resolved distribution of electron traps.