Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats.

Silibinin, a natural polyphenolic flavonoid, possesses anti-oxidant, anti-inflammation and anti-cancer properties. The present study was designed to investigate the effects of silibinin on rheumatoid arthritis (RA) pathogenesis-related cells and collagen-induced arthritis (CIA) and further explore the potential underlying mechanisms. Our results showed that silibinin suppressed cell viability and increased the percentage of apoptotic RA-fibroblast-like synoviocytes (FLS). Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model was effectively inhibited by silibinin. Silibinin also induced macrophage M2 polarization in RAW264.7 cells. We further demonstrated that silibinin inhibits Th17 cell differentiation in vitro. The nuclear factor kappa B (NF-κB) pathway was suppressed in RA-FLS. In addition, Sirtuin1 (SIRT1) was decreased after silibinin treatment, and RA-FLS transfection with a short hairpin RNA (shRNA) of SIRT1 enhanced silibinin-induced apoptosis. Autophagy was markedly decreased in a dose-dependent manner following silibinin treatment. These findings indicate that silibinin inhibited inflammation by inhibiting the NF-κB pathway, and SIRT1 may participate in silibinin-induced apoptosis. Silibinin also inhibited autophagy in RA-FLS. Thus, silibinin may be a potential therapeutic agent for the treatment of RA.

Development of a Chinese version of the Western Ontario Meniscal Evaluation Tool: cross-cultural adaptation and psychometric evaluation.

BACKGROUND: The Western Ontario Meniscal Evaluation Tool (WOMET) is a questionnaire designed to evaluate the health-related quality of life (HRQOL) of patients with meniscal pathology. Our study aims to culturally adapt and validate the WOMET into a Chinese version. METHODS: We translated the WOMET into Chinese. Then, a total of 121 patients with meniscal pathology were invited to participate in this study. To assess the test-retest reliability, the Chinese version WOMET was completed twice at 7-day intervals by the participants. The construct validity was assessed using Pearson's correlation coefficient or Spearman's correlation to test for correlations among the Chinese version WOMET and the eight domains of Short Form-36 (SF-36), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the International Knee Documentation Committee (IKDC) score. Responsiveness was tested by comparison of the preoperative and postoperative scores of the Chinese version WOMET. RESULTS: The test-retest reliability of the overall scale and different domains were all found to be excellent. The Cronbach's α was 0.90. The Chinese version WOMET correlated well with other questionnaires which suggested good construct validity. We observed no ceiling and floor effects of the Chinese version WOMET. We also found good responsiveness for the effect size, and the standardized response mean values were 0.86 and 1.11. CONCLUSIONS: The Chinese version of the WOMET appears to be reliable and valid in evaluating patients with meniscal pathology.

Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks.

BACKGROUND: Tenofovir, particularly when given with a ritonavir-boosted protease inhibitor (rPI), reduces bone mineral density (BMD) and increases bone turnover markers (BTMs), both of which are associated with increased fracture risk. Raltegravir has not been associated with bone loss. METHODS: In an open-label, nonrandomized, pilot study, tenofovir was switched to raltegravir in adults also receiving a rPI for at least 6 months with a spine or hip T-score ≤ -1.0 and plasma HIV RNA < 50 HIV-1 RNA copies/mL for at least 3 months. The primary endpoint was BMD change by dual-energy X-ray absorptiometry. Student's paired t-test was used to compare continuous variables. Factors associated with BMD increase were assessed using linear regression. RESULTS: Thirty-seven patients were enrolled in the study: 97% were male, the mean age was 49 years, the mean T-scores were -1.4 (spine) and -1.3 (total left hip), and the mean tenofovir treatment duration was 3.1 years. BMD increases were significant at weeks 24 and 48. At week 48, spine BMD increased by 3.0% [95% confidence interval (CI) 1.9, 4.0%; P < 0.0001] and left total hip BMD increased by 2.5% (95% CI 1.6, 3.3%; P < 0.0001). BTMs (N-telopeptide, osteocalcin and bone alkaline phosphatase) all decreased significantly at week 24 (P ≤ 0.0017). There were no raltegravir-related serious or grade 3-4 adverse events. HIV viral load remained <50 copies/mL plasma on raltegravir/rPI therapy. CONCLUSIONS: Switching virologically suppressed HIV-infected adults with low BMD taking an rPI from tenofovir to raltegravir was safe and significantly improved hip and spine BMD and reduced markers of bone turnover over 48 weeks.

Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence.

OBJECTIVES: Three-drug nonoccupational post-exposure prophylaxis (NPEP) typically includes co-formulated emtricitabine-tenofovir (FTC-TDF) and a protease inhibitor. However, protease inhibitors can cause significant toxicities, can interact with prescribed and illicit drugs, and work late in the viral cycle. Agents that act before viral integration into host DNA may have efficacy advantages. Raltegravir (RAL) is a good candidate for NPEP as it has few side effects or drug interactions and acts prior to HIV integration. The objective of this study was to investigate the use of RAL in 3-drug NPEP in terms of safety, adherence and tolerability. METHODS: We evaluated 28 days of RAL-FTC-TDF treatment in 86 men and FTC-TDF treatment in 34 men eligible for three- and two-drug NPEP, respectively. We assessed adherence (compared between groups and with nonstudy controls) and clinical and adverse events at weeks 1, 2 and 4, and efficacy at week 12. Analyses were by intention to treat, excluding from the adherence analysis subjects who ceased NPEP because their source was HIV-uninfected. RESULTS: No participant became infected with HIV. For RAL-FTC-TDF and FTC-TDF, regimen completion rates were 92% and 91% and medication adherence rates were 89% and 90%, respectively. Eight (9%) RAL recipients developed mild myalgias, with four developing transient grade 4 elevations in creatine kinase (two developed both), all of which improved to grade 2 or less by week 4 without RAL discontinuation. Eight prescribed and 37 potential illicit drug interactions with a protease inhibitor were avoided by use of RAL. CONCLUSIONS: RAL-FTC-TDF is well tolerated as NPEP, results in high levels of adherence and avoids potential drug-drug interactions. Patients and clinicians should be aware of the potential for acute muscle toxicity when RAL is used as NPEP.

Anal intraepithelial neoplasia and squamous cell carcinoma in HIV-infected adults.

Anal cancer is one of the most common non-AIDS-defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV-infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV-related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV-infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV-infected adults.

Transmission of triple-class, drug-resistant HIV-1 in Australia.

We report the first two cases of transmitted triple-class, drug-resistant HIV-1 in Australia. Baseline testing of a newly diagnosed man showed four reverse transcriptase resistance mutations (affecting two drug classes) and six protease resistance mutations. A source patient was identified, and a likely second case newly infected 1 year later, suggesting sequential transmission. This raises therapeutic implications for the individual patients, as well as public health concerns.