Vanishing bile duct syndrome in human immunodeficiency virus infected adults:A report of two cases

Vanishing bile duct syndrome(VBDS) is a group of rare disorders characterized by ductopenia,the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis.Described in association with medications,autoimmune disorders,cancer,transplantation,and infections,the specific mechanisms of disease are not known.To date,only 4 cases of VBDS have been reported in human immunodeficiency virus(HIV) infected patients.We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases.Presentation includes hyperbilirubinemia,normal liver imaging,and negative viral and autoimmune hepatitis studies.In HIV-infected subjects,VBDS occurred at a range of CD4+ T-cell counts,in some cases following initiation or change in antiretroviral therapy.Lymphoma was associated with two cases;nevirapine,antibiotics,and viral co-infection were suggested as etiologies in the other cases.In HIV-positive patients with progressive cholestasis,early identification of VBDS and referral for transplantation may improve outcomes.

Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

Fecal microbiota transplantation(FMT)is a successful method for treating recurrent Clostridioides difficile(C.difficile)infection(rCDI)with around 90%efficacy.Due to the relative simplicity of this approach,it is being widely used and currently,thousands of patients have been treated with FMT worldwide.Nonetheless,the mechanisms underlying its effects are just beginning to be understood.Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C.difficile,but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids.Moreover,the modulation of the strong inflammatory response triggered by C.difficile after FMT seems to rely on a pivotal role of regulatory T cells,which would be responsible for the reduction of several cells and soluble inflammatory mediators,ensuing normalization of the intestinal mucosal immune system.In this minireview,we analyze recent advances in these immunological aspects associated with the efficacy of FMT.

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment

AIM To study impact of baseline mental health disease on hepatitis C virus(HCV) treatment; and Beck's Depression Inventory(BDI) changes with sofosbuvir- andinterferon-based therapy.METHODS This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and na?ve to HCV therapy. Two of the studies included HCV mono-infected participants only(SPARE, SYNERGY-A), and 3 included human immunodeficiency virus(HIV)/HCV co-infected participants only(ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon(IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease(MHD) were identified(defined as either a DSM Ⅳ diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response(SVR) and adherence(pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher's Exact, and t-test with significance defined as a P value less than 0.05.RESULTS Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without(SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment(P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon(sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral(DAA)-based therapy, mean BDI scores decreased from 5.24(pre-treatment) to 3.28 during treatment(1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant(-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDIscore increased from 6.96 at pre-treatment to 9.19 during treatment(an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment(mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant(-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR(-2.0 and +4.36, respectively; P = 0.0004).CONCLUSION Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.

结核感染若干年后特异性γ-干扰素应答减弱

假设:随着时间的流逝,结核感染者记忆性T细胞对特异性抗原的应答减弱。背景:很多证据表明特异性全血γ-干扰素(IFN-γ)检测试验Quanti-FERON-TB Gold (QFT-G)能够检测出近期结核感染者,并具有较高的灵敏度和特异性。目的:我们应用此项技术检测日本一个社区的成人群体以确定其流行病学应用价值。方法:1559例参加定期体检的健康志愿者入选本研究。结果:40～49岁人群QFT-G的阳性率为3.1%,50～59岁人群的阳性率为5.9%,60～69岁人群的阳性率为9.8%。作者根据一系列研究估计40～49岁、50～59岁、60～69岁的预期结核感染率分别为11.1%、29.6%、53.1%。预期阳性率与实际阳性率之间存在的巨大差异提示结核感染后随着时间的延长IFN-γ应答减弱。那些经胸部X线证实存在陈旧性结核病灶者阳性率大大低于100%。结论:特异性IFN-γ应答可能在结核感染后随着时间的推移大大地减弱。需要在感染者中长期地纵向研究细胞介导的免疫动力学。

Physalin B reduces Aβ secretion through down-regulation of BACE1 expression by activating FoxO1 and inhibiting STAT3 phosphorylation

Physalin B(PB),one of the major active steroidal constituents of Solanaceae Physalis plants,has a wide variety of biological activities.We found that PB significantly down-regulatedβ-amyloid(Aβ)secretion in N2a/APPsw cells.However,the underlying mechanisms are not well understood.In the current study,we investigated the changes in key enzymes involved inβ-amyloid precursor protein(APP)metabolism and other APP metabolites by treating N2a/APPsw cells with PB at different concentrations.The results indicated that PB reduced Aβ secretion,which was caused by down-regulation of β-secretase(BACE1)expression,as indicated at both the protein and mRNA levels.Further research revealed that PB regulated BACE1 expression by inducing the activation of forkhead box O1(FoxO1)and inhibiting the phosphorylation of signal transducer and activator of transcription 3(STAT3).In addition,the effect of PB on BACE1 expression and Aβsecretion was reversed by treatment with FoxO1 siRNA and STAT3 antagonist S3I-201.In conclusion,these data demonstrated that PB can effectively down-regulate the expression of BACE1 to reduce Aβsecretion by activating the expression of FoxO1 and inhibiting the phosphorylation of STAT3.

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B （NF-κB）, a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-κB activation in inflammatory bowel diseases （IBDs） increases risk of colorectal cancer （CRC） in the patients with the number of years of active disease. NF-κB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-κB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation （Cyclin D1）, angiogenesis （VEGF, IL-8, COX2）, and metastasis （MMP9）. These findings implicate NF-κB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-r,B subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-κB family, it will be a long time before the coming of targeting NF-κB in CRC therapy.