Alterations to the Gastrointestinal Microbiome Associated with Methamphetamine Use among Young Men who have Sex with Men.

Methamphetamine (MA) use is a major public health problem in the United States, especially among people living with HIV (PLWH). Many MA-induced neurotoxic effects are mediated by inflammation and gut microbiota may play a role in this process, yet the effects of MA on the microbiome have not been adequately explored. Therefore, we performed 16S rRNA gene sequencing on rectal swab samples from 381 men who have sex with men, 48% of whom were PLWH and 41% of whom used MA. We compared microbiome composition between MA users and non-users while testing for potential interactions with HIV and controlling for numerous confounders using inverse probability of treatment weighting. We found that MA use explained significant variation in overall composition (R2 = 0.005, p = 0.008) and was associated with elevated Finegoldia, Parvimonas, Peptoniphilus, and Porphyromonas and reduced Butyricicoccus and Faecalibacterium, among others. Genera including Actinomyces and Streptobacillus interacted with HIV status, such that they were increased in HIV+ MA users. Finegoldia and Peptoniphilus increased with increasing frequency of MA use, among others. In summary, MA use was associated with a microbial imbalance favoring pro-inflammatory bacteria, including some with neuroactive potential and others that have previously been associated with poor HIV outcomes

Evaluation of histopathological on maedi disease with serological confirmation in North-East of Iran

BACKGROUND: The described pulmonary lesions are compatible with lesions previously described for maedi. In this study, one of the most important ovine slow viral infections is "Maedi disease" which was evaluated in Mashhad province. METHODS: During the study, ovine lung samples from 170 sheep (>1 year old) with their serum samples were collected in the Mashhad industrial abattoir. Initially, histopathological study for lung samples was carried out by providing H&E staining, serological test and an indirect ELISA on the serum samples. Histopathological study indicated all three lesions of Maedi disease in ovine lung which included smooth muscle hyperplasia (SMH) of alveolar walls, lymphofollicular hyperplasia (LFH) and interstitial pneumonia (IP). Furthermore, some involvement of each lung sample was estimated from mild-moderate and severe. RESULTS AND DISCUSSION: Results of histopathological study demonstrated 45 cases (26.5%) and 15 cases (8.8%) with moderate degree and severe degree of involvement respectively. Liked-maedi disease included 60 cases (35.3%) of the whole ovine lung samples. Results of serological study showed 34 positive serums (20.0%). In addition, 15 cases (8.8%) of pulmonary lesions which were observed in histopathological study were equal and similar to the lesions previously described for maedi disease, and serological results confirmed them as well. However, there are some pathogens that can cause nearly pathological lesions like maedi in ovine lung. CONCLUSION: This study showed that the pathogen causing maedi disease (maedi-visna virus) can be one of the pathogens causing chronic to subacute lymphoid interstitial pneumonia in Iran. Thus, study on histopathological and serological results correlation was performed.Farhang Sasani, Javad Javanbakht, Farhid Hemmatzadeh, Mehdi R. Moghadam and Mehdi A. Mohammad Hassa

Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces

TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5αrh) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5αrh containing coiled-coil and SPRY domains (CC-SPRYrh). Concentration-dependent binding of CC-SPRYrh to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRYrh, but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5αrh on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction. © 2011 Zhao et al

Cost-Effectiveness Analysis of a Medial Meniscus Replacement Prosthesis for the Treatment of Patients with Medial Compartment Pain in the United Kingdom.

BACKGROUND: The most common intra-articular knee injury is a meniscal tear, which commonly occurs secondary to trauma following twisting or hyperflexion. Treatment options for meniscal tears can either be surgical or non-surgical, and range from rest, exercise, bracing and physical therapy to surgical intervention, including meniscal repair and partial meniscectomy. In patients with persistent pain following loss of meniscus tissue, treatment can include partial replacement or meniscal allograft transplantation. The NUsurface® prosthesis has been developed as a treatment option for patients experiencing persistent knee pain post medial meniscus (MM) surgery. OBJECTIVE: The aim of this study was to assess the cost effectiveness of MM replacement using NUsurface for the treatment of patients with medial compartment pain following previous partial medial meniscectomy, from a UK health service perspective. METHODS: An economic decision-analytic model was developed to assess the cost per quality-adjusted life-year (QALY) gained associated with the introduction of MM replacement using NUsurface compared with non-surgical standard of care, over a lifetime time horizon. The model structure was primarily informed by a previous clinical trial (VENUS) and was developed based on the clinical pathways typically followed by patients with this condition, with treatment pathways and probabilities of clinical progression adjusted depending on whether patients were receiving the intervention or undergoing current practice. A hypothetical cohort of adult patients (mean age of 50 years) was modelled, with clinical data sourced from the VENUS study as well as relevant UK literature. Both deterministic and probabilistic sensitivity analyses were carried out to explore uncertainty in the model results. RESULTS: The base-case probabilistic results indicate that MM replacement using NUsurface is likely to be cost effective across a range of willingness-to-pay (WTP) thresholds (95% probability of being cost effective at the National Institute for Health and Care Excellence (NICE)-recommended £20,000 WTP threshold). Although per-patient costs increase, QALYs are also gained, with the incremental cost per QALY (probabilistic value = £5011) being below £20,000. Deterministic sensitivity analyses indicate that the parameters that have the greatest impact on results are the failure rate in the control group (current practice), utility scores, and the cost of undergoing MM replacement using NUsurface. CONCLUSIONS: Based on the analysis presented, MM replacement with the NUsurface prosthetic implant is likely to be a cost-effective use of UK health care service resources compared with current standard care

Effects of human TRIM5α polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection

AbstractTRIM5α acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5α on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5α 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5α 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5α R136 protein. The 43Y variant of TRIM5α was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts

Vitamin D and antimicrobial peptide levels in patients with atopic dermatitis and atopic dermatitis complicated by eczema herpeticum: A pilot study.

In this study, Vitamin D supplementation results in improved clinical severity of atopic dermatitis and increased skin surface LL-37 levels, analyzed by a novel, non-invasive method. Vitamin D supplementation could be a therapeutic option in AD

Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: re-modelling of antiviral and regulatory mediators

Background & Aims: GS‐9688 (selgantolimod) is a toll‐like receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been evaluated in vitro in hepatitis B virus (HBV)‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators. Approach & Results: We characterised the effect of GS‐9688 on immune cell subsets in vitro in PBMC of healthy controls and CHB patients. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and CHB patients. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T‐cells (MAITs), CD4+ follicular helper T‐cells (TFH) and, in ~50% of patients, HBV‐specific CD8+T‐cells expressing interferon‐γ (IFNγ). Moreover, in vitro stimulation with GS‐9688 induced NK cell expression of IFNγ and TNFα and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4+ regulatory T‐cells and monocytic myeloid‐derived suppressor cells (MDSC). Residual MDSC expressed higher levels of negative immune regulators, galectin‐9 and PD‐L1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand+ (TRAIL) regulatory NK cells and degranulation of arginase‐I+ polymorphonuclear‐MDSC (PMN‐MDSC). Conclusions: GS‐9688 induces cytokines in human PBMC that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8+T‐cells, TFH, NK cells and MAITs). Whilst reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimise the antiviral efficacy of GS‐9688

Retraction note: Cutaneous mast cell tumor (Mastocytoma): Cyto-histopathological and haematological investigations Diagn Pathol., 9 (2014) (9)

The Editor-in-Chief and Publisher have retracted this article 1 because the scientific integrity of the content cannot be guaranteed. An investigation by the Publisher found it to be one of a group of articles we have identified as showing evidence suggestive of attempts to subvert the peer review and publication system to inappropriately obtain or allocate authorship. This article showed evidence of plagiarism (most notably from the articles cited 2-7) and peer review and authorship manipulation. © The Author(s). 2016

TRIM5α Modulates Immunodeficiency Virus Control in Rhesus Monkeys

The cytoplasmic TRIM5α proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5α proteins of the natural hosts. To address whether TRIM5α contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5α cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5α B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5α in limiting the replication of an immunodeficiency virus infection in a primate host