Autoimmune hepatitis: clinical experience after liver transplantation and molecular study using surface plasmon resonance imaging-based strategy

De novo autoimmune hepatitis in patients with HCV recurrence (HCV-R) after liver transplantation (LT) is of challenging diagnosis and the impact of autoimmune therapy (AT) is still a matter of debate. In the first part of this work the aim was to evaluate clinical, serological, histological characteristics of these patients and the impact of AT. Patients have been evaluated in two European transplant centers .Liver biopsies were retrospectively by experts pathologists. Three parameters, plasma cells infiltrate, interface hepatitis and central vein necrosis, were evaluated applying a new semi-quantitative method. Final diagnosis was of prevalent viral lesions: HCV-R, or prevalent immunological lesions: AIH. Forty patients, transplanted between 1983-2009, were included, 16 (40%) patients were HCV-R and 24 (60%) AIH. High grade of interface hepatitis and confluent central vein necrosis were significantly more represented in AIH patients, moreover AST/ALT were significantly higher in AIH group (p=0.05 and p=0.003, respectively). No difference was found regarding baseline immunosuppression, autoantibodies and gammaglobulin levels. No relationship between HCV antiviral therapy and AIH was observed. Ten years survival was lower for AIH compared to HCVâR patients (65%, versus 93%, p=0.050). The AT improved the cytolysis but did not modify long-term survival (50% treated versus 87.5% non treated patients, p=ns), which was impaired by severe HCV disease progression. Anti-dsDNA autoantibodies (Abs) are highly diagnostic for systemic lupus erythematosus (SLE), however, they can be found in autoimmune hepatitis (AIH) but it remains uncertain which antigen triggers the production of these antibodies. Moreover the characteristics of antigenâantibodies interaction are still a matter of concern. In the second part of this work the aim was to differentiate the binding characteristics of dsDNA and anti-dsDNA Abs obtained from AIH and SLE patient's sera using Surface Plasmon Resonance imaging (SPRi) strategy. Sera from AIH (n=14), SLE patients (n= 7) with anti-dsDNA Abs positive Farr test, as well as from healthy controls (n= 7) were collected. IgGs and IgMs were purified from sera. Ten different types of oligonucleotides (OG) were spotted over the chip surface of SPRi. Kinetic SPRi study was also performed. All sera from both patients and controls showed a reactivity signal on SPRi, nevertheless when monoclonal mouse anti-IgGs were injected after the sera injection, only for AIH patients the signal was still evident, being lower for SLE patients and controls. When purified IgGs from sera were injected an interaction signal with OG was observed only for AIH patients. Mean IgGs koff were comparable among patients, meaning they have the same dissociation kinetic. SPRi method identifies interactions between sera from AIH, SLE patients and controls and dsDNA of OG used. However using purified IgGs a binding signal is observed only for AIH. These results suggest that immunocomplex found in AIH and SLE patients are different, in SLE patients the complex might require a third partner, or probably, recognize a specific dsDNA conformation. Results from our work suggest that new promising methods can be applied both in clinical and laboratory field for the comprehension and monitoring of autoimmune hepatitis

Direct-Coupling Analysis of nucleotide coevolution facilitates RNA secondary and tertiary structure prediction

Despite the biological importance of non-coding RNA, their structural characterization remains challenging. Making use of the rapidly growing sequence databases, we analyze nucleotide coevolution across homologous sequences via Direct-Coupling Analysis to detect nucleotide-nucleotide contacts. For a representative set of riboswitches, we show that the results of Direct-Coupling Analysis in combination with a generalized Nussinov algorithm systematically improve the results of RNA secondary structure prediction beyond traditional covariance approaches based on mutual information. Even more importantly, we show that the results of Direct-Coupling Analysis are enriched in tertiary structure contacts. By integrating these predictions into molecular modeling tools, systematically improved tertiary structure predictions can be obtained, as compared to using secondary structure information alone.Comment: 22 pages, 8 figures, supplemental information available on the publisher's webpage (http://nar.oxfordjournals.org/content/early/2015/09/29/nar.gkv932.abstract

Use of benzylglycinamide by a HIV-seropositive polysubstance user: : the changing pattern of novel psychoactive substance use among youths

This document is the Accepted Manuscript of the following article: Matteo Caloro, et al, ‘Use of benzylglycinamide by a HIV-seropositive polysubstance user: The changing pattern of novel psychoactive substance use among youths’, Addictive Behaviors, Vol. 60, pp. 53-57, September 2016. The Version of Record is available online at doi: https://doi.org/10.1016/j.addbeh.2016.03.032. © 2016 Elsevier Ltd. All rights reserved.A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with psychosis, agitation, and insomnia at the emergency department of a university hospital. She had been abusive and physically aggressive frequently without specific reasons and was involved in criminal legal cases. She was hospitalized twice. During her first hospital stay she experienced a brief episode of detachment from her environment, similar to episodes reportedly suffered at home. Psychosis had developed following heavy polysubstance abuse. Her mother provided sachets containing benzylglycinamide, a substance with no known psychotropic effects, which were also present in the patient's urine. She was occasionally positive for cannabinoids. She used to buy various novel psychoactive substances (NPSs) from the internet and used experimentally various substances freely made available to her by drug suppliers/dealers. She was unable to explain clearly why she was taking any of the identified NPS. She stated she was taking benzylglycinamide to calm her when smoking synthetic cannabinoids. While it appears that benzylglycinamide is not likely to constitute a novel drug of abuse, her polysubstance use exemplifies trends in NPS use patterns among the youths in the Western world and should alert mental health workers as to the possible dangers of such behavior and its reflection on social behavior and psychopathology.Peer reviewedFinal Accepted Versio

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

BACKGROUND AND AIMS There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. METHODS Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). RESULTS 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. CONCLUSION Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response

Transmembrane protein TMEM230, regulator of metalloproteins and motor proteins in gliomas and gliosis

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis

Identification of vehicle related risk factors, deliverable 6.1 of the H2020 project SafetyCube

The present Deliverable (D6.1) describes the identification and evaluation of vehicle related risk factors. It outlines the results of Task 6.1 of Work Package 6 (WP6) of SafetyCube, which aimed to identify and evaluate vehicle related risk factors and related road safety problems by (i) presenting a taxonomy of vehicle related risks, (ii) identifying “hot topics” of concern for relevant stakeholders and (iii) evaluating the relative importance for road safety outcomes (crash risk, crash frequency and severity etc.) within the scientific literature for each identified risk factor. To reach this objective, Task 6.1 has initially exploited current knowledge (e.g. existing studies) and existing accident data (macroscopic and in-depth) in order to quantify scenarios (defined in Work Package 8) related to the vehicle element. This information will help further on in WP6 to identify countermeasures for addressing these risk factors and finally to undertake an assessment of the effects of these countermeasures (...continues)

A lanthanide-rich kilonova in the aftermath of a long gamma-ray burst

Kilonovae are a rare class of astrophysical transients powered by the radioactive decay of nuclei heavier than iron, synthesized in the merger of two compact objects. Over the first few days, the kilonova evolution is dominated by a large number of radioactive isotopes contributing to the heating rate. On timescales of weeks to months, its behavior is predicted to differ depending on the ejecta composition and merger remnant. However, late-time observations of known kilonovae are either missing or limited. Here we report observations of a luminous red transient with a quasi-thermal spectrum, following an unusual gamma-ray burst of long duration. We classify this thermal emission as a kilonova and track its evolution up to two months after the burst. At these late times, the recession of the photospheric radius and the rapidly-decaying bolometric luminosity ($L_{\rm bol}\propto t^{-2.7\pm 0.4}$) support the recombination of lanthanide-rich ejecta as they cool.Comment: 47 pages, 14 figures, 9 tables; submitted; a minor typo fixe

Methodological issues associated with collecting sensitive information over the telephone - experience from an Australian non-suicidal self-injury (NSSI) prevalence study

<p>Abstract</p> <p>Background</p> <p>Collecting population data on sensitive issues such as non-suicidal self-injury (NSSI) is problematic. Case note audits or hospital/clinic based presentations only record severe cases and do not distinguish between suicidal and non-suicidal intent. Community surveys have largely been limited to school and university students, resulting in little much needed population-based data on NSSI. Collecting these data via a large scale population survey presents challenges to survey methodologists. This paper addresses the methodological issues associated with collecting this type of data via CATI.</p> <p>Methods</p> <p>An Australia-wide population survey was funded by the Australian Government to determine prevalence estimates of NSSI and associations, predictors, relationships to suicide attempts and suicide ideation, and outcomes. Computer assisted telephone interviewing (CATI) on a random sample of the Australian population aged 10+ years of age from randomly selected households, was undertaken.</p> <p>Results</p> <p>Overall, from 31,216 eligible households, 12,006 interviews were undertaken (response rate 38.5%). The 4-week prevalence of NSSI was 1.1% (95% ci 0.9-1.3%) and lifetime prevalence was 8.1% (95% ci 7.6-8.6).</p> <p>Methodological concerns and challenges in regard to collection of these data included extensive interviewer training and post interview counselling. Ethical considerations, especially with children as young as 10 years of age being asked sensitive questions, were addressed prior to data collection. The solution required a large amount of information to be sent to each selected household prior to the telephone interview which contributed to a lower than expected response rate. Non-coverage error caused by the population of interest being highly mobile, homeless or institutionalised was also a suspected issue in this low prevalence condition. In many circumstances the numbers missing from the sampling frame are small enough to not cause worry, especially when compared with the population as a whole, but within the population of interest to us, we believe that the most likely direction of bias is towards an underestimation of our prevalence estimates.</p> <p>Conclusion</p> <p>Collecting valid and reliable data is a paramount concern of health researchers and survey research methodologists. The challenge is to design cost-effective studies especially those associated with low-prevalence issues, and to balance time and convenience against validity, reliability, sampling, coverage, non-response and measurement error issues.</p