Persistence of Hepatitis C RNA in Liver Allografts Is Associated with Histologic Progression Independent of Serologic Viral Clearance

Background. Hepatitis C virus (HCV) nondetectability in the liver may predict a sustained viral response (SVR) in patients with an end of treatment response. HCV RNA can be detected in liver tissue by in situ hybridization (ISH). Aim. To determine if HCV nondetectability in liver allografts by ISH can predict SVR in patients who cleared virus serologically on treatment. Methods. Twenty five patients with undetectable serum HCV on Interferon/Ribavirin therapy for HCV recurrence post liver transplant (LT) were studied. All had biopsies at 4 months post LT (baseline) and follow up with HCV ISH analysis performed. Results. 10 were ISH positive (group 1); 15 were ISH negative (group 2). Groups 1 and 2 had similar patient, donor, and viral characteristics at LT, as well as treatment duration at the time of the ISH assayed liver biopsy (13 ± 16 versus 10 ± 4 months P = .24). However, group 1 had longer total treatment duration (24 ± 10 versus 14 ± 5 months, P = .001). Eight (80%) group 1 and 9 (60%) group 2 patients achieved SVR. Mean grade and stage (modified Ishak score) were similar at 4 months, however, group 1 had higher grade (3 ± 1.7 versus 1.6 ± 1.3, P = .039) and stage (1.4 ± 1.4 versus 0.5 ± 0.6, P = .084) on the ISH assayed biopsy, after similar post LT intervals (23 ± 10 versus 24 ± 12 months, P = .91). Conclusion. Allograft HCV ISH nondetectability does not predict SVR in treatment responsive HCV recurrence, but is associated with less severe histologic disease

Cellular and humoral immune responses and protection against schistosomes induced by a radiation-attenuated vaccine in chimpanzees

The radiation-attenuated Schistosoma mansoni vaccine is highly effective in rodents and primates but has never been tested in humans, primarily for safety reasons. To strengthen its status as a paradigm for a human recombinant antigen vaccine, we have undertaken a small-scale vaccination and challenge experiment in chimpanzees (Pan troglodytes). Immunological, clinical, and parasitological parameters were measured in three animals after multiple vaccinations, together with three controls, during the acute and chronic stages of challenge infection up to chemotherapeutic cure. Vaccination induced a strong in vitro proliferative response and early gamma interferon production, but type 2 cytokines were dominant by the time of challenge. The controls showed little response to challenge infection before the acute stage of the disease, initiated by egg deposition. In contrast, the responses of vaccinated animals were muted throughout the challenge period. Vaccination also induced parasite-specific immunoglobulin M (IgM) and IgG, which reached high levels at the time of challenge, while in control animals levels did not rise markedly before egg deposition. The protective effects of vaccination were manifested as an amelioration of acute disease and overall morbidity, revealed by differences in gamma-glutamyl transferase level, leukocytosis, eosinophilia, and hematocrit. Moreover, vaccinated chimpanzees had a 46% lower level of circulating cathodic antigen and a 38% reduction in fecal egg output, compared to controls, during the chronic phase of infection

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Fusion between Leishmania amazonensis and Leishmania major Parasitophorous Vacuoles: Live Imaging of Coinfected Macrophages

Protozoan parasites of the genus Leishmania alternate between flagellated, elongated extracellular promastigotes found in insect vectors, and round-shaped amastigotes enclosed in phagolysosome-like Parasitophorous Vacuoles (PVs) of infected mammalian host cells. Leishmania amazonensis amastigotes occupy large PVs which may contain many parasites; in contrast, single amastigotes of Leishmania major lodge in small, tight PVs, which undergo fission as parasites divide. To determine if PVs of these Leishmania species can fuse with each other, mouse macrophages in culture were infected with non-fluorescent L. amazonensis amastigotes and, 48 h later, superinfected with fluorescent L. major amastigotes or promastigotes. Fusion was investigated by time-lapse image acquisition of living cells and inferred from the colocalization of parasites of the two species in the same PVs. Survival, multiplication and differentiation of parasites that did or did not share the same vacuoles were also investigated. Fusion of PVs containing L. amazonensis and L. major amastigotes was not found. However, PVs containing L. major promastigotes did fuse with pre-established L. amazonensis PVs. In these chimeric vacuoles, L. major promastigotes remained motile and multiplied, but did not differentiate into amastigotes. In contrast, in doubly infected cells, within their own, unfused PVs metacyclic-enriched L. major promastigotes, but not log phase promastigotes - which were destroyed - differentiated into proliferating amastigotes. The results indicate that PVs, presumably customized by L. major amastigotes or promastigotes, differ in their ability to fuse with L. amazonensis PVs. Additionally, a species-specific PV was required for L. major destruction or differentiation – a requirement for which mechanisms remain unknown. The observations reported in this paper should be useful in further studies of the interactions between PVs to different species of Leishmania parasites, and of the mechanisms involved in the recognition and fusion of PVs

A life-course and time perspective on the construct validity of psychological distress in women and men. Measurement invariance of the K6 across gender

<p>Abstract</p> <p>Background</p> <p>Psychological distress is a widespread indicator of mental health and mental illness in research and clinical settings. A recurrent finding from epidemiological studies and population surveys is that women report a higher mean level and a higher prevalence of psychological distress than men. These differences may reflect, to some extent, cultural norms associated with the expression of distress in women and men. Assuming that these norms differ across age groups and that they evolve over time, one would expect gender differences in psychological distress to vary over the life-course and over time. The objective of this study was to investigate the construct validity of a psychological distress scale, the K6, across gender in different age groups and over a twelve-year period.</p> <p>Methods</p> <p>This study is based on data from the Canadian National Population Health Survey (C-NPHS). Psychological distress was assessed with the K6, a scale developed by Kessler and his colleagues. Data were examined through multi-group confirmatory factor analyses. Increasing levels of measurement and structural invariance across gender were assessed cross-sectionally with data from cycle 1 (n = 13019) of the C-NPHS and longitudinally with cycles 1 (1994-1995), 4 (2000-2001) and 7 (2006-2007).</p> <p>Results</p> <p>Higher levels of measurement and structural invariance across gender were reached only after the constraint of equivalence was relaxed for various parameters of a few items of the K6. Some items had a different pattern of gender non invariance across age groups and over the course of the study. Gender differences in the expression of psychological distress may vary over the lifespan and over a 12-year period without markedly affecting the construct validity of the K6.</p> <p>Conclusions</p> <p>This study confirms the cross-gender construct validity of psychological distress as assessed with the K6 despite differences in the expression of some symptoms in women and in men over the life-course and over time. Findings suggest that the higher mean level of psychological distress observed in women reflects a true difference in distress and is unlikely to be gender-biased. Gender differences in psychological distress are an important public health and clinical issue and further researches are needed to decipher the factors underlying these differences.</p

Th17 Cytokines and the Gut Mucosal Barrier

Local immune responses serve to contain infections by pathogens to the gut while preventing pathogen dissemination to systemic sites. Several subsets of T cells in the gut (T-helper 17 cells, γδ T cells, natural killer (NK), and NK-T cells) contribute to the mucosal response to pathogens by secreting a subset of cytokines including interleukin (IL)-17A, IL-17F, IL-22, and IL-26. These cytokines induce the secretion of chemokines and antimicrobial proteins, thereby orchestrating the mucosal barrier against gastrointestinal pathogens. While the mucosal barrier prevents bacterial dissemination from the gut, it also promotes colonization by pathogens that are resistant to some of the inducible antimicrobial responses. In this review, we describe the contribution of Th17 cytokines to the gut mucosal barrier during bacterial infections

Organization of multiprotein complexes at cell–cell junctions

The formation of stable cell–cell contacts is required for the generation of barrier-forming sheets of epithelial and endothelial cells. During various physiological processes like tissue development, wound healing or tumorigenesis, cellular junctions are reorganized to allow the release or the incorporation of individual cells. Cell–cell contact formation is regulated by multiprotein complexes which are localized at specific structures along the lateral cell junctions like the tight junctions and adherens junctions and which are targeted to these site through their association with cell adhesion molecules. Recent evidence indicates that several major protein complexes exist which have distinct functions during junction formation. However, this evidence also indicates that their composition is dynamic and subject to changes depending on the state of junction maturation. Thus, cell–cell contact formation and integrity is regulated by a complex network of protein complexes. Imbalancing this network by oncogenic proteins or pathogens results in barrier breakdown and eventually in cancer. Here, I will review the molecular organization of the major multiprotein complexes at junctions of epithelial cells and discuss their function in cell–cell contact formation and maintenance

All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration < 1 s over the frequency band 64-5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc^3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range 5 10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see also the public announcement at http://www.ligo.org/science/Publication-S6BurstAllSky

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe