Lithium in strong magnetic fields

The electronic structure of the lithium atom in a strong magnetic field 0 <= gamma <= 10 is investigated. Our computational approach is a full configuration interaction method based on a set of anisotropic Gaussian orbitals that is nonlinearly optimized for each field strength. Accurate results for the total energies and one-electron ionization energies for the ground and several excited states for each of the symmetries ^20^+, ^2(-1)^+, ^4(-1)^+, ^4(-1)^-, ^2(-2)^+, ^4(-2)^+, $^4(-3)^{+}$ are presented. The behaviour of these energies as a function of the field strength is discussed and classified. Transition wave lengths for linear and circular polarized transitions are presented as well.Comment: 12 pages, 13 figures, accepted for publication in Phys. Rev.

Predictors of in-hospital mortality and complications in very elderly patients undergoing emergency surgery

INTRODUCTION: With the increasing aging population demographics and life expectancies the number of very elderly patients (age ≥ 80) undergoing emergency surgery is expected to rise. This investigation examines the outcomes in very elderly patients undergoing emergency general surgery, including predictors of in-hospital mortality and morbidity. METHODS: A retrospective study of patients aged 80 and above undergoing emergency surgery between 2008 and 2010 at a tertiary care facility in Canada was conducted. Demographics, comorbidities, surgical indications, and perioperative risk assessment data were collected. Outcomes included length of hospitalization, discharge destination, and in-hospital mortality and morbidity. Multivariable logistic regression was used to identify predictors of in-hospital mortality and complications. RESULTS: Of the 170 patient admissions, the mean age was 84 years and the in-hospital mortality rate was 14.7%. Comorbidities were present in 91% of this older patient population. Over 60% of the patients required further services or alternate level of care on discharge. American Society of Anesthesiologist Physical Status (ASA) Classification (OR 5.30, 95% CI 1.774-15.817, p = 0.003) and the development of an in-hospital complications (OR 2.51, 95% CI 1.210-5.187, p = 0.013) were independent predictors of postoperative mortality. Chronological age or number of comorbidities was not predictive of surgical outcome. CONCLUSIONS: Mortality, complication rates and post-discharge care requirements were high in very elderly patients undergoing emergency general surgery. Advanced age and medical comorbidities alone should not be the limiting factors for surgical referral or treatment. This study illustrates the importance of preventing an in-hospital complication in this very vulnerable population. ASA class is a robust tool which is predictive of mortality in the very elderly population and can be used to guide patient and family counseling in the emergency setting

Phase-resolved HST/STIS spectroscopy of the exposed white dwarf in the high-field polar AR UMa

Phase-resolved HST/STIS ultraviolet spectroscopy of the high-field polar AR UMa confirms that the WD photospheric Ly alpha Zeeman features are formed in a magnetic field of ~200 MG. In addition to the Ly alpha pi and sigma+ components, we detect the forbidden hydrogen 1s0->2s0 transition, which becomes ``enabled'' in the presence of both strong magnetic and electric fields. Our attempt in fitting the overall optical+UV low state spectrum with single temperature magnetic WD models remains rather unsatisfactory, indicating either a shortcoming in the present models or a new physical process acting in AR UMa. As a result, our estimate of the WD temperature remains somewhat uncertain, Twd=20000+-5000K. We detect a broad emission bump centered at ~1445A and present throughout the entire binary orbit, and a second bump near ~1650A, which appears only near the inferior conjunction of the secondary star. These are suggestive of low harmonic cyclotron emission produced by low-level (M-dot~1e-13 Msun/yr) accretion onto both magnetic poles. However, there is no evidence in the power spectrum of light variations for accretion in gas blobs. The observed Ly alpha emission line shows a strong phase dependence with maximum flux and redshift near orbital phase phi~0.3, strongly indicating an origin on the trailing hemisphere of the secondary star. An additional Ly alpha absorption feature with similar phasing as the Ly alpha emission, but a \~700km/s blueshift could tentatively be ascribed to absorption of WD emission in a moderately fast wind. We derive a column density of neutral hydrogen of NH=(1.1+-1.0)1e18 cm**-2, the lowest of any known polar.Comment: 26 pages, 10 figures, AAS TeX 5.0, accepted for publication in the Astrophysical Journa

Anti-Hepatitis C virus T-Cell immunity in the context of multiple exposures to the virus

Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype-specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T-cell targets, and their adapted form, were used in individualised IFN-γ ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV-seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV-infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design

New Low Accretion-Rate Magnetic Binary Systems and their Significance for the Evolution of Cataclysmic Variables

Discoveries of two new white dwarf plus M star binaries with striking optical cyclotron emission features from the Sloan Digital Sky Survey (SDSS) brings to six the total number of X-ray faint, magnetic accretion binaries that accrete at rates < 10^{-13} Msun/yr, or <1% of the values normally encountered in cataclysmic variables. This fact, coupled with donor stars that underfill their Roche lobes and very cool white dwarfs, brand the binaries as post common-envelope systems whose orbits have not yet decayed to the point of Roche-lobe contact. They are pre-magnetic CVs, or pre-Polars. The systems exhibit spin/orbit synchronism and apparently accrete by efficient capture of the stellar wind from the secondary star, a process that has been dubbed a ``magnetic siphon''. Because of this, period evolution of the binaries will occur solely by gravitational radiation, which is very slow for periods >3 hr. Optical surveys for the cyclotron harmonics appear to be the only means of discovery, so the space density of pre-Polars could rival that of Polars, and the binaries provide an important channel of progenitors (in addition to the asynchronous Intermediate Polars). Both physical and SDSS observational selection effects are identified that may help to explain the clumping of all six systems in a narrow range of magnetic field strength around 60 MG.Comment: 25 pages, 13 figures, Accepted to Ap

Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice

OBJECTIVE: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS: Although treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity. CONCLUSIONS: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease

Protection of pancreatic INS-1 β-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin

Hyperglycemia is detrimental to β-cell viability, playing a major role in the progression of β-cell loss in diabetes mellitus. The permeability transition pore (PTP) is a mitochondrial channel involved in cell death. Recent evidence suggests that PTP inhibitors prevent hyperglycemia-induced cell death in human endothelial cells. In this work, we have examined the involvement of PTP opening in INS-1 cell death induced by high levels of glucose or fructose. PTP regulation was studied by measuring the calcium retention capacity in permeabilized INS-1 cells and by confocal microscopy in intact INS-1 cells. Cell death was analyzed by flow cytometry. We first reported that metformin and cyclosporin A (CsA) prevented Ca2+-induced PTP opening in permeabilized and intact INS-1 cells. We then showed that incubation of INS-1 cells in the presence of 30 mM glucose or 2.5 mM fructose induced PTP opening and led to cell death. As both metformin and CsA prevented glucose- and fructose- induced PTP opening, and hampered glucose- and fructose- induced cell death, we conclude that PTP opening is involved in high glucose- and high fructose- induced INS-1 cell death. We therefore suggest that preventing PTP opening might be a new approach to preserve β-cell viability

Evidence of CD4+ T cell-mediated immune pressure on the Hepatitis C virus genome

Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8+ T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4+ T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4+ T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher’s exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4+ T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4+ T cell epitopes

Sequential Bottlenecks Drive Viral Evolution in Early Acute Hepatitis C Virus Infection

Hepatitis C is a pandemic human RNA virus, which commonly causes chronic infection and liver disease. The characterization of viral populations that successfully initiate infection, and also those that drive progression to chronicity is instrumental for understanding pathogenesis and vaccine design. A comprehensive and longitudinal analysis of the viral population was conducted in four subjects followed from very early acute infection to resolution of disease outcome. By means of next generation sequencing (NGS) and standard cloning/Sanger sequencing, genetic diversity and viral variants were quantified over the course of the infection at frequencies as low as 0.1%. Phylogenetic analysis of reassembled viral variants revealed acute infection was dominated by two sequential bottleneck events, irrespective of subsequent chronicity or clearance. The first bottleneck was associated with transmission, with one to two viral variants successfully establishing infection. The second occurred approximately 100 days post-infection, and was characterized by a decline in viral diversity. In the two subjects who developed chronic infection, this second bottleneck was followed by the emergence of a new viral population, which evolved from the founder variants via a selective sweep with fixation in a small number of mutated sites. The diversity at sites with non-synonymous mutation was higher in predicted cytotoxic T cell epitopes, suggesting immune-driven evolution. These results provide the first detailed analysis of early within-host evolution of HCV, indicating strong selective forces limit viral evolution in the acute phase of infection

FEM-based oxygen consumption and cell viability models for avascular pancreatic islets

<p>Abstract</p> <p>Background</p> <p>The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans) are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM) based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media.</p> <p>Methods</p> <p>Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration.</p> <p>Results</p> <p>Partial differential equation (PDE) based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 <it>μ</it>m diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations.</p> <p>Conclusion</p> <p>Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for non-vascularised islet and can lead to considerable cell death (necrosis), especially in the core region of larger islets. Such models are of considerable interest to improve the function and viability of cultured, transplanted, or encapsulated islets. The present implementation allows convenient extension to true multiphysics applications that solve coupled physics phenomena such as diffusion and consumption with convection due to flowing or moving media.</p