On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3−/− mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustio

Do Predictors Exist for a Successful Withdrawal of Preoperative Prostaglandin E1 from Neonates with d-Transposition of the Great Arteries and Intact Ventricular Septum?

Prostaglandin E1 (PGE1) is given to neonates with d-transposition of the great arteries (d-TGA) to reduce cyanosis by reopening and maintaining the patency of the ductus arteriosus. To avoid side effects, this medication can be stopped for hemodynamically stable patients after balloon atrial septostomy (BAS). A consecutive series of neonates with d-TGA and an intact ventricular septum (IVS) presenting from 2000 through 2005 was analyzed retrospectively to search for side effects of PGE1 and to identify predictors for a safe preoperative withdrawal. The medication was stopped for hemodynamically stable patients with transcutaneous oxygen saturations higher than 80% after BAS and reinitiated for patients with an oxygen saturation lower than 65%. Patients successfully weaned were compared with those who had failed weaning in terms of atrial septal defect (ASD) size, ductus arteriosus size, and the transcutaneous oxygen saturation. Prostaglandin E1 was initiated for all 43 neonates with d-TGA. The median maintenance dose of PGE1 was 0.00625μg/kg/min (range, 0.00313-0.050μg/kg/min) for a median duration of 6days (range, 1-12days). For 16 patients, PGE1 was preoperatively withdrawn but then had to be reinitiated for 7 of the 16 patients. No predictors for a successful weaning of PGE1 were found based on ASD size, ductus arteriosus size, or oxygen saturation. The adverse effects of PGE1 were apnea in 10 patients and fever in 19 patients. Neither seizures nor necrotizing enterocolitis was documented. Prostaglandin E1 was successfully withdrawn for a minority of hemodynamically stable patients with d-TGA. No predictors for a successful weaning could be identified. Because apnea and fever are common side effects, withdrawal of PGE1 after BAS may improve patient safety and comfort. In this patient group, if PGE1 withdrawal was not well tolerated, it could be safely reinitiated. There were no serious side effects of PGE

Estimating the in vivo killing efficacy of cytotoxic T lymphocytes across different peptide-MHC complex densities

Cytotoxic T lymphocytes (CTLs) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. Recently developed experimental methods allow the estimation of the CTL's efficacy in detecting and clearing infected host cells. One method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. Surprisingly, killing efficacies measured by this method are often much higher than estimates obtained by other methods based on, for instance, the dynamics of escape mutations. In this study, we investigated what fraction of this variation can be explained by differences in peptide loads employed in in vivo killing assays. We addressed this question in mice immunized with lymphocytic choriomeningitis virus (LCMV). We conducted in vivo killing assays varying the loads of the immunodominant epitope GP33 on target cells. Using a mathematical model, we determined the efficacy of effector and memory CTL, as well as CTL in chronically infected mice. We found that the killing efficacy is substantially reduced at lower peptide loads. For physiological peptide loads, our analysis predicts more than a factor 10 lower CTL efficacies than at maximum peptide loads. Assuming that the efficacy scales linearly with the frequency of CTL, a clear hierarchy emerges among the groups across all peptide antigen concentrations. The group of mice with chronic LCMV infections shows a consistently higher killing efficacy per CTL than the acutely infected mouse group, which in turn has a consistently larger efficacy than the memory mouse group. We conclude that CTL killing efficacy dependence on surface epitope frequencies can only partially explain the variation in in vivo killing efficacy estimates across experimental methods and viral systems, which vary about four orders of magnitude. In contrast, peptide load differences can explain at most two orders of magnitude

Outcome of Biventricular Repair in Infants With Multiple Left Heart Obstructive Lesions

The decision to perform biventricular repair for infants with multiple obstructive or hypoplastic left heart lesions (LHL) and borderline left ventricle (LV) may be controversial. This study sought to assess the mortality and morbidity of patients with LHL after biventricular repair and to determine the growth of the left-sided cardiac structures. Retrospective analysis of 39 consecutive infants with LHL who underwent biventricular repair was performed. The median age at surgery was 7days (range 1-225days), and the median follow-up period was 34months (range 1-177months). Between diagnosis and the end of the follow-up period, the size of the aortic annulus (z-score −4.1±2.8 vs. −0.1±2.7) and the LV (LV end-diastolic diameter z-score −1.7±2.8 vs. 0.21±1.7) normalized. During the follow-up period, 23 patients required 39 reinterventions (62%) consisting of redo surgery for 21 patients (57%) and catheter-guided reinterventions for 8 patients (22%). At the end of the follow-up period, 25 of 34 patients were doing subjectively well; 10 children (29%) received cardiac medication; 12 (35%) presented with failure to thrive (weight ≤ P3) and 5 (15%) with pulmonary hypertension. The overall mortality rate was 13%. Biventricular repair for patients with multiple LHL results in sufficient growth of the left-sided cardiac structures. Nevertheless, residual or newly developing obstructive lesions and pulmonary hypertension are frequent, causing significant morbidity that requires reinterventio

Management and outcome of Ebstein's anomaly in children

Abstract Objectives To assess clinical presentation, treatment, and outcome of children with Ebstein's anomaly. Background Data on long-term outcome of children with Ebstein's anomaly are scarce. Methods Retrospective analysis of all children with Ebstein's anomaly treated between February, 1979 and January, 2009 in a single tertiary institution. Primary outcomes included patient survival and need for intervention, either cardiac surgery or catheter intervention. Results A total of 42 patients were diagnosed with Ebstein's anomaly at a median age of 5 days ranging from 1 day to 11.7 years. Symptoms included cyanosis, heart murmur, and/or dyspnoea. Associated cardiac anomalies occurred in 90% of the patients. Average follow-up was 9.5 plus or minus 7.0 years. The overall mortality rate was 14%. Of the six patients, three died postnatally before treatment. Cardiac surgery and/or catheter-guided interventions were required in 33 patients (79%). Cardiac surgery was performed in 21 (50%) patients at a median age of 9.1 years (range 0.1-16.5 years), including biventricular repair in 13 (62%), one-and-a-half chamber repair in seven (33%), and a staged single-ventricle repair in one. Peri-operative mortality was 4%. Catheter-guided interventions consisted of device closure of an atrial septal defect in three cases and radiofrequency ablation of accessory pathways in nine patients. The estimated 10-year survival was 85.3 plus or minus 5.6%. Conclusion In children, Ebstein's anomaly is usually diagnosed in the first year of age. Even though children with Ebstein's anomaly often require an intervention, their peri-operative mortality is low and long-term survival is good. Symptomatic newborns requiring an intervention may have a worse outcom

Dynamics of Relativistic Interacting Gases : from a Kinetic to a Fluid Description

Starting from a microscopic approach, we develop a covariant formalism to describe a set of interacting gases. For that purpose, we model the collision term entering the Boltzmann equation for a class of interactions and then integrate this equation to obtain an effective macroscopic description. This formalism will be useful to study the cosmic microwave background non-perturbatively in inhomogeneous cosmologies. It should also be useful for the study of the dynamics of the early universe and can be applied, if one considers fluids of galaxies, to the study of structure formation.Comment: Latex file, 28 pages, accepted for publication in Class. Quant. Gra

HIV-Specific Cellular Immune Response Is Inversely Correlated with Disease Progression as Defined by Decline of CD4+ T Cells in Relation to HIV RNA Load

The average time between infection with human immunodeficiency virus (HIV) and development of acquired immune deficiency syndrome is ∼8 years. However, progression rates vary widely, depending on several determinants, including HIV-specific immunity, host genetic factors, and virulence of the infecting strain. In untreated HIV-infected patients with different progression rates, we examined HIV-specific T cell responses in combination with host genetic markers, such as chemokine/chemokine-receptor (CCR) polymorphisms and human leukocyte antigen (HLA) genotypes. HIV-specific CD4+ T cell responses and, to a lesser extent, HIVspecific CD8+ T cell responses were inversely correlated with progression rate. Slower progression was not related to polymorphisms in CCR genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV-specific T cell responses are involved in protecting the host from disease progressio

Swiss Adult Congenital HEart disease Registry (SACHER) - rationale, design and first results.

In 2013, a prospective registry for adults with congenital heart disease (CHD) was established in Switzerland, providing detailed data on disease characteristics and outcomes: Swiss Adult Congenital HEart disease Registry (SACHER). Its aim is to improve the knowledge base of outcomes in adults with CHD. The registry design and baseline patient characteristics are reported. All patients with structural congenital heart defects or hereditary aortopathies, followed-up at dedicated adult CHD clinics, are asked to participate in SACHER. Data of participants are pseudonymised and collected in an electronic, web-based, database (secuTrial®). Collected data include detailed diagnosis, type of repair procedures, previous complications and adverse outcomes during follow-up. From May 2014 to December 2016, 2836 patients (54% male, mean age 34 ± 14 years), with a wide variety of congenital heart lesions, have been enrolled into SACHER. Most prevalent were valve lesions (25%), followed by shunt lesions (22%), cyanotic and other complex congenital heart disease (16%), diseases affecting the right heart, i.e., tetralogy of Fallot or Ebstein anomaly (15%), and diseases of the left ventricular outflow tract (13%); 337 patients (12%) had concomitant congenital syndromes. The majority had undergone previous repair procedures (71%), 47% of those had one or more reinterventions. SACHER collects multicentre data on adults with CHD. Its structure enables prospective data analysis to assess detailed, lesion-specific outcomes with the aim to finally improve long-term outcomes

Failure to Detect Xenotropic Murine Leukemia Virus-Related Virus in Blood of Individuals at High Risk of Blood-Borne Viral Infections

A xenotropic murine leukemia virus-related virus (XMRV) has recently been reported in association with prostate cancer and chronic fatigue syndrome, with a prevalence of up to 3.7% in the healthy population. We looked for XMRV in 230 patients with human immunodeficiency virus type 1 or hepatitis C infection. XMRV was undetectable in plasma or peripheral blood mononuclear cells by polymerase chain reaction targeting XMRV gag or env. T cell responses to XMRV Gag were undetectable in peripheral blood mononuclear cells by ex vivo gamma interferon enzyme-linked immunospot assay. In our cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections fromthe United Kingdom and Western Europ