Immunopathological Basis of Virus-induced Myocarditis

Heart diseases are an important cause of morbidity and mortality in industrialized countries. Dilated cardiomyopathy (DCM), one of the most common heart diseases, may be the consequence of infectionassociated myocardits. Coxsackievirus B3 (CVB3) can be frequently detected in the inflamed heart muscle. CVB3-induced acute myocarditis is most likely the consequence of direct virus-induced myocyte damage, whereas chronic CVB3 infection-associated heart disease is dominated by its immunopathological sequelae. Bona fide autoimmunity, for example, directed against cardiac myosin, may favor chronic destructive immune damage in the heart muscle and thereby promote the development of DCM. The immunopathogenesis of myocarditis and subsequent DCM induced either by pathogens or autoantigens can be investigated in well-established animal models. In this article, we review recent studies on the role of viruses, with particular emphasis on CVB3, and different immunological effector mechanisms in initiation and progression of myocarditis

Towards a Coronavirus-Based HIV Multigene Vaccine

Human immunodeficiency virus (HIV) infection represents one of the major health threats in the developing world. The costly treatment of infected individuals with multiple highly efficient anti-HIV drugs is only affordable in industrialized countries. Thus, an efficient vaccination strategy is required to prevent the further spread of the infection. The molecular biology of coronaviruses and particular features of the human coronavirus 229E (HCoV 229E) indicate that HCoV 229E-based vaccine vectors can become a new class of highly efficient vaccines. First, the receptor of HCoV 229E, human aminopeptidase N (hAPN or CD13) is expressed mainly on human dendritic cells (DCs) and macrophages indicating that targeting of HCoV 229E-based vectors to professional antigen presenting cells can be achieved by receptor-mediated transduction. Second, HCoV 229E structural genes can be replaced by multiple transcriptional units encoding various antigens. These virus-like particles (VLPs) containing HCoV 229E-based vector RNA have the ability to transduce human DCs and to mediate heterologous gene expression in these cells. Finally, coronavirus infections are associated with mainly respiratory and enteric diseases, and natural transmission of coronaviruses occurs via mucosal surfaces. In humans, HCoV 229E causes common cold by infecting the upper respiratory tract. HCoV 229E infections are mainly encountered in children and re-infection occurs frequently in adults. It is thus most likely that pre-existing immunity against HCoV 229E will not significantly impact on the vaccination efficiency if HCoV 229E-based vectors are used in humans

Study of exclusive one-pion and one-eta production using hadron and dielectron channels in pp reactions at kinetic beam energies of 1.25 GeV and 2.2 GeV with HADES

We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions

Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

The 5'-cap-structures of higher eukaryote mRNAs are ribose 2'-O-methylated. Likewise, a number of viruses replicating in the cytoplasm of eukayotes have evolved 2'-O-methyltransferases to modify autonomously their mRNAs. However, a defined biological role of mRNA 2'-O-methylation remains elusive. Here we show that viral mRNA 2'-O-methylation is critically involved in subversion of type-I-interferon (IFN-I) induction. We demonstrate that human and murine coronavirus 2'-O-methyltransferase mutants induce increased IFN-I expression, and are highly IFN-I sensitive. Importantly, IFN-I induction by 2'-O-methyltransferase-deficient viruses is dependent on the cytoplasmic RNA sensor melanoma differentiation-associated gene 5 (MDA5). This link between MDA5-mediated sensing of viral RNA and mRNA 2'-O-methylation suggests that RNA modifications, such as 2'-O-methylation, provide a molecular signature for the discrimination of self and non-self mRNA

The effect of time-to-surgery on outcome in elderly patients with proximal femoral fractures

<p>Abstract</p> <p>Background</p> <p>Whether reducing time-to-surgery for elderly patients suffering from hip fracture results in better outcomes remains subject to controversial debates.</p> <p>Methods</p> <p>As part of a prospective observational study conducted between January 2002 and September 2003 on hip-fracture patients from 268 acute-care hospitals all over Germany, we investigated the relationship of time-to-surgery with frequency of post-operative complications and one-year mortality in elderly patients (age ≥65) with isolated proximal femoral fracture (femoral neck fracture or pertrochanteric femoral fracture). Patients with short (≤12 h), medium (> 12 h to ≤36 h) and long (> 36 h) times-to-surgery, counting from the time of the fracture event, were compared for patient characteristics, operative procedures, post-operative complications and one-year mortality.</p> <p>Results</p> <p>Hospital data were available for 2916 hip-fracture patients (mean age (SD) in years: 82.1 (7.4), median age: 82; 79.7% women). Comparison of groups with short (n = 802), medium (n = 1191) and long (n = 923) time-to-surgery revealed statistically significant differences in a few patient characteristics (age, American Society of Anesthesiologists ratings classification and type of admission) and in operative procedures (total hip endoprosthesis, hemi-endoprosthetic implants, other osteosynthetic procedures). However, comparison of these same groups for frequency of postoperative complications revealed only some non-significant associations with certain complications such as post-operative bleeding requiring treatment (early surgery patients) and urinary tract infections (delayed surgery patients). Both unadjusted rates of one-year all-cause mortality (between 18.1% and 20.5%), and the multivariate-adjusted hazard ratios (HR for time-to-surgery: 1.04; p = 0.55) showed no association between mortality and time-to-surgery.</p> <p>Conclusion</p> <p>Although this study found a trend toward more frequent post-operative complications in the longest time-to-surgery group, there was no effect of time-to-surgery on mortality. Shorter time-to-surgery may be associated with somewhat lower rates of post-operative complications such as decubitus ulcers, urinary tract infections, thromboses, pneumonia and cardiovascular events, and with somewhat higher rates of others such as post-operative bleeding or implant complications.</p

Medium effects in proton-induced K0K^{0} production at 3.5 GeV

We present the analysis of the inclusive $K^{0}$ production in p+p and p+Nb collisions measured with the HADES detector at a beam kinetic energy of 3.5 GeV. Data are compared to the GiBUU transport model. The data suggest the presence of a repulsive momentum-dependent kaon potential as predicted by the Chiral Perturbation Theory (ChPT). For the kaon at rest and at normal nuclear density, the ChPT potential amounts to $\approx 35$ MeV. A detailed tuning of the kaon production cross sections implemented in the model has been carried out to reproduce the experimental data measured in p+p collisions. The uncertainties in the parameters of the model were examined with respect to the sensitivity of the experimental results from p+Nb collisions to the in-medium kaon potential.Comment: 13 pages, 14 figure

The High-Acceptance Dielectron Spectrometer HADES

HADES is a versatile magnetic spectrometer aimed at studying dielectron production in pion, proton and heavy-ion induced collisions. Its main features include a ring imaging gas Cherenkov detector for electron-hadron discrimination, a tracking system consisting of a set of 6 superconducting coils producing a toroidal field and drift chambers and a multiplicity and electron trigger array for additional electron-hadron discrimination and event characterization. A two-stage trigger system enhances events containing electrons. The physics program is focused on the investigation of hadron properties in nuclei and in the hot and dense hadronic matter. The detector system is characterized by an 85% azimuthal coverage over a polar angle interval from 18 to 85 degree, a single electron efficiency of 50% and a vector meson mass resolution of 2.5%. Identification of pions, kaons and protons is achieved combining time-of-flight and energy loss measurements over a large momentum range. This paper describes the main features and the performance of the detector system

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.status: publishe