Activation of Jun N-terminal Kinase/Stress-activated Protein Kinase Pathway by Tumor Necrosis Factor α Leads to Intercellular Adhesion Molecule-1 Expression

Tumor necrosis factor alpha (TNF-alpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. We have previously shown that mouse Sertoli cells respond to TNF-alpha by increasing interleukin-6 production and intercellular adhesion molecule-1 (ICAM-1) expression (1). In this cell type TNF-alpha activates the mitogen-activated protein kinase (MAPK) pathways p42/p44 MAPK, JNK/SAPK, and p38, the last of which is responsible for interleukin-6 production (1). To determine which MAPK signaling pathway is required for TNF-alpha induction of ICAM-1 expression, we have utilized the protein kinase inhibitor dimethylaminopurine, demonstrating that treatment of Sertoli cells with such compound significantly reduced ICAM-1 expression and JNK/SAPK activation. Moreover, dimethylaminopurine treatment increased the expression of MAPK phosphatase-2, providing a possible mechanism of action of this compound. By using agonist antibodies to p55 and to p75 TNF-alpha receptors and both human and mouse TNF-alpha, we demonstrate that both TNF receptors are expressed and that only the p55 receptor is involved in ICAM-1 expression. The p55 receptor activates all of the three pathways, whereas p75 failed to activate any of the MAPKs. Altogether our results demonstrate that TNF-alpha up-regulates ICAM-1 expression through the activation of the JNK/SAPK transduction pathway mediated by the p55 receptor

Steady and Time-Resolved Photoelectron Spectra Based on Nuclear Ensembles

Semiclassical methods to simulate both steady and time-resolved photoelectron spectra are presented. These approaches provide spectra with absolute band shapes and vibrational broadening beyond the Condon approximation, using an ensemble of nuclear configurations built either via distribution samplings or nonadiabatic dynamics simulations. Two models to account for the electron kinetic energy modulation due to vibrational overlaps between initial and final states are discussed. As illustrative examples, the steady photoelectron spectra of imidazole and adenine and the time- and kinetic-energy-resolved photoelectron spectrum of imidazole were simulated within the frame of time-dependent density functional theory. While for steady spectra only electrons ejected with maximum allowed kinetic energy need to be considered, it is shown that to properly describe time-resolved spectra, electrons ejected with low kinetic energies must be considered in the simulations as well. The results also show that simulations based either on full computation of photoelectron cross section or on simple Dyson orbital norms provide results of similar quality

Cohort profile : demographic and clinical characteristics of the MILESTONE longitudinal cohort of young people approaching the upper age limit of their child mental health care service in Europe

Purpose: The presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports. Participants: Seven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at. Findings to date: This cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be ‘markedly ill’, ‘severely ill’ or ‘among the most extremely ill’ by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year. Future plans: Analysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared. Trial registration number: NCT03013595

Different Clinical Outcomes of COVID-19 in Two Healthcare Workers Vaccinated with BNT162b2 Vaccine, Infected with the Same Viral Variant but with Different Predisposing Conditions for the Progression of the Disease

Safe and effective vaccines are available to face the global threat of the COVID-19 pandemic. In this article, we report on the clinical cases of two healthcare workers vaccinated with two doses of BNT162b2 vaccine who were infected by the same viral clade but had different clinical outcomes

Clinical significance of hepatitis B surface antigen mutants

Hepatitis B virus (HBV) infection is a major public health problem in many countries, with nearly 300 million people worldwide carrying HBV chronic infection and over 1 million deaths per year due to cirrhosis and liver cancer. Several hepatitis B surface antigen (HBsAg) mutations have been described, most frequently due to a single amino acid substitution and seldom to a nucleotide deletion. The majority of mutations are located in the S region, but they have also been found in the pre-S1 and pre-S2 regions. Single amino acid substitutions in the major hydrophilic region of HBsAg, called the “a” determinant, have been associated with immune escape and the consequent failure of HBV vaccination and HBsAg detection, whereas deletions in the pre-S1 or pre-S2 regions have been associated with the development of hepatocellular carcinoma. This review article will focus on the HBsAg mutants and their biological and clinical implications

HCV-genotype 3h, a difficult-to-diagnose sub-genotype in the DAA era

No data are available on the clinical presentation and virological pattern in the case of failure to IFN-free regimens in patients with genotype 3h. In this paper authors identified the virological and clinical characteristics of patients with genotype 3h treated with suboptimal or not indicated Interferon (IFN)-free regimens for the misclassification of HCV genotype METHODS: 87 consecutive patients with failure to an IFN-free regimen were re-tested for HCV genotype by HCV NS5B sequencing; the 26 patients identified as harboring HCV-3 were enrolled

Clinical findings of HCV chronic infection in undocumented immigrants and low-income refugees in three areas of southern Italy

Introduction and aim. In recent decades, Italy has become a land of immigration from countries suffering a socio-economic crisis. The aim of this study was to perform an organized screening to identify and offer care to immigrants with HCV infection. Material and methods. The screening, performed from 2012 to 2015, involved 1,727 immigrants in the Campania and Apulia regions in southern Italy. Results. Screening was accepted by 1,727 (85%) out of 2,032 immigrants interviewed; 70 (4.1%) of the 1,727 were anti-HCV-positive, all unaware of their serological condition, 31 (44.3%) of whom were HCV-RNA-positive and 39 negative. The 31 HCV-RNA-positive immigrants were further investigated at a third-level clinic of infectious diseases. The HCV viral load was 2.6 x 107± 7.7 x107IU/mL, and 35.5% showed HCV-genotype 1a or 1b, 23.8% genotype 2 and 22.6% genotype 3. Two immigrants had liver cirrhosis and, in accordance with the Italian Healthcare Authority guidelines, received an interferon-free regimen and achieved a sustained virological response (SVR); 18 had chronic hepatitis, 6 of whom with a high risk of progression and received interferon-based therapy, with SVR in 4, whereas 12 at low risk were put on a waiting list for future interferon-free treatment, once licensed. The remaining 11 HCV-RNA-positive immigrants were considered HCV inactive chronic carriers and were included in a long-term observational program. Conclusion. The screening program can be considered successful since it was accepted by 85% of the subjects interviewed and identified 70 anti-HCV-positive immigrants, all unaware of their clinical and virological condition