Decreased CD8<Superscript>+</Superscript>T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

Background  

Patients with multiple sclerosis (MS) have a decreased frequency of CD8⁺ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8⁺ T cell response to EBV results from a general CD8⁺ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8⁺ T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8⁺ T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS.     

Oxidation of phosphatidylserine: a mechanism for plasma membrane phospholipid scrambling during apoptosis?

Selective oxidation of phosphatidylserine (PS) during apoptosis precedes its externalization in plasma membrane and is essential for the engulfment of apoptotic cells. To experimentally test whether PS oxidation stimulates its externalization via its effects on aminophospholipid translocase (APT) or by enhanced PS scrambling, action of oxidized PS (PSox) was studied using leukemia HL-60 cells and lymphoma Raji cells. Both PS and PSox were equally well recognized by APT. PSox did not inhibit APT. Rate of transmembrane PS diffusion was fourfold higher in cells with integrated PSox than with PS. Thus, PSox acts as a "non-enzymatic scramblase" likely contributing to PS externalization.     

Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies

Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC₅₀) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC₅₀. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study.     

Protective role of glutathione reductase in paraquat induced neurotoxicity

Paraquat (PQ), a widely used herbicide is a well-known free radical producing agent. The mechanistic pathways of PQ neurotoxicity were examined by assessing oxidative/nitrosative stress markers. Focus was on the role of glutathione (GSH) cycle and to examine whether the pre-treatment with enzyme glutathione reductase (GR) could protect the vulnerable brain regions (VBRs) against harmful oxidative effect of PQ. The study was conducted on Wistar rats, randomly divided in five groups: intact-control group, (n=8) and four experimental groups (n=24). All tested compounds were administered intrastriatally (i.s.) in one single dose. The following parameters of oxidative status were measured in the striatum, hippocampus and cortex, at 30min, 24h and 7days post treatment: superoxide anion radical (O(2)(-)), nitrate (NO(3)(-)), malondialdehyde (MDA), superoxide dismutase (SOD), total GSH (tGSH) and its oxidized, disulfide form (GSSG) and glutathione peroxidase (GPx). Results obtained from the intact and the sham operated groups were not statistically different, confirming that invasive i.s. route of administration would not influence the reliability of results. Also, similar pattern of changes were observed between ipsi- and contra- lateral side of examined VBRs, indicating rapid spatial spreading of oxidative stress. Mortality of the animals (10%), within 24h, along with symptoms of Parkinsonism, after awakening from anesthesia for 2-3h, were observed in the PQ group, only. Increased levels of O(2)(-), NO(3)(-) and MDA, increased ratio of GSSG/GSH and considerably high activity of GPx were measured at 30min after the treatment. Cytotoxic effect of PQ was documented by drastic drop of all measured parameters and extremely high peak of the ratio GSSG/GSH at 24th hrs after the PQ i.s. injection. In the GR+PQ group, markedly low activity of GPx and low content of NO(3)(-) (in striatum and cortex) were measured during whole experiment, while increase value was observed only for O(2)(-), at 7th days. We concluded that oxidative/nitrosative stress and excitotoxicity are the most important events since the early stage of PQ induced neurotoxicity. Based on the ratio GSSG/GSH, the oxidation of GSH to GSSG is probably dominant way of GHS depletion and main reason for reduced antioxidative defense against PQ harmful oxidative effect. The GR pre-treatment resulted in the absence of Parkinson's disease-like symptoms and mortality of the rats. Additionally, oxidative/nitrosative stress did not developed, as well as almost diminished metabolism of the VBRs at 24th hours (as has been documented in the PQ group) did not occurred in the GR+PQ, suggesting a neuroprotective role for the GR in PQ induced neurotoxicity.     

Upregulated glutathione transferase omega-1 correlates with progression of urinary bladder carcinoma

Objectives: Newly discovered glutathione transferase omega 1 (GSTO1-1) plays an important role in the glutathionylation cycle, a significant mechanism of protein function regulation. GSTO1-1 expression pattern has not been studied in transitional cell carcinoma (TCC), as yet.

Methods: A total of 56 TCC tumor and corresponding non-tumor specimens were investigated. Glutathione content and thioltransferase activity were measured spectrophotometrically. Protein-glutathione mixed disulfides were measured fluorimetrically. GSTO1-1 expression was determined by immunoblot and qPCR. Immunoprecipitation with GSTO1-1 antibody was followed by immunoblot using anti-GSTO1, GSTP1, c-Jun, JNK, Akt, phospho-Akt, and ASK1 antibody, while for the total S-glutathionylation levels non-reducing electrophoresis was performed.

Results: The contents of reduced glutathione and thioltransferase activity were significantly increased in tumor compared to non-tumor tissue. The increased GSTO1 expression in tumor tissue showed clear correlation with grade and stage. However, decreased total protein glutathionylation level in tumor compared to non-tumor samples was found. Immunoprecipitation has shown an association of GSTO1-1 with GSTP1, Akt, phospho-Akt, and ASK1 proteins.

Conclusions: GSTO1 deglutathionylase activity suggests its potential important role in redox perturbations present in TCC. Increased GSTO1-1 expression might contribute to TCC development and/or progression supporting the notion that GSTO1-1 may be a promising novel cancer target.     

Rheumatoid factor and anti-citrullinated protein antibody positivity,but not level,are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts

Introduction

This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).

Methods

Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.

Results

A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).

Conclusions

Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0483-3) contains supplementary material, which is available to authorized users.     

AChemS: the beginning. Association for Chemoreception Sciences

This paper unfolds the events, the people and the times that led up to the founding of AChemS and fashioned its character during its early formative years. It describes the path over which AChemS came, going from the original assertions and denials for the need of such an organization to its later inception and nascent development. This narration highlights such topics as the debate over the need for AChemS, the role of National Science Foundation in the founding of AChemS, the derivation of the Association's name, the choice of Sarasota and the Hyatt House as the meeting site, the generation of the programs for the early annual meetings, the adoption of the bylaws, the process of incorporation and tax deferment, and the birth of the Givaudan Lectureship. Most emphatically highlighted, however, is the enthusiasm, commitment and hard work that the members of the chemosensory research community displayed in bringing AChemS to fruition.