Evidence for the involvement of the adenosine A(2A) receptor in the lowered susceptibility to pentylenetetrazol-induced seizures produced in mice by long-term treatment with caffeine

Long-term caffeine intake has been reported to decrease the susceptibility to convulsants in mice. Occurrence of seizures following long-term oral administration of caffeine (0.3g/l) was investigated using adenosine A(2A) receptor knockout (A(2A)R KO) and control (A(2A)R WT) mice. Clonic seizures induced by acute pentylenetetrazol (PTZ, 50mg/kg i.p.) were significantly attenuated in adenosine A(2A)R KO mice drinking only water and reduced by a 14-day caffeine treatment in adenosine A(2A)R WT mice. In addition we showed a protecting effect of a 21-day caffeine treatment in A(2A)R WT mice against kindled seizures induced by PTZ in an increasing dose schedule. Summing up, these protective effects against PTZ-induced seizures occurring when adenosine A(2A)R is absent or chronically blocked by a relevant dose of caffeine may be related to a decreased neuronal excitability.     

A subset of functional effector-memory CD8+ T lymphocytes in human immunodeficiency virus-infected patients

CD8(+) T cells provide protective immune responses via both cytolytic and non-cytolytic mechanisms in subjects infected with human immunodeficiency virus (HIV). In the present study, we investigated the CD28 expression of CD8(+) T cells present in the peripheral blood lymphocyte subset isolated from chronically HIV-infected subjects. Using flow cytometric analysis, a continuous spectrum of CD28 intensity ranging from negative to high, which could be separated into CD28-negative, intermediate (int) and high, was seen for CD8(+) T cells. Our study focused mostly on the CD28(int) CD8(+) T cells. The CD28(int) CD8(+) T cells are CD57(-) CD27(+) CD45RO(+) CD45RA(-) CCR7(low) CD62L(int). The proliferative capacity of CD28(int) CD8(+) T cells was intermediate between those of CD28(-) CD8(+) T cells and CD28(high) CD8(+) T cells. The CD28(int) CD8(+) T cells are specific for HIV, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) antigens as measured by human leucocyte antigen pentamer binding and produce both intracellular interferon-gamma and tumour necrosis factor-alpha in response to their cognate viral peptides. The CD28(int) CD8(+) T cells have HIV-specific, CMV-specific and EBV-specific cytotoxic activity in response to their cognate viral peptides. These findings indicate that a subset of functional effector-memory CD8(+) T cells specific for HIV, CMV and EBV antigens may contribute to an efficient immune response in HIV-infected subjects.     

Identification of candidates for a subunit vaccine against extraintestinal pathogenic Escherichia coli

Extraintestinal pathogenic Escherichia coli (ExPEC) strains cause a large spectrum of infections. The majority of ExPEC strains are closely related to the B2 or the D phylogenetic group. The aim of our study was to develop a protein-based vaccine against these ExPEC strains. To this end, we identified ExPEC-specific genomic regions, using a comparative genome analysis, between the nonpathogenic E. coli strain K-12 MG1655 and ExPEC strains C5 (meningitis isolate) and CFT073 (urinary tract infection isolate). The analysis of these genomic regions allowed the selection of 40 open reading frames, which are conserved among B2/D clinical isolates and encode proteins with putative outer membrane localization. These genes were cloned, and recombinant proteins were purified and assessed as vaccine candidates. After immunization of BALB/c mice, five proteins induced a significant protective immunity against a lethal challenge with a clinical E. coli strain of the B2 group. In passive immunization assays, antigen-specific antibodies afforded protection to naive mice against a lethal challenge. Three of these antigens were related to iron acquisition metabolism, an important virulence factor of the ExPEC, and two corresponded to new, uncharacterized proteins. Due to the large number of genetic differences that exists between commensal and pathogenic strains of E. coli, our results demonstrate that it is possible to identify targets that elicit protective immune responses specific to those strains. The five protective antigens could constitute the basis for a preventive subunit vaccine against diseases caused by ExPEC strains.     

Night shift decreases cognitive performance of ICU physicians

Background

The relationship between tiredness and the risk of medical errors is now commonly accepted. The main objective of this study was to assess the impact of an intensive care unit (ICU) night shift on the cognitive performance of a group of intensivists. The influence of professional experience and the amount of sleep on cognitive performance was also investigated.

Methods

A total of 51 intensivists from three ICUs (24 seniors and 27 residents) were included. The study participants were evaluated after a night of rest and after a night shift according to a randomized order. Four cognitive skills were tested according to the Wechsler Adult Intelligence Scale and the Wisconsin Card Sorting Test.

Results

All cognitive abilities worsened after a night shift: working memory capacity (11.3 ± 0.3 vs. 9.4 ± 0.3; p < 0.001), speed of processing information (13.5 ± 0.4 vs. 10.9 ± 0.3; p < 0.001), perceptual reasoning (10.6 ± 0.3 vs. 9.3 ± 0.3; p < 0.002), and cognitive flexibility (41.2 ± 1.2 vs. 44.2 ± 1.3; p = 0.063). There was no significant difference in terms of level of cognitive impairment between the residents and ICU physicians. Only cognitive flexibility appeared to be restored after 2 h of sleep. The other three cognitive skills were altered, regardless of the amount of sleep during the night shift.

Conclusions

The cognitive abilities of intensivists were significantly altered following a night shift in the ICU, regardless of either the amount of professional experience or the duration of sleep during the shift. The consequences for patients’ safety and physicians’ health should be further evaluated.

     

An e-health interactive self-assessment website (Sanoia®) in rheumatoid arthritis. A 12-month randomized controlled trial in 320 patients

Introduction

Sanoia is an online interactive electronic e-health platform developed to allow patient self-assessment and self-monitoring. The objective was to assess in rheumatoid arthritis (RA) patients, the efficacy on patient-physician interactions, of giving access to Sanoia.

Stretching of roots contributes to the pathophysiology of radiculopathies

Purpose

To perform a synthesis of articles addressing the role of stretching on roots in the pathophysiology of radiculopathy.

Molecular basis of macrolide resistance in Campylobacter: role of efflux pumps and target mutations

BACKGROUND: Erythromycin is the drug of choice to treat human campylobacteriosis. Campylobacter isolates exhibit two different phenotypes with regard to erythromycin resistance: high-level resistant strains (HLR) and low-level resistant strains (LLR). OBJECTIVES: To study the mechanisms of resistance of Campylobacter to erythromycin, its 6-O-methyl derivative clarithromycin and the ketolide telithromycin. RESULTS: We observed a cross-resistance against these three molecules but in contrast, no cross-resistance to quinolones. Analyses of LLR showed no mutation on the 23S rDNA and the presence of a drug transport system, which can be inhibited by phenylalanine arginine beta-naphthylamide (PAbetaN), an efflux-pump inhibitor. In contrast, no PAbetaN-sensitive drug transport was identified in HLR but we found mutations in the rDNA, which were responsible for decreased binding of telithromycin to purified ribosomes. We further showed that the CmeB efflux pump already described in Campylobacter is not involved in the PAbetaN-sensitive transport of telithromycin. CONCLUSIONS: Mutations in the ribosome confer high-level macrolide/ketolide resistance. Low-level resistance was mediated by an efflux mechanism which is sensitive to PAbetaN. This efflux pump was selective to macrolides/ketolide and was different from the previously described Campylobacter efflux pump.     

Tumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.