IntroductionSeptic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients.MethodsThis prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed.ResultsWe observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration.ConclusionsThese findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.

Killer cell immunoglobulin-like receptors (KIRs) belong to a diverse family of natural killer (NK) cell receptors recognizing human leukocyte antigen (HLA) class I molecules. Due to this functional link, KIR molecules are expected to display a high polymorphism, such as their HLA ligands. Moreover, many studies conducted in mouse and human models have shown that NK-KIR receptors play an important role in haematopoietic stem cell transplantation (HSCT). A beneficial impact of peculiar KIR ligand (HLA) mismatching has been reported suggesting a role to this combinatory HLA-KIR polymorphism. It is thus important to investigate KIR diversity in various human populations. To this end, we used polymerase chain reaction-sequence-specific primers to evaluate KIR gene in five selected populations (France, Guadeloupe, Senegal, Finland and Réunion). Genotypic and haplotypic frequencies were computed, as well as genetic distances and dendrogram (phylip package). These data illustrate the genetic relationship of these five populations through the KIR polymorphism. Results revealed a wide diversity in KIR gene frequencies in Guadeloupe and Réunion, and a high specificity in Senegal. The obtained dendrogram indicated small genetic distances between France, Guadeloupe and Réunion as well as between France and Finland. Senegal showed a distant genetic relationship with the other countries and, interestingly, an inverted ratio of coding/non-coding (KIR2DS4/1D) alleles compared with Caucasians. These data expose the broad diversity in KIR genes worldwide and show that KIR genes are pertinent tools in human population genetics. If the role of KIR donor-recipient incompatibilities is confirmed, KIR diversity according to ethnicity should be taken into account during the selection of HSCT donors.

BackgroundThe great majority of mental disorders begin during adolescence or early adulthood, although they are often detected and treated later in life. To compare mental health status of college students and their non-college-attending peers whether working, attending a secondary school, or non-college-attending peers who are neither employed nor students or trainees (NENST) will allow to focus on high risk group.MethodsData were drawn from a large cross-sectional survey conducted by phone in 2005 in four French regions in a randomly selected sample of 22,138 adults. Analyses were restricted to the college-age subsample, defined as those aged 18 to 24 (n = 2424). Sociodemographic, educational, and occupational status were determined. In addition, respondents were administered standardized instruments to assess mental health and well-being (CIDI-SF, SF-36, Sheehan Disability Scale, CAGE), mastery, social support, and isolation. The four occupational groups were compared. All analyses were stratified by gender.ResultsMental health disorders were more prevalent among the NENST group, with significant differences among men for anxiety disorders including phobias, post-traumatic stress disorder (PTSD) and panic disorder, impairing at least one role in their daily life. This was also true among women except for panic disorder. The NENST group also reported the lowest level of mastery and social support for both genders and the highest level of social isolation for women only. After adjustment, occupational status remained an independent correlate of PTSD (OR = 2.92 95 % CI = 1.4–6.1), agoraphobia (OR = 1.86 95 % CI 1.07–3.22) and alcohol dependence (OR = 2.1 95 % CI = 1.03–4.16).ConclusionCompared with their peers at work or in education/training, the prevalence of certain common mental health disorders was higher among college-aged individuals in the NENST group. Efforts should be made to help young adults in the transition between school or academic contexts and joining the workforce. It is also important to help youths with psychiatric disorders find an occupational activity and provide them information, care, support and counseling, particularly in times of economic hardship. Schools and universities may be adequate institutional settings to set health promotion programs in mental health and well-being.

cancérologie, UMR892, UFR Médecine et Techniques médicales, Nantes, France NK-cell function is regulated by a balance between inhibitory and activating killer cell immunoglobulin-like receptors (KIR) that specifically recognize HLA class I molecules. Using KIR-specific mAb to discriminate between KIR2DS1 and KIR2DL1 receptors, we show that KIR2DS1 + NK cells are C2-alloreactive only from C2 À individuals. Moreover, using an in vitro model of NK-cell expansion, we show here that the frequency of KIR2DL1 + NK cells is significantly higher in the absence of C2 ligand on stimulator EBV-B cells than in its presence. This observation was made regardless of the presence or absence of the autologous C2 ligand, suggesting that the C2 À EBV-B stimulator cells used in this in vitro model could activate unlicensed KIR2DL1 + NK cells. In the case of KIR2DL1 + /S1 + genotyped individuals, KIR2DS1 + NK-cell frequency was increased after stimulation with C2 + compared with C2 À stimulator B cells, but only from C2 À individuals. Altogether, these data highlight the C2 alloreactivity of KIR2DS1 + NK cells that is only observed in C2 À individuals. These results provide new insights into the way in which NK KIR cell expansion might be regulated in an allogeneic environment.

for the French Vasculitis Study Group and the European EGPA Study Group Objective. To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). Methods. A retrospective European collaborative study was conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease. Results. Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range [IQR] 5-13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1-4.5) and the median BVAS in the MEPO group was 2 (IQR 1-5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0-4.5) and at 12 months (median 0, IQR 0-2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)-dependent asthma, patients who received MEPO had a much better GC-sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively. Conclusion. These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC-dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first-line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.

Background: Quinolone hypersensitivity reactions are being more frequently reported. Skin tests in investigations of patients are known to not be fully reliable. The provocation test thus remains the gold standard in the definitive diagnosis of allergy, despite the risks involved. The aim of this study was to evaluate basophil activation tests (BATs) in the diagnosis of immediate-type reactions to quinolones. Methods: Thirty-four patients who presented an immediate-type hypersensivity reaction less than an hour after quinolone administration were studied. The allergologic workup of these patients consisted of a careful clinical history, a skin test and a BAT with the culprit quinolone. If not contraindicated, and in the case of high probability of a nonallergic reaction, provocation tests were performed to assess the nonimmunologic nature of the hypersensitivity. Results: Among the 34 patients studied, 17 (50%) presented a negative BAT to the suspected quinolone, while the other 17 (50%) patients presented a positive BAT for quinolone at the time of their reaction. Among the 17 patients with negative BATs, 15 (2 of whom had had positive skin tests) had quinolone successfully reintroduced. Conclusions: Our report suggests that the BAT, if negative for the culprit quinolone, is a valuable tool in the decision whether or not to perform provocation tests in patients with a history of immediate-type reaction to quinolones, in order to exclude an allergic reaction.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

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