Orally administered exosomes suppress mouse delayed-type hypersensitivity by delivering miRNA-150 to antigen-primed macrophage APC targeted by exosome-surface anti-peptide antibody light chains

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies are aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes similarly induced CD3+CD8+ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced an exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration

Criterion Validity of a Field-Based Assessment of Aerobic Capacity in Wheelchair Rugby Athletes

Purpose: To confirm whether peak aerobic capacity determined during laboratory testing could be replicated during an on-court field-based test in wheelchair rugby (WR) players. Methods: Sixteen WR players performed an incremental speed-based peak oxygen uptake (V̇O2peak) test on a motorised treadmill (TM) and completed a Multi-stage Fitness Test (MFT) on a basketball court in a counter-balanced order while spirometric data were recorded. A paired t-test was performed to check for systematic error between tests. A Bland-Altman plot for V̇O2peak illustrated the agreement between the TM and MFT results and how this related to the boundaries of practical equivalence. Results: No significant differences between mean V̇O2peak were reported (TM:1.85±0.63 vs. MFT: 1.81±0.63 L.min-1; p=0.33). Bland-Altman plot for V̇O2peak suggests that the mean values are in good agreement at the group level; i.e., the exact 95% confidence limits for the ratio systematic error (0.95 to 1.02) are within the boundaries of practical equivalence (0.88 to 1.13) showing the group average TM and MFT values are interchangeable. However, consideration of the data at the level of the individual athlete suggests the TM and MFT results were not interchangeable because the 95% ratio limits of agreement either coincide with the boundaries of practical equivalence (upper limit) or fall outside (lower limit). Conclusions: Results suggest that the MFT provides a suitable test at a group level with this cohort of WR players for the assessment of V̇O2peak (range 0.97 – 3.64 L∙min-1), yet caution is noted for interchangeable use of values between tests for individual players

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

Contains fulltext : 76036.pdf (publisher's version ) (Closed access)15 p

Sex differences in leukocyte profile in ST-elevation myocardial infarction patients

BACKGROUND: Whether sex differences exist in the inflammatory response after ST-elevation myocardial infarction (STEMI) remains to be elucidated. We studied leukocyte profiles and their prognostic value in men and women presenting with STEMI. METHODS: From a total of 552 consecutive STEMI patients, blood samples were collected at hospital admission. Linear regression was used to assess the relationship between leukocyte profiles and enzymatic infarct size. Cox regression was used to assess the association between leukocyte profiles and one-year mortality. RESULTS: Women presented with higher lymphocyte counts (2.3·109 cells/L (IQR 1.6-3.1) vs. 1.8·109 cells/L (IQR 1.4-2.5), p = 3.00 ∙ 10-4) and percentages (21.1% (IQR 14.4-28.1) vs. 17.1% (IQR 12.3-24.3), p = 0.004). Lymphocyte to monocyte ratio (LMR) was also higher in women (3.25 (IQR 2.56-4.5) vs. 2.68 (IQR 2.08-3.59), p = 7.28 ∙ 10-7). Higher LMR was associated with lower peak CK-MB (β = -0.27 (95% CI: -0.50, -0.03), p = 0.026), lower peak troponin T (β = -0.45 (95% CI: -0.77, -0.13), p = 0.006) and lower one-year mortality risk (HR 0.35 (95% CI: 0.13, 0.96), p = 0.042). CONCLUSION: At admission for STEMI, women present with higher lymphocyte count and LMR. Higher LMR is associated with smaller infarct size and decreased one-year mortality risk and could be used as a biomarker to predict outcome

Treatment with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children is associated with a sustained effect on growth

INTRODUCTION: Growth failure is a common feature of children with human immunodeficiency virus type 1 (HIV-1) infection. Children who are treated with mono or dual nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy show a temporary increase in weight gain and linear growth rate. In adults, protease-inhibitor-containing antiretroviral therapy is associated with a sustained weight gain and increased body mass index (BMI). Experience with protease inhibitors and growth in children is still limited. The data mainly deal with short-term effects on growth. OBJECTIVE: To evaluate the effect of highly active antiretroviral therapy (HAART) on growth in children with HIV-1 infection. DESIGN AND METHODS: We analyzed selected growth parameters, clinical data, and laboratory results as part of a prospective, open, uncontrolled, multicenter study to evaluate the clinical, immunologic, and virologic response to HAART consisting of indinavir, zidovudine, and lamivudine in children with HIV-1 infection. Height and weight were measured at 0, 12, 24, 36, 48, 60, 72, 84, and 96 weeks after initiation of HAART. Information about the children's growth before enrollment in the study was retrieved from the hospital medical records and/or the school doctor or health center. BMI was calculated. z Scores were used to express the standard deviation (SD) in SD units from the Dutch reference curves for age and gender. Viral loads and CD4+ T-cell counts were examined prospectively and related to these growth parameters. z Scores were also calculated for CD4+ T-cell counts to correct for age-related differences. A z score of 0 represents the P50, which is exactly the age/sex-appropriate median. A height z score of -1 indicates that a child's height is 1 SD below the age- and gender-specific median height for the normal population. Virologic responders were defined as those who either reached an undetectable viral load (1.5 log reduction in viral load compared with baseline at week 12 after the initiation of HAART, which was maintained during the follow-up period. RESULTS. PATIENTS: Twenty-four patients were included (age: 0.4-16.3 years at baseline), with a median HIV-1 RNA load of 105 925 copies/mL (5.03 log), a median CD4+ T-cell count of 0.586 x 10(9)/L (median z score: -2.28 SD), a median height z score of -1.22, a median weight z score of -0.74, and a median baseline BMI z score of -0.32. Eleven patients were naive to antiretroviral therapy, and 13 patients had received previous treatment with NRTI monotherapy. Twenty children used indinavir and 4 children used nelfinavir as part of HAART. VIROLOGIC AND IMMUNOLOGIC RESPONSES TO HAART: Seventeen children were virologic responders, and 7 children were virologic nonresponders. In patients naive to NRTIs, median baseline viral loads were significantly higher than in pretreated patients. However, at weeks 48 and 96, there was no significant difference between the viral loads of both groups. At baseline, there was no significant difference in CD4+a T-cell z scores between virologic responders and nonresponders or between naive and pretreated patients. During 96 weeks of HAART, the increase of CD4+ T-cell z score was significantly higher in responders than in nonresponders. The increase in CD4+ T-cell z score was not significantly different for naive and pretreated patients. HEIGHT, WEIGHT, AND BMI z SCORE CHANGES: We found that