Intracellular Adenosine Inhibits IgE-Dependent Degranulation of Human Skin Mast Cells

Purpose

Adenosine (ADO) can enhance and inhibit mast cell degranulation. Potentiation of degranulation occurs at relatively low concentrations of ADO (10^?6–10^?5 M) through triggering of A3AR, whereas, inhibition occurs at higher concentrations of ADO reportedly through triggering of A2aAR. However, the discrepancy in the concentration of ADO that inhibits degranulation and that required to trigger ADORs suggests a different mechanism. The purpose of this study is to determine the mechanism by which ADO inhibits human mast cell degranulation.

Methods

We compare the effectiveness of A2aAR specific antagonist ZM241385 and equilibrative nucleoside transporter inhibitors Dipyridamole and NBMPR in preventing ADO-mediated inhibition of FcεRI-induced degranulation of human skin mast cells (hSMCs). Western blotting is done to analyze the effect of ADO on FcεRI-induced Syk phosphorylation.

Results

Dipyridamole and NBMPR completely and dose-dependently prevented ADO from inhibiting FcεRI-induced degranulation in all hSMC preparations. In contrast, ZM241385 at 10^?5 M was effective in only 3 of 10 hSMC preparations. Moreover, NBMPR was effective even in those hSMC preparations not responsive to ZM241385. ADO inhibited degranulation induced by FcεRI crosslinking, but not that induced by complement component 5a (C5a), Substance P or calcium ionophore. Accordingly, ADO significantly attenuated FcεRI-induced phosphorylation of Syk at the critical activating tyrosine (Y525).

Conclusion

Blocking the influx of ADO, but not A2aAR signals, is necessary and sufficient to prevent ADO from inhibiting FcεRI-induced mast cell degranulation. Thus, ADO specifically inhibits FcεRI-induced degranulation of hSMCs primarily by an intracellular mechanism that requires its influx via equilibrative nucleoside transporter 1 (ENT1).     

Depression or resilience? A participatory study to identify an appropriate assessment tool with Kanien’kéha (Mohawk) and Inuit in Quebec

Purpose

We present a study on selection of a psychometric scale to be clinically used among Indigenous people with depression. Our aim was to select a psychometric tool for cultural adaptation with Mohawk and Inuit in Quebec.

Methods

We selected three depression scales and three protective factor scales based on: strong validity for psychometric properties, evidence for good psychometric qualities across translations, avoidance of cognitively complex sentences, brevity, and clarity. We submitted the scales for consultation, and followed qualitative participatory methods with Mohawks of Kahnawake and Inuit from Nunavik living in an urban environment. We collected data through ten focus groups with advisory committees, and carried out a thematic analysis of the information.

Results

The advisory groups considered the measurement scales to be unsafe. The major components that hindered their acceptance were: numeric rating, self-evaluation (versus supportive interaction), and a focus on symptoms rather than supportive factors. The participants preferred the Growth and Empowerment Measure due to its empowering approach. They voiced that it is necessary to develop a culturally sensitive and safe tool which facilitates interactions between the person and the practitioner.

Conclusion

This project provides valuable information about the perspectives of local Indigenous peoples regarding mental health and factors of empowerment and resilience. The ideal tool should be flexible in terms of the content and its use as compared to the conventional psychometric strategies. A tool developed with the Indigenous perspective on wellbeing could be used in psychological and psychiatric intervention as well as in social and community services.

     

Longitudinal associations of physical fitness and body mass index with academic performance

No studies have analyzed the longitudinal associations of change in physical fitness components and obesity with academic performance. The aim of the study was to examine longitudinal associations of changes in physical fitness components and body mass index with academic performance among youth, and whether the physical fitness components are moderators of the longitudinal association between obesity and academic performance in youth. Longitudinal analyses (2 years) included 1802 youths. Physical fitness components were assessed following the ALPHA health‐related fitness test battery. Academic performance was assessed via school records. Youth in the persistently high cardiorespiratory fitness and motor ability categories (ie, fit at baseline and at 2‐year follow‐up) had higher academic performance at follow‐up than those in the persistently low category. Further, youth with normal weight at baseline and overweight/obesity at follow‐up had lower academic performance scores at follow‐up compared to those with normal weight. Also, cardiorespiratory fitness may ameliorate the negative influence of excess body mass index on academic performance at follow‐up. Promoting physical activity programs at school that include both aerobic exercise and motor tasks to improve physical fitness and reduce body mass index may not only improve physical health, but also contribute toward successful academic development.     

Alcohol Consumption and Periodontitis: Quantification of Periodontal Pathogens and Cytokines

Background: There are few studies on periodontal status related to microbiologic and immunologic profiles among individuals not or occasionally using alcohol and those with alcohol dependence. The aim of this study is to determine the effect of alcohol consumption on the levels of subgingival periodontal pathogens and proinflammatory cytokines (interleukin [IL]‐1β and tumor necrosis factor [TNF]‐α) in the gingival fluid among individuals with and without periodontitis. Methods: This observational analytic study includes 88 volunteers allocated in four groups (n = 22): individuals with alcohol dependence and periodontitis (ADP), individuals with alcohol dependence and without periodontitis (ADNP), individuals not or occasionally using alcohol with periodontitis (NAP), and individuals not or occasionally using alcohol without periodontitis (NANP). Levels of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Eikenella corrodens, and Fusobacterium nucleatum were determined by real‐time polymerase chain reaction on the basis of the subgingival biofilm, and IL‐1β and TNF‐α were quantified by enzyme‐linked immunosorbent assay in gingival fluid samples. Results: Individuals with alcohol dependence showed worse periodontal status and higher levels of P. intermedia, E. corrodens, F. nucleatum, and IL‐1β than non‐users. No significant correlations between TNF‐α and bacterial levels were observed. However, in the ADP group, higher levels of E. corrodens were correlated with higher levels of IL‐1β. Conclusion: A negative influence of alcohol consumption was observed on clinical and microbiologic periodontal parameters, as well as a slight influence on immunologic parameters, signaling the need for additional studies.     

A large‐scale computational study of inhibitor risk in non‐severe haemophilia A

Over 500 missense F8 mutations have been reported to cause non‐severe haemophilia A. Some F8 genotypes appear to confer a higher risk of inhibitor formation than others and individuals with the same F8 genotype may have differing risks of inhibitor formation. We present an in silico strategy demonstrating the heterogeneity of factor VIII (FVIII)‐derived antigen presentation whilst identifying patterns of human leucocyte antigen (HLA) peptide binding that might predict future inhibitor risk. A well‐validated computational tool, NetMHCII, enabled large‐scale comparison of predicted antigen presentation between endogenous, mutated FVIII‐derived peptides and wild‐type, therapeutic FVIII‐derived peptides spanning all F8 missense mutation positions reported to The Haemophilia A Mutation, Structure and Resource Site (HADB). We identify 40 F8 genotypes to be ‘low risk’ at a 50% inhibitory concentration (IC₅₀)‐binding threshold of 300 nmol/l (P = 0·00005), defined as absence of novel peptide‐major histocompatibility complex (MHC) surfaces for all 14 common HLA‐DR alleles assessed. Analysing each of the possible 7280 F8 genotype/HLA‐DR permutations individually at an IC₅₀ threshold of 300 nmol/l, 65% are predicted to not generate a novel peptide‐MHC surface that would be necessary to engage T cell help for subsequent anti‐FVIII antibody generation. This study demonstrates the future importance of interpreting F8 genotype in the context of an individual's HLA profile to personalize inhibitor risk prediction.