JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs

Cohabiter sans coexister : division sociale de l'espace et relations interraciales entre les aborigènes et les euro-australiens à Alice Springs

Ce mémoire de maîtrise porte sur la division sociale et spatiale entre les Euro-Australiens et les Aborigènes à Alice Springs en Australie Centrale et résulte d'une recherche de terrain de trois mois en 2006. Il met en relation les notions d'espace, de lieu et de race. Il vise à souligner les rapports qu'entretiennent les groupes sociaux envers certains lieux publics et ce, sur la base de l'occupation quotidienne des espaces urbains. Il est non seulement question d'attachement aux lieux, mais aussi de ségrégation raciale spatiale. Ces notions, bien qu'elles soient contradictoires, prennent formes dans une même réalité sociale. Les Euro-Australiens. et les Aborigènes à Alice Springs s'approprient des lieux spécifiques d'où ils se ±sentent à l'aise¿ et ±confortables¿ tout en excluant de ces mêmes lieux les individus, aborigènes et euro-australiens, qui n'adhèrent pas au mode de vie et aux comportements de leur groupe. Ce contexte de ségrégation spatiale est en fait le reflet de la dynamique sociale entre les Aborigènes et les Euro-Australiens. C'est ainsi dire que leur distanciation spatiale est équivalente à leur distanciation sociale. Les Euro-Australiens et les Aborigènes, ne pratiquant pas leurs activités quotidiemes dans les mêmes endroits publics, ne peuvent partager leur existence

: Volume 5

La mise en place effective d'un « espace de liberté, de sécurité et de justice » nesaurait faire l'économie d'une réflexion sur l'harmonisation des sanctions pénales.Réflexion indispensable mais encore neuve, ce qui impliquait davantage une mise enquestions que la recherche de solutions.Mise en questions réalisée en trois temps : le Constat, tout d'abord, des droits internesen matière de sanctions encourues, prononcées et exécutées ; les Enjeux et débats, ensuite,ceux de la faisabilité, de l'opportunité et de la légitimité d'une harmonisation ; lesProspectives, enfin, de voies susceptibles de conduire à l'harmonisation, non seulement dansle but de permettre la reconnaissance mutuelle des décisions pénales mais encore de dessinerdes principes communs de sanction, participant ainsi du renforcement d'une communauté dedroits en Europe

Ten Years of Valuation of the Local Impact of Atmospheric Pollution: from Scientific Assessments to Political Decisions

This paper focuses on the economic valuation of the impact of local air pollution. Two main issues are considered: 1. The scientific issue: what is estimated, how and why? The main studies from the nineties are presented here. Two strong issues are stressed, with the diversity of valuation methods, on the one hand, and the debates on how to take the long term into account and the discount technique, on the other. 2. The political issue: how the results from the economic field are analysed and used to establish official values for public policies? The methods used in the transport sector in three different European countries (France, Sweden and Switzerland) are studied here.To conclude, we highlight the discrepancy between these two processes and, wherever possible, offer solutions to reach better synergy.Local air pollution ; External costs ; Economic valuation ; Official values ; Public decision ; International comparison

Knockdown of Myosin Va Isoforms by RNAi as a Tool to Block Melanosome Transport in Primary Human Melanocytes

The movement of melanosomes, dense melanin-containing organelles, within human melanocytes is actin-dependent and mediated through the formation of a Rab27a-Slac2-a–myosin Va (MyoVa) protein complex. We previously showed that only the melanocyte-specific exon F isoforms of MyoVa are involved in melanosome transport to the dendrite extremities. Here, we investigate siRNA to downregulate the exon F-containing isoforms of MyoVa in primary human melanocytes. Efficient and specific knockdown of the MyoVa exon F isofoms were shown at both mRNA and protein levels. Further, a stable shRNA against the MyoVa exon F isoforms was prepared by using a lentiviral system to improve and confirm the silencing effect in hard-to-transfect melanocyte cells. Immunofluorescence microscopy shows that knockdown of the exon F isoforms results in blockade of intramelanocytic melanosome transport due to the inability to form the Rab27a-Slac2-a–MyoVa tripartite complex. Interestingly, the observed phenotypic effect (that is, perinuclear accumulation of melanosomes) is the same as that seen in melanocytes from patients with human Griscelli syndrome causing abnormal pigmentation. We conclude that our siRNA-based strategy provides a previously unreported tool to block the intracellular melanosome movement in primary human melanocytes and may become an innovative drug to treat hyperpigmentation

Key factors of case management interventions for frequent users of healthcare services : a thematic analysis review

Objective : The aim of this paper was to identify the key factors of case management (CM) interventions among frequent users of healthcare services found in empirical studies of effectiveness. Design : Thematic analysis review of CM studies. Methods : We built on a previously published review that aimed to report the effectiveness of CM interventions for frequent users of healthcare services, using the Medline, Scopus and CINAHL databases covering the January 2004–December 2015 period, then updated to July 2017, with the keywords ‘CM’ and ‘frequent use’. We extracted factors of successful (n=7) and unsuccessful (n=6) CM interventions and conducted a mixed thematic analysis to synthesise findings. Chaudoir’s implementation of health innovations framework was used to organise results into four broad levels of factors: (1) ,environmental/organisational level, (2) practitioner level, (3) patient level and (4) programme level. Results : Access to, and close partnerships with, healthcare providers and community services resources were key factors of successful CM interventions that should target patients with the greatest needs and promote frequent contacts with the healthcare team. The selection and training of the case manager was also an important factor to foster patient engagement in CM. Coordination of care, self-management support and assistance with care navigation were key CM activities. The main issues reported by unsuccessful CM interventions were problems with case finding or lack of care integration. Conclusions : CM interventions for frequent users of healthcare services should ensure adequate case finding processes, rigorous selection and training of the case manager, sufficient intensity of the intervention, as well as good care integration among all partners. Other studies could further evaluate the influence of contextual factors on intervention impacts

Generic self-reported questionnaires measuring self-management: a scoping review

This study aimed to (1) identify generic questionnaires that measure self-management in people with chronic conditions, (2) describe their characteristics, (3) describe their development and theoretical foundations, and (4) identify categories of self-management strategies they assessed. This scoping review was based on the methodological framework developed by Arksey and O’Malley and completed by Levac et al. A thematic analysis was used to examine self-management strategies assessed by the questionnaires published between 1976 and 2019. A total of 21 articles on 10 generic, self-reported questionnaires were identified. The questionnaires were developed using various theoretical foundations. The Patient Assessment of Self-Management Tasks and Partners in Health scale questionnaires possessed characteristics that made them suitable for use in clinical and research settings and for evaluating all categories of self-management strategies. This study provides clinicians and researchers with an overview of generic, self-reported questionnaires and highlights some of their practical characteristics

Dix ans de monétarisation des effets locaux de la pollution atmosphérique : des évaluations scientifiques aux décisions politiques

Cette communication s'intéresse à la valorisation monétaire des impacts environnementaux de la pollution atmosphérique locale. Comment, d'un côté, ces chiffres sont-ils construits par les économistes, et comment, de l'autre, sont-ils repris et utilisés pour établir des valeurs officielles dans le cadre des politiques publiques ? Nous mettons en lumière les écarts existant entre les deux et proposons des solutions pour les réduire.Pollution locale ; effets ; monétarisation ; actualisation ; valeurs tutélaires ; décision publique ; comparaison internationale

Effectiveness of case management interventions for frequent users of healthcare services: a scoping review

OBJECTIVE: Frequent users of healthcare services are a vulnerable population, often socioeconomically disadvantaged, who can present multiple chronic conditions as well as mental health problems. Case management (CM) is the most frequently performed intervention to reduce healthcare use and cost. This study aimed to examine the evidence of the effectiveness of CM interventions for frequent users of healthcare services. DESIGN: Scoping review. DATA SOURCES: An electronic literature search was conducted using the MEDLINE, Scopus and CINAHL databases covering January 2004 to December 2015. A specific search strategy was developed for each database using keywords 'case management' and 'frequent use'. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: To be included in the review, studies had to report effects of a CM intervention on healthcare use and cost or patient outcomes. Eligible designs included randomised and non-randomised controlled trials and controlled and non-controlled before-after studies. Studies limited to specific groups of patients or targeting a single disease were excluded. Three reviewers screened abstracts, screened each full-text article and extracted data, and discrepancies were resolved by consensus. RESULTS: The final review included 11 articles evaluating the effectiveness of CM interventions among frequent users of healthcare services. Two non-randomised controlled studies and 4 before-after studies reported positives outcomes on healthcare use or cost. Two randomised controlled trials, 2 before-after studies and 1 non-randomised controlled study presented mitigated results. Patient outcomes such as drug and alcohol use, health locus of control, patient satisfaction and psychological functioning were evaluated in 3 studies, but no change was reported. CONCLUSIONS: Many studies suggest that CM could reduce emergency department visits and hospitalisations as well as cost. However, pragmatic randomised controlled trials of adequate power that recruit the most frequent users of healthcare services are still needed to clearly confirm its effectiveness

The Chronic Disease Self-Management Program: the experience of frequent users of health care services and peer leaders

BACKGROUND: Large amount of evidence supports the contribution of the Stanford Chronic Disease Self-Management Program (CDSMP) to a global chronic disease management strategy. However, many studies have suggested further exploring of the factors influencing acceptance and completion of participants in this program. OBJECTIVE: This study aimed to describe and examine factors associated with acceptance and completion rates of the CDSMP among frequent users of health care services, and to highlight the experience of patients and peer leaders who facilitated the program. METHODS: A descriptive design with mixed sequential data was used. Acceptance and completion rates were calculated and their relationship with patient characteristics was examined in regression analysis (n = 167). Interviews were conducted among patients who accepted (n = 11) and refused (n = 13) to participate and with the program coordinator. Focus groups were held with the seven peer leaders who facilitated the program. Data were analysed using thematic analysis. RESULTS: Of the 167 patients invited, 60 (36%) accepted to participate in the program. Group format was the most frequent reason to decline the invitation to participate. Twenty-eight participants (47%) completed the program. Participants who dropped out during the program raised different reasons such as poor health and too much heterogeneity among participants. Factors such as location, schedule, content, group composition and facilitation were considered as important elements contributing to the success of the program. CONCLUSION: The CDSMP could therefore be considered as a self-management support option for this vulnerable clientele, while taking measures to avoid too much heterogeneity among participants to improve completion rates