Assessment of the therapeutic potential of the atypical chemokine receptor, D6

Infiltration of inflammatory cells into the tissue during the inflammatory response is beneficial to the host. Chemokines and their receptors are instrumental in this process by influencing the migration and behaviour of leukocytes in the tissue. However, prolonged inflammation is associated with many diseases. In recent years, a family of atypical receptors have emerged which do not seem to signal. One of these receptors, D6, is able to internalise and degrade 12 pro-inflammatory CC chemokines and has a role in the resolution of the inflammatory response. Here, using a murine transgenic approach, the potential therapeutic role of D6 in suppressing cutaneous inflammation in vivo has been investigated, using a well-characterised model of skin inflammation. In addition, expression of D6 in a range of inflammatory disorders has also been characterised. Transgenic mice were generated (K14D6), using an epidermis-specific transgene, in which expression of the D6 transgene was driven by the human keratin 14 promoter in epidermal keratinocytes. K14D6 mice were validated and we have shown that D6 is expressed in K14D6 but not in wild-type epidermal keratinocytes. The K14D6 transgene was shown to be functional as only K14D6 keratinocytes were able to bind CCL2 and progressively deplete extracellular CCL3. K14D6 mice can dampen down cutaneous inflammation in response to a topical application of TPA. In addition, K14D6 mice displayed reduced infiltration of epidermal T cells and mast cells compared to wild-type mice. Using a microarray approach, we examined the transcriptional consequences of non-ligated D6 and after ligand binding in primary murine keratinocytes from K14D6 and wild-type mice. Although limited conclusions could be made from the microarray data, our results suggest the possibility that non-ligated D6 in murine keratinocytes may have a negative impact on the transcription of some genes, such as chemokines. In a previous study, D6 null mice displayed a human psoriasis-like pathology after chemical induced skin inflammation, suggesting a possible involvement of D6-dysfunction as a contributing factor in the pathogenesis of psoriasis. We have investigated the possible correlation between D6 expression levels and cutaneous disease development. Analysis of skin biopsies revealed that D6 mRNA levels were 8-fold higher in uninvolved psoriatic skin compared to matching psoriatic lesional skin, atopic dermatitis and control skin. In PBMCs, there was no significant difference in D6 mRNA expression in psoriasis patients compared to control. A preliminary study examining surface D6 expression on leukocytes from control and rheumatoid arthritis patients revealed enhanced D6 expression on B cells and myeloid DCs. In this study, we have shown for the first time that increased expression of D6 in vivo can limit cutaneous inflammation, therefore providing a rationale for exploring the therapeutic potential of D6 in human inflammatory diseases. In addition, we provide evidence that D6 expression is dysregulated in inflammatory disorders further suggesting an involvement of this receptor in the pathogenesis of these diseases

Le rôle de l’émotion exprimée dans le cours de la schizophrénie

Au cours d'une décennie consacrée à d'abondantes recherches sur le cerveau, une avenue s'est, entre autre, ouverte pour démontrer l'importance de prendre en ligne de compte les facteurs psychosociaux dans le cours de la schizophrénie. Le but de cet article est de décrire brièvement le concept « d'émotion exprimée » qui s'est souvent révélé utile comme facteur de prévisibilité de la rechute dans différents types de maladies mentales graves. Nous y décrirons également un programme de recherches entrepris au Centre de recherche de l'Hôpital Douglas dans le but d'approfondir notre compréhension du lien entre la famille et le cours de la schizophrénie. Certains résultats seront également présentés pour souligner la complexité du rôle de la dynamique familiale dans la maladie mentale.In a decade dedicated to the brain, one particular line of research has been demonstrating the value of considering psychosocial factors in the course of schizophrenia. The purpose of this article is to briefly describe the concept of "expressed emotion" which has been shown repeatedly to predict relapse in a variety of severe mental disorders. We will, as well, describe a research program undertaken at the Douglas Hospital Research Centre which has been developed to deepen our understanding of the association between the family and outcome in schizophrenia. Selected results will be presented that highlight the complexity of the family process in mental illness

Switching patients from other inhaled corticosteroid devices to the Easyhaler(®) : historical, matched-cohort study of real-life asthma patients

Peer reviewedPublisher PD

Self-Grading: A Commentary

The theoretical perspectives and the various ways for implementing the self-grading strategy have been extensively discussed in the literature. In this paper, we aim to synthesize pertinent information and resources to deepen our understanding around self-grading and demystify any uncertainties about this concept, if any

Impact of Short Lifetime Limits on Child Neglect

The Great Recession that officially began in December 2007 nationally resulted in a loss of income on the part of many families with children who in turn, relied on a variety of safety nets, including cash assistance from Temporary Assistance for Needy Families (TANF) program. Loss of income has been recognized as a major risk factor of child maltreatment, in particular child neglect. During its 2007 recession, Arizona shortened its TANF lifetime limits substantially which resulted in transfer income losses for many families with children on TANF. Using time-series analysis, the present study determines the relative impact of TANF’s shorter than 60-month time limits on the Arizona’s child neglect caseload. This paper shows that there is a strong inverse relationship between child neglect and the decrease in the number of families receiving cash assistance from TANF. Key findings reveal that all else constant, under the presence of 36-month time limit there was an increase of 190 more children substantiated for neglect in the state of Arizona (p \u3c .001). The corresponding figure under the 24 month life time limit was 461 cases per month (p \u3c .001). This study reminds us that policies in one program should not be implemented in a vacuum but rather that their consequences for children and families in related programs need to be closely analyzed

The Impact of the Economy and Welfare Policy on Welfare Accessions: Implications for Future Reforms

This longitudinal study analyzes the impact of labor market conditions and welfare policies accompanying the 1990s waivers granted by the federal government to California and the 1996 Personal Responsibility and Work Opportunity Act (PRWOA) on families entering welfare (accessions). A time series model was specified for analyzing the number of families entering welfare from January 1983 to December 1998. The findings suggest that in 1998 under PRWOA, all else constant, there were fewer case openings. Prior to the PRWOA, policy shifts of the 1990s did not have an impact on case openings. The findings also show that under economic recovery fewer families applied for welfare. The implications of these findings are that drastic measures such as time-limited welfare should be re-examined since a favorable economic environment allows many recipients to remain off public assistance even in the absence of such measures

The Impact of the Economy and Welfare Policy on Welfare Accessions: Implications for Future Reforms

This longitudinal study analyzes the impact of labor market conditions and welfare policies accompanying the 1990s waivers granted by the federal government to California and the 1996 Personal Responsibility and Work Opportunity Act (PRWOA) on families entering welfare (accessions). A time series model was specified for analyzing the number of families entering welfare from January 1983 to December 1998. The findings suggest that in 1998 under PRWOA, all else constant, there were fewer case openings. Prior to the PRWOA, policy shifts of the 1990s did not have an impact on case openings. The findings also show that under economic recovery fewer families applied for welfare. The implications of these findings are that drastic measures such as time-limited welfare should be re-examined since a favorable economic environment allows many recipients to remain off public assistance even in the absence of such measures

Elevated ACKR2 expression is a common feature of inflammatory arthropathies

Objectives. Chemokines are essential contributors to leucocyte accumulation at sites of inflammatory pathology. Interfering with chemokine or chemokine receptor function therefore represents a plausible therapeutic option. However, our currently limited understanding of chemokine orchestration of inflammatory responses means that such therapies have not yet been fully developed. We have a particular interest in the family of atypical chemokine receptors that fine-tune, or resolve, chemokine-driven responses. In particular we are interested in atypical chemokine receptor 2 (ACKR2), which is a scavenging receptor for inflammatory CC-chemokines and that therefore helps to resolve in vivo inflammatory responses. The objective of the current study was to examine ACKR2 expression in common arthropathies. Methods. ACKR2 expression was measured by a combination of qPCR and immuno-histochemistry. In addition, circulating cytokine and chemokine levels in patient plasma were assessed using multiplexing approaches. Results. Expression of ACKR2 was elevated on peripheral blood cells as well as on leucocytes and stromal cells in synovial tissue. Expression on peripheral blood leucocytes correlated with, and could be regulated by, circulating cytokines with particularly strong associations being seen with IL-6 and hepatocyte growth factor. In addition, expression within the synovium was coincident with aggregates of lymphocytes, potentially atopic follicles and sites of high inflammatory chemokine expression. Similarly increased levels of ACKR2 have been reported in psoriasis and SSc. Conclusion. Our data clearly show increased ACKR2 in a variety of arthropathies and taking into account our, and others’, previous data we now propose that elevated ACKR2 expression is a common feature of inflammatory pathologies

Post-weaning diet determines metabolic risk in mice exposed to overnutrition in early life

BACKGROUND: Maternal overnutrition during pregnancy is associated with an increased risk of obesity and cardiometabolic disease in the offspring; a phenomenon attributed to ‘developmental programming’. The post-weaning development of obesity may associate with exacerbation of the programmed metabolic phenotype. In mice, we have previously shown that exposure to maternal overnutrition causes increased weight gain in offspring before weaning, but exerts no persistent effects on weight or glucose tolerance in adulthood. In order to determine whether post-weaning exposure to a cafeteria diet might lead to an exacerbation of programmed effects, offspring born and raised by mothers on control (CON) or cafeteria (DIO) diets were transferred onto either CON or DIO diets at weaning. FINDINGS: Post-weaning DIO caused the development of obesity, with hyperglycaemia and hyperinsulinaemia in males; and obesity with hyperinsulinaemia in females and with increased cholesterol levels in both sexes. Exposure to maternal overnutrition during pregnancy and lactation caused only subtle additional effects on offspring phenotype. CONCLUSIONS: These results suggest that post-weaning exposure to a high-fat high-sugar diet has a more profound effect on offspring weight gain and glucose tolerance than exposure to maternal overnutrition. These data emphasise the importance of optimising early life nutrition in offspring of both obese and lean mothers

Maternal obesity has little effect on the immediate offspring but impacts on the next generation

Maternal obesity during pregnancy has been linked to an increased risk of obesity and cardiometabolic disease in the offspring, a phenomenon attributed to developmental programming. Programming effects may be transmissible across generations through both maternal and paternal inheritance, although the mechanisms remain unclear. Using a mouse model, we explored the effects of moderate maternal diet-induced obesity (DIO) on weight gain and glucose-insulin homeostasis in first-generation (F1) and second-generation offspring. DIO was associated with insulin resistance, hyperglycemia and dyslipidemia before pregnancy. Birth weight was reduced in female offspring of DIO mothers (by 6%, P = .039), and DIO offspring were heavier than controls at weaning (males by 47%, females by 27%), however there were no differences in glucose tolerance, plasma lipids, or hepatic gene expression at 6 months. Despite the relative lack of effects in the F1, we found clear fetal growth restriction and persistent metabolic changes in otherwise unmanipulated second-generation offspring with effects on birth weight, insulin levels, and hepatic gene expression that were transmitted through both maternal and paternal lines. This suggests that the consequences of the current dietary obesity epidemic may also have an impact on the descendants of obese individuals, even when the phenotype of the F1 appears largely unaffected