Unbounded? Gender and body in a recreational drug culture

THESIS 7912This dissertation explores how a sample of young adults in Dublin experience issues of gendered embodiment in their recreational engagement with the drug ecstasy (MDMA). The study applies a gender studies theoretical framework to analyse potential for change in the experience of gender, and compares how women and men experience a drug culture. Key themes that hinge on the corporeal body are developed throughout the study. Findings are examined in the context of discourse on gender and the body, including a focus on health, sexuality, interpersonal relationships, risk and ethics

Prevalence, profiles and policy: a case study of drug use in north inner city Dublin.

Research for this project was carried out by the Isis Research Group in the Centre for Womenís Studies, Trinity College, Dublin, in partnership with the Inter-Agency Drugs Project/North Inner City Drugs Task Force. The project was funded by Enterprise Ireland (Science and Technology Against Drugs Programme) and the Combat Poverty Agency. Both qualitative and quantitative data were collected over a 10-month period on the prevalence of heroin use and the experiences of heroin users. After describing the background to the study, the report detailed the findings of the prevalence survey, including patterns of use found amongst clients of drug treatment agencies, multiple users and waiting lists, and data from the street survey. Profiles of heroin users are presented, including information on the social settings of heroin use, supply issues, experiences of seeking treatment, treatment needs, and prevention. Case studies of two heroin users are presented. The report concluded with a discussion of research and policy perspectives on the heroin problem

Towards a drugs service development plan for Bray: report for the Bray Drugs Working Group.

This report deals with the issue of service provision in response to illegal drug use in Bray. The report identifies deficiencies in rehabilitation programmes, suitable premises for youth counselling etc., needle exchanges, information services, counselling services, youth workers and sport and leisure activities. The profile of the young people using drugs in Bray is mixed in terms of class, gender, educational attainment and family background. The long-term challenges that were identified in the report can only be met within a well-resourced set of structures that knit together the expertise and knowledge of the community as well as the statutory agencies. These should come into play as the primary source for understanding local needs and the impact, successful or otherwise of programmes which are put in place. The researchers recommend that a process involving all of the above be started which would lead to the development of a coherent, integrated and holistic drugs service plan for Bray

P127 Disrupting the cartilage mechanostat: the role of the ciliary protein IFT88 in the adolescent growth plate

Background/sims: as long bone elongation draws to a close, the cartilaginous growth plate begins to ossify in preparation of growth plate fusion. Previous embryonic developmental in vivo work has identified the crucial Parathyroid Hormone-related Protein-Indian hedgehog (PTHrP-Ihh) feedback loop that is responsible for the proliferation of chondrocytes at the epiphysis, whilst also allowing for the hypertrophic differentiation of chondrocytes before ossification at the diaphysis. Indian hedgehog signalling relies upon the microtubule-based organelle the primary cilium, as disruption to either results in similar musculoskeletal phenotypes. Here, we asked for the first time whether juvenile and adolescent primary cilia disruption affected chondrocyte differentiation in the growth plate.Methods: we used a chondrocyte-specific conditional knockout (AggrecanCreERT2; Ift88fl/fl, cKO) of a key primary ciliary protein (Ift88) administering tamoxifen at (4, 6, 8 weeks-of-age) to both cKO and control (Ift88fl/fl) animals, collecting two weeks later (6, 8, 10-weeks-of-age). Immunohistochemistry was performed using type X collagen (ColX), a specific marker of hypertrophic chondrocytes.Results: deletion of IFT88 resulted in large bi-lateral cartilaginous regions filled with disorganised ColX positive hypertrophic chondrocytes, indicating failed ossification. Our results indicate that deletion of IFT88 does not impact hypertrophic differentiation, but disrupts ossification processes downstream at the chondro-osseous junction, such as matrix remodelling and angiogenesis, necessary for growth plate closure. Interestingly, this phenotype was observed only in the bi-lateral most loaded regions of the tibia whilst the middle was unaffected.Conclusion: this observation indicates that the primary cilium could be involved in transducing mechanically regulated biophysical and signalling cues in the adolescent growth plate

Ciliary IFT88 protects coordinated adolescent growth plate ossification from disruptive physiological mechanical forces

Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88fl/fl) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreERT2 Ift88fl/fl). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces

Role of ciliary protein intraflagellar transport protein 88 in the regulation of cartilage thickness and osteoarthritis development in mice

Objective: mechanical and biologic cues drive cellular signaling in cartilage development, health, and disease. Primary cilia proteins, which are implicated in the transduction of biologic and physiochemical signals, control cartilage formation during skeletal development. This study was undertaken to assess the influence of the ciliary protein intraflagellar transport protein 88 (IFT88) on postnatal cartilage from mice with conditional knockout of the Ift88 gene (Ift88-KO).Methods: Ift88fl/fl and aggrecanCreERT2 mice were crossed to create a strain of cartilage-specific Ift88-KO mice (aggrecanCreERT2;Ift88fl/fl). In these Ift88-KO mice and Ift88fl/fl control mice, tibial articular cartilage thickness was assessed by histomorphometry, and the integrity of the cartilage was assessed using Osteoarthritis Research Society International (OARSI) damage scores, from adolescence through adulthood. In situ mechanisms of cartilage damage were investigated in the microdissected cartilage sections using immunohistochemistry, RNAScope analysis, and quantitative polymerase chain reaction. Osteoarthritis (OA) was induced in aggrecanCreERT2;Ift88fl/fl mice and Ift88fl/fl control mice using surgical destabilization of the medial meniscus (DMM). Following tamoxifen injection and DMM surgery, the mice were given free access to exercise on a wheel.Results: deletion of Ift88 resulted in progressive reduction in the thickness of the medial tibial cartilage in adolescent mice, as well as marked atrophy of the cartilage in mice during adulthood. In aggrecanCreERT2;Ift88fl/fl mice at age 34 weeks, the median thickness of the medial tibial cartilage was 89.42 μm (95% confidence interval [95% CI] 84.00–93.49), whereas in Ift88fl/fl controls at the same age, the median cartilage thickness was 104.00 μm (95% CI 100.30–110.50; P < 0.0001). At all time points, the median thickness of the calcified cartilage was reduced. In some mice, atrophy of the medial tibial cartilage was associated with complete, spontaneous degradation of the cartilage. Following DMM, aggrecanCreERT2;Ift88fl/fl mice were found to have increased OARSI scores of cartilage damage. In articular cartilage from maturing mice, atrophy was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy. Of the 44 candidate genes analyzed, only Tcf7l2 expression levels correlated with Ift88 expression levels in the microdissected cartilage. However, RNAScope analysis revealed that increased hedgehog (Hh) signaling (as indicated by increased expression of Gli1) was associated with the reductions in Ift88 expression in the tibial cartilage from Ift88-deficient mice. Wheel exercise restored both the articular cartilage thickness and levels of Hh signaling in these mice.Conclusion: our results in a mouse model of OA demonstrate that IFT88 performs a chondroprotective role in articular cartilage by controlling the calcification of cartilage via maintenance of a threshold of Hh signaling during physiologic loading