237 research outputs found

    The local control of vascular tone by perivascular nerves and the endothelium: Changes after X-irradiation and in atherosclerosis

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    In this thesis, the local regulation of vascular tone has been studied in normal, X-irradiated and atherosclerotic blood vessels, primarily using in vitro pharmacological techniques. In the first section, the early effects of a single dose of 4500 rad X-radiation on vasomotor control was studied in the NZW rabbit central ear artery 1, 4 and 6 weeks following exposure. Sympathetic neurotransmission was attenuated by 1 week postirradiation, with a greater reduction occuring after 4 and 6 weeks respectively. A reduction in both endothelium-dependent and independent relaxations, with no change in the contractile response to NA, indicated that the relaxant efficiency of the smooth muscle was reduced following irradiation. The neuromodulatory actions of CGRP and NPY were enhanced 6 weeks following irradiation. The second section studies the development of atherosclerosis- induced alterations in local vasomotor control during maturation in the WHHL rabbit (an animal model of familial hypercholesterolemia). Animals were examined at 4, 6 and 12 months of age, with NZW rabbits being used as controls. In the WHHL rabbit ear and mesenteric arteries, endothelium-dependent relaxant responses increased with age, unlike responses in NZW rabbit arteries. Endothelium-independent relaxations in the ear and mesenteric arteries were not altered during maturation in WHHL rabbit arteries and also when compared with NZW arteries. In contrast, the thoracic aorta from 12-month-old WHHL rabbits exhibited reduced endothelium-dependent relaxant responses to ACh, which appeared to be linked to the degree of occlusion of the vessel wall by atheromatous plaque. In the WHHL rabbit basilar artery, endothelium-dependent relaxations also increased with age. However, the basilar artery was shown to differ from the ear and mesenteric arteries in that endothelium-independent relaxant responses also increased with age. In the WHHL rabbit ear and mesenteric arteries, sympathetic neurotransmission was significantly reduced when compared with NZW rabbits. In both arteries, the reduction in sympathetic neurotransmission appeared to be due to pre- as opposed to post-junctional factors. In an addendum, relaxation by substance P in the NZW rabbit mesenteric artery was found to be mediated by neurokinin-l (NK-l) receptors located on the endothelium, with substance P and [Glp6, L- Pro9]SP6-11 being selective agonists

    Dear friend, I can no longer hear your voice…: Reclaiming Eliza Soane.

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    This was a contribution to the Gender & Otherness conference hosted by the Open University. I took part in the session on women and buildings, chaired by Clare Taylor & Christine Plastow. I shared a presentation with Dr Louise Stewart (Head of Exhibitions, Sir John Soane’s Museum) on my artwork Dear Friend, I Can No Longer Hear Your Voice, part of the exhibition of the same name that took place at Sir John Soane’s Museum March 8 - June 5, 2022

    The impact of self-harm by young people on parents and families:A qualitative study

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    Objectives: Little research has explored the full extent of the impact of self-harm on the family. This study aimed to explore the emotional, physical and practical effects of a young person’s self-harm on parents and family. Design and Participants: We used qualitative methods to explore the emotional, physical and practical effects of a young person’s self-harm on their parents and family. We conducted a thematic analysis of thirty-seven semi-structured narrative interviews with parents of young people who had self-harmed. Results: After the discovery of self-harm, parents described initial feelings of shock, anger and disbelief. Later reactions included stress, anxiety, feelings of guilt, and in some cases the onset or worsening of clinical depression. Social isolation was reported, as parents withdrew from social contact due to the perceived stigma associated with self-harm. Parents also described significant impacts on siblings, ranging from upset and stress to feelings of responsibility and worries about stigma at school. Siblings had mixed responses, but were often supportive. Practically speaking, parents found the necessity of being available to their child often conflicted with the demands of full-time work. This, along with costs of, for example, travel and private care, affected family finances. However, parents generally viewed the future as positive and hoped that with help, their child would develop better coping mechanisms. Conclusions: Self-harm by young people has major impacts on parents and other family members. Clinicians and staff who work with young people who self-harm should be sensitive to these issues and offer appropriate support and guidance for families

    Duplication of the EFNB1 Gene in Familial Hypertelorism: Imbalance in Ephrin-B1 Expression and Abnormal Phenotypes in Humans and Mice

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    Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc

    Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS): a mixed-methods study to inform trial design

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    Background: Smoking in pregnancy and/or not breastfeeding have considerable negative health outcomes for mother and baby. Aim: To understand incentive mechanisms of action for smoking cessation in pregnancy and breastfeeding, develop a taxonomy and identify promising, acceptable and feasible interventions to inform trial design. Design: Evidence syntheses, primary qualitative survey, and discrete choice experiment (DCE) research using multidisciplinary, mixed methods. Two mother-and-baby groups in disadvantaged areas collaborated throughout. Setting: UK. Participants: The qualitative study included 88 pregnant women/recent mothers/partners, 53 service providers, 24 experts/decision-makers and 63 conference attendees. The surveys included 1144 members of the general public and 497 health professionals. The DCE study included 320 women with a history of smoking. Methods: (1) Evidence syntheses: incentive effectiveness (including meta-analysis and effect size estimates), delivery processes, barriers to and facilitators of smoking cessation in pregnancy and/or breastfeeding, scoping review of incentives for lifestyle behaviours; (2) qualitative research: grounded theory to understand incentive mechanisms of action and a framework approach for trial design; (3) survey: multivariable ordered logit models; (4) DCE: conditional logit regression and the log-likelihood ratio test. Results: Out of 1469 smoking cessation and 5408 breastfeeding multicomponent studies identified, 23 smoking cessation and 19 breastfeeding studies were included in the review. Vouchers contingent on biochemically proven smoking cessation in pregnancy were effective, with a relative risk of 2.58 (95% confidence interval 1.63 to 4.07) compared with non-contingent incentives for participation (four studies, 344 participants). Effects continued until 3 months post partum. Inconclusive effects were found for breastfeeding incentives compared with no/smaller incentives (13 studies) but provider commitment contracts for breastfeeding show promise. Intervention intensity is a possible confounder. The acceptability of seven promising incentives was mixed. Women (for vouchers) and those with a lower level of education (except for breastfeeding incentives) were more likely to disagree. Those aged ≤ 44 years and ethnic minority groups were more likely to agree. Agreement was greatest for a free breast pump and least for vouchers for breastfeeding. Universal incentives were preferred to those targeting low-income women. Initial daily text/telephone support, a quitting pal, vouchers for > £20.00 per month and values up to £80.00 increase the likelihood of smoking cessation. Doctors disagreed with provider incentives. A ‘ladder’ logic model emerged through data synthesis and had face validity with service users. It combined an incentive typology and behaviour change taxonomy. Autonomy and well-being matter. Personal difficulties, emotions, socialising and attitudes of others are challenges to climbing a metaphorical ‘ladder’ towards smoking cessation and breastfeeding. Incentive interventions provide opportunity ‘rungs’ to help, including regular skilled flexible support, a pal, setting goals, monitoring and outcome verification. Individually tailored and non-judgemental continuity of care can bolster women’s capabilities to succeed. Rigid, prescriptive interventions placing the onus on women to behave ‘healthily’ risk them feeling pressurised and failing. To avoid ‘losing face’, women may disengage. Limitations: Included studies were heterogeneous and of variable quality, limiting the assessment of incentive effectiveness. No cost-effectiveness data were reported. In surveys, selection bias and confounding are possible. The validity and utility of the ladder logic model requires evaluation with more diverse samples of the target population. Conclusions: Incentives provided with other tailored components show promise but reach is a concern. Formal evaluation is recommended. Collaborative service-user involvement is importan

    Forensic child and Adolescent Psychiatry and mental health in Europe

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    Background When faced with the discovery of their child’s self-harm, mothers and fathers may re-evaluate their parenting strategies. This can include changes to the amount of support they provide their child and changes to the degree to which they control and monitor their child. Methods We conducted an in-depth qualitative study with 37 parents of young people who had self-harmed in which we explored how and why their parenting changed after the discovery of self-harm. Results Early on, parents often found themselves “walking on eggshells” so as not to upset their child, but later they felt more able to take some control. Parents’ reactions to the self-harm often depended on how they conceptualised it: as part of adolescence, as a mental health issue or as “naughty behaviour”. Parenting of other children in the family could also be affected, with parents worrying about less of their time being available for siblings. Many parents developed specific strategies they felt helped them to be more effective parents, such as learning to avoid blaming themselves or their child for the self-harm and developing new ways to communicate with their child. Parents were generally eager to pass their knowledge on to other people in the same situation. Conclusions Parents reported changes in their parenting behaviours after the discovery of a child’s self-harm. Professionals involved in the care of young people who self-harm might use this information in supporting and advising parents.</p

    Tissue Glucocorticoid Metabolism in Adrenal Insufficiency:A Prospective Study of Dual-release Hydrocortisone Therapy

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    Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo.Study Design and Methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls.Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue.Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC

    Population-based type-specific prevalence of high-risk human papillomavirus infection in Estonia

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    <p>Abstract</p> <p>Background</p> <p>Effective prophylactic vaccines are available against human papillomavirus (HPV) types 6, 11, 16, and 18 which are licensed for routine use among young women. Monitoring is needed to demonstrate protection against cervical cancer, to verify duration of protection, and assess replacement frequency of non-vaccine types among vaccinated cohorts.</p> <p>Methods</p> <p>Data from a population-based study were used to assess the type-specific prevalence of HPV in a non-vaccinated population in Estonia: 845 self-administered surveys and self-collected vaginal swabs were distributed, 346 were collected by mail and tested for HPV DNA from female participants 18-35 years of age.</p> <p>Results</p> <p>The overall HPV prevalence (weighted estimate to account for the sampling method) in the study population (unvaccinated women aged 18-35) was calculated to be 38% (95% CI 31-45%), with estimated prevalences of high- and low-risk HPV types 21% (95% CI 16-26%), and 10% (95% CI 7-14%), respectively. Of the high-risk HPV types, HPV 16 was detected most frequently (6.4%; 95% CI 4.0-9.8%) followed by HPV 53 (4.3%; 95% CI 2.3-7.2%) and HPV 66 (2.8%; 95% CI 1.3-5.2%).</p> <p>Conclusions</p> <p>We observed a high prevalence of total and high-risk type HPV in an Eastern European country. The most common high-risk HPV types detected were HPV 16, 53, and 66.</p

    Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

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    Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

    The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

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    The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure
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