Intravenous delivery of adeno-associated virus 9-encoded IGF-1Ea propeptide improves post-infarct cardiac remodelling

The insulin-like growth factor Ea propeptide (IGF-1Ea) is a powerful enhancer of cardiac muscle growth and regeneration, also blocking age-related atrophy and beneficial in multiple skeletal muscle diseases. The therapeutic potential of IGF-1Ea compared with mature IGF-1 derives from its local action in the area of synthesis. We have developed an adeno-associated virus (AAV) vector for IGF-1Ea delivery to the heart to treat mice after myocardial infarction and examine the reparative effects of local IGF-1Ea production on left ventricular remodelling. A cardiotropic AAV9 vector carrying a cardiomyocyte-specific IGF-1Ea-luciferase bi-cistronic gene expression cassette (AAV9.IGF-1Ea) was administered intravenously to infarcted mice, 5 h after ischemia followed by reperfusion (I/R), as a model of myocardial infarction. Virally encoded IGF-1Ea in the heart improved global left ventricular function and remodelling, as measured by wall motion and thickness, 28 days after delivery, with higher viral titers yielding better improvement. The present study demonstrates that single intravenous AAV9-mediated IGF-1Ea Gene Therapy represents a tissue-targeted therapeutic approach to prevent the adverse remodelling after myocardial infarct

Evidence-based restructuring of health and social care

In this Perspective, Aziz Sheikh discusses research to evaluate health policy changes in the provision of care, commenting on a study by James Lopez Bernal and colleagues that examined specialist-dominated hospital care versus community-based care in the United Kingdom

Flavour physics constraints in the BMSSM

We study the implications of the presence of the two leading-order, non-renormalizable operators in the Higgs sector of the MSSM to flavour physics observables. We identify the constraints of flavour physics on the parameters of the BMSSM when we: a) focus on a region of parameters for which electroweak baryogenesis is feasible, b) use a CMSSM-like parametrization, and c) consider the case of a generic NUHM-type model. We find significant differences as compared to the standard MSSM case.Comment: 22 pages, 7 figure

CD300a inhibits CD16-mediated NK cell effector functions in HIV-1-infected patients

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) through CD16 has a critical role in anti-human immunodeficiency virus (HIV) responses. CD300a, an inhibitory receptor highly expressed on NK cells, has the capacity to diminish NK cell killing of pseudorabies-infected cells. CD300a expression is altered during HIV-1 infection on B cells and CD4+ T lymphocytes. In this work, we have investigated in a cross-sectional study the expression and function of CD300a on NK cells from healthy donors, untreated HIV-1 infected subjects and patients on combined antiretroviral treatment (cART). First, we detected an expansion of a CD300a-expressing CD56neg NK cell subset in untreated HIV-1 infected patients. In addition, an association between CD300a expression and other NK cell surface receptors was observed in both healthy and HIV-1 infected people. Notably, we also described that CD300a exerted an inhibitory effect in CD16-mediated effector functions, including degranulation and cytokine production, in all donors and NK cell subsets and, more importantly, this inhibitory effect was higher in HIV-1 infected patients. Therefore, the CD300a inhibitory receptor could be proposed as a new target for therapies aimed to improve NK cells effector functions in HIV-1 infected patients

Differential spatial repositioning of activated genes in Biomphalaria glabrata snails infected with Schistosoma mansoni

Copyright @ 2014 Arican-Goktas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Schistosomiasis is an infectious disease infecting mammals as the definitive host and fresh water snails as the intermediate host. Understanding the molecular and biochemical relationship between the causative schistosome parasite and its hosts will be key to understanding and ultimately treating and/or eradicating the disease. There is increasing evidence that pathogens that have co-evolved with their hosts can manipulate their hosts' behaviour at various levels to augment an infection. Bacteria, for example, can induce beneficial chromatin remodelling of the host genome. We have previously shown in vitro that Biomphalaria glabrata embryonic cells co-cultured with schistosome miracidia display genes changing their nuclear location and becoming up-regulated. This also happens in vivo in live intact snails, where early exposure to miracidia also elicits non-random repositioning of genes. We reveal differences in the nuclear repositioning between the response of parasite susceptible snails as compared to resistant snails and with normal or live, attenuated parasites. Interestingly, the stress response gene heat shock protein (Hsp) 70 is only repositioned and then up-regulated in susceptible snails with the normal parasite. This movement and change in gene expression seems to be controlled by the parasite. Other differences in the behaviour of genes support the view that some genes are responding to tissue damage, for example the ferritin genes move and are up-regulated whether the snails are either susceptible or resistant and upon exposure to either normal or attenuated parasite. This is the first time host genome reorganisation has been seen in a parasitic host and only the second time for any pathogen. We believe that the parasite elicits a spatio-epigenetic reorganisation of the host genome to induce favourable gene expression for itself and this might represent a fundamental mechanism present in the human host infected with schistosome cercariae as well as in other host-pathogen relationships.NIH and Sandler Borroughs Wellcome Travel Fellowshi

Mood instability, mental illness and suicidal ideas : results from a household survey

Purpose: There is weak and inconsistent evidence that mood instability (MI) is associated with depression, post traumatic stress disorder (PTSD) and suicidality although the basis of this is unclear. Our objectives were first to test whether there is an association between depression and PTSD, and MI and secondly whether MI exerts an independent effect on suicidal thinking over and above that explained by common mental disorders. Methods: We used data from the Adult Psychiatric Morbidity Survey 2007 (N = 7,131). Chi-square tests were used to examine associations between depression and PTSD, and MI, followed by regression modelling to examine associations between MI and depression, and with PTSD. Multiple logistic regression analyses were used to assess the independent effect of MI on suicidal thinking, after adjustment for demographic factors and the effects of common mental disorder diagnoses. Results: There are high rates of MI in depression and PTSD and the presence of MI increases the odds of depression by 10.66 [95 % confidence interval (CI) 7.51–15.13] and PTSD by 8.69 (95 % CI 5.90–12.79), respectively, after adjusting for other factors. Mood instability independently explained suicidal thinking, multiplying the odds by nearly five (odds ratio 4.82; 95 % CI 3.39–6.85), and was individually by some way the most important single factor in explaining suicidal thoughts. Conclusions: MI is strongly associated with depression and PTSD. In people with common mental disorders MI is clinically significant as it acts as an additional factor exacerbating the risk of suicidal thinking. It is important to enquire about MI as part of clinical assessment and treatment studies are required

CP violation Beyond the MSSM: Baryogenesis and Electric Dipole Moments

We study electroweak baryogenesis and electric dipole moments in the presence of the two leading-order, non-renormalizable operators in the Higgs sector of the MSSM. Significant qualitative and quantitative differences from MSSM baryogenesis arise due to the presence of new CP-violating phases and to the relaxation of constraints on the supersymmetric spectrum (in particular, both stops can be light). We find: (1) spontaneous baryogenesis, driven by a change in the phase of the Higgs vevs across the bubble wall, becomes possible; (2) the top and stop CP-violating sources can become effective; (3) baryogenesis is viable in larger parts of parameter space, alleviating the well-known fine-tuning associated with MSSM baryogenesis. Nevertheless, electric dipole moments should be measured if experimental sensitivities are improved by about one order of magnitude.Comment: 33 pages, 6 figure

Campus Mental Health: Implications for Instructors Supporting Students

The recent escalation in student suicides due to mental health problems has encouraged higher education institutions to not only modify their overall support structures, but to also (re)define the role of faculty and staff. Despite the increased attention given to student mental health in Canadian higher education institutions, little is known and understood about how instructors view their role as supporters or promoters of student mental health. The purpose of this study was to explore the role of college instructors in supporting students with mental health problems or illnesses. Participants were 42 instructors between the ages of 25 to 64 from Molize College in Toronto, Ontario. Qualitative ethnography was employed to gather data from participants, specifically through a survey questionnaire and interviews. A constructivist framework was adopted to analyze and understand the values, perceptions, meanings, and practices post-secondary instructors carry around notions of student mental health and intervention. Findings revealed that instructors were generally aware of student mental health concerns in post-secondary institutions, but that greater awareness was still warranted, namely in the areas of instructor mental health and location of support services. Findings also demonstrated that most instructors evaluated their knowledge and confidence in relation to student mental health as poor, which was often credited to limited relevant professional development and training. Additionally, data indicated that instructors carried skepticism towards the role of some student support services departments, as well as towards their own role when supporting the mental health and well-being of students. On a final note, findings revealed that instructors commonly employed four practices to support the mental health and well-being of students: conversation, referral, accommodations, and curricular inclusion and instruction. Future studies are encouraged to acknowledge the narratives of instructors through ethnographic inquiry, to allow for greater insights into their awareness, knowledge/confidence, responsibilities, and practices when it comes to supporting the mental health and well-being of students in higher education settings. Incorporating the instructor may not be a panacea for the shortcomings of current mental health policies and practices in higher education settings, but it can certainly represent a colossal step in that direction. KEYWORDS: student mental health, higher education, instructor