Common Genetic Variants Explain the Majority of the Correlation Between Height and Intelligence : The Generation Scotland Study

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Dysfunction of Nrf-2 in CF Epithelia Leads to Excess Intracellular H2O2 and Inflammatory Cytokine Production

Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1β mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by ≥2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by ∼70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses

A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats

Accepted ManuscriptChronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post-synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats.CPN was funded by CIHR Vanier Graduate Scholarship (338319); APVS was funded by Fundação para a Ciência e Tecnologia (SFRH/BPD/52078/2013); ERH was funded by CIHR Postdoctoral Fellowship (MFE-123712); SA was funded by a Queen Elizabeth II Graduate Scholarship in Science and Technology; ÉCD was funded by the Canadian Institute of Health Research (MOP-25953)info:eu-repo/semantics/publishedVersio

Sperm Chromatin-Induced Ectopic Polar Body Extrusion in Mouse Eggs after ICSI and Delayed Egg Activation

Meiotic chromosomes in an oocyte are not only a maternal genome carrier but also provide a positional signal to induce cortical polarization and define asymmetric meiotic division of the oocyte, resulting in polar body extrusion and haploidization of the maternal genome. The meiotic chromosomes play dual function in determination of meiosis: 1) organizing a bipolar spindle formation and 2) inducing cortical polarization and assembly of a distinct cortical cytoskeleton structure in the overlying cortex for polar body extrusion. At fertilization, a sperm brings exogenous paternal chromatin into the egg, which induces ectopic cortical polarization at the sperm entry site and leads to a cone formation, known as fertilization cone. Here we show that the sperm chromatin-induced fertilization cone formation is an abortive polar body extrusion due to lack of spindle induction by the sperm chromatin during fertilization. If experimentally manipulating the fertilization process to allow sperm chromatin to induce both cortical polarization and spindle formation, the fertilization cone can be converted into polar body extrusion. This suggests that sperm chromatin is also able to induce polar body extrusion, like its maternal counterpart. The usually observed cone formation instead of ectopic polar body extrusion induced by sperm chromatin during fertilization is due to special sperm chromatin compaction which restrains it from rapid spindle induction and therefore provides a protective mechanism to prevent a possible paternal genome loss during ectopic polar body extrusion

Regulation of BRCA1 expression and its relationship to sporadic breast cancer

Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression

Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.National Science Council of Taiwan (NSC 99-2221-E-039-013-)Committee on Chinese Medicine and Pharmacy (CCMP100-RD-030)China Medical University and Asia University (CMU98-TCM)China Medical University and Asia University (CMU99-TCM)China Medical University and Asia University (CMU99-S-02)China Medical University and Asia University (CMU99-ASIA-25)China Medical University and Asia University (CMU99-ASIA-26)China Medical University and Asia University (CMU99-ASIA-27)China Medical University and Asia University (CMU99-ASIA-28)Taiwan Department of Health. Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004)Taiwan Department of Health. Cancer Research Center of Excellence (DOH100-TD-C-111-005

A Patient-Specific in silico Model of Inflammation and Healing Tested in Acute Vocal Fold Injury

The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level. We extended this approach to the case of a novel, patient-specific ABM that we generated for vocal fold inflammation, with the ultimate goal of identifying individually optimized treatments. ABM simulations reproduced trajectories of inflammatory mediators in laryngeal secretions of individuals subjected to experimental phonotrauma up to 4 hrs post-injury, and predicted the levels of inflammatory mediators 24 hrs post-injury. Subject-specific simulations also predicted different outcomes from behavioral treatment regimens to which subjects had not been exposed. We propose that this translational application of computational modeling could be used to design patient-specific therapies for the larynx, and will serve as a paradigm for future extension to other clinical domains

Tai Chi for osteopenic women: design and rationale of a pragmatic randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Post-menopausal osteopenic women are at increased risk for skeletal fractures. Current osteopenia treatment guidelines include exercise, however, optimal exercise regimens for attenuating bone mineral density (BMD) loss, or for addressing other fracture-related risk factors (e.g. poor balance, decreased muscle strength) are not well-defined. Tai Chi is an increasingly popular weight bearing mind-body exercise that has been reported to positively impact BMD dynamics and improve postural control, however, current evidence is inconclusive. This study will determine the effectiveness of Tai Chi in reducing rates of bone turnover in post-menopausal osteopenic women, compared with standard care, and will preliminarily explore biomechanical processes that might inform how Tai Chi impacts BMD and associated fracture risks.</p> <p>Methods/Design</p> <p>A total of 86 post-menopausal women, aged 45-70y, T-score of the hip and/or spine -1.0 and -2.5, have been recruited from primary care clinics of a large healthcare system based in Boston. They have been randomized to a group-based 9-month Tai Chi program plus standard care or to standard care only. A unique aspect of this trial is its pragmatic design, which allows participants randomized to Tai Chi to choose from a pre-screened list of community-based Tai Chi programs. Interviewers masked to participants' treatment group assess outcomes at baseline and 3 and 9 months after randomization. Primary outcomes are serum markers of bone resorption (C-terminal cross linking telopeptide of type I collagen), bone formation (osteocalcin), and BMD of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry). Secondary outcomes include health-related quality-of-life, exercise behavior, and psychological well-being. In addition, kinetic and kinematic characterization of gait, standing, and rising from a chair are assessed in subset of participants (n = 16) to explore the feasibility of modeling skeletal mechanical loads and postural control as mediators of fracture risk.</p> <p>Discussion</p> <p>Results of this study will provide preliminary evidence regarding the value of Tai Chi as an intervention for decreasing fracture risk in osteopenic women. They will also inform the feasibility, value and potential limitations related to the use of pragmatic designs for the study of Tai Chi and related mind-body exercise. If the results are positive, this will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study.</p> <p>Trial registration</p> <p>This trial is registered in Clinical Trials.gov, with the ID number of NCT01039012.</p

Effect of a web-based chronic disease management system on asthma control and health-related quality of life: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Asthma is a prevalent and costly disease resulting in reduced quality of life for a large proportion of individuals. Effective patient self-management is critical for improving health outcomes. However, key aspects of self-management such as self-monitoring of behaviours and symptoms, coupled with regular feedback from the health care team, are rarely addressed or integrated into ongoing care. Health information technology (HIT) provides unique opportunities to facilitate this by providing a means for two way communication and exchange of information between the patient and care team, and access to their health information, presented in personalized ways that can alert them when there is a need for action. The objective of this study is to evaluate the acceptability and efficacy of using a web-based self-management system, My Asthma Portal (MAP), linked to a case-management system on asthma control, and asthma health-related quality of life.</p> <p>Methods</p> <p>The trial is a parallel multi-centered 2-arm pilot randomized controlled trial. Participants are randomly assigned to one of two conditions: a) MAP and usual care; or b) usual care alone. Individuals will be included if they are between 18 and 70, have a confirmed asthma diagnosis, and their asthma is classified as not well controlled by their physician. Asthma control will be evaluated by calculating the amount of fast acting beta agonists recorded as dispensed in the provincial drug database, and asthma quality of life using the Mini Asthma Related Quality of Life Questionnaire. Power calculations indicated a needed total sample size of 80 subjects. Data are collected at baseline, 3, 6, and 9 months post randomization. Recruitment started in March 2010 and the inclusion of patients in the trial in June 2010.</p> <p>Discussion</p> <p>Self-management support from the care team is critical for improving chronic disease outcomes. Given the high volume of patients and time constraints during clinical visits, primary care physicians have limited time to teach and reinforce use of proven self-management strategies. HIT has the potential to provide clinicians and a large number of patients with tools to support health behaviour change.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN34326236">ISRCTN34326236</a>.</p