Physical and mental health comorbidity is common in people with multiple sclerosis: nationally representative cross-sectional population database analysis

<b>Background</b> Comorbidity in Multiple Sclerosis (MS) is associated with worse health and higher mortality. This study aims to describe clinician recorded comorbidities in people with MS. <p></p> <b>Methods</b> 39 comorbidities in 3826 people with MS aged ≥25 years were compared against 1,268,859 controls. Results were analysed by age, gender, and socioeconomic status, with unadjusted and adjusted Odds Ratios (ORs) calculated using logistic regression. <p></p> <b>Results</b> People with MS were more likely to have one (OR 2.44; 95% CI 2.26-2.64), two (OR 1.49; 95% CI 1.38-1.62), three (OR 1.86; 95% CI 1.69-2.04), four or more (OR 1.61; 95% CI 1.47-1.77) non-MS chronic conditions than controls, and greater mental health comorbidity (OR 2.94; 95% CI 2.75-3.14), which increased as the number of physical comorbidities rose. Cardiovascular conditions, including atrial fibrillation (OR 0.49; 95% CI 0.36-0.67), chronic kidney disease (OR 0.51; 95% CI 0.40-0.65), heart failure (OR 0.62; 95% CI 0.45-0.85), coronary heart disease (OR 0.64; 95% CI 0.52-0.71), and hypertension (OR 0.65; 95% CI 0.59-0.72) were significantly less common in people with MS. <p></p> <b>Conclusion</b> People with MS have excess multiple chronic conditions, with associated increased mental health comorbidity. The low recorded cardiovascular comorbidity warrants further investigation

Mitochondrial function is involved in regulation of cholesterol efflux to apolipoprotein (apo)A-I from murine RAW 264.7 macrophages

<p>Abstract</p> <p>Background</p> <p>Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function.</p> <p>Methods</p> <p>Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [³H]cholesterol to apolipoprotein (apo) A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, <it>Gapdh</it>, and combined with studies of this molecule on cholesterol esterification, <it>de novo</it> lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett’s or Bonferroni post <it>t</it>-tests, as appropriate.</p> <p>Results</p> <p>The positive control, resveratrol (24 h), significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; <it>p</it><0.01) and oligomycin (55%; <it>p</it><0.01), under conditions (10 μM, 3 h) which did not induce cellular toxicity or deplete total cellular ATP content. Levels of ATP binding cassette transporter A1 (ABCA1) protein were repressed by oligomycin under optimal efflux conditions, despite paradoxical increases in <it>Abca1</it> mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (<it>Abca1</it>, <it>Abcg4</it>, <it>Stard1</it>) and cholesterol biosynthesis (<it>Hmgr</it>, <it>Mvk</it>, <it>Scap</it>, <it>Srebf2</it>), indicating profound dysregulation of cholesterol homeostasis.</p> <p>Conclusions</p> <p>Acute loss of mitochondrial function, and in particular Δψ_m, reduces cholesterol efflux to apoA-I and dysregulates macrophage cholesterol homeostasis mechanisms. Bioavailable antioxidants, targeted to mitochondria and capable of sustaining effective mitochondrial function, may therefore prove effective in maintenance of arterial health.</p

Community Health Environment Scan Survey (CHESS): a novel tool that captures the impact of the built environment on lifestyle factors

Background: Novel1 1This study was performed on behalf of the Community Interventions for Health (CIH) collaboration. efforts and accompanying tools are needed to tackle the global burden of chronic disease. This paper presents an approach to describe the environments in which people live, work, and play. Community Health Environment Scan Survey (CHESS) is an empirical assessment tool that measures the availability and accessibility, of healthy lifestyle options lifestyle options. CHESS reveals existing community assets as well as opportunities for change, shaping community intervention planning efforts by focusing on community-relevant opportunities to address the three key risk factors for chronic disease (i.e. unhealthy diet, physical inactivity, and tobacco use). Methods: The CHESS tool was developed following a review of existing auditing tools and in consultation with experts. It is based on the social-ecological model and is adaptable to diverse settings in developed and developing countries throughout the world. Results: For illustrative purposes, baseline results from the Community Interventions for Health (CIH) Mexico site are used, where the CHESS tool assessed 583 food stores and 168 restaurants. Comparisons between individual-level survey data from schools and community-level CHESS data are made to demonstrate the utility of the tool in strategically guiding intervention activities. Conclusion: The environments where people live, work, and play are key factors in determining their diet, levels of physical activity, and tobacco use. CHESS is the first tool of its kind that systematically and simultaneously examines how built environments encourage/discourage healthy eating, physical activity, and tobacco use. CHESS can help to design community interventions to prevent chronic disease and guide healthy urban planning

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

Hedgehog Signaling in Tumor Cells Facilitates Osteoblast-Enhanced Osteolytic Metastases

The remodeling process in bone yields numerous cytokines and chemokines that mediate crosstalk between osteoblasts and osteoclasts and also serve to attract and support metastatic tumor cells. The metastatic tumor cells disturb the equilibrium in bone that manifests as skeletal complications. The Hedgehog (Hh) pathway plays an important role in skeletogenesis. We hypothesized that the Hh pathway mediates an interaction between tumor cells and osteoblasts and influences osteoblast differentiation in response to tumor cells. We have determined that breast tumor cells have an activated Hh pathway characterized by upregulation of the ligand, IHH and transcription factor GLI1. Breast cancer cells interact with osteoblasts and cause an enhanced differentiation of pre-osteoblasts to osteoblasts that express increased levels of the osteoclastogenesis factors, RANKL and PTHrP. There is sustained expression of osteoclast-promoting factors, RANKL and PTHrP, even after the osteoblast differentiation ceases and apoptosis sets in. Moreover, tumor cells that are deficient in Hh signaling are compromised in their ability to induce osteoblast differentiation and consequently are inefficient in causing osteolysis. The stimulation of osteoblast differentiation sets the stage for osteoclast differentiation and overall promotes osteolysis. Thus, in the process of developing newer therapeutic strategies against breast cancer metastasis to bone it would worthwhile to keep in mind the role of the Hh pathway in osteoblast differentiation in an otherwise predominant osteolytic phenomenon

Squaring the circle: a priority-setting method for evidence-based service development, reconciling research with multiple stakeholder views.

BACKGROUND: This study demonstrates a technique to aid the implementation of research findings through an example of improving services and self-management in longer-term depression. In common with other long-term conditions, policy in this field requires innovation to be undertaken in the context of a whole system of care, be cost-effective, evidence-based and to comply with national clinical guidelines. At the same time, successful service development must be acceptable to clinicians and service users and choices must be made within limited resources. This paper describes a novel way of resolving these competing requirements by reconciling different sources and types of evidence and systematically engaging multiple stakeholder views. METHODS: The study combined results from mathematical modelling of the care pathway, research evidence on effective interventions and findings from qualitative research with service users in a series of workshops to define, refine and select candidate service improvements. A final consensus-generating workshop used structured discussion and anonymised electronic voting. This was followed by an email survey to all stakeholders, to achieve a pre-defined criterion of consensus for six suggestions for implementation. RESULTS: An initial list of over 20 ideas was grouped into four main areas. At the final workshop, each idea was presented in person, visually and in writing to 40 people, who assigned themselves to one or more of five stakeholder groups: i) service users and carers, ii) clinicians, iii) managers, iv) commissioners and v) researchers. Many belonged to more than one group. After two rounds of voting, consensus was reached on seven ideas and one runner up. The survey then confirmed the top six ideas to be tested in practice. CONCLUSIONS: The method recruited and retained people with diverse experience and views within a health community and took account of a full range of evidence. It enabled a diverse group of stakeholders to travel together in a direction that converged with the messages coming out of the research and successfully yielded priorities for service improvement that met competing requirements

Photoperiod Regulates Lean Mass Accretion, but Not Adiposity, in Growing F344 Rats Fed a High Fat Diet

yesIn this study the effects of photoperiod and diet, and their interaction, were examined for their effects on growth and body composition in juvenile F344 rats over a 4-week period. On long (16L:8D), relative to short (8L:16D), photoperiod food intake and growth rate were increased, but percentage adiposity remained constant (ca 3-4%). On a high fat diet (HFD), containing 22.8% fat (45% energy as fat), food intake was reduced, but energy intake increased on both photoperiods. This led to a small increase in adiposity (up to 10%) without overt change in body weight. These changes were also reflected in plasma leptin and lipid levels. Importantly while both lean and adipose tissue were strongly regulated by photoperiod on a chow diet, this regulation was lost for adipose, but not lean tissue, on HFD. This implies that a primary effect of photoperiod is the regulation of growth and lean mass accretion. Consistent with this both hypothalamic GHRH gene expression and serum IGF-1 levels were photoperiod dependent. As for other animals and humans, there was evidence of central hyposomatotropism in response to obesity, as GHRH gene expression was suppressed by the HFD. Gene expression of hypothalamic AgRP and CRH, but not NPY nor POMC, accorded with the energy balance status on long and short photoperiod. However, there was a general dissociation between plasma leptin levels and expression of these hypothalamic energy balance genes. Similarly there was no interaction between the HFD and photoperiod at the level of the genes involved in thyroid hormone metabolism (Dio2, Dio3, TSHβ or NMU), which are important mediators of the photoperiodic response. These data suggest that photoperiod and HFD influence body weight and body composition through independent mechanisms but in each case the role of the hypothalamic energy balance genes is not predictable based on their known function.Scottish Government (Rural and Environment Science and Analytical Services Division, http://www.scotland.gov.uk/), AWR LR LMT PJM and the BBSRC, (http://www.bbsrc.ac.uk/home/home.aspx, grant BB/K001043/1), AWR GH PJ

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012