Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6

The secreted hexameric form of the dengue virus (DENV) non-structural protein 1 (NS1) has recently been shown to elicit inflammatory cytokine release and disrupt endothelial cell monolayer integrity. This suggests that circulating NS1 contributes to the vascular leak that plays a major role in the pathology of dengue haemorrhagic fever and shock. Pathways activated by NS1 are thus of great interest as potential therapeutic targets. Recent works have separately implicated both toll-like receptor 4 (TLR4) and the TLR2/6 heterodimer in immune cell activation by NS1. Here we have used mouse gene knockout macrophages and antibodies blocking TLR function in human peripheral blood mononuclear cells to show that recombinant NS1, expressed and purified from eukaryotic cells, induces cytokine production via TLR4 but not TLR2/6. Furthermore, the commercial Escherichia coli-derived recombinant NS1 preparation used in other work to implicate TLR2/6 in the response is not correctly folded and appears to be contaminated by several microbial TLR ligands. Thus TLR4 remains a therapeutic target for DENV infections, with TLR4 antagonists holding promise for the treatment of dengue disease

Significant evidence for a heritable contribution to cancer predisposition: a review of cancer familiality by site

<p>Abstract</p> <p>Background/Aims</p> <p>Sound and rigorous well-established, and newly extended, methods for genetic epidemiological analysis were used to analyze population evidence for genetic contributions to risk for numerous common cancer sites in Utah. The Utah Population Database (UPDB) has provided important illumination of the familial contribution to cancer risk by cancer site.</p> <p>Methods</p> <p>With over 15 years of new cancer data since the previous comprehensive familial cancer analysis, we tested for excess familial clustering using an expanded Genealogical Index of Familiality (dGIF) methodology that provides for a more informative, but conservative test for the existence of a genetic contribution to familial relatedness in cancer.</p> <p>Results</p> <p>Some new cancer sites have been analyzed for the first time, having achieved sufficiently large sample size with additions to the UPDB. This new analysis has identified 6 cancer sites with significant evidence for a heritable contribution to risk, including lip, chronic lymphocytic leukemia, thyroid, lung, prostate, and melanoma.</p> <p>Conclusions</p> <p>Both environmentally and genetically-based familial clustering have clinical significance, and these results support increased surveillance for cancer of the same sites among close relatives of affected individuals for many more cancers than are typically considered.</p

Cosmic Ray Anomalies from the MSSM?

The recent positron excess in cosmic rays (CR) observed by the PAMELA satellite may be a signal for dark matter (DM) annihilation. When these measurements are combined with those from FERMI on the total ($e^++e^-$) flux and from PAMELA itself on the $\bar p/p$ ratio, these and other results are difficult to reconcile with traditional models of DM, including the conventional mSUGRA version of Supersymmetry even if boosts as large as $10^{3-4}$ are allowed. In this paper, we combine the results of a previously obtained scan over a more general 19-parameter subspace of the MSSM with a corresponding scan over astrophysical parameters that describe the propagation of CR. We then ascertain whether or not a good fit to this CR data can be obtained with relatively small boost factors while simultaneously satisfying the additional constraints arising from gamma ray data. We find that a specific subclass of MSSM models where the LSP is mostly pure bino and annihilates almost exclusively into $\tau$ pairs comes very close to satisfying these requirements. The lightest $\tilde \tau$ in this set of models is found to be relatively close in mass to the LSP and is in some cases the nLSP. These models lead to a significant improvement in the overall fit to the data by an amount $\Delta \chi^2 \sim 1/$dof in comparison to the best fit without Supersymmetry while employing boosts $\sim 100$. The implications of these models for future experiments are discussed.Comment: 57 pages, 31 figures, references adde

Are you PEPped and PrEPped for travel? Risk mitigation of HIV infection for travelers

The HIV pandemic persists globally and travelers are at risk for infection by the Human Immunodeficiency Virus (HIV). While HIV-focused guidelines delineate risk stratification and mitigation strategies for people in their home communities, travel issues are not addressed. In this review, direct and indirect evidence on HIV risk among travelers is explored. The burgeoning practice of employing pre-exposure prophylaxis (PrEP) with anti-retroviral therapy in the non-travel setting is introduced, as well as the more established use of post-exposure prophylaxis (PEP). Challenges in applying these lessons to travelers are discussed, and a new guidelines process is scoped and recommended

The heteronomy of choice architecture

Choice architecture is heralded as a policy approach that does not coercively reduce freedom of choice. Still we might worry that this approach fails to respect individual choice because it subversively manipulates individuals, thus contravening their personal autonomy. In this article I address two arguments to this effect. First, I deny that choice architecture is necessarily heteronomous. I explain the reasons we have for avoiding heteronomous policy-making and offer a set of four conditions for non-heteronomy. I then provide examples of nudges that meet these conditions. I argue that these policies are capable of respecting and promoting personal autonomy, and show this claim to be true across contrasting conceptions of autonomy. Second, I deny that choice architecture is disrespectful because it is epistemically paternalistic. This critique appears to loom large even against non-heteronomous nudges. However, I argue that while some of these policies may exhibit epistemically paternalistic tendencies, these tendencies do not necessarily undermine personal autonomy. Thus, if we are to find such policies objectionable, we cannot do so on the grounds of respect for autonomy

Multiple Chronic Conditions: Prevalence, Health Consequences, and Implications for Quality, Care Management, and Costs

Persons with multiple chronic conditions are a large and growing segment of the US population. However, little is known about how chronic conditions cluster, and the ramifications of having specific combinations of chronic conditions. Clinical guidelines and disease management programs focus on single conditions, and clinical research often excludes persons with multiple chronic conditions. Understanding how conditions in combination impact the burden of disease and the costs and quality of care received is critical to improving care for the 1 in 5 Americans with multiple chronic conditions. This Medline review of publications examining somatic chronic conditions co-occurring with 1 or more additional specific chronic illness between January 2000 and March 2007 summarizes the state of our understanding of the prevalence and health challenges of multiple chronic conditions and the implications for quality, care management, and costs

Effectiveness of temozolomide for primary glioblastoma multiforme in routine clinical practice

Temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiforme since 2005. To assess the effectiveness of temozolomide in routine clinical practice, we conducted an observational study at Maastricht University Medical Centre (MUMC). Data of patients receiving radiotherapy and temozolomide between January 2005 and January 2008 were retrieved from a clinical database (radiochemotherapy group), as were data of patients in a historical control group from the period before 2005 treated with radiotherapy only (radiotherapy group). The primary endpoint was overall survival. A total of 125 patients with GBM were selected to form the study cohort. Median survival benefit was 4 months: the median overall survival was 12 months (95% CI, 9.7–14.3) in the group with radiochemotherapy with temozolomide, versus 8 months (95% CI, 5.3–10.7) in the group with only radiotherapy. Progression-free survival was 7 months (95% CI, 5.5–8.5) in the radiochemotherapy group and 4 months (95% CI, 2.9-5.1) in the group with only radiotherapy. The two-year survival rate was 18% with radiochemotherapy with temozolomide against 4% with radiotherapy alone. Concomitant treatment with radiotherapy and temozolomide followed by adjuvant temozolomide resulted in grade III or IV haematological toxic effects in 9% of patients. The addition of temozolomide to radiotherapy in routine clinical practice for newly diagnosed glioblastoma resulted in a clinically meaningful survival benefit with minimal haematological toxicity, which confirms the experience of previous trials and justifies the continued use of temozolomide in routine clinical practice

Familial risks in nervous system tumours: joint Nordic study

Background:Familial nervous system cancers are rare and limited data on familial aspects are available particularly on site-specific tumours.Methods:Data from five Nordic countries were used to analyse familial risks of nervous system tumours. Standardised incidence ratios (SIRs) were calculated for offspring of affected relatives compared with offspring of non-affected relatives.Results:The total number of patients with nervous system tumour was 63 307, of whom 32 347 belonged to the offspring generation. Of 851 familial patients (2.6%) in the offspring generation, 42 (4.7%) belonged to the families of a parent and at least two siblings affected. The SIR of brain tumours was 1.7 in offspring of affected parents; it was 2.0 in siblings and 9.4 in families with a parent and sibling affected. For spinal tumours, the SIRs were much higher for offspring of early onset tumours, 14.0 for offspring of affected parents and 22.7 for siblings. The SIRs for peripheral nerve tumours were 16.3 in offspring of affected parents, 27.7 in siblings and 943.9 in multiplex families.Conclusion:The results of this population-based study on medically diagnosed tumours show site-, proband- and age-specific risks for familial tumours, with implications for clinical genetic counselling and identification of the underlying genes.British Journal of Cancer advance online publication, 25 May 2010; doi:10.1038/sj.bjc.6605708 www.bjcancer.com

Development and preliminary validation of Brace Questionnaire (BrQ): a new instrument for measuring quality of life of brace treated scoliotics

BACKGROUND: The quality of life among children with idiopathic scoliosis during their adolescence has been reported to be affected by the brace itself. However, a controversy exists whether brace treated scoliotics experience a poor quality of life, thus there is a need for the development of a brace-oriented instrument, as the now-existing questionnaires that are commonly used, such as the SRS -22, take into consideration the effects of both the conservative and the surgical treatment on quality of life of scoliotic children. The aim of the present study is to assess the validity and reliability of Brace Questionnaire (BrQ), a new instrument for measuring quality of life of scoliotic adolescents who are treated conservatively with a brace. MATERIAL-METHOD: Methodology of development involved literature review, patient and health care professionals' in-depth interviews and content validity analysis on patients. A validation study was performed on 28 brace treated scoliotic children aged between 9 and 18 years old. BrQ was assessed for the following psychometric properties: item convergent validity, floor and ceiling effects, internal consistency reliability, clinical validity and responsiveness to change. RESULTS: BrQ is self administrated and developmentally appropriate for ages 9 to 18 years old and is consisted of 34 Likert-scale items associated with eight domains: general health perception, physical functioning, emotional functioning, self esteem and aesthetics, vitality, school activity, bodily pain and social functioning of scoliotic children treated conservatively with a brace. The subscales of these eight dimensions can be combined to produce a total score. Higher scores mean a better quality of life. An item convergent validity ≥ 0.40 was satisfied by all items in the present study. A satisfactory internal consistency reliability for the BrQ was recorded (Cronbach's alpha coefficient was 0.82). There were no floor or ceiling effects. The correlation between BrQ overall scores and mild and moderate scoliosis was statistically significant (p < 0.001), revealing high clinical validity. An increase in effect sizes for the patient with improved scoliotic curves indicates that the BrQ is responsive to change in health status. CONCLUSION: BrQ is reliable, valid and responsive to change in adolescents with IS who are treated conservatively with a brace

Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whether statins can benefit patients with dementia remains unclear because of conflicting results. We hypothesized that some of the confusion in the literature might arise from differences in efficacy of different statins. We used a large database to compare the action of several different statins to investigate whether some statins might be differentially associated with a reduction in the incidence of dementia and Parkinson's disease.</p> <p>Methods</p> <p>We analyzed data from the decision support system of the US Veterans Affairs database, which contains diagnostic, medication and demographic information on 4.5 million subjects. The association of lovastatin, simvastatin and atorvastatin with dementia was examined with Cox proportional hazard models for subjects taking statins compared with subjects taking cardiovascular medications other than statins, after adjusting for covariates associated with dementia or Parkinson's disease.</p> <p>Results</p> <p>We observed that simvastatin is associated with a significant reduction in the incidence of dementia in subjects ≥65 years, using any of three models. The first model incorporated adjustment for age, the second model included adjusted for three known risk factors for dementia, hypertension, cardiovascular disease or diabetes, and the third model incorporated adjustment for the Charlson index, which is an index that provides a broad assessment of chronic disease. Data were obtained for over 700000 subjects taking simvastatin and over 50000 subjects taking atorvastatin who were aged >64 years. Using model 3, the hazard ratio for incident dementia for simvastatin and atorvastatin are 0.46 (CI 0.44–0.48, <it>p </it>< 0.0001) and 0.91 (CI 0.80–1.02, <it>p </it>= 0.11), respectively. Lovastatin was not associated with a reduction in the incidence of dementia. Simvastatin also exhibited a reduced hazard ratio for newly acquired Parkinson's disease (HR 0.51, CI 0.4–0.55, <it>p </it>< 0.0001).</p> <p>Conclusion</p> <p>Simvastatin is associated with a strong reduction in the incidence of dementia and Parkinson's disease, whereas atorvastatin is associated with a modest reduction in incident dementia and Parkinson's disease, which shows only a trend towards significance.</p