Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages.

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine

Interviewer: 'Are women and girls ever responsible for the domestic violence they encounter?' Student: 'No, well, unless they did something really, really bad …'

Research shows the ‘gendered nature’ of domestic violence, with Women’s Aid (a UK-based charity) estimating that 1 in 4 women are affected (2014). This paper reports on a project - funded by Comic Relief, completed by Nottinghamshire Domestic Violence Forum (now known as Equation) and evaluated by Nottingham Trent University. The project adopts a Whole School Approach in seeking to prevent domestic violence. Students at three secondary schools attended between one and five blocks of work, and special events. There is evidence of positive developments - with young people showing understanding of domestic violence as well as the margins between healthy and unhealthy relationships. However, not all students could reply ‘never’ to the question of ‘are women and girls to blame for the domestic violence they experience?’, remarking that if the woman had done something ‘really, really bad’ then violence might be justified. We argue that young people’s uncertainties need to be situated within the gender-unequal socio-contexts of contemporary society, and further call for a WSA to domestic violence prevention to be a compulsory part of the UK national curriculum

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

BACKGROUND L’Hermitte’s sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. METHODS 117 patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. RESULTS 42 patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95%CI 0.51 – 2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95%CI 0.051 – 3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95%CI 0.15 – 0.84}) were more likely to develop LS. Higher V40Gy (p = 0.047, OR = 1.06 {95%CI 1.00 – 1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95%CI 0.92 – 1.00}) were associated with elevated risk of LS, with borderline significance. CONCLUSIONS In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Kochen-Specker Vectors

We give a constructive and exhaustive definition of Kochen-Specker (KS) vectors in a Hilbert space of any dimension as well as of all the remaining vectors of the space. KS vectors are elements of any set of orthonormal states, i.e., vectors in n-dim Hilbert space, H^n, n>3 to which it is impossible to assign 1s and 0s in such a way that no two mutually orthogonal vectors from the set are both assigned 1 and that not all mutually orthogonal vectors are assigned 0. Our constructive definition of such KS vectors is based on algorithms that generate MMP diagrams corresponding to blocks of orthogonal vectors in R^n, on algorithms that single out those diagrams on which algebraic 0-1 states cannot be defined, and on algorithms that solve nonlinear equations describing the orthogonalities of the vectors by means of statistically polynomially complex interval analysis and self-teaching programs. The algorithms are limited neither by the number of dimensions nor by the number of vectors. To demonstrate the power of the algorithms, all 4-dim KS vector systems containing up to 24 vectors were generated and described, all 3-dim vector systems containing up to 30 vectors were scanned, and several general properties of KS vectors were found.Comment: 19 pages, 6 figures, title changed, introduction thoroughly rewritten, n-dim rotation of KS vectors defined, original Kochen-Specker 192 (117) vector system translated into MMP diagram notation with a new graphical representation, results on Tkadlec's dual diagrams added, several other new results added, journal version: to be published in J. Phys. A, 38 (2005). Web page: http://m3k.grad.hr/pavici

Improving prevention, monitoring and management of diabetes among ethnic minorities: contextualizing the six G’s approach

Objective: People from Black, Asian and Minority Ethnic (BAME) groups are known to have an increased risk of devel-oping diabetes and face greater barriers to accessing healthcare resources compared to their ‘white British’ counter-parts. The extent of these barriers varies by demographics and different socioeconomic circumstances that people find themselves in. The purpose of this paper is to present and discuss a new framework to understand, disentangle and tackle these barriers so that improvements in the effectiveness of diabetes interventions for BAME communities can be achieved. Results: The main mediators of lifestyle behavioural change are gender, generation, geography, genes, God/religion, and gaps in knowledge and economic resources. Dietary and cultural practices of these individuals significantly vary according to gender, generation, geographical origin and religion. Recognition of these factors is essential in increas-ing knowledge of healthy eating, engagement in physical activity and utilisation of healthcare services. Use of the six G’s framework alongside a community centred approach is crucial in developing and implementing culturally sensi-tive interventions for diabetes prevention and management in BAME communities. This could improve their health outcomes and overall wellbeing

Minimising disability and falls in older people through a post-hospital exercise program: a protocol for a randomised controlled trial and economic evaluation

Background: Disability and falls are particularly common among older people who have recently been hospitalised. There is evidence that disability severity and fall rates can be reduced by well-designed exercise interventions. However, the potential for exercise to have these benefits in older people who have spent time in hospital has not been established. This randomised controlled trial will investigate the effects of a home-based exercise program on disability and falls among people who have had recent hospital stays. The cost-effectiveness of the exercise program from the health and community service provider's perspective will be established. In addition, predictors for adherence with the exercise program will be determined. Methods and design: Three hundred and fifty older people who have recently had hospital stays will participate in the study. Participants will have no medical contraindications to exercise and will be cognitively and physically able to complete the assessments and exercise program. The primary outcome measures will be mobility-related disability (measured with 12 monthly questionnaires and the Short Physical Performance Battery) and falls (measured with 12 monthly calendars). Secondary measures will be tests of risk of falling, additional measures of mobility, strength and flexibility, quality of life, fall-related self efficacy, health-system and community-service contact, assistance from others, difficulty with daily tasks, physical activity levels and adverse events. After discharge from hospital and completion of all hospital-related treatments, participants will be randomly allocated to an intervention group or usual-care control group. For the intervention group, an individualised home exercise program will be established and progressed during ten home visits from a physiotherapist. Participants will be asked to exercise at home up to 6 times per week for the 12-month study period. Discussion: The study will determine the impact of this exercise intervention on mobility-related disability and falls in older people who have been in hospital as well as cost-effectiveness and predictors of adherence to the program. Thus, the results will have direct implications for the design and implementation of interventions for this high-risk group of older people.7 page(s

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Search for New Physics with Jets and Missing Transverse Momentum in pp collisions at sqrt(s) = 7 TeV

A search for new physics is presented based on an event signature of at least three jets accompanied by large missing transverse momentum, using a data sample corresponding to an integrated luminosity of 36 inverse picobarns collected in proton--proton collisions at sqrt(s)=7 TeV with the CMS detector at the LHC. No excess of events is observed above the expected standard model backgrounds, which are all estimated from the data. Exclusion limits are presented for the constrained minimal supersymmetric extension of the standard model. Cross section limits are also presented using simplified models with new particles decaying to an undetected particle and one or two jets