Persistent variations in national asthma mortality, hospital admissions and prevalence by socioeconomic status and region in England

Background The UK-wide National Review of Asthma Deaths sought to identify avoidable factors from the high numbers of deaths, but did not examine variation by socioeconomic status (SES) or region. Methods We used asthma deaths in England over the period 2002–2015 obtained from national deaths registers, summarised by quintiles of Index of Multiple Deprivation (IMD) and Government Office Region. Emergency asthma admissions were obtained from Hospital Episode Statistics for England 2001–2011. The prevalence of asthma was derived from the Health Survey for England 2010. Associations of mortality, admissions and prevalence with IMD quintile and region were estimated cross-sectionally using incidence rate ratios (IRRs) adjusted for age and sex and, where possible, smoking. Results Asthma mortality decreased among more deprived groups at younger ages. Among 5–44 year olds, those in the most deprived quintile, mortality was 19% lower than those in the least deprived quintile (IRR 0.81 (95% CI 0.69 to 0.96). In older adults, this pattern was reversed (45–74 years: IRR 1.37 (1.24–1.52), ≥75 years: IRR 1.30 (1.22–1.39)). In 5–44 year olds the inverse trend with asthma mortality contrasted with large positive associations for admissions (IRR 3.34 (3.30–3.38)) and prevalence of severe symptoms (IRR 2.38 (1.70–3.33)). Prevalence trends remained after adjustment for smoking. IRRs for asthma mortality, admissions and prevalence showed significant heterogeneity between English regions. Conclusions Despite asthma mortality, emergency admissions and prevalence decreasing over recent decades, England still experiences significant SES and regional variations. The previously undocumented inverse relation between deprivation and mortality in the young requires further investigation

Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia 1 (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number

BKM Lie superalgebra for the Z_5 orbifolded CHL string

We study the Z_5-orbifolding of the CHL string theory by explicitly constructing the modular form tilde{Phi}_2 generating the degeneracies of the 1/4-BPS states in the theory. Since the additive seed for the sum form is a weak Jacobi form in this case, a mismatch is found between the modular forms generated from the additive lift and the product form derived from threshold corrections. We also construct the BKM Lie superalgebra, tilde{G}_5, corresponding to the modular form tilde{Delta}_1 (Z) = tilde{Phi}_2 (Z)^{1/2} which happens to be a hyperbolic algebra. This is the first occurrence of a hyperbolic BKM Lie superalgebra. We also study the walls of marginal stability of this theory in detail, and extend the arithmetic structure found by Cheng and Dabholkar for the N=1,2,3 orbifoldings to the N=4,5 and 6 models, all of which have an infinite number of walls in the fundamental domain. We find that analogous to the Stern-Brocot tree, which generated the intercepts of the walls on the real line, the intercepts for the N >3 cases are generated by linear recurrence relations. Using the correspondence between the walls of marginal stability and the walls of the Weyl chamber of the corresponding BKM Lie superalgebra, we propose the Cartan matrices for the BKM Lie superalgebras corresponding to the N=5 and 6 models.Comment: 30 pages, 2 figure

Prediction of myelopathic level in cervical spondylotic myelopathy using diffusion tensor imaging

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Yoga programme for type-2 diabetes prevention (YOGA-DP) among high risk people in India: a multicentre feasibility randomised controlled trial protocol.

INTRODUCTION: A huge population in India is at high risk of type-2 diabetes (T2DM). Physical activity and a healthy diet (healthy lifestyle) improve blood glucose levels in people at high risk of T2DM. However, an unhealthy lifestyle is common among Indians. Yoga covers physical activity and a healthy diet and can help to prevent T2DM. The research question to be addressed by the main randomised controlled trial (RCT) is whether a Yoga programme for T2DM prevention (YOGA-DP) is effective in preventing T2DM among high risk people in India as compared with enhanced standard care. In this current study, we are determining the feasibility of undertaking the main RCT. INTERVENTION: YOGA-DP is a structured lifestyle education and exercise programme. The exercise part is based on Yoga and includes Shithilikarana Vyayama (loosening exercises), Surya Namaskar (sun salutation exercises), Asana (Yogic poses), Pranayama (breathing practices) and Dhyana (meditation) and relaxation practices. METHODS AND ANALYSIS: This is a multicentre, two-arm, parallel-group, feasibility RCT with blinded outcome assessment and integrated mixed-methods process evaluation. Eligible participants should be aged 18-74 years, at high risk of T2DM (fasting plasma glucose level 5.6-6.9 mmol/L) and safe to participate in physical activities. At least 64 participants will be randomised to intervention or control group with final follow-up at 6 months. Important parameters, needed to design the main RCT, will be estimated, such as SD of the outcome measure (fasting plasma glucose level at 6-month follow-up), recruitment, intervention adherence, follow-up, potential contamination and time needed to conduct the study. Semistructured qualitative interviews will be conducted with up to 20-30 participants, a sample of those declining to participate, four YOGA-DP instructors and around eight study staff to explore their perceptions and experiences of taking part in the study and of the intervention, reasons behind non-participation, experiences of delivering the intervention and running the study, respectively. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the following Research Ethics Committees: Faculty of Medicine and Health Sciences, University of Nottingham (UK); Centre for Chronic Disease Control (CCDC, India); Bapu Nature Cure Hospital and Yogashram (BNCHY, India) and Swami Vivekananda Yoga Anusandhana Samsthana (S-VYASA, India). The results will be widely disseminated among key stakeholders through various avenues. TRIAL REGISTRATION NUMBER: CTRI/2019/05/018893

Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2. © 2013 Falcon et al

Use of Site-Specifically Tethered Chemical Nucleases to Study Macromolecular Reactions

During a complex macromolecular reaction multiple changes in molecular conformation and interactions with ligands may occur. X-ray crystallography may provide only a limited set of snapshots of these changes. Solution methods can augment such structural information to provide a more complete picture of a macromolecular reaction. We analyzed the changes in protein conformation and protein:nucleic acid interactions which occur during transcription initiation by using a chemical nuclease tethered to cysteines introduced site-specifically into the RNA polymerase of bacteriophage T7 (T7 RNAP). Changes in cleavage patterns as the polymerase steps through transcription reveal a series of structural transitions which mediate transcription initiation. Cleavage by tethered chemical nucleases is seen to be a powerful method for revealing the conformational dynamics of macromolecular reactions, and has certain advantages over cross-linking or energy transfer approaches

Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease. © 2013 McEvoy et al

Restoration of Altered MicroRNA Expression in the Ischemic Heart with Resveratrol

Resveratrol, a constituent of red wine, is important for cardioprotection. MicroRNAs are known regulators for genes involved in resveratrol-mediated cardiac remodeling and the regulatory pathway involving microRNA has not been studied so far.We explored the cardioprotection by resveratrol in ischemia/reperfusion model of rat and determined cardiac functions. miRNA profile was determined from isolated RNA using quantitative Real-time PCR based array. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches.Cardioprotection by resveratrol and its derivative in ischemia/reperfusion [I/R] rat model was examined with miRNA expression profile. Unique expression pattern were found for each sample, particularly with resveratrol [pure compound] and longevinex [commercial resveratrol formulation] pretreated hearts. Longevinex and resveratrol pretreatment modulates the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 25 miRNAs, some of them, such as miR-21 were previously implicated in cardiac remodeling. The target genes for the differentially expressed miRNA include genes of various molecular function such as metal ion binding, sodium-potassium ion, transcription factors, which may play key role in reducing I/R injury.Rats pretreated with resveratrol for 3 weeks leads to significant cardioprotection against ischemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or longevinex. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R mice