Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation

Determinants of Salivary Cotinine among Smokeless Tobacco Users : A Cross-Sectional Survey in Bangladesh

INTRODUCTION: More than 80% of all smokeless tobacco (ST) products in the world are consumed in South Asia; yet little is known about their consumption behaviour, addictiveness, and toxic properties. This paper, for the first time, describes associations between salivary cotinine concentrations among ST users in Bangladesh and their socio-demographic characteristics and tobacco use behaviours. METHODS: In a survey of ST users in Dhaka, Bangladesh, we purposively recruited 200 adults who were non-smokers but consumed ST on a regular basis. In-person interviews were conducted to obtain information about socio-demographic and ST use behaviours, and saliva samples were collected to measure cotinine concentration. Simple and multiple linear regression analyses were conducted to test associations between the log transformed salivary cotinine concentration and other study variables. RESULTS: The geometric mean of cotinine concentration among ST users was 380ng/ml (GSD:2). Total duration of daily ST use in months had a statistically significant association with cotinine concentration. Other ST use characteristics including type and quantity of ST use, swallowing of tobacco juice, urges and strength of urges and attempts to cut down on tobacco use were not found to be associated with cotinine concentration in a multivariable model. CONCLUSION: This is the first report from Bangladesh studying cotinine concentration among ST users and it points towards high levels of addiction. This warrants effective tobacco control policies to help ST cessation and prevention

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology

Effect of remote ischemic preConditioning on liver injury in patients undergoing liver resection: the ERIC-LIVER trial

OBJECTIVE: Novel hepatoprotective strategies are needed to improve clinical outcomes during liver surgery. There is mixed data on the role of remote ischemic preconditioning (RIPC). We investigated RIPC in partial hepatectomy for primary hepatocellular carcinoma (HCC). METHODS: This was a Phase II, single-center, sham-controlled, randomized controlled trial (RCT). The primary hypothesis was that RIPC would reduce acute liver injury following surgery indicated by serum alanine transferase (ALT) 24 h following hepatectomy in patients with primary HCC, compared to sham. Patients were randomized to receive either four cycles of 5 min/5 min arm cuff inflation/deflation immediately prior to surgery, or sham. Secondary endpoints included clinical, biochemical and pathological outcomes. Liver function measured by Indocyanine Green pulse densitometry was performed in a subset of patients. RESULTS: 24 and 26 patients were randomized to RIPC and control groups respectively. The groups were balanced for baseline characteristics, except the duration of operation was longer in the RIPC group. Median ALT at 24 h was similar between groups (196 IU/L IQR 113.5-419.5 versus 172.5 IU/L IQR 115-298 respectively, p = 0.61). Groups were similar in secondary endpoints. CONCLUSION: This RCT did not demonstrate beneficial effects with RIPC on serum ALT levels 24 h after partial hepatectomy

Is there an impact of public smoking bans on self-reported smoking status and exposure to secondhand smoke?

<p>Abstract</p> <p>Background</p> <p>Implementation of smoke free policies has potentially substantial effects on health by reducing secondhand smoke exposure. However little is known about whether the introduction of anti-smoking legislation translates into decreased secondhand smoke exposure. We examined whether smoking bans impact rates of secondhand smoke exposure in public places and rates of complete workplace smoking restriction.</p> <p>Methods</p> <p>Canadian Community Health Survey was used to obtain secondhand smoking exposure rates in 15 Ontario municipalities. Data analysis included descriptive summaries and 95% confidence intervals were calculated and compared across groups</p> <p>Results</p> <p>Across all studied municipalities, secondhand smoke exposure in public places decreased by 4.7% and workplace exposure decreased by 2.3% between the 2003 and 2005 survey years. The only jurisdiction to implement a full ban from no previous ban was also the only setting that experienced significant decreases in both individual exposure to secondhand smoke in a public place (-17.3%, 95% CI -22.8, -11.8) and workplace exposure (-18.1%, 95% CI -24.9, -11.3). Exposures in vehicles and homes declined in almost all settings over time.</p> <p>Conclusions</p> <p>Implementation of a full smoking ban was associated with the largest decreases in secondhand smoke exposure while partial bans and changes in existing bans had inconsistent effects. In addition to decreasing exposure in public places as would be expected from legislation, bans may have additional benefits by decreasing rates of current smokers and decreasing exposures to secondhand smoke in private settings.</p

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS

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Fibulin-2: A Novel Biomarker for Differentiating Grade II from Grade I Meningiomas

There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (p &lt; 0.05), Western blotting (p &lt; 0.05) and RT-qPCR (p &lt; 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.</jats:p

Illiteracy, low educational status, and cardiovascular mortality in India

Background: Influence of education, a marker of SES, on cardiovascular disease (CVD) mortality has not been evaluated in low-income countries. To determine influence of education on CVD mortality a cohort study was performed in India. Methods: 148,173 individuals aged ≥ 35 years were recruited in Mumbai during 1991-1997 and followed to ascertain vital status during 1997-2003. Subjects were divided according to educational status into one of the five groups: illiterate, primary school ( ≦ 5 years of formal education), middle school (6-8 years), secondary school (9-10 years) and college (&gt; 10 years). Multivariate analyses using Cox proportional hazard model was performed an

Is There Any Association between Use of Smokeless Tobacco Products and Coronary Heart Disease in Bangladesh?

BACKGROUND: Most epidemiological studies exploring the association between smokeless tobacco (SLT) use and coronary heart disease (CHD) have been in Western populations, and have focused on SLT products used in those countries. Few studies come from South Asian countries. Our objective was to determine the association between SLT use and CHD among non-smoking adults in Bangladesh. METHODS: A matched case-control study of non-smoking Bangladeshi adults aged 40–75 years was conducted in 2010. Incident cases of CHD were selected from two cardiac hospitals. Community controls, matched to CHD cases, were selected from neighbourhoods, and hospital controls were selected from outpatient departments of the same hospitals. The Rose Angina Questionnaire (RAQ) was also used to re-classify cases and controls. RESULTS: The study enrolled 302 cases, 1,208 community controls and 302 hospital controls. Current use was higher among community controls (38%) compared to cases (33%) and hospital controls (32%). Current use of SLT was not significantly associated with an increased risk of CHD when community controls were used (adjusted OR 0.87, 95% CI 0.63–1.19), or when hospital controls were used (adjusted OR 1.00, 95% CI 0.63–1.60), or when both control groups were combined (adjusted OR 1.00, 95% CI 0.74–1.34). Risk of CHD did not increase with use of individual types except gul, frequency, duration, past use of SLT products, or using the RAQ to re-classify cases and controls. There was a significant association between gul use and CHD when both controls were combined (adjusted OR 2.93, 95% CI 1.28–6.70). CONCLUSIONS: There was no statistically significant association between SLT use in general and CHD among non-smoking adults in Bangladesh. Further research on the association between gul use and CHD in Bangladesh along with SLT use and CHD in other parts of the subcontinent will guide public health policy and interventions that focus on SLT-related diseases.Muhammad Azia Rahman, Nicola Spurrier, Mohammad Afzal Mahmood, Mahmudur Rahman, Soehl Reza Choudhury and Stephen Leede