A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics

Predictors of utilisation of dental care services in a nationally representative sample of adults.

OBJECTIVE: The objective of this study was to identify the predictors of utilisation of dental care services in Ireland. PARTICIPANTS: The 2007 Irish Survey of Lifestyle, Attitudes and Nutrition is a cross-sectional study, conducted in 2006/2007 (n = 10,364), by interviews at home to a representative sample of adults aged 18 years or over. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to investigate the influence of socioeconomic, predisposing and enabling factors on the odds of males and females having a dental visit in the past year. RESULTS: The significant predictors of visiting the dentist in the past year were for males: having 3rd level education, employment status, earning 50,000 euros or more, location of residence, use of a car, brushing frequently, and dentition status. For females, the predictors were being between 25-34 or 55-64 years-old, education level, earning 50,000 euros or more, location of residence, use of a car, brushing frequently and dentition status. CONCLUSIONS: Predictors of the use of dental services vary by gender. Predictors common to both genders were education level, higher income, location of residence, use of a car, brushing frequently and dentition status. Many of the predictors of dental visiting in the past year are also related to social inequalities in health. These predictors may be useful markers of impact for policies designed to address inequalities in access to oral health services

Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment:Identification of metabolic correlates of fatigue

OBJECTIVE: In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA).METHODS: Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms.RESULTS: The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 &gt; 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R 2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 &gt; 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION: PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.</p

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers:An FMRI study

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5‐5/week) completed a decision‐making task. First, participants stated how much they were willing‐to‐pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision‐making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and “value signals” where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness‐to‐pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision‐related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain

Desmopressin for prevention of bleeding for thrombocytopenic, critically ill patients undergoing invasive procedures: A randomised, double‐blind, placebo‐controlled feasibility trial

Thrombocytopenic patients have an increased risk of bleeding when undergoing invasive procedures. In a multicentre, phase II, blinded, randomised, controlled feasibility trial, critically ill patients with platelet count 100 × 109/L or less were randomised 1:1 to intravenous desmopressin (0.3 µg/kg) or placebo before an invasive procedure. Forty‐three participants (18.8% of those eligible) were recruited, with 41 eligible for analysis. Post‐procedure bleeding occurred in one of 22 (4.5%) in the placebo arm and zero of 19 in the desmopressin arm. Despite liberal inclusion criteria, there were significant feasibility challenges recruiting patients in the critical care setting prior to invasive procedures

Policing unacceptable protest in England and Wales: A case study of the policing of anti-fracking protests

In recent years public order policing policy in England and Wales has undergone significant changes. A ‘human rights compliant’ model of protest policing has been developed since 2009 and this article makes a contribution to the body of academic work considering the impact of these changes on operational policing. Drawing upon a longitudinal case study of the policing of protests against ‘fracking’ in Salford, Greater Manchester, in 2013-2014, the article contrasts post-2009 policy and academic discourses on protest policing with the experiences of anti-fracking protesters. To develop this assessment, the article also draws attention to previously unexplored definitions of acceptable and unacceptable protest set out by police in more recent policy, and considers the extent to which these definitions are reflected in the police response to anti-fracking protest. The article suggests that a police commitment to a human rights approach to protest facilitation is, at least in the case of anti-fracking protest, contingent on the focus and form of political activism