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Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders. Refereed/Peer-reviewed

BackgroundAbout 15.4 million people in the UK live with a long-term condition. Of the health and social care spend, 70% is invested in caring for this population. Evidence suggests that group-work interventions offer patient support, improved outcomes, and reduce the costs of care.AimTo review the current evidence base examining the effectiveness of group work in long-term physical disease where such groups are facilitated by healthcare professionals.Design and settingSystematic review and narrative synthesis of studies of group-work interventions led by health professionals for adults with specified long-term illnesses.MethodMEDLINE, EMBASE, PsycINFO, and Cochrane databases were systematically searched using terms relating to group work and long-term conditions. Studies were included if they were randomised controlled trials (RCTs) with a control group that did not include group work.ResultsThe 14 included studies demonstrated a high degree of heterogeneity in terms of participant characteristics, interventions, and outcome measures and were of varying quality. The studies demonstrated some statistically significant improvements in pain, psychological outcomes, self-efficacy, self-care, and quality of life resulting from intervention.ConclusionThis review demonstrates significant benefits resulting from group participation, in adults with long-term disease. Results were mixed and some benefits were short-lived. Nevertheless, these results suggest that group work should be more widely used in the management and support of adults with long-term illness. There is a need for larger and better-quality studies to explore this potentially important area further.

Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and &alpha, glucoside (&alpha, MG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and &alpha, MG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p &lt, 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p &lt, 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.

This article presents findings related to the role parents can play in the prevention of cyberbullying and the promotion of cyber-kindness. The findings are drawn from a study conducted at a private school in Western Canada, involving 177 student survey participants in Grades 8 through 10 (including both day students and boarding students) and interviews with 15 educators employed at the same school. Findings relate to parental supervision of computer usage, students&rsquo, willingness to inform parents about cyberbullying, and how students and educators view the role of parents in relation to the prevention of cyberbullying and the promotion of cyber-kindness. Education, dialogue, relationship strengthening, computer usage monitoring, and partnerships between schools and parents are emphasized as solutions, which are highly consistent with the existing research literature on this topic. Additionally, the study reveals the particular vulnerability of boarding students to cyberbullying victimization and perpetration.

The small intestine is traditionally viewed as an organ that mediates nutrient digestion and absorption. This view has recently been revised owing to the ability of the duodenum to sense nutrient influx and trigger negative feedback loops to inhibit glucose production and food intake to maintain metabolic homeostasis. Further, duodenal nutrient-sensing defects are acquired in diabetes and obesity, leading to increased glucose production. In contrast, jejunal nutrient sensing inhibits glucose production and mediates the early antidiabetic effect of bariatric surgery, and gut microbiota composition may alter intestinal nutrient-sensing mechanisms to regain better control of glucose homeostasis in diabetes and obesity in the long term. This perspective highlights nutrient-sensing mechanisms in the gut that regulate glucose homeostasis and the potential of targeting gut nutrient-sensing mechanisms as a therapeutic strategy to lower blood glucose concentrations in diabetes.

Simple Privacy provides a system for Australian organisations to create privacy policies for the personal information they collect online. The privacy policies it creates are legally compliant and easy to understand. We developed this system because small Australian organisations seemed to find privacy policies too complicated to manage with the resources they have available.This paper describes the framework behind Simple Privacy and discusses the choices that we made during development. These choices balance the requirements of the privacy legislation and the needs of both organisations and customers.

Objective To assess the contribution of neurocysticercosis (NCC) to the burden of epilepsy in a rural Tanzanian population. Methods We identified adult people with epilepsy (PWE) in a door-to-door study in an established demographic surveillance site. PWE and community controls were tested for antibodies to Taenia solium, the causative agent of NCC, and all PWE were offered a computed tomography (CT) head scan. Data on household occupancy and sanitation, pig-keeping and pork consumption were collected from PWE and controls and associations with epilepsy were assessed using chi-square or Fisher's exact tests. Results Six of 218 PWE had antibodies to T. solium (2.8%; 95% CI 0.6–4.9), compared to none of 174 controls (Fisher's exact test, P = 0.04). Lesions compatible with NCC were seen in eight of 200 CT scans (4.0%; 95% CI 1.3–6.7). A total of 176 PWE had both investigations of whom two had positive serology along with NCC-compatible lesions on CT (1.1%; 95% 0.3–4.0). No associations between epilepsy and any risk factors for NCC were identified. Conclusions Neurocysticercosis is present in this population but at a lower prevalence than elsewhere in Tanzania and sub-Saharan Africa. Insights from low-prevalence areas may inform public health interventions designed to reduce the burden of preventable epilepsy. Objectif Evaluer la contribution de la neurocysticercose (NCC) a la charge de l’epilepsie dans une population rurale de la Tanzanie. Methodes Nous avons identifie les personnes adultes souffrant d’epilepsie (PSE) dans une etude de porte-a-porte dans un site etabli de surveillance demographique. Les PSE et des temoins communautaires ont ete testes pour les anticorps de Taenia solium, l'agent causal de la NCC et toutes les PSE ont ete offertes une tomodensitometrie (TDM) de la tete. Les donnees sur l'occupation des menages et l'assainissement, l’elevage et la consommation de porc ont ete recueillies chez les PSE et les temoins et les associations avec l’epilepsie ont ete evaluees en utilisant les tests Exacts de Fisher ou de Chi-carre. Resultats Six des 218 PSE avaient des anticorps de T. Solium (2,8%; IC95%: 0,6 a 4,9) compares a aucun des 174 temoins (test Exact de Fisher, p = 0,04). Les lesions compatibles avec la NCC ont ete observees dans 8 des 200 TDM (4,0%; IC95%: 1,3 a 6,7). Les deux investigations ont ete menees chez 176 PSE, dont deux avaient une serologie positive ainsi que des lesions compatibles avec la NCC sur la TDM (1,1%; IC95%: 0,3 a 4,0). Aucune association entre l’epilepsie et les facteurs de risque categorises pour la NCC n'a ete identifiee. Conclusions La NCC est presente dans cette population, mais a un taux de prevalence plus faible qu'ailleurs en Tanzanie et en Afrique subsaharienne. Les donnees des zones a faible prevalence pourraient eclairer les interventions de sante publique visant a reduire la charge evitable de l’epilepsie. Objetivo Evaluar la contribucion de la neurocisticercosis (NCC) a la carga de epilepsia entre la poblacion rural de Tanzania. Metodos Identificamos a adultos con epilepsia (ACE) en un estudio puerta-a-puerta, en un lugar con vigilancia demografica establecida. A los ACE y a los controles comunitarios se les realizaron pruebas en busca de anticuerpos contra Taenia solium, el agente causal de la NCC, y a todos los ACE se les ofrecio una tomografia computarizada de la cabeza (TC). Se recolectaron los datos sobre ocupacion del hogar y saneamiento, la crianza y consumo del cerdo de los ACE y de los controles, y se evaluaron las asociaciones con la epilepsia utilizando las pruebas del Chi-cuadrado y de Fisher. Resultados Seis de 218 PCE tenian anticuerpos contra T. solium (2.8%; IC 95% 0.6 a 4.9), comparado con ninguno de los 174 controles (prueba de Fisher, p=0.04). Las lesiones compatibles con la NCC se observaron en ocho de 200 TC (4.0%; IC95% 1.3 a 6.7). A 176 ACE se les realizaron ambas pruebas, y de estos, dos tenian una serologia positiva junto con lesiones compatibles con NCC en la TC (1.1%; 95% 0.3 a 4.0). No se identificaron asociaciones entre la epilepsia y factores de riesgo categoricos para NCC. Conclusiones La NCC esta presente en esta poblacion, pero en una menor prevalencia que en cualquier otro lugar en Tanzania y Africa subsahariana. La comprension de lo que sucede en areas de baja prevalencia podria informar intervenciones de salud publica disenadas para reducir la carga de epilepsia prevenible.

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

Cyberbullying is an emerging issue in the context of higher education as information and communication technologies (ICT) increasingly become part of daily life in university. This paper presents findings from 1925 student surveys from four Canadian universities. The overall findings are broken down to determine gender similarities and differences that exist between male and female respondents’ backgrounds, ICT usage, experiences with cyberbullying, opinions about the issue, and solutions to the problem. We also examine the continuities between these findings and those of earlier studies on cyberbullying among younger students. Our findings also suggest that gender differences, which do emerge, provide some support for each of the three theoretical frameworks considered for understanding this issue, that is, relational aggression, cognitive-affective deficits, and power and control. However, none of these three models offers a full explanation on its own. The study thus provides information about cyberbullying behaviour at the university level, which has the potential to inform the development of more appropriate policies and intervention programs/solutions to address the gendered nature of this behaviour.

International audience; Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Cyber-bullying increasingly is becoming a problem for students, educators and policy makers. In this paper, we consider cyber-bullying as a form of relational aggression; that is, behaviour designed to damage, harm or disrupt friendship or interpersonal relationships through covert means. We draw on the findings from a study of students in Grades 6 through 9, conducted in five schools, in a large ethnically diverse metropolitan region of British Columbia, Canada, to demonstrate the interconnection between cyber-bullying and relational aggression. Consistent with the relational aggression framework, girls were found more likely than boys to participate in these behaviours. We conclude that intervention strategies should consider gender differences and also aim at changing the trajectory of relational aggression to providing relational support and care.Keywords: cyber-bullying; relational aggression; intervention strategies; gender differences

Summary Background Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. Methods SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. Findings For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Interpretation Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

In an attempt to understand the relationship between the 'species-based' and 'spaces-based' approaches to marine conservation, this thesis examined: first, their relative efficiencies at selecting a set of marine reserves and second, the influence spatial aggregation had on the shape of the reserve system. Results demonstrated that: (a) a reserve system designed with a moderate degree of spatial aggregation most minimised the area, number of reserves and perimeter of the system most effectively; (b) neither focal species nor habitats alone were capable of capturing the desired level of representation; but (c) habitats acted as a better surrogate for capturing conservation features than do species; (d) 'species-based' and 'spaces-based' approaches can be combined to create an efficient reserve system designed to capture the full range of biodiversity; and, (e) when that approach was taken, reserve designs built using benthic habitat data, were more efficient at meeting the representation targets than species or other habitats alone.

1. Action potential-evoked Ca(2+) transients in postganglionic sympathetic axon bundles in mouse vas deferens have been characterized using confocal microscopy and Ca(2+) imaging. 2. Axonal Ca(2+) transients were tetrodotoxin sensitive. The amplitude depended on both the frequency of stimulation and the number of stimuli in a train. 3. Removal of extracellular Ca(2+) abolished the Ca(2+) transient. Cd(2+)(100 microM) inhibited the Ca(2+) transient by 78 +/- 10 %. The N-type Ca(2+) channel blocker omega-conotoxin GVIA (0.1 microM) reduced the amplitude by -35 +/-4 %, whereas nifedipine (10 microM; L-type) and omega-conotoxin MVIIC (0.1 microM; P/Q type) were ineffective. 4. Caffeine (10 mM), ryanodine (10 microM), cyclopiazonic acid (30 microM) or CCCP (10 microM) had no detectable effects. 5. Blockade of large and small conductance Ca(2+)-dependent K+ channels with iberiotoxin (0.1 microM) and apamin (1 microM), respectively, or Ca(2+)-dependent Cl(-) channels by niflumic acid (100 microM) did not alter Ca(2+) transients. 6. In contrast, the non-specific K+ channel blockers tetraethylammonium (10 mM) and 4-aminopyridine (10 mM) markedly increased the amplitude of the Ca(2+) transient. Blockade of delayed rectifiers and A-like K+ channels, by tityustoxin-K (alpha) (0.1 microM) and pandinustoxin-K (alpha) (10 nM), respectively, also increased the Ca(2+) transient amplitude. 7. Thus, Ca(2+) transients are evoked by Na(+)-dependent action potentials in axons. These transients originate mainly from Ca(2+) entry through voltage-dependent Ca(2+) channels (80 % Cd(2+) sensitive of which 40 % was attributable to N-type). Twenty per cent of the Ca(2+) transient was not due to Ca(2+) entry through voltage-gated Ca(2+) channels. Intracellular stores and mitochondria were not involved in the generation of the transient. Ca(2+) transients are modulated by A-like K+ channels and delayed rectifiers (possibly K(V)1.2) but not by Ca(2+)-activated ion channels.

Development of epilepsy services in the northern region has included a baseline audit of the availability of pre-conceptual advice, AED prescribing, folic acid usage, vitamin K administration and pregnancy outcome in women with epilepsy which we now report. Patients, identified by community midwives, complete a standardized interview questionnaire with a research nurse. Delivery outcome is recorded using obstetric notes. 333 notifications have been received in 18 months, 247 questionnaires and 150 outcome forms completed. Forty-six women requested no contact, 63% receive epilepsy care from their GP, only 35% recalled pre-conceptual advice, and 12% took polytherapy. Of those on monotherapy 50% take carbamazepine, 39% sodium valproate, 9% phenytoin and 1% lamotrigine. Folic acid was taken pre-conceptually by 28% and during pregnancy by 87%. Only 36% took 5 mg folic acid. Vitamin K was given to 72% babies, 38% by intramuscular injection. Adverse outcomes include a baby with phocomelia and a pregnancy terminated for spina bifida in mothers taking valproate. A baby with short ribs was born to a mother on valproate and lamotrigine.