Regional differences in nutrient-induced secretion of gut serotonin

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Enterochromaffin (EC) cells located in the gastrointestinal (GI) tract provide the vast majority of serotonin (5‐HT) in the body and constitute half of all enteroendocrine cells. EC cells respond to an array of stimuli, including various ingested nutrients. Ensuing 5‐HT release from these cells plays a diverse role in regulating gut motility as well as other important responses to nutrient ingestion such as glucose absorption and fluid balance. Recent data also highlight the role of peripheral 5‐HT in various pathways related to metabolic control. Details related to the manner by which EC cells respond to ingested nutrients are scarce and as that the nutrient environment changes along the length of the gut, it is unknown whether the response of EC cells to nutrients is dependent on their GI location. The aim of the present study was to identify whether regional differences in nutrient sensing capability exist in mouse EC cells. We isolated mouse EC cells from duodenum and colon to demonstrate differential responses to sugars depending on location. Measurements of intracellular calcium concentration and 5‐HT secretion demonstrated that colonic EC cells are more sensitive to glucose, while duodenal EC cells are more sensitive to fructose and sucrose. Short‐chain fatty acids (SCFAs), which are predominantly synthesized by intestinal bacteria, have been previously associated with an increase in circulating 5‐HT; however, we find that SCFAs do not acutely stimulate EC cell 5‐HT release. Thus, we highlight that EC cell physiology is dictated by regional location within the GI tract, and identify differences in the regional responsiveness of EC cells to dietary sugars

The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release

The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release

The Regulation of Peripheral Metabolism by Gut-Derived Hormones

Enteroendocrine cells lining the gut epithelium constitute the largest endocrine organ in the body and secrete over 20 different hormones in response to cues from ingested foods and changes in nutritional status. Not only do these hormones convey signals from the gut to the brain via the gut-brain axis, they also act directly on metabolically important peripheral targets in a highly concerted fashion to maintain energy balance and glucose homeostasis. Gut-derived hormones released during fasting tend to be orexigenic and have hyperglycaemic potential. Conversely, gut hormones secreted postprandially generally promote satiety and facilitate glucose clearance. Although some of the metabolic benefits conferred by bariatric surgeries have been ascribed to changes in the secretory profiles of various gut hormones, the therapeutic potential of the enteroendocrine system as a viable target against metabolic diseases remain largely underexploited, except for incretin-mimetics. This review provides a brief overview of the physiological importance and highlights the therapeutic potential of the following gut hormones: serotonin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1, oxyntomodulin, peptide YY, insulin-like peptide 5, and ghrelin

Childhood aggression and the co-occurrence of behavioural and emotional problems

Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychop

Randomized Controlled Trial of Fish Oil and Montelukast and Their Combination on Airway Inflammation and Hyperpnea-Induced Bronchoconstriction

Both fish oil and montelukast have been shown to reduce the severity of exercise-induced bronchoconstriction (EIB). The purpose of this study was to compare the effects of fish oil and montelukast, alone and in combination, on airway inflammation and bronchoconstriction induced by eucapnic voluntary hyperpnea (EVH) in asthmatics. In this model of EIB, twenty asthmatic subjects with documented hyperpnea-induced bronchoconstriction (HIB) entered a randomized double-blind trial. All subjects entered on their usual diet (pre-treatment, n = 20) and then were randomly assigned to receive either one active 10 mg montelukast tablet and 10 placebo fish oil capsules (n = 10) or one placebo montelukast tablet and 10 active fish oil capsules totaling 3.2 g EPA and 2.0 g DHA (n = 10) taken daily for 3-wk. Thereafter, all subjects (combination treatment; n = 20) underwent another 3-wk treatment period consisting of a 10 mg active montelukast tablet or 10 active fish oil capsules taken daily. While HIB was significantly inhibited (p0.017) between treatment groups; percent fall in forced expiratory volume in 1-sec was −18.4±2.1%, −9.3±2.8%, −11.6±2.8% and −10.8±1.7% on usual diet (pre-treatment), fish oil, montelukast and combination treatment respectively. All three treatments were associated with a significant reduction (p0.017) in these biomarkers between treatments. While fish oil and montelukast are both effective in attenuating airway inflammation and HIB, combining fish oil with montelukast did not confer a greater protective effect than either intervention alone. Fish oil supplementation should be considered as an alternative treatment for EIB

The return of the fifties: Trends in college students' values between 1952 and 1984

Five identical surveys were carried out in 1952, 1968–1969, 1974, 1979, and 1984 among undergraduate men at Dartmouth College and the University of Michigan to measure value trends. In most value domains the trends are U-shaped, showing that the trends from the fifties to the sixties and seventies have reversed, and attitudes in 1984 were either similar to the fifties or moving in that direction. The domains include traditional religion, career choice, faith in government and the military, advocacy of social constraints on deviant social groups, attitudes about free enterprise, government and economics, sexual morality, marijuana use, and personal moral obligations. Two attitude areas do not show a return of the fifties: (1) other-direction was high in 1952, then dropped to the sixties and did not rise; (2) the level of politicization rose greatly from 1952 to the sixties, then dropped again only slightly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45659/1/11206_2005_Article_BF01106623.pd

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p