Chronic administration of hydrolysed pine nut oil to mice improves insulin sensitivity and glucose tolerance and increases energy expenditure via a free fatty acid receptor 4-dependent mechanism.

A healthy diet is at the forefront of measures to prevent type 2 diabetes. Certain vegetable and fish oils, such as pine nut oil (PNO), have been demonstrated to ameliorate the adverse metabolic effects of a high-fat diet. The present study investigates the involvement of the free fatty acid receptors 1 (FFAR1) and 4 (FFAR4) in the chronic activity of hydrolysed PNO (hPNO) on high-fat diet-induced obesity and insulin resistance. Male C57BL/6J wild-type, FFAR1 knockout (-/-) and FFAR4-/- mice were placed on 60 % high-fat diet for 3 months. Mice were then dosed hPNO for 24 d, during which time body composition, energy intake and expenditure, glucose tolerance and fasting plasma insulin, leptin and adiponectin were measured. hPNO improved glucose tolerance and decreased plasma insulin in the wild-type and FFAR1-/- mice, but not the FFAR4-/- mice. hPNO also decreased high-fat diet-induced body weight gain and fat mass, whilst increasing energy expenditure and plasma adiponectin. None of these effects on energy balance were statistically significant in FFAR4-/- mice, but it was not shown that they were significantly less than in wild-type mice. In conclusion, chronic hPNO supplementation reduces the metabolically detrimental effects of high-fat diet on obesity and insulin resistance in a manner that is dependent on the presence of FFAR4.

Mindfulness practice correlates with reduced exam-induced stress and improved exam performance in preclinical medical students with the "acting with awareness", "non-judging" and "non-reacting" facets of mindfulness particularly associated with improved exam performance.

BACKGROUND: Medical students demonstrate higher levels of psychological distress compared with the general population and other student groups, especially at exam times. Mindfulness interventions show promise in stress reduction for this group, and in the reduction of cortisol, an established clinical marker of the body's stress response. This study investigated the relationship of mindfulness to exam-induced stress, salivary cortisol and exam performance in undergraduate medical students. METHODS: A controlled pre-post analysis design with within-groups comparisons. 67 medical students completed the five facet mindfulness questionnaire (FFMQ) and provided saliva samples, from which cortisol was extracted, during group work (control/baseline) and immediately prior to end of year 2 examinations (experimental). Academic performance data was extracted for comparison with measures. RESULTS: Exam-induced salivary cortisol concentration showed a significant negative relation with exam performance. Total FFMQ score showed a significant positive relation with exam performance and a significant negative relation with exam-induced salivary cortisol. The specific mindfulness facets of acting with awareness, non-judging and non-reacting also showed a positive correlation with exam performance. CONCLUSIONS: This study suggests that there exists an important relationship between mindfulness and the physiological biomarker of stress, cortisol, and this manifests into improved assessment outcomes potentially through healthier, more adaptive coping and stress management strategies. In particular, this study identifies the acting with awareness, non-judging and non-reacting facets of mindfulness to be significantly associated with exam performance suggesting that these may be important facets for clinical educators to target when helping students with mindfulness practice.

Leanness and Low Plasma Leptin in GPR17 Knockout Mice Are Dependent on Strain and Associated With Increased Energy Intake That Is Not Suppressed by Exogenous Leptin.

Previous studies have shown that agonists of GPR17 stimulate, while antagonists inhibit feeding. However, whole body knockout of GPR17 in mice of the C57Bl/6 strain did not affect energy balance, whereas selective knockout in oligodendrocytes or pro-opiomelanocortin neurons provided protection from high fat diet-induced obesity and impaired glucose homeostasis. We reasoned that whole body knockout of GPR17 in mice of the 129 strain might elicit more marked effects because the 129 strain is more susceptible than the C57Bl/6 strain to increased sympathetic activity and less susceptible to high fat diet-induced obesity. Consistent with this hypothesis, compared to wild-type mice, and when fed on either a chow or a high fat diet, GPR17 -/- mice of the 129 strain displayed increased expression of uncoupling protein-1 in white adipose tissue, lower body weight and fat content, reduced plasma leptin, non-esterified fatty acids and triglycerides, and resistance to high fat diet-induced glucose intolerance. Not only energy expenditure, but also energy intake was raised. Administration of leptin did not suppress the increased food intake in GPR17 -/- mice of the 129 strain, whereas it did suppress food intake in GPR17 +/+ mice. The only difference between GPR17 +/- and GPR17 +/+ mice of the C57Bl/6 strain was that the body weight of the GPR17 -/- mice was lower than that of the GPR17 +/+ mice when the mice were fed on a standard chow diet. We propose that the absence of GPR17 raises sympathetic activity in mice of the 129 strain in response to a low plasma fuel supply, and that the consequent loss of body fat is partly mitigated by increased energy intake.

Successful instillation of professionalism in our future doctors.

This article was migrated. The article was marked as recommended. Dynamic approaches are required in teaching professionalism to medical students. Awareness of this issue has both arisen from and generated by a dramatic increase in publications relating to professionalism teaching in medical education. This report explores the current state of defining professionalism and shows that current literature reveals a strong proclivity to adopting "Communities of Practice" as the learning paradigm most likely to successfully instil professional values. This pedagogy is then critiqued with regards to the requirement of an undergraduate curriculum with the conclusion that Communities of Practice should be pertinent to successfully empowering medical students' professionalism.

Metabolic and energetic benefits of microRNA-22 inhibition.

INTRODUCTION: We previously demonstrated in primary cultures of human subcutaneous adipocytes and in a mouse model of diet-induced obesity that specific microRNA-22-3p antagomirs produce a significant reduction of fat mass and an improvement of several metabolic parameters. These effects are related to the activation of target genes such as KDM3A, KDM6B, PPARA, PPARGC1B and SIRT1 involved in lipid catabolism, thermogenesis, insulin sensitivity and glucose homeostasis. RESEARCH DESIGN AND METHODS: We now report a dedicated study exploring over the course of 3 months the metabolic and energetic effects of subcutaneous administration of our first miR-22-3p antagomir drug candidate (APT-110) in adult C57BL/6 male mice. Body composition, various blood parameters and energy expenditure were measured at several timepoints between week 12 and week 27 of age. RESULTS: Weekly subcutaneous injections of APT-110 for 12 weeks produced a sustained increase of energy expenditure as early as day 11 of treatment, a significant fat mass reduction, but no change of appetite nor physical activity. Insulin sensitivity as well as circulating glucose, cholesterol and leptin were improved. There was a dramatic reduction of liver steatosis after 3 months of active treatment. RNA sequencing revealed an activation of lipid metabolism pathways in a tissue-specific manner. CONCLUSIONS: These original findings suggest that microRNA-22-3p inhibition could lead to a potent treatment of fat accumulation, insulin resistance, and related complex metabolic disorders such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease.

High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain.

BACKGROUND: The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied. METHODS: In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg-1 po) and rimonabant (10 mg kg-1 po) were compared in the two genotypes. RESULTS: There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice. CONCLUSIONS: Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.

Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity.

BACKGROUND: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. METHODS: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. RESULTS: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. CONCLUSIONS: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

A systematic review and taxonomy of tools for evaluating evidence-based medicine teaching in medical education.

BACKGROUND: The importance of teaching the skills and practice of evidence-based medicine (EBM) for medical professionals has steadily grown in recent years. Alongside this growth is a need to evaluate the effectiveness of EBM curriculum as assessed by competency in the five 'A's': asking, acquiring, appraising, applying and assessing (impact and performance). EBM educators in medical education will benefit from a compendium of existing assessment tools for assessing EBM competencies in their settings. The purpose of this review is to provide a systematic review and taxonomy of validated tools that evaluate EBM teaching in medical education. METHODS: We searched MEDLINE, EMBASE, Cochrane library, Educational Resources Information Centre (ERIC), Best Evidence Medical Education (BEME) databases and references of retrieved articles published between January 2005 and March 2019. We have presented the identified tools along with their psychometric properties including validity, reliability and relevance to the five domains of EBM practice and dimensions of EBM learning. We also assessed the quality of the tools to identify high quality tools as those supported by established interrater reliability (if applicable), objective (non-self-reported) outcome measures and achieved ≥ 3 types of established validity evidence. We have reported our study in accordance with the PRISMA guidelines. RESULTS: We identified 1719 potentially relevant articles of which 63 full text articles were assessed for eligibility against inclusion and exclusion criteria. Twelve articles each with a unique and newly identified tool were included in the final analysis. Of the twelve tools, all of them assessed the third step of EBM practice (appraise) and four assessed just that one step. None of the twelve tools assessed the last step of EBM practice (assess). Of the seven domains of EBM learning, ten tools assessed knowledge gain, nine assessed skills and-one assessed attitude. None addressed reaction to EBM teaching, self-efficacy, behaviours or patient benefit. Of the twelve tools identified, six were high quality. We have also provided a taxonomy of tools using the CREATE framework, for EBM teachers in medical education. CONCLUSIONS: Six tools of reasonable validity are available for evaluating most steps of EBM and some domains of EBM learning. Further development and validation of tools that evaluate all the steps in EBM and all educational outcome domains are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018116203.

Citation classics in general medical journals: assessing the quality of evidence; a systematic review.

AIM: This review provides a comprehensive overview of more than 100 of the most cited studies in general medical journals and evaluates whether citations predict the quality of a scientific article. BACKGROUND: The number of citations is commonly used as a measure of the quality and impact of a scientific article. However, it is often criticised that the number of citations is in fact a poor indicator of the true quality, as it can be influenced by different factors such as current trends. METHODS: This review was conducted in line with the PRISMA guidelines. The Journal Citation Report (JCR) within Incites allowed the evaluation and comparison of articles, published in general medical journals, using far-reaching citation data drawn from scholarly and technical journals and conference proceedings. All steps of the review were performed in duplicate and conflicts were resolved through consensus. RESULTS: The 100 most cited articles published from 1963 until the end of 2018 were identified. The number of citations ranged from 4012 to 31853. Most of the articles were published in the 2000's, followed by the 1990's, 1980's, 1970's and 1960's, respectively. All of the articles were published in five journals. There were 50 studies at level II, 28 at level V, 10 at level IV, 7 at level III, and 5 at Level I. CONCLUSION: This systematic review provides an overview of the most cited articles, published in general medical journals. The number of citations provides an indication of the quality of evidence. However, researchers and clinicians should use standardized assessment tools rather than solely rely on the number of citations in order to judge the quality of published articles.

Isolation and Purification of Rodent Pancreatic Islets of Langerhans.

This chapter describes the detailed protocol for the isolation and purification of islets of Langerhans from rodent pancreas using collagenase digestion. The first step of the process is to separate and isolate the insulin-producing islets of Langerhans from the rest of the pancreas. The pancreas is excised from the animal, trimmed of nonpancreatic tissues before being inflated and chopped into small pieces. The connective tissue is then broken down with a collagenase enzyme solution to selectively digest the bulk of the exocrine tissue while leaving the endocrine islets intact and separated from their surrounding non-islet tissue. Once this process is completed, the islets of Langerhans are separated from the remaining mixture by centrifugation and purified by the means of hand picking. Once isolated, the subsequent islets can be used for several varied experimental processes, including transplantation, the study of pathophysiological mechanisms in diabetic conditions, and in the screening of novel therapeutic approaches in pharmacological research.

Patient-centered medical education: A proposed definition.

Multiple papers have been presented to define patient-centered care, with regulatory bodies such as the General Medical Council mapping this in their professional standards. Educational institutions clearly value instilling appreciation of patient-centredness in medical training, and attempts have been made to make medical education more patient-centered in practice. Such attempts are often limited to expert patients sharing personal stories, and public involvement in teaching. Despite the drive towards patient-centered care and medical education, there has been no attempt to formally define what patient-centered medical education is and what it means to medical educators globally. This paper proposes a definition of patient-centered medical education that is about the patients, with the patients, and for the patients, to ensure current and future doctors remain sensitive to all of the needs of the people they care for. This should be considered at both the micro and macro community levels.

Gallbladder perforation into the greater omentum following sleeve gastrectomy: A case report study.

INTRODUCTION: Obesity is considered a major risk factor for gallstone formation and is important due to its increasing prevalence worldwide. Many studies have reported an increased incidence of gallstone formation following bariatric surgery. This report documents a rare case of a complicated cholecystitis following sleeve gastrectomy and describes our management of the case and the management options for gallbladder disease in bariatric patients. PRESENTATION OF CASE: A 60-year-old male was diagnosed with asymptomatic cholelithiasis at the time of sleeve gastrectomy for obesity treatment. Two months after the procedure, he presented to the emergency department with symptoms of acute cholecystitis, which were initially managed conservatively. Six weeks later, he underwent a laparoscopic cholecystectomy. Intra-operative findings revealed a rare case of a complicated cholecystitis where the gallstone was half-eroded into the greater omentum. DISCUSSION: A notable proportion of bariatric patients develop symptomatic complicated cholecystitis following laparoscopic sleeve gastrectomy, compared to the normal population. Furthermore, complications develop quickly and technical difficulties are associated with subsequent surgeries. Thus, early cholecystectomy is justified. CONCLUSION: Patients with asymptomatic cholelithiasis, undergoing sleeve gastrectomy, may benefit from concomitant cholecystectomy. The question is yet controversial. This highlights the need for more clinical research in the field.

Schwartz rounds in undergraduate medical education facilitates active reflection and individual identification of learning need.

This article was migrated. The article was marked as recommended. Strategies applying Schwartz Rounds to improve wellbeing of medical students has focused on the clinical years of study. This pilot study investigates whether Schwartz Rounds could be effective in developing students' reflective practice in Year 2 undergraduates. Engagement with the Schwartz Round was high with over 50% of the students identifying learning needs through reflection on the Round. Schwartz Rounds promoted recognition of the value of reflective practice and increased self-awareness of student needs.

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity.

The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.

Chronic Activation of γ2 AMPK Induces Obesity and Reduces ß Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy.

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.

Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases.

Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.