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The gut–brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut–brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake. [ABSTRACT FROM AUTHOR]

Gastrointestinal vagal afferents play an important role in communicating food related information from the gut to the brain. This information initiates vago‐vagal reflexes essential for gut functions, including gut motility and secretions. These afferents also play a role in energy homeostasis, signalling the arrival, amount and nutrient composition of a meal to the central nervous system where it is processed ultimately leading to termination of a meal. Vagal afferent responses to food related stimuli demonstrate a high degree of plasticity, responding to short term changes in nutritional demand, such as the fluctuations that occur across a 24‐hr or in response to a fast, as well as long term changes in energy demand, such as occurs during pregnancy. This plasticity is disrupted in disease states, such as obesity or chronic stress where there is hypo‐ and hypersensitivity of these afferents, respectively. Improved understanding of the plasticity of these afferents will enable identification of new treatment options for diseases associated with vagal afferent function. [ABSTRACT FROM AUTHOR]

Purpose: To our knowledge, no studies have examined the association of diet quality and plant-based diets (PBD) with inflammatory-related mortality in obesity. Therefore, this study aimed to determine the joint associations of Healthy Eating Index-2015 (HEI-2015), plant-based dietary index (PDI), healthy PDI (hPDI), unhealthy PDI (uPDI), pro-vegetarian dietary index (PVD), and systemic inflammation with all-cause, cardiovascular disease (CVD), and cancer mortality risks by obesity status. Methods: Participants from NHANES were included in cross-sectional (N = 27,915, cycle 1999–2010, 2015–2018) and longitudinal analysis (N = 11,939, cycle 1999–2008). HEI-2015, PDI, hPDI, uPDI, and PVD were constructed based on the 24-h recall dietary interview. The grade of inflammation (low, moderate, and high) was determined based on C-reactive protein (CRP) values and multivariable ordinal logistic regression was used to determine the association. Cox proportional hazard models were used to determine the joint associations of diet and inflammation with mortality. Results: In the fully adjusted model, HEI-2015 (ORT3vsT1 = 0.76, 95% CI 0.69–0.84; p-trend = < 0.001), PDI (ORT3vsT1 = 0.83, 95% CI 0.75–0.91; p trend = < 0.001), hPDI (ORT3vsT1 = 0.79, 95% CI 0.71–0.88; p trend = < 0.001), and PVD (ORT3vsT1 = 0.85, 95% CI 0.75–0.97; p trend = 0.02) were associated with lower systemic inflammation. In contrast, uPDI was associated with higher systemic inflammation (ORT3vsT1 = 1.18, 95% CI 1.06–1.31; p-trend = 0.03). Severe inflammation was associated with a 25% increase in all-cause mortality (ORT3vsT1 = 1.25, 95% CI 1.03–1.53, p trend = 0.02). No association was found between PDI, hPDI, uPDI, and PVD with mortality. The joint association, between HEI-2015, levels of systemic inflammation, and all-cause, CVD and cancer mortality, was not significant. However, a greater reduction in mortality risk with an increase in HEI-2015 scores was observed in individuals with low and moderate inflammation, especially those with obesity. Conclusion: Higher scores of HEI-2015 and increased intake of a healthy plant-based diet were associated with lower inflammation, while an unhealthy plant-based diet was associated with higher inflammation. A greater adherence to the 2015 dietary guidelines may reduce the risk of mortality associated with inflammation and may also benefit individuals with obesity who had low and moderate inflammation. [ABSTRACT FROM AUTHOR]

A catamenial pneumothorax is a very rare condition resulting in spontaneous and recurrent pneumothoraces that occur in relationship with menses (T. Marja' nski et al., 2016). Although rare, emergency providers should consider this condition when female patients present to the emergency department with chest discomfort and dyspnea during menstruation. This case describes a patient who presented to the emergency department with abdominal pain who was incidentally found to have a catamenial pneumothorax on diagnostic imaging for her complaint of acute abdominal pain. [ABSTRACT FROM AUTHOR]

Diets which have a low glycaemic index (GI) and high levels of dietary fibre are generally considered to be beneficial for promoting weight loss and improving insulin sensitivity, and are therefore recommended for the management of diabesity (the coexistence of obesity and type 2 diabetes mellitus). In addition, high dietary fibre intake is also positively associated with gut health. High-amylose wheat (HAW) is a type of wheat which has a lower GI value and contains higher amounts of dietary fibre, including resistant starch, compared with standard wheat, and therefore has potential applications as a functional food for improving metabolic and gut health. The aim of this review is to describe the characteristics of HAW and the current evidence in support of its potential effects on metabolic and gut health, as well as identifying important areas for future research. [ABSTRACT FROM AUTHOR]

Gastric vagal afferent (GVA) sensing of food-related mechanical stimuli is a crucial mechanism in the control of feeding behavior and gastric function. Stress is an important factor contributing to eating disorders and gastric diseases. Chronic stress has been shown to increase the mechanosensitivity of GVAs in mice and to reduce food intake and body weight. Whether the mechanosensitivity of GVAs is modulated by stress hormones is not known. This study aimed to determine the effect of stress hormones on GVA mechanosensitivity. The expression of stress hormone receptors in GVA cell bodies was determined in 8-wk-old male C57BL/6 mice using quantitative RT-PCR combined with laser capture microdissection. The mechanosensitivity of GVAs was determined in the absence and presence of stress hormones using an in vitro single-fiber recording preparation. NR3C1 and CRHR2 (mRNA isoforms of glucocorticoid receptor and CRF2 receptor, respectively) were expressed in GVA neurons. The glucocorticoid receptor agonist corticosterone had no effect on the mechanosensitivity of either tension or mucosal GVAs. Activation of CRF2 receptor by its specific analog, urocortin 3, significantly increased the mechanosensitivity of both tension and mucosal GVAs, an effect prevented by the CRF2 receptor antagonist astressin 2B. In conclusion, activation of CRF2 receptor increases the mechanosensitivity of GVAs. This may contribute to the stress- and CRF2 receptor-associated changes in feeding behavior and gastric function, possibly contributing to the hypersensitivity of GVAs in chronic stress conditions.NEW & NOTEWORTHY Gastric vagal afferents (GVAs) relay food-related signals to the central nervous system, where they are processed, eventually leading to modulation of food intake and gastric function. GVA signaling can be modulated by an array of hormones. Stress has been shown to induce GVA hypersensitivity. This study demonstrates that GVA neurons express subtypes of stress hormone receptors, specifically CRF2. Furthermore, activation of CRF2 receptor increases GVA mechanosensitivity, which could have implications for food intake and gastric function. [ABSTRACT FROM AUTHOR]

Endocannabinoids (ECs) mediate effects via cannabinoid receptor types 1 and 2 (CB1 and 2) and transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) channels. In high-fat diet (HFD)-induced obese mice overactivity of the EC system and inhibition of CB1 increase skeletal muscle glucose uptake. We explored the role of TRPV1. Male TRPV1-/-(WT) and TRPV1-/-(KO)-mice were fed (20 wk) a standard laboratory diet (SLD) or HFD. An intraperitoneal glucose tolerance test was performed. RT-PCR was performed to measure mRNA of genes involved in glucose/lipid metabolism and the EC system in soleus (SOL) and extensor digitorum longus (EDL) muscles. Cultured L6 cells were used to measure glucose uptake in skeletal muscle. HFD mice weighed more and had higher insulin levels than SLD mice, with no genotype differences. Basal and peak glucose were higher in HFD mice irrespective of genotype, but glucose cleared faster in HFD WT vs. HFD KO-mice. 2-Arachidonoylglycerol augmented insulin-induced glucose uptake in skeletal L6-cells, an effect blocked by the TRPV1 antagonist SB-366791. In EDL, fatty acid amide hydrolase (FAAH) mRNA was increased in KO vs. WT mice, irrespective of diet. Pyruvate dehydrogenase kinase isozyme 4 (PDK4) and mitochondrial uncoupling protein 3 (UCP3) were elevated and FA desaturase 2 (FADS2) mRNA lower in HFD mice, irrespective of genotype. CB1 and stearoyl-CoA desaturase 1 (SCD1) were lower in HFD WT mice only. In SOL, PDK4, UCP3, hormone-sensitive lipase (LIPE), fatty acid translocase (CD36), and carnitine palmitoyl transferase 2 (CPT2) were elevated and SCD1, FAAH, FADS2, and Troponin 1 (TNNC1) mRNA lower in HFD mice, irrespective of genotype. In conclusion, TRPV1 regulates glucose disposal in HFD mice. We propose that TRPV1 plays a role in coordinating glucose metabolism in EDL under conditions of metabolic stress. [ABSTRACT FROM AUTHOR]

MobilePDR is a platform and mobile application from the Physicians' Desk Reference. Specifically focusing on diagnostic care, mobilePDR houses a collection of pharmaceutical and drug information. This article will explore the functionality and usability of the mobilePDR platform including how to access, browse, and search for pharmaceutical information. It will discuss management of privacy and data. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) vagal afferents are a key mediatory of food intake. Through a balance of responses to chemical and mechanical stimuli food intake can be tightly controlled via the ascending satiety signals initiated in the GI tract. However, vagal responses to both mechanical and chemical stimuli are modified in diet-induced obesity (DIO). Much of the research to date whilst in relatively isolated/controlled circumstances indicates a shift between a balance of orexigenic and anorexigenic vagal signals to blunted anorexigenic and potentiated orexigenic capacity. Although the mechanism responsible for the DIO shift in GI vagal afferent signalling is unknown, one possible contributing factor is the gut microbiota. Nevertheless, whatever the mechanism, the observed changes in gastrointestinal vagal afferent signalling may underlie the pathophysiological changes in food consumption that are pivotal for the development and maintenance of obesity. [ABSTRACT FROM AUTHOR]

Vagal afferents are a vital link between the peripheral tissue and central nervous system (CNS). There is an abundance of vagal afferents present within the proximal gastrointestinal tract which are responsible for monitoring and controlling gastrointestinal function. Whilst essential for maintaining homeostasis there is a vast amount of literature emerging which describes remarkable plasticity of vagal afferents in response to endogenous as well as exogenous stimuli. This plasticity for the most part is vital in maintaining healthy processes; however, there are increased reports of vagal plasticity being disrupted in pathological states, such as obesity. Many of the disruptions, observed in obesity, have the potential to reduce vagal afferent satiety signalling which could ultimately perpetuate the obese state. Understanding how plasticity occurs within vagal afferents will open a whole new understanding of gut function as well as identify new treatment options for obesity. [ABSTRACT FROM AUTHOR]

Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano- and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non-surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient-sensing mechanisms throughout the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Duration and start time of respirometry experiments have significant effects on the measurement of basal values for several commonly measured physiological variables (metabolic rate, evaporative water loss and body temperature). A longer measurement duration reduced values for all variables for all start times, and this was an effect of reduced animal activity rather than random sampling. However, there was also an effect of circadian rhythm on the timing of minimal physiological values. Experiment start time had a significant effect on time taken to reach minimal values for all variables, ranging from 0400 hours ± 38 min (body temperature, start time 2300 hours) to 0854 hours ± 52 min (evaporative water loss, start time 1700 hours). It also influenced the time of day that minimal values were obtained, ranging from 2224 hours ± 40 min (carbon dioxide production, start time 1500 hours) to 0600 hours ± 57 min (oxygen consumption, start time 2300 hours), and the minimum values measured. Consequently, both the measurement duration and the experiment start time should be considered in experimental design to account for both a handling and a circadian effect on the animal's physiology. We suggest that experiments to measure standard physiological variables for small diurnal birds should commence between 1700 and 2100 hours, and measurement duration should be at least 9 h. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) plays important roles in CNS and smooth muscle function. Here we reveal an additional function in peripheral sensory transmission. We hypothesized that endogenous NO modulates the function of gastrointestinal vagal afferent endings. The nonselective NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)-cGMP pathway was confirmed using the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one and the cGMP phosphodiesterase 5′ inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor S-nitroso-Nacetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system. [ABSTRACT FROM AUTHOR]

Presents literary criticism of the novel "The Autobiography of an Ex-Colored Man" by James Weldon Johnson. It examines issues related to the significance of skin color in the United States and Latin America and explores how Johnson's time spent working for U.S. consulates in Latin American shaped his attitudes. It explores how the novel categorizes individuals of color and discusses the impact of racial boundaries that exist in the U.S. and Latin America.

Despite universal use of opioids in the clinic to inhibit pain, there is relatively little known of their peripheral actions on sensory nerve endings, where in fact they may be better targeted with more widespread applications. Here we show differential effects of μ-, κ-, and δ-opioids on mechanosensitive ferret esophageal vagal afferent endings investigated in vitro. The effects of selective agonists [D-Ala²,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO), 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1phenyl-2-(1-pyrrolidinyl) ethyl] acetamide hydrochlorine (ICI 199441), and (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenz- amide (SNC-80), respectively, on mechanosensory stimulus-response functions were quantified. DAMGO (10-7 to 10-5 M) reduced the responses of tension receptors to circumferential tension (1 -5 g) by up to 50%, and the responses of mucosal receptors to mucosal stroking (10-1,000 mg von Frey hair) by >50%. DAMGO effects were reversed by naloxone (10-5 M). Tension/mucosal (TM) receptor responses to tension and stroking were unaffected by DAMGO. ICI 199441 (10-6 to 10-5 M) potently inhibited all responses except TM receptor responses to tension, and SNC-80 (10-5 to 10-3 M) had no effect other than a minor inhibition of mucosal receptor responses to intense stimuli at 10-3 M. We conclude that μ- and κ-opioids have potent and selective peripheral effects on esophageal vagal afferents that may have applications in treatment of disorders of visceral sensation. [ABSTRACT FROM AUTHOR]

Abstract: The Deg/ENaC family of ion channels, including ASIC1, 2 and 3, are candidate mechanotransducers in visceral and somatic sensory neurons, although each channel may play a different role in different sensory pathways. Here we determined which distinct populations of visceral sensory neurons are sensitive to the non-selective Deg/ENaC blocker benzamil, and which ASIC channels are targets for benzamil by studying its actions in knockout mice. Single afferent fiber recordings were made in vitro from mouse high threshold colonic thoracolumbar splanchnic afferents and low threshold gastroesophageal vagal afferents. mRNA expression of ASIC subtypes was compared between colonic and gastroesophageal afferents by quantitative RT-PCR of transcripts following laser capture microdissection of retrogradely labeled cell bodies. Mechanosensitivity of colonic afferents was potently reduced by benzamil (10−6–3×10−4 M), whereas gastroesophageal afferents were marginally inhibited. Inhibition of colonic afferent mechanosensitivity by benzamil was markedly diminished in ASIC2−/− and ASIC3−/− mice, but unchanged in ASIC1a−/−. Therefore ASIC2 and 3 are targets for benzamil to inhibit colonic afferent mechanosensitivity. Conversely, gastroesophageal afferents are less sensitive to benzamil, and its action depends less on ASIC expression. mRNA for ASIC3 showed higher and ASIC1a showed lower relative expression in colonic afferents from thoracolumbar dorsal root ganglia than in gastric afferents from nodose (vagal) ganglia. These data indicate that ASICs on colonic afferents present distinct pharmacological targets for visceral pain. [Copyright &y& Elsevier]

It is established that the gut peptide galanin reduces neuronal excitability via galanin receptor subtypes GALR1 and GALR3 and increases excitability via subtype GALR2. We have previously shown that galanin potently reduces mechanosensitivity in the majority of gastro-oesophageal vagal afferents, and potentiates sensitivity in a minority. These actions may have implications for therapeutic inhibition of gut afferent signalling. Here we investigated which galanin receptors are likely to mediate these effects. We performed quantitative RT-PCR on RNA from vagal (nodose) sensory ganglia, which indicated that all three GALR subtypes were expressed at similar levels. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of galanin receptor ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors which respond only to mucosal stroking. Galanin induced potent inhibition of mechanosensitivity in both types of afferents. This effect was totally lost in mice with targeted deletion of Galr1. The GALR1/2 agonist AR-M961 caused inhibition of mechanosensitivity in Galr1+/+ mice, but this was reversed to potentiation in Galr1−/− mice, indicating a minor role for GALR2 in potentiation of vagal afferents. We observed no functional evidence of GALR3 involvement, despite its expression in nodose ganglia. The current study highlights the complex actions of galanin at different receptor subtypes exhibiting parallels with the function of galanin in other systems. [ABSTRACT FROM AUTHOR]

Ghrelin is a peptide released from gastric endocrine cells that has an orexigenic effect via a vagal pathway. Here we determine the effect of ghrelin on mechanosensitivity of upper-intestinal vagal afferent fibers in ferret and mouse. The responses of gastroesophageal vagal afferents to graded mechanical stimulation were determined in vitro before and during application of ghrelin to their peripheral endings. Three types of vagal afferent were tested: tension receptors responding to circumferential tension, mucosal receptors responding only to mucosal stroking, and tension/mucosal (TM) receptors in ferret esophagus that responded to both stimuli. In the mouse, ghrelin did not significantly affect the response of mucosal receptors to mucosal stroking with calibrated von Frey hairs. However, it significantly reduced responses of tension receptors to circumferential tension (P < 0.005; two-way ANOVA) by up to 40%. This inhibition was reversed by the ghrelin receptor antagonist [D-Lys-31-growth hormone-releasing peptide (GHRP)-6. In the ferret, ghrelin significantly reduced the response of mucosal and TM receptors to mucosal stroking with calibrated von Frey hairs. Surprisingly, ghrelin did not significantly alter the response to circumferential tension in either tension or TM receptors. RT-PCR analysis indicated that both ghrelin and its receptor are expressed in vagal afferent cell bodies in mouse nodose ganglia. In conclusion, ghrelin selectively inhibits subpopulations of mechanically sensitive gastroesophageal vagal afferents; there is also potential for ghrelin release from vagal afferents. However, the subpopulation of afferents inhibited differs between species. These data have broad implications for ghrelin's role in food intake regulation and reflex control of gastrointestinal function. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGIuR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 µM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Glutamate acts at central synapses via ionotropic (iGluR – NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). Group I mGluRs are excitatory whilst group II and III are inhibitory. Inhibitory mGluRs also modulate peripherally the mechanosensitivity of gastro-oesophageal vagal afferents. Here we determined the potential of excitatory GluRs to play an opposing role in modulating vagal afferent mechanosensitivity , and investigated expression of receptor subunit mRNA within the nodose ganglion. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of selective GluR ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors, which respond only to mucosal stroking. The selective iGluR agonists NMDA and AMPA concentration-dependently potentiated afferent responses. Their corresponding antagonists AP-5 and NBQX alone attenuated mechanosensory responses as did the non-selective antagonist kynurenate. The kainate selective agonist SYM-2081 had minor effects on mechanosensitivity, and the antagonist UBP 302 was ineffective. The mGluR5 antagonist MTEP concentration-dependently inhibited mechanosensitivity. Efficacy of agonists and antagonists differed on mucosal and tension receptors. We conclude that excitatory modulation of afferent mechanosensitivity occurs mainly via NMDA, AMPA and mGlu5 receptors, and the role of each differs according to afferent subtypes. PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed. [ABSTRACT FROM AUTHOR]

The neuropeptide galanin is found in the central and peripheral nervous systems. It may have excitatory or inhibitory actions via three subtypes of G-protein-coupled receptor, and it modulates the mechanosensitivity of somatic sensory fibres. We aimed to determine if galanin also modulates vagal afferent mechanosensitivity, and to localize endogenous sources. The responses of ferret and mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigatedin vitro.The effects of galanin and/or the galanin receptor antagonist galantide on these responses were quantified. Immunohistochemistry for galanin was performed in ferret and mouse proximal stomach and nodose ganglion. In ferrets, retrograde labelling of gastric afferents to the nodose ganglion was combined with immunohistochemistry. When exposed to galanin (1–10 nm), 18/31 ferret and 12/15 mouse gastro-oesophageal afferents (tension, mucosal and tension/mucosal receptors) showed inhibition of mechanosensitivity. Four of 31 ferret afferents showed potentiation of mechanosensitivity, and 9/31 were unaffected (2/15 and 1/15 in mouse, respectively). Galanin effects were reversed after washout or by galantide (10–30 nm). Galantide given alone increased mechanosensitivity. Galanin immunoreactivity was found in nodose neurones, including those innervating the stomach in ferret. Enteric neurones were also galanin immunoreactive, as were endings associated with myenteric ganglia and smooth muscle. We conclude that galanin potently modulates mechanosensitivity of gastro-oesophageal vagal afferents with either facilitatory or inhibitory actions on individual afferent fibres. Both intrinsic and extrinsic (vagal) neurones contain galanin and are therefore potential sources of endogenous galanin. [ABSTRACT FROM AUTHOR]

Food intake and activity adapt during pregnancy to meet the increased energy demands. In comparison to non‐pregnant females, pregnant mice consume more food, eating larger meals during the light phase, and reduce physical activity. How pregnancy changes the circadian timing of behaviour was less clear. We therefore randomised female C57BL/6J mice to mating for study until early (n = 10), mid‐ (n = 10) or late pregnancy (n = 11) or as age‐matched, non‐pregnant controls (n = 12). Mice were housed individually in Promethion cages with a 12 h light–12 h dark cycle [lights on at 07.00 h, Zeitgeber (ZT)0] for behavioural analysis. Food intake between ZT10 and ZT11 was greater in pregnant than non‐pregnant mice on days 6.5–12.5 and 12.5–17.5. In mice that exhibited a peak in the last 4 h of the light phase (ZT8–ZT12), peaks were delayed by 1.6 h in the pregnant compared with the non‐pregnant group. Food intake immediately after dark‐phase onset (ZT13–ZT14) was greater in the pregnant than non‐pregnant group during days 12.5–17.5. Water intake patterns corresponded to food intake. From days 0.5–6.5 onwards, the pregnant group moved less during the dark phase, with decreased probability of being awake, in comparison to the non‐pregnant group. The onset of dark‐phase activity, peaks in activity, and wakefulness were all delayed during pregnancy. In conclusion, increased food intake during pregnancy reflects increased amplitude of eating behaviour, without longer duration. Decreases in activity also contribute to positive energy balance in pregnancy, with delays to all measured behaviours evident from mid‐pregnancy onwards. Key points: Circadian rhythms synchronise daily behaviours including eating, drinking and sleep, but how these change in pregnancy is unclear.Food intake increased, with delays in peaks of food intake behaviour late in the light phase from days 6.5 to 12.5 of pregnancy, in comparison to the non‐pregnant group.The onset of activity after lights off (dark phase) was delayed in pregnant compared with non‐pregnant mice.Activity decreased by ∼70% in the pregnant group, particularly in the dark (active) phase, with delays in peaks of wakefulness evident from days 0.5–6.5 of pregnancy onwards.These behavioural changes contribute to positive energy balance during pregnancy.Delays in circadian behaviours during mouse pregnancy were time period and pregnancy stage specific, implying different regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Background Systemic inflammation is a precursor of many chronic diseases that contributes to morbidity and mortality. In this study, we examined the joint association of systemic inflammation and diet quality with all-cause mortality. Methods A total of 27,305 adults (mean age = 50 years, male: 50.6%) from the National Health and Nutrition Examination Survey (1999-2010 and 2015-2018) were included in the study. A serum inflammatory marker, C-reactive protein (CRP), was measured. The Healthy Eating Index-2015 (HEI-15) was computed. Multivariable logistic regression analysis was used to determine the cross-sectional association between HEI-15 and inflammation. Multivariable Cox proportional hazard models were performed to assess the risk of all-cause mortality associated with the joint classification of inflammation and diet quality. Results In the cross-sectional study, a higher tertile of HEI-15 was associated with reduced odds of inflammation (OR = 0.85, 95% CI: 0.78-0.93) in all participants. Similar results were observed in obese and non-obese groups. In the prospective study (median follow-up = 9.4 years), a higher adherence to HEI-15 was associated with a reduced risk of mortality. Compared to non-obese group, obese participants with high levels of inflammation had a higher risk of all-cause mortality (HR = 1.26, 95% CI: 1.08-1.47; HR = 1.60, 95% CI: 1.19-2.17, respectively). Conclusions A higher adherence to HEI-15 was associated with reduced inflammation. Higher diet quality may reduce mortality risks associated with inflammation, particularly in non-obese groups and obese participants with moderate inflammation. Key messages Adhering to a high quality diet may mitigate the mortality risk associated with increased inflammation. [ABSTRACT FROM AUTHOR]

The article comments on the role of nitric oxide (NO) regulation of gut-brain signalling in obesity. Topics include the interaction of the dietary nutrients which initiates the release of gut hormones, the impact of obesity on inducible nitric oxide synthase expression and NO production and the need for improved understanding on the role of NO in modulating gastrointestinal vagal afferent signalling and subcellular signalling pathways.

Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode C. elegans (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD+ hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage. [Display omitted] • C. elegans TIR-1 is expressed on the membranes of lysosome-related organelles (LROs) • Positioning of TIR-1 on LROs enables surveillance of pathogen effector-triggered damage • A pathogen-derived toxic metabolite disrupts LROs, which causes TIR-1 multimerization • TIR-1 aggregation on LROs activates the p38 innate immunity in intestinal epithelial cells TIR-domain proteins with enzymatic activity are essential for immunity across the tree of life. Tse-Kang et al. show that C. elegans TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage. These data characterize a mechanism of enzymatic TIR activation by a bacterial pathogen in animal immunity. [ABSTRACT FROM AUTHOR]

• The circadian system plays an important role in the temporal regulation of food intake and metabolism. • This is controlled by the master clock, the superchiasmatic nucleus with receives input from the retina allowing regulation by the light:dark cycle. • The timing of food intake is another important zeitgeber playing a role in food-entrainable oscillations. • Misalignment of these oscillatory systems can have a huge impact on weight gain and metabolic disease. The circadian system plays an important role in the temporal regulation of metabolic processes as well as food intake to ensure energy efficiency. The 'master' clock is located within the superchiasmatic nucleus and receives input from the retina so that it can be entrained by the light:dark cycle. In turn, the master clock entrains other clocks in the central nervous system, including areas involved in energy homeostasis such as the arcuate nucleus, and the periphery (e.g. adipose tissue and the gastrointestinal tract). This master clock is reinforced by other zeitgebers such as the timing of food intake and activity. If these zeitgebers desynchronise, such as occurs in high fat diet-induced obesity or shift work conditions, it can lead to a misalignment of circadian clocks, disruption of metabolic processes and the development of metabolic disorders. The timing of food intake is a strong zeitgeber, particularly in the gastrointestinal tract, and therefore time restricted feeding offers potential for the treatment of diet and shift work induced metabolic disorders. This review will focus on the role of the circadian system in food intake regulation and the effect of environment factors, such as high fat diet feeding or shift work, on the temporal regulation of food intake along with the benefits of time restricted feeding. [ABSTRACT FROM AUTHOR]

The article offers information on a study related to circadian rhythms (CR). Topics discussed include role of CR in improving energy efficiency by separating incompatible metabolic processes, such as anabolism and catabolism; the molecular mechanism for circadian clock that consists of interlocked transcription-translation feedback loop (TTFL); and the results that shows the close association between diurnal oscillations of the host and diurnal oscillations of the microbiota.

Purpose: Much of the current literature on the associations between diet and depression focus on single nutrients rather than nutrient patterns (NPs). We investigated the association between NPs and depressive symptoms (DepS) in an Australian adult population. Methods: DepS were examined at two different time points, in 2010 (Stage 3, n = 1743, 49.0% males) and 2015 [North West 2015 (NW15), n = 1,024, 46.6% males] of the North West Adelaide Health Study (NWAHS). Dietary habits were evaluated using a food frequency questionnaire (FFQ) at Stage 3. DepS were assessed using the Center for Epidemiological Studies Depression (CES-D) scale at Stage 3 and NW15. Principal component analysis was used to identify NPs as well as the factor structure of the CES-D. Log- and negative binomial regression analyses were used to assess the association between NPs and DepS scores. Ordinal logistic regression analysis was undertaken between the NPs and identified factors of the CES-D score. Results: Three NPs (from the FFQ) and two-factors (from the CES-D score) were obtained. After adjusting for known confounding variables, a 'plant-sourced' NP (β-carotene, fibre, vitamin C, potassium and α-carotene) was inversely associated with DepS at Stage 3 [prevalence ratio (PR)Q4VsQ1, 0.78; 95% CI 0.66–0.92; p = 0.003], whereas an 'animal-sourced' (ω-3 fatty acid, monounsaturated fat, vitamin E and cholesterol) or 'mixed-source' (phosphorous, protein, vitamin B2, iodine and zinc) NP was not associated with DepS. There was an inverse relationship between the 'plant-sourced' NP and the '(absence of) positive-affect' factor from the CES-D in both stages. Conclusion: The 'plant-sourced' NP is consistently and inversely associated with DepS; however, longitudinal studies are recommended to confirm these results. [ABSTRACT FROM AUTHOR]

Time-restricted feeding (TRF) initiated early during the dark phase prevents the metabolic consequences of a high-fat diet in rodent models. However, the metabolic consequences of delaying the initiation of TRF, akin to breakfast skipping in humans, is unclear. We assigned 8-week-old male C57BL/6J mice (n = 192) to chow or high-fat diet ad libitum (AL) for 4 weeks, before randomization to continue AL or 10 h of TRF, initiated at lights off (TRFe) or 4-h after lights off (TRFd) for a further 8 weeks. Oral glucose tolerance tests (1 g/kg), metabolic monitoring and body composition by echoMRI were performed, and tissues were collected at six time points. TRF reduced weight and fat mass vs AL, with a greater reduction in TRFe vs TRFd. TRF improved glucose tolerance and protected mice from high-fat diet-induced hepatosteatosis v s AL, with no difference between TRFe and TRFd. TRF increased the amplitude of Bmal1, Cry1, Per2, Nampt, and Nocturnin mRNA levels in liver. A phase delay in Bmal1, Cry1, Per2, Reverba, Nampt, NAD, Sirt1, and Nocturnin was observed in TRFd. Thus, delaying TRF limited the weight be nefit and induced a phase delay in the hepatic clock, but improved metabolic health. Allowing more flexibility in when TRF is initiated may increase the trans lational potential of this dietary approach in humans. [ABSTRACT FROM AUTHOR]

The author discusses the causes and effects of vagal afferent dysfunction in obesity. Topics include vagal afferent nerves as an important link between the gastrointestinal (GI) tract and the central nervous system (CNS), importance of connections between the nucleus tractus solitarii (NTS) and the dorsal motor nucleus of the vagus (DMV) for vago-vagal reflex control of gastric function, and the effects observed in high fat diet-induced obesity as a concerning factor.

Objective: To compare the kinetics of manual wheelchair (MWC) propulsion on ramps of varying slopes that may be encountered when accessing large accessible transit vehicles (LATVs). Design: Observational study. Setting: Biomechanics research laboratory. Participants: A convenience sample of able-bodied adults (n = 7) having no propulsion experience propelled a MWC on ramps of slope 3.5°, 9.5° and 15°. Interventions: Not applicable. Main outcome measures: Resultant (Fres), radial (Fr) and tangential (Ft) forces applied to the wheelchair pushrim, rate of rise of resultant force (ROR), peak power output (P), temporal characteristics and thigh to trunk angle were analyzed across three ramp slopes. Results: Pushrim forces and power output significantly increased with increasing slope, with peak Fres more than doubling from 107 N on a 3.5° slope to 230 N on a 15° slope. ROR was 1.76 times higher at 9.5° and 2.47 times higher at 15° compared to a 3.5° slope. Minimum thigh to trunk angle decreased sharply from 80° (3.5° slope) to 50° (9.5° slope) and then to 30° (15° slope) as ramp slope increased. Conclusions: Ascending bus ramps require greater power and pushrim force on steeper ramp slopes, presenting a potential barrier to transportation accessibility. Given this finding, it is imperative that bus operators minimize ramp slope to assure MWC users are able to access LATVs. Although transit bus ramps are intended to provide wheelchair access to public transportation, limitations in MWC user physical strength and function may prevent safe access. Transit bus ramp slopes encountered during ingress can present a challenge to MWC users given power output and pushrim force requirements to ascend the ramp. MWC users and therapists should be aware of ramp slopes that may be encountered when boarding transit buses; wheelchair training should incorporate skills needed to ascend transit bus ramps. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigates the effects of geometrical surfaces on nucleation in the crystallization process. It focuses on the heterogeneous nucleation of a wedge-shaped groove which is faster compared to flat surfaces through computer simulations. It emphasizes the Lennard-Jones model in the crystallization of noble gases at low pressure and temperature.

Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance. Author summary: Individual micronutrients and metabolites are essential for animals to survive challenge with infectious pathogens. Defining the metabolic requirements for pathogen resistance is therefore important to understand the links between nutrient acquisition, metabolism and host susceptibility to bacterial infection. Here we demonstrate that the cellular regulation of sphingolipids, complex macromolecules that are required for diverse biological processes, is required for the nematode C. elegans to survive infection with the pathogen Pseudomonas aeruginosa. We show that the C. elegans nuclear hormone receptor NHR-66, a ligand-gated transcription factor, directly regulates sphingolipid catabolism by repressing the transcription of two enzymes, sphingosine phosphate lyase (SPL-2) and acid ceramidase (ASAH-2). Transcriptional repression of these catabolic enzymes by NHR-66 controls the levels of sphingolipids in the cell in a manner that is required for host survival during pathogen challenge. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Body mass and food intake change during the female ovarian cycle: does glucose transport by the small intestine also vary?What is the main finding and its importance?We have optimised Ussing chamber methodology to measure region‐specific active glucose transport in the small intestine of adult C57BL/6 mice. Our study provides the first evidence that jejunal active glucose transport changes during the oestrous cycle in mice, and is higher at pro‐oestrus than oestrus. These results demonstrate adaptation in active glucose uptake, concurrent with previously reported changes in food intake. Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre‐ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8–9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short‐circuit current (∆Isc) induced by glucose. Tissue viability was confirmed by a positive ∆Isc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d‐glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum (P < 0.01). Incubation with the sodium–glucose cotransporter 1 (SGLT1) inhibitor phlorizin reduced active glucose transport in a dose‐dependent manner in all regions (P < 0.01). Active glucose uptake induced by addition of 45 mM glucose to the mucosal chamber in the absence or presence of phlorizin was assessed in jejunum at each oestrous cycle stage (n = 9–10 mice per stage). Overall, active glucose uptake was lower at oestrus compared to pro‐oestrus (P = 0.025). This study establishes an ex vivo method to measure region‐specific glucose transport in the mouse small intestine. Our results provide the first direct evidence that SGLT1‐mediated glucose transport in the jejunum changes across the ovarian cycle. The mechanisms underlying these adaptations in nutrient absorption remain to be elucidated. [ABSTRACT FROM AUTHOR]

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. [ABSTRACT FROM AUTHOR]

Objective Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. Design and results mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. Conclusions Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes. [ABSTRACT FROM AUTHOR]

Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), has been reported in individuals with post-acute sequelae of COVID-19 (PASC). However, the degree of dysautonomia in PASC has not been compared to those with POTS and healthy controls. All participants were prospectively enrolled between August 5, 2021 and October 31, 2022. Autonomic testing included beat-to-beat hemodynamic monitoring to assess respiratory sinus arrhythmia, Valsalva ratio, and orthostatic changes during a 10-minute active standing test, as well as sudomotor assessment. The Composite Autonomic Symptom Score (COMPASS-31) was used to assess symptoms and the EuroQuol 5-Dimension survey (EQ-5D-5L) was used to assess health-related quality of life (HrQoL) measures. A total of 99 participants (n = 33 PASC, n = 33 POTS, and n = 33 healthy controls; median age 32 years, 85.9% females) were included. Compared with healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (P <.001), greater heart rate increase during 10-minute active standing test (P <.001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all P <.001), and poor HrQoL across all EQ-5D-5L domains (all P <.001), lower median EuroQol-visual analogue scale (P <.001), and lower utility scores (P <.001). The majority (79%) of those with PASC met the internationally established criteria for POTS. The prevalence of autonomic symptomology for POTS was high in those with PASC, leading to poor HrQoL and high health disutility. Autonomic testing should be routinely undertaken in those with PASC to aid diagnosis and direct appropriate management to improve health outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Successful pulmonary vein isolation (PVI) for atrial fibrillation (AF) depends on the formation of durable transmural lesions. Recently, novel indices have emerged to guide lesion delivery. The aim of the systematic review of literature was to determine AF recurrence following ablation guided by indices incorporating force, power and time, and compare acute procedural outcomes and 12-month AF recurrence with ablation guided by contact force (CF) guided only.Methods: PubMed, EMBASE, and Web of Science Core Collection databases were searched on 27 January 2020 using the keywords; catheter ablation, ablation index (AI), lesion size index (LSI), contact force, atrial fibrillation.Results: After exclusions, seven studies were included in the analysis. AI-guided catheter ablation was associated with a 91% (n=5, 0.91 95% CI; 0.88-0.93) and 80% (n=5, 0.80, 95% CI; 0.77-0.84) freedom from AF at 12 months with and without the use of anti-arhythmic drugs respectively. As compared to CF guided ablation, AI-guided catheter ablation was associated with a 49% increase in successful first pass isolation (n=3; RR: 1.49, 95% CI; 1.38, 1.61), a 50% decrease in number of acute reconnections (n=4; RR: 0.50, 95% CI; 0.39-0.65) and a 22% (n=4, RR: 1.22, 95% CI; 1.10-1.35) increase in AF freedom without anti-arrhythmic drugs at 12 months.Conclusions: Radiofrequency ablation guided by AI was associated with higher successful first pass isolation and lower rates of acute reconnection which translates to greater freedom from AF at 12 months [CRD42019131469]. [ABSTRACT FROM AUTHOR]

Background The link between diet, inflammation and depressive symptoms (DepS) are of increasing interest. The study aims to assess the association between the dietary inflammatory index (DII®) and DepS using the North-West Adelaide Health Study (NWAHS) cohort and update the previous meta-analysis. Methods A total of 1743 (mean□SD age 56.6±13.6 years, 51% female) and 859 (mean□SD age 58.4±12.1 years, 52.6% female) of NWAHS participants were included for cross-sectional and longitudinal analysis respectively. DII was determined using food frequency questionnaires, and the Center for Epidemiologic Studies Depression Scale (CES-D) assessed DepS. Log- and negative binomial regression were used to assess the association between quartiles of DII and DepS. Results In a fully adjusted model, higher DII score (i.e. pro-inflammatory diet) was associated with 79% increase in odds of reporting DepS (ORQuartile4vs1:1.79; 95% CI: 1.14-2.81; p trend =0.026). Men with higher DII had two-fold higher odds of DepS (ORQuartile4vs1:2.27; 95% CI: 1.02-5.06; p trend =0.089). Women with higher DII had an 81% increase in odds of DepS (ORQuartile4vs1:1.81; 95% CI: 1.01-3.26; p trend =0.068). These associations were consistent in the longitudinal analysis. The meta-analysis (n = 12) showed that a pro-inflammatory diet was associated with a 45% increase in odds of having DepS (ORQuartile4vs1:1.45; 95% CI: 1.20,1.74, p-value<0.01). Conclusions A pro-inflammatory diet was positively associated with increased risk of DepS. Our findings support the current evidence that shows the role of pro-inflammatory diet in DepS. Key messages Increase the consumption of anti-inflammatory diet to reduce depressive symptoms [ABSTRACT FROM AUTHOR]

Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader‐Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge‐eating disorder are also discussed. [ABSTRACT FROM AUTHOR]

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy. NEW & NOTEWORTHY This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The ability of the gut to detect nutrients is critical to the regulation of gut hormone secretion, food intake, and postprandial blood glucose control. Ingested nutrients are detected by specific gut chemosensors. However, knowledge of these chemosensors has primarily been derived from the intestine, while available information on gastric chemosensors is limited. This study aimed to investigate the nutrient‐sensing repertoire of the mouse stomach with particular emphasis on ghrelin cells. Methods: Quantitative RT‐PCR was used to determine mRNA levels of nutrient chemosensors (protein: G protein–coupled receptor 93 [GPR93], calcium‐sensing receptor [CaSR], metabotropic glutamate receptor type 4 [mGluR4]; fatty acids: CD36, FFAR2&4; sweet/umami taste: T1R3), taste transduction components (TRPM5, GNAT2&3), and ghrelin and ghrelin‐processing enzymes (PC1/3, ghrelin O‐acyltransferase [GOAT]) in the gastric corpus and antrum of adult male C57BL/6 mice. Immunohistochemistry was performed to assess protein expression of chemosensors (GPR93, T1R3, CD36, and FFAR4) and their co‐localization with ghrelin. Key Results: Most nutrient chemosensors had higher mRNA levels in the antrum compared to the corpus, except for CD36, GNAT2, ghrelin, and GOAT. Similar regional distribution was observed at the protein level. At least 60% of ghrelin‐positive cells expressed T1R3 and FFAR4, and over 80% expressed GPR93 and CD36. Conclusions and Inferences: The cellular mechanisms for the detection of nutrients are expressed in a region‐specific manner in the mouse stomach and gastric ghrelin cells. These gastric nutrient chemosensors may play a role modulating gastrointestinal responses, such as the inhibition of ghrelin secretion following food intake. [ABSTRACT FROM AUTHOR]

Significance Statement: Gastric vagal afferent responses to tension are dampened in high fat diet‐induced obesity.Endocannabinoids are known to dose‐dependently inhibit and excite gastric vagal afferents but their effect on gastric vagal afferents in diet‐induced obesity are unknown.In individual gastric vagal afferent neurons of diet‐induced obese mice the co‐expression of components of the endocannabinoid system, including CB1, GHSR, TRPV1 and FAAH, was increased compared with lean mice.In high fat diet‐induced obese mice, methanandamide only inhibited gastric vagal afferent responses to tension, possibly due to the observed change in the balance of receptors, hormones and breakdown enzymes in this system.Collectively, these data suggest that endocannabinoid signalling, by gastric vagal afferents, is altered in diet‐induced obesity which may impact satiety and gastrointestinal function. Gastric vagal afferents (GVAs) play a role in appetite regulation. The endocannabinoid anandamide (AEA) dose‐dependently inhibits and excites tension‐sensitive GVAs. However, it is also known that high fat diet (HFD) feeding alters GVA responses to stretch. The aim of this study was to determine the role of AEA in GVA signalling in lean and HFD‐induced obese mice. Male C57BL/6 mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Protein and mRNA expression of components of the cannabinoid system was determined in individual GVA cell bodies and the gastric mucosa. An in vitro GVA preparation was used to assess the effect of methanandamide (mAEA) on tension‐sensitive GVAs and the second messenger pathways involved. In individual GVA cell bodies, cannabinoid 1 (CB1) and ghrelin (GHSR) receptor mRNA was higher in HFD mice than SLD mice. Conversely, gastric mucosal AEA and ghrelin protein levels were lower in HFD mice than SLD mice. In SLD mice, mAEA exerted dose‐dependent inhibitory and excitatory effects on tension‐sensitive GVAs. Only an inhibitory effect of mAEA was observed in HFD mice. The excitatory effect of mAEA was dependent on CB1, transient receptor potential vanilloid 1 (TRPV1) and the protein kinase C. Conversely, the inhibitory effect was dependent on CB1, growth hormone secretagogue receptor, TRPV1 and the protein kinase A. Endocannabinoids, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD mice only an inhibitory effect was observed. These changes may contribute to the development and/or maintenance of obesity. [ABSTRACT FROM AUTHOR]

Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice. Female C57BL/6J mice (10–12 weeks old) were randomized to mating and then tissue collection at early- (6.5 d), mid- (12.5 d) or late-pregnancy (17.5 d), or to an unmated age matched control group. Relative transcript expression of intestinal fatty acid, peptide and amino acid and carbohydrate chemoreceptors, as well as gut hormones was determined across pregnancy. The density of G-protein coupled receptor 93 (GPR93), free fatty acid receptor (FFAR) 4, cholecystokinin (CCK) and glucagon-like peptide1 (GLP-1) immunopositive cells was then compared between non-pregnant and late-pregnant mice. Duodenal GPR93 expression was lower in late pregnant than non-pregnant mice (P < 0.05). Ileal FFAR1 expression was higher at mid- than at early- or late-pregnancy. Ileal FFAR2 expression was higher at mid-pregnancy than in early pregnancy. Although FFAR4 expression was consistently lower in late-pregnant than non-pregnant mice (P < 0.001), the density of FFAR4 immunopositive cells was higher in the jejunum of late-pregnant than non-pregnant mice. A subset of protein and fatty acid chemoreceptor transcripts undergo region-specific change during murine pregnancy, which could augment hormone release and contribute to increased food intake. Further investigations are needed to determine the functional relevance of these changes. • Adaptations in intestinal chemoreceptors and hormones during pregnancy is unknown. • Duodenal GPR93 and intestinal FFAR4 expression was lower in late-pregnant mice. • FFAR4 positive cells were greater in the jejunum of late- vs. non-pregnant mice. • Gut hormone (CCK & GLP-1) expression and cell density was unchanged in pregnancy. [ABSTRACT FROM AUTHOR]

Key points: The fine control of food intake is important for the maintenance of a healthy metabolic state.Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety.This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration‐dependent biphasic manner.This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors.These data have important implications for the peripheral control of food intake. Gastric vagal afferents (GVAs) signal to the hindbrain resulting in satiety. Endocannabinoids are endogenous ligands of cannabinoid 1 receptor (CB1) and transient receptor potential vanilloid‐1 (TRPV1) channels. The endocannabinoid anandamide (AEA) is expressed in the stomach, and its receptor CB1 is expressed in ghrelin‐positive gastric mucosal cells. Further, TRPV1, CB1 and growth hormone secretagogue receptor (ghrelin receptor, GHSR) are expressed in subpopulations of GVA neurons. This study aimed to determine the interaction between TRPV1, CB1, GHSR and endocannabinoids in the modulation of GVA signalling. An in vitro electrophysiology preparation was used to assess GVA mechanosensitivity in male C57BL/6 mice. Effects of methanandamide (mAEA; 1–100 nm), on GVA responses to stretch were determined in the absence and presence of antagonists of CB1, TRPV1, GHSR, protein kinase‐A (PKA), protein kinase‐C (PKC) and G‐protein subunits Gαi/o, or Gαq. Low doses (1–10 nm) of mAEA reduced GVA responses to 3 g stretch, whereas high doses (30–100 nm) increased the response. The inhibitory and excitatory effects of mAEA (1–100 nm) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, Gαi/o or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or Gαq antagonist the excitatory effect of mAEA was reduced or lost, respectively. Activation of CB1, by mAEA, can activate or inhibit TRPV1 to increase or decrease GVA responses to stretch, depending on the pathway activated. These interactions could play an important role in the fine control of food intake. Key points: The fine control of food intake is important for the maintenance of a healthy metabolic state.Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety.This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration‐dependent biphasic manner.This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors.These data have important implications for the peripheral control of food intake. [ABSTRACT FROM AUTHOR]

Key points: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architectureTNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively.TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity.Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice.TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology.TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. Tenascin‐X (TNX) is a glycoprotein that regulates tissue structure via anti‐adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers–Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX‐deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin‐immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB‐deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved using GABAB agonists. Key points: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architectureTNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively.TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity.Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice.TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology.TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. [ABSTRACT FROM AUTHOR]