Farrugia, Gianrico

AbstractBackgroundNormal gastrointestinal motility depends on electrical slow‐wave activity generated by interstitial cells of Cajal (ICC) in the tunica muscularis of the gastrointestinal tract. A requirement for HCO3− in extracellular solutions used to record slow waves indicates a role for HCO3− transport in ICC pacemaking. The Slc4a4 gene transcript encoding the electrogenic Na+/HCO3− cotransporter, NBCe1, is enriched in mouse small intestinal myenteric region ICC (ICC‐MY) that generate slow waves. This study aimed to determine how extracellular HCO3− concentrations affect electrical activity in mouse small intestine and to determine the contribution of NBCe1 activity to these effects.MethodsImmunohistochemistry and sharp electrode electrical recordings were used.Key ResultsThe NBCe1 immunoreactivity was localized to ICC‐MY of the tunica muscularis. In sharp electrode electrical recordings, removal of HCO3‐ from extracellular solutions caused significant, reversible, depolarization of the smooth muscle and a reduction in slow‐wave amplitude and frequency. In 100 mM HCO3−, the muscle hyperpolarized and slow wave amplitude and frequency increased. The effects of replacing extracellular Na+ with Li+, an ion that does not support NBCe1 activity, were similar to, but larger than, the effects of removing HCO3‐. There were no additional changes to electrical activity when HCO3‐ was removed from Li+ containing solutions. The Na+/HCO3− cotransport inhibitor, S‐0859 (30µM) significantly reduced the effect of removing HCO3− on electrical activity.Conclusions & InferencesThese studies demonstrate a major role for Na+/HCO3− cotransport by NBCe1 in electrical activity of mouse small intestine and indicated that regulation of intracellular acid:base homeostasis contributes to generation of normal pacemaker activity in the gastrointestinal tract.

Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiological reactions. Nonspecialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells use various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G protein-coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex—the ability of smooth muscle to contract in response to stretch rapidly—is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and mechanosensitive ion channels, which alter their ion pores’ opening in response to force, allowing fast electrical and Ca 2+ responses. Although GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and mechanosensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and mechanosensitive ion channels.

Abstract Background Several vaccines are now available under emergency use authorization in the United States and have demonstrated efficacy against symptomatic COVID-19. Vaccine impact on asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is largely unknown. Methods We conducted a retrospective cohort study of consecutive, asymptomatic adult patients (n = 39 156) within a large US healthcare system who underwent 48 333 preprocedural SARS-CoV-2 molecular screening tests between 17 December 2020 and 8 February 2021. The primary exposure of interest was vaccination with ≥1 dose of an mRNA COVID-19 vaccine. The primary outcome was relative risk (RR) of a positive SARS-CoV-2 molecular test among those asymptomatic persons who had received ≥1 dose of vaccine compared with persons who had not received vaccine during the same time period. RR was adjusted for age, sex, race/ethnicity, patient residence relative to the hospital (local vs nonlocal), healthcare system regions, and repeated screenings among patients using mixed-effects log-binomial regression. Results Positive molecular tests in asymptomatic individuals were reported in 42 (1.4%) of 3006 tests and 1436 (3.2%) of 45 327 tests performed on vaccinated and unvaccinated patients, respectively (RR, .44; 95% CI, .33–.60; P < .0001). Compared with unvaccinated patients, risk of asymptomatic SARS-CoV-2 infection was lower among those >10 days after the first dose (RR, .21; 95% CI, .12–.37; P < .0001) and >0 days after the second dose (RR, .20; 95% CI, .09–.44; P < .0001) in the adjusted analysis. Conclusions COVID-19 vaccination with an mRNA-based vaccine showed a significant association with reduced risk of asymptomatic SARS-CoV-2 infection as measured during preprocedural molecular screening. Results of this study demonstrate the impact of the vaccines on reduction in asymptomatic infections supplementing the randomized trial results on symptomatic patients.

AbstractBackgroundThe classic clinical picture of gastroparesis is a symptomatic patient losing weight. In addition, a number of patients with delayed gastric emptying are obese and/or gaining weight. Our aim was to investigate the factors impacting body weight in patients with idiopathic gastroparesis.MethodsIn patients with idiopathic gastroparesis, detailed history and weight were acquired at enrollment and after 48 weeks. Questionnaires assessed symptoms, food intake, physical activity, and quality of life. Patients underwent laboratory testing, gastric emptying scintigraphy, and water load testing.ResultsOf 138 patients with idiopathic gastroparesis, 10% were underweight (BMI < 18.5), 39% were normal weight (BMI 18.5‐25), 20% were overweight with BMI 25 to 30 kg/m2, and 29% were obese with BMI > 30 kg/m2. Body weight at enrollment was positively associated with oral caloric consumption (P < .001), following a gastroparesis diet (P = .04), nutrition consultation (P = .001), upper abdominal pain (P = .01); and negatively associated with energy expenditure (P = .05), alcohol use (P = .003) and severity of bloating (P < .001). When followed over 48 weeks, 53% patients stayed stable (within 5% of baseline weight), 30% gained, and 17% lost weight. Weight gain over 48 weeks was positively associated with oral caloric consumption (P = .003) and constipation severity (P = .005) at enrollment, and negatively associated with lower abdominal pain severity (P = .007) at enrollment, and associated with improvement in inability to finish meal score (P < .001) at 48 weeks.ConclusionsIn this series of patients with idiopathic gastroparesis, 10% were underweight whereas 29% were obese. Over 48 weeks, 30% of patients increased their body weight ≥ 5%. Diet, activity, and symptoms are important factors associated with body weight in patients with idiopathic gastroparesis.

AbstractBackgroundUnderstanding factors that impair quality of life (QOL) in gastroparesis is important for clinical management. Aims: (a) Determine QOL in patients with gastroparesis; (b) Determine factors that impair QOL.MethodsGastroparetic patientsAQ6 underwent history and questionnaires assessing symptoms (PAGI‐SYM and Rome III), QOL (SF‐36v2 and PAGI‐QOL), depression (Beck Depression Inventory [BDI]), and anxiety (State Trait Anxiety InventoryAQ7).Key Results715 gastroparesis patients (256 diabetic (DG), 459 idiopathic (IG)) were evaluated. SF‐36 physical component (PC) score averaged 33.3 ± 10.5; 41% had impaired score <30. SF‐36 PC scores were similar between diabetic and idiopathic gastroparesis. Impaired SF‐36 PC associated with increased nausea/vomiting and upper abdominal pain subscores, acute onset of symptoms, higher number of comorbidities, use of narcotic pain medications, and irritable bowel syndrome (IBS). SF‐36 mental component (MC) score averaged 38.9 ± 13.0; 26% had impaired score <30. Poor SF‐36 MC associated with diabetic etiology, higher Beck depression inventory, and state anxiety scores. PAGI‐QOL score averaged 2.6 ± 1.1; 50% had a score of <2.6. Low PAGI‐QOL associated with higher fullness, bloating, and upper abdominal pain subscores, more depression and Trait anxiety, smoking cigarettes, need for nutritional support, progressively worsening symptoms and periodic exacerbations.Conclusions & InferencesMultiple measures show poor QOL present in gastroparesis. Several areas impacted on reduced QOL: (a) Symptoms of nausea, vomiting, and abdominal pain, as well as IBS; (b) Etiology and acute onset and progressively worsening symptoms; (c) Comorbidities and psychological factors such as anxiety and depression; (d) Patient‐related factors such as smoking. Targeting the modifiable factors may improve patient outcomes in gastroparesis.

This study presents gastric ablation as a new method for modulating slow wave activation and propagation in vivo, by creating localized electrical conduction blocks in the stomach, validated by high-resolution electrical mapping and histological tissue analysis. The results define the effective energy dose range for creating conduction blocks, while maintaining the mucosal and submucosal integrity, and demonstrate the electrophysiological effects of ablation. In future, gastric ablation can now be translated toward disrupting dysrhythmic slow wave activation.

In this study, we show that the electrogenic Na+/HCO3− cotransporter, NBCe1/Slc4a4, is expressed in subtypes of interstitial cells of Cajal (ICCs) responsible for electrical slow wave generation throughout the mouse gastrointestinal tract and is absent in other types of ICCs. The transcripts of Slc4a4 expressed in mouse ICCs and human gastrointestinal smooth muscle are the regulated isoforms. This indicates a key role for HCO3- transport in generation of gastrointestinal motility patterns.