Acid Perfusion Research Articles

Challenges, limitations, and pitfalls of PET and advanced MRI in patients with brain tumors: A report of the PET/RANO group.

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach

Metabolic zonation refers to the spatial separation of metabolic functions along the sinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepatic metabolism to physiological requirements in health and disease (e.g., metabolic dysfunction-associated steatotic liver disease/MASLD). Zonated metabolic functions are influenced by zonal morphological abnormalities in the liver, such as periportal fibrosis and pericentral steatosis. We aim to analyze the interplay between microperfusion, oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule. Therefore we developed a continuum biomechanical, tri-phasic, bi-scale, and multicomponent in silico model, which allows to numerically simulate coupled perfusion-function-growth interactions two-dimensionally in liver lobules. The developed homogenized model has the following specifications: (i) thermodynamically consistent, (ii) tri-phase model (tissue, fat, blood), (iii) penta-substances (glycogen, glucose, lactate, FFA, and oxygen), and (iv) bi-scale approach (lobule, cell). Our presented in silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion, metabolic pathways and fat accumulation. The model thus allows the prediction of fat development in the liver lobule, depending on perfusion, oxygen and plasma concentration of free fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs). The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus, we will investigate how changes at the cellular scale affect perfusion at the lobular scale and vice versa. This allows to predict the zonation of fat distribution (periportal or pericentral) depending on initial conditions, as well as external and internal boundary value conditions.

Ziverel for PPI-refractory reflux symptoms: efficacy and mechanisms of action in humans

Objectives It is thought that esophageal hypersensitivity in combination with an impaired mucosal barrier function contributes to PPI-resistant reflux symptoms. Ziverel, a bioadhesive agent that coats the esophageal wall, was shown to have a positive effect on reflux symptoms. However, the mechanisms of action are unclear. We aimed to assess the effect of Ziverel on esophageal sensitivity to acid and mucosal barrier function. Methods We performed a double-blind randomized placebo-controlled crossover trial in PPI-refractory patients with reflux symptoms. Patients were assigned (1:1) to 14 days of Ziverel followed by 14 days of placebo or opposite treatment order. The effect was evaluated using acid perfusion tests, an upper endoscopy with electrical tissue impedance spectroscopy (ETIS) and esophageal biopsies. The primary outcome was the esophageal sensitivity based on perfusion sensitivity score. Secondary outcomes included mucosal barrier function and reflux symptoms and correlations between the different outcomes. Results Perfusion sensitivity score was not significantly different during treatment with Ziverel (106 (73–115)) and placebo (102 (67–110)) (p = 0.508) along with total RDQ score (2.6 (1.9–3.3) vs 2.8 (1.6–3.5) p = 0.456). ETIS showed comparable values during treatment with Ziverel (13514 (8846–19734)Ω·m) and placebo (13217 (9127–24942)Ω·m (p = 0.650)). Comparing Ziverel and placebo no difference was seen in transepithelial electrical resistance (TEER) 203 (163–267) Ω.cm2 vs 205 (176–240) Ω.cm2 (p = 0.445) and fluorescein flux 775 (17–6964) nmol/cm2/h vs 187 (4–12209) nmol/cm2/h (p = 0.638). Conclusion Ziverel did not show a benefit on acid sensitivity, reflux symptoms or esophageal mucosal integrity compared to placebo in PPI-refractory patients with reflux symptoms. Trial registration: Netherlands Trial Register number: NL7670

The Effect of STW5 (Iberogast) on Reflux Symptoms in Patients With Concurrent Dyspeptic Symptoms: A Double-blind Randomized Placebo-controlled Crossover Trial.

It has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events. We performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring. A total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, "gastroesophageal reflux disease" and "regurgitation" subscale scores were lower after STW5 treatment compared to placebo (P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events (P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment (P = 0.042). We found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.

Atractylenolide III ameliorated reflux esophagitis via PI3K/AKT/NF-κB/iNOS pathway in rats

Reflux esophagitis (RE), an esophageal inflammation caused by reflux of gastric contents, often damages the lower esophagus, seriously affecting the quality of life of patients. This study aims to investigate the therapeutic effects and underlying molecular mechanisms of atractylenolide III (ATL III) on RE model rats. In this research, the RE rat model is established sequentially following hemipyloric ligation, cardia transection, and hydrochloric acid perfusion. Further, the RE-induced rats are intragastrically administrated with ATL III (0.6, 1.2, and 2.4 mg/kg/D) for 28 days to evaluate ATL III therapeutic effects. To study the molecular mechanism, RE rats are treated with a phosphoinositide-3 kinase (PI3K) agonist (740 Y–P) combined with ATL III. The histopathological changes in the esophagus are eventually observed by hematoxylin & eosin (H&E) staining. In addition to changes in gastric pH and levels of reactive oxygen species (ROS), enzyme-linked immunosorbent assay (ELISA) and Western blot analyses are used to detect the expression levels of tumor necrosis factor-α (TNF-α, mmol/L), interleukin (IL)-8, IL-6, IL-1β in the esophageal tissues. As a result, the lesions in the esophageal tissues of RE rats are alleviated, decreasing the macroscopic observation scores of the esophageal mucosa after ATL III treatment,. The experimental results indicated significantly increased pH value of the gastric contents and reduced ROS, thiobarbituric acid reactants (TBARS), TNF-α, IL-8, IL-6, and IL-1β levels, as well as expression levels of p-PI3K, p-AKT, iNOS, and nuclear NF-κB proteins in esophageal tissues. In conclusion, the study indicated that ATL III could efficiently treat RE in rats by inhibiting oxidative stress and inflammatory damage through the PI3K/AKT/NF-κB/iNOS pathway.

Gabapentin alleviated the cough hypersensitivity and neurogenic inflammation in a guinea pig model with repeated intra-esophageal acid perfusion

ObjectiveThe anti-tussive effect of gabapentin and its underlying neuromodulatory mechanism were investigated via a modified guinea pig model of gastroesophageal reflux-related cough (GERC). MethodsIntra-esophageal perfusion with hydrochloric acid (HCl) was performed every other day 12 times to establish the GERC model. High-dose gabapentin (48 mg/kg), low-dose gabapentin (8 mg/kg), or saline was orally administered for 2 weeks after modeling. Cough sensitivity, airway inflammation, lung and esophagus histology, levels of substance P (SP), and neurokinin-1 (NK1)-receptors were monitored. ResultsRepeated intra-esophageal acid perfusion aggravated the cough sensitivity in guinea pigs in a time-dependent manner. The number of cough events was significantly increased after 12 times HCl perfusion, and the hypersensitivity period was maintained for 2 weeks. The SP levels in BALF, trachea, lung, distal esophagus, and vagal ganglia were increased in guinea pigs receiving HCl perfusion. The intensity of cough hypersensitivity in the GERC model was significantly correlated with increased SP expression in the airways. Both high and low doses of gabapentin administration could reduce cough hypersensitivity exposed to HCl perfusion, attenuate airway inflammatory damage, and inhibit neurogenic inflammation by reducing SP expression from the airway and vagal ganglia. ConclusionsGabapentin can desensitize the cough sensitivity in the GERC model of guinea pig. The anti-tussive effect is associated with the alleviated peripheral neurogenic inflammation as reflected in the decreased level of SP.

Comparative Analysis of Morphological, Physiological, Anatomic and Biochemical Responses in Relatively Sensitive Zinnia elegans ‘Zinnita Scarlet’ and Relatively Tolerant Zinnia marylandica ‘Double Zahara Fire Improved’ under Saline Conditions

Salinity is one of the major abiotic stresses in plants. The aim of the present study was to determine the effects of salinity on relatively sensitive Zinnia elegans Jacq. ‘Zinnita Scarlet’ and relatively tolerant Zinnia marylandica D.M. Spooner et al. ‘Double Zahara Fire Improved’ through a comparative analysis of morphological, physiological, anatomic, and biochemical traits. Plants were irrigated at five levels of salt concentrations (0 [control], 50, 100, 150, 200 mM NaCl) for three weeks at one-day intervals in pots under greenhouse conditions. The effects of salinity stress on plant growth parameters, ion leakage, the loss of turgidity, minimum fluorescence (FO’), plant nutrient elements, leaf anatomic parameters, stoma response to the application of light and abscisic acid perfusion, proline content, chlorophyll a, b and total chlorophyll, and carotenoid content were investigated. Differences in the stages and levels of plant response in the relatively sensitive and relatively tolerant cultivar were determined. Proline accumulation appeared to be higher in Double Zahara Fire Improved (D.Za.F.I.) than Zinnita Scarlet (Zi.S.) in the low concentration of salinity. After the application of abscsic acid perfusion to intact leaf surfaces, the stomata of the relatively tolerant cultivar D.Za.F.I. closed earlier (7 min) than Zi.S. (29 min). Ion leakage (32.3%) and Na accumulation (0.9%) in the aerial parts increased dramatically for Zi.S in the 50 mM NaCl treatment. Moreover, values of plant growth parameters, minimum fluorescence (FO’), photosynthetic pigments, and plant nutrient elements all showed a greater decreasing percentage in Zi.S. compared to D.Za.F.I. Stomatal densities for both the abaxial and adaxial surfaces of the leaf decreased in parallel with the increase in salt stress. Palisade parenchyma cell height and leaf thickness values decreased in Zi.S. as salinity increased. In D.Za.F.I., leaf thickness increased by up to 100 mM NaCl while the height of palisade parenchyma cells decreased under high salt stress conditions (100 mM and above). Recommendations for future research include molecular-level evaluations and the study of how to increase salt tolerance in these potentially valuable ornamental cultivars.

The brain-esophagus axis in subjects with and without obesity assessed by esophageal acid perfusion and functional brain imaging.

Gastroesophageal reflux disease (GERD) has a complex pathophysiology and a heterogeneous symptom profile. The brain-esophageal axis in GERD has been studied with functional brain imaging during the last decades, but data from obese patients was just recently reported. A comparison of such a group with non-obese subjects is lacking in the literature. This study aimed to evaluate heartburn perception and brain connectivity responses during esophageal acid stimulation in subjects with and without obesity, controlling for the presence of typical reflux symptoms. In this cross-sectional study, 25 patients with obesity (body mass index ≥30 kg/m2) and 46 subjects without obesity underwent functional magnetic resonance imaging (fMRI) of the brain with esophageal water and acid perfusion. The fMRI paradigm and connectivity were assessed. About two-thirds of the participants had reflux symptoms. Heartburn perception during fMRI did not differ between subjects with and without obesity. The presence of reflux symptoms was associated with lower activation in frontal brain regions during acid perfusion compared to water perfusion. Compared to subjects without obesity, patients with obesity presented significantly lower connectivity within the anterior salience network. Corrected clusters included left caudate, left putamen and left anterior cingulate gyrus. The brain-esophagus axis showed differences between subjects with and without obesity. Even without symptomatic differences following esophageal acid perfusion, patients with reflux symptoms showed less brain activation in frontal areas, while obese individuals presented lower connectivity within the anterior salience network.

Esophageal secondary peristalsis following acid infusion and chemical clearance correlate with mucosal integrity and acid sensitivity in GERD patients.

Acid sensitivity can be altered in patients with gastroesophageal reflux disease (GERD). Secondary peristalsis helps clear gastro-esophageal refluxate and residual ingested food bolus. The aim of this study was to investigate the associations among acid sensitivity, esophageal mucosal integrity, chemical clearance, and secondary peristalsis before and after esophageal acid infusion. This was an investigator-initiated, prospective, cross-sectional study. Adult reflux patients underwent high resolution manometry and 24 h impedance-pH monitoring off acid suppression to identify GERD phenotypes, including non-erosive reflux disease (NERD), reflux hypersensitivity (RH), and functional heartburn (FH). Secondary peristalsis was assessed using five rapid 20 mL air injections into the esophagus before and after infusion of hydrochloric acid (0.1 N) into the mid-esophagus. Conventional acid infusion parameters recorded included lag time, intensity rating, and sensitivity score. Chemical clearance was evaluated using the post-reflux swallow-induced peristaltic wave (PSPW), and mucosal integrity was assessed by the mean nocturnal baseline impedance (MNBI) derived from impedance-pH monitoring. A total of 88 patients (age 21-64 years, 62.5% women) completed the study including 12 patients with NERD, 45 with RH, and 31 with FH. There was no significant difference in acid infusion parameters between patients with NERD, RH, and FH. Upon acid infusion, patients who exhibited successful secondary peristalsis had longer lag time, higher MNBI, and shorter bolus contact time than those without secondary peristalsis. Meanwhile, patients with intact PSPW demonstrated significantly higher intensity ratings in response to acid perfusion and higher MNBI than those with impaired PSPW. The lag time correlated positively with MNBI (r = 0.285; p = 0.007). In conclusion, the protective effect of esophageal secondary peristalsis and chemical clearance on esophageal mucosal integrity was demonstrated. Concerning acid sensitivity, longer lag time in patients with intact secondary peristalsis may be attributed to better esophageal mucosal integrity, while stronger intensity ratings may have a greater tendency to induce PSPW and protect esophageal mucosal integrity.

Zhizhu Kuanzhong, a traditional Chinese medicine, alleviates gastric hypersensitivity and motor dysfunction on a rat model of functional dyspepsia.

Ethnopharmacological relevance: Zhizhu Kuanzhong (ZZKZ) is a traditional Chinese medicine modified from classic formula Zhizhu decoction in "Synopsis of Golden Chamber" (Han Dynasty in the 3rd century) and the Zhizhu pill in "Differentiation on Endogenous" in Jin Dynasty (1,115-1,234). ZZKZ contains four botanical drugs, including Citrus × Aurantium L [Rutaceae; Aurantii Fructus Immaturus], Atractylodes Macrocephala Koidz. [Compositae; Rhizoma Atractylodis Macrocephalae], Bupleurum Chinense DC [Apiaceae; Radix Bupleuri Chinensis], and Crataegus Pinnatifida Bunge [Rosaceae; Fructus Crataegi Pinnatifidae], which have been widely used in clinical therapy for functional dyspepsia (FD). Aim of the study: This study aimed to evaluate the pharmacological effects and mechanisms of action of ZZKZ on gastric hypersensitivity and motor dysfunction in a rat model of FD. Materials and methods: FD was induced in Sprague-Dawley rats by neonatal gastric irritation with 0.1% iodoacetamide. The FD rats were treated with ZZKZ (0.5g/kg, 1.0g/kg, or 1.5g/kg respectively) by gavage for 7days, while domperidone (3mg/kg) acted as treatment control. Body weight gain, food intake, gastric emptying, and intestinal propulsion were also measured. Ex vivo gastric smooth muscle activity recordings and greater splanchnic afferent (GSN) firing recordings were employed to evaluate gastric motility and sensation. Particularly, the role of 5-HT in the action of ZZKZ in improving gastric dysmotility and hypersensitivity was explored. Results: ZZKZ promoted weight gain, food intake, gastric emptying, and intestinal propulsion in FD rats. ZZKZ promoted spontaneous and ACh-induced contractions of gastric smooth muscle strips in FD rats, alleviated spontaneous activity, and chemical (acid perfusion) and mechanical (intragastric distension) stimulated GSN firing in FD rats. ZZKZ ameliorated gastric smooth muscle contraction and GSN firing induced by 5-HT in FD rats. ZZKZ stimulated the release of serum 5-HT, with reduced 5-HT3 receptor and increased 5-HT4 receptor mRNA expression in the guts of FD rats. Conclusion: This study demonstrated that ZZKZ improves FD-related gastric hypersensitivity and motor dysfunction and should be an effective compound for relieving FD symptoms. The gastric 5-HT system with lower 5-HT3 activity and increased 5-HT4 distribution is involved in the mechanisms of ZZKZ underlying the treatment of FD.

Amino Acid Solutions for 177Lu-Oxodotreotide Premedication: A Tolerance Study.

The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) containing 10% amino acids, and a 2.5% lysine-arginine (LysArg) hospital preparation, produced by a referral laboratory. The aim of the present study was to analyze the tolerance of the two amino acid solutions. The patient files were analyzed and double-checked. The study parameters comprised the gender, age, primary tumor site, type of amino acid perfusion, adverse events (AE) and WHO AE grades, antiemetic premedication, creatinine, and serum potassium level. From February 2016 to February 2019, 76 patients were treated, for a total 235 cycles. AEs occurred in 71% of the CS cycles (n = 82/116), versus 18% (n = 21/119) in the LysArg group (p < 0.0001). In the CS group, the AEs were mostly WHO grade 4 (n = 24/82), and mostly grade 1 in the LysArg group (n = 13/21). Poisson regression showed a higher risk of AE overall and of grades 3 and 4 in the females and with CS. The mean creatinine clearance was identical before and after the PRRT cycles, whichever amino acid perfusion was used. The lysine-arginine preparation showed better tolerance than the commercial solution. The change to LysArg reduced the antiemetic premedication from four molecules to one.

Effects of bladder perfusion of pentosan polysulfate sodium and hyaluronic acid on mucosal mast cells of rats with interstitial cystitis.

article: Effects of bladder perfusion of pentosan polysulfate sodium and hyaluronic acid on mucosal mast cells of rats with interstitial cystitis - Minerva Surgery 2022 Jun 16 - Minerva Medica - Journals

Disruption of the brain-esophagus axis in obese patients with heartburn.

Obesity is a risk factor for gastroesophageal reflux disease. Studies addressing the brain-esophagus axis in obese are lacking. In obese with and without heartburn, we assessed: (i) the brain responses to esophageal acid perfusion during functional brain imaging; (ii) esophageal impedance baseline before and after acid perfusion; and (iii) abdominal fat distribution. In this exploratory study, 26 obese underwent functional magnetic resonance imaging (fMRI) of the brain combined with esophageal acid perfusion. Esophageal impedance baseline was determined before and after fMRI, followed by tomographic quantification of the abdominal fat. Among 26 obese (54% men, 39.7years old, 33.5kg/m2), there were 17 with heartburn and 9 without heartburn. Before fMRI, the esophageal impedance baseline was lower in obese with heartburn than without heartburn (median 1187 vs. 1890Ω; P = 0.025). After acid perfusion, impedance baseline decreased in obese with heartburn (from 1187 to 899Ω; P = 0.011) and was lower in this group than in obese without heartburn (899 vs. 1614Ω; P = 0.001). fMRI task-residual analysis showed that obese with heartburn presented higher functional connectivity in several brain regions than obese without heartburn. Abdominal fat area did not differ between obese with and without heartburn either for total (72.8 ± 4.4% vs. 70.3 ± 6.0%; P = 0.280), subcutaneous (42.2 ± 9.0% vs. 37.4 ± 9.0%; P = 0.226), or visceral (30.6 ± 7.9% vs. 33.0 ± 7.8%; P = 0.484). In subjects with obesity, the brain-esophagus axis is disrupted centrally with higher functional brain connectivity and peripherally with decreased esophageal mucosa integrity in the presence of heartburn.

Imaging of Heart Type Fatty Acid Binding Protein Under Acute Reperfusion Ischemia Using Radio-labeled Antibody in Rat Heart Model.

Purpose: Heart-type fatty acid binding protein (H-FABP) is primary transporter of free fatty acid and plays an important role in myocardial metabolism, which is characterized by high specificity and rapid appearance under ischemic condition. The objective of this study was to clarify the usefulness of imaging study of targeting H-FABP appearance using radio-labeled antibody, and correlation with myocardial fatty acid metabolism and perfusion in acute reperfusion ischemia. Method: Wistar rats were allotted to sham-operated control group (sham; n=4), ischemia non-reperfused group (IG; n=5), and ischemia-reperfusion group (RG; n=5). Ligation of left coronary artery (LCA) was performed for IG and RG. 20 min of ischemia was followed by 60min of reperfusion for RG. 125I labeled anti H-FABP antibody (anti H-FABP), BMIPP and 99mTc-sestamibi (MIBI) was injected intravenously. Multi-tracer digital autoradiogram was performed using µ-imager®. The ratio of radioactivity in LCA related (culprit) area to the inferior (remote) area (target uptake ratio=TUR) was generated. Results: In sham group, no visually detectable accumulation was observed for the anti H-FABP image, and TURMIBI and TURBMIPP were equivalent to 1. In IG, TURMIBI and TURBMIPP were remarkably low (0.12±0.01, 0.24±0.07). In RG, TURMIBI was significantly lower (0.20±0.03, p<0.05 vs. other groups). However, TURBMIPP was significantly higher (2.78±1.28, p<0.05) compared to the sham and IG, whereas anti H-FABP showed markedly higher ratio in the reperfused area compared to the sham and IG (3.43±0.73 vs. 0.31±0.13 and 1.09±0.07 for IG and sham; p<0.05, and <0.01, respectively). Conclusion: Anti H-FABP accumulated specifically in reperfused area under acute ischemia, and it accorded to the area where fatty acid metabolism was activated. This study has shown the future potential for clinical application in vivo imaging of acute coronary syndrome.

Acid increases PGE2 in the duodenal mucosa in rats.

Attention has recently been paid to the duodenum as the pathophysiologic center of functional dyspepsia. However, the precise mechanisms of symptom generation remain unknown. We here investigated the effect of acid on duodenal prostaglandin E2 and localization of prostaglandin E2 related receptors. Sprague–Dawley rats were used for this study. Hydrochloric acid was administered in the duodenum, then prostaglandin E2 levels in the duodenum were measured using the ELISA. The expression and localization of prostaglandin receptors (EP1–4) and the mRNAs of prostaglandin synthases were investigated using in situ hybridization histochemistry in duodenal tissue. After acid perfusion, prostaglandin E2 levels in the duodenum significantly increased. EP3 was expressed mainly at the myenteric plexus in the duodenal mucosa, and EP4 at both the epithelial surface and myenteric plexus. Contrary, EP2 was sparsely distributed in the villi and EP1 were not clearly seen on in situ hybridization histochemistry. Prostaglandin-synthetic enzymes were also distributed in the duodenal mucosa. The prostaglandin E2 levels in the duodenum increased after acidification. Prostaglandin E2 receptors and prostaglandin E2-producing enzymes were both observed in rat duodenum. These observations suggest that duodenal prostaglandin E2 possibly play a role in the symptom generation of functional dyspepsia.

Esophageal pH increments associated with post-reflux swallow-induced peristaltic waves show the occurrence and relevance of esophago-salivary reflex in clinical setting.

Following acid perfusion, esophageal pH is restored by swallowed bicarbonate-containing saliva secreted in response to a vagal esophago-salivary reflex. At impedance-pH monitoring, the post-reflux swallow-induced peristaltic wave (PSPW) index puts into relationship timely post-reflux swallows with the number of reflux events: Low values typify reflux-related heartburn (RRH) and lack of on-therapy improvement characterizes proton pump inhibitor (PPI) failure. Considerable esophageal pH increments associated with PSPWs could demonstrate the occurrence of esophago-salivary reflex in clinical setting, while its relevance could be shown by lower esophageal pH increments in PPI-refractory RRH. Prospective multicenter study in patients with PPI-refractory or PPI-responsive RRH evaluated with off-PPI impedance-pH monitoring. Increments in pH associated with PSPWs were measured and the mean calculated to obtain the PSPW-associated ∆pH. The mean PSPW-associated ∆pH in 294 RRH patients was 1.2±0.7 and was lower in 137 PPI-refractory (1.0±0.6) than in 157 PPI-responsive (1.5±0.6) cases (p<0.0001). Lower PSPW-associated ∆pH was independently related to PPI failure at multivariable logistic regression analysis (OR 0.16, 95% CI 0.09-0.26). At ROC analysis, comparing PPI-refractory to PPI-responsive cases the AUC for PSPW-associated ∆pH was 0.76 (95% CI 0.71-0.82), the best cutoff value being 1.2. Considerable PSPW-associated pH increments demonstrate the occurrence of esophago-salivary reflex in clinical setting. Lower increments in PPI-refractory RRH cases show the clinical relevance of esophago-salivary reflex, confirming that PSPW represents a defense mechanism against reflux. PSPW-associated ∆pH can efficiently predict PPI response in patients undergoing off-therapy impedance-pH monitoring.

Duodenal acidification induces gastric relaxation and alters epithelial barrier function by a mast cell independent mechanism

Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation.

Reflux symptoms and oesophageal acidification in treated achalasia patients are often not reflux related

ObjectiveAfter treatment, achalasia patients often develop reflux symptoms. Aim of this case–control study was to investigate mechanisms underlying reflux symptoms in treated achalasia patients by analysing oesophageal function, acidification patterns...

LncRNA XIST modulates 5-hydroxytrytophan-induced visceral hypersensitivity by epigenetic silencing of the SERT gene in mice with diarrhea-predominant IBS

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a prevalent gastrointestinal disorder with a high incidence in children. The role of long non-coding RNAs (lncRNAs) in gastrointestinal diseases has been previously highlighted. Nevertheless, the underlying regulatory mechanism of lncRNA X inactivate-specific transcript (XIST) in IBS-D requires further studies. Thus, the present study was conducted with the main objective of elucidating the underlying mechanism of lncRNA XIST in visceral hypersensitivity in IBS-D. An in vivo mouse model of IBS-D was constructed via rectal perfusion of acetic acid. Next, in order to evaluate the effect of lncRNA XIST on the development of visceral hypersensitivity in IBS-D, different vector plasmids were injected into mice along with rectal mucosal epithelial cells, followed by the measurement of abdominal withdrawal reflex (AWR) score, counts of peristaltic wave, abdominal wall contraction and defecation particles. Furthermore, luciferase reporter assay, FISH, RIP and ChIP assays were conducted to determine the interactions between lncRNA XIST and SERT. Subsequently, MS-PCR was adopted to test the methylation level of SERT promoter. 5-hydroxytrytophan (HT) content in rectal tissues was detected using immunohistochemistry. The IBS-D mouse models presented with a high expression of lncRNA XIST along with low expression of SERT. LncRNA XIST was observed to recruit methylase DNMT1, DNMT3A and DNMT3B to promote SERT promoter methylation, reducing its expression. Restoration of lncRNA XIST resulted in increased AWR score, counts of peristaltic wave, abdominal wall contraction and defecation particles along with stimulated 5-HT expression and SERT methylation level, while downregulation of lncRNA XIST reversed these effects. In conclusion, the key findings from our study indicated that lncRNA XIST acts as a regulator in 5-HT-induced visceral hypersensitivity in mice with IBS-D, providing a new insight into the regulatory effect of lncRNA XIST and its epigenetic diagnostic and therapeutic properties in IBS-D.

CLINICAL AND FUNCTIONAL FEATURES OF GASTROESOPHAGEAL REIFLUX DISEASE, COMORBID WITH PEPTIC ULCER DISEASE

Objective: to study the clinical and functional manifestations of various forms of gastroesophageal reflux disease (GERD) with comorbid peptic ulcer of the duodenum (PUD) and gastric ulcer (GU) to clarify the diagnosis and identify targets for pathogenetic therapy at the stage of primary health care. Materials and methods: 287 patients with GERD, comorbid with uncomplicated ulcer, were examined. Questioning of patients was carried out, An in-depth endoscopic examination (EGDS) was performed in combination with an acid perfusion test (APT) to detect non-erosive reflux disease (NERD) and gastric endoscopic chromoscopy to determine the acid production of the stomach. Results: in patients with GERD with comorbid PUD, heartburn and acid regurgitation were more often detected in comparison with NERD. According to the results of chromoscopy, hyperand normochlorhydria were characteristic for patients with PUD, hypochlorhydria - for patients with GU. An acute GERD stage and the frequency of positive CBT are associated with an exacerbation of the PUD. There was a direct correlation between the age of patients and the stage of GERD. Moreover, the age and stage of GERD revealed a direct correlation with a positive APT, which reflects a violation of the permeability of mucosae of the esophagus. Conclusion: in patients with GERD with comorbid PU, patient-oriented diagnosis may consist of endoscopic chromoscopic determination of stomach acid production and endoscopic APT to confirm NERD and identify GERD phenotypes comorbid with acid-dependent diseases in order to determine treatment tactics.