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This study aimed to investigate the changes in oxidative stress, adenosine monophosphate-activated protein kinase (AMPK), connexin43 (Cx43), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and extracellular matrix (ECM) in the gastric smooth muscle tissues of rats with diabetic gastroparesis (DGP) and high glucose-cultured gastric smooth muscle cells, determine the existence of oxidative stress-AMPK-Cx43-NLRP3 pathway under high glucose condition, and the involvement of this pathway in ECM remodeling in DGP rats. The results showed that with increasing duration of diabetes, oxidation stress levels gradually increased, the AMPK activity decreased first and then increased, NLRP3, CX43 expression, and membrane/cytoplasm ratio of Cx43 expression were increased in the gastric smooth muscle tissues of diabetic rats. Changes in ECM of gastric smooth muscle cells were observed in DGP rats. The DGP group showed higher collagen type I content, increased expression of Caspase-1, transforming growth factor-beta 3 (TGF-β 3 ), and matrix metalloproteinase-2 (MMP-2), decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, and higher interleukin-1 beta content when compared with the control group. For gastric smooth muscle cells cultured under higher glucose, the MMP-2 and TGF-β3 expression was decreased, TGF-β1 and TIMP-1 expression was increased, the interleukin-1 beta content was decreased in cells after inhibition of NLRP3 expression; the NLRP3 and Caspase-1 expression was decreased, and adenosine triphosphate content was lower after inhibition of Cx43; the expression of NLRP3, Caspase-1, P2X7, and the membrane/cytoplasm ratio of CX43 expression was decreased in cells after inhibition of AMPK and oxidative stress, the phospho-AMPK expression was also decreased after suppressing oxidative stress. Our findings suggest that high glucose induced the activation of the AMPK-Cx43-NLRP3 pathway through oxidative stress, and this pathway was involved in the ECM remodeling of gastric smooth muscles in DGP rats by regulating the biological functions of TGF-β3, TGF-β1, MMP-2, and TIMP-1., Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/aims: We investigated the validity and safety of endoscopic submucosal dissection for gastric tumors by examining shortand long-term outcomes by tumor diameter., Materials and Methods: Endoscopic submucosal dissection for gastric tumor was performed on 4259 lesions at our hospital between January 2005 and June 2021. [Study 1] Patients were divided into 5 tumor diameter groups: 3751 lesions, ≤30 mm; 366 lesions, 31-50 mm; 106 lesions, 51-75 mm; 24 lesions, 76-100 mm; and 12 lesions, ≥101 mm. Short-term gastric endoscopic submucosal dissection outcomes were investigated. [Study 2] Long-term outcomes (delayed gastric emptying and prognosis) were investigated in 508 cases with tumor diameter ≥31 mm., Results: [Study 1] Perforation rate (%) was 1.2, 3.6, 3.8, 12.5, and 25.0 for lesions with tumor diameter ≤30 mm, in the range 31-50 mm, 51-75 mm, and 76-100 mm, and ≥101 mm, respectively. Postoperative bleeding rate (%) was 4.8, 9.0, 6.6, 20.8, and 33.3, respectively, R0 resection rate (%) was 96.8, 90.2, 89.6, 70.8, and 66.6, respectively, and curative resection rate (%) was 92.0, 61.2, 63.2, 45.8, and 8.3, respectively. [Study 2] There were 7 cases of delayed gastric emptying after wide resection, with 3 patients requiring balloon dilatation, 1 of whom subsequently underwent distal gastrectomy. Among 205 cases of noncurative resection, 110 underwent additional surgery, residual cancer was present in 11 cases, and lymph node metastasis was observed in 7 cases (1 patient died of disease). To date, 1 of the 95 patients being followed up has died of disease (mean follow-up: 2042 days)., Conclusion: Even with a tumor diameter ≥31 mm, curative resection was achieved in about 60% of cases in which intramucosal lesions were considered possible preoperatively, but the rate was low at 8.3% for tumor diameter ≥101 mm. Long-term outcomes appear favorable, with only 0.4% of the patients dying of disease but delayed gastric emptying observed in 1.7% of cases.

Background: The role of Interstitial Cells of Cajal (ICC) in the pathogenesis of gastroparesis has been suggested by previous studies due to their involvement in the transmission of neuronal signaling to the smooth muscles of the GI tract. However, studies have been limited by the inability to obtain a gastric muscle sample, since routine endoscopy can only biopsy the mucosa. We present a new technique of muscle biopsy during per-oral endoscopic pyloromyotomy (GPOEM), a novel endoscopic procedure for treatment of gastroparesis., Patients and Methods: All enrolled patients had diagnosed gastroparesis and had biopsies of the muscular layer at the antrum/pylorus during POEM. All GPOEM procedures took place from August 2019 to December 2019. Various demographic, disease-related, and procedure-related data were collected from chart review. ICC in the biopsy specimen was examined and quantitated., Results: Through this method, we readily expose the gastric muscle of 21 patients through dissection of a gastric submucosal tunnel during GPOEM and provide reliable muscle sample for ICC quantification. Average number of ICC were higher in clinical responders (88 ICC ± 63 vs. 39 ICC ± 24, p = 0.02), defined as those who experienced significant improvement in nausea and vomiting symptoms after GPOEM., Conclusions: This study provides a reliable novel biopsy method for safely biopsy gastric muscle for quantitating the number of gastric ICC in patients with gastroparesis. The number of ICC may be related to the outcome of GPOEM therapy. However, further studies with larger number of patients are needed to confirm the results., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described steroid-responsive meningoencephalomyelitis positive for cerebrospinal fluid (CSF) anti-GFAP antibody. Area postrema syndrome (APS) involves intractable hiccups, nausea, and vomiting, which is caused by medulla oblongata (MO) impairment. APS is a characteristic symptom of aquaporin-4 (AQP4) autoimmunity, and it helps to differentiate between AQP4 and GFAP autoimmunity. Conversely, although 6 cases of autoimmune GFAP astrocytopathy with APS and MO lesions have been reported, the association between GFAP autoimmunity and APS is unclear. We report the case of a patient with autoimmune GFAP astrocytopathy presenting with APS-like symptoms without MO lesions and discuss the mechanisms underlying the symptoms., Methods: CSF anti-GFAP antibody was detected using cell-based assays and immunohistochemical assays., Results: A 54-year-old Japanese man developed persistent hiccups, intermittent vomiting, fever, anorexia, and inattention. Brain magnetic resonance imaging (MRI) showed periventricular lesions with radial linear periventricular enhancement, suggesting autoimmune GFAP astrocytopathy. However, no obvious MO lesions were identified on thin-slice images. Spinal cord MRI revealed hazy lesions with patchy enhancement along the cervical and thoracic cord. CSF analysis demonstrated inflammation, with positive results for anti-GFAP antibodies. Anti-AQP4 antibodies in the serum and CSF were negative. Esophagogastroduodenoscopy revealed gastroparesis and gastroesophageal reflux disease, and vonoprazan, mosapride, and rikkunshito were effective only against persistent hiccups. Steroid therapy was initiated, allowing clinical and radiological improvements. Repeated MRIs demonstrated no obvious MO lesions., Conclusion: This report suggests that autoimmune GFAP astrocytopathy presents with APS-like symptoms without obvious MO lesions. The possible causes of hiccups were gastroparesis and cervical cord lesions. Gastroesophageal reflux disease was not considered a major cause of the hiccups. Intermittent vomiting appeared to be associated with gastroparesis, cervical cord lesions, and viral-like symptoms. Testing for anti-GFAP antibodies should be considered in patients with APS-like symptoms in the context of typical clinical-MRI features of autoimmune GFAP astrocytopathy., (© 2022 S. Karger AG, Basel.)

Background: The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis., Methods: Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models., Results: Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206 + macrophages in both groups compared with obese controls., Conclusions: A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. CLINICALTRIALS., Gov Identifier: NCT00398801, NCT01696747., (Copyright © 2021 AGA Institute. All rights reserved.)

Gastric motility is coordinated by underlying bioelectrical "slow wave" activity. Slow wave dysrhythmias are associated with motility disorders, including gastroparesis, offering an underexplored potential therapeutic target. Although ablation is widely used to treat cardiac arrhythmias, this approach has not yet been trialed for gastric electrical abnormalities. We hypothesized that ablation can create localized conduction blocks and modulate slow wave activation. Radiofrequency ablation was performed on the porcine serosa in vivo, encompassing a range of parameters (55-85°C, adjacent points forming a line, 5-10 s/point). High-resolution electrical mapping (16 × 16 electrodes; 6 × 6 cm) was applied to define baseline and acute postablation activation patterns. Tissue damage was evaluated by hematoxylin and eosin and c-Kit stains. Results demonstrated that RF ablation successfully induced complete conduction block and a full thickness lesion in the muscle layer at energy doses of 65-75°C for 5-10 s/point. Gastric ablation may hold therapeutic potential for gastric electrical abnormalities in the future. NEW & NOTEWORTHY 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.

The cellular and molecular understanding of human gastroparesis has markedly improved due to studies on full-thickness gastric biopsies. A decrease in the number of interstitial cells of Cajal (ICC) and functional changes in ICC constitutes the hallmark cellular feature of gastroparesis. More recently, in animal models, macrophages have also been identified to play a central role in development of delayed gastric emptying. Activation of macrophages leads to loss of ICC. In human gastroparesis, loss of anti-inflammatory macrophages in gastric muscle has been shown. Deeper molecular characterization using transcriptomics and proteomics has identified macrophage-based immune dysregulation in human gastroparesis., Competing Interests: Disclosure MG and GF are supported by NIH DK068055 and DK74008. MG is also supported by NIH K23 DK 103911 and R03 DK 120745. GF is also supported by NIH DK057061., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gastroparesis is a common symptom in Parkinson's disease (PD) and whether any change occurs in gastric smooth muscle cells (SMCs) of PD patients is unclear. We previously reported that rats with bilateral substantia nigra lesions induced by 6-hydroxydopamine (6-OHDA), referred to as 6-OHDA rats, manifest typical gastroparesis. In the present study, we further investigate the underlying mechanism. By means of an organ bath system and an implantable radiotelemetry system, both a weakened contractile force of gastric circular smooth muscle and gastric myoelectric activity were detected in the 6-OHDA rats and phasic and tonic contractions elicited by carbachol or high concentration of potassium were significantly reduced in gastric circular muscle strips. A thickened smooth muscle layer was observed under a light microscope and an ultrastructure of hypertrophic SMCs, with increased caveolae and decreased dense bodies, was observed under transmission electron microscope. Furthermore, the mRNA and protein expression levels of contractile markers (myosin light chain 20, myosin heavy chain 11 and α-smooth muscle actin) and the transcription factor serum response factor (SRF) were significantly decreased, while the TNFα and IL-1β content was increased in the 6-OHDA rats. These results suggest that the decreased contractile force in 6-OHDA rats may be associated with the phenotypic abnormality observed in SMCs, which is due to downregulated contractile proteins induced by decreased SRF expression in the inflammatory muscular microenvironment.

Background: Pylorus-preserving gastrectomy (PPG) is a function-preserving procedure for cT1N0 gastric cancer located in the middle-third of stomach, which is currently performed through a laparoscopic approach (LPPG). PPG is sometimes associated with a crucial problem during the early postoperative course, designated gastric stasis. However, information regarding gastric stasis remains to be fully elucidated., Methods: The study included 897 patients who underwent LPPG between 2005 and 2017. Early postoperative gastric stasis (E-stasis) was defined when the following conditions were fulfilled: upper abdominal distension, remnant stomach fullness on radiography image, and period of starvation exceeding 72 h within 1 month postoperatively. To evaluate long-term outcomes of E-stasis, late postoperative food residue (L-residue) was defined as grade 2 or higher food residue endoscopically according to the RGB (residue, gastritis, bile) classification at 1 year postoperatively. Risk factors and long-term outcomes of E-stasis were retrospectively analyzed., Results: E-stasis was the most common complication during the early postoperative course. E-stasis occurred in 68 (7.6%) patients. Multivariate analysis identified age (≥ 61 years), DM, and postoperative intraabdominal infection as risk factors. At 1 year postoperatively, relative body weight ratio and postoperative serum albumin in the patients who experienced E-stasis was significantly lower than those in the other patients (P = 0.042 and 0.011, respectively). Of the patients who suffered from E-stasis, 42.5% experienced L-residue., Conclusions: E-stasis after LPPG occurs in 7.6% of patients. Age, DM, and intraabdominal infection are significantly related to E-stasis. E-stasis is associated with poorer nutritional and functional outcomes even at 1 year postoperatively.

Background: Enteric nervous system (ENS) abnormalities have been implicated in delayed gastric emptying but studies exploring potential treatment options are limited by the lack of an experimental animal model. We examined the ENS abnormalities in the mouse stomach associated with aging, developed a novel model of gastroparesis, and established a new approach to measure gastric emptying., Methods: A modified gastric emptying assay was developed, validated in nNOS -/- mice, and tested in mice at multiple ages. Age-related changes in ENS structure were analyzed by immunohistochemistry. Gastric aganglionosis was generated in Wnt1-iDTR mice using focal administration of diphtheria toxin (DT) into the anterior antral wall., Key Results: Older mice (>5 months) exhibit hypoganglionosis in the gastric antrum and a decreased proportion of nNOS neurons as compared to younger mice (age 5-7 weeks). This was associated with a significant age-dependent decrease in liquid and solid gastric emptying. A novel model of gastric antrum hypoganglionosis was established using neural crest-specific expression of diphtheria toxin receptor. In this model, a significant reduction in liquid and solid gastric emptying is observed., Conclusions & Inferences: Older mice exhibit delayed gastric emptying associated with hypoganglionosis and a reduction in nNOS-expressing neurons in the antrum. The causal relationship between antral hypoganglionosis and delayed gastric emptying was verified using a novel experimental model of ENS ablation. This study provides new information regarding the pathogenesis of delayed gastric emptying and provides a robust model system to study this disease and develop novel treatments., (© 2019 John Wiley & Sons Ltd.)

In the precedent research conducted by the same team, it concluded that the activities in C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP)/β-type phospholipase C (PLCβ) pathways of rat antral smooth muscle were changed due to diabetes, which was the key pathogenetic mechanism for diabetic gastric dysmotility. As the follow-on step, this study was designed to probe into the downstream signaling pathway of CNP/PLCβ. The results showed that level of α-type protein kinase C (PKCα),cell membrane to cytoplasm ratio of PKCα, cell membrane to cytoplasmic ratio of βI-type protein kinase C (PKCβI) and level of Phosphor-PKCα (P-PKCα) were significantly reduced in diabetes rat antral smooth muscle samples. The content of tetraphosphate inositol (IP4) in gastric antral smooth muscle of diabetic rats reduced, and the content of diacyl-glycerol (DG) was unchanged. CNP significantly decreased the content of IP4 and DG, this effect was more obvious in diabetic rats. Subsequent to the addition of protein kinase A (PKA) blocker N-[2- (p-Bromocin-namylamino)ethyl]-5 -isoquinolinesulfonamide dihydrochloride (H-89) before CNP treatment, the inhibitory effect of CNP was reduced; subsequent to the addition of protein kinase G (PKG) blocker KT5823 before CNP treatment, the inhibitory effect of CNP was also reduced. With the addition of the combination of H-89 and KT5823 before CNP treatment, the inhibition by CNP could be offset. These results were concluded that CNP inhibited the activity of PKC family in rat smooth muscle and reduced the levels of IP4 and DG through the PKG/PKA-PLCβ pathways, causing inhibited muscular contractions, which may be a key pathogenetic factor for diabetic gastroparesis.

This study aimed to investigate the effect of AMPK on apoptosis and energy metabolism of gastric smooth muscle cells in diabetic rats and to explore the role of AMPK in the pathogenesis of diabetic gastroparesis (DGP). After establishment of a diabetic rat model, rats were divided into normal control (NC), 4-week (DM4W), 6-week (DM6W), and 8-week (DM8W) diabetic model groups. The gastric residual pigment ratio, intestinal transit rate, and intestinal propulsion rate in each group were detected to confirm the successful establishment of the DGP model. The spontaneous contraction in isolated gastric smooth muscle strips of the NC and DM8W groups was experimentally observed. The expression of phospho-AMPK, AMPK, phospho-LKB1, LKB1, phospho-TAK1, TAK1, and CaMMKβ in rat gastric smooth muscle tissues was detected by western blot analysis; ADP, AMP, ATP contents, and the energy charge were detected using Elisa; and apoptosis of gastric smooth muscle cells was detected by flow cytometry. The rat gastric smooth muscle cells were cultured in vitro, and treated with an AMPK inhibitor and an agonist. At 24 and 48 h, the effects of AMPK on apoptosis and energy metabolism of gastric smooth muscle cells were observed. Reduced spontaneous contractions, AMPK activation, cell apoptosis, and energy metabolism disorders were observed in gastric smooth muscle tissues of a diabetic rat, and AMPK activation was associated with an increased ratio of ADP/ATP, AMP/ATP, LKB1 activity, and CaMMKβ expression. From in vitro cell culture experiments, we found that AMPK activation of high-glucose conditions promoted cell apoptosis. Inhibition of AMPK had no obvious effect on apoptosis at the early stage with high glucose, but the inhibitory effect was significant at the late stage with high glucose. AMPK can regulate both mitochondrial metabolism and glycolysis pathways under high-glucose conditions. During the early stage with high glucose, AMPK was the main promotion factor of the mitochondrial metabolism pathway, but did not increase the ATP production, AMPK also promoted the glycolysis pathway. During the late stage with high glucose, AMPK was a major inhibitor of the mitochondrial pathway, and still played a role in promoting the glycolytic pathway, which acted as the main regulator. Apoptosis and energy metabolism disorders were present in gastric smooth muscle cells during the occurrence of DGP. Under high-glucose condition, AMPK was activated, which can promote apoptosis, change the energetic metabolism pathway of cells, inhibit mitochondrial energy metabolism, and promote glycolysis.

Background and Aims: Cajal cells serve as the pacemaker cells of the gastrointestinal tract and regulates peristalsis. On the baisis of that fact, it has been hypothesized that a decrease in Cajal cells can lead to gastroparesis and other motility issues. Treatment with medications has a limited efficacy and most resort to gastric electrical stimulation (GES) devices for symptomatic relief. We believe that the number of Cajal cells present is directly proportional to symptomatic relief with GES., Materials and Methods: Twenty-three (white female) subjects were recruited from the gastric motility clinic University of Mississipi for this study with the criteria of drug refractory gastropersis. Symptoms were measured using Likert scale and gastric emptying times were measured pre-GES and post-GES. Serosal electrogram measurements were recorded during surgical placement of permanent electrical stimulator under various modes. Cajal cell count scoring via immunohistochemistry were performed during the implantaion of the GES., Results: The data were grouped in 2 categories based on the Cajal cells that is ≥2.00 and <2.00. Subjects with higher Cajal cells reported a statiscially improvement in gastroperesis symptoms. Significant differences were also noted in the first hour gastric emptying study. The mean group difference is 17.5 (95% confidence interval, 1.41-33.58; P=0.035). Serosal amplitude differences were noted being significantly higher in the group with ≥2 cajal cells., Conclusions: Electrograms obtained after GES demonstrates immediate improvement in gastric electrical activity and gastroparesis symptoms in patients with relatively higher Cajal cell counts when compared with patients with extensive loss of Cajal cells.

Rationale: Herpes zoster infection typically involves the posterior root ganglia and most of the symptoms are sensory. Motor involvement can occur in the same distribution but is relatively uncommon. Segmental zoster paresis is a rare motor complication of Herpes zoster, mimicking an abdominal hernia, but it needs no surgery different from the real abdominal wall hernia., Patient Concerns: We present a case of a 58-year-old man with an abdominal protrusion and characteristical herpes zoster rash., Diagnoses: Initially, the surgeon regarded it as an abdominal hernia, while ultrasonography excluded the abdominal wall defect, and then the dermatologist diagnosed it as segmental herpes zoster abdominal paralysis., Interventions: He received a treatment with oral acyclovir, mecobalamin, and vitamin B1., Outcomes: The abdominal wall bulge disappeared after 2 months, avoiding unnecessary surgery., Lessons: Segmental zoster abdominal paresis, mimicking an abdominal hernia needs no surgery.

Background and Aim: Delayed gastric emptying occurs in more than 50% of chronic diabetic patients, and this is associated with significant impairments in quality of life. Traditional therapy for delayed gastric emptying has focused on supportive treatment, and there is no significant effective therapy. The effect of low-energy shock wave on gastric motility is never studied. We investigated low-energy shock wave on gastric motility in a diabetic rat model., Methods: Twenty-eight male Wistar rats were studied and separated in three groups in randomized order as control, diabetic rats received shock wave, and diabetic rats received the sham procedure. Antral area and motility were recorded using the transabdominal ultrasound. Blood was taken for measurement of gastric motility peptides. Subjects were killed for immunohistochemical stain analysis of enteric plexus of the stomach., Results: We successfully induced 20 diabetic rats and set ultrasound for measuring rat gastric contract and emptying model and demonstrated that 6 weeks of low-energy shock wave could promote gastric contraction and emptying in diabetic rats. Moreover, we demonstrated that shock wave could increase defecation and feces and decrease serum cholesterol and triglycerol. However, no effect on glycohemoglobin and gastric motility peptides was recorded. In the immunohistochemical staining, shock wave increased expression of gastric myenteric neuron plexus., Conclusion: Low-energy shock wave can increase gastric contraction and emptying by activating axonal regeneration and increasing myenteric plexus, but not related with motility peptides., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice., Methods: Full-thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)-PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined., Key Results: Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis., Conclusions and Inferences: Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients., (© 2018 John Wiley & Sons Ltd.)

Background & Aims: Gastric peroral endoscopic pyloromyotomy (GPOEM) is becoming a promising treatment option for patients with refractory gastroparesis. We aimed to systematically assess the efficacy of GPOEM and its effects on health care use., Methods: We performed a retrospective study on 30 patients with refractory gastroparesis who underwent GPOEM from June 2015 through July 2017 at a tertiary center. We compared outcomes with those of 7 patients with refractory gastroparesis who did not undergo the procedure (controls). The primary outcomes were patient-reported reductions in symptoms, based on the gastroparesis cardinal symptom index (GCSI), and increases in 8 aspects of quality of life, based on Short Form 36 (SF-36) scores. Data were collected on the day of the procedure (baseline) and at 1 month, 6 months, 12 months, and 18 months afterward. Secondary outcomes included visits to the emergency department or hospitalization for gastroparesis-related symptoms., Results: GPOEM was technically successful in all patients and significantly reduced GCSI scores in repeated-measure analysis of variance (F 2.044, 38.838  = 22.319; P < .0005). The mean score at baseline was 3.5 ± 0.6, at 1 month after GPOEM was 1.8 ± 1.0 (P < .0005), at 6 months after was 1.9 ± 1.2 (P < .0005), at 12 months after was 2.6 ± 1.5 (P < .026), and at 18 months after was 2.1 ± 1.3 (P < .016). GPOEM was associated with improved quality of life: 77.8%, 76.5%, and 70% of patients had significant increases in SF-36 scores, compared with baseline, at 1 month, 6 months, and 12 months after GPOEM, respectively (F 1.71,18.83  = 14.16; P < .0005). Compared with controls, patients who underwent GPOEM had significant reductions in GCSI, after we controlled for baseline score and duration of the disease (F 1,31  = 9.001; P = .005). Patients who received GPOEM had significant reductions in number of emergency department visits (from 2.2 ± 3.1 times/mo at baseline to 0.3 ± 0.8 times/mo; P = .003) and hospitalizations (from 1.7 ± 2 times/mo at baseline to 0.2 ± 0.4 times/mo; P = .0002)., Conclusions: In a retrospective study of patients who underwent GPOEM for refractory gastroparesis, we found the procedure significantly improved symptoms, increased quality of life, and reduced health care use related to gastroparesis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear., Methods: Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR., Results: 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log 2 fold difference of | ≥ 2| and false detection rate (FDR) < 5%. Top canonical pathways in diabetic gastroparesis included genes involved with macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, osteoarthritis pathway and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F. Top canonical pathways in idiopathic gastroparesis included genes involved in granulocyte adhesion and diapedesis, agranulocyte adhesion and diapedesis, and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Sixty-five differentially expressed genes (log 2 fold difference | ≥ 2|, FDR < 5%) were common in both diabetic and idiopathic gastroparesis with genes in the top 5 canonical pathways associated with immune signaling. 4/5 highly differentially expressed genes (SGK1, APOLD1, CXCR4, CXCL2, and FOS) in diabetic gastroparesis were validated in a separate cohort of patients using RT-PCR. Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05)., Conclusions: Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.

Interstitial cells of Cajal (ICC), especially myenteric interstitial cells of Cajal (ICC-MY), are key to gastrointestinal motility. However, their role in the pathogenesis of functional dyspepsia (FD) is unclear. Therefore, autophagy and differentiation of ICC-MY were investigated to elucidate the pathogenesis of gastric motility disorder in FD. FD model was induced by chronic stress via tail clamping in rats, which was assessed by the vital signs of rats, gastric emptying rate result, and histology. The ultrastructure of ICC-MY was examined using transmission electron microscope. In ICC-MY, changes in autophagic biomarkers (Beclin1 and LC3B) and differentiation biomarkers (c-kit and SCF) were evaluated with in situ hybridization, quantitative real time PCR, immunofluorescence, and Western blot, respectively. The FD model was successfully induced in rats, as evidenced by the abnormal vital signs (such as loss of appetite, liquid excreta, less activity, and slower weight gain), the decrease in gastric emptying rates, and little pathological change in gastric antrum tissue. Compared with the control group, FD caused increased organelle denaturation or reduction and increase in vacuolization. FD also promoted generation of autophagosomes in ICC-MY. Moreover, increased the expression of Beclin1 and LC3B, but decreased expression of c-kit and SCF. Excessive autophagy and abnormal differentiation of ICC-MY may contribute to the pathogenesis of gastric motility disorder in FD., (© 2017 International Union of Biochemistry and Molecular Biology, Inc.)

Background: Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases., Aim: Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of individuals with gastroparesis than in controls without upper gastrointestinal motility disorders., Methods: Repeat length was determined in genomic DNA. Controls with diabetes (84 type 1, 84 type 2) and without diabetes (n = 170) were compared to diabetic gastroparetics (99 type 1, 72 type 2) and idiopathic gastroparetics (n = 234). Correlations of repeat lengths with clinical symptom sub-scores on the gastroparesis cardinal symptom index (GCSI) were done. Statistical analyses of short (<29), medium and long (>32) repeat alleles and differences in allele length were used to test for associations with gastroparesis., Results: The distribution of allele lengths was different between groups (P = 0.016). Allele lengths were longest in type 2 diabetics with gastroparesis (29.18±0.35, mean ± SEM) and longer in gastroparetics compared to non-diabetic controls (28.50±0.14 vs 27.64±0.20 GT repeats/allele, P = 0.0008). Type 2 diabetic controls had longer alleles than non-diabetic controls. In all gastroparetic groups, allele lengths were longer in African Americans compared to other racial groups, differences in the proportion of African Americans in the groups accounted for the differences between gastroparetics and controls. Diabetic gastroparetics with 1 or 2 long alleles had worse GCSI nausea sub-scores (3.30±0.23) as compared to those with 0 long alleles (2.66±0.12), P = 0.022., Conclusions: Longer poly-GT repeats in the HMOX1 gene are more common in African Americans with gastroparesis. Nausea symptoms are worse in subjects with longer alleles.

Diabetic gastroparesis is a common complication of diabetes mellitus (DM) that is characterized by decreased serum insulin and insulin-like growth factor-1 (IGF-1). Despite the fact that insulin treatment not glycemic control potently accelerated gastric emptying in type 1 DM patients, the role of insulin/InsR and IGF-1/IGF-1R signaling in diabetic gastroparesis remains incompletely elucidated. In the present study, type 1 DM mice were established and treated with insulin or Voglibose for 8 weeks. The gastric emptying was delayed from DM week 4 when the gastric InsR and IGF-1R were declined. Meanwhile, the gastric choline acetyltransferase (ChAT) was significantly reduced and the myenteric cholinergic neurones and their fibers were significantly diminished. The production of stem cell factor (SCF) was dramatically repressed in the gastric smooth muscles in DM week 6. TWereafter, interstitial cells of Cajal (ICC) were clearly lost and their networks were impaired in DM week 8. Significantly, compared with Voglibose, an 8-week treatment with insulin more efficiently delayed diabetic gastroparesis development by protecting the myenteric cholinergic neurones and ICC. In conclusion, diabetic gastroparesis was an aggressive process due to the successive damages of myenteric cholinergic neurones and ICC by impairing the insulin/InsR and IGF-1/IGF-1R signaling. Insulin therapy in the early stage may delay diabetic gastroparesis., (© 2017 The Author(s).)

Background: Gastroparesis (GP)-like syndrome presents with the symptoms of GP but without delayed gastric emptying (GE). Whether GP-like syndrome is part of a spectrum of GP is not clear. This study aimed to compare the histopathological features of antral and pyloric smooth muscle tissue in GP and GP-like syndrome., Methods: Full-thickness antral and/or pyloric biopsies were obtained from 37 GP and 18 GP-like syndrome patients who underwent abdominal surgery to place a gastric electrical stimulator or jejunal feeding tube and/or pyloroplasty. The tissues were stained with H&E, C-Kit, and trichrome. Based on previous control data, an interstitial cells of Cajal (ICC) count of <10 per high power field in the antrum and/or pylorus was considered depletion. Baseline total symptom score (TSS) was recorded., Results: Twenty-four GP and 7 GP-like patients had pyloric biopsies. Pyloric ICC loss was observed in 20/24 (83.3%) GP and 2/7 (28.6%) GP-like patients (p < 0.01). Fibrosis was detected in the pyloric tissue of 20/24 (83.3%) GP and 2/7 (28.6%) GP-like patients who had pyloric trichrome staining (p < 0.01). Seventeen out of 24 (70.8%) GP patients with pyloric biopsies had concomitant pyloric ICC loss and fibrosis, while only one GP-like patient had ICC loss and simultaneous pyloric fibrosis. GP patients had a greater TSS compared to GP-like patients. In GP patients, those with pyloric ICC loss had a greater TSS compared to those with normal ICC. GP patients with pyloric fibrosis had a higher TSS compared to those without pyloric fibrosis., Conclusions: Compared to GP-like patients, the pyloric histopathological findings of ICC loss and fibrosis are common in GP and predict a greater symptom score. These pathological findings might be considered as markers of "pyloric dysfunction" and explain delayed GE in GP.

Gastroparesis (Gp) is a chronic disease that presents with clinical symptoms of early satiety, bloating, nausea, vomiting, and abdominal pain. Along with these symptoms, an objective finding of delayed gastric emptying, along with a documented absence of gastric outlet obstruction, are required for diagnosis. This article focuses on updates in the pathogenesis and management of Gp. Recent studies on full thickness biopsies of Gp patients have shed light on the complex interactions of the central, autonomic, and enteric nervous systems, which all play key roles in maintaining normal gut motility. The management of Gp has evolved beyond prokinetics and antiemetics with the use of gastric electrical stimulators (GES). In addition, this review aims to introduce the concept of gastroparesis-like syndrome (GLS). GLS helps groups of patients who have the cardinal symptoms of Gp but have a normal or rapid emptying test. Recent tests have shown that patients with Gp and GLS have similar pathophysiology, benefit greatly from GES placement, and likely should be treated in a similar manner.

The aim of the present study was to investigate the significance of cell apoptosis, the phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, and the 5' adenosine monophosphate-activated protein kinase (AMPK)‑mTOR pathways in the process of diabetic gastroparesis. Changes in gastric smooth muscle cells of diabetic rats with induced gastroparesis were examined. The diabetic rat model was established by dividing animals into a normal control group and diabetic model groups examined at 2, 4 and 6 weeks. Diabetic gastroparesis was evaluated by examining the rates of gastric residual pigment, whereas flow cytometry was used to detect the apoptosis of gastric smooth muscle cells. The expression levels of PI3K and phosphorylated (p‑) AKT, AMPK, mTOR, tuberous sclerosis complex 2, p70 ribosomal S6 kinase, and eukaryotic translation initiation factor 4‑binding protein 1 were determined in gastric muscles using western blot analysis. Diabetic gastroparesis was confirmed in models at 6 weeks. The apoptosis of gastric smooth muscle cells gradually increased in all diabetic groups, and significant changes were observed in key proteins involved in PI3K‑AKT‑mTOR and AMPK‑mTOR signaling. The results indicated that apoptosis was important in the occurrence of diabetic gastroparesis, and the PI3K‑AKT‑mTOR and AMPK‑mTOR pathways were activated during the apoptotic processes, but were incapable of regulating apoptosis.

Background: The aims of this study were to describe the histology in gastroparesis, specifically to relate histopathology to etiology of gastroparesis (idiopathic and diabetic gastroparesis), gastric emptying, and clinical response to gastric electric stimulation., Methods: Full thickness gastric body sections obtained during insertion of gastric stimulator in gastroparetics were stained with Hematoxylin & Eosin, Masson Trichrome and immunohistochemical stains for Neuron-Specific Enolase and c-Kit., Key Results: In all, 145 gastroparetics (71 diabetics, 71 idiopathic, 2 post-surgical, and 1 chronic intestinal pseudo-obstruction) had full thickness gastric body biopsies. A lymphocytic infiltrate was seen in the intermyenteric plexus in 22 diabetic and 23 idiopathic gastroparesis patients. Fibrosis was present in the inner circular layer in 13 diabetic and 15 idiopathics and in the outer longitudinal layer in 46 diabetic and 51 idiopathics. Diabetic gastroparesis had less ganglion cells (3.27±1.82 vs 4.81±2.81/hpf; P<.01) and less ganglia (0.90±0.44 vs 1.10±0.50/hpf; P=.01) than idiopathic gastroparesis. Interstitial cells of Cajal (ICC) count was slightly lower in the inner circular layer in diabetic than idiopathics (2.77±1.47 vs 3.18±1.34/hpf; P=.08). Delayed gastric emptying was associated with reduced ICCs in the myenteric plexus. Global therapeutic response to gastric electric stimulation was inversely related to ganglia/hpf (R=-.22; P=.008). In diabetics, improvements in nausea, vomiting, and abdominal pain were inversely related to fibrosis., Conclusion and Inferences: Histologic assessment of full thickness gastric biopsy specimens allows correlation of histopathology to the gastroparesis disease process, its etiology, gastric emptying, and response to gastric electric stimulation treatment., (© 2017 John Wiley & Sons Ltd.)

Objectives: The aim of the study was to quantify the diagnostic yield of upper endoscopy in children with gastroparesis and to develop a clinical model for gastroparesis using common symptoms and screening blood tests., Methods: We retrospectively reviewed charts of 196 patients of age 4 to 18 years evaluated for gastroparesis between 2009 and 2013. All patients completed a standard solid-phase gastric emptying scan and upper endoscopy within a 12-month period. We analyzed gross and histologic endoscopy findings. Symptom-based data were collected on dyspeptic symptoms and classic "red-flag" symptoms., Results: Seventy patients with gastroparesis and 126 controls were included. Clinically significant endoscopic findings were noted in 35% of controls (44/126) and 43% of gastroparetics (30/70), P = 0.345. Concordance between gross and histologic findings was low at 50%. Histologic findings included gastritis 60% (17/28), esophagitis 39% (11/28), and duodenitis 7% (2/28). In univariate and multivariate analyses, there was no meaningful correlation between symptoms and/or screening laboratory values and diagnosis of gastroparesis., Conclusions: Clinically significant endoscopy findings were common in both controls and gastroparetics. As more than one-third of patients had findings on endoscopy, we conclude that upper endoscopy remains an important part of the evaluation process of patients with dyspeptic symptoms and suspected gastroparesis. As gross abnormalities were frequently not present with histologic changes, routine biopsy is required. There was no association between studied symptoms and the presence of gastroparesis. A comprehensive evaluation of children with dyspeptic symptoms requires endoscopy with biopsy and solid-phase gastric emptying scan to determine the underlying diagnosis.

Background: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis., Methods: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index., Results: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04)., Conclusion: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss., (© 2017 John Wiley & Sons Ltd.)

Background and Aims: The pathophysiology of some GI neuromuscular diseases remains largely unknown. This is in part due to the inability to obtain ample deep gastric wall biopsies that include the intermuscular layer of the muscularis propria (MP) to evaluate the enteric nervous system, interstitial cells of Cajal (ICCs), and related cells. We report on a novel technique for gastric endoscopic muscle biopsy (gEMB)., Methods: Patients with idiopathic gastroparesis were prospectively enrolled in a feasibility study by using a novel "no hole" gEMB. Main outcome measures were technical success, adverse events, and histologic confirmation of the intermuscular layer, including myenteric neurons and ICC. The gEMB was a double resection clip-assist technique. A site was identified on the anterior wall of the gastric body as recommended by the International Working Group on histologic techniques. EMR was performed to unroof and expose the underlying MP. The exposed MP was then retracted into the cap of an over-the-scope clip. The clip was deployed, and the pseudopolyp of MP created was resected. This resulted in a no-hole gEMB., Results: Three patients with idiopathic gastroparesis underwent gEMB. Patients had severe delayed gastric emptying with a mean (± standard deviation [SD]) of 49 ± 16.8% of retained gastric contents at 4 hours. They had no history of gastric or small-bowel surgery and did not use steroids or other immunosuppressive drugs. The gEMB procedure was successfully performed, with no procedural adverse events. Postprocedural abdominal pain was controlled with nonsteroidal anti-inflammatory agents and opioid analgesics. Mean length of resected MP was 10.3 ± 1.5 mm. Mean procedure time was 25.7 ± 6 minutes. Hematoxylin and eosin (H&E) staining of tissue samples confirmed the presence of both inner circular and outer longitudinal muscle, as well as the intermuscular layer. H&E staining showed reduced myenteric ganglia in 1 patient. In 2 patients, specialized immunohistochemistry was performed, which showed a marked decrease in myenteric neurons as delineated by an antibody to protein gene product 9.5 and a severe decrease in ICC levels across the muscle layers. At 1 month follow-up, upper endoscopy showed a well-healed scar in 2 patients and minimal ulceration with a retained clip in 1 patient. CT of the abdomen confirmed the integrity of the gastric wall in all patients. Because of lack of an immune infiltrate in the resected samples, patients were not considered suitable for immunosuppressive or steroid therapy., Conclusions: gEMB is feasible and easy to perform, with acquisition of tissue close to surgical samples to identify myenteric ganglia, ICCs, and multiple cell types. The ability to perform gEMB represents a paradigm shift in endoscopic tissue diagnosis of gastric neuromuscular pathologies., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Hyperglycemia is implicated as a major risk factor for delayed gastric emptying in diabetes mellitus and vice versa. However, the extent to which hyperglycemia can affect gastric emptying and vice versa and the implications for clinical practice are unclear. We systematically reviewed the evidence for this bidirectional relationship and the effects of pharmacotherapy for diabetes on gastric emptying., Methods: Full-length articles investigating the relationship between diabetes mellitus and gastroparesis were reviewed primarily to quantify the relationship between blood glucose concentrations and gastrointestinal sensorimotor functions, particularly gastric emptying, and gastrointestinal symptoms. The effects of drugs and hormones that affect glycemia on gastrointestinal sensorimotor functions were also evaluated., Results: Acute severe hyperglycemia delayed gastric emptying relative to euglycemia in type 1 diabetes; the corresponding effects in type 2 diabetes are unknown. Limited evidence suggests that even mild hyperglycemia (8 mmol/L) can delay gastric emptying in type 1 diabetes. Long-term hyperglycemia is an independent risk factor for delayed gastric emptying in type 1 diabetes. There is little evidence that delayed gastric emptying causes hypoglycemia in diabetes and no evidence that improved control of glycemia improves gastric emptying or vice versa. Glucagon-like peptide-1 agonists but not dipeptidylpeptidase-4 inhibitors given acutely delay gastric emptying, but tachyphylaxis may occur., Conclusions: Although acute severe and chronic hyperglycemia can delay gastric emptying, there is limited evidence that delayed gastric emptying is an independent risk factor for impaired glycemic control or hypoglycemia in diabetes. The impact of improved glycemic control on gastric emptying and vice versa in diabetes is unknown., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Depletion and ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric body and antrum have been observed in gastroparesis. This research was performed to investigate the ICC population in the muscularis propria and fibrosis of the muscular layer of the pylorus in gastroparesis., Methods: Full thickness pyloric and antral biopsies were obtained from 17 gastroparetic and 6 non-gastroparetic controls. Biopsies were stained with C-Kit for ICC and Trichrome for collagen fibrosis. Interstitial cells of Cajal depletion in the antrum was defined as mean ICC count <10 per 20 high power fields (HPF) based on established data., Key Results: The average pyloric ICC count was ≥10/HPF in the control patients. Twelve (70.5%) gastroparetic patients had pyloric ICC loss. Only five patients (29.4%) had ICC loss in the antrum. Gastric emptying (GE) was not significantly different in patients with depleted vs normal pyloric ICC. However, GE at 2 h was slower in patients with antral ICC <10/HPF compared to those with normal antral ICC populations. Collagen fibrosis was observed in the pylorus of 14 (82.3%) patients. Inclusion bodies in the muscularis propria of the pylorus were identified in four patients, all with diabetic gastroparesis., Conclusions & Inferences: In gastroparetic patients, ICC loss in the pylorus is twice as common as in the antrum and fibrosis in the pyloric smooth muscle is nearly three times more common than the antrum. These findings can provide one explanation for pyloric dysfunction which is a contributing factor to the pathophysiology of gastroparesis., (© 2016 John Wiley & Sons Ltd.)

Aim: Enteric glial cells (EGCs) modulate colonic motility in a maternal separation model. We aimed to investigate structural changes in gastric EGC and gastric emptying as responses to maternal separation and acute adulthood stress in rats to elucidate the pathophysiological roles of gastric EGC., Main Methods: As a chronic stress, we subjected male Wistar rats to 3h of maternal separation during postnatal days 2-14. As an acute adulthood stress (7weeks of age), we used the 8-h water-immersion method. We morphologically evaluated gastric EGCs using whole-mount longitudinal muscle-myenteric plexus preparations. We analyzed gastric emptying by the phenol red method., Key Finding: The area of EGC processes that apparently overlapped with neurons increased according to stress intensity (acute stress, 10.4%; maternal separation, 10.2%; maternal separation plus acute stress, 26.6%; control, 5.0%). Ratios of morphologically changed leaf-like processes to the total processes were 8.1%, acute stress; 10.3%, maternal separation; 4.0%, control. Ratio dramatically increased in the combined stress group (20.5%, p=0.026 vs. control). The mean bulging head area of leaf-like processes in the combined stress group was greater by 6.4μm(2) (control, 2.4μm(2); p=0.042). Gastric emptying in the maternal separation group was gradually delayed (104.1% at 7weeks, 66.7% at 17weeks, and 48.5% at 48weeks; p<0.05, respectively). Gastric emptying in the combined stress group tended to be delayed at 17weeks (45.7% vs. 81% in controls, p=0.066)., Significance: Gastric EGCs exhibited structural changes according to stress intensity, which may be associated with stress-induced dysfunction of the stomach., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This article discusses the most interesting studies on functional and motor gastrointestinal disorders presented at Digestive Diseases Week (DDW), 2015. Researchers are still seeking biomarkers for irritable bowel syndrome and have presented new data. One study confirmed that the use of low-dose antidepressants has an antinociceptive effect without altering the psychological features of patients with functional dyspepsia. A contribution that could have immediate application is the use of transcutaneous electroacupuncture, which has demonstrated effectiveness in controlling nausea in patients with gastroparesis. New data have come to light on the importance of diet in irritable bowel syndrome, although the effectiveness of a low-FODMAP diet seems to be losing momentum with time. Multiple data were presented on the long-term efficacy of rifaximin therapy in patients with irritable bowel syndrome and diarrhoea. In addition, among other contributions, and more as a curiosity, a study evaluated the effect of histamine in the diet of patients with irritable bowel syndrome., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)

Purpose of Review: This review covers the cause, evaluation and treatment options for gastroparesis. Symptoms of delayed gastric emptying are increasingly seen by gastroenterologists and gastrointestinal surgeons. Endoscopy - both laparoscopic and flexible - is increasingly important in treatment algorithms for this problem., Recent Findings: Gastroparesis is increasingly being seen in clinical practice. A progressive algorithm needs to be followed in these challenging cases: starting with medical treatment and diet modification, progressing through endoscopic treatments including new ones such as per-oral pyloromyotomy, and finally laparoscopic treatments including gastrectomy., Summary: Endoscopic interventions are effective treatments for certain gastroparesis patients. New procedures offer a minimally invasive alternative to more radical options and should probably be more widely adopted.

The cellular abnormalities that lead to diabetic gastroparesis are increasingly being understood. Several key cell types are affected by diabetes, leading to gastroparesis. These changes include abnormalities in the extrinsic innervation to the stomach, loss of key neurotransmitters at the level of the enteric nervous system, smooth muscle abnormalities, loss of interstitial cells of Cajal, and changes in the macrophage population resident in the muscle wall. This article reviews the current understanding with a focus on data from human studies when available., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The aim of the present study was to develop an ultrasonographic approach to comparatively assess gastric emptying in newborn wild-type and guanosine triphosphate cyclohydrolase knockout hph-1 mice, because we previously reported gastroparesis early in life in this strain., Methods: Stomach transverse, anteroposterior, and longitudinal ultrasonographic measurements were obtained with a 40-MHz transducer in pups immediately after maternal separation and 4 hours later. A conventional equation was used and the predicted values validated by obtaining postmortem gastric content volume measurements. Wild-type and hph-1 mice gastric emptying rates were comparatively evaluated at 1 to 3 and 5 to 8 days of age, respectively., Results: The ultrasound equation closely predicted the newborn stomach content volumes with a correlation coefficient (R) of 0.93 and 0.81 (P < 0.01) for measurements obtained on full stomach and after 4 hours of fasting, respectively. In wild-type mice, gastric emptying was age dependent and associated with a greater residual volume at 1 to 3 days (65% ± 7%), as compared with 5- to 8-day-old pups (33% ± 4%; P  < 0.01), after fasting. In contrast, an equal duration of fasting resulted in a significantly greater residual gastric content volume in 5- to 8-day-old hph-1 mice (68%  ± 7%; P < 0.01), as compared with same-age wild-type mice., Conclusions: Ultrasonography offers a sensitive and accurate estimate of gastric content volume in newborn mice. In wild-type newborn mice, gastric emptying rate is age dependent and significantly reduced in the immediate postnatal period. The newborn hph-1 mice have a significantly higher gastric residual volume, as compared with wild-type same-age animals.

An original technique has been developed for the biomicroscopy of small-intestine mesentery blood vessels in rats. Using this method, specific features of mic- rocirculatory process disturbances caused by isoniazid in high doses have been elucidated for the first time. It is established that intragastric introduction of iso- niazid (single daily dose of 542 mg/kg for 6 days) leads to pronounced disturbances of the microcirculatory process, accompanied by intravascular aggregation of erythrocytes, stasis, destructive changes in vessel walls, diapedesis, and hemorrhage over an area of (1.9-9.9) x 10⁻³ mm².

Gastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high-resolution (HR) electrical mapping studies have now redefined the human 'gastric conduction system', providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background: There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC., Methods: Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer., Key Results: Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types., Conclusions & Inferences: Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages., (© 2014 John Wiley & Sons Ltd.)

Aim: To investigate the gastric muscle injury caused by endoplasmic reticulum (ER) stress in rats with diabetic gastroparesis., Methods: Forty rats were randomly divided into two groups: a control group and a diabetic group. Diabetes was induced by intraperitoneal injection of 60 mg/kg of streptozotocin. Gastric emptying was determined at the 4(th) and 12(th) week. The ultrastructural changes in gastric smooth muscle cells (SMCs) were investigated by transmission electron microscopy. TdT-mediated dUTP nick end labeling (TUNEL) assay was performed to assess apoptosis of SMCs. Expression of the ER stress marker, glucose-regulated protein 78 (GRP78), and the ER-specific apoptosis mediator, caspase-12 protein, was determined by immunohistochemistry., Results: Gastric emptying was significantly lower in the diabetic rats than in the control rats at the 12(th) wk (40.71% ± 2.50%, control rats vs 54.65% ± 5.22%, diabetic rats; P < 0.05). Swollen and distended ER with an irregular shape was observed in gastric SMCs in diabetic rats. Apoptosis of gastric SMCs increased in the diabetic rats in addition to increased expression of GRP78 and caspase-12 proteins., Conclusion: ER stress and ER stress-mediated apoptosis are activated in gastric SMCs in diabetic rats with gastroparesis.

The aim of the present study was to explore the role of orphan G protein-coupled receptor 55 (GPR55) in diabetic gastroparesis (DG). Streptozotocin (STZ) was used to mimic the DG model, and the body weight and blood glucose concentration were tested 4 weeks after STZ injection (i.p.). Electrogastrogram and phenolsulfonphthalein test were used for detecting gastric emptying. Motilin (MTL), gastrin (GAS), vasoactive intestinal peptide (VIP), and somatostatin (SS) levels in plasma were determined using radioimmunology. Real-time PCR and Western blot were applied to identify the expression of GPR55 in gastric tissue, and immunohistochemistry was used to detect the distribution. The effect of lysophosphatidylinositol (LPI), an agonist of GPR55, was observed. STZ mice showed increased blood glucose concentration, lower body weight, decreased amplitude of slow wave, and delayed gastric emptying. LPI antagonized these effects of STZ. Compared to the control group, STZ caused significant decreases of MTL and GAS levels (P < 0.01), as well as increases of SS and VIP levels (P < 0.01). The changes of these hormones induced by STZ were counteracted when using LPI. GPR55 located in mice stomach, and it was up-regulated in DG. Although LPI showed no effects on the distribution and expression of GPR55 in normal mice, it could inhibit STZ-induced GPR55 up-regulation. These results suggest GPR55 is involved in the regulation of gastric movement of DG, and may serve as a new target of DG treatment. LPI, an agonist of GPR55, can protect against STZ-induced DG, and the mechanism may involve the change of GPR55 expression and modification of gastrointestinal movement regulating hormones.

Background: Although rare, atrioesophageal fistula is a serious and often lethal complication of radiofrequency catheter ablation in patients with atrial fibrillation (AF). Consequently, esophagogastroduodenoscopy after AF catheter ablation has been suggested to detect thermal esophageal lesions., Objective: To report the incidence of thermal lesions and other incidental gastrointestinal (GI) abnormalities in patients with AF after radiofrequency catheter ablation., Methods: Four hundred twenty-five (mean age 59 ± 10 years; 64% men) consecutive patients with symptomatic AF who underwent left atrial radiofrequency catheter ablation were scheduled for upper GI endoscopy 1-3 days after the procedure. Patients were asymptomatic for GI diseases, that is, exhibiting no dysphagia, heart burn, or abdominal pain., Results: Pathological GI findings were observed in 328 (77%) patients and included gastral erosions (22%), esophageal erythema (21%), gastroparesis (17%), hiatal hernia (16%), reflux esophagitis (12%), thermal esophageal lesion (11%), and suspected Barrett's esophagus (5%). Biopsies were performed in 70 (17%) patients, showing gastritis (84%), Helicobacter pylori colonization (17%) and mucosa-associated lymphoid tissue (17%), esophagitis (9%), and Barrett's esophagus (4%). Further diagnostic workup or treatment was initiated in 105 (25%) patients., Conclusions: Upper GI pathologies are observed frequently in asymptomatic patients. Half of all patients have a requirement for treatment. Among the findings, thermal esophageal lesions and gastroparesis can be attributed to AF catheter ablation. The high incidence of gastroparesis is a novel finding that deserves further investigation., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Esophagogastroduodenoscopy (EGD) and gastric emptying scintigraphy (GES) are commonly performed in the evaluation of children with upper gastrointestinal symptoms. It has been presumed, but not clarified, that gastroparesis increases the likelihood of identifying abnormalities on EGD. We sought to determine whether the presence of gastroparesis influenced the diagnostic yield of EGD in children., Methods: We conducted a retrospective chart review of children who underwent both an EGD and GES within 3 months of each other for evaluation of upper gastrointestinal symptoms (eg, abdominal pain). Clinical history (symptoms, comorbidities, medications, and surgical procedures), GES results, and EGD histology reports were captured., Results: A total of 125 children (46% female) were included, of whom, 70 (56%) had gastroparesis. Thirty-three (26%) children had liquid meal GES (1.2 ± 1.1 y of age, mean ± SD) and 92 (64%) had solid meal GES (12.4 ± 3.6 y of age). There was an overall trend toward a decreased frequency of biopsy abnormalities in those with gastroparesis (P=0.09). Those with gastroparesis identified through liquid meal GES were less likely to have reflux esophagitis on biopsy (P=0.002). Those with gastroparesis identified on solid meal GES were less likely to have gastritis (P=0.04). Symptoms, comorbidities, or medications were not predictive of GES or EGD results., Conclusions: Children with gastroparesis may be less likely to have biopsy abnormalities identified on EGD in comparison to those without gastroparesis. Further prospective, larger, and multicenter studies are needed to validate our findings.

The basic science and clinical interest in the networks of interstitial cells of Cajal (ICC) keep growing, and here, research from 2010 to mid-2013 is highlighted. High-resolution gastrointestinal manometry and spatiotemporal mapping are bringing exciting new insights into motor patterns, their function and their myogenic and neurogenic origins, as well as the role of ICC. Critically important knowledge is emerging on the partaking of PDGFRα+ cells in ICC pacemaker networks. Evidence is emerging that ICC and PDGFRα+ cells have unique direct roles in muscle innervation. Chronic constipation is associated with loss and injury to ICC, which is stimulating extensive research into maintenance and repair of ICC after injury. In gastroparesis, high-resolution electrical and mechanical studies are beginning to elucidate the pathophysiological role of ICC and the pacemaker system in this condition. Receptors and ion channels that play a role in ICC function are being discovered and characterized, which paves the way for pharmacological interventions in gut motility disorders through ICC.

The advent of high-resolution (HR) electrical mapping of slow wave activity has significantly improved the understanding of gastric slow wave activity in normal and dysrhythmic states. One of the current limitations of this technique is it generates a vast amount of data, making manual analysis a tedious task for research and clinical development. In this study we present new automated methods to classify, identify, and locate patterns of interest in gastric slow wave propagation. The classification method uses a similarity metric to classify slow wave propagations, while the identification algorithm uses the divergence and mean curvature of the slow wave propagation to identify and regionalize patterns of interest. The methods were applied to synthetic and experimental datasets and were also compared to manual analysis. The methods classified and identified patterns of slow wave propagation in less than 1 s, compared to manual analysis which took up to 40 min. The automated methods achieved 96% accuracy in classifying AT maps, and 95% accuracy in identifying the propagation pattern with a mean spatial error of 1.5 mm in comparison to manual methods. These new methods will facilitate the efficient translation of gastrointestinal HR mapping techniques to clinical practice.

Diabetic gastroparesis is a common complication of diabetes, adversely affecting quality of life with symptoms of abdominal discomfort, nausea, and vomiting. The pathogenesis of this complex disorder is not well understood, involving abnormalities in the extrinsic and enteric nervous systems, interstitial cells of Cajal (ICCs), smooth muscles and immune cells. The ob/ob mouse model of obesity and diabetes develops delayed gastric emptying, providing an animal model for investigating how gastric smooth muscle dysfunction contributes to the pathophysiology of diabetic gastroparesis. Although ROCK2, MYPT1, and CPI-17 activities are reduced in intestinal motility disorders, their functioning has not been investigated in diabetic gastroparesis. We hypothesized that reduced expression and phosphorylation of the myosin light chain phosphatase (MLCP) inhibitory proteins MYPT1 and CPI-17 in ob/ob gastric antrum smooth muscles could contribute to the impaired antrum smooth muscle function of diabetic gastroparesis. Spontaneous and carbachol- and high K(+)-evoked contractions of gastric antrum smooth muscles from 7 to 12 week old male ob/ob mice were reduced compared to age- and strain-matched controls. There were no differences in spontaneous and agonist-evoked intracellular Ca(2+) transients and myosin light chain kinase expression. The F-actin:G-actin ratios were similar. Rho kinase 2 (ROCK2) expression was decreased at both ages. Basal and agonist-evoked MYPT1 and myosin light chain 20 phosphorylation, but not CPI-17 phosphorylation, was reduced compared to age-matched controls. These findings suggest that reduced MLCP inhibition due to decreased ROCK2 phosphorylation of MYPT1 in gastric antrum smooth muscles contributes to the antral dysmotility of diabetic gastroparesis.

Abdominal pain physiology may be better understood studying electrophysiology, histology, and symptom scores in patients with the symptoms of gastroparesis (Gp) treated with gastric electrical stimulation (GES). Ninety-five Gp patients' symptoms were recorded at baseline and during temporary and permanent GES. Gastric-emptying times and cutaneous, mucosal, and serosal electrogastrograms were obtained. S100-stained, full-thickness gastric biopsies were compared with autopsy controls. Sixty-eight patients reported severe pain at baseline. Severe pain patients' mean pain scores decreased with temporary GES from 3.62 to 1.29 (P < 0.001) and nonsevere pain from 1.26 to 0.67 (P = 0.01). With permanent GES, severe mean pain scores fell to 2.30 (P < 0.001); nonsevere pain changed to 1.60 (P = 0.221). Mean follow-up was 275 days. Mean cutaneous, mucosal, and serosal frequencies and frequency-to-amplitude ratios were markedly higher than literature controls. For patients with Gp overall and subdivided by etiology and severity of pain, S-100 neuronal fibers were significantly reduced in both muscularis propria layers. GES improved severe pain associated with symptoms of Gp. This severe pain is associated with abnormal electrogastrographic activity and loss of S100 neuronal fibers in the stomach's inner and outer muscularis propria and, therefore, could be the result of gastric neuropathy.

Background & Aims: Interstitial cells of Cajal (ICC) generate slow waves. Disrupted ICC networks and gastric dysrhythmias are each associated with gastroparesis. However, there are no data on the initiation and propagation of slow waves in gastroparesis because research tools have lacked spatial resolution. We applied high-resolution electrical mapping to quantify and classify gastroparesis slow-wave abnormalities in spatiotemporal detail., Methods: Serosal high-resolution mapping was performed using flexible arrays (256 electrodes; 36 cm(2)) at stimulator implantation in 12 patients with diabetic or idiopathic gastroparesis. Data were analyzed by isochronal mapping, velocity and amplitude field mapping, and propagation animation. ICC numbers were determined from gastric biopsy specimens., Results: Mean ICC counts were reduced in patients with gastroparesis (2.3 vs 5.4 bodies/field; P < .001). Slow-wave abnormalities were detected by high-resolution mapping in 11 of 12 patients. Several new patterns were observed and classified as abnormal initiation (10/12; stable ectopic pacemakers or diffuse focal events; median, 3.3 cycles/min; range, 2.1-5.7 cycles/min) or abnormal conduction (7/10; reduced velocities or conduction blocks; median, 2.9 cycles/min; range, 2.1-3.6 cycles/min). Circumferential conduction emerged during aberrant initiation or incomplete block and was associated with velocity elevation (7.3 vs 2.9 mm s(-1); P = .002) and increased amplitudes beyond a low base value (415 vs 170 μV; P = .002)., Conclusions: High-resolution mapping revealed new categories of abnormal human slow-wave activity. Abnormalities of slow-wave initiation and conduction occur in gastroparesis, often at normal frequency, which could be missed by tests that lack spatial resolution. Irregular initiation, aberrant conduction, and low amplitude activity could contribute to the pathogenesis of gastroparesis., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)