BACKGROUND/AIMS: Detailed characterization of the ultrastructural morphology of intercellular space in gastroesophageal reflux disease has not been fully studied. We aimed to investigate whether subtle alteration in intercellular space structure and tight junction proteins might differ among patients with gastroesophageal reflux disease. METHODS: Esophageal biopsies at 5 cm above the gastroesophageal junction were obtained from 6 asymptomatic controls, 10 patients with reflux symptoms but without erosions, and 18 patients with erosions. The biopsies were morphologically evaluated by transmission electron microscopy, and by using immunohistochemistry for tight junction proteins (claudin-1 and claudin-2 proteins). RESULTS: The expressions of tight junction proteins did not differ between asymptomatic controls and gastroesophageal reflux disease patients. In patients with gastroesophageal reflux disease, altered desmosomal junction morphology was only found in upper stratified squamous epithelium. Dilated intercellular space occurred only in upper stratified squamous epithelium and in patients with erosive esophagitis. CONCLUSIONS: This study suggests that dilated intercellular space may not be uniformly present inside the esophageal mucosa and predominantly it is located in upper squamous epithelium. Presence of desmosomal junction alterations is associated with increased severity of gastroesophageal reflux disease. Besides dilated intercellular space, subtle changes in ultrastructural morphology of intercellular space allow better identification of inflamed esophageal mucosa relevant to acid reflux.
Biopsy ; Claudin-2 ; Epithelium ; Esophagogastric Junction ; Esophagus ; Extracellular Space ; Gastroesophageal Reflux ; Humans ; Immunohistochemistry ; Intercellular Junctions ; Microscopy, Electron, Transmission ; Mucous Membrane ; Tight Junction Proteins ; Tight Junctions

BACKGROUND/AIMS: Atypical symptoms are common in gastroesophageal reflux disease (GERD). Patients with non-erosive reflux disease (NERD) and erosive reflux disease (ERD) exhibit different clinical characteristics and responses to acid suppression treatment. We aimed to compare atypical characteristics in patients with NERD and ERD. We also investigated the presence of histological esophagitis in patients with NERD and ERD. METHODS: Eligible patients completed a questionnaire regarding reflux symptoms and concomitant atypical symptoms. Endoscopic biopsies with histological examination were performed. RESULTS: Of the 210 patients with GERD, 90 patients with ERD and 120 patients with NERD were studied. ERD patients were characterized by higher prevalence of hiatal hernia (P = 0.001) and smoking (P = 0.047). The prevalence of GERD was greater in the age group between 41 and 60 years regardless of endoscopic finding. There was no difference in the prevalence of atypical symptoms or histological esophagitis between NERD and ERD. In all subjects, heartburn was associated with dysphagia (r = 0.16, P = 0.01), dyspepsia (r = 0.22, P = 0.008) and hiccup (r = 0.19, P = 0.003), whereas acid regurgitation was associated with dyspepsia (r = 0.21, P = 0.014), belching (r = 0.15, P = 0.018) and hiccup (r = 0.19, P = 0.002). CONCLUSIONS: Atypical symptoms did not correlate with the presence of histological esophagitis. Atypical symptoms were equally prevalent in patients with NERD and ERD. The existence of atypical symptoms appears to be associated with the presence of typical reflux symptoms irrespective of endoscopic and histological reflux esophagitis.
Biopsy ; Deglutition Disorders ; Dyspepsia ; Eructation ; Esophagitis ; Esophagitis, Peptic ; Gastroesophageal Reflux ; Heartburn ; Hernia, Hiatal ; Hiccup ; Humans ; Prevalence ; Surveys and Questionnaires ; Smoke ; Smoking

BACKGROUND/AIMS: Sleep dysfunction is associated with altered gastrointestinal function and subsequently exacerbations of gastrointestinal problems. We aimed to investigate whether sleep dysfunction would influence anorectal motility as determined by anorectal manometry. The effect of anxiety on anorectal motility was also determined. METHODS: A total of 24 healthy volunteers underwent anorectal manometry. The anorectal parameters included resting and squeeze sphincter pressure, sensory thresholds in response to balloon distension, sphincter length, rectal compliance, and rectoanal inhibitory reflex. Sleep dysfunction was subjectively assessed by using Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the application of the State-Trait Anxiety Inventory questionnaire. RESULTS: There were sixteen subjects without sleep dysfunction (7 women; mean age, 22 years) and eight subjects with sleep dysfunction (2 women; mean age, 22 years). There was no group difference in the volume threshold for rectoanal inhibitory reflux, rectal compliance or sphincter length (P = NS). Anal sphincter pressure did not differ between the groups (P = NS). The rectal sensitivity for different levels of stimulation did not differ between the groups (P = NS). Sleep quality as determined by PSQI correlated with rectal compliance (r = 0.66, P = 0.007). Although there was no differences in any manometric parameters between subjects with and without anxiety, the anxiety score correlated with rectal compliance (r = 0.57, P = 0.003). CONCLUSIONS: Despite a positive association between rectal compliance and the level of subjective sleep or anxiety, sleep dysfunction did not apparently affect most of anorectal function in healthy subjects, nor did anxiety.
Anal Canal ; Anxiety ; Compliance ; Humans ; Manometry ; Reflex ; Sensory Thresholds

Background: Feline mammary carcinoma (FMC) is one of the most prevalent malignancies of female cats. FMC is highly metastatic and thus leads to poor disease outcomes. Among all metastases, liver metastasis occurs in about 25% of FMC patients. However, the mechanism underlying hepatic metastasis of FMC remains largely uncharacterized. Results: Herein, we demonstrate that FMC-derived extracellular vesicles (FMC-EVs) promotes the liver metastasis of FMC by activating hepatic stellate cells (HSCs) to prime a hepatic premetastatic niche (PMN). Moreover, we provide evidence that sphingosine kinase 1 (SK1) delivered by FMC-EV was pivotal for the activation of HSC and the formation of hepatic PMN. Depletion of SK1 impaired cargo sorting in FMC-EV and the EV-potentiated HSC activation, and abol‑ ished hepatic colonization of FMC cells. Conclusions Taken together, our findings uncover a previously uncharacterized mechanism underlying liver-metas‑ tasis of FMC and provide new insights into prognosis and treatment of this feline malignancy.

Background/Aims: Activation of the cold receptor, transient receptor potential melastatin 8 (TRPM8) by menthol inhibits esophageal secondary peristalsis in healthy adults. Ineffective esophageal motility (IEM) is common. This study is to evaluate the effects of acute infusion of menthol on esophageal peristalsis in patients with IEM. Methods: Twenty patients with IEM (males 11, mean age 36) were studied for esophageal peristalsis using high-resolution manometry. All participant had primary peristalsis performed with 10 water swallows and secondary peristalsis generated with 10 rapid air injections of 20 mL via mid-esophageal infusion port. Two different sessions by randomly performing acute administration of placebo or menthol (3 mM) were used for testing their effects on esophageal peristalsis. Results: Menthol infusion had no effects on distal contractile integral (P = 0.471), distal latency (P = 0.58), or complete peristalsis (P = 0.251). Menthol infusion did not change basal lower esophageal sphincter pressure (P = 0.321), esophagogastric junction contractile integral (P = 0.758), or integrated relaxation pressure (P = 0.375) of primary peristalsis, but reduced upper esophageal sphincter pressure (P = 0.037). Infusion of menthol significantly reduced the frequency of secondary peristalsis for air injects of 20 mL (P = 0.002), but did not affect distal contractile integral of secondary peristalsis for air injections of 20 mL. Conclusion This work has suggested that activation of TRPM8 by menthol can attenuate mechanosensitivity of secondary peristalsis in response to rapid air distension regardless of the presence of IEM.

Background/Aims: Activation of the cold receptor, transient receptor potential melastatin 8 (TRPM8) by menthol inhibits esophageal secondary peristalsis in healthy adults. Ineffective esophageal motility (IEM) is common. This study is to evaluate the effects of acute infusion of menthol on esophageal peristalsis in patients with IEM. Methods: Twenty patients with IEM (males 11, mean age 36) were studied for esophageal peristalsis using high-resolution manometry. All participant had primary peristalsis performed with 10 water swallows and secondary peristalsis generated with 10 rapid air injections of 20 mL via mid-esophageal infusion port. Two different sessions by randomly performing acute administration of placebo or menthol (3 mM) were used for testing their effects on esophageal peristalsis. Results: Menthol infusion had no effects on distal contractile integral (P = 0.471), distal latency (P = 0.58), or complete peristalsis (P = 0.251). Menthol infusion did not change basal lower esophageal sphincter pressure (P = 0.321), esophagogastric junction contractile integral (P = 0.758), or integrated relaxation pressure (P = 0.375) of primary peristalsis, but reduced upper esophageal sphincter pressure (P = 0.037). Infusion of menthol significantly reduced the frequency of secondary peristalsis for air injects of 20 mL (P = 0.002), but did not affect distal contractile integral of secondary peristalsis for air injections of 20 mL. Conclusion This work has suggested that activation of TRPM8 by menthol can attenuate mechanosensitivity of secondary peristalsis in response to rapid air distension regardless of the presence of IEM.

Background/Aims: Activation of the cold receptor, transient receptor potential melastatin 8 (TRPM8) by menthol inhibits esophageal secondary peristalsis in healthy adults. Ineffective esophageal motility (IEM) is common. This study is to evaluate the effects of acute infusion of menthol on esophageal peristalsis in patients with IEM. Methods: Twenty patients with IEM (males 11, mean age 36) were studied for esophageal peristalsis using high-resolution manometry. All participant had primary peristalsis performed with 10 water swallows and secondary peristalsis generated with 10 rapid air injections of 20 mL via mid-esophageal infusion port. Two different sessions by randomly performing acute administration of placebo or menthol (3 mM) were used for testing their effects on esophageal peristalsis. Results: Menthol infusion had no effects on distal contractile integral (P = 0.471), distal latency (P = 0.58), or complete peristalsis (P = 0.251). Menthol infusion did not change basal lower esophageal sphincter pressure (P = 0.321), esophagogastric junction contractile integral (P = 0.758), or integrated relaxation pressure (P = 0.375) of primary peristalsis, but reduced upper esophageal sphincter pressure (P = 0.037). Infusion of menthol significantly reduced the frequency of secondary peristalsis for air injects of 20 mL (P = 0.002), but did not affect distal contractile integral of secondary peristalsis for air injections of 20 mL. Conclusion This work has suggested that activation of TRPM8 by menthol can attenuate mechanosensitivity of secondary peristalsis in response to rapid air distension regardless of the presence of IEM.

The objectives of this cohort analysis were to explore the relationship between insulin resistance (IR) and the criteria for metabolic syndrome (MetS) and to evaluate the ability to detect IR in subjects fulfilling those criteria. We enrolled 511 healthy subjects (218 men and 283 women) and measured their blood pressure (BP), body mass index, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and fasting plasma glucose levels. Insulin suppression testing was done to measure insulin sensitivity as the steady-state plasma glucose (SSPG) value. Subjects with an SSPG value within the top 25% were considered to have IR. The commonest abnormality was a low HDL-C level, followed by high BP. The sensitivity to detect IR in subjects with MetS was about 47%, with a positive predictive value of about 64.8%, which has higher in men than in women. In general, the addition of components to the criteria for MetS increased the predictive value for IR. The most common combination of components in subjects with MetS and IR were obesity, high BP, and low HDL-C levels. All of the components were positive except for HDL-C, which was negatively correlated with SSPG. The correlation was strongest for obesity, followed by high TG values. In subjects with MetS, sensitivity for IR was low. However, body mass index and TG values were associated with IR and may be important markers for IR in subjects with MetS.
Adult ; Aged ; *Biological Markers ; Blood Glucose/metabolism ; Blood Pressure ; Body Mass Index ; Cholesterol, HDL/blood ; Female ; Humans ; *Insulin Resistance ; Male ; Metabolic Syndrome X/*diagnosis/*epidemiology ; Middle Aged ; Obesity, Morbid/diagnosis/epidemiology ; Predictive Value of Tests ; Prevalence ; Risk Factors ; Sensitivity and Specificity ; Triglycerides/blood

Background/Aims: Intrabolus pressures are important for esophageal bolus transport and may detect obstructed bolus flow. This study measured the effect esophageal outflow obstruction experimentally induce by a leg-lift protocol. Methods: Twenty-five gastroesophageal reflux disease patients referred for esophageal manometry and a normal motility diagnosis were included. Supine liquid swallows were tested. Leg-lift protocol generated esophageal outflow obstruction by increasing abdominal pressure. Esophageal pressure topography and intrabolus pressure metrics were calculated. These included, (1) mid-domain bolus distension pressure during esophageal emptying (DPE, mmHg) and (2) ramp pressure (mmHg/sec), generated by compression of the bolus between the peristaltic contraction and esophagogastric junction (EGJ). Results: EGJ relaxation pressure was increased by leg-lift from 13 (11-17) to 19 (14-30) mmHg (P< 0.005) and distal contractile integral also increased from 1077 (883-1349) to 1620 (1268-2072) mmHg · cm · sec (P < 0.001) as a physiological response to obstruction. All bolus pressures were increased by leg lift; DPE increased from 17 (15-20) to 27 (19-32) mmHg (P< 0.001), and ramp pressure increased from 3 (1-4) to 5 (2-9) mmHg/sec (P < 0.05). Conclusion Measuring pressures within the intrabolus domain can quantify changes related to obstruction to outflow and may serve as adjunct measures for confirming a diagnosis EGJ outflow obstruction.

Background/Aims: Straight leg raise (SLR) can be utilized to evaluate the integrity of the esophagogastric junction during high-resolution manometry (HRM). We aim to assess the value of transient hiatal separation during SLR in symptomatic reflux patients. Methods: Consecutive reflux patients undergoing esophageal HRM and pH monitoring were included. Transient hiatal separation was defined by a ≥ 1 cm separation between the lower esophageal sphincter and crural diaphragm during SLR. We compared esophageal motor patterns and reflux monitoring parameters between patients with normal, transiently abnormal and consistently abnormal esophagogastric junction morphology during SLR. Results: Of 85 (56.3% female, mean age: 46.7 ± 12.3 years) completed SLR, esophagogastric junction morphology was normal in 31 (36.5%), transient hiatal separation in 19 (22.3%), and consistently hiatal hernia in 35 (41.2%). The values of total acid exposure time (P= 0.016), longest acid reflux episodes (P = 0.024), and DeMeester scores (P = 0.016) were higher in hiatal hernia compared to patients with non-transient hiatal separation, but there were no differences between those with and without transient hiatal separation. Within ineffective esophageal motility, the presence of transient hiatal separation during SLR significantly associated with a higher total acid exposure time (P = 0.014), higher DeMeester scores (P = 0.019), higher total acid reflux events (P = 0.037), and higher longest acid reflux episodes (P = 0.006). Conclusion Our work suggests that SLR may have value as a provocative test during HRM, and future outcome studies are warranted to elucidate the clinical relevance of motor abnormalities depicted from SLR.