Comparing Patients Diagnosed With Ineffective Esophageal Motility by the Chicago Classification Version 3.0 and Version 4.0 Criteria.

Background: The Chicago Classification version 4.0 (CCv4.0) of ineffective esophageal motility (IEM) is more stringent than the Chicago Classification version 3.0 (CCv3.0) definition. We aimed to compare the clinical and manometric features of patients meeting CCv4.0 IEM criteria (group 1) versus patients meeting CCv3.0 IEM but not CCv4.0 criteria (group 2). Methods: We collected retrospective clinical, manometric, endoscopic, and radiographic data on 174 adults diagnosed with IEM from 2011 to 2019. Complete bolus clearance was defined as evidence of exit of the bolus by impedance measurement at all distal recording sites. Barium studies included barium swallow, modified barium swallow, and barium upper gastrointestinal series studies, and collected data from these reports include abnormal motility and delay in the passage of liquid barium or barium tablet. These data along with other clinical and manometric data were analyzed using comparison and correlation tests. All records were reviewed for repeated studies and the stability of the manometric diagnoses. Results: Most demographic and clinical variables were not different between the groups. A lower mean lower esophageal sphincter pressure was correlated with greater percent of ineffective swallows in group 1 (n = 128) (r = -0.2495, P = 0.0050) and not in group 2. In group 1, increased percent of failed contractions on manometry was associated with increased incomplete bolus clearance (r = 0.3689, P = 0.0001). No such association was observed in group 2. A lower median integrated relaxation pressure was correlated with greater percent of ineffective contractions in group 1 (r = -0.1825, P = 0.0407) and not group 2. Symptom of dysphagia was more prevalent (51.6% versus 69.6%, P = 0.0347) in group 2. Dysphagia was not associated with intrabolus pressure, bolus clearance, barium delay, or weak or failed contractions in either group. In the small number of subjects with repeated studies, a CCv4.0 diagnosis appeared more stable over time. Conclusions: CCv4.0 IEM was associated with worse esophageal function indicated by reduced bolus clearance. Most other features studied did not differ. Symptom presentation cannot predict if patients are likely to have IEM by CCv4.0. Dysphagia was not associated with worse motility, suggesting it may not be primarily dependent on bolus transit.

Factors that Influence Work Family Conflict for Women Faculty.

This article was migrated. The article was marked as recommended. Purpose: This study examined the interaction between work role overload, work-to-family conflict, and departmental/division culture conducive to women's academic success. Methods: All women assistant and associate professors eligible for promotion from the Departments of Family Medicine, Internal Medicine, and Pediatrics were invited to complete a validated web-based survey that measured work-to-family conflict, work hours, work role overload, and culture conducive to women's academic success ( Westring et al., 2012). Results: With 88 survey respondents, high work role overload was associated with increased levels of work-to-family conflict while those who reported a higher culture conducive to women's academic success reported less work-to-family conflict. Culture conducive to women's academic success did not moderate the impact of work demand on work-to-family conflict. Conclusions: While departmental/division culture was important, it was not sufficient to completely mitigate work-to-family conflict. Work demand appears to impact work-to-family conflict related to strain, in which women report being too stressed by work to focus on their family and their own health and wellness. Employers can greatly impact work culture by reducing the strain of work demands that interfere with women pursuing promotion, increase burnout, and contribute to women faculty deciding to work part-time.

Effects of cell type and configuration on anabolic and catabolic activity in 3D co-culture of mesenchymal stem cells and nucleus pulposus cells.

Tissue engineering constructs to treat intervertebral disc degeneration must adapt to the hypoxic and inflammatory degenerative disc microenvironment. The objective of this study was to determine the effects of two key design factors, cell type and cell configuration, on the regenerative potential of nucleus pulposus cell (NPC) and mesenchymal stem cell (MSC) constructs. Anabolic and catabolic activity was quantified in constructs of varying cell type (NPCs, MSCs, and a 50:50 co-culture) and varying configuration (individual cells and micropellets). Anabolic and catabolic outcomes were both dependent on cell type. Gene expression of Agg and Col2A1, glycosaminoglycan (GAG) content, and aggrecan immunohistochemistry (IHC), were significantly higher in NPC-only and co-culture groups than in MSC-only groups, with NPC-only groups exhibiting the highest anabolic gene expression levels. However, NPC-only constructs also responded to inflammation and hypoxia with significant upregulation of catabolic genes (MMP-1, MMP-9, MMP-13, and ADAMTS-5). MSC-only groups were unaffected by degenerative media conditions, and co-culture with MSCs modulated catabolic induction of the NPCs. Culturing cells in a micropellet configuration dramatically reduced catabolic induction in co-culture and NPC-only groups. Co-culture micropellets, which take advantage of both cell type and configuration effects, had the most immunomodulatory response, with a significant decrease in MMP-13 and ADAMTS-5 expression in hypoxic and inflammatory media conditions. Co-culture micropellets were also found to self-organize into bilaminar formations with an MSC core and NPC outer layer. Further understanding of these cell type and configuration effects can improve tissue engineering designs. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:61-73, 2017.

Neurogenic [corrected] and oropharyngeal dysphagia.

Oropharyngeal dysphagia (OD) is a swallowing disorder caused by congenital abnormalities and structural damage and disease-associated damage of the oral cavity, pharynx, and upper esophageal sphincter. Patients with OD lack the protective mechanisms necessary for effective swallowing, exhibiting difficulty controlling food in the mouth and initiating a swallow, leading to choking, coughing, and nasal regurgitation. OD is a major risk factor for malnutrition, dehydration, and aspiration pneumonia. The following on OD includes commentaries on the application of simulation of oropharyngeal transient receptor potential vanilloid 1 (TRPV1) and maneuvers like the Shaker exercise to improve the safety and efficacy of swallow in OD patients; the prevalence of esophageal pathologies in OD patients and the need to evaluate the esophagus, esophagogastric junction, and stomach; and strategies for clinical screening to detect OD and aspiration among high-risk patients and to improve oral health care, maintain nutrition and hydration, and prevent aspiration pneumonia.

Physiology of the upper segment, body, and lower segment of the esophagus.

The following discussion on the physiology of the esophagus includes commentaries on the function of the muscularis mucosa and submucosa as a mechanical antireflux barrier in the esophagus; the different mechanisms of neurological control in the esophageal striated and smooth muscle; new insights from animal models into the neurotransmitters mediating lower esophageal sphincter (LES) relaxation, peristalsis in the esophageal body (EB), and motility of esophageal smooth muscle; differentiation between in vitro properties of the lower esophageal circular muscle, clasp muscle, and sling fibers; alterations in the relationship between pharyngeal contraction and relaxation of the upper esophageal sphincter (UES) in patients with dysphagia; the mechanical relationships between anterior hyoid movement, the extent of upper esophageal opening, and aspiration; the application of fluoroscopy and manometry with biomechanics to define the stages of UES opening; and nonpharmacological approaches to alter the gastroesophageal junction (GEJ).

Cholecystokinin-cholescintigraphy in adults: consensus recommendations of an interdisciplinary panel.

BACKGROUND AND AIMS: Cholecystokinin-cholescintigraphy (CCK-CS) provides a physiologic, noninvasive, and quantitative method for assessing gallbladder contraction and calculation of a gallbladder ejection fraction (GBEF). At present, it is used most commonly to identify patients with suspected functional gallbladder disorder. However, the methodology of CCK infusion and normal values differ markedly among imaging centers. METHODS: This document represents the consensus opinion of an interdisciplinary panel that gathered to assess the current optimal method for performing CCK-CS in adults, potential uses and limitations of CCK-CS, and questions that require further investigation. RESULTS: The panel recommended the use of a single, standardized, recently described CCK-CS protocol that involves infusion of 0.02 µg/kg of sincalide over 60 minutes with a normal GBEF defined as ≥38%. The panel emphasized the need for a large, multicenter, prospective clinical trial to establish the utility of CCK-CS in the diagnosis of functional gallbladder disease. Although not without controversy regarding its clinical utility, the primary indication for CCK-CS at present is the well-selected patient with suspected functional gallbladder disorder. CONCLUSION: Agreement was reached that the adoption of this standardized protocol is critical to improve how CCK-CS is used to direct patient care and will represent an improvement over the diverse methods currently in use by eliminating the current lack of uniformity and adding both reliability and credibility to the results.

Effect of synthetic cationic protein on mechanoexcitability of vagal afferent nerve subtypes in guinea pig esophagus.

Eosinophilic esophagitis is characterized by increased infiltration and degranulation of eosinophils in the esophagus. Whether eosinophil-derived cationic proteins regulate esophageal sensory nerve function is still unknown. Using synthetic cationic protein to investigate such effect, we performed extracellular recordings from vagal nodose or jugular neurons in ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Nerve excitabilities were determined by comparing action potentials evoked by esophageal distensions before and after perfusion of synthetic cationic protein poly-L-lysine (PLL) with or without pretreatment with poly-L-glutamic acid (PLGA), which neutralized cationic charges of PLL. Perfusion with PLL did not evoke action potentials in esophageal nodose C fibers but increased their responses to esophageal distension. This potentiation effect lasted for 30 min after washing out of PLL. Pretreatment with PLGA significantly inhibited PLL-induced mechanohyperexcitability of esophageal nodose C fibers. In esophageal nodose Aδ fibers, perfusion with PLL did not evoke action potentials. In contrast to nodose C fibers, both the spontaneous discharges and the responses to esophageal distension in nodose Aδ fibers were decreased by perfusion with PLL, which can be restored after washing out PLL for 30-60 min. Pretreatment with PLGA attenuated PLL-induced decrease in spontaneous discharge and mechanoexcitability of esophageal nodose Aδ fibers. In esophageal jugular C fibers, PLL neither evoked action potentials nor changed their responses to esophageal distension. Collectively, these data demonstrated that synthetic cationic protein did not evoke action potential discharges of esophageal vagal afferents but had distinctive sensitization effects on their responses to esophageal distension.

Cholecystokinin-cholescintigraphy in adults: consensus recommendations of an interdisciplinary panel.

BACKGROUND & AIMS: Cholecystokinin-cholescintigraphy (CCK-CS) provides a physiologic, noninvasive, and quantitative method for assessing gallbladder contraction and calculation of a gallbladder ejection fraction (GBEF). At present, it is used most commonly to identify patients with suspected functional gallbladder disorder. However, the methodology of CCK infusion and normal values differ markedly among imaging centers. METHODS: This document represents the consensus opinion of an interdisciplinary panel that gathered to assess the current optimal method for performing CCK-CS in adults, potential uses and limitations of CCK-CS, and questions that require further investigation. RESULTS: The panel recommended the use of a single, standardized, recently described CCK-CS protocol that involves infusion of 0.02 µg/kg of sincalide over 60 minutes with a normal gallbladder ejection fraction defined as ≥38%. The panel emphasized the need for a large, multicenter, prospective clinical trial to establish the utility of CCK-CS in the diagnosis of functional gallbladder disease. Although not without controversy regarding its clinical utility, the primary indication for CCK-CS at present is the well-selected patient with suspected functional gallbladder disorder. CONCLUSIONS: Agreement was reached that the adoption of this standardized protocol is critical to improve how CCK-CS is used to direct patient care and will represent an improvement over the diverse methods currently in use by eliminating the current lack of uniformity and adding both reliability and credibility to the results.

TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus.

Sensitization of esophageal sensory afferents by inflammatory mediators plays an important role in esophageal nociception. We have shown esophageal mast cell activation induces long-lasting mechanical hypersensitivity in vagal nodose C-fibers. However, the roles of mast cell mediators and downstream ion channels in this process are unclear. Mast cell tryptase via protease-activated receptor 2 (PAR2)-mediated pathways sensitizes sensory nerves and induces hyperalgesia. Transient receptor potential A1 (TRPA1) plays an important role in mechanosensory transduction and nociception. Here we tested the hypothesis that mast cell activation via a PAR2-dependent mechanism sensitizes TRPA1 to induce mechanical hypersensitivity in esophageal vagal C-fibers. The expression profiles of PAR2 and TRPA1 in vagal nodose ganglia were determined by immunostaining, Western blot, and RT-PCR. Extracellular recordings from esophageal nodose neurons were performed in ex vivo guinea pig esophageal-vagal preparations. Action potentials evoked by esophageal distention and chemical perfusion were compared. Both PAR2 and TRPA1 expressions were identified in vagal nodose neurons by immunostaining, Western blot, and RT-PCR. Ninety-one percent of TRPA1-positive neurons were of small and medium diameters, and 80% coexpressed PAR2. Esophageal mast cell activation significantly enhanced the response of nodose C-fibers to esophageal distension (mechanical hypersensitivity). This was mimicked by PAR2-activating peptide, which sustained for 90 min after wash, but not by PAR2 reverse peptide. TRPA1 inhibitor HC-030031 pretreatment significantly inhibited mechanical hypersensitivity induced by either mast cell activation or PAR2 agonist. Collectively, our data provide new evidence that sensitizing TRPA1 via a PAR2-dependent mechanism plays an important role in mast cell activation-induced mechanical hypersensitivity of vagal nodose C-fibers in guinea pig esophagus.

TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus.

Bradykinin (BK) activates sensory nerves and causes hyperalgesia. Transient receptor potential A1 (TRPA1) is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception. TRPA1 can be activated by BK. TRPA1 knockout mice show impaired responses to BK and mechanical nociception. However, direct evidence from sensory nerve terminals is lacking. This study aims to determine the role of TRPA1 in BK-induced visceral mechanical hypersensitivity. Extracellular recordings of action potentials from vagal nodose and jugular neurons are performed in an ex vivo guinea pig esophageal-vagal preparation. Peak frequencies of action potentials of afferent nerves evoked by esophageal distension and chemical perfusion are recorded and compared. BK activates most nodose and all jugular C fibers. This activation is repeatable and associated with a significant increase in response to esophageal distension, which can be prevented by the B2 receptor antagonist WIN64338. TRPA1 agonist allyl isothiocyanate (AITC) activates most BK-positive nodose and jugular C fibers. This is associated with a transient loss of response to mechanical distensions and desensitization to a second AITC perfusion. Desensitization with AITC and pretreatment with TRPA1 inhibitor HC-030031 both inhibit BK-induced mechanical hypersensitivity but do not affect BK-evoked activation in nodose and jugular C fibers. In contrast, esophageal vagal afferent Adelta fibers do not respond to BK or AITC and fail to show mechanical hypersensitivity after BK perfusion. This provides the first evidence directly from visceral sensory afferent nerve terminals that TRPA1 mediates BK-induced mechanical hypersensitivity. This reveals a novel mechanism of visceral peripheral sensitization.

Antigen inhalation induces mast cells and eosinophils infiltration in the guinea pig esophageal epithelium involving histamine-mediated pathway.

Antigen challenge in sensitized guinea pig esophagus in vitro induces mast cell degranulation and histamine release. This study tests the hypothesis that antigen inhalation in vivo induces infiltration of the esophageal epithelium by mast cells and eosinophils via a histamine pathway. Actively sensitized guinea pigs were exposed to inhaled 0.1% ovalbumin. One or 24 h after inhalation exposure, the esophagus was processed for immunofluorescent staining of mast cell tryptase and eosinophil major basic protein (MBP). Additional animals were pretreated with thioperamide, a histamine H4/H3 receptor antagonist. Total tryptase- and MBP-labeled cells and percent of positive cells in the epithelial layer were counted. The total number of mast cells was unchanged after inhalation challenge, but the percentage in the epithelium increased 1 h after challenge. The total number of eosinophils increased 1 h after challenge, and the percentage migrating to the epithelium increased by 24 h after challenge. Mast cell migration into the mucosal epithelium preceded that of eosinophils. Thioperamide inhibited mast cell and eosinophil migration. In conclusion, antigen inhalation in sensitized animals induces mast cells and eosinophils to infiltrate in the esophageal epithelium via histamine-mediated mechanism.

Overview of neurogastroenterology-gastrointestinal motility and functional GI disorders: classification, prevalence, and epidemiology.

The classification of gastrointestinal (GI) motility and functional gastrointestinal disorders is in a state of transition. Functional GI disorders are classified by their symptom complex, and the epidemiology of these conditions is based on symptom surveys. In contrast, GI motility disorders are classified by results of GI motility testing; the epidemiology of these conditions is often derived from tertiary care centers. Over time, with increasingly sophisticated methods of studying the brain-gut axis, the classification will likely shift from symptoms to a classification based on pathophysiology. This article reviews the epidemiology of these common disorders from the esophagus to the anorectum.

Holistic acupuncture approach to idiopathic refractory nausea, abdominal pain and bloating.

AIM: To evaluate the effectiveness of a holistic acupuncture approach on nausea, pain, bloating and electrogastrogram (EGG) parameters in patients with intractable symptoms. METHODS: Twelve patients with no or mild nausea (those without nausea had bloating or pain) and 10 with a history of moderate to severe nausea were referred for acupuncture. All underwent an EGG and were treated at acupuncture points PC6, SP4 and DU20. Visual analog scales (VAS) assessing severity of nausea, pain and bloating were obtained before and after acupuncture treatment. Nineteen patients received three and three patients received two treatments. RESULTS: VAS scores for nausea reflected the clinical assessment and differed significantly between mild and moderate/severe nausea groups. Acupuncture significantly improved severity of nausea in both groups with improved pre-treatment nausea between the first and third treatments in the moderate/severe nausea group. Pain scores improved with acupuncture in the mild nausea group only and bloating improved only with the first treatment in this group. Patients with bloating with VAS scores greater than 35 pre-treatment improved with acupuncture and over all VAS scores for pain improved with treatment. Acupuncture increased the power in the 2.7 to 3.5 cpm range in the EGG. CONCLUSION: In this uncontrolled clinical study, a holistic acupuncture approach significantly improved nausea in patients with refractory symptoms and increased the power in the 2.7-3.5 cpm component of the electrogastrogram. Bloating and pain VAS scores improved acutely with treatment. This study suggests that acupuncture may be effective in this refractory group of patients and further study using appropriate controls is warranted.

Mast cell-mediated long-lasting increases in excitability of vagal C fibers in guinea pig esophagus.

Several esophageal pathologies are associated with an increased number of mast cells in the esophageal wall. We addressed the hypothesis that activation of esophageal mast cells leads to an increase in the excitability of local sensory C fibers. Guinea pigs were actively sensitized to ovalbumin. The mast cells in the esophagus were selectively activated ex vivo by superfusion with ovalbumin. Action potential discharge in guinea pig vagal nodose esophageal C-fiber nerve endings was monitored in the isolated (ex vivo) vagally innervated esophagus by extracellular recordings. Ovalbumin activated esophageal mast cells, leading to the rapid release of approximately 20% of the tissue histamine stores. This was associated with a consistent and significant increase in excitability of the nodose C fibers as reflected in a two- to threefold increase in action potential discharge frequency evoked by mechanical (increases in intraluminal pressure) stimulation. The increase in excitability persisted unchanged for at least 90 min (longest time period tested) after ovalbumin was washed from the tissue. This effect could be prevented by the histamine H1 receptor antagonist pyrilamine, but once the increase in excitability occurred, it persisted in the nominal absence of histamine and could not be reversed even with large concentrations of the histamine receptor antagonist. In conclusion, activation of esophageal mast cells leads to a pronounced and long-lived increase in nociceptive C-fiber excitability such that any sensation or reflex evoked via the vagal nociceptors will likely be enhanced. The effect is initiated by histamine acting via H1 receptor activation and maintained in the absence of the initiating stimulus.

Contribution of gender to pathophysiology and clinical presentation of IBS: should management be different in women?

The irritable bowel syndrome (IBS) is found more commonly in women than men. It is more prevalent in patients with chronic fatigue syndrome, fibromyalgia, and chronic pelvic pain, all syndromes characterized by pain and found predominantly in women. This article reviews evidence for a role of biological sex factors and gender on the pathways mediating visceral pain. The effect of gonadal hormones on gastrointestinal motility and the sensory afferent pathway and central processing of visceral stimuli and the contribution of gender role to the clinical presentation are discussed. Although differences in responses to treatment modalities between genders exist, the approach to IBS patients in both genders is quite similar. Nevertheless, a special attention to gender role and stress-related factors should be addressed. New developments in research, outlined in the paper, might bring more gender-specific treatments in the future.

Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats.

AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS: Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cis-dioxolane (cD), a nonspecific muscarinic agonist, at 10(-8)-10(-4) mol/L, in the presence of tetrodotoxin (TTX, 10(-7) mol/L). Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1 (pirenzepine), M2 (methoctramine) and M3 (darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS: A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in response from 2.5+/-0.4 g/mm2 to 1.2+/-0.4 g/mm(2) (P<0.05). The dose-response curves were shifted to the right by muscarinic antagonists in the following order of affinity: darifenacin (M(3))>methocramine (M(2)) >pirenzepine (M(1)). CONCLUSION: The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the residual contractile response after the treatment with nifedipine, suggests that an additional pathway could mediate the cholinergic contraction. The involvement of more than one muscarinic receptor (functionally predominant type 3 over type 2) also suggests more than one pathway mediating the cholinergic contraction in rat antrum.

Cost-saving approach to patients on long-term anticoagulation who need endoscopy: a decision analysis.

OBJECTIVES: The management strategies used when patients requiring long-term anticoagulation need endoscopic procedures vary considerably. Two commonly used approaches are a "heparin window" strategy in the inpatient setting and, more recently, a "switch to low molecular weight heparin (LMWH)" strategy for elective procedures. The aim of this study was to determine whether an initial diagnostic endoscopy (visualization only) is a cost-effective strategy in these patients. METHODS: Decision analysis was performed for two scenarios using probability estimates from our retrospective study. Scenario 1: Patients with any (urgent and elective) indication for endoscopy while on anticoagulation. A decision tree was made outlining two strategies: 1) a diagnostic endoscopy on full anticoagulation followed by therapeutic endoscopy if needed using standard practice; and 2) standard approach. Scenario 2: Patients requiring elective endoscopy. Here, the decision tree outlined three strategies: 1) initial diagnostic endoscopy on full anticoagulation followed by a therapeutic endoscopy if needed using a "heparin window"; 2) initial diagnostic endoscopy followed by therapeutic endoscopy if needed using "switch to LMWH" strategy; and 3) "direct switch to LMWH strategy." RESULTS: Initial diagnostic endoscopy is the preferred strategy when patients requiring anticoagulation need endoscopy. In scenario 1 (all patients), the diagnostic endoscopy approach will reduce need for hospital stay and save $85,006 per 100 patients when a therapeutic impact is not predictable before endoscopy. Similarly, in scenario 2, an initial diagnostic endoscopy followed by switch to LMWH strategy is the most cost saving. CONCLUSIONS: In anticoagulated patients, an initial diagnostic endoscopy approach on anticoagulation is the most cost-saving strategy, when a direct therapeutic impact is not predictable.