Impaired Gastrointestinal Motility Research Articles

Thyroid disorders and gastrointestinal dysmotility: an old association.

Gastrointestinal motility symptoms may be closely related to thyroid diseases. Sometimes, such symptoms are the only thyroid disease-related clue although the degree of the symptoms may vary. The exact mechanism of action of thyroid hormones on gastrointestinal motility is not completely understood, however, a clue lies in the fact that muscle cell receptors can be directly acted upon by thyroxines. Both hypo- and hyperthyroidism can cause impairment of gastrointestinal motility, modifying structure and function of pharynx and esophagus, and regulating esophageal peristalsis through neuro-humoral interaction. In hyperthyroid patients, alterations of postprandial and basic electric rhythms have been observed at gastro-duodenal level, often resulting in slower gastric emptying. Gastric emptying may also be delayed in hypothyroidism, but an unrelated gastric mucosa-affecting chronic modification may also cause such pattern. Hyperthyroidism commonly show malabsorption and diarrhoea, while hypothyroidism frequently show constipation. In summary, it can be stated that symptoms of gastrointestinal motility dysfunction can be related to thyroid diseases, affecting any of the gastrointestinal segment. Clinically, the typical thyroid disease manifestations may be missing, borderline, or concealed because of intercurrent sicknesses. Motility-linked gastrointestinal problems may easily conceal a misdetected, underlying dysthyroidism that should be carefully analyzed. Here, we aim to elaborate on the associations between thyroid disorders and GI dysmotility and the common clinical manifestations associated with GI dysmotility.

Cannabidiol improves the cognitive function of SAMP8 AD model mice involving the microbiota-gut-brain axis

ABSTRACT Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer’s disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aβ). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive. The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model. Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death. Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.

Gastrointestinal Dysmotility Predisposes to Colitis through Regulation of Gut Microbial Composition and Linoleic Acid Metabolism.

Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation.

A key genetic factor governing arabinan utilization in the gut microbiome alleviates constipation

Impaired gastrointestinal motility is associated with gut dysbiosis. Probiotics, such as Bifidobacteria, can improve this bowel disorder; however, efficacy is strain-dependent. We determine that a genetic factor, the abfA cluster governing arabinan utilization, in Bifidobacterium longum impacts treatment efficacy against functional constipation (FC). In mice with FC, B.longum, but not an abfA mutant, improved gastrointestinal transit time, an affect that was dependent upon dietary arabinan. abfA genes were identified in other commensal bacteria, whose effects in ameliorating murine FC were similarly abfA-dependent. In a double-blind, randomized, placebo-controlled clinical trial, supplementation with abfA-cluster-carrying B.longum, but not an abfA-deficient strain, enriched arabinan-utilization residents, increased beneficial metabolites, and improved FC symptoms. Across human cohorts, abfA-cluster abundance can predict FC, and transplantation of abfA cluster-enriched human microbiota to FC-induced germ-free mice improved gut motility. Collectively, these findings demonstrate a role for microbial abfA cluster in ameliorating FC, establishing principles for genomics-directed probiotic therapies.

Celecoxib-Loaded Self-micellizing Solid Dispersion Suppresses Its Delayed Absorption in Rats with Impaired Gastrointestinal Motility.

The aim of this study was to develop a self-micellizing solid dispersion of celecoxib (SMSD/CEL) with enhanced dissolution to suppress a delay in absorption under impairment of gastrointestinal (GI) secretion and motility induced by severe pain. Soluplus®-based SMSD/CEL was prepared by lyophilization and physiochemically characterized. A pharmacokinetic study of orally-dosed CEL samples was carried out in rats with propantheline (PPT)-induced the impairment of GI secretion and motility. SMSD/CEL was micellized in aqueous media with a mean diameter of 153 nm, and it showed improved dissolution behavior of CEL under acidic conditions with 2.1-fold higher dissolved CEL at 120 min than crystalline CEL. SMSD/CEL was found to be in an amorphous state, and there was no significant crystallization even after storage under accelerated conditions for 8 weeks, indicating relatively high storage stability of the amorphous form. Orally-dosed crystalline CEL in PPT-treated rats showed a delayed mean absorption time (MAT) and area under the curve of plasma concentration versus time from 0 to 4 h (AUC0-4) was reduced to 12% compared with that in normal rats, whereas SMSD/CEL suppressed the delay and decrease of absorption in PPT-treated rats. From these findings, SMSD/CEL might be efficacious to suppress poor and delayed absorption of CEL for better pain medication in the presence of impaired GI secretion and motility associated with severe pain.

Estrogen increases the expression of BKCa and impairs the contraction of colon smooth muscle via upregulation of sphingosine kinase 1.

Estrogen (E2) may impair the contraction of colonic smooth muscle (SM) leading to constipation. Large conductance Ca2+ -activated K+ channels (BKCa ) are widely expressed in the smooth muscle cells (SMCs) contributing to hyperpolarization and relaxation of SMCs. Sphingosine kinase 1 (SphK1) is known to influence the expression of BKCa . We aimed to elucidate the potential underlying molecular mechanism of BKCa and SphK1 that may influence E2-induced colonic dysmotility. In ovariectomized rats, SMcontraction and expression of BKCa , SphK1, sphingosine-1-phosphate receptor (S1PR) were analyzed after the treatment with vehicle, BSA-E2, E2, and E2receptor antagonist. The role of BKCa , SphK1, and S1PR in E2-induced SMdysmotility was investigated in rat colonic SMCs. The effect of SphK1 on SMcontraction as well as on the expression of BKCa and S1PR was analyzed in SphK1 knock-out mutant mice and wild-type (WT) mice treated with or without E2. The E2-treated group exhibited a weak contraction of colonic SMand a delayed colonic transit. The treatment with E2 significantly upregulated the expression of BKCa , SphK1, S1PR1, and S1PR2, but not S1PR3, in colon SMand SMCs. Inhibition of BKCa , SphK1, S1PR1, and S1PR2 expression attenuated the effect of E2 on Ca2+ mobilization in rat colon SMCs. WTmice treated with E2 showed impaired gastrointestinal motility and enhanced expression of BKCa , S1PR1, and S1PR2 compared with those without E2 treatment. Conversely, in SphK1 knock-out mice treated with E2, these effects were partially reversed. E2 increased the release of S1P which in turn could have activated S1PR1 and S1PR2. Loss of SphK1 attenuated the effect of E2 on the upregulation of S1PR1 and S1PR2 expression. These findings indicated that E2 impaired the contraction of colon SMthrough activation of BKCa via the upregulation of SphK1 and the release of S1P. In the E2-induced BKCa upregulation, S1PR1 and S1PR2 might also be involved. These results may provide further insights into a therapeutic target and optional treatment approaches for patients with constipation.

Carbohydrate Loading and Aspiration Risk in Bariatric Patients: Safety in Preoperative Enhanced Recovery Protocols.

Enhanced recovery protocols have been developed to improve perioperative outcomes; however, there is ongoing concern for aspiration with recent oral intake in patients with obesity, who may be predisposed to impaired gastrointestinal motility and greater gastric volumes. We aim to study the safety of a 300-mL preoperative carbohydrate-loading drink preceding bariatric surgery. Data were collected prospectively from patients undergoing primary bariatric surgery. All bariatric patients at our institution are prescribed a proton pump inhibitor for 4 weeks before surgery and undergo a screening preoperative esophagogastroduodenoscopy (EGD) before surgery with a traditional 8-hour fast (NOCARB), followed by an intraoperative day-of-operation EGD with carbohydrate loading (CARB) 2 to 4 hours before incision. Gastric volumes and pH are measured after being endoscopically suctioned via direct visualization during both settings. We identified 203 patients: 94 patients (46.3%) in the CARB group and 109 patients (53.7%) in the NOCARB group. The patients were 82.3% female with a mean age of 42.8 years and average BMI of 41.7 kg/m 2 . There was no difference in gastric volume between NOCARB and CARB (17.0 vs 16.1 mL, p = 0.59). The NOCARB group had lower pH values than the CARB group (2.8 vs 3.8, p = 0.001). Subset analysis of 23 patients who had measurements on both screening and intraoperative EGD revealed lower gastric volumes in CARB patients (13.3 vs 18.3, p < 0.0001). When included in an enhanced recovery protocol, proton pump inhibitor use and preoperative carbohydrate loading 2 to 4 hours before bariatric surgery does not increase aspiration risk based on gastric volumes and pH and should be strongly considered in all eligible bariatric patients.

Damage-induced NAD release activates intestinal CD4+ and CD8+ T cell via P2X7R signaling

BackgroundPostoperative ileus (POI) is characterized by the activation of inflammation triggered by tissue damage. Damage-associated molecular patterns (DAMPs) reportedly induce local inflammation after injury. However, the impact of DAMPs on intestinal resident lymphocytes during POI remains poorly elucidated. MethodsPOI in mice was induced via intestinal manipulation (IM). The concentration of nicotinamide adenine dinucleotide (NAD) was detected after IM. The gastrointestinal motility of the mice was assessed after IM or NAD injection. Cytokine production and calcium influx in T cells were investigated after NAD stimulation using flow cytometry. ResultsThe concentration of extracellular NAD significantly increased after IM administration, and NAD directly impaired gastrointestinal motility. Intraperitoneal injection of NAD promoted the expression of TNF-α in intestinal CD8+ and CD4+ T cells, but only IFN-γ production by CD8+ T cells was significantly promoted by NAD injection. Granzyme B production in CD8+ and CD4+ T cells decreased after administration. Concordantly, the same results were observed in NAD stimulation of intestinal CD3+ T cells in vitro. Blocking the P2X7R-related membrane enzyme ART2.2 significantly diminished the pro-inflammatory effect of NAD. ConclusionIM includes the release of NAD derived from damaged tissues, consequently promoting pro-inflammatory cytokine production in intestinal CD4+ and CD8+ T lymphocytes. NAD-induced intestinal T cells activation may be associated with POI progression in the mouse.

Application of optogenetics in the study of gastrointestinal motility: A mini review

Disorders of gastrointestinal (GI) motility are associated with various symptoms such as nausea, vomiting, and constipation. However, the underlying causes of impaired GI motility remain unclear, which has led to variation in the efficacy of therapies to treat GI dysfunction. Optogenetics is a novel approach through which target cells can be precisely controlled by light and has shown great potential in GI motility research. Here, we summarized recent studies of GI motility patterns utilizing optogenetic devices and focused on the ability of opsins, which are genetically expressed in different types of cells in the gut, to regulate the excitability of target cells. We hope that our review of recent findings regarding optogenetic control of GI cells broadens the scope of application for optogenetics in GI motility studies.

Enhanced Recovery after Surgery Carbohydrate Loading Does Not Increase Aspiration Risk in Bariatric Patients

INTRODUCTION: Enhanced recovery after surgery (ERAS) pathways have been developed to improve perioperative outcomes; however, there is ongoing concern for aspiration with recent oral intake in obese patients, who may be predisposed to impaired gastrointestinal motility and greater gastric volume. We aim to study the safety of preoperative carbohydrate loading before bariatric surgery. METHODS: Data was collected prospectively from patients undergoing primary bariatric surgery. All bariatric patients at our institution undergo a screening preoperative esophagogastroduodenoscopy (EGD) before operation with a traditional 8-hour fast (NOCARB), followed by an intraoperative day-of-surgery EGD with carbohydrate loading (CARB) 2 to 4 hours before incision. Gastric volume and pH were measured after being endoscopically suctioned via direct visualization during both settings. RESULTS: We identified 121 patients: 64 patients (52.9%) in the CARB group, and 57 patients (47.1%) in the NOCARB group. The patients were 81.1% female with a mean age of 43 years (range 19 to 71) and average BMI of 41.9 kg/m2. CARB patients had lower gastric volume with a mean of 15.7 vs 41.8 mL in the NOCARB patients (p = 0.0084). There was no significant difference in pH between the 2 groups, 3.9 CARB vs 3.4 NOCARB (p = 0.25). Subset analysis of 18 patients who had measurements on both screening and intraoperative EGD revealed lower gastric volume in CARB patients (14.4 vs 57.8 mL, p = 0.085). CONCLUSION: Preoperative carbohydrate loading 2 to 4 hours before bariatric surgery does not increase aspiration risk based on gastric volume and pH and should be the standard of care in all eligible bariatric patients.

Avian Bornavirus Research-A Comprehensive Review.

Avian bornaviruses constitute a genetically diverse group of at least 15 viruses belonging to the genus Orthobornavirus within the family Bornaviridae. After the discovery of the first avian bornaviruses in diseased psittacines in 2008, further viruses have been detected in passerines and aquatic birds. Parrot bornaviruses (PaBVs) possess the highest veterinary relevance amongst the avian bornaviruses as the causative agents of proventricular dilatation disease (PDD). PDD is a chronic and often fatal disease that may engulf a broad range of clinical presentations, typically including neurologic signs as well as impaired gastrointestinal motility, leading to proventricular dilatation. It occurs worldwide in captive psittacine populations and threatens private bird collections, zoological gardens and rehabilitation projects of endangered species. In contrast, only little is known about the pathogenic roles of passerine and waterbird bornaviruses. This comprehensive review summarizes the current knowledge on avian bornavirus infections, including their taxonomy, pathogenesis of associated diseases, epidemiology, diagnostic strategies and recent developments on prophylactic and therapeutic countermeasures.

Моделирование миелоабляционной цитостатической терапии циклофосфаном сопровождается желудочно-кишечным стазом у крыс

Cyclophosphamide is used for the treatment of lymphoma, leukaemia, some solid tumours, and autoimmune disorders. When carrying out myeloablative cytostatic therapy, the doses of cyclophosphamide are prescribed, which cause irreversible pancytopenia. Early toxic effects of such doses are manifested by asthenic and emetic syndromes, limiting the treatment tolerance. Administration of cyclophosphamide in a dose of ≥ 600 mg/kg is accompanied by hyperammonaemia and symptoms, specific to the acute ammonium salt intoxication. Endotoxemia, resulting from the increase in the intestinal barrier permeability due to the impaired gastrointestinal motility, is considered the possible mechanism underlying these phenomena. The study was aimed to test this hypothesis. Radiographic assessment of the rat gastrointestinal peristalsis was performed within 25 h after administration of cyclophosphamide in a dose of 1000 mg/kg, which was equivalent to myeloablative dose for humans. Intraperitoneal, subcutaneous or intragastric administration of cyclophosphamide slowed down the gastrointestinal transit of bariumsulfate. In the case of subcutaneous cyclophosphamide injection, a moderate effect was observed. In the case of cyclophosphamide administered by gavage, the effect was manifested by a complete halt of transit. Thus, modelling myeloablative cytostatic therapy with cyclophosphamide in rats is associated with gastrointestinal stasis. The changes reported may promote the entry of the gut microbial products into the bloodstream and ensuing endotoxemia.

Патогенетические аспекты нарушений метаболома кишечника и эндотоксемии у лиц высокого кардио-метаболического риска

Aim. To study the relationship between the functional activity of the intestinal microbiota and endotoxemia with impaired gastrointestinal motility and excessive bacterial growth in patients with metabolic syndrome (MS). Materials and methods. 64 patients with MS were examined. Comprehensive examination included collection of complaints, anamnesis of the disease, questionnaires on actual nutrition, clinical examination, anthropometric study, assessment of indicators of carbohydrate and lipid metabolism, a marker of systemic inflammatory response of the body (CRP) in the blood. Determination of the blood endotoxin level, quantitative and qualitative composition of the parietal microbiota of the small intestine was carried out on an Agilent gas chromatograph with mass selective and flame ionization detectors (Agilent Technologies, USA). A chromatographic study of metabolites of microorganisms (SCFA) in coprofiltrate was carried out. The motor function of the gastrointestinal tract (GIT) was studied using peripheral electrogastroenterocolography using a Gastroscan-GEM device. The control group consisted of 30 apparently healthy individuals aged from 18 to 62 years. Statistical processing of the obtained results was carried out using the Statistica 6.1 software. Results. In 82.9% of the examined patients with MS, clinical signs of intestinal lesions were noted. The electrical activity of the MC departments in the postprandial period was low in 70% of patients. It was found that with MS with a decrease in the daily consumption of dietary fiber in the composition of the diet, the BMI value increases, the energy value of the diet and the use of simple carbohydrates increase. During the analysis of the main biochemical blood constants, it was possible to establish that MS is accompanied by a violation of carbohydrate and lipid metabolism. The CRP level was statistically significantly different from the CG in MS regardless of the degree of excess body weight, while a direct correlation of moderate strength was established between the BMI values and the CRP level. During the chromatographic study of metabolites of microorganisms in feces, it was possible to establish statistically significant differences in the profile and concentration of short-chain fatty acids (SCFA) of persons with MS, both in comparison with CG and in comparison with groups with different BMI values. According to the results of the study of the blood endotoxin level in patients with MS, its significant increase was revealed, more than 6 times, in comparison with the CG. The electrical activity of the colon on an empty stomach was unchanged, but decreased after a food load. Discoordination of motility is observed between the small intestine (SI) and the large intestine, aggravated after food stimulation. A significant decrease in the rhythm of contractions is observed at the frequencies of the jejunum, ileum, and colon both on an empty stomach and in the postprandial period, which indicates a weakening of propulsive bowel contractions in patients with MS. In patients with MS, excessive bacterial growth in MC is observed mainly due to opportunistic microbiota strains. Correlation analysis showed a moderate negative relationship between endotoxin levels and MC electrical activity, between endotoxin levels and the colon-to-ileum ratio. Conclusion. The study of the level of endotoxin, intestinal microbiota metabolites (SCFA), indicators of bacterial overgrowth, motor-evacuation functions of the gastrointestinal tract made it possible to identify important pathogenetic patterns concerning the contributing role of the latter in the development of endotoxemia and intestinal metabolic disorders in patients with MS.

An Unusual Case of Polyautoimmunity with Concomitant Presentation of Postural Tachycardia Syndrome, Antiphospholipid Syndrome and Hashimoto’s Thyroiditis

Introduction: Postural tachycardia syndrome (POTS) is a chronic form of autonomic dysfunction characterized by symptoms of orthostatic intolerance, often accompanied by sudomotor dysfunction and gastrointestinal dysmotility. In a subgroup of patients with POTS, autoantibodies against adrenergic or cholinergic receptors suggest an immune-mediated etiology. Antiphospholipid syndrome (APS) is a hypercoagulative autoimmune disorder associated with anti-phospholipid-antibodies that causes arterial and venous thromboses. Concurrent occurrence of APS and immune-mediated POTS is rare. Methods and Results: Here, we report a 28-year-old female that experiences symptoms of orthostatic intolerance, vasovagal syncopes, gastrointestinal dysmotility and sudomotor dysfunction. She fulfills the formal diagnostic criteria of POTS showing a heart rate increment of ≥30 beats per minute (bpm) within 10 m of head-up tilt in the absence of orthostatic hypotension, accompanied by symptoms of orthostatic intolerance. The thermoregulatory sweat test reveals severe patchy anhidrotic areas. Gastric emptying scintigraphy shows an impaired gastrointestinal motility. Plasma norepinephrine levels and a skin biopsy appear normal. Finally, serological persistence of anti-alpha-1-adrenergic autoantibodies suggest an immune-mediated pathogenesis. Several years after initial presentation of POTS symptoms, the patient develops APS with recurrent venous emboli and persistent anti-phospholipid-antibodies. Recently the patient is diagnosed with Hashimoto’s thyroiditis (HT) expressing high levels of thyroid-stimulating hormone and high titers of anti-thyroid antibodies. Conclusion: To our knowledge, this is the first report of consecutive immune-mediated POTS, APS and HT in a young woman, possibly displaying a unique combination of three disorders of autoimmune etiology.

Evaluation of peripheral amyloid neuropathy

Symptoms of peripheral nervous system (PNS) damage are common clinical manifestations of systemic amyloidosis. Peripheral amyloid neuropathy is characterized by a progressive course, leading to the disability of patients; however, the current possibilities of pathogenetic therapy make the early diagnosis of amyloid neuropathy particularly urgent.Objective: to evaluate the informative value of laser confocal microscopy (LCM) of the cornea in diagnosing small fiber neuropathy of peripheral nerves in patients with systemic amyloidosis.Patients and methods. The study included nine patients (three men and six women) with morphologically confirmed primary amyloidosis (ALamyloidosis) and 12 patients (three men and nine women) with hereditary transthyretin amyloidosis (TTR-amyloidosis) verified by genetic and morphological methods. At baseline, the mean age of patients with AL-amyloidosis was 60.6±10.7 years, with hereditary TTR-amyloidosis – 57.1±13.1 years. According to the history of the disease in AL-amyloidosis, the mean duration of clinical symptoms was 2.7±1.4 years, with TTR-amyloidosis – 5.5±3.6 years. 20 age- and sex-adjusted healthy volunteers were included in the control group. All patients underwent a clinical neurological examination with an assessment of the severity of neuropathy according to the Neuropathy Impairment Score (NIS); 21 patients with systemic amyloidosis and all volunteers of the control group underwent LCM of the corneal nerve fibers (CNF). The coefficients of anisotropy (КΔL) and orientation symmetry (Ksym) of the CNF were calculated to assess the severity of damage to the corneal nerves.Results and discussion. Clinical neurological examination in patients with AL-amyloidosis revealed polyneuropathic syndrome (45%), tunnel syndrome (22%), their combination (22%), and autonomic dysfunction in the form of orthostatic hypotension and impaired motility of the gastrointestinal tract (GI tract; 56%). Symptoms in patients with TTR-amyloidosis were characterized by a combination of tunnel neuropathy and sensory-motor polyneuropathy (50%), distal symmetric polyneuropathy (42%). Frequent symptoms of PNS damage in systemic amyloidosis include autonomic neuropathy (56% – in AL-amyloidosis, 92% – in TTR-amyloidosis) presenting with orthostatic hypotension, impaired gastrointestinal motility, hypohidrosis, and dysuria. The mean NIS score, which characterizes the severity of somatic neuropathy, was significantly higher in patients with TTR-amyloidosis than AL-amyloidosis (p&lt;0.02). LCM of the cornea showed disturbances in the course and structure of the corneal nerve fibers in all examined patients with systemic amyloidosis. The mean anisotropy coefficient values were lower in patients with systemic amyloidosis than in the control group. There were no significant differences in the AL- and TTR-amyloidosis groups. An inverse correlation of average strength between the values of the anisotropy coefficient and NIS was revealed (r=-0.6; p=0.04) in the group of patients with TTR-amyloidosis.Conclusion. Clinical polymorphism of peripheral somatic and autonomic nervous systems lesions is typical for patients with systemic amyloidosis. LCM of the cornea is informative in the diagnosis of small fibers neuropathy of peripheral nerves in systemic amyloidosis; however, it cannot establish the nosology of neuropathy.

Impact of morphine dose on ticagrelor uptake and platelet inhibition in patients with ST-segment elevation myocardial infarction – A substudy from the prospective randomized MOVEMENT trial

BackgroundMorphine delays ticagrelor effect in ST-segment elevation myocardial infarction (STEMI) patients, likely due to impaired gastrointestinal motility. The aim was to evaluate if the morphine dose impacts ticagrelor effect in STEMI patients presenting for percutaneous coronary intervention. MethodsThe patient cohort was divided into quartiles based on morphine dose (mg/kg). Platelet inhibition was measured with vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and high on-treatment platelet reactivity (HPR) was defined as ≥50% PRI. Blood samples for analyses of VASP PRI and plasma concentrations of morphine, ticagrelor, and AR-C124910XX were taken at baseline (arrival in the catherization lab) and one and 2 h later. The primary endpoint was PRI difference between the highest morphine dose quartile compared with the lowest morphine dose quartile 2 h after study inclusion. ResultsA total of 80 STEMI patients treated with morphine and ticagrelor were included in the study. The time from ticagrelor administration to randomization did not differ significantly between the different morphine dose quartiles, with an overall median of 44 min (interquartile range, IQR: 35–57 min). The primary outcome variable PRI at 2 h after study inclusion was significantly higher in patients in quartile 4 compared with quartile 1 (61.7% [42.4–91.2] vs. 26.6% [9.17–73.6], p = 0.024). Ticagrelor concentrations were significantly lower in both quartile 3 and 4 compared with quartile 1 at all the three timepoints. ConclusionSTEMI patients with higher weight-based morphine doses had significantly lower uptake and antiplatelet effect after a 180 mg loading dose ticagrelor.

Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects.

The breakpoint cluster region (BCR) is a protein that originally forms a fusion protein with c-Abl tyrosine kinase and induces leukemia. Researchers have shown that BCR is enriched in the central nervous system and may contribute to neurological disorders. We aimed to investigate the physiological function of BCR in neural development in the gastrointestinal (GI) tract and brain. Whole-exome sequencing was used to screen for mutations in the BCR. Bcr knockout mice (Bcr-/- , ΔExon 2-22) were generated using the CRISPR/Cas9system. Transit of carmine red dye and glass bead expulsion assays were used to record total and proximal GI transit and distal colonic transit. In an infant with pediatric intestinal pseudo-obstruction, we found a heterozygous de novo mutation (NM_004327.3:c.3072+1G>A) in BCR. Bcr deficiency mice (Bcr-/- ) exhibited growth retardation and impaired gastrointestinal motility. Bcr-/- mice had a prolonged average total GI transit time with increased distal colonic transit and proximal GI transit in isolation. Morphology analysis indicated that Bcr-/- mice had a less number of neurons in the submucosal plexus and myenteric plexus. Bcr-/- mice exhibited apparent structural defects in the brain, particularly in the cortex. Additionally, Bcr- depletion in the mouse cortex altered the expression of Ras homologous (Rho) family small GTPases. BCR mutations are associated with intestinal obstruction in children. Loss of Bcr can cause intestinal dysmotility and brain developmental defects may via regulation of Rho GTPases.

Paraneoplastic vs. non-paraneoplastic anti-Hu associated dysmotility: a case series and literature review.

This work aimed to report the demographic and clinical characteristics of two new cases with non-paraneoplastic anti-Hu-associated gut motility impairment, and perform a thorough revision covering anti-Hu-associated paraneoplastic (PGID) and non-paraneoplastic (nPGID) gastrointestinal dysmotility. Several case series have clearly established a relationship between certain type of cancers, the development of circulating anti-Hu antibodies, and the concomitant usually severe gastrointestinal dysmotility; in contrast, a few studies focused on anti-Hu-associated nPGID. We searched for studies regarding anti-Hu-associated gastrointestinal manifestations and extracted data concerning clinical characteristics of patients, including specific demographic, oncological, neurological, gastrointestinal, histological, and treatment response features. Forty-nine articles with a total of 59 cases of anti-Hu-associated gastrointestinal dysmotility were analyzed. The patients' age at symptom onset significantly differed between PGID and nPGID (median 61 vs 31years, p < 0.001). Most cancers (95%) in PGID were detected within 24months from the beginning of gastrointestinal symptoms. The impairment of gastrointestinal motility was generalized (i.e., involving the whole gut) in 59.3% of patients, with no significant differences between PGID vs nPGID group. nPGID patients showed a better response to immunomodulatory/immunosuppressive treatment and a longer life expectancy. Anti-Hu-associated gastrointestinal dysmotility covers a wide clinical spectrum. Patients with otherwise unexplained gastrointestinal dysmotility, especially when associated with other neurological symptoms, should be tested for anti-Hu antibodies regardless age of onset and disease duration. Compared to PGID, nPGID occurs in younger patients with a long duration of disease.

A143 ACUTE ESOPHAGEAL NECROSIS: A COMPLICATION OF DIABETIC KETOACIDOSIS

Abstract Background Acute esophageal necrosis (AEN) is a rare entity associated with diabetic ketoacidosis (DKA). The pathogenesis is thought to be linked to low volume state, microvascular disease, impaired gastric and esophageal motility increasing acid reflex, all rendering the esophagus prone to injury. Aims We report a case of AEN as a complication of DKA in a patient without any overt gastrointestinal bleeding (GIB), along with a literature review. Methods Keywords “esophageal necrosis” and “diabetic ketoacidosis” were used in MEDLINE and BASE to retrieve English articles reporting cases of AEN in DKA. Results A 63 year old male with history of hypertension, dyslipidemia and non-insulin dependent diabetes mellitus presented to Emergency with 5 day history of severe epigastric pain, dysphagia to solids and liquids, nausea and vomiting (without any overt GIB). Most recent HbA1c was 8.4%. His diabetes was managed with metformin and semaglutide. Bloodwork revealed a hemoglobin of 165g/L and leukocytes of 17.9x109/L. Chemistries showed an anion gap of 25 with bicarbonate of 5mmol/L. Venous blood gas showed acidemia (pH=7.02). B-hydroxybutyrate level was 10.2mmol/L. Urinalysis was negative for leukocytes or nitrites. An abdominal CT ruled out bowel obstruction or intra-abdominal infection/abscess as the source of his discomfort but demonstrated circumferential wall thickening of the distal esophagus. No other triggers were found for this patient’s DKA except perhaps a recently started ketogenic diet. After resolution of DKA, he continued to experience severe epigastric pain, reflux symptoms, and dysphagia. An esophagogastroduodenoscopy (EGD) was performed, which showed AEN with circumferential black, necrotic inflammatory changes in the mid to distal esophagus. Erosions were seen in the body and antrum of the stomach, and multiple clean based ulcers were seen in the duodenum. Patient was started on an insulin regimen prior to discharge. Review of literature shows a total of 13 cases of AEN in DKA, with only one case where the patient did not present with any clinical bleeding. Risk factors for AEN include, hypertension, diabetes mellitus, malignancy, male gender, older age, chronic kidney disease, alcohol abuse and cardiovascular disease. While no medications have been linked to AEN, our patient was recently started on semiglutide, which has been implicated in impaired gastric emptying and increased GERD symptoms. This may further explain why the patient developed AEN. Conclusions AEN is a rare entity, especially in the context of DKA. Usually patients present with overt GIB; however, on occasion dysphagia, nausea, and vomiting can be the predominant symptoms. Hence, the threshold to perform EGD in patients with DKA should be low, given their low volume state and potentially impaired gastrointestinal motility due to microvascular disease or medications, putting them at higher risk for AEN. Funding Agencies None

Clostridioides difficile Infection in Chronic Kidney Disease-An Overview for Clinicians.

Increased incidence of Clostridioides difficile infection (CDI), occurrence of severe and complicated CDI, and more frequent occurrence of drug-resistant, recurrent or non-hospital CDI has become a worldwide clinical problem. CDI is more common in patients with chronic kidney disease (CKD) than in the general population. CDI seems to be associated with frequent hospitalization, frequently used antibiotic therapy, dysbiosis, and abnormalities of the immune system observed in CKD patients. Dysbiosis is a common disorder found in CKD patients. It may be related to insufficient fiber content in the diet, reduced amount of consumed fluids and often reduced physical activity, constipation, impaired gastrointestinal motility, multidrug pharmacotherapy, and uremic milieu in CKD stage 5. In patients with CKD the clinical manifestations of CDI are similar to the general population; however, more frequent recurrence of CDI and higher prevalence of severe CDI are reported. Moreover, the increase in CDI related mortality is observed more in CKD patients than in the general population. The aim of this review paper is to summarize the current knowledge concerning the epidemiology, pathogenesis, clinical picture, and prevention and treatment in CKD patients.