Identification of Genetic Susceptibility Factors Associated with Canine Gastric Dilatation-Volvulus.

Canine gastric dilatation-volvulus (GDV) is a common life-threatening condition occurring primarily in large and giant breeds with a 3.9% to 36.7% lifetime risk. The genetic correlates of GDV have not previously been systematically explored. We undertook an inter-breed genome-wide association analysis (GWAS) of 253 dogs from ten breeds including 106 healthy dogs and 147 dogs with at least one GDV episode. SNP array genotyping followed by imputation was conducted on 241 samples to identify GDV-associated single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs). A subset of 33 dogs (15 healthy dogs and 18 GDV patients from the three most represented breeds) was characterized by whole genome sequencing (WGS). After genome-wide Bonferroni correction, we identified a significant putatively protective intergenic SNP (rs851737064) across all breeds. The signal was most significant in Collies, German Shorthaired Pointers, and Great Danes. Subsequent focused analysis across these three breeds identified 12 significant additional putatively protective or deleterious SNPs. Notable significant SNPs included those occurring in genes involved in gastric tone and motility including VHL, NALCN, and PRKCZ. These data provide important new clues to canine GDV risk factors and facilitate generation of hypotheses regarding the genetic and molecular underpinnings this syndrome.

Autoimmune autonomic ganglionopathy associated with Sjögren's syndrome presenting with recurrent abdominal distension.

A 65-year-old woman with Sjögren's syndrome presented with recurrent abdominal distension, constipation, weight loss, orthostatic dizziness, loss of sweating and incomplete emptying of the bladder. Gastrointestinal dilatation but no evidence of malignancy or obstruction was found on CT of the abdomen, oesophagogastroduodenoscopy or colonoscopy. Postvoiding residual urine volume was increased. Antiganglionic acetylcholine receptor antibody was positive. We diagnosed as autoimmune autonomic ganglionopathy. The patient responded to corticosteroid treatment. One year after treatment, she continued to have mild gastrointestinal symptoms, but overall condition was stable without further intervention.

Case report of gastric distension due to superior mesenteric artery syndrome mimicking hollow viscus perforation: Considerations in critical care ultrasound.

RATIONALE: Critical care ultrasound identifies the signs of free intraperitoneal air and echogenic free fluid always indicates hollow viscus perforation (HVP) and needs immediate surgical interventions. However, in rare cases, these classic signs may also mislead proper clinical decisions. We report perforated viscus associated large peritoneal effusion with initial critical care ultrasound findings, whereas computed tomography (CT) examination confirmed a giant stomach due to superior mesenteric artery syndrome (SMAS). PATIENT CONCERNS: A 70-year-old man was admitted to our emergency department with a complaint of recurrent vomiting with coffee ground emesis for 15 hours and worsen with hypotension for 6 hours. During gastric tube placement, the sudden cardiac arrest occurred. With 22 minutes resuscitation, sinus rhythm was restored. DIAGNOSES: Quick ultrasound screen showed large echogenic fluid distributed in the whole abdomen. Diagnostic paracentesis collected "unclotted blood" and combined with a past history of duodenal ulcer, HVP was highly suspected. However, surgical intervention was not performed immediately as unstable vital signs and unfavorable coma states. After adequate resuscitation in intensive care unit, the patient was transferred to perform enhanced CT. Surprisingly, there was no evidence of HVP. Instead, CT showed a giant stomach possibly explained by SMAS. INTERVENTIONS: Continuous gastric decompression was performed and 3100 mL coffee ground content was drainage within 24 hours of admission. OUTCOMES: Abdominal distension was significantly relieved with improved vital signs. However, as the poor neurological outcome, family members abandon further treatment, and the patient died. LESSONS: SMAS is a rare disorder, characterized by small bowel obstruction and severe gastric distension. Nasogastric tube insertion should be aware to protect airway against aspiration. Caution should be utilized to avoid over interpretation of ultrasonography findings on this condition.

Evaluation of echocardiography and cardiac biomarker concentrations in dogs with gastric dilatation volvulus.

OBJECTIVE: To assess abnormalities in concentrations of cardiac troponin I (cTnI), lactate, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in relation to arrhythmias, echocardiographic measurements, and survival in dogs with gastric dilatation volvulus (GDV). DESIGN: Prospective observational study. SETTING: University hospital. ANIMALS: Twenty-two dogs with naturally occurring GDV. SAMPLES: Concentrations of cTnI, plasma lactate, and NT-proBNP were recorded at presentation to the emergency room, the time closest to echocardiography, and the highest recorded concentrations during hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cardiac rhythms were categorized on a 0-4 scale (0 = no ventricular premature complexes [VPCs], 1 = single VPCs, 2 = bigeminy or trigeminy, 3 = couplets or triplets, and 4 = R-on-T phenomenon or ventricular tachycardia). Echocardiography was performed 6-18 hours postoperatively. Fifteen dogs had ventricular arrhythmias during hospitalization (Grade 1 [n = 9], Grade 4 [n = 6]). The highest recorded cTnI concentration was significantly higher in the dogs with Grade 4 (P = 0.002) or Grade 1 (P = 0.001) arrhythmias compared to dogs without arrhythmias. Plasma lactate was significantly correlated with left ventricular internal diameter in diastole (r = -0.52, P = 0.01) and systole (r = -0.57, P = 0.006), left ventricular free wall in diastole (LWDd, r = 0.59, P = 0.004), and interventricular septal thickness in diastole (IVDs, r = 0.65, P = 0.001). Dogs that did not survive to 1 week postdischarge (3/22) had a significantly thicker LVWd (P = 0.04) and IVSd (P = 0.05), and received significantly less fluids in the first 24 (P = 0.02) and 48 hours (P = 0.03) of hospitalization. CONCLUSIONS: Concentrations of cTnI and NT-proBNP increased during hospitalization, but only cTnI concentrations were significantly higher in dogs with a higher arrhythmia grade. Additional research on the potential role of serial measurement of biomarkers in dogs with GDV is warranted.

Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone-responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation.

Nesfatin-1, a recently discovered neuropeptide involved in satiety. Recent studies have revealed that central nesfatin-1 inhibits gastric emptying and gastric acid secretion, though the mechanisms involved in these processes are not known. We aim to explore the effects of nesfatin-1 on a population of gastric distension (GD)-sensitive neurons in the lateral hypothalamus (LHA), gastric motility, and gastric secretion and the role for an arcuate nucleus (Arc)-LHA neural pathway in these processes. Single unit extracellular discharge recordings were made in of LHA. Further, gastric motility and gastric secretion in rats were monitored. Retrograde tracing and fluorescent immunohistochemical staining were used to explore nesfatin-1 neuron projection. The results revealed that administration of nesfatin-1 to the LHA or electric stimulation of the Arc could alter the neuronal activity of melanin-concentrating hormone (MCH)-responsive, GD-responsive neurons in LHA, which could be blocked by pretreatment with MCH receptor-1 antagonist PMC-3881-PI or weakened by pretreatment of a nesfatin-1 antibody in LHA. Administration of nesfatin-1 into LHA could inhibit gastric motility and gastric secretion, and these effects could be enhanced by administration of PMC-3881-PI. Electrical stimulation of Arc promoted the gastric motility and gastric secretion. Nesfatin-1 antibody or PMC-3881-PI pretreatment to LHA had no effect on Arc stimulation-induced gastric motility, but these pretreatments did alter Arc stimulation-induced effects on gastric secretion. Our findings suggest that nesfatin-1 signaling in LHA participates in the regulation of efferent information from the gastrointestinal tract and gastric secretion which also involve MCH signaling. Further, they show that a nesfatin-1-positive Arc to LHA pathway is critical for these effects.

Impact of electrical stimulation of the stomach on gastric distension-induced emesis in the musk shrew.

BACKGROUND: Gastric electrical stimulation (GES) is implicated as a potential therapy for difficult-to-treat nausea and vomiting; however, there is a lack of insight into the mechanisms responsible for these effects. This study tested the relationship between acute GES and emesis in musk shrews, an established emetic model system. METHODS: Urethane-anesthetized shrews were used to record emetic responses (monitoring intra-tracheal pressure and esophageal contractions), respiration rate, heart rate variability, blood pressure, and gastrointestinal electromyograms. We investigated the effects of acute GES pulse duration (0.3, 1, 5, and 10 ms), current amplitude (0.5, 1, and 2 mA), pulse frequency (8, 15, 30, and 60 Hz), and electrode placement (antrum, body, and fundus) on emesis induced by gastric stretch, using a balloon. KEY RESULTS: There were four outcomes: (i) GES did not modify the effects of gastric stretch-induced emesis; (ii) GES produced emesis, depending on the stimulation parameters, but was less effective than gastric stretch; (iii) other physiological changes were closely associated with emesis and could be related to a sub-threshold activation of the emetic system, including suppression of breathing and rise in blood pressure; and (iv) a control experiment showed that 8-OH-DPAT, a reported 5-HT1A receptor agonist that acts centrally as an antiemetic, blocked gastric stretch-induced emesis. CONCLUSIONS AND INFERENCES: These results do not support an antiemetic effect of acute GES on gastric distension-induced emesis within the range of conditions tested, but further evaluation should focus on a broader range of emetic stimuli and GES stimulation parameters.

Orexin-A affects gastric distention sensitive neurons in the hippocampus and gastric motility and regulation by the perifornical area in rats.

Orexin-A is mainly produced in the lateral hypothalamus (LHA) and the perifornical area (PeF). Here, we aim to elucidate the effects of orexin-A in the hippocampus (Hi) on gastric distention (GD)-sensitive neurons and gastric motility, and potential regulation mechanisms by the PeF. Retrograde tracing and fluorescent-immunohistochemical staining were used to determine orexin-A neuronal projections. Single unit discharges in the Hi were recorded extracellularly and gastric motility in conscious rats was monitored during administration of orexin-A to the Hi or electrical stimulation of the PeF. Orexin-A administration to the Hi excited most of the GD-excitatory (GD-E) neurons and GD-inhibitory (GD-I) neurons, and increased gastric motility in a dose-dependent manner. All of effects induced by orexin-A could be partly blocked by pretreatment with orexin-A antagonist, SB-334867. Electrical stimulation of the PeF excited the majority of the orexin-A-responsive GD neurons in the Hi and promoted gastric motility. Additionally, pretreatment with SB-334867 in the Hi increased the firing rate of GDI and GDE neurons following electrical stimulation of the PeF. These findings suggest that orexin-A could regulate activities of GD-sensitive neurons and gastric motility. Furthermore, the PeF may be involved in this regulatory pathway.

[Effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention in LHA-FN circuit in rats].

OBJECTIVE: To observe the regulation effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention (GD) in lateral hypothalamus area (LHA) and fastigial nuclear (FN) circuit, and to explore the central mechanism of acupuncture for gastric function. METHODS: A total of 101 rats were randomly assigned into a LHA group (50 rats) and a FN group (51 rats). Gastric distension surgery was performed in all the rats. According to the stereotaxic atlas of rat brain, the LHA and FN were located, followed by craniotomy. The endocranium was removed to exposure brain tissue, and warm paraffin oil was used to prevent desiccation. The electrical activities of neurons were probed by glass microelectrode to perform extracellular recording. The electrical activities of GD sensitive neurons in LHA were observed in LHA group, while those in FN were observed in FN group. One min after the electrical signal of neurons was recorded, acupuncture was given at left "Zusanli" (ST 36) with mild reinforcing and attenuating technique, 120~180 times/min for 1 min. The effects of acupuncture at "Zusanli" (ST 36) on spontaneous discharge of GD sensitive neurons in LHA and FN were observed. RESULTS: (1) Totally 54 LHA neurons of spontaneous discharge in LHA group and 85 FN neurons in FN group were recorded. GD-excitatory (GD-E) neurons were mainly in the LHA group (46.3%) and GD-non-response (GD-N) neurons were mainly in the FN group (54.12%). The average discharge frequency of GD-N neurons was (39.03±14.91) spikes/s, that of GD-E neurons was (19.67±12.08) spikes/s, and that of GD-inhibitory (GD-I) neurons was (28.76±7.26) spikes/s, which were statistically different from those before GD (all P<0.01). (2) In LHA group, acupuncture excited the activity of GD-E neurons, and inhibited the activity of GD-I neurons (P<0.05); in FN group, acupuncture excited the activity of GD-I neurons, but showed no effect on GD-E neurons (P<0.01). CONCLUSIONS: The signal of GD and acupuncture could converge in LHA and FN; acupuncture presented different regulation effects on identical type of GD-sensitive neurons in different nuclear groups; LHA-FN circuit might participate in central integration mechanism of acupuncture on gastric function.

The relationship between gastrointestinal motility and gastric dilatation-volvulus in dogs.

Gastric dilatation-volvulus (GDV) is a devastating disease that most commonly affects large and giant-breed dogs. Though a number of risk factors have been associated with the development of GDV, the etiology of GDV remains unclear. Abnormal gastric motility patterns and delayed gastric emptying have been previously described in dogs following GDV. Work evaluating the effects of gastropexy procedures and changes to gastric motility after experimental GDV has not found the same changes as those found in dogs with naturally occurring GDV. Although the role of abnormal gastric motility in dogs with GDV will need to be clarified with additional research, such study is likely to be facilitated by improved access to and development of noninvasive measurement techniques for the evaluation of gastric emptying and other motility parameters. In particular, the availability of Food and Drug Administration-approved wireless motility devices for the evaluation of gastrointestinal motility is particularly promising in the study of GDV and other functional gastrointestinal diseases of large and giant-breed dogs.

Cardiovascular and systemic effects of gastric dilatation and volvulus in dogs.

Gastric dilatation and volvulus (GDV) is a common emergency condition in large and giant breed dogs that is associated with high morbidity and mortality. Dogs with GDV classically fulfill the criteria for the systemic inflammatory response syndrome (SIRS) and can go on to develop multiple organ dysfunction syndrome (MODS). Previously reported organ dysfunctions in dogs with GDV include cardiovascular, respiratory, gastrointestinal, coagulation and renal dysfunction. Cardiovascular manifestations of GDV include shock, cardiac arrhythmias and myocardial dysfunction. Respiratory dysfunction is also multifactorial, with contributory factors including decreased respiratory excursion due to gastric dilatation, decreased pulmonary perfusion and aspiration pneumonia. Gastrointestinal dysfunction includes gastric necrosis and post-operative gastrointestinal upset such as regurgitation, vomiting, and ileus. Coagulation dysfunction is another common feature of MODS in dogs with GDV. Disseminated intravascular coagulation can occur, putting them at risk of complications associated with thrombosis in the early hypercoagulable state and hemorrhage in the subsequent hypocoagulable state. Acute kidney injury, acid-base and electrolyte disturbances are also reported in dogs with GDV. Understanding the potential for systemic effects of GDV allows the clinician to monitor patients astutely and detect such complications early, facilitating early intervention to maximize the chance of successful management.

Effects of exogenous nesfatin-1 on gastric distention-sensitive neurons in the central nucleus of the amygdala and gastric motility in rats.

Nesfatin-1 is a novel brain-gut peptide identified in several brain regions associated with feeding and gastrointestinal function. Our study explored the effects of nesfatin-1 in the central nucleus of the amygdala (CNA) on the activity of gastric distention (GD)-sensitive neurons, gastric motility, and the potential regulation mechanisms by the dorsal motor nucleus of the vagus (DMV). Following retrograde injection of fluorogold (FG) into the DMV, we found that nesfatin-1/FG dual-labeled neurons were detected in the CNA, which indicates that some of the nesfatin-1-immunoreactive neurons arising from the DMV may project to the CNA. Single unit discharges in the CNA were recorded extracellularly, and gastric motility was monitored by implantation of a force transducer into the stomach of conscious rats. These results showed that nesfatin-1 administration to the CNA excited most of the GD-excitatory neurons, inhibited GD-inhibitory neurons, and dose-dependently reduced gastric motility. All of the above effects induced by nesfatin-1 could be partially blocked by pretreatment with the melanocortin 3/4 receptors antagonist, SHU9119. Electrical stimulation of the DMV excited the majority of the nesfatin-1-responsive GD neurons in the CNA. Additionally, pretreatment with an anti-NUCB2/nesfatin-1 antibody in the CNA increased the firing rate of nesfatin-1-responsive GD-inhibitory neurons but decreased the firing rate in nesfatin-1-responsive GD-excitatory neurons following electrical stimulation of the DMV. Finally, a subdiaphragmatic vagotomy eliminated the diminished gastric motility induced by nesfatin-1 injection. Taken together, these findings suggest that nesfatin-1 regulates the activity of GD-sensitive neurons and gastric motility via the melanocortin pathway in the CNA. Furthermore, the DMV may be involved in this regulatory pathway.

13C-sodium acetate breath test for evaluation of gastric emptying times in dogs with gastric dilatation-volvulus.

OBJECTIVE: The aim of the study was to assess solid phase gastric emptying via non-invasive 13C-sodium acetate breath test in large breed dogs with or without gastric dilatation-volvulus (GDV). MATERIAL AND METHODS: Dogs were recruited into one of the following groups: group 1 = healthy large breed dogs with no history of GDV, group 2 = dogs that underwent elective abdominal surgery for reasons unrelated to the gastrointestinal tract, and group 3 = dogs that underwent laparotomy and gastropexy to correct GDV. The dogs were fed a test meal containing 100 mg 13C-sodium acetate (for group 2 and 3, this was < 48 hours post-operatively). Breath samples were obtained at baseline and every 30 minutes for 3 hours, then every hour for a total of 7 hours. 12CO2/13CO2 ratio was measured for each breath sample via non-dispersive infrared spectroscopy and 25%, 50% and 75% gastric emptying times were calculated and compared between groups. RESULTS: Gastric emptying times were significantly prolonged in dogs undergoing surgery (group 2) compared to group 1 and 3. Also, gastric emptying times of dogs with GDV were significantly prolonged compared to controls, but not to the same extent as dogs in group 2. CONCLUSION AND CLINICAL SIGNIFICANCE: There was a significant effect of abdominal surgery on gastric emptying times. Surprisingly, dogs after GDV surgery and gastropexy had shorter gastric emptying times than dogs undergoing laparotomy for reasons other than GDV, but still prolonged compared to healthy controls. The reason for these differences requires further study.