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Abstract Existing gastrointestinal (GI) diagnostic tools are unable to non-invasively monitor mucosal tight junction integrity in vivo beyond the esophagus. In the GI tract, local inflammatory processes induce alterations in tight junction proteins, enhancing paracellular ion permeability. Although transepithelial electrical resistance (TEER) may be used in the laboratory to assess mucosal barrier integrity, there are no existing methodologies for characterizing tight junction dilation in vivo. Addressing this technology gap, intraluminal bioimpedance sensing may be employed as a localized, non-invasive surrogate to TEER electrodes used in cell cultures. Thus far, bioimpedance has only been implemented in esophagogastroduodenoscopy (EGD) due to the need for external electronics connections. In this work, we develop a novel, noise-resilient Bluetooth-enabled ingestible device for the continuous, non-invasive measurement of intestinal mucosal “leakiness.” As a proof-of-concept, we validate wireless impedance readout on excised porcine tissues in motion. Through an animal study, we demonstrate how the device exhibits altered impedance response to tight junction dilation induced on mice colonic tissue through calcium-chelator exposure. Device measurements are validated using standard benchtop methods for assessing mucosal permeability.

Summary: Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from the gastric tissue of 20 subjects. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.

Introduction The use of balloon guide catheters (BGC) during endovascular thrombectomy (EVT) has been suggested to lower the risk of distal embolization and improve first pass revascularization rates in patients with acute ischemic stroke. However, a recent large randomized controlled trial suggests there is no significant difference in initial and final revascularization scores among EVT performed with a BGC versus without. We assessed the influence of BGC use during EVT on first pass (FP) and revascularization (RV) success in a historical database from a multi‐hospital health system. Methods Patients with anterior circulation large vessel occlusion undergoing EVT with stent‐retriever or aspiration between 2012 and 2018 at three Kaiser Permanente Southern California (KPSC) region hospitals were identified from the database. BGC use was determined through manual chart review. A chi‐squared test compared the relationship of BGC use with the primary outcomes. The primary outcomes were FP and RV success using a dichotomized TICI score of 2b or greater. Results 218 patients were included in the study. BGC was used in 35/218 (16%) of patients. There was no significant difference in age (p = 0.65), gender (p = 0.92), presenting NIHSS (p = 0.45), hypertension (p = 0.66), diabetes (p = 0.85), atrial fibrillation (p = 0.36), serum glucose (p = 0.43), or pre‐EVT TPA administration (p = 0.36). Among EVT with BGC, FP success was 13/35 (37%) and EVT without BGC had a FP success of 76/183 (42%); p = 0.71. Successful final RV with BGC occurred in 30/35 (86%) while EVT without BGC had a successful final RV of 162/183 (89%); p = 0.78. Because BGC use occurred only with stent‐retriever treatment, subgroup analysis was performed comparing the BGC group (N = 35) with the non‐BGC stent‐retriever (N = 88) and aspiration thrombectomy (N = 95) groups. There was no significant difference in FP (p = 0.88) or RV success (p = 0.42) between the BGC (37% FP and 86% RV), non‐BGC stent‐retriever (42% FP and 92% RV), and aspiration thrombectomy groups (41% FP and 86% RV). Conclusions Among our population, BGC use was not associated with higher first pass or final revascularization success.

Background: Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model.Methods: An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates.Key Results: We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals.Conclusion: In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases.

Abstract We sought to quantify the characteristics of acid reflux episodes in patients with extraesophageal GERD symptoms (EES), hiatal hernia (HH), and erosive esophagitis (EroE) using multichannel intraluminal impedance pH (MII‐pH) and investigate the correlation between impedance parameters and high resolution esophageal manometry (HREM). This was a retrospective analysis of esophageal manometric and impedance data inpatients with typical GERD symptoms who underwent both HREM and 24 h MII‐pH tests. Within the three patient subgroups, we evaluated impedance metrics such as average height of reflux, total duration of reflux, maximum duration of reflux, average pH, and average area of reflux. We also introduce a novel composite reflux index (CRI) metric, which is a measure of reflux height, duration, and acidity. Patients with EES exhibited a 29.3% increase in average height of reflux, compared to non‐EES patients (p < 0.01); the average height of reflux was found to be an independent predictor of EES (p < 0.01). Patients with HH showed a 190% longer total reflux duration (p < 0.01, vs. non‐HH patients). Total reflux duration was twice as long in EroE patients compared to those without (p = 0.02). Average CRI was significantly different within all three subgroup comparisons (p < 0.01). Impedance metrics shared weak negative correlations with lower esophageal sphincter (LES) rest pressure and distal contractile integral (DCI), and weak positive correlations with % absent peristalsis (p < 0.05 to p < 0.01 for various parameters). Quantitative impedance metrics provide useful insight into the pathophysiology of reflux in patients with EES, HH, and EroE.

Background: The lymphatic system is involved in metastasis in pancreatic cancer progression. In cancer staging, lymphatic spread has been used to assess the invasiveness of tumor cells. However, from the endothelium's perspective, the analysis downplays the peri-lesional activities of lymphatic vessels. This unintended bias is largely due to the lack of 3-dimensional (3-D) tissue information to depict the lesion microstructure and vasculature in a global and integrated fashion. Methods: We targeted the pancreas as the model organ to investigate lymphatic vessel remodeling in cancer lesion progression. Transparent pancreases were prepared by tissue clearing to facilitate deep-tissue, tile-scanning microscopy for 3-D lymphatic network imaging. Findings: In human pancreatic ductal adenocarcinoma, we identify the close association between the pancreatic intraepithelial neoplasia (PanIN) lesions and the lymphatic network. In mouse models of PanIN (elastase-CreER;LSL-KrasG12D and elastase-CreER;LSL-KrasG12D;p53+/−), the 3-D image data reveal the peri-lesional lymphangiogenesis, endothelial invagination, formation of the bridge/valve-like luminal tubules, vasodilation, and luminal invasion. In the orthotopic mouse model of pancreatic cancer, we identify the localized, graft-induced lymphangiogenesis and the peri- and intra-tumoral lymphatic vessel invasion. Interpretation: The integrated view of duct lesions and vascular remodeling suggests an active role, rather than a passive target, of lymphatic vessels in the metastasis of pancreatic cancer. Our 3-D image data provide insights into the pancreatic cancer microenvironment and establish the technical and morphological foundation for systematic detection and 3-D analysis of lymphatic vessel invasion. Fund: Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI). Keywords: Cancer invasion, Metastasis, KrasG12D mutation, Lymphangiogenesis, Lymphatic vessel, Lymphovascular invasion, Pancreatic cancer, Pancreatic intraepithelial neoplasia, Pancreatic ductal adenocarcinoma, p53 mutation

Abstract Background Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear. Methods Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR. Results 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log2fold difference of | ≥ 2| and false detection rate (FDR)

IntroductionIndividuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase-65 antibody (GADA) is the most commonly used test to assess autoimmunity while C-peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA).ObjectiveTo characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity.Design113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide.ResultsDelayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide.ConclusionGADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity.ClinicalTrials.gov IdentifierNCT01696747.

Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body's stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P

Background & Aims: Interstitial cells of Cajal (ICC) closely associate with nerves and smooth muscles to modulate gut motility. In the ICC microenvironment, although the circulating hormones/factors have been shown to influence ICC activities, the association between ICC and microvessels in the gut wall has not been described. We applied three-dimensional (3D) vascular histology with c-kit staining to identify the perivascular ICC and characterize their morphologic and population features in the human colon wall. Methods: Full-thickness colons were obtained from colectomies performed for colorectal cancer. We targeted the colon wall away from the tumor site. Confocal microscopy with optical clearing (use of immersion solution to reduce scattering in optical imaging) was performed to simultaneously reveal the ICC and vascular networks in space. 3D image rendering and projection were digitally conducted to illustrate the ICCâvessel contact patterns. Results: Perivascular ICC were identified in the submucosal border, myenteric plexus, and circular and longitudinal muscles via high-definition 3D microscopy. Through in-depth image projection, we specified two contact patternsâthe intimate cell body-to-vessel contact (type I, 18% of ICC in circular muscle) and the long-distance process-to-vessel contact (type II, 16%)âto classify perivascular ICC. Particularly, type I perivascular ICC were detected with elevated c-kit staining levels and were routinely found in clusters, making them readily distinguishable from other ICC in the network. Conclusions: We propose a new subclass of ICC that closely associates with microvessels in the human colon. Our finding suggests a functional relationship between these mural ICC and microvessels based on the morphologic proximity. Keywords: 3D Histology, c-kit, ICC, Mural Cells

Abstract. Introduction:. Chronic pancreatitis (CP) is a disease characterized by inflammation of the pancreas resulting in replacement of the normal functioning parenchyma by fibrotic connective tissue. This process leads to progressively impairment of exocrine and endocrine function and many patients develop a chronic pain syndrome. Objectives:. We aimed to characterize the neurobiological signature of pain associated with CP and to discuss its implications for treatment strategies. Methods:. Relevant basic and clinical articles were selected for review following an extensive search of the literature. Results:. Pathophysiological changes in the peripheral (pancreatic gland) and central nervous system characterize the pain syndrome associated with CP; involved mechanisms can be broken down to 3 main branches: (1) peripheral sensitization, (2) pancreatic neuropathy, and (3) neuroplastic changes in the central pain pathways. Disease flares (recurrent pancreatitis) may accelerate the pathophysiological process and further sensitize the pain system, which ultimately results in an autonomous and self-perpetuating pain state that may become independent of the peripheral nociceptive drive. These findings share many similarities with those observed in neuropathic pain disorders and have important implications for treatment; adjuvant analgesics are effective in a subset of patients, and neuromodulation and neuropsychological interventions may prove useful in the future. Conclusion:. Chronic pancreatitis is associated with abnormal processing of pain at the peripheral and central level of the pain system. This neurobiological understanding of pain has important clinical implications for treatment and prevention of pain chronification.

Aim and Objectives: To assess the efficacy of cone-beam computed tomography (CBCT) in comparison with multislice-computed tomography (MSCT) in the radiographic evaluation of cysts and tumors of the jaws. Materials and Methods: The study was conducted on 25 subjects diagnosed histopathologically with cysts or tumors of the jaws. They were subjected to MSCT and CBCT. The image pairs obtained were compared for diagnostic quality and dimensional accuracy. Also radiation monitoring was done with a newly devised calculative method. Statistics: Descriptive statistical analysis was carried out for all the groups in this study. The Kappa coefficient (k) for intraclass agreement was used for evaluating the scorings given by the evaluator for the diagnostic quality of the image. Results: A total of 28 lesions were found in 25 subjects. The diagnostic quality assessment suggested that the appearance of the internal structure and the soft tissue resolution of CBCT were inferior to MSCT. The radiation dosages from CBCT were noticeably less than MSCT. The dimensional accuracy of CBCT images was found to match those of the MSCT images. Conclusion: The results from the present study showed that CBCT could provide an image with MSCT-comparable diagnostic quality and accuracy, with a lesser radiation dose and risk, at a lower cost.

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

Aim: The aim of this study was to evaluate and compare the importance of amount of gingival display on smile esthetics and facial attractiveness in males and females with different facial forms by orthodontists as well as lay person. Materials and Methods: Frontal photographs of 18 male and female patients (9 male and 9 female) each, at a posed smile, seeking treatment in the Department of Orthodontics and Dentofacial Orthopedics were obtained. The photographs were divided in 3 groups based on their facial forms (Short face, Average face and Long face) and were altered by moving the dentition within the lip frame of the captured photograph to bring about different gingival display at smile. The pictures were divided into six groups with gingival exposures of 0 mm, 1 mm, 2 mm, 3 mm, 4 mm and 5 mm. The pictures were rated for attractiveness by four sets of evaluators - male and female Orthodontists and male and female lay evaluators. The statistical analysis methods used for the study included Mean score calculation, standard deviation and Analysis of variance: [test (Mono- Variance)]. The Student t test (two tailed, independent) has been used to find the significance of rating scores between lay person and orthodontist, and also between males and females evaluators. Results: No significant difference in ratings of gingival display in the 3 groups of photographs was noted by lay person and orthodontists. The results point to the fact that the influence of amount of gingival display on smile esthetics was independent of the facial form. It was also observed that gingival display of 0 mm to 2 mm was acceptable to both the lay person and the orthodontists. Conclusion: As the amount of gingival display increased, the ratings for facial attractiveness by both orthodontists and lay person decreased. Higher scores were given by both orthodontists and lay person for photographs which showed gingival display of 0-2 mm, suggesting this value to be most acceptable.

We report an unusual case of simultaneous hemorrhage in intracranial aneurysms and in renal cyst in a case of polycystic kidney disease. A 27-year-old gentleman presented with progressive headache and intermittent vomiting of one month duration. Initial computerized tomography (CT) scan and magnetic resonance imaging/angiography revealed a large mass lesion in the right temporal fossa. Over the previous 15 days, he developed progressive weakness in his left upper and lower limbs, and the headache worsened in severity. A repeat of CT scan showed an evidence of aneurysmal bleed and a large temporal lobe hematoma. The patient underwent urgent evacuation of the intracerebral of hematoma and excision of the redundant aneurysmal sac. The patient made excellent recovery in the post-operative period; however, for him, the pain abdomen was persisting. Detailed work-up with contrast-enhanced abdominal CT scan revealed bilateral multiple cysts in the kidneys with evidence of intracystic hemorrhage on the left side. An extensive search of the literature revealed that this kind of presentation has not been reported previously.

BACKGROUND:Most antibodies recognize conformational or discontinuous epitopes that have a specific 3-dimensional shape; however, determination of discontinuous B-cell epitopes is a major challenge in bioscience. Moreover, the current methods for identifying peptide epitopes often involve laborious, high-cost peptide screening programs. Here, we present a novel microarray method for identifying discontinuous B-cell epitopes in celiac disease (CD) by using a silicon-based peptide array and computational methods. METHODS:Using a novel silicon-based microarray platform with a multi-pillar chip, overlapping 12-mer peptide sequences of all native and deamidated gliadins, which are known to trigger CD, were synthesized in situ and used to identify peptide epitopes. RESULTS:Using a computational algorithm that considered disease specificity of peptide sequences, 2 distinct epitope sets were identified. Further, by combining the most discriminative 3-mer gliadin sequences with randomly interpolated3- or 6-mer peptide sequences, novel discontinuous epitopes were identified and further optimized to maximize disease discrimination. The final discontinuous epitope sets were tested in a confirmatory cohort of CD patients and controls, yielding 99% sensitivity and 100% specificity. CONCLUSIONS:These novel sets of epitopes derived from gliadin have a high degree of accuracy in differentiating CD from controls, compared with standard serologic tests. The method of ultra-high-density peptide microarray described here would be broadly useful to develop high-fidelity diagnostic tests and explore pathogenesis.

Background: The incidence of myocardial infarction is increasing specially in developing countries. Different electrolytes such as potassium and sodium play an important role in the cell metabolism, electrical conduction and membrane excitability. Abnormalities of these electrolytes due to different causes can lead to a significant cardiac life threatening events. Objective :To ascertain the electrolytes status in patients of acute ST elevation myocardial infarction (STEMI) at the time of hospitalization and to study the relationship between hyponatremia and hypokalemia with ventricular arrhythmia and survival status of the patient on day seven of the admission. Methods: Fifty patients of acute myocardial infarction were interrogated for history of presenting illness, examined for vitals, systemic examination and investigated by collection of blood sample and ECG. Conclusion: There was increased mortality in patients with hyponatremia, but p value was not statistically significant (p value 0.15). There was definite correlation between hypokalemia and ventricular arrhythmias and there was increased tendency towards developing ventricular arrhythmias in patients with hypokalemia.( p value 0.009).

Background: Infection is a common cause of thrombocytopenia. Fever with thrombocytopenia is a common condition that is associated with an increased risk of morbidity and mortality. Infections like Malaria, Dengue, Typhoid and septicaemia are some of the common causes of fever with thrombocytopenia. Methods: 112 patients aged > 18 years with fever and thrombocytopenias were observed for bleeding manifestations. Aims and objectives: To determine the relative frequency of different diseases in fever with thrombocytopenia and to observe the different bleeding manifestations in order of their incidence in fever with thrombocytopenia and their relation with platelet count. Results: Dengue was the commonest cause of fever with thrombocytopenia (26.79%) followed by P.falciparum malaria (20.54%) and P. Vivax malaria (16.07%). Bleeding manifestations were seen in38.40% of patients. 76.74% of patients had patechie/purpura as the commonest bleeding manifestation followed by gum bleeding in 16.28 %. Conclusions: Dengue was the commonest cause of fever with thrombocytopenia. Common Bleeding manifestations were patechie /purpura and gum bleeding.

Aim: To compare the tongue position of normal and open bite subjects at rest and to study if there is any difference in the hyoid bone and posterior pharyngeal wall positions in normal and open bite subjects. Materials and Methods: Sample size consisted of 48 individuals with 24 subjects having normal occlusion and 24 subjects having open bite malocclusion within the age range of 16 to 25 y. Standardized Lateral cephalograms were taken for all the subjects. The subjects were asked to protrude their tongue as much as possible. The dorsum of the tongue was then coated with a palatable suspension of Barium Sulphate (MICROBAR). The subjects were asked to swallow on command, after 10 sec of the swallow, lateral cephalograms were taken. Statistical Analysis: t-test Results: The antero-posterior relationship of maxilla and mandible to the cranial base is normal in both the groups. The open bite subjects had a larger over jet and as compared to the normal subjects, and had steeper mandibular planes. It was also seen that as the total tongue occupancy area increased so did the partial tongue occupancy area. Conclusion: A significant positive correlation was found between the horizontal position of the tongue tip and the lower incisor position in the normal group, also for the ratio of total tongue area to total oral area & the ratio of upper tongue area to the anterior oral area in the normal and openbite groups. There was no difference in the position of the tongue, hyoid bone and posterior wall in the normal and openbite groups. The mandibular plane angle and palatal plane - mandibular plane angles were found to be larger in the openbite subjects as compared to normal subjects. Supra-eruption of the maxillary molars was seen in the openbite group leading to a downward and backward rotation of the mandible. The maxillary and mandibular incisors were more proclinated in the normal as well as openbite groups.

The aim of all current forms of treatment of achalasia is to enable the patient to eat without disabling symptoms such as dysphagia, regurgitation, coughing or choking. Historically, this has been accomplished by mechanical disruption of the lower esophageal sphincter fibres, either by means of pneumatic dilation (PD) or by open surgical myotomy. The addition of laparoscopic myotomy and botulinum toxin (BTX) injection to the therapeutic armamentarium has triggered a recent series of reviews to determine the optimal therapeutic approach. Both PD and BTX have excellent short term (less than three months) efficacy in the majority of patients. New data have been published that suggest that PD and BTX (with repeat injections) can potentially obtain long term efficacy. PD is still considered the first-line treatment by most physicians; its main disadvantage is risk of perforation. BTX injection is evolving as an excellent, safe option for patients who are considered high risk for more invasive procedures. Laparoscopic myotomy with combined antireflux surgery is an increasingly attractive option in younger patients with achalasia, but long term follow-up studies are required to establish its efficacy and the potential for reflux-related sequelae.

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders.

Objective: To investigate whether the application of thyroid collars (TCs) affects the results of cephalometric study. Study Design: The Steiner cephalometric analysis of the patients was performed using lateral cephalometric radiographs, which were taken twice for each patient: Once using TCs (TC group; n0 = 50) and once without using TCs (NTC group; n = 50). A randomized and observer-blinded diagnostic study with head films taken from the two aforementioned groups was performed and results were evaluated with the t-test and Z-test, using GraphPad® Prism 4 software. Results : Statistical analysis using t-test was performed. The values of the line angles used in Steiner cephalometric analysis were compared for which values of each angle remained unchanged when done using TCs and without TC to the same samples. Conclusions : Lead shielding of the thyroid gland does not affect landmark identification or the specific measurements of the angulations traced during cephalometric analysis. TCs should be routinely applied during cephalometric radiography if cephalometric analyses are limited to the structures above the second cervical vertebra.

Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity - in response to gastric distention - was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a "bottom-up" pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.

Existing gastrointestinal (GI) diagnostic tools are unable to non-invasively monitor mucosal tight junction integrity in vivo beyond the esophagus. In the GI tract, local inflammatory processes induce alterations in tight junction proteins, enhancing paracellular ion permeability. Although transepithelial electrical resistance (TEER) may be used in the laboratory to assess mucosal barrier integrity, there are no existing methodologies for characterizing tight junction dilation in vivo. Addressing this technology gap, intraluminal bioimpedance sensing may be employed as a localized, non-invasive surrogate to TEER electrodes used in cell cultures. Thus far, bioimpedance has only been implemented in esophagogastroduodenoscopy (EGD) due to the need for external electronics connections. In this work, we develop a novel, noise-resilient Bluetooth-enabled ingestible device for the continuous, non-invasive measurement of intestinal mucosal "leakiness." As a proof-of-concept, we validate wireless impedance readout on excised porcine tissues in motion. Through an animal study, we demonstrate how the device exhibits altered impedance response to tight junction dilation induced on mice colonic tissue through calcium-chelator exposure. Device measurements are validated using standard benchtop methods for assessing mucosal permeability. [ABSTRACT FROM AUTHOR]

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body's stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

INTRODUCTION: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD). METHODS: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG). RESULTS: AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had autoinflammatory disorder. Significantlymore patients with AIM had elevations of C-reactive protein (31% vs 15%, P < 0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% vs 29%; P < 0.001), small fiber neuropathy (20% vs 9%; P = 0.002), and HLADQ8 positivity (24% vs 13%, P = 0.01). Patients with JH/HSD were more likely to have AIM (43% vs 15%, P = 0.001) along with more severe autonomic and gastrointestinal (GI) symptom scores. IVIG treatment was associated with robust improvement in pain, GI, and autonomic symptoms, but adverse events were experienced by 62% of patients. DISCUSSION: Autoimmune markers and autonomic dysfunction are common in patients with unexplained GI symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment, but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials. gov, NCT04859829. [ABSTRACT FROM AUTHOR]