Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood.

Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

Restarting elective endoscopy safely amidst an evolving pandemic and the impact of patient perception.

BACKGROUND: The COVID-19 pandemic has led to disruptions in elective and outpatient procedures. Guidance from the Centers for Medicare and Medicaid Services provided a framework for gradual reopening of outpatient clinical operations. As the infrastructure to restart endoscopy has been more clearly described, patient concerns regarding viral transmission during the procedure have been identified. Moreover, the efficacy of the measures in preventing transmission have not been clearly delineated. METHODS: We identified patients with pandemic-related procedure cancellations from 3/16/2020 to 4/20/2020. Patients were stratified into tier groups (1-4) by urgency. Procedures were performed using our hospital risk mitigation strategies to minimize transmission risk. Patients who subsequently developed symptoms or tested for COVID-19 were recorded. RESULTS: Among patients requiring emergent procedures, 57.14% could be scheduled at their originally intended interval. COVID-19 concerns represented the most common rescheduling barrier. No patients who underwent post-procedure testing were positive for COVID-19. No cases of endoscopy staff transmission were identified. CONCLUSIONS: Non-COVID-19 related patient care during the pandemic is a challenging process that evolved with the spread of infection, requiring dynamic monitoring and protocol optimization. We describe our successful model for reopening endoscopy suites using a tier-based system for safe reintroduction of elective procedures while minimizing transmission to patients and staff. Important barriers included financial and transmission concerns that need to be addressed to enable the return to pre-pandemic utilization of elective endoscopic procedures.

Trends in same-admission cholecystectomy and endoscopic retrograde cholangiopancreatography for acute gallstone pancreatitis: A nationwide analysis across a decade.

BACKGROUND/OBJECTIVES: Gallstones are the leading cause of acute pancreatitis in developed countries. National and international guidelines recommend that a cholecystectomy should be performed during the index hospitalization for acute gallstone pancreatitis. We aimed to delineate the national trends for same-admission cholecystectomy and ERCP for acute gallstone pancreatitis over the last ten years. METHODS: We used the 2004, 2009 and 2014 National Inpatient Sample database including patients with a principal diagnosis of acute pancreatitis and a secondary diagnosis of choledocholithiasis or cholelithiasis. Exclusion criteria were age <18 years and elective admission. Primary outcome was the trend in incidence rate of same admission cholecystectomy from 2004 to 2014. The secondary outcomes were: 10-year trend in 1) Incidence of gallstone pancreatitis, 2) proportion of gallstone pancreatitis compared to all other etiologies of acute pancreatitis, 3) incidence rate of same-admission ERCP, 4) length of hospital stay, and 5) total hospitalization costs and charges. RESULTS: The proportion of admissions during which a same-admission cholecystectomy was performed decreased from 48.7% in 2004 to 46.9% in 2009 to 45% in 2014 (trend p < 0.01). During the same time interval, the percentage of admissions during which an ERCP was performed decreased from 25.1% to 18.7% (Trend p < 0.01). CONCLUSIONS: Adherence to the guidelines for same-admission cholecystectomy for patients admitted with acute gallstone pancreatitis have been declining over the past decade. On the other hand, decline in rate of ERCP in patients with acute gallstone pancreatitis and no signs of cholangitis demonstrates adherence to guidelines in this regard.

Cancer surveillance for transgender and gender diverse patients with Lynch syndrome: a practice resource of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Transgender and gender diverse (TGD) populations with hereditary cancer syndromes face unique obstacles to identifying and obtaining appropriate cancer surveillance and risk-reducing procedures. There is a lack of care provider knowledge about TGD health management. Lynch syndrome (LS) is one of the most common hereditary cancer syndromes, affecting an estimated 1 in 279 individuals. There are no clinical guidelines specific for TGD individuals with LS, highlighting a need to improve the quality of care for this population. There is an urgent need for cancer surveillance recommendations for TGD patients. This commentary provides recommendations for cancer surveillance, risk-reducing strategies, and genetic counseling considerations for TGD patients with LS.

Small duct primary sclerosing cholangitis: A discrete variant or a bridge to large duct disease, a practical review.

The natural history, associations with inflammatory bowel disease (IBD), and long-term outcomes of large duct primary sclerosing cholangitis (ldPSC) have been well documented. Small duct primary sclerosing cholangitis (sdPSC) is a much less common and relatively more benign variant. The natural history of sdPSC has been difficult to characterize given the limited number of studies in the literature especially with regards to the subset of patients who progress to large duct involvement. It has been unclear whether sdPSC represented a subset of ldPSC, an earlier staging of ldPSC, or a completely separate and distinct entity of its own. Strong associations between sdPSC and IBD have been established with suspicion that concurrent sdPSC-IBD may be a key prognostic factor in determining which patients are at risk of progression to ldPSC. Little is known regarding the discrete circumstances that predisposes some patients with sdPSC to progress to ldPSC. It has been suspected that progression to large biliary duct involvement subjects this subset of patients to potentially developing life-threatening complications. Here the authors conducted a thorough review of the published sdPSC literature using Pubmed searches and cross-referencing to compile all accessible studies regarding cohorts of sdPSC patients in order better characterize the subset of sdPSC patients who progress to ldPSC and the associated outcomes.

Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.

Ulcerative colitis and Crohn's disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1ß as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1ß neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1ß→miR-155→BDNF signaling axis.

The Great Spiral Masquerader: A Case of Concurrent Secondary Syphilis and Autoimmune Hepatitis.

We describe a unique case of rash and acute hepatitis confounded by the presence of syphilis that created suspicion for syphilitic hepatitis, a rare and often misdiagnosed condition. Investigation concerning the etiology alternatively lead to the diagnosis of 2 concomitant conditions: active autoimmune hepatitis and secondary syphilis. To our knowledge, this is the first description in the literature of the simultaneous occurrence of secondary syphilis and autoimmune hepatitis. This case serves to increase the recognition of the clinical characteristics and diagnostic challenges of syphilitic hepatitis and to discuss the potential role of pathogens in the induction of autoimmunity.

Aortic Stenosis Complicated by Gastrointestinal Arteriovenous Malformations: It is not Always Heyde Syndrome.

Aortic stenosis (AS) and arteriovenous malformations (AVM) are a common coexisting pathology in the elderly. When both pathologies are combined, Heyde syndrome is a differential that is widely explored among clinicians. Unfortunately, this may not always be the case. We present a case of an 82-year-old female admitted for acute gastrointestinal (GI) bleeding with a history of AVMs and AS, as well as, an algorithm in diagnosing elderly patients with both pathologies.

Portal vein thrombosis leading to pre-sinusoidal non-cirrhotic portal hypertension resulting in decreased synthetic function of the liver.

Non-cirrhotic portal hypertension (NCPH), defined as elevated portal pressures in the absence of cirrhosis, is a relatively rare cause of elevated portal pressures in western countries. In NCPH decompensated liver disease is common, but complications are often mitigated by appropriate medical therapy. Liver synthetic function loss is uncommon. We present a unique case of a patient with biopsy proven NCPH, who eventually developed progressive loss of hepatic synthetic function in the setting of long standing portal hypertension. This loss of synthetic function corresponded with the interval development of incomplete septal cirrhosis (ISC), and progression of previously noted nodular regenerative hyperplasia in biopsies performed 7 years apart. Our patient's clinical course was complicated by multiple hospitalizations for gastrointestinal hemorrhage. Patients with ISC have higher rates of bleeding varices when compared to patients with macronodular cirrhosis. While patients with NCPH typically have better overall survival and fewer bleeding complications than cirrhotic patients, this is typically attributed to the former having preserved synthetic function. It appears that the presence of ISC may be a poor prognosticator in patients with NCPH.

Endocrine and metabolic profile of peripubertal Standardbred colts.

The objectives of this study were to determine the concentrations of reproductive and metabolic hormones during the peripubertal period and to assess their relationship with testicular development and body fat deposition. Blood samples were collected from 23 healthy Standardbred colts every four weeks for twelve months. Colts were weighed monthly, and percent of body fat and testicular volume estimated by ultrasound. Onset of puberty was determined as the month when testosterone was two standard deviations above the previous mean. Plasma FSH, LH, leptin, estradiol-17ß, androstenedione, IGF-1, insulin, inhibin-A, and inhibin-B were analyzed for a seven month peripubertal period. Spring born Standardbred colts underwent puberty at 13 months of age; onset of puberty coincided with exponential testicular growth but did not coincide with an increase in cutaneous body fat deposition or leptin (p > 0.05). Plasma inhibin-B concentrations were significantly increased in the postpubertal period (p < 0.05), but no increase was seen in inhibin-A, androstenedione, FSH, LH, or estradiol-17ß. In conclusion, the rise in testosterone and subsequent onset of puberty coincides with rapid testicular growth but is not correlated with an increase in gonadotropins, IGF-1, cutaneous body fat or leptin in the horse.

Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life.

BACKGROUND & AIMS: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1ß. METHODS: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. RESULTS: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1ß and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a ß-blocker, markedly ameliorated the inflammatory response and IL1ß overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1ß than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a ß2-agonist, induced a greater IL1ß expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1ß activation in human THP-1-derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. CONCLUSIONS: NI sensitizes the colon epithelium for exacerbated IL1ß activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that ß blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.

Use of manual alveolar recruitment maneuvers to eliminate atelectasis artifacts identified during thoracic computed tomography of healthy neonatal foals.

OBJECTIVE To evaluate use of single manual alveolar recruitment maneuvers (ARMs) to eliminate atelectasis during CT of anesthetized foals. ANIMALS 6 neonatal Standardbred foals. PROCEDURES Thoracic CT was performed on spontaneously breathing anesthetized foals positioned in sternal (n = 3) or dorsal (3) recumbency when foals were 24 to 36 hours old (time 1), 4 days old (time 2), 7 days old (time 3), and 10 days old (time 4). The CT images were collected without ARMs (all times) and during ARMs with an internal airway pressure of 10, 20, and 30 cm H2O (times 2 and 3). Quantitative analysis of CT images measured whole lung and regional changes in attenuation or volume with ARMs. RESULTS Increased attenuation and an alveolar pattern were most prominent in the dependent portion of the lungs. Subjectively, ARMs did not eliminate atelectasis; however, they did incrementally reduce attenuation, particularly in the nondependent portion of the lungs. Quantitative differences in lung attenuation attributable to position of foal were not identified. Lung attenuation decreased significantly (times 2 and 3) and lung volume increased significantly (times 2 and 3) after ARMs. Changes in attenuation and volume were most pronounced in the nondependent portion of the lungs and at ARMs of 20 and 30 cm H2O. CONCLUSIONS AND CLINICAL RELEVANCE Manual ARMs did not eliminate atelectasis but reduced attenuation in nondependent portions of the lungs. Positioning of foals in dorsal recumbency for CT may be appropriate when pathological changes in the ventral portion of the lungs are suspected.

Comparison of radiographic and computed tomographic images of the lungs in healthy neonatal foals.

OBJECTIVE: To compare CT and radiographic images of the lungs in sedated healthy foals positioned in sternal recumbency and to investigate whether a relationship exists between CT-derived measurements of lung attenuation and Paco2 and Pao2. ANIMALS: 6 healthy Standardbred foals < 14 days of age. PROCEDURES: Thoracic CT images were acquired followed by radiographic views with each foal sedated and positioned in sternal recumbency. For each foal, both CT and radiographic images were evaluated for severity and extent of changes by lung regions on the basis of a subjective scoring system by 3 investigators. Quantitative analysis of CT images was also performed. Assessments of Pao2 and Paco2 were performed before sedation, following sedation prior to CT, and after CT prior to radiography. RESULTS: Interobserver agreement for CT and radiographic image scoring was strong (0.73) and fair (0.65), respectively; intraobserver agreement was near perfect for CT (0.97) and radiographic (0.94) image scoring. Increased CT attenuation and radiographic changes were identified for all foals and were preferentially distributed in the caudoventral portion of the lungs. Radiographic scores were significantly lower than CT image scores. A positive correlation (r = 0.872) between lung attenuation and CT image score was identified. A significant increase in Paco2 was not considered clinically relevant. Significant changes in Pao2 were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that interpretation of CT images may be less subjective, compared with interpretation of radiographic images. These findings may aid in the evaluation of CT and radiographic images of neonatal foals with respiratory tract disease.

Equine total carbon dioxide testing in Illinois in 2012.

During prolonged strenuous exercise, racehorses can experience acidemia. To counteract this phenomenon, trainers can administer blood alkalizing agents that raise the plasma pH and total carbon dioxide (TCO2) concentration. In Illinois, the administrative threshold for TCO2 in plasma is 37.0 mmol/L. Because accuracy in the reported measurement of TCO2 must be ensured, uncertainty measurements are often issued alongside the reported concentrations. We report a validated method for measuring TCO2 levels in equine plasma using the Beckman UniCel DxC 600. A six-point calibration curve ranging from 5 to 50 mmol/L is analyzed along with controls at four TCO2 levels with each set of samples. Using this method, we collected data from 5,199 race samples during 2012, with 134 being from thoroughbred horses and 5,065 from standardbred horses. During method validation, uncertainty was determined using the simplified Guide to the Expression of Uncertainty in Measurement approach and was found to be 3% at 99.7% confidence level with eight measurements. Additionally, to investigate other variables that could have an effect on TCO2 levels, we collected the gender, breed, Lasix(®) status, strong ion concentration, pre- or post-race collection time and track location of all horses tested during that year. The samples had an overall mean TCO2 concentration of 30.5 ± 2.0 mmol/L. The other physiological and environmental data were analyzed using analysis of covariance tables. These results indicate gender, breed, furosemide status, collection time and track location to be strongly correlated (P < 0.0001) to TCO2 levels. Thoroughbred status was found to have no effect. Finally, TCO2 concentrations were highly correlated (P < 0.0001) to sodium and chloride ion concentrations. No correlation was found between TCO2 and potassium concentrations. The results show that there are several environmental and physiological factors that can affect TCO2 concentrations. The concentration of other strong ions present in the blood may indicate doping status.

Neglected tropical diseases of Oceania: review of their prevalence, distribution, and opportunities for control.

Among Oceania's population of 35 million people, the greatest number living in poverty currently live in Papua New Guinea (PNG), Fiji, Vanuatu, and the Solomon Islands. These impoverished populations are at high risk for selected NTDs, including Necator americanus hookworm infection, strongyloidiasis, lymphatic filariasis (LF), balantidiasis, yaws, trachoma, leprosy, and scabies, in addition to outbreaks of dengue and other arboviral infections including Japanese encephalitis virus infection. PNG stands out for having the largest number of cases and highest prevalence for most of these NTDs. However, Australia's Aboriginal population also suffers from a range of significant NTDs. Through the Pacific Programme to Eliminate Lymphatic Filariasis, enormous strides have been made in eliminating LF in Oceania through programs of mass drug administration (MDA), although LF remains widespread in PNG. There are opportunities to scale up MDA for PNG's major NTDs, which could be accomplished through an integrated package that combines albendazole, ivermectin, diethylcarbamazine, and azithromycin, in a program of national control. Australia's Aboriginal population may benefit from appropriately integrated MDA into primary health care systems. Several emerging viral NTDs remain important threats to the region.