Sridhar Chilimuri

Alleviation of Gut Inflammation by Cdx2/Pxr Pathway in a Mouse Model of Chemical Colitis

Pregnane X Receptor (PXR), a master regulator of drug metabolism and inflammation, is abundantly expressed in the gastrointestinal tract. Baicalein and its O-glucuronide baicalin are potent anti-inflammatory and anti-cancer herbal flavonoids that undergo a complex cycle of interconversion in the liver and gut. We sought to investigate the role these flavonoids play in inhibiting gut inflammation by an axis involving PXR and other potential factors. The consequences of PXR regulation and activation by the herbal flavonoids, baicalein and baicalin were evaluated in vitro in human colon carcinoma cells and in vivo using wild-type, Pxr-null, and humanized (hPXR) PXR mice. Baicalein, but not its glucuronidated metabolite baicalin, activates PXR in a Cdx2-dependent manner in vitro, in human colon carcinoma LS174T cells, and in the murine colon in vivo. While both flavonoids abrogate dextran sodium sulfate (DSS)-mediated colon inflammation in vivo, oral delivery of a potent bacterial β-glucuronidase inhibitor eliminates baicalin’s effect on gastrointestinal inflammation by preventing the microbial conversion of baicalin to baicalien. Finally, reduction of gastrointestinal inflammation requires the binding of Cdx2 to a specific proximal site on the PXR promoter. Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions.

Genetic epidemiology of irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder characterized by presence of abdominal pain or discomfort associated with altered bowel habits. It has three main subtypes - constipation predominant IBS (C-IBS), diarrhea predominant IBS (D-IBS) and IBS with mixed features of both diarrhea as well as constipation (M-IBS). Its pathophysiology and underlying mechanisms remain elusive. It is traditionally believed that IBS is a result of multiple factors including hypersensitivity of the bowel, altered bowel motility, inflammation and stress. Initial studies have shown familial aggregation of IBS suggesting shared genetic or environmental factors. Twin studies of IBS from different parts of world have shown higher concordance rates among monozygotic twins than dizygotic twins, and thus suggesting a genetic component to this disorder. Multiple studies have tried to link single-nucleotide polymorphisms (SNPs) to IBS but there is little evidence that these SNPs are functional. Various molecules have been studied and investigated by the researchers. Serotonin, a known neurotransmitter and a local hormone in the enteric nervous system, has been most extensively explored. At this time, the underlying gene pathways, genes and functional variants linked with IBS remain unknown and the promise of genetically-determined risk prediction and personalize medicine remain unfulfilled. However, molecular biological technologies continue to evolve rapidly and genetic investigations offer much promise in the intervention, treatment and prevention of IBS.

Non-Alcoholic Fatty Pancreatic Disease: A Review of Literature

There is an epidemic of obesity worldwide. The prevalence of obesity has doubled over the last three decades. Obesity, especially abdominal obesity is associated with insulin resistance that can lead to pancreatic steatosis and non-alcoholic fatty pancreatic disease (NAFPD). NAFPD describes a phenotype entity ranging from deposition of fat in the pancreas to pancreatic inflammation, and resultant fibrosis, which is similar to that of non-alcoholic fatty liver disease (NAFLD). NAFPD may represent a meaningful manifestation of metabolic syndrome. Pancreatic steatosis can be diagnosed on ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI). In addition to a correlation between pancreatic steatosis and metabolic syndrome, pancreatic steatosis may lead to a worse outcome in pancreatitis and may be an etiological factor in pancreatic cancer, but we need further research to examine the associations, pathophysiology, and the impact of pancreatic steatosis and NAFPD on the human health.

Serum Triglyceride Level: A Predictor of Complications and Outcomes in Acute Pancreatitis?

Aim. To study serum triglyceride level as a predictor of complications and outcomes in acute pancreatitis. Methods. In this retrospective observational study, 582 patients admitted with acute pancreatitis, who had serum triglyceride levels measured within the first 24 hours, were divided into two groups. The study group consisted of patients with a triglyceride level ≥2.26 mmol/L (group 2) and the control group consisted of triglyceride level of <2.26 mmol/L (group 1). We collected data for baseline demographics, laboratory values, incidence of complications (local and systemic), admission to the intensive care unit (ICU), ICU length of stay, length of total hospital stay, and death in the two groups. Results. A triglyceride level of ≥2.26 mmol/L was found to be an independent predictor of developing altered mental status (p: 0.004), pancreatic necrosis (p: 0.001), acute respiratory distress syndrome (p: 0001), systemic Inflammatory response syndrome (p: 0.001), acute kidney injury (p: 0.001), hospital length of stay (LOS) (p: 0.002), admission to intensive care unit (ICU) (p: 0.002), and ICU LOS (p: 0.003). Conclusion. A triglyceride level of ≥2.26 mmol/L on admission in acute pancreatitis is an independent predictor of developing local and systemic complications, hospital LOS, admission to ICU, and ICU LOS.

Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis

Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100). Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other - primary as well as secondary - causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation.

Prognostic Value of AIMS65 Score in Cirrhotic Patients with Upper Gastrointestinal Bleeding

Introduction. Unlike Rockall scoring system, AIMS65 is based only on clinical and laboratory features. In this study we investigated the correlation between the AIMS65 score and Endoscopic Rockall score, in cirrhotic and noncirrhotic patients. Methods. This is a retrospective study of patients admitted with overt UGIB and undergoing esophagogastroduodenoscopy (EGD). AIMS65 and Rockall scores were calculated at the time of admission. We investigated the correlation between both scores along with stigmata of bleed seen on endoscopy. Results. A total of 1255 patients were studied. 152 patients were cirrhotic while 1103 patients were noncirrhotic. There was significant correlation between AIMS65 and Total Rockall scores in patients of both groups. There was significant correlation between AIMS65 score and Endoscopic Rockall score in noncirrhotics but not cirrhotics. AIMS65 scores in both cirrhotic and noncirrhotic groups were significantly higher in patients who died from UGIB than in patients who did not. Conclusion. We observed statistically significant correlation between AIMS65 score and length of hospitalization and mortality in noncirrhotic patients. We found that AIMS65 score paralleled the endoscopic grading of lesion causing UGIB in noncirrhotics. AIMS65 score correlated only with mortality but not the length of hospitalization or endoscopic stigmata of bleed in cirrhotics.

Significance of Bowel Wall Thickening on Computed Tomography Scan: Higher Risk of Pathology Among African Americans Compared to Hispanics

PURPOSE The aims of our study were to examine the role of colonoscopy as further workup for bowel wall thickening reported on computed tomography (CT) scans and to investigate whether there were significant differences in pathology found among the racial groups in our study population. METHODS This is a retrospective study from March 2005 and January 2007 of all patients who have undergone colonoscopy for bowel wall thickening found on CT scans of the abdomen. RESULTS Of 94 patients with bowel wall thickening on CT scans, 7 (8%) had adenocarcinoma, 5 (5%) had large adenomas, 3 (3%) had infectious colitis, 2 (2%) ischemic colitis, 1 (1%) had inflammatory bowel disease, and 1 (1%) had a benign stricture. Bowel wall thickening on CT scan predicted clinical pathology in 34% of African Americans, as compared to 14% of Hispanics. Patients with significant pathology were more likely to have anemia and lower albumin levels. CONCLUSION Patients with bowel wall thickening found on CT scans should be referred for colonoscopy, given that significant pathology is found in 20% of the cases. African Americans were 2.5 times more likely to have clinically significant pathology as compared to Hispanics.

Symptomatic Gallstones in the Young: Changing Trends of the Gallstone Disease-Related Hospitalization in the State of New York: 1996 - 2010

Background The aim of the study was to evaluate if the gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. Methods We retrospectively reviewed 15 years (1996 - 2010) of Statewide Planning and Research Cooperative System (SPARCS) data of New York State Department of Health. Patients with ICD-9 code diagnosis of 574 (cholelithiasis) among the first three discharge diagnoses were reviewed. Results Total number of all cause admissions to hospitals had increased from 2.44 million to 2.77 million (1996 - 2010). However, gallstone-related hospitalizations had decreased from 1.7% to 1.2%. It was noted that there was a 30% increment in the proportion of those below 20 years of age with gallstone disease requiring hospitalization over the same period. This young patient population contributed only 2.04% to all gallstone-related hospitalizations in 1996, whereas it had increased to 2.96% in 2010. This trend was more pronounced in women, Hispanics and in those who were residing in the Bronx County as compared to all other New York counties combined. Conclusion The gallstone-related hospitalizations in the young (< 20 years of age) have increased over time in both the Bronx County and New York State as a whole. This could be due to increasing prevalence of risk factors such as obesity, physical inactivity, diabetes and early pregnancy.

Cytomegalovirus related fatal duodenal diverticular bleeding: Case report and literature review

Involvement of gastrointestinal tract by cytomegalovirus (CMV) is common. CMV infections mainly run their course without any clinical signs in immunocompetent hosts. In contrast, CMV can cause severe infections with serious consequences in a immunocompromised state typically associated with organ transplants, highly immunosuppressive cancer chemotherapy, advanced HIV infection or treatment with corticosteroids. The incidence and severity of these manifestations of CMV is directly proportional with the degree of cellular immune dysfunction, i.e., CD8+ Cytotoxic T-cell response. Clinical manifestations of CMV can become apparent in different situations including reactivation of CMV from latency, primary infection in a seronegative host, or exposure of a seropositive host to a new strain of CMV. As the clinical signs of CMV in immunodeficient patients are usually sparse, physicians should be highly vigilant about CMV infection, a treatable condition that otherwise is associated with significant mortality. Here we report a rare case of severe gastrointestinal CMV infection with sustained immunodeficiency secondary to treatment with steroids manifesting as fatal duodenal diverticular bleeding.

Development, Functioning, and Effectiveness of a Preoperative Risk Assessment Clinic

Lee first described the concept of preoperative assessment testing (PAT) clinic in 1949. An efficiently run clinic is associated with increased cost-effectiveness by lowering preoperative admission time and thus reducing the length of stay and the associated costs. The setup of the PAT clinic should be based on the needs, culture, and resources of the institution. Various models for the setup of PAT clinic have been described, including the concept of a perioperative surgical home, which is a patient-centered model designed to improve health and the delivery of health care and to reduce the cost of care. Although there are several constraints in the development of PAT clinics, with increasing awareness about the usefulness of pre-operative risk assessments, growing bodies of literature, and evidence-based guidelines, these clinics are becoming a medical necessity for the improvement of perioperative care.