Crohn's disease and acute pancreatitis. A review of literature.

Crohn's disease, a transmural inflammatory bowel disease, has many well-known extra-intestinal manifestations and complications. Although acute pancreatitis has a higher incidence in patients with Crohn's disease as compared to the general population, acute pancreatitis is still relatively uncommon in patients with Crohn's disease. Patients with Crohn's disease are at an approximately fourfold higher risk than the general population to develop acute pancreatitis. The risk of developing acute pancreatitis is higher in females as compared to males. Acute pancreatitis can occur at any age with higher incidence reported in patients in their 20s and between 40-50 years of age. The severity and prognosis of acute pancreatitis in patients with Crohn's disease is the same as in general population. Acute pancreatitis can occur before onset of intestinal Crohn's disease, this presentation being more common in children than adults. It can also occur as the presenting symptom. However, most commonly it occurs after intestinal symptoms have manifest with a mean time interval between the initial presentation and development of acute pancreatitis being 2 years. There are several etiological factors contributing to acute pancreatitis in patients with Crohn's disease. It is not clear whether acute pancreatitis is a direct extra-intestinal manifestation of Crohn's disease; however, majority of the cases of acute pancreatitis in patients with Crohn's disease are due to GS and medications. Drugs used for the treatment of Crohn's disease that have been reported to cause acute pancreatitis include 5-ASA agents, azathioprine and 6 mercaptopurine, metornidazole and corticosteroids. Recent evidence has emerged correlating both type 1 and 2 autoimmune pancreatitis with Crohn's disease. Understanding the association between the two disease entities is key to effectively manage patients with Crohn's disease and acute pancreatitis.

Prevalence of migraine in patients with celiac disease and inflammatory bowel disease.

OBJECTIVE: To assess the prevalence of headache in clinic and support group patients with celiac disease and inflammatory bowel disease (IBD) compared with a sample of healthy controls. BACKGROUND: European studies have demonstrated increased prevalence of headache of patients with celiac disease compared with controls. METHODS: Subjects took a self-administered survey containing clinical, demographic, and dietary data, as well as questions about headache type and frequency. The ID-Migraine screening tool and the Headache Impact Test (HIT-6) were also used. RESULTS: Five hundred and two subjects who met exclusion criteria were analyzed - 188 with celiac disease, 111 with IBD, 25 with gluten sensitivity (GS), and 178 controls (C). Chronic headaches were reported by 30% of celiac disease, 56% of GS, 23% of IBD, and 14% of control subjects (P<.0001). On multivariate logistic regression, celiac disease (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.78-8.10), GS (OR 9.53, 95%CI 3.24-28.09), and IBD (OR 2.66, 95%CI 1.08-6.54) subjects all had significantly higher prevalence of migraine headaches compared with controls. Female sex (P=.01), depression, and anxiety (P=.0059) were independent predictors of migraine headaches, whereas age >65 was protective (P=.0345). Seventy-two percent of celiac disease subjects graded their migraine as severe in impact, compared with 30% of IBD, 60% of GS, and 50% of C subjects (P=.0919). There was no correlation between years on gluten-free diet and migraine severity. CONCLUSIONS: Migraine was more prevalent in celiac disease and IBD subjects than in controls. Future studies should include screening migraine patients for celiac disease and assessing the effects of gluten-free diet on migraines in celiac disease.

Prevalence of resident burnout at the start of training.

BACKGROUND: Job burnout is characterized by emotional exhaustion, depersonalization, and feelings of decreased personal accomplishment, and it may be linked to depression and suboptimal patient care. Burnout among American internal medicine residents ranges between 55% and 76%. PURPOSE: We aim to further characterize burnout prevalence at the start of residency. METHODS: Between 2006 and 2007, all incoming internal medicine interns at Mount Sinai Hospital and Elmhurst Hospital Center were asked to complete a survey at orientation. The survey included an instrument to measure burnout, a sleep deprivation screen, a personality inventory and demographic information. Comparison tests were conducted to identify statistically significant differences. RESULTS: The response rate was 94% (145/154). Overall burnout prevalence was 34% (50/145). Interns self-identifying as anxious (51% vs. 28%, p= .01) or disorganized (60% vs. 31%, p= .03) were more likely to have burnout. CONCLUSIONS: Our study found higher levels of burnout among beginning medical interns than reported in the literature. Burnout correlated with some self-reported personality features.

Trefoil factor family-3 is associated with aggressive behavior of colon cancer cells.

BACKGROUND AND AIM: Trefoil factor family 3 (TFF3) is expressed by intestinal epithelial cells and it mainly functions to protect the mucosa from injury. Expression of TFF3 has been correlated with a poor prognosis in patients with cancer, but little is known about whether TFF3 directly contributes to the malignant behavior of cancer cells. The present study was conducted to determine whether TFF3 expression contributes to the malignant behavior of cancer cells in vitro and in vivo. METHODS: Two subclones of a metastatic rat colorectal cancer cell line, demonstrated previously to manifest aggressive (LN cells) and non-aggressive (LP cells) growth in vivo, were analyzed for expression of TFF3 and tested in assays of cancer cell migration, invasion, and apoptosis in vitro, and mortality in vivo. RESULTS: The aggressive LN cell line endogenously expressed TFF3 and supported the transcription of a TFF3 promoter-driven reporter construct, whereas the non-aggressive LP cell line did not express TFF3. LN cells demonstrated enhanced migration, invasion, and less apoptosis compared to LP cells. Transfecting TFF3 into LP cells enhanced their ability to migrate, invade, block apoptosis, and behave more aggressively in vivo, thereby resembling the phenotype of LN cells. CONCLUSIONS: In rat colon cancer cells, both endogenous and constitutive expression of TFF3 correlates with an aggressive phenotype. These data provide direct evidence that TFF3 contributes to the malignant behavior of cancer cells.

Intestinal trefoil factor: a marker of poor prognosis in gastric carcinoma.

PURPOSE: Intestinal trefoil factor (ITF) is a marker of intestinal differentiation that may also play a role in cancer cell biology by inhibiting cell adhesion, promoting cell invasion, and blocking apoptosis. Gastric adenocarcinomas can arise through a process of intestinalization, but no study has yet comprehensively examined the expression of ITF in gastric cancer or correlated ITF expression with clinical outcome in any cancer type. EXPERIMENTAL DESIGN: Patients (209) with primary gastric adenocarcinoma were evaluated for ITF expression by immunohistochemistry. Results of immunostaining were correlated with clinicopathological variables and overall survival. RESULTS: In normal gastric mucosa, ITF expression was absent, whereas areas of intestinal metaplasia revealed strong ITF expression by goblet cells. A portion of gastric cancers (55%) demonstrated ITF expression. Women were more likely than men to express ITF in gastric cancers. However, in men, the expression of ITF correlated with aggressive phenotype of tumors (advanced stage, infiltrative growth pattern, and positive lymph nodes). Multivariate analysis revealed that expression of ITF was associated with a poor prognosis, independent of tumor stage. CONCLUSIONS: This is the first study to correlate ITF expression with clinicopathological features or outcome in any cancer type. ITF expression in gastric cancer exhibited a curious gender-associated relationship, being more frequently expressed in tumors of women, but associated with more aggressive pathological features in men. The poor prognosis of patients with ITF-positive gastric cancers further implicates ITF in cancer cell biology.

Syndrome of inappropriate anti-diuretic hormone secondary to non-cirrhotic primary hepatocellular carcinoma.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is usually seen in pulmonary malignancies, central nervous system disorders, and secondary to medications. SIADH has very rarely been encountered in primary hepatocellular carcinoma. Two cases were reported in Japan and 1 case in Spain after extensive investigation of the medical records. CASE REPORT: We report a case of a 71-year-old man who presented with confusion, cachexia, and abdominal symptoms in the form of vomiting and abdominal discomfort. On the initial work-up, SIADH diagnosis was made. After an extensive work-up, the reason for SIADH turned out to be a newly diagnosed hepatocellular carcinoma. The precipitating factor for the cancer was not identified by history or by work-up. No metastasis was identified. Liver functions were preserved but patient was severely malnourished. CONCLUSIONS: SIADH can occur as a para-malignant feature of the malignancy. In our case, it was related to the hepatocellular carcinoma, which is a malignancy very rare to cause SIADH.

Chronic nicotine administration differentially alters jejunal and colonic inflammation in interleukin-10 deficient mice.

BACKGROUND: Cigarette smoking alters the course of inflammatory bowel disease, is associated with protection against ulcerative colitis, but aggravates or has no effect on Crohn's disease. While the aetiology of this discrepancy remains unclear, differences between location of involvement in ulcerative colitis and Crohn's disease have not been examined in these studies. AIM: To examine the effects of nicotine administration on the course of jejunitis and colitis in interleukin-10 deficient mice. METHODS: Male C57/BL10 IL-10 -/- and wild type mice were given nicotine (12.5 microg/ml) in their drinking water at age 12-14 weeks when they had developed clinical signs of inflammatory bowel disease. Gender and age matched control mice received tap water alone. All mice were killed after 2 weeks of treatment. Whole tissue sections of jejunum, proximal and distal colon were separated and examined by macroscopic and histological score. Northern blots were examined for somatostatin, intestinal trefoil factor and mucin-2. RESULTS: At 14-16 weeks, when the mice were killed, IL-10 -/- untreated control mice developed jejunitis (macroscopic score 1.4 +/- 0.5, microscopic score 2.0 +/- 0.2) and colitis (2.0 +/- 0.2 and 5.9 +/- 0.9, respectively). IL-10 -/- mice treated for 2 weeks with nicotine had significantly reduced colonic scores (1.4 +/- 0.6 and 2.2 +/- 0.15, respectively). In contrast, the jejunum was more severely damaged (2.6 +/- 0.4 and 4.0 +/- 0.3; P = 0.01, respectively). Nicotine significantly increased both somatostatin and intestinal trefoil factor mRNA expression in the colon but not in the jejunum; no effect was noted on mucin-2 or beta-actin mRNA expression. CONCLUSIONS: (1) Two weeks of nicotine administration leads to contrasting effects on jejunal and colonic inflammation in IL-10 -/- mice. (2) Nicotine ameliorated inflammation in the colon, which was associated with enhanced expression of two protective peptides.

Ontogeny and prenatal expression of trefoil factor 3/ITF in the human intestine.

BACKGROUND: Trefoil factor 3 (TFF3) or intestinal trefoil factor (ITF), a peptide normally expressed and secreted by goblet cells at the mucosal surface of the small intestine and colon, is important for the maintenance and repair of the intestinal mucosal barrier. AIM: To study the ontogeny and developmental expression of TFF3 in human intestine. SUBJECTS: We examined TFF3 expression in formalin-fixed and paraffin-embedded intestinal tissues from 24 fetuses (gestational age [GA] 12-23 weeks) and 5 adults by immunohistochemical staining. To determine whether TFF3 is excreted into the fetal intestinal tract, first-passed meconium samples were collected from 43 newborn infants (gestational age 24-41 weeks). The presence of TFF3 was examined by Western blot analysis and the relative levels of TFF3 in the meconium were quantified with a slot blot assay. RESULTS: TFF3 can be detected by immunohistochemistry in human intestine as early as 12 weeks gestation. TFF3 is present in the meconium of newborn infants; no significant difference exists in TFF3 levels in the meconium of premature infants with birth weight (BW) less than 1500 g compared to those with birth weight equal to or more than 1500 g. CONCLUSION: Premature infant's susceptibility to intestinal mucosal injury is unlikely to be explained by developmental expression of TFF3 in human intestine since secreted TFF3 is not deficient in premature infants.

Putting genome analysis to good use: lessons from C-reactive protein and cardiovascular disease.

New methods of studying the human genome offer novel ways to examine the relationship between biomarkers and common, chronic human diseases. As an example, we will review a large genomics study (Elliott et al, JAMA 2009; 302:37-48) that concluded that C-reactive protein (CRP) is likely not a cause of coronary heart disease, although it is a marker for it.

Protein-losing enteropathy in ulcerative colitis.

Protein-losing enteropathy (PLE) is a debilitating potential complication of ulcerative colitis (UC). We report a case of PLE in a 26-year-old male patient with UC. The patient lost 50 pounds in the setting of a UC flare and was found to have an albumin level of 1.2 g/dl. Although the patient's UC was clinically controlled with steroids, the weight loss and hypoalbuminemia persisted with the patient's course complicated by development of deep vein thrombosis and pulmonary embolism. The diagnosis of PLE was confirmed with measurement of stool alpha-1-antitrypsin clearance. The patient's condition significantly improved following procto-colectomy.

Durability of the effect of online diabetes training for medical residents on knowledge, confidence, and inpatient glycemia.

BACKGROUND: Inpatient dysglycemia is associated with increased morbidity, mortality and cost. Medical education must not only address knowledge gaps, but also improve clinical care. METHODS: All 129 medicine residents at a large academic medical center were offered a case-based online curriculum on the management of inpatient dysglycemia in the fall of 2009. First-year residents took a 3-h course with 10 modules. Second and third-year residents, who had been educated the prior year, underwent abbreviated training. All residents were offered a 20-min refresher course in the spring of 2009. We assessed resident knowledge, resident confidence, and patient glycemia on two teaching wards before and after the initial intervention, as well as after the refresher course. RESULTS: A total of 117 residents (91%) completed the initial training; 299 analyzed admissions generated 11, 089 blood glucose values and 4799 event blood glucose values. Admissions with target glycemia increased from 19.4% to 33.0% (P = 0.035) by the end of the curriculum. There was a strong downward trend in hyperglycemia from 22.4% to 11.3% (P = 0.055) without increased hypoglycemia. Confidence and knowledge increased significantly among first-time and repeat participants. Residents rated the intervention as highly relevant to their practice and technologically well implemented. CONCLUSION: Optimization of an online curriculum covering the management of inpatient glycemia over the course of 2 years led to significantly more admissions in the target glycemia range. Given its scalability, modularity and applicability, this web-based educational intervention may become the standard curriculum for the management of inpatient glycemia.

Effect of case-based training for medical residents on inpatient glycemia.

OBJECTIVE: To determine whether an educational intervention for medical house staff improves blood glucose (BG) in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medicine residents at an academic medical center were assigned to online or classroom training on inpatient dysglycemia in fall 2008. Both groups were offered an online refresher course in spring 2009 addressing gaps in clinical practice identified on chart review. We assessed event BG, the first BG of any 3-h period, on two teaching wards. RESULTS: A total of 108 residents (93.1%) completed the initial training. The primary outcome, median event BG, decreased from 152 mg/dL in August 2008 to 139 mg/dL in December 2008 (P < 0.0001). Prevalence of event BG >200 mg/dL decreased from 25.5 to 22.7% (P = 0.0207), at the expense of more event BGs <70 mg/dL (2.0-3.9%, P = 0.0124). CONCLUSIONS: A curriculum for medicine residents on inpatient glycemia led to lower inpatient BG.

The incidence and predictors of job burnout in first-year internal medicine residents: a five-institution study.

PURPOSE: Job burnout is prevalent among U.S. internal medicine (IM) residents and may lead to depression, suboptimal patient care, and medical errors. This study sought to identify factors predicting new burnout to better identify at-risk residents. METHOD: The authors administered surveys to first-year IM residents at five institutions twice between June 2008 and June 2009, linking individual pre- and postresponses. Surveys measured job burnout, sleepiness, personality traits, and other characteristics. Burnout was defined using the most commonly identified definition and another stricter definition. RESULTS: Of 263 eligible residents, 185 (70%) completed both surveys. Among 114 residents who began free of burnout and completed both surveys, 86 (75%) developed burnout, with no differences across institutions. They were significantly more likely to report a disorganized personality style (9 versus 0; 11% versus 0%; P = .019) and less likely to report receiving regular performance feedback (34 versus 13; 63% versus 87%; P = .057). Using a stricter definition, 50% (78/156) of residents developed burnout. They were less likely to plan to pursue subspecialty training (49 versus 63; 78% versus 93%; P = .016) or have a calm personality style (59 versus 70; 77% versus 90%; P = .029). There were no significant associations between burnout incidence and duty hours, clinical rotation, demographics, social supports, loan debt, or psychiatric history. CONCLUSIONS: This study identified a high burnout incidence. The associations observed between burnout incidence and personality style, lack of feedback, and career choice uncertainty may inform interventions to prevent burnout and associated hazards.

Genomics of cardiovascular disease.

As the leading cause of death worldwide and a major cause of disability, cardiovascular disease remains a central focus of basic research, pharmacological treatment, surgical interventions, and long-term care. Inherited, monogenic syndromes have provided insight into pathophysiological mechanisms across the range of cardiovascular diseases. With the advent of post-Human Genome Project resources and technology, there has been a flood of research aimed at genome-wide predisposition markers, pharmacogenetics, and genomic signatures in complex cardiovascular disorders. Genomic research has both further elucidated the impact of genes previously identified in cardiovascular disease development and progression and discovered genomic regions as yet unknown to be associated with cardiovascular outcomes. The promise of personalized medicine lies in combining this genetic information with other biomarkers to tailor preventive and therapeutic strategies to individual patients for effective management, fewer adverse events, and preventive care.

Trefoil factor-3 expression in human colon cancer liver metastasis.

Deaths from colorectal cancer are often due to liver metastasis. Trefoil factor-3 (TFF3) is expressed by normal intestinal epithelial cells and its expression is maintained throughout the colon adenoma-carcinoma sequence. Our previous work demonstrated a correlation between TFF3 expression and metastatic potential in an animal model of colon cancer. The aim of this study was to determine whether TFF3 is expressed in human colon cancer liver metastasis (CCLM) and whether inhibiting TFF3 expression in colon cancer cells would alter their invasive potential in vitro. Human CCLMs were analyzed at the mRNA and protein level for TFF3 expression. Two highly metastatic rat colon cancer cell lines that either natively express TFF3 (LN cells) or were transfected with TFF3 (LPCRI-2 cells), were treated with two rat TFF3 siRNA constructs (si78 and si365), and analyzed in an in vitro invasion assay. At the mRNA and protein level, TFF3 was expressed in 17/17 (100%) CCLMs and 10/11 (91%) primary colon cancers, but not in normal liver tissue. By real time PCR, TFF3 expression was markedly inhibited by both siRNA constructs in LN and LPCRI-2 cells. The si365 and si78 constructs inhibited invasion by 44% and 53%, respectively, in LN cells, and by 74% and 50%, respectively, in LPCRI-2 cells. These results provide further evidence that TFF3 contributes to the malignant behavior of colon cancer cells. These observations may have relevance for designing new diagnostic and treatment approaches to colorectal cancer.

Short-chain fatty acid induces intestinal mucosal injury in newborn rats and down-regulates intestinal trefoil factor gene expression in vivo and in vitro.

BACKGROUND: Luminal administration of short-chain fatty acids (SCFAs) induces dose-dependent intestinal mucosal injury in newborn rats. However, the mechanism underlying the injurious effects of SCFAs on intestinal mucosa in neonates is unclear. Intestinal trefoil factor (ITF) is a factor important for the maintenance and repair of the intestinal mucosal barrier. Regulation of ITF gene expression by SCFAs may be involved as one of the mechanisms. OBJECTIVES: To examine the effect of butyrate-induced colonic injury on ITF gene expression in vivo and to determine the molecular mechanisms underlying the butyrate regulation of ITF gene expression in vitro. METHODS: Whole-section colonic tissues from 9- to 10-day-old Sprague-Dawley rats that have received butyric acid at two different concentrations (150 mmol/L and 300 mmol/L) and for different time periods were processed for total RNA extraction and Northern blot analysis. Littermates that received normal saline or lactic acid at 300 mmol/L served as controls. The effect of butyrate on ITF gene expression was also examined in vitro with human colonic epithelial LS 174T cells. To further define ITF gene regulation by butyrate, transient transfection assays were performed on a 930 bp human ITF promoter-luciferase reporter gene plasmid in LS174T cells with or without the presence of butyrate. RESULTS: Concurrent with mucosal injury, butyric acid inhibited ITF gene expression in colonic tissues of newborn rats as well as in intestinal epithelial cells in a dose- and time-dependent manner. Furthermore, butyrate reduced ITF promoter report gene activity in transfected LS174T cell, suggesting that butyric acid regulation of ITF gene is by way of a specific ITF promoter. CONCLUSIONS: Butyric acid induced-intestinal mucosal injury in newborn rats is associated with down-regulation of ITF gene expression. The changes in ITF gene expression in vivo may play a role in the pathogenesis of SCFA-induced intestinal mucosal injury.

Short-chain fatty acids induce colonic mucosal injury in rats with various postnatal ages.

Short chain fatty acids (SCFAs) may play a role in the pathogenesis of neonatal necrotizing enterocolitis. To evaluate the injurious effect of SCFAs on the colonic mucosa of rats at various postnatal developmental stages, we studied a total of 170 newborn Sprague-Dawley rats at postnatal ages days 3, 9, and 23. A 1.8-F silastic catheter or umbilical catheter was inserted rectally deep into the proximal colon of the rats. Rats from each of the three postnatal age groups were randomly divided to receive one of the following distinct SCFA solutions: acetic acid, butyric acid, propionic acid, or a mixture of above SCFAs solutions. An additional subgroup of rats from each of the age groups received normal saline as a control. The concentration of each SCFA solution was 300 mM, and the pH of all solutions was adjusted to 4.0. The volume of administered solution was 0.1 mL/10 g of body weight. After 24 h, all rats were killed and the daily weight change was recorded and proximal colon was collected for histologic examination. A histologic injury score was used to quantify the severity of mucosal injury. The severity of mucosal injury induced by luminal SCFAs administration decreased as the rats matured; by postnatal day 23, the injury caused by SCFAs was minimal. Thus, the severity of the colonic mucosal injury induced by luminal SCFAs is maturation dependent; the immature state of the mucosal defense in early postnatal age in newborn rat may explain its greater vulnerability to luminal SCFAs.