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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.

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.

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., (© 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

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.

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.

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.

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.

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.

Nitric oxide (NO), an important effector molecule of the innate immune system, can also regulate adaptive immunity. In this study, the molecular effects of NO on the toll-like receptor signaling pathway were determined using interleukin-12 (IL-12) as an immunologically relevant target gene. The principal conclusion of these experiments is that NO inhibits IL-1 receptor-associated kinase (IRAK) activity and attenuates the molecular interaction between tumor necrosis factor receptor-associated factor-6 and IRAK. As a consequence, the NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibits lipopolysaccharide (LPS)-induced IL-12 p40 mRNA expression, protein production, and promoter activity in murine macrophages, dendritic cells, and the murine macrophage cell line RAW 264.7. Splenocytes from inducible nitric-oxide synthase-deficient mice demonstrate markedly increased IL-12 p40 protein and mRNA expression compared with wild type splenocytes. The inhibitory action of NO on IL-12 p40 is independent of the cytokine IL-10. The effects of NO can be directly attributed to inhibition of NF-kappaB activation through IRAK-dependent pathways. Accordingly, SNAP strongly reduces LPS-induced NF-kappaB DNA binding to the p40 promoter and inhibits LPS-induced IkappaB phosphorylation. Similarly, NO attenuates IL-1beta-induced NF-kappaB activation. These experiments provide another example of how an innate immune molecule may have a profound effect on adaptive immunity.

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.

Intestinal trefoil factor (ITF or TFF3), a small peptide secreted at the mucosal surface by goblet cells throughout the mature intestine, appears to play important roles in the maintenance and repair of the intestinal mucosal barrier. To study the expression of TFF3 during development, intestinal tissues were collected from rats at different development stages and examined by Northern blot analysis, Western blot analysis and immunohistochemical staining for TFF3 mRNA and protein expression. The results demonstrate that rat TFF3 mRNA is not detected until the 17th gestational day (term = 22 days), the expression is greater on gestational day 20 and increased further postnatally. TFF3 protein is first detected by Western blotting and immunohistochemical staining on gestational day 20. Further increases in TFF3 protein expression are demonstrated at around the weaning period. In conclusion, significant expression of rat TFF3 commences late in gestation and its expression is relatively deficient in immature rats. Expression of TFF3 may be deficient in premature infants and, therefore, may have a role in the development of necrotizing enterocolitis.

Background & Aims: Transforming growth factors (TGFs) alpha and beta are key regulatory peptides that modulate mucosal cell populations critical to inflammatory bowel disease. The aim of this study was to assess TGF-alpha and TGF-beta expression in human colonic mucosa., Methods: TGF-alpha and TGF-beta expression was assessed in colonic mucosa from patients with ulcerative colitis, patients with Crohn's disease, and controls by Northern blot analysis, in situ hybridization, and bioassay., Results: TGF-alpha messenger RNA expression localized to the villous tips of the small intestine and the surface epithelium of the colon. TGF-alpha expression was enhanced 2.3-fold in inactive ulcerative colitis mucosa relative to active ulcerative colitis, Crohn's disease, or normal controls. Enhanced expression correlated with duration of disease. TGF-beta expression was increased in affected mucosa from both patients with ulcerative colitis and Crohn's disease with active disease. TGF-beta1 messenger RNA expression in ulcerative colitis and Crohn's disease localized mostly to cells of the lamina propria with the highest concentration in inflammatory cells closest to the luminal surface., Conclusions: TGF-alpha may contribute to epithelial hyperproliferation and the increased risk of malignancy in long-standing ulcerative colitis. TGF-beta may be a key cytokine during periods of active inflammation, modulating epithelial cell restitution and functional features of cells within the lamina propria.

Background & Aims: The trefoil factors, a family of proteins abundantly expressed in gastrointestinal mucous cells, protect the epithelium in vitro. This study determines the effects of exogenously administered trefoil peptides on experimental injury in rats in vivo., Methods: Gastric injury was induced by either intragastric absolute ethanol (1.0 mL) or subcutaneous indomethacin (20 mg/kg). Recombinant human spasmolytic polypeptide (rHSP) or rat intestinal trefoil factor (ITF) were administered at different doses and time points before or after injury. Vehicle or bovine serum albumin was used as control. The pH of the stomach contents was assessed when the rats were killed. Gastric injury was blindly evaluated macroscopically and histologically. Serum levels of rHSP and ITF were determined by an enzyme-linked immunosorbent assay., Results: Oral rHSP and ITF markedly protected against both ethanol- and indomethacin-induced gastric injury (P < 0.005 at doses of 1-15 mg/rat) when given up to 2 hours before injury; no protection was noted by intraperitoneal rHSP against ethanol injury. Intraperitoneal rHSP protected against indomethacin-induced injury only at the maximal dose given (15 mg). Neither rHSP nor ITF altered gastric pH. Protection was not associated with systemic absorption of trefoil peptides., Conclusions: Topical trefoil peptides protect the gastric mucosa against ethanol- and indomethacin-induced gastric injuries. These peptides contribute to surface mucosal defense.

Transforming growth factor alpha (TGF alpha) evokes diverse responses in transgenic mouse tissues in which it is over-expressed, including the gastric mucosa, which experiences aberrant growth and a coincident repression of hydrochloric acid production. Here we show that ectopically expressed TGF alpha induces an age-dependent cellular reorganization of the transgenic stomach, in which the surface mucous cell population in the gastric pit is greatly expanded at the expense of cells in the glandular base. Immunohistochemical analysis of BrdU incorporation into DNA demonstrated that although mature surface mucous cells were not proliferating, DNA synthesis was enhanced by approximately 67% in the glandular base and isthmus, where progenitor cells reside. RNA blot and in situ hybridization were employed to determine temporal and spatial expression patterns of specific markers representing a variety of exocrine and endocrine gastric cell types. Mature parietal and chief cells were specifically depleted from the glandular mucosa, as judged by a 6- to 7-fold decrease in the expression of genes encoding H+,K(+)-ATPase, which is required for acid secretion, and pepsinogen C, respectively. The reduction of these markers coincided in time with the activation of TGF alpha transgene expression in the neonatal stomach. The rate of cell death in the glandular region was not overtly different. Significantly, the loss of parietal and chief cells occurred without a concomitant loss of their respective cellular precursors. In contrast to exocrine cells, D and G endocrine cells were much less severely affected, based on analysis of somatostatin and gastrin expression. Analysis of these dynamic changes indicates that TGF alpha can induce selective alterations in terminal differentiation and proliferation in the gastric mucosa, and suggests that TGF alpha plays an important physiological role in the normal regulation of epithelial cell renewal.

Background/aims: Spasmolytic polypeptide (SP) is a trefoil peptide expressed in the digestive tract. This study aimed to determine the structure and distribution of SP expression in the rat gastrointestinal tract., Methods: The structure of rat SP was determined from the sequence of complementary DNAs isolated from antral RNA. SP gene expression was localized by Northern blotting and in situ hybridization in the adult and fetal rat digestive tract. Expression of the SP peptide was localized by immunocytochemistry and Western blot analysis., Results: SP messenger (m)RNA was found predominantly in the stomach with highest expression in the antrum. High levels of SP mRNA were expressed in the fetal stomach before gastrin and somatostatin expression. Surprisingly, SP mRNA and peptide did not colocalize in the gastric mucosa, SP mRNA being superficial to SP peptide immunoreactivity throughout the gastric mucosa. Abundant SP immunoreactivity was seen in the lumen of the gastric glands and the mucus layer adherent to the gastric mucosa, indicating luminal secretion., Conclusions: In the rat, SP is a peptide secreted predominantly from antral mucous cell. The high concentrations of SP in the adherent gastric mucus layer (approximately 10 mumol/L) suggest that SP functions as a structural peptide rather than a regulatory peptide.

Chlorpromazine administered to Sprague-Dawley rats 30 minutes prior to burning dramatically minimized burn oedema by a factor of 7 compared with controls. Reburning of the rats 72 hours later demonstrated acquisition of local (but not systemic) resistance to subsequent burning among the control animals, and prevention of the acquisition of local resistance by the previously treated chlorpromazine group. The pharmacological actions of chlorpromazine are discussed in relation to the above phenomena, and mechanisms for the results obtained are described.