Refaat Hegazi

Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1–dependent pathway

Heme oxygenase (HO)-1 and its metabolic product carbon monoxide (CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10–deficient (IL-10 −/−) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-γ on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-γ signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-γ on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.

An Anti-Inflammatory Role for Carbon Monoxide and Heme Oxygenase-1 in Chronic Th2-Mediated Murine Colitis

Cigarette smoking is a significant environmental factor in the human inflammatory bowel diseases, remarkably, conferring protection in ulcerative colitis. We previously demonstrated that a prominent component of cigarette smoke, CO, suppresses Th17-mediated experimental colitis in IL-10−/− mice through a heme oxygenase (HO)-1–dependent pathway. In this study, homeostatic and therapeutic effects of CO and HO-1 were determined in chronic colonic inflammation in TCR-α–deficient (−/−) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCRα−/− mice exposed to CO or treated with the pharmacologic HO-1 inducer cobalt protoporphyrin demonstrated amelioration of active colitis. CO and cobalt protoporphyrin suppressed colonic IL-1β, TNF, and IL-4 production, whereas IL-10 protein secretion was increased. CO induced IL-10 expression in macrophages and in vivo through an HO-1–dependent pathway. Bacterial products regulate HO-1 expression in macrophages through MyD88- and IL-10–dependent pathways. CO exposure and pharmacologic HO-1 induction in vivo resulted in increased expression of HO-1 and IL-10 in CD11b+ lamina propria mononuclear cells. Moreover, induction of the IL-10 family member IL-22 was demonstrated in CD11b− lamina propria mononuclear cells. In conclusion, CO and HO-1 induction ameliorated active colitis in TCRα−/− mice, and therapeutic effects correlated with induction of IL-10. This study provides further evidence that HO-1 mediates an important homeostatic pathway with pleiotropic anti-inflammatory effects in different experimental models of colitis and that targeting HO-1, therefore, is a potential therapeutic strategy in human inflammatory bowel diseases.

Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial.

BACKGROUND Hospitalized, malnourished older adults have a high risk of readmission and mortality. OBJECTIVE Evaluation of a high-protein oral nutritional supplement (HP-HMB) containing beta-hydroxy-beta-methylbutyrate on postdischarge outcomes of nonelective readmission and mortality in malnourished, hospitalized older adults. DESIGN Multicenter, randomized, placebo-controlled, double-blind trial. SETTING Inpatient and posthospital discharge. PATIENTS Older (≥65 years), malnourished (Subjective Global Assessment [SGA] class B or C) adults hospitalized for congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. INTERVENTIONS Standard-of-care plus HP-HMB (n = 328) or a placebo supplement (n = 324), 2 servings/day. MEASUREMENTS Primary composite endpoint was 90-day postdischarge incidence of death or nonelective readmission. Other endpoints included 30- and 60-day postdischarge incidence of death or readmission, length of stay (LOS), SGA class, body weight, and activities of daily living (ADL). RESULTS The primary composite endpoint was similar between HP-HMB (26.8%) and placebo (31.1%). No between-group differences were observed for 90-day readmission rate, but 90-day mortality was significantly lower with HP-HMB relative to placebo (4.8% vs. 9.7%; relative risk 0.49, 95% confidence interval [CI], 0.27 to 0.90; p = 0.018). The number-needed-to-treat to prevent 1 death was 20.3 (95% CI: 10.9, 121.4). Compared with placebo, HP-HMB resulted in improved odds of better nutritional status (SGA class, OR, 2.04, 95% CI: 1.28, 3.25, p = 0.009) at day 90, and an increase in body weight at day 30 (p = 0.035). LOS and ADL were similar between treatments. LIMITATIONS Limited generalizability; patients represent a selected hospitalized population. CONCLUSIONS Although no effects were observed for the primary composite endpoint, compared with placebo HP-HMB decreased mortality and improved indices of nutritional status during the 90-day observation period. CLINICAL TRIAL REGISTRATION www.ClinicalTrials.govNCT01626742.

Innate immune receptor genetic polymorphisms in pouchitis: Is CARD15 a susceptibility factor?

Background: Pouchitis is a frequent complication after ileal pouch‐anal anastamosis (IPAA) for ulcerative colitis (UC). The aim of this study was to determine whether genetic polymorphisms in the innate immune receptors toll‐like receptor (TLR)4 and caspase activation and recruitment domain family member 15 (CARD15) genes are associated with pouchitis. Methods: From a retrospectively ascertained cohort of patients with UC 5 to 12 years after IPAA (n = 101), subjects were classified into 3 groups: no pouchitis (n = 52); 1 to 2 episodes per year (n = 11), and more than 2 episodes per year (n = 38). Single nucleotide polymorphisms in the tlr4 gene (D299G, T399I) were determined by a real‐time polymerase chain reaction‐based fluorogenic probe technique; and card15 polymorphisms (L1007fsinsC, R702W, G908R) were determined by pyrosequencing. Results: Pouchitis affected 49% (49/101) of the study population. No correlation between pouchitis and the presence of TLR4 polymorphisms was found. The percentage of patients who harbored CARD15 mutations was significantly higher in patients with pouchitis than in patients without pouchitis (18% versus 8%; P < 0.05); 24% of pouchitis patients with more than 2 episodes per year harbored CARD15 mutations (P < 0.01 compared with the no pouchitis group). The CARD15 insertion mutation L1007fsinsC was present in 14% of patients with pouchitis and in 0% without pouchitis (P < 0.05). All patients who carried L1007fsinsC developed more than 2 episodes per year. Conclusions: CARD15 polymorphisms are seen in greater frequency in patients with pouchitis after IPAA for UC. These findings, if borne out in prospective analyses, suggest that CARD15 mutations, particularly L1007fsinsC, may predispose to the development of pouchitis after IPAA for UC.

Cigarette smoking and age at diagnosis of inflammatory bowel disease

Objectives: The incidence and age of onset of inflammatory bowel disease (IBD) appear to be changing. The aim of this study was to determine whether the prevalence of cigarette smoking differs among patients with Crohns disease (CD) or ulcerative colitis (UC) at the time of diagnosis compared with the general population and whether smoking history is related to the type and age of IBD onset. Methods: Prevalence rates of smoking at the time of IBD diagnosis were compared between patients with CD and UC from the IBD Center at the University of Pittsburgh Medical Center versus age‐, gender‐, and time period‐adjusted rates in the Pennsylvania general population. Analyses also were stratified by gender and diagnoses before and after 40 years of age, i.e., early and late onset. Results: There were 263 IBD patients (144 UC patients and 119 CD patients) seen in the IBD center between August 2000 and December 2002. The prevalence of active smoking was significantly higher at diagnosis in CD patients compared with the Pennsylvania general population (33% versus 24%, P = 0.04), particularly in those with CD onset at 40 years of age or later (47% versus 27%, P = 0.005). In contrast, smoking prevalence was significantly lower in UC patients than the general population (9% versus 28%, P < 0.0001), particularly among those with UC onset before the age of 40 years (6% versus 27%, P < 0.0001). Smoking cessation was associated with an approximate, but nonsignificant, 3‐fold higher likelihood of late‐onset UC compared with CD. Conclusions: Cigarette smoking is associated with the development of late‐onset CD and is protective against developing UC at any age, particularly early onset. Former smoking is associated with a high likelihood of developing late‐onset UC, but not CD.

Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice

Nonsteroidal anti-inflammatory drugs decrease sporadic colorectal carcinoma and adenomas in patients with familial adenomatous polyposis and in rodent models of sporadic colon cancer and familial adenomatous polyposis. Similarly, selective cyclooxygenase 2 inhibitors decrease adenomas in humans and rodents. However, their effects on chronic colitis and colitis-associated neoplasia are unknown. Interleukin 10−/− mice (C57/B6) were fed regular chow (n = 20) or chow with celecoxib (1,500 ppm, n = 18) or rofecoxib (75 ppm, n = 20) for 12 weeks. Twenty-eight percent of the celecoxib group died versus 5% of the control and rofecoxib groups (p < 0.05 compared with control). Celecoxib and rofecoxib increased the incidence of colitis (26% vs. 92% and 68%, p < 0.01), colitis score (0.4 ± 0.2 vs. 2.5 ± 0.3 and 2 ± 0.4, p < 0.01), aberrant crypt foci (0.5 ± 0.3 vs. 3.7 ± 2.6 and 2.8 ± 0.7, p < 0.01), aberrant crypts per mouse (4.11 ± 2.1 vs. 41.2 ± 9.7 and 27.1 ± 7.5, p < 0.01) and dysplasia (11% vs. 54% and 42%, p < 0.01). Similarly, indomethacin (9 ppm, n = 15) increased colitis score, aberrant crypt foci, and dysplasia after 27 days of treatment. Two selective cyclooxygenase 2 inhibitors exacerbate colitis and premalignant changes in the interleukin 10−/− mouse model of chronic colitis and colitis-associated colon carcinoma.

Early Jejunal Feeding Initiation and Clinical Outcomes in Patients with Severe Acute Pancreatitis

BACKGROUND Compared with parenteral nutrition, enteral nutrition reduces infectious complications and mortality in patients with severe acute pancreatitis (SAP). This study used clinical outcomes to investigate the association between time to initiation of distal jejunal feeding (DJF) and time to achievement of goal enteral feeding with clinical outcomes. METHODS A retrospective chart review was performed on all patients with SAP admitted to the medical intensive care unit (ICU) during a 1-year period. Collected data included demographic information, body mass index (BMI; kg/m(2)), Acute Physiology and Chronic Health Evaluation (APACHE) II scores at admission, time of onset of DJF, time to goal feeding, ICU length of stay, and mortality. RESULTS Time to starting DJF was longer in nonsurvivors (n = 4) than in survivors (n = 12) (17 vs 7 days, P < .05). All nonsurvivors had BMI >30 kg/m(2) (50% had BMI > 50 kg/m(2)). ICU length of stay was significantly associated with achievement of goal feeding. Three patients never reached goal feeding and spent 45.3 ± 19.6 days in the ICU; 7 patients reached goal feeding within 3 days of initiating DJF and spent 18 ± 1.7 days in the ICU; and 4 patients reached goal feeding within 3 days and spent 10.5 ± 3.5 days in the ICU. APACHE II scores were not significantly different among the 3 groups (16.7 ± 1.5, 12 ± 0.7, and 16.2 ± 1.2, respectively, P > .05). CONCLUSIONS Early initiation of DJF in the ICU was associated with reduced mortality in this cohort of patients with SAP. Early achievement of jejunal feeding goal early was associated with a shorter ICU length of stay, irrespective of the severity of SAP.

Economic Burden of Community-Based Disease-Associated Malnutrition in the United States

BACKGROUND The burden imposed by disease-associated malnutrition (DAM) on patients and the healthcare system in food-abundant industrialized countries is often underappreciated. This study measured the economic burden of community-based DAM in the United States. METHODS The burden of DAM was quantified in terms of direct medical costs, quality-adjusted life years lost, and mortality across 8 diseases (breast cancer, chronic obstructive pulmonary disease [COPD], colorectal cancer [CRC], coronary heart disease [CHD], dementia, depression, musculoskeletal disorders, and stroke). To estimate the total economic burden, the morbidity and mortality burden was monetized using a standard value of a life year and combined with direct medical costs of treating DAM. Disease-specific prevalence and malnutrition estimates were taken from the National Health Interview Survey and the National Health and Nutrition Examination Survey. Deaths by disease were taken from the Center for Disease Control and Prevention. Estimates of costs and morbidity were taken from the literature. RESULTS The annual burden of DAM across the 8 diseases was

Enteral Feeding Patients With Gastric Outlet Obstruction

156.7 billion, or

A Comprehensive Nutrition-Focused Quality Improvement Program Reduces 30-Day Readmissions and Length of Stay in Hospitalized Patients:

508 per U.S. resident. Nearly 80% of this burden was derived from morbidity associated with DAM; around 16% derived from mortality and the remainder from direct medical costs of treating DAM. The total burden was highest in COPD and depression, while the burden per malnourished individual was highest in CRC and CHD. CONCLUSION DAM exacts a large burden on American society. Therefore, improved diagnosis and management of community-based DAM to alleviate this burden are needed.