Improving the detection of environmental enteric dysfunction: a lactulose, rhamnose assay of intestinal permeability in children aged under 5 years exposed to poor sanitation and hygiene.

BACKGROUND: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder affecting populations living in conditions of poor sanitation and hygiene. The study tested intestinal barrier function in infants with EED. METHODS: We prospectively studied an advanced high-performance liquid chromatography mass spectrometry assay of urine collected after oral intake of the monosaccharide, L-rhamnose and the disaccharide, lactulose, in 112 children from three continents. FINDINGS: Compared to the US cohort (n=27), the cohorts of children from Peru (n=19) and Zambia (n=85) were older with evidence of growth impairment. The median (range) of age (months) was 8.0 (2.0 to 13.0), 27.0 (15.0 to 29.0) and 21.0 (12.0 to 36.0), respectively. The median (range) of height for age Z score was -0.1 (-1.8 to 2.4), -1.8 (-3.3 to -0.2) and -2.3 (-8.5 to 1.2), respectively. Among children with valid sugar data (n=22 USA, n=19 Peru, n=73 Zambia), there were no significant differences in the median rhamnose urine concentrations between the three groups. The median (range) lactulose concentration (µg/mL) was 6.78 (0.29 to 31.90), 47.60 (4.23 to 379.00) and 75.40 (0.67 to 873.00) in the US, Peruvian and Zambian cohorts, respectively (p<0.001). The lactulose/rhamnose ratio (LRR) was higher in cohorts from Peru (0.75, 0.15, 5.02) and Zambia (2.26, 0.08, 14.48) compared to the US (0.14, 0.06, 1.00) cohort (p<0.001). In a multivariate effect modification model, higher weight-for-age z scores were associated with lower post-dose lactulose when rhamnose excretion was constant (p=0.003). CONCLUSIONS: This non-invasive two saccharide permeability protocol measures changes in intestinal permeability in children with EED and permits the identification of individuals for interventional trials.

Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients.

BACKGROUND: Anti-TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD). AIM: To determine if anti-TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD. METHODS: We retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti-TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti-TNFα exposure was estimated for IBD; CD and UC groups separately. RESULTS: A total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti-TNFα agents (4/2054) and five patients with CD without anti-TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti-TNFα agents (1/1371) and five patients with UC without anti-TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti-TNFα exposure was; IBD: 0.15% and 0.18% (RR = 0.83, 95% CI: 0.28-2.42; P = 0.729); CD: 0.19% and 0.22% (RR = 0.89, 95% CI: 0.24-3.31; P = 0.863); UC: 0.07% and 0.15% (RR = 0.49, 95% CI: 0.06-4.22; P = 0.510). CONCLUSION: Anti-TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease.

Natalizumab for moderate to severe Crohn's disease in clinical practice: the Mayo Clinic Rochester experience.

BACKGROUND: Not all patients with Crohn's disease (CD) respond or maintain response to anti-tumor necrosis factor (TNF) agents and alternative treatment is necessary. Natalizumab, a monoclonal antibody to alpha-4 integrin approved for CD, has demonstrated efficacy in randomized clinical trials. We describe our experience with natalizumab in clinical practice at Mayo Clinic Rochester. METHODS: Consecutive patients prescribed natalizumab for active CD were invited to participate and were followed prospectively. Incidence of infection, hospitalization, neoplasm, or other adverse events were recorded. Clinical activity was assessed using the Harvey-Bradshaw Index at each 30-day infusion visit. RESULTS: Between April 2008 and September 2010, 36 patients were prescribed natalizumab and 30 (83.3%) agreed to participate. Median disease duration was 9 years (range, 3-43). Twenty-three patients had prior exposure to two anti-TNF agents, seven to one agent. All patients experienced at least one adverse event; none of the 13 patients in whom natalizumab was stopped (43%) discontinued due to adverse events. Five patients had infusions held for infection. No patient developed progressive multifocal leukoencephalopathy (PML). Fourteen patients (46%) had clinical response. The cumulative probability of achieving complete response within 1 year was 56% (28%-73%). Four of seven patients were weaned off corticosteroids. CONCLUSIONS: In our experience with natalizumab in clinical practice, adverse events were manageable and did not result in treatment cessation. No PML cases were seen and clinical response was similar to that in clinical trials. Natalizumab results in clinical benefit in patients who have active disease and have failed anti-TNF therapy.

Review article: biological activity markers in inflammatory bowel disease.

BACKGROUND: Traditionally, inflammatory bowel disease activity is assessed by clinical activity indices that measure clinical symptoms and endoscopic indices that measure endoscopic inflammation. Biological markers are a non-invasive way of objectively measuring inflammation and can play an adjunctive or primary role in the assessment of disease activity. AIM: To review the data on biological markers for assessment of disease activity and prediction of relapse in inflammatory bowel disease. METHODS: To collect relevant articles, a PubMed search was performed from 1980 to 2006 using following search terms in combination: inflammatory bowel disease, biomarkers, inflammation, disease activity, relapse, acute phase reactants cytokines, interleukins, adhesion molecules, integrins, calprotectin and lactoferrin. RESULTS: Biological activity markers can be classified into serological, faecal and miscellaneous categories. Acute phase reactants levels correlate with disease activity and some can be used to help predict relapse. Cytokines and adhesion molecules are elevated in active disease inconsistently. Faecal markers are useful in assessment of disease activity and relapse. CONCLUSIONS: Acute phase reactants and faecal markers are useful to assess the disease activity in clinical practice. More data are required on cytokines and adhesion molecules. C-reactive protein, erythrocyte sedimentation rate, interleukins and faecal markers may be useful in predicting a relapse.

Pediatric "PSC-IBD": a descriptive report of associated inflammatory bowel disease among pediatric patients with psc.

BACKGROUND: Inflammatory bowel disease (IBD) in adults with primary sclerosing cholangitis (PSC) is characterized by pancolonic involvement, a high frequency of rectal sparing, and an increased risk of pouchitis and colorectal neoplasia. The clinical features of IBD in pediatric patients with PSC have not been well described. The aim of this study was to characterize the frequency, clinical features, and natural history of IBD in pediatric patients diagnosed with PSC. METHODS: A retrospective chart review was performed for all patients 18 years of age or younger diagnosed with PSC seen at the Mayo Clinic between 1975 and 1999. Endoscopic and histologic features and surgical and postsurgical outcomes were recorded. RESULTS: Fifty-two children with PSC were identified. Forty-three patients (84%) were also diagnosed with IBD. In 36 of 43 cases, there was a sufficient diagnostic evaluation to allow a detailed review. Thirty-two of 36 patients (89%) had ulcerative colitis and 4 of 36 patients (11%) had Crohn's disease. In 4 of 36 patients (11%), IBD was asymptomatic. Although the most frequent endoscopic presentation of IBD was universal colitis, endoscopic rectal sparing was frequently noted (27% of colonoscopic studies). Of the four patients diagnosed with Crohn disease, in none did perianal, fistulizing, or stricturing disease develop. Proctocolectomy was performed in six patients (17%); three operations were performed for dysplasia. Pouchitis complicated four of the five ileal pouch-anal anastomoses procedures. CONCLUSIONS: Among pediatric patients (1) PSC without IBD is uncommon; (2) asymptomatic IBD may be associated with PSC; (3) because the time to dysplasia may be accelerated, once the diagnosis of IBD is made in the setting of PSC, heightened endoscopic surveillance may be indicated; (4) pouchitis occurs frequently in these patients.

Development of chronic colitis is dependent on the cytokine MIF.

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.

The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.

BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. RESULTS: Seventy-four (43%) patients with Crohn's disease and 63 (34%) with ulcerative colitis were treated with corticosteroids. Immediate outcomes for Crohn's disease were complete remission in 43 (58%), partial remission in 19 (26%), and no response in 12 (16%). Immediate outcomes for ulcerative colitis were complete remission in 34 (54%), partial remission in 19 (30%), and no response in 10 (16%). One-year outcomes for Crohn's disease were prolonged response in 24 (32%), corticosteroid dependence in 21 (28%), operation in 28 (38%), and lost to follow-up in 1 (1%). One-year outcomes for ulcerative colitis were prolonged response in 31 (49%), corticosteroid dependence in 14 (22%), and operation in 18 (29%). CONCLUSIONS: Most patients with Crohn's disease and ulcerative colitis initially respond to corticosteroids. At 1 year, 32% of patients with Crohn's disease and 48% with ulcerative colitis are corticosteroid free without operation.

Clinical pharmacology of inflammatory bowel disease therapies.

Knowledge about the clinical pharmacology of medical therapy of inflammatory bowel disease has incrementally advanced. Small studies with mesalamine have suggested that intestinal mucosal concentrations of mesalamine may predict clinical response to mesalamine therapy. Increased expression of glucocorticoid receptor beta and increased expression of the multidrug resistance drug pump P-glycoprotein 170 have been proposed as markers of drug resistance to glucocorticoids. A baseline determination of thiopurine methyltransferase phenotype or genotype may predict early leukopenia in patients treated with azathioprine or 6- mercaptopurine. Serial measurement of erythrocyte 6-thioguanine nucleotides may be useful in tailoring the dose of these medications. A loading dose of intravenous azathioprine does not accelerate the time to response in patients with steroid-treated Crohn's disease; however, standard azathioprine may work more quickly than previously reported. Methotrexate, 15 to 25 mg/wk, is effective for the treatment of Crohn's disease (active or in remission), and there is no significant difference in the erythrocyte concentrations of methotrexate polyglutamate in patients with inflammatory bowel disease receiving 15 mg, compared with 25 mg, subcutaneously on a weekly basis.

Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas.

Cholestatic liver injury appears to result from the induction of hepatocyte apoptosis by toxic bile salts such as glycochenodeoxycholate (GCDC). Previous studies from this laboratory indicate that cathepsin B is a downstream effector protease during the hepatocyte apoptotic process. Because caspases can initiate apoptosis, the present studies were undertaken to determine the role of caspases in cathepsin B activation. Immunoblotting of GCDC-treated McNtcp.24 hepatoma cells demonstrated cleavage of poly(ADP-ribose) polymerase and lamin B1 to fragments that indicate activation of effector caspases. Transfection with CrmA, an inhibitor of caspase 8, prevented GCDC-induced cathepsin B activation and apoptosis. Consistent with these results, an increase in caspase 8-like activity was observed in GCDC-treated cells. Examination of the mechanism of GCDC-induced caspase 8 activation revealed that dominant-negative FADD inhibited apoptosis and that hepatocytes isolated from Fas-deficient lymphoproliferative mice were resistant to GCDC-induced apoptosis. After GCDC treatment, immunoprecipitation experiments demonstrated Fas oligomerization, and confocal microscopy demonstrated DeltaFADD-GFP (Fas-associated death domain-green fluorescent protein, aggregation in the absence of detectable Fas ligand mRNA. Collectively, these data suggest that GCDC-induced hepatocyte apoptosis involves ligand-independent oligomerization of Fas, recruitment of FADD, activation of caspase 8, and subsequent activation of effector proteases, including downstream caspases and cathepsin B.

Cystatin A expression reduces bile salt-induced apoptosis in a rat hepatoma cell line.

We have previously demonstrated abrogation of bile salt-induced apoptosis by cathepsin B inhibitors. However, caspases have been strongly implicated in apoptosis, and the mechanistic interface between caspase and cathepsin B activation is unclear. Thus our aims were to determine the mechanistic relationship between caspases and cathepsin B in bile salt-induced apoptosis in a rat hepatoma cell line. Expression of cystatin A was used to inhibit cathepsin B, whereas Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) was used to inhibit caspases. Cystatin A expression prevented cathepsin B activation and apoptosis during treatment with glycochenodeoxycholate (GCDC), a toxic bile salt. Caspase N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin (DEVD-AMC) hydrolytic activity increased in both wild-type and cystatin A-transfected cells treated with GCDC, demonstrating caspase activation despite inhibition of cathepsin B. In contrast, Z-VAD-FMK blocked both DEVD-AMC hydrolytic activity and cathepsin B activity during GCDC treatment. Our data demonstrate that 1) bile salt-induced apoptosis can be inhibited by the cystatin A transgene and 2) caspase and cathepsin B activation are linked mechanistically with cathepsin B downstream of caspases.

Gastroesophageal reflux in infants and children.

Gastroesophageal reflux is a common pediatric complaint and a frequent reason for pediatric patients to be referred to a gastroenterologist. The pathophysiology and clinical manifestations of this disorder differ according to patient age. The diagnosis is suggested by the history and can be confirmed by a pH probe. In the appropriate clinical setting, anatomic obstruction may need to be ruled out by contrast study. Endoscopy is used to assess associated complications, including esophagitis, esophageal strictures, Barrett's transformation, and failure to thrive. Other complications are controversial, including pulmonary disease, apnea, and sudden infant death syndrome. Treatment depends on the severity of disease. Conservative therapy includes behavorial modifications, prokinetic agents, and H2 antagonists. Proton pump inhibitors are generally reserved for refractory esophagitis. Surgical treatment may be necessary for gastroesophageal reflux resistant to medical management or for severe complications. Gastroesophageal reflux beyond infancy tends to be chronic; therefore, lifelong behavioral modifications or repeated courses of medical therapy may be necessary. An algorithm for the suggested diagnostic approach to gastroesophageal reflux is presented herein.

Spinal cord surgery and galactorrhea: a case report.

We report the case of a 39-year-old nonpregnant woman with amenorrhea and galactorrhea after spinal cord surgery. Activation of the afferent neuroendocrine pathway is postulated to have occurred at surgery.