Background and aim: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.

Background-Current guidelines for the treatment of hypertension do not provide specific recommendations for obese hypertensive patients. To identify an optimal treatment regimen for obese hypertensive patients, we studied the interactions between a drug-based weight loss approach by sibutramine and different antihypertensive drug regimens. Methods and Results-This was a prospective, 16-week double-blind placebo-controlled randomized multicenter study in 171 obese hypertensive patients. After a 2-week run-in period, patients receiving 1 of the 3 antihypertensive combination therapies (felodipine 5 mg/ramipril 5 mg [nϭ57], verapamil 180 mg/trandolapril 2 mg [nϭ55], or metoprolol succinate 95 mg/hydrochlorothiazide 12.5 mg [metoprolol/hydrochlorothiazide; nϭ59]) were assigned randomly to sibutramine (15 mg) or placebo. Sibutramine treatment resulted in a significantly greater decrease in body weight, body mass index, and waist circumference and a significant increase in diastolic blood pressure during 24-hour blood pressure monitoring compared with placebo treatment. Sibutramine-induced weight loss and reduction of visceral obesity were markedly attenuated in the metoprolol/hydrochlorothiazide group compared with the other groups. Consistently, improvement in glucose tolerance and hypertriglyceridemia by sibutramine was abrogated in the cohort treated with metoprolol/ hydrochlorothiazide compared with the other groups. Conclusions-The present study demonstrates for the first time that an antihypertensive combination therapy regimen with angiotensin-converting enzyme inhibitors and calcium channel blockers is more advantageous than a ␤-blocker/diuretic-based regimen in supporting the weight-reducing actions and concomitant metabolic changes induced by sibutramine in obese hypertensive patients. These data may help to develop future comprehensive treatment strategies and guidelines for this high-risk patient population.

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