Does Obesity Influence the Risk of Clostridium difficile Infection Among Patients with Ulcerative Colitis?

BACKGROUND: Patients with ulcerative colitis (UC) are at an increased risk of Clostridium difficile infection (CDI) compared with the general population. Recent data suggest that obesity also increases the risk of CDI. AIMS: To examine whether obesity influences the risk of CDI among patients with UC. STUDY: We conducted a retrospective cross-sectional study of UC patients seen in gastroenterology clinic between January 1, 2014, and December 31, 2015. Records were reviewed for patients with the diagnosis of UC prior to 2014, and the first diagnosis of CDI between January 1, 2014, and December 31, 2015. Using body mass index (BMI), patients were classified into underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). Age-adjusted and multivariate logistic regression was performed including gender, tobacco use, UC disease duration, medication exposure, and vitamin D deficiency. RESULTS: Of the 636 patients with UC, 114 (18%) were obese, 232 (36%) overweight, 274 (43%) normal weight, and 16 (2.5%) underweight. Nineteen patients (3.0%) developed CDI during the study period. CDI risk was not associated with BMI (OR 0.90, 95% CI 0.79-1.02). Compared to normal weight patients, risk of CDI was not influenced by being obese (multivariate OR 0.63, 95% CI 0.15-2.58), overweight (multivariate OR 0.33, 95% CI 0.08-1.30), or underweight (multivariate OR 2.98, 95% CI 0.45-19.83). CDI was associated with ever use of TNF therapy (multivariate OR 6.09, 95% CI 2.07-17.93) but not vedolizumab (multivariate OR 0.76, 95% CI 0.08-7.36). CONCLUSIONS: Obesity does not appear to be associated with the risk of C. difficile infection among patients with UC.

Conservation of apolipoprotein A-I's central domain structural elements upon lipid association on different high-density lipoprotein subclasses.

The antiatherogenic properties of apolipoprotein A-I (apoA-I) are derived, in part, from lipidation-state-dependent structural elements that manifest at different stages of apoA-I's progression from lipid-free protein to spherical high-density lipoprotein (HDL). Previously, we reported the structure of apoA-I's N-terminus on reconstituted HDLs (rHDLs) of different sizes. We have now investigated at the single-residue level the conformational adaptations of three regions in the central domain of apoA-I (residues 119-124, 139-144, and 164-170) upon apoA-I lipid binding and HDL formation. An important function associated with these residues of apoA-I is the activation of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for catalyzing HDL maturation. Structural examination was performed by site-directed tryptophan fluorescence and spin-label electron paramagnetic resonance spectroscopies for both the lipid-free protein and rHDL particles 7.8, 8.4, and 9.6 nm in diameter. The two methods provide complementary information about residue side chain mobility and molecular accessibility, as well as the polarity of the local environment at the targeted positions. The modulation of these biophysical parameters yielded new insight into the importance of structural elements in the central domain of apoA-I. In particular, we determined that the loosely lipid-associated structure of residues 134-145 is conserved in all rHDL particles. Truncation of this region completely abolished LCAT activation but did not significantly affect rHDL size, reaffirming the important role of this structural element in HDL function.

Antagonistic roles of four SR proteins in the biosynthesis of alternatively spliced tissue factor transcripts in monocytic cells.

Following recruitment to solid tissues, peripheral blood monocytes express a number of proinflammatory molecules including TF, a trigger of coagulation that also promotes cell-cell interactions and tissue remodeling. Monocytes express two forms of TF: flTF, a highly coagulant transmembrane form, and asTF, a highly proangiogenic, soluble TF form. Biosynthesis of the two TF forms occurs via alternative processing of exon 5 during pre-mRNA splicing. Its inclusion results in flTF mRNA and its exclusion, asTF mRNA. We developed a splicing reporter system recently and determined that two spliceosomal constituents, SR proteins ASF/SF2 and SRp55, play a pivotal role in exon 5 inclusion. In this report, we show for the first time that two other SR proteins expressed in human monocytes, SRp40 and SC35, antagonize ASF/SF2 and SRp55 by competing for binding to certain sites in exon 5, thereby promoting TF exon 5 exclusion, an event unique to asTF biosynthesis. We also show that the intron preceding TF exon 5 possesses characteristics rarely found in U2 introns. Our findings indicate that modulation of TF pre-mRNA splicing can be accomplished via modification of SR proteins' activity, facilitating development of novel therapeutic strategies to modulate the "TF profile" of monocytes/macrophages.