NAD+ ameliorates inflammation-induced epithelial barrier dysfunction in cultured enterocytes and mouse ileal mucosa

In the course of other experiments, we serendipitously observed that extracellular nicotinamide adenine dinucleotide (NAD+) ameliorated the development of epithelial hyperpermeability when monolayers of Caco-2 enterocyte-like cells were incubated with cytomix, a mixture containing interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha. We sought to characterize the effects of NAD+ on inflammation-induced epithelial barrier dysfunction using Caco-2 monolayers that were exposed to cytomix in the absence or presence of NAD+ or other purine-containing molecules. Paracellular barrier function measured as the apical-to-basolateral passage of fluorescein isothiocyanate-conjugated dextran (mol. wt. approximately 4000) was preserved in a concentration-dependent manner when immunostimulated Caco-2 cells were exposed to extracellular NAD+. Incubation with NAD+ prevented cytomix-induced derangements in the expression and localization of the tight junction proteins occludin and zonula occludens-1 in Caco-2 cells. Treatment of cytomix-stimulated cells with NAD+ also blocked nuclear factor-kappaB (NF-kappaB) activation, inducible nitric-oxide synthase induction, and increased production of nitric oxide (NO.). Ileal mucosal permeability to fluorescein isothiocyanate-dextran mol. wt. approximately 4000 was increased in mice 18 h after lipopolysaccharide (endotoxin) injection, but treatment of endotoxemic mice with NAD+ ameliorated the development of gut mucosal hyperpermeability. Thus, extracellular NAD+ seems to ameliorate inflammation-induced intestinal epithelial barrier dysfunction by inhibiting NF-kappaB activation and increased NO. production.     

Roundtable Conference on Tissue Oxygenation in Acute Medicine, Brussels, Belgium, 14–16 March 1998

* Nutritional tissue perfusion and tissue metabolic demand are heterogeneously distributed. * Oxygen diffusion occurs preferentially at the precapillary arteriolar level. * Determination of adequacy of tissue oxygenation requires local organ measurements. * While there remains considerable variability in individual RBC transfusion practices, a recent clinical trial questioned the efficacy of RBC transfusion to hemoglobin concentrations greater than 80 gm/l in patients without heart disease [63]. * RBC substitutes, including cell-free hemoglobin solutions and PFC solutions are efficacious, yet may exhibit a number of direct vascular effects.     

Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis

OBJECTIVE: To evaluate the effectiveness of ingesting creatine monohydrate in elevating intramuscular creatine stores and improving exercise capacity in individuals with multiple sclerosis (MS). DESIGN: Randomized, double-blind, placebo-controlled, pre-posttrial. SETTING: A university-based exercise physiology laboratory. PARTICIPANTS: Sixteen individuals with relapsing-remitting MS (median Expanded Disability Status Scale score, 4.75; range, 1.5-6.0). INTERVENTION: Eight individuals with MS were randomized to the creatine group (20g/d of creatine monohydrate for 5d), and 8 others were randomized to the placebo group. Needle biopsies were performed on the vastus lateralis at rest before and after treatment. Subjects performed 3 bouts of 30 maximal knee extensions and flexions at 180 degrees /s with 1 minute of recovery between bouts before and after treatment. MAIN OUTCOME MEASURES: Intramuscular total creatine, phosphocreatine, free creatine, and total work output. RESULTS: Creatine ingestion did not significantly elevate intramuscular total creatine, phosphocreatine, or free creatine or improve total work production. CONCLUSION: Creatine ingestion had no significant effect on muscle creatine stores or high-intensity exercise capacity in individuals with MS.     

Randomized clinical trials: issues for researchers

The clinical trial is a randomized prospective study of human subjects in which the effectiveness of an intervention is compared against a control. Such a trial is considered to be a critical test of an innovative therapy. Trials require careful design and planning to be scientifically valid and clinically pertinent. In this review the clinical trial and its role in research are defined, and major ethical, methodological, and feasibility issues associated with trial design and organization are described.     

Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]

OBJECTIVE: The aim of this randomized cross-over study was the comparison between a sequential 28-day hormone replacement therapy (HRT) using micronized estradiol and a cyclic 21-day HRT using estradiol valerate with regard to the pharmacokinetics of estradiol. - MATERIAL AND METHODS: Fifty postmenopausal women were randomly assigned to be treated either with Trisequens(R) for 28 days or with Sisare(R) for 21 days. After a wash-out cycle, the women were treated for one cycle with the other preparation in a cross-over fashion. The pharmacokinetic profile of the serum concentrations of estradiol was measured on day 1, 21 and 28 each immediately before and 1, 2, 4, 6, 8, and 10 hours after intake of a tablet, and the AUC (area under the curve) was calculated. - RESULTS: The serum concentrations of estradiol increased from a mean of 10 pg/ml up to 40 pg/ml (Trisequens(R)) and 30 pg/ml (Sisare(R)) on day 1, and to 80 pg/ml (Trisequens(R)) and 60 pg/ml (Sisare(R)) on day 21, and declined to 40 pg/ml (Trisequens(R)) and 10 pg/ml (Sisare(R)) on day 28. The AUC as calculated from both treatment cycles, was significantly higher on day 1, 21, and 28 during treatment with Trisequens(R) than with Sisare(R). This difference was, however, not signifcant on day 1 and 21 of the first treatment cycle. - CONCLUSION: During treatment with 2 mg micronized estradiol the serum concentrations are significantly higher than with 2 mg estradiol valerate. On day 28 of treatment with Sisare(R), the estradiol levels decline to baseline values, while using Trisequens(R) they remain in the range of those measured on day 1.