Patients with end-stage renal disease have increased circulating concentrations of oxidatively modified circulating proteins. Therefore, we examined the ability of vitamin E alpha (alpha-tocopherol) to alter levels of these modified proteins.

We investigated the effect of elevated plasma free fatty acid and insulin concentrations on PDK4 mRNA transcript and protein content and long-chain acyl-coenzyme A accumulation in human skeletal muscle.

Our objective was to determine the impact of carbohydrate and/or protein ingestion before and after exercise on ribosomal protein S6 kinase (S6K1) and S6 phosphorylation status in human skeletal muscle tissue. Seven healthy, untrained men (22.5 +/- 0.9 y) were randomly assigned to 2 cross-over experiments. Before, immediately after, and 1 h after a single bout of resistance exercise, subjects consumed 0.3 g x kg(-1) carbohydrate with or without 0.3 g x kg(-1) protein hydrolysate (CHO+PRO and CHO, respectively). Muscle biopsies were taken before and immediately after exercise and after 1 and 4 h of postexercise recovery to determine 4E-BP1, S6K1 (both T(421)/S(424) and T(389)), and S6 phosphorylation status. Following resistance exercise, 4E-BP1 phosphorylation was reduced to a greater extent in the CHO treatment (-48 +/- 7%) than in the CHO+PRO treatment (-15 +/- 14%, P < 0.01). During recovery, 4E-BP1 phosphorylation increased in both experiments (P < 0.01), and tended to be higher in the CHO+PRO test (P = 0.08). S6K1 phosphorylation at T(421)/S(424) substantially increased following exercise and remained elevated during recovery with no differences between treatments. In contrast to the CHO treatment (-4 +/- 2%), S6K1 phosphorylation at T(389) was higher following exercise in the CHO+PRO treatment only (+78 +/- 2%, P < 0.01). During recovery, S6K1 phosphorylation at T(389) remained higher in CHO+PRO than in CHO (P < 0.05). S6 phosphorylation was substantially higher following exercise in the CHO+PRO (1.69 +/- 0.35) than in the CHO experiment (0.45 +/- 0.07, P < 0.01) and remained elevated during recovery (P < 0.05). We conclude that the availability of dietary protein further enhances phosphorylation of S6K1 during recovery from resistance type exercise.

Interleukin-17 (IL-17) is a pro-inflammatory cytokine produced from CD4+ T cells and is associated with neutrophilia in infection, ischemia-reperfusion injury, and possibly acute and chronic rejection (bronchiolitis obliterans syndrome, or BOS) after lung transplantation (LTx). Everolimus (ERL) decreases acute rejection, possibly via decreasing airway CD4+ cells and neutrophils. This prospective study aims to assess: (1) the possible role of IL-17 as a link between LTx clinical outcomes (such as infection, acute rejection and BOS) and airway immunopathologic measures from endobronchial biopsy (EBB) and bronchoalveolar lavage (BAL); and (2) any differences in IL-17 production between ERL and azathioprine (AZA)-based immunosuppression.

The purpose of this study was to determine the effects of soy protein isolate consumption on circulating hormone profiles and hormone receptor expression patterns in men at high risk for developing advanced prostate cancer. Fifty-eight men were randomly assigned to consume 1 of 3 protein isolates containing 40 g/d protein: 1) soy protein isolate (SPI+) (107 mg/d isoflavones); 2) alcohol-washed soy protein isolate (SPI-) (<6 mg/d isoflavones); or 3) milk protein isolate (0 mg/d isoflavones). For 6 mo, the men consumed the protein isolates in divided doses twice daily as a partial meal replacement. Serum samples collected at 0, 3, and 6 mo were analyzed for circulating estradiol, estrone, sex hormone-binding globulin, androstenedione, androstanediol glucuronide, dehydroepiandrosterone sulfate, dihydrotestosterone, testosterone, and free testosterone concentrations by RIA. Prostate biopsy samples obtained pre- and postintervention were analyzed for androgen receptor (AR) and estrogen receptor-beta expression by immunohistochemistry. At 6 mo, consumption of SPI+ significantly suppressed AR expression but did not alter estrogen receptor-beta expression or circulating hormones. Consumption of SPI- significantly increased estradiol and androstenedione concentrations, and tended to suppress AR expression (P = 0.09). Although the effects of SPI- consumption on estradiol and androstenedione are difficult to interpret and the clinical relevance is uncertain, these data show that AR expression in the prostate is suppressed by soy protein isolate consumption, which may be beneficial in preventing prostate cancer.

Epidemiological studies suggest that a diet rich in broccoli can reduce the risk of cancer at several sites. The anticarcinogenic activity has been largely attributed to the biological activity of sulforaphane (SF), the isothiocyanate derived from 4-methylsulphinylbutyl glucosinolate, which accumulates in broccoli. SF induces xenobiotic metabolizing genes in both cell cultures and animal models and induces genes associated with cell cycle arrest and apoptosis. However, it is not known whether these genes are induced in humans after consumption of broccoli. Sixteen subjects were recruited into a randomized, 3-phase crossover dietary trial of standard broccoli, high glucosinolate broccoli, and water. Global changes in gene expression that occurred 6 h after consuming broccoli soups or water were quantified in gastric mucosal tissue, using Affymetrix whole genome microarrays (n = 4), and in selected genes by real-time RT-PCR in the other individuals. Consumption of high glucosinolate broccoli resulted in up-regulation of several xenobiotic metabolizing genes, including thioredoxin reductase, aldoketoreductases, and glutamate cysteine ligase modifier subunit, which have previously been reported to be induced in cell and animal models after exposure to SF. Only 1 such gene was significantly up-regulated after consumption of standard broccoli. The consequences of these results in relation to the potential anticarcinogenic action of broccoli are discussed.

Chronic allograft nephropathy (CAN) remains a great challenge for the transplant clinician. The introduction of sirolimus (RAPA) with cyclosporine (CsA) reduction maybe shed new light to improve graft survival. The aim of this study was to investigate the overall effects of sirolimus conversion on biopsy-proven CAN.

In various observational studies, an inverse relation between calcium intake and body weight has been observed. A possible explanation could be an increased calcium excretion through the faeces caused by an increased dietary calcium intake.

NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH).

Aromatase inhibitors such as anastrozole and letrozole are highly effective suppressants of estrogen synthesis in postmenopausal women and are the most effective endocrine treatments for hormone receptor positive breast cancer in such women. Little is known of the molecular effects of these agents on human breast carcinomas in vivo.

This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients (P < 0.05). C(max) of PEG-IFN occurred 12-48 h after the initial administration, with t(1/2) and C(min) being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs (P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression.

The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.

Suppression subtractive hybridization was used to detect differential expression of genes in the livers of laying and prelaying geese. Liver tissues from prelaying and laying geese were dissected for mRNA extraction. The cDNA, reverse transcribed from liver mRNA of prelaying geese, was subtracted from the cDNA generated from the laying geese (forward subtraction). Five hundred seventy-six clones with possible differentially expressed gene fragments were observed by forward subtraction hybridization. After differential screening using the reverse and forward subtraction cDNA, 164 clones were subjected to gene sequence determination and further analysis. Using Northern analysis, 5 known and 8 unknown genes were shown to be highly expressed in the livers of laying geese compared with prelaying geese. Vitellogenin I, apoVLDL-II, ethanolamine kinase, G-protein gamma-5 subunit, and leucyl-tRNA synthase were highly expressed in the livers of laying geese compared with that from the prelaying geese (P<0.05). The expression of these known genes suggests that their function in the liver of laying geese is primarily involved in lipid and lipoprotein metabolism. Several of these differentially expressed genes were found to be responsive to estrogen stimulation, confirming the involvement of these genes in the egg-laying function of the goose.

The current study investigated whole-body O2 consumption, intestinal O2 consumption, and intestinal inflammation status through mucosal cytokine production on broiler chicks fed the direct-fed microbial PrimaLac. One hundred twenty 1-d-old broiler chicks were randomly assigned to 1 of 3 experimental diets: standard starter diet (control), standard starter diet with added salinomycin (SAL), and standard starter diet with added PrimaLac (DFM). Birds were housed in 2 separate rooms, the control and SAL treatments in one room and the DFM in another. Intact ileal and cecal samples were collected on d 19, 20, and 21 after measuring whole-body O2 consumption using indirect calorimetry. The O2 up-take of ileal tissue was measured using an in vitro O2 monitor. Analysis of intestinal immune status of broilers was measured by the relative differences in mRNA of both pro- and antiinflammatory cytokines: interleukin-(IL) 1beta, IL-6, and IL-10 using real-time reverse transcription-PCR. Broilers exhibited a 6 to 16% decrease in whole-body energy expenditures and up to a 47% decrease (P<0.05) in ileal energy expenditures in the DFM group compared with other treatments. The reverse transcription-PCR data demonstrated that DFM consortium numerically altered both pro- and antiinflammatory cytokines within the ileum of 19-d posthatch broilers. These data suggest that direct-fed microbials like PrimaLac increase metabolic efficiency via changes in intestinal physiology and metabolism.

The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis.

Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction.

Hepatic lipase (HL) catalyzes the hydrolysis of triglycerides and phospholipids from lipoproteins, and promotes the hepatic uptake of lipoproteins. A common G-250A polymorphism in the promoter of the hepatic lipase gene (LIPC) has been described. The aim was to study the effects of the G-250A polymorphism on HL activity, serum lipid profile and insulin sensitivity.

Anesthetic gases modulate gene expression and provide organ protection. This study aimed at identifying myocardial transcriptional phenotypes to predict cardiovascular biomarkers and function in patients undergoing off-pump coronary artery bypass graft surgery.

The role of oxidative stress in the pathogenesis of vascular diseases such as hypertension has been well recognized. Angiotensin (Ang) II is regarded as a pro-oxidant because it can stimulate the production of reactive oxygen species. The purpose of this study was to evaluate whether treatment with the Ang II type 1 (AT(1)) receptor antagonist valsartan has an antioxidant effect in patients with mild to moderate hypertension. A randomized, double-blind, placebo-controlled study was conducted in 48 stage I and II hypertensive subjects. Patients were followed every 4 weeks for 12 weeks after randomization to valsartan titrated to 80 to 160 mg once or twice daily or matching placebo. The erythrocyte superoxide dismutase (SOD) activity and expression of SOD-mRNA in polymorphonuclear leukocytes were measured before and after treatment. Valsartan showed concentration-dependent inhibition of reactive oxygen species generation in polymorphonuclear leukocytes from hypertensive patients. The erythrocyte superoxide dismutase activity before treatment was more than 2 times higher in hypertensive subjects compared to normal controls. Superoxide dismutase activity decreased significantly after 12 weeks of treatment with valsartan but did not change with placebo. The amount of SOD-mRNA in the polymorphonuclear leukocytes decreased progressively over 3 months in the hypertensive subjects receiving valsartan treatment but did not change in the placebo group. The production of reactive oxygen species is increased in hypertension, and superoxide dismutase activity is increased, presumably as a compensatory mechanism. Treatment with valsartan but not placebo resulted in a progressive down-regulation of SOD-mRNA expression and a reduction in superoxide dismutase activity, suggesting antioxidant activity and a reduction of reactive oxygen species generation. These findings imply that AT(1) receptor antagonists may provide benefits to hypertensive patients beyond blood pressure reduction.

Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results suggest that an increased serotonergic activity disrupts habituation, but not PPI in healthy volunteers.