In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects.

To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6.

To evaluate the mechanism of action of recombinant human tumor necrosis factor (TNF)-binding protein-1 by assessing differential expression of messenger RNA (mRNA) for cytokines, matrix metalloproteinases, and growth and adhesion factors in baboons.

The purpose of this study was to determine the influence of gender and antioxidant supplementation on exercise-induced oxidative stress. Twenty-five men and 23 women ran for 30 min at 80% VO2 max, once before and once after 2 weeks of supplementation, and again after a 1-week wash-out period. Subjects were randomly assigned to either placebo (P), antioxidant (A: 400 IU vitamin E+1 g vitamin C), or a fruit and vegetable powder (FV) treatment. Blood was obtained at rest and immediately after exercise. Before supplementation, women had higher resting reduced glutathione, total glutathione, and plasma vitamin E compared with men. With both A and FV supplementations, plasma vitamin E gender differences disappeared. Protein carbonyls, oxidized glutathione, and malondialdehyde all increased similarly for both genders in response to exercise. Both A and FV attenuated the reduced glutathione decrease and the oxidized glutathione and protein carbonyls increase compared with P, with no gender differences. 8-hydroxydeoxyguanosine was lower with treatment A compared with FV and P only for men. Plasma vitamin C increased 39% (A) and 21% (FV) compared with P. These data indicate that women have higher resting antioxidant levels than men. Markers of oxidative stress increased similarly in both genders in response to exercise of similar intensity and duration. Two weeks of antioxidant supplementation can attenuate exercise-induced oxidative stress equally in both genders.

Our previous study showed that aspirin induced apoptosis of esophageal cancer cells in vitro by inhibiting the pathway of NF-kappaB downstream regulation of cyclooxygenase-2. The purpose of this study was to determine if similar changes occurred in vivo in the tumors of patients with SCC of the esophagus who were given a preferential COX-2 inhibitor, meloxicam. Fifty-three patients who had an esophagectomy for SCC were allocated randomly to either a Treatment group (n = 25) or a control group (n = 28). Patients in the Treatment group were given 7.5 mg/day of meloxicam, for between 10 and 14 days before surgery. Patients in the control group did not take any type of NSAID during this time interval. Samples of the tumor taken from the resected specimens were collected. Proliferation and apoptosis were measured by flow cytometry. The concentration of 6-keto-prostaglandin F(1)alpha in cancer tissue was determined by radio-immuno-assay. Expression of COX-2 mRNA was measured with RT-PCR and COX-2 protein levels with Western blot analysis. Nuclear NF-kappaB and cytoplasmic I kappaB protein levels were determined by electrophoretic mobility shift assay and Western blot, respectively. There were significantly more apoptotic cells in the tumors of patients who were using meloxicam. It also decreased the levels of COX-2 mRNA, COX-2 protein and nuclear NF-kappaB protein and increased the cytoplasmic I kappaB protein in the cancer. We conclude that meloxicam induces apoptosis in SCC of the esophagus in vivo by inhibiting the pathway of NF-kappaB downstream regulation of COX-2.

Behcet's disease (BD) is an inflammatory disorder of an unknown cause, but growing evidence indicates that the oxidative stress is increased in BD, owing to the overproduction of reactive oxygen species (ROS) and decreased efficiency of antioxidant defenses. ROS affect proteins and lipids and cause their oxidation, therefore, contributing to the formation of oxidation products: carbonyl, a marker of protein oxidation, and malondialdehyde (MDA), a marker of lipid peroxidation. The investigation was undertaken to evaluate protein oxidation (carbonyl group) levels and lipid peroxidation (MDA) levels, and the role of colchicine and vitamin E therapy on protein carbonyl group and MDA levels in serum samples of patients with BD. In this study, subjects were classified as control group, colchicine therapy group alone and colchicine and vitamin E therapy group. Protein carbonyl and MDA levels at the beginning of the study were significantly (p < 0.05) higher in both therapy groups compared with those of the control group. We found that the protein carbonyl and MDA levels at the end of the study showed no significant (p > 0.05) differences between the therapy groups and control group. These results provide some evidence for a potential effect of colchicine and vitamin E therapies on increased protein oxidation and lipid peroxidation in BD.

The combination of simvastatin, an HMG-CoA reductase inhibitor, and ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, decreases cholesterol synthesis and absorption and reduces circulating LDL-cholesterol concentrations. The molecular mechanisms underlying the pronounced lipid-lowering effects of this combination have not been fully elucidated in humans.

Bu-zhong-yi-qi-tang, an ancient formula of Chinese medicine usually used in the treatment of allergic diseases, was evaluated in the treatment of patients with perennial allergic rhinitis. In this study, 60 patients allergic to house dust mite allergen confirmed by skin test and MAST test were recruited and randomized. An experimental group of 36 patients was treated with Bu-zhong-yi-qi-tang, whereas a control group of 24 patients was treated with a non-effective formula Ping-wei-san for 3 months. The nasal symptomatic scores and the responses of polymorphonuclear neutrophils (PMN) to IL-4-stimulation were measured after treatment. The nasal symptomatic scores in the experimental group were significantly improved (3.78+/-0.09 before treatment vs. 0.57+/-0.06 after treatment). In contrast, no change was found in symptomatic scores in the control group (3.17+/-0.12 before treatment vs. 2.79+/-0.14 after treatment). Moreover, total serum IgE and the IL-4-stimulated production of PGE(2) and LTC(4) by PMN was significantly suppressed in the experimental group after treatment compared to the control group. The COX-2 mRNA expression in IL-4-stimulated PMN was also significantly suppressed after Bu-zhong-yi-qi-tang treatment. These results suggest that Bu-zhong-yi-qi-tang but not Ping-wei-san was beneficial to the patients with perennial allergic rhinitis via suppressed nasal inflammation by an antiinflammatory effect.

Creatine monohydrate (CrM) supplementation has been shown to increase fat-free mass and muscle power output possibly via cell swelling. Little is known about the cellular response to CrM. We investigated the effect of short-term CrM supplementation on global and targeted mRNA expression and protein content in human skeletal muscle. In a randomized, placebo-controlled, crossover, double-blind design, 12 young, healthy, nonobese men were supplemented with either a placebo (PL) or CrM (loading phase, 20 g/day x 3 days; maintenance phase, 5 g/day x 7 days) for 10 days. Following a 28-day washout period, subjects were put on the alternate supplementation for 10 days. Muscle biopsies of the vastus lateralis were obtained and were assessed for mRNA expression (cDNA microarrays + real-time PCR) and protein content (Kinetworks KPKS 1.0 Protein Kinase screen). CrM supplementation significantly increased fat-free mass, total body water, and body weight of the participants (P < 0.05). Also, CrM supplementation significantly upregulated (1.3- to 5.0-fold) the mRNA content of genes and protein content of kinases involved in osmosensing and signal transduction, cytoskeleton remodeling, protein and glycogen synthesis regulation, satellite cell proliferation and differentiation, DNA replication and repair, RNA transcription control, and cell survival. We are the first to report this large-scale gene expression in the skeletal muscle with short-term CrM supplementation, a response that suggests changes in cellular osmolarity.

Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group.

The present study was undertaken to explore the effect of administration of high doses of sodium selenite on the expression of Bcl-2 in patients with non-Hodgkin's lymphoma (NHL). Fifty patients with newly diagnosed NHL were randomly divided into two groups. Group A-I received standard chemotherapy whereas group A-II received adjuvant sodium selenite 0.2 mg kg-1 day-1 for 30 days in addition to chemotherapy. Enzyme-linked immunosorbent assay was used to assess Bcl-2 at the time of diagnosis and after therapy in the two groups. Sodium selenite administration resulted in significant decline of Bcl-2 level after therapy in group A-II (8.6 +/- 6.9 ng/ml vs 3 6.9 +/- 7.9 ng/ml, P < 0.05). Also, complete response reached 60% in group A-II compared to 40% in group A-I. Significant increase in CD4/CD8 ratio was noticed in group A-II compared to group A-I after therapy (1.45 +/- 0.36 vs 1.10 +/- 0.28 p 0.04). Overall survival time in months was significantly longer in complete remission patients in group A-II (21.87 +/- 1.41) compared to group A-I (19.70 +/- 1.95) (p = 0.01). It is concluded that sodium selenite administration at the dosage and duration chosen acts as a down regulator of Bcl-2 and improves clinical outcome.

We report the effects of supplemental chromium (Cr) on interferon-gamma (IFN-gamma) expression in response to Newcastle disease virus (NDV) vaccine in broiler chicken. Two hundred and eighty day old straight run broiler chicks were randomly selected and allocated at random to one of the seven treatment groups replicated four times having 10 chicks in each replication. Treatment 1 (C) was a standard control diet in which no Cr was offered to birds either through feed or drinking water. In treatments 2-4 (F500, F1000 and F1500), Cr in the form of chromium picolinate (CrPic) was added at rates of 500, 1000 and 1500 ppb in diets, respectively. In treatments 5-7 (W250, W500 and W750), Cr as added to the drinking water at rates of 250, 500 and 750 ppb, respectively. The feeding was continued from 1 to 49 d of age. On 49 d, three birds from each replicate, i.e. 12 birds/treatment were inoculated intramuscularly with R(2)B strain of NDV. Twelve unvaccinated birds along with 12 vaccinated birds from each treatment (four birds each day) were then sacrificed on 1, 3 and 7 days post-immunization to study the IFN-gamma expression using quantitative real time PCR. Following the immunization, the IFN-gamma mRNA expression in spleen was significantly (P<0.01) either up-regulated or down-regulated at day 1 and day 3 post-stimulation. Whereas, IFN-gamma mRNA expression reached basal level in all the vaccinated groups at day 7 post-stimulation. IFN-gamma mRNA expression on day 1 was approximately two and four times higher than the control (C) levels in F500 and W500 groups, respectively. On 3 day post-immunization, IFN-gamma mRNA expression in spleen was about 40 and 27 times higher than controls (C) in F500 and W500 groups, respectively. Other groups (F1000, F1500, W250 and W750) showed down-regulation of IFN-gamma mRNA expression. The results suggested that the dosage of chromium modulates the expression of IFN-gamma and route has effect on the onset and duration of the response. Thus, the supplementation of chromium at appropriate dose might be helpful to enhance the IFN-gamma mRNA expression in response to NDV.

Warfarin prevents stroke in atrial fibrillation (AF); however, concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly. The oral direct thrombin inhibitors (DTIs) are potential alternatives to warfarin, offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring. Although ximelagatran, a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials, has been withdrawn, development of other DTIs continues. We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy.

To investigate the relationship between HER-2 expression and the efficacy of neoadjuvant chemotherapy in local advanced breast cancer.

Increased cardiovascular risk in hemodialysis patients may be related to augmented oxidative stress and inflammation, for which no proven beneficial therapies are available.

Oxidative stress is associated with maladaptive cardiac remodeling and vascular dysfunction and may be an important contributor to chronic heart failure (CHF) deterioration. We sought to investigate if the calcium sensitizer levosimendan beneficially modulates circulating markers of oxidative and nitrosative stress thus lessening their deleterious effects in patients with advanced CHF.

Increased dietary protein intake rapidly (3 h) decreases malic enzyme and increases hepatic histidase mRNA expression. Experiments were conducted to determine the role that individual dispensable amino acids and nonprotein N sources might have in regulating the activity of these enzymes and to determine if the addition of a N supplement to a practical broiler diet during the entire rearing period would reduce abdominal fat accumulation in broilers. Broiler chicks were fed a basal diet containing 22% protein or this diet supplemented with 9.5% l-Glu, 5% Gly, 6% l-Ala, 5.08% ammonium bicarbonate, or 4.25% dibasic ammonium phosphate for 24 h. Each of the dietary supplements added 0.90% total N to the diet. Hepatic malic enzyme mRNA expression was significantly (P < 0.05) depressed in chicks fed any of the supplemented diets compared with chicks fed the basal diet. Histidase mRNA expression, however, was only significantly increased in the chicks fed the basal diet supplemented with Gly. Broilers fed practical corn-soybean meal starter and developer diets supplemented with 2.3, 4.7, or 9.5% Glu from 0 to 40 d of age had significantly smaller abdominal fat pads relative to BW than broilers fed the unsupplemented corn-soybean meal diets. Feeding the Glu supplements, however, reduced the overall BW gain of broilers by 100 to 150 g compared with broilers fed the unsupplemented diets. The results suggest that hepatic mRNA expression of malic enzyme may be regulated by total dietary N intake, whereas hepatic mRNA expression of histidase may be regulated by specific amino acids.

The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p'-chlorophenyl)ethane (o,p'-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p'-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18-60 years, the CYP3A4 activity was determined based on the urinary 6beta-hydroxycortisol/cortisol (6beta-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6beta-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6beta-OHC/FC ratio than men (p=0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6beta-OHC/FC ratios and summation PCB, PCB-TEQ and p,p'-DDE, o,p'-DDT and HCB, respectively, but the associations were statistically significant for men only.

Probiotics are currently employed for control of pathogens and enhancement of immune response in chickens. In this study, we investigated the underlying immunological mechanisms of the action of probiotics against colonization of the chicken intestine by Salmonella enterica subsp. enterica serovar Typhimurium (Salmonella serovar Typhimurium). Birds received probiotics by oral gavage on day 1 of age and, subsequently, received Salmonella serovar Typhimurium on day 2 of age. Cecal tonsils were removed on days 1, 3 and 5 post-infection (p.i.), RNA was extracted and subjected to real-time quantitative RT-PCR for measurement of interleukin (IL)-6, IL-10, IL-12 and interferon (IFN)-gamma gene expression. There was no significant difference in IL-6 and IL-10 gene expression in cecal tonsils of chickens belonging to various treatment groups. Salmonella serovar Typhimurium infection resulted in a significant increase in IL-12 expression in cecal tonsils on days 1 and 5p.i. However, when chickens were treated with probiotics prior to experimental infection with Salmonella, the level of IL-12 expression was similar to that observed in uninfected control chickens. Treatment of birds with probiotics resulted in a significant decrease in IFN-gamma gene expression in cecal tonsils of chickens infected with Salmonella compared to the Salmonella-infected birds not treated with probiotics. These findings reveal that repression of IL-12 and IFN-gamma expression is associated with probiotic-mediated reduction in intestinal colonization with Salmonella serovar Typhimurium.

We recently reported increased leg lean mass and strength in men with chronic obstructive pulmonary disease (COPD) receiving 10 wk of testosterone (T) and leg resistance training (R) (Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis M, Fournier M, Storer T. Am J Respir Crit Care Med 170: 870-878, 2004). The present study evaluates the role of muscle IGF and related factors as potential mechanisms for our findings, using quadriceps muscle biopsies from the same cohort. Patient groups were 1) weekly placebo (P) injections + no R; 2) P and R; 3) weekly injections of T + no R; and 4) T + R (TR). Muscle fibers were classified histochemically, and their cross-sectional areas (CSAs) and fiber density (number of fibers per unit area) were determined. Gene transcripts were determined by real-time PCR and protein expression by RIA. While no significant changes in fiber CSAs were noted across groups, increased trends were observed after 10 wk, and significant decrements in muscle fiber density were noted in all treated groups. A global increase in all myosin heavy chain (MyHC) mRNA isoforms was observed in TR patients. Muscle IGF-IEa and IGF-IEc mRNAs were significantly increased with TR group. Muscle IGF-I protein was increased in all intervention groups (greatest in TR). While TR IGF-II mRNA was increased, protein levels were unaltered. IGF binding protein-4 mRNA was increased with TR. Myogenin mRNA was increased in both T groups, while MyoD and myostatin were unchanged. Muscle atrophy F-box mRNA tended to increase with TR. Our data suggest that the combined interventions produced an enhanced local anabolic milieu driven in large part by the muscle IGF system, despite potentially negative biochemical influences present in COPD patients.