Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants

Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome P450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6-hydroxypaclitaxel (6-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K_m and V_max) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.     

Religious coping,health, and health service use among bereaved adults

OBJECTIVE: This report examined associations between religious coping, health, and health service use among a sample of 265 recently bereaved adults. METHOD: Participants were interviewed an average of 6.3 (SD = 7.4) months after their loss and again 4 months later. Multivariate regression models and repeated measures ANOVA analyses estimated the influence of religious coping on health and health service use at baseline and follow-up, controlling for significant confounding influences, such as health promoting behaviors. RESULTS: At baseline, those high on religious coping had significantly more functional disabilities than did those low on religious coping. Controlling for health status, participants with higher religious coping scores were significantly less likely to visit their doctor during the 60 days prior to the baseline interview. Despite worse health and less health service use at baseline, those high on religious coping had equivalent health status to those low on religious coping at follow-up. CONCLUSIONS: Greater use of religious coping is associated with more functional disabilities and fewer outpatient physical health care visits at baseline, but a lack of decline in health at 4-month follow-up among the bereaved, a sub-group at risk for numerous health impairments. Possible reasons for this association and its implications are discussed.     

Fatigue and psychological distress in the working population: psychometrics,prevalence, and correlates

Objective: The purposes of this study were: (1) to explore the relationship between fatigue and psychological distress in the working population; (2) to examine associations with demographic and health factors; and (3) to determine the prevalence of fatigue and psychological distress. Methods: Data were taken from 12,095 employees. Fatigue was measured with the Checklist Individual Strength, and the General Health Questionnaire (GHQ) was used to measure psychological distress. Results: Fatigue was fairly well associated with psychological distress. A separation between fatigue items and GHQ items was shown. No clear, distinct pattern of associations was found for fatigue vs. psychological distress with respect to demographic factors. The prevalence was 22% for fatigue and 23% for psychological distress. Of the employees reporting fatigue, 43% had fatigue only, whereas 57% had fatigue and psychological distress. Conclusions: The results indicate that fatigue and psychological distress are common in the working population. Although closely associated, there is some evidence suggesting that fatigue and psychological distress are different conditions, which can be measured independently.     

Correlations between clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally edentulous patients with peri-implant disease

PURPOSE: The purpose of the present study was (1) to assess the relationship between clinical parameters and concentrations of the proinflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 in the saliva of totally edentulous patients with implant-supported overdentures; (2) to assess whether estimation of IL-6 and IL-10 levels in saliva could be a useful laboratory tool to detect changes preceding serious clinical complications. MATERIALS AND METHODS: Thirty healthy adult volunteers (14 men and 16 women) with implant-supported overdentures were recruited from Tallinn Dental Clinic. The biochemical and clinical parameters evaluated were the levels of IL-6 and IL-10 in saliva, pocket probing depth (mm), Gingival Index (0,1, 2, or 3), and bleeding on probing (0 or 1). RESULTS: The level of IL-6 in saliva in the peri-implant disease group was significantly elevated compared to the healthy group. IL-10 could be detected only in the saliva of patients with peri-implant disease, and it did not appear at detectable amounts in saliva of healthy controls. In addition, the levels of IL-6 and IL-10 in peri-implant disease group were positively correlated with clinical parameters. CONCLUSIONS: These data suggest that a significant relationship exists between the amount of a proinflammatory cytokine (IL-6) and the inflammatory response in peri-implant tissue. The results also suggest that IL-6 and IL-10 could be used as markers of peri-implant disease together and that the level of the latter cytokine gives additional information about the potency of an organism's integrated immune response for maintenance of inflammatory balance.     

Social support and change in health-related quality of life 6 months after coronary artery bypass grafting

OBJECTIVE: We determined whether perceived social support predicted change in health-related quality of life, operationalized as change in mental health and physical functioning, 6 months after coronary artery bypass grafting (CABG). METHODS: A prospective cohort of 1164 patients undergoing first CABG was interviewed prior to hospital discharge and 6 months later. Perceived instrumental and emotional support were assessed predischarge. Change in mental health and physical functioning was calculated as the difference between 6-month and predischarge SF-36 subscale scores. Stepwise linear regression analyses controlling for prior health-related quality of life, demographics, and clinical presentation were conducted. RESULTS: A total of 1072 (1072/1164=92%) participants completed the 6-month interview; mean age 65.7 (+/-11.1) years. Frequent instrumental support predicted positive change in mental health (beta=3.27, P=.02); change scores were higher when participants had low pre-CABG mental health. Neither social support variable predicted change in physical functioning. CONCLUSIONS: Assessing perceived instrumental support may help clinicians predict post-CABG mental health. More research regarding this relationship is needed before recommending intervention efforts.     

Impact of disparity of minor histocompatibility antigens HA-1, CD31, and CD49b in hematopoietic stem cell transplantation of patients with chronic myeloid leukemia with sibling and unrelated donors

Despite human leukocyte antigen (HLA) identity between donor and recipient, several patients develop acute graft-versus-host disease (aGVHD) after hematopoetic stem cell transplantation (HSCT) because of minor histocompatibility antigen (mHag) incompatibilities. The impact of multiple mHag disparities on the clinical outcome after HSCT still remains to be determined. We studied the genomic polymorphisms of HA-1, CD31, and CD49b and correlated mHag distribution with the occurrence of aGVHD after HSCT from HLA-matched sibling and unrelated donors. All 163 patients examined in our single-center study underwent HSCT for chronic myeloid leukemia in the first chronic phase. HA-1 and CD31 disparities are associated with increased aGVHD incidence in a subgroup of patients who test HLA-B44 supertype positive in univariate analysis. However, in a multivariate analysis, only increased patient age was confirmed as an independent aGVHD risk factor. Our findings indicate that the impact of mHag disparity on aGVHD development in HSCT from HLA-matched sibling and unrelated donors seems to be subordinated to classic aGVHD risk factors.     

Conjunctivodacryocystorhinostomy tube placement with a urologic catheter

In an endoscopically performed conjunctivodacryocystorhinostomy, insertion of a Jones glass tube can be difficult if the nasal end of the tube draws soft tissue around the tunnel in front of the tube. A urologic Tiemann catheter has been used for Jones tube placement in 44 cases since 2001. The tube is put in the lumen end of the catheter, the tip of which is bulbous and gradually tapered in its diameter. The catheter can be easily inserted into the tunnel and pulled out of the nose with forceps, leaving the glass tube in the tunnel.     

Antibody-cytotoxic agent conjugates for cancer therapy

Antibody-based delivery of cytotoxic agents, including toxins, to tumours can dramatically reduce systemic toxicity and increase therapeutic efficacy. The advantage of a monoclonal antibody (mAb) is superior selectivity towards antigens expressed on the surface of cancer cells. Recent advances in biotechnology accelerated progress in the pharmaceutical applications of mAbs. A cytotoxic warhead is attached to a mAb in an immunoconjugate via a linker, which is stable in circulation but efficiently cleaved in the tumour tissue. The warhead, mAb and linker play important roles in the successful design of potent and efficient immunoconjugates. To date, one mAb-cytotoxic agent conjugate has been approved by the FDA and several other candidates are in various stages of clinical trials. This review describes the recent progress in the design and development of mAb-based immunoconjugates of cytotoxic agents, and summarises the criteria for the critical choices of a suitable mAb, linker and cytotoxic agent to design an efficacious immunoconjugate.     

Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results.

Review articles have focused attention on and cited possible reasons for the nonreplication of genetic association studies. Herein, we illustrate how one might work through these possible reasons to make a judgment about the most plausible reason(s) when faced with two or more studies which yield seemingly inconsistent results. In the first study, 342 treatment-seeking smokers were genotyped for the Val108Met polymorphism in the functional catechol-O-methyl-transferase (COMT) locus. Alleles coding Val at codon 108 are denoted as H and those coding Met are denoted as L. An association between presence of the "H" (high activity) allele and pretreatment level of nicotine dependence level using the Fagerstrom Test for Nicotine Dependence was detected (P = 0.0072), after controlling for baseline body mass index (BMI, kg/m2), depression symptoms, and age. To validate this initial finding, 443 treatment-seeking smokers from an independent smoking cessation clinical trial were genotyped for the COMT polymorphism. Within the second study, no association between presence of the "H" allele and nicotine dependence was detected (P = 0.6418) after controlling for baseline BMI, depression symptoms, and age. We critically reviewed both studies with regard to often cited reasons for nonreplication, including type I error, population stratification, low statistical power, and imprecise measures of phenotype. Although in our opinion the failure to replicate the initial association in the second study is likely either the result of low statistical power to detect a small effect or effect heterogeneity, thorough analyses failed to definitively identify the reason for nonreplication.