Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies 相似文献   

Opioid receptors and acetaminophen (paracetamol)

We report that the acetaminophen (paracetamol)-induced spinal (intrathecal, i.t.)/supraspinal (intracerebroventricular, i.c.v.) site/site antinociceptive 'self-synergy' in mice is attenuated by the opioid receptor subtype selective antagonists beta-funaltrexamine hydrochloride (beta-FNA; mu), naltrindole (delta), and nor-binaltorphine hydrochloride (nor-BNI; kappa). These findings further implicate endogenous opioids (viz., endorphins, enkephalins, and dynorphins) and their pathways as contributors to the central antinociceptive action of acetaminophen.     

Effects of progesterone treatment on cocaine responses in male and female cocaine users

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials.     

Organochlorines affect the steroid hormone cortisol in free-ranging polar bears (Ursus maritimus) at Svalbard, Norway

Since the polar bear (Ursus maritimus) is among the most highly organochlorine-contaminated species of the Arctic mammals, there is growing concern that in addition to the natural stressors in the polar bear's environment, several organochlorines (OCs) may be able to change basic endocrine pathways. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis may affect plasma cortisol concentrations and inhibit physiological processes involved in the maintenance of homeostasis in a way that may endanger the animal's health. Between 1995 and 1998, samples were collected from 121 male and 130 female free-ranging polar bears from the Svalbard area. The aim of the study was to investigate relationships between plasma cortisol concentrations, biological factors, and OCs. The variation in plasma cortisol concentrations was determined for the total sample. Axillary girth and body mass together with their interactions explained more than 50% of the variation in the plasma cortisol concentration. The sum of pesticides (Sigma pesticides) combined with the sum of polychlorinated biphenyls (Sigma PCBs) and their interactions explained over 25% of the variation in the cortisol concentration. Although Sigma pesticides contributed negatively and Sigma PCBs contributed positively to the variation in the plasma cortisol, the over-all contribution of the OCs to the plasma cortisol variation was negative. Despite the complexity on stress responses and the interactions with environmental factors, this study demonstrated that high concentrations of OCs in polar bears might alter plasma cortisol concentrations.     

Effects of perinatal exposure to low doses of PCB 153 and PCB 126 on lymphocyte proliferation and hematology in goat kids

Pregnant does (10 goats/group) were dosed orally with either PCB 153 or PCB 126 dissolved in corn oil or only corn oil (control group) from day 60 of gestation until delivery. Effects on in vitro mitogen-induced lymphocyte proliferation and blood cell counts in their goat kids exposed to low levels of PCB 153 and PCB 126 during gestation and lactation were assessed. The concentrations of PCB 153 and PCB 126 in adipose tissue in the goat kids 9 mo postpartum were 5800 ng/g (fat weight) and 0.49 ng/g (fat weight), respectively. Kids exposed to PCB 153 had a significantly higher number of white blood cells, neutrophils, and lymphocytes at 2 wk of age compared to controls. In the kids exposed to PCB 126 there was a significantly lower concentration of monocytes at 2, 4, and 8 wk of age. The mean lymphocyte response to phytohemagglutinin (PHA) and to concanavalin A (Con A) was significant lower in the PCB 153 compared to the control group at wk 2, 4, and 8 postnatally. The results of the present study support previous reports on immunotoxic effects of PCB exposure in animals. However, this is the first report to demonstrate immunotoxicity in animals by using low doses of PCB 153. The difference in results between PCB 126 and PCB 153 treatment groups may strengthen the hypothesis that PCBs mediate immunotoxic effects through both AhR-dependent and -independent mechanisms.     

Postsurgical disparity in survival between African Americans and Caucasians with colonic adenocarcinoma

BACKGROUND: Studies of colorectal adenocarcinoma (CRC) indicate a higher mortality rate for African Americans compared with Caucasians in the United States. In the current study, the authors evaluated the racial differences in survival based on tumor location and pathologic stage between African-American patients and Caucasian patients who underwent surgery alone for CRC. METHODS: All 199 African American patients and 292 randomly selected, non-Hispanic Caucasian patients who underwent surgery between 1981 and 1993 for first primary sporadic CRC at the University of Alabama-Birmingham (Birmingham, AL) or an affiliated Veterans Affairs hospital were assessed for differences in survival. None of these patients received preoperative or postoperative neoadjuvant or adjuvant therapy. Survival curves were generated using the Kaplan-Meier method, and hazard ratios with 95% confidence intervals (95% CI) were estimated from Cox proportional hazards models, adjusting for demographic and tumor characteristics. RESULTS: African Americans were 1.67 (95% CI, 1.21-2.33) and 1.52 (95% CI, 1.12-2.07) times more likely to die of colonic adenocarcinoma (CAC) within 5 years and 10 years of surgery, respectively, compared with Caucasians. Racial differences in survival were observed among patients with Stage II, III, and IV CAC; however, the strongest and statistically significant association was observed among patients with Stage II CAC. There were no significant racial differences in survival in patients with rectal adenocarcinomas. CONCLUSIONS: The current findings suggest that the decreased overall survival at 5 years and 10 years postsurgery observed in African-American patients with CAC may not be attributable to tumor stage at diagnosis or treatment but may be due to differences in other biologic or genetic characteristics between African-American patients and Caucasian patients.     

Preoperative somatic symptoms are associated with disease progression in patients with bladder carcinoma after cystectomy

BACKGROUND: A link between patient psychologic factors and bladder carcinoma outcome has not been demonstrated. The purpose of the current study was to assess the association of psychologic factors measured preoperatively with bladder carcinoma progression after cystectomy. METHODS: The Brief Symptom Inventory (BSI)-18 was administered prospectively to 65 patients with clinically localized bladder carcinoma before surgery. The BSI-18 measures distress in three specific domains-depression, anxiety, and somatization (i.e., distress due to somatic symptoms)-as well as general distress. Preoperative BSI-18 scores, tumor pathologic stage, and certain clinical variables were compared with disease status. Disease progression was defined as the development of either local disease recurrence or distant metastasis. Univariate and multivariate Cox proportional hazards models were constructed for statistical analysis. RESULTS: Of the 65 patients, 49 (79.4%) had no evidence of disease, 4 (6.2%) had local disease recurrence, and 12 (18.5%) had metastatic disease at last follow-up. The mean follow-up time was 1.3 years and did not differ significantly between survival outcomes (P = 0.577). Both tumor pathologic stage and preoperative somatic distress scores were associated with time to disease progression by univariate analysis (P = 0.038 and P = 0.055, respectively). After adjusting for tumor pathologic stage, a somatic distress score of > or = 2.00 was a significant predictor of disease progression (P = 0.044, hazard ratio = 3.31, 95% confidence interval = 1.03-10.60). Patient age, gender, reconstruction type, and BSI-18 scores for depression, anxiety, and general distress were not significantly associated with disease outcome. CONCLUSIONS: The authors found no correlation between psychologic symptoms measured preoperatively (i.e., depression, anxiety, and general distress) and bladder carcinoma progression. However, they reported an association between somatic symptoms and cancer outcome. If confirmed by other studies, these results may have important implications for the diagnosis, staging, and potential treatment of patients with bladder carcinoma.     

Alcohol intake and risk of non-Hodgkin lymphoma in men and women

Objective: The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk. Methods: 613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk. Results: Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1g of ethanol per day, compared to those who consumed on average 0–2.2g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); p _trend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); p _trend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia. Conclusions: Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.     

Losartan reduces the costs associated with nephropathy and end-stage renal disease from type 2 diabetes: Economic evaluation of the RENAAL study from a Canadian perspective

BACKGROUND: The Reduction of Endpoints in NIDDM [non-insulin-dependent diabetes mellitus] with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated the renoprotective effects of losartan in patients with nephropathy from type 2 diabetes. OBJECTIVE: To perform an economic evaluation of the costs associated with end-stage renal disease (ESRD) from a Canadian public health perspective, based on the clinical outcomes reported in the RENAAL study. METHODS: ESRD-related costs were determined by estimating the mean number of days with ESRD multiplied by the daily cost of ESRD (140 dollars); mean days with ESRD were calculated by subtracting the area under the Kaplan-Meier survival curve for time to the first event of ESRD or all-cause mortality from the area under the curve for all-cause mortality. Daily ESRD cost was determined using Canadian specific data sources. ESRD-related cost savings with losartan were obtained by subtracting the ESRD-related costs of the losartan group from those of the placebo group. Net cost savings were ESRD-related cost savings with losartan minus the drug cost of losartan. RESULTS: Losartan reduced the number of ESRD days by 33.6 per patient over 3.5 years (95% CI 10.9 to 56.3) compared with placebo. Losartan reduced ESRD-related costs by 4,695 dollars per randomized patient over 3.5 years (95% CI 1,523 dollars to 7,868 dollars). After accounting for the drug cost of losartan, net cost savings with losartan were 3,675 dollars per randomized patient over 3.5 years. CONCLUSION: Losartan therapy for patients with nephropathy from type 2 diabetes reduces the clinical incidence of ESRD and can result in considerable cost savings for the Canadian public health system.     

Recognition of late-life depression in home care: accuracy of the outcome and assessment information set

This study evaluated the accuracy of home care nurses' ratings of the Outcome and Assessment Information Set (OASIS) depression items. The accuracy of home care nurses' depression assessments was studied by comparing nurse ratings of OASIS depression items with a research diagnostic assessment based on the Structured Clinical Interview for Axis I Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID). The setting for this study was a nonprofit, Medicare-certified, voluntary home healthcare agency. Sixty-four home care nurses assessed 220 patients aged 65 and older with the OASIS upon admission. Of the 220 patients, using standard SCID criteria, 35 cases of major or minor depression were identified. The home care nurses accurately documented the presence of depression in 13 of 35 cases (sensitivity=37.1%; positive predictive value=0.56). Of the 220 patients, 185 had no SCID-identified major or minor depression. The nurses agreed on the absence of depression in 175 of 185 cases (specificity=94.6%; negative predictive value=88.8%). This study indicates that home care nurses often do not accurately rate OASIS depression items for older adult patients.