Substance use and sexual risk: a participant- and episode-level analysis among a cohort of men who have sex with men

Prior reports associating substance use with sexual risk behavior have generally used summary measures and have not adjusted for participants' background levels of substance use. In this 1999-2001 US study (the EXPLORE study), the authors determined whether substance use during sex was independently associated with sexual risk during recent sexual episodes, as reported by 4,295 human immunodeficiency virus-negative men who have sex with men. The main outcome measure was serodiscordant unprotected anal sex (SDUA). The influence of participant-level characteristics was examined by using repeated-measures logistic models. In assessing the influence of episode-level predictors on SDUA, the influence of participant-level characteristics, including 6-month substance use, was removed by using conditional logistic regression, in effect making each participant his own control. The authors also adjusted for partner characteristics. Eleven percent of participants reported heavy alcohol use, 37% used poppers, 19% sniffed cocaine, and 13% used amphetamines. In the participant-level analysis, use of poppers, amphetamines, and sniffed cocaine as well as heavy alcohol use in the prior 6 months were independently associated with SDUA. In the conditional analysis, consumption of > or = 6 alcoholic drinks or use of poppers, amphetamines, or sniffed cocaine just before or during sex was independently associated with SDUA. The authors concluded that programs aimed at preventing human immunodeficiency virus transmission should emphasize the influence of substance use during sex on increased risk behavior.     

Reactive oxygen species in the cerebral circulation: physiological roles and therapeutic implications for hypertension and stroke

It is now clear that reactive oxygen species (ROS) can act as signalling molecules in the cerebral circulation under both physiological and pathological conditions. Some major products of superoxide (O(2)(.)(-)) metabolism, such as hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH(.)), appear to be particularly good cerebral vasodilators and may, surprisingly, represent important molecules for increasing local cerebral blood flow. A major determinant of overall ROS levels in the cerebral circulation is the rate of generation of the parent molecule, O(2)(.)(-). Although the major enzymatic source of O(2)(.)(-) in cerebral arteries is yet to be conclusively established, the two most likely candidates are cyclo-oxygenase and nicotinamide adenine dinucleotide phosphate (reduced form) [NADPH] oxidase. The activity of endogenous superoxide dismutases (SODs) play a vital role in determining levels and effects of all individual ROS derived from metabolism of O(2)(.)(-). The term 'oxidative stress' may be an over-simplification that hides the complexity and diversity of the ROS family in cerebrovascular health and disease. Although a generalised increase in ROS levels seems to occur during several vascular disease states, the consequences of this for cerebrovascular function are still unclear.Because enhanced breakdown of O(2)(.)(-) by SOD will increase the generation of the powerful cerebral vasodilator H(2)O(2), this latter molecule could conceivably act as a compensatory vasodilator mechanism in the cerebral circulation under conditions of elevated O(2)(.)(-) production. Some recent clinical data support the concept of a protective role for cerebrovascular NADPH oxidase activity. Although it is quite speculative at present, if NADPH oxidase were to emerge as a major source of beneficial vasodilator ROS in the cerebral circulation, this may represent a significant dilemma for treatment of ischaemic cerebrovascular conditions, as excessive NADPH oxidase activity is associated with the progression of several systemic vascular disease states, including hypertension and atherosclerosis. Despite data suggesting that antioxidant vitamins can have beneficial effects on vascular function and that their plasma levels are inversely correlated with risk of cardiovascular disease and stroke, the results of several recent large-scale clinical trials of antioxidant supplementation have been disappointing. Future work must establish whether or not increased ROS generation is necessarily detrimental to cerebral vascular function, as has been generally assumed, or whether localised increases in ROS in the vicinity of the arterial wall could be beneficial in disease states for the maintenance of cerebral blood flow.     

Serum proteomic profiles suggest celecoxib-modulated targets and response predictors

Cyclooxygenase-2 is a valid target for cancer prevention and treatment. This has been shown in preclinical and clinical cancer prevention studies by using a cyclooxygenase-2 inhibitor, celecoxib. When used in a randomized cancer prevention clinical trial on patients with the inherited autosomal dominant condition, familial adenomatous polyposis, celecoxib proved efficacious. However, a remarkable heterogeneity in patients' responses to the chemopreventive effects of celecoxib was observed. Proteomic profiling of sera from these patients identified several markers, the expression of which was specifically modulated after treatment with celecoxib. A decision tree algorithm identified classifiers for response to celecoxib with relatively high sensitivity but moderate to low specificity. In particular, a spectral feature at m/z 16,961.4 was identified as a strong discriminator between response and nonresponse to celecoxib at the highest dose.     

Brca1 inactivation induces p27(Kip1)-dependent cell cycle arrest and delayed development in the mouse mammary gland

One common characteristic of breast cancers arising in carriers of the predisposition gene BRCA1 is a loss of expression of the CDK inhibitor p27(Kip1) (p27), suggesting that p27 interacts epistatically with BRCA1. To investigate this relationship, we examined expression of p27 in mice expressing a dominant negative allele of Brca1 (MMTV-trBr) in the mammary gland. While these mice rarely develop tumors, they showed a 50% increase in p27 protein and a delay in mammary gland development associated with reduced proliferation. In contrast, on a p27 heterozygote background, MMTV-trBrca1 mice showed an increase in S phase cells, and normal mammary development. p27 was the only protein in the cyclin-cyclin-dependent kinase network to show altered expression, suggesting that it may be a central mediator of cell cycle arrest in response to loss of function of BRCA1. Furthermore, in human mammary epithelial MCF7 cells expressing BRCA1-specific RNAi and in the BRCA1-deficient human tumor cell line HCC1937, p27 is elevated at the mRNA level compared to cells expressing wild-type BRCA1. We hypothesize that disruption of BRCA1 induces an increase in p27 that inhibits proliferation. Accordingly, reduction in p27 expression leads to enhancement of cellular proliferation in the absence of BRCA1.     

Diagnostic cardiac catheterization and revascularization rates for coronary heart disease

BACKGROUND: Despite evidence of regional variation across North America, there have been no comprehensive studies of cardiac procedure rates for coronary heart disease in Canada. OBJECTIVES: To use available administrative data and a survey of catheterization facilities to examine regional and demographic variations in cardiovascular procedure rates. METHODS: A survey of all cardiac catheterization facilities in Canada was conducted, and the procedure counts from these facilities were used to determine provincial catheterization rates from 1997/1998 to 2001/2002. Procedure counts for 1997/1998 to 1999/2000 for coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) were provided by the Canadian Institute for Health Information and used to calculate revascularization procedure rates. Population projections provided by Statistics Canada were used as denominators for calculating the rates, and direct standardization was used to obtain age- and sex-adjusted rates. RESULTS AND CONCLUSIONS: The crude rate of cardiac catheterization in Canada increased from 359.9 to 471.5 per 100,000 population across the five years studied. There was considerable variation in revascularization procedure rates across health regions and provinces. Between 1997/1998 and 1999/2000, there was little increase in the rate of CABGs performed in Canada but a marked increase in the rate of PCIs. For both CABG and PCI, rates were higher for men than women, and highest in the 65- to 74-year-old age category. This study provides a valuable 'snapshot' of cardiac procedure use rates but indicates a clear need for more comprehensive collection of cardiac care data in Canada.