Activation of the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: 'Do not use ACEI and ARB in combination'. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations.

Early endoscopy has been advocated for the management of upper gastrointestinal bleeding, but the optimal timing for early endoscopy is still uncertain. The aim of this Review is to evaluate the optimal timing of early endoscopy by examining the findings of randomized clinical trials and retrospective cohort studies that used comparable outcome measures and have been reported in the literature. Outcome measurements included recurrent bleeding, surgery, mortality, length of hospital stay, and blood transfusion. Studies were categorized into those in which endoscopy was performed within 2-3 h, 6-8 h, 12 h or 24 h of the patient's presentation to hospital. We conclude that early endoscopy aids risk stratification of patients and reduces the need for hospitalization. However, it may also expose additional cases of active bleeding and hence increase the use of therapeutic endoscopy. No evidence exists that very early endoscopy (within a few hours of presentation) can reduce the risk of rebleeding or improve survival.

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.

The information contained in pathology reports of radical prostatectomy specimens is critically important to treating physicians for selecting adjuvant therapy, evaluating therapy, estimating prognosis, and analyzing outcomes. This information is also of importance to patients and their families. In recent years, the Cancer Committee of the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology developed suggested protocols for reporting the findings on radical prostatectomy specimens. The objectives of this study were to assess radical prostatectomy-specimen reports by using quality indicators derived from existing suggested protocols and to thereby assist pathologists in improving the quality of their reports on such specimens. A retrospective chart review of 554 cases for the second 6-month period of 1996 focused on 10 quality indicators: submission of a frozen section; location of the adenocarcinoma; proportion of the specimen involved by adenocarcinoma; perineural involvement; vascular involvement; seminal vesicle involvement; periprostatic fat status; number of nodes submitted; status of nodes; and prostate intraepithelial neoplasia (PIN). The findings of this study were shared with the pathology departments in all hospitals in New York State. In addition, the 113 hospitals from which the 554 cases were drawn were given their institution-specific data. Teleconferences were held with the 37 hospitals that accounted for 72.4% of all cases. These conferences included directors of pathology and laboratories and focused on the aggregate statewide findings. The presence of quality indicators in reports varied from a mean of 14.8% (periprostatic fat) to a mean of 85.9% (seminal vesicle involvement). For all hospitals, 4 indicators (proportion of the specimen involved by adenocarcinoma, vascular involvement, periprostatic fat status, and PIN) were included in fewer than 50% of cases. These 4 quality indicators and an additional 3 others (submission of a frozen section, perineural involvement, and the number of nodes submitted) were included in fewer than 70% of cases. Only 3 indicators (location of the adenocarcinoma, seminal vesicle involvement, and the status of nodes) were found in more than 70% of cases. Although the mean level of quality indicator inclusion ranged from 14.8% to 85.9% for all cases examined, the absolute range for any individual indicator was 0% to 100%. Thus, some hospitals included a given indicator 100% of the time; others never included it. This pattern held true for all 10 indicators. High-volume hospitals (10 or more cases) performed significantly better than low-volume hospitals (1-4 cases) on 5 indicators (P < .05), and better, but not significantly so, for an additional 2 indicators. Overall, the mean inclusion levels for all 10 indicators were 10% higher for high-volume hospitals compared with low-volume and medium-volume hospitals (5-9 cases). This study demonstrated wide variations in the inclusion of quality indicators by pathologists i...