Budesonide once versus twice-daily administration: meta-analysis

OBJECTIVES: The aim of this study was to examine the efficacy of budesonide administered once daily compared to twice daily in asthma. METHODOLOGY: Meta-analysis of randomised controlled trials comparing budesonide administered once versus twice a day that presented data on at least one clinical outcome measure was conducted. RESULTS: A total of 10 studies, with 1922 children and adults with asthma, met the inclusion criteria. These studies were performed predominantly with mild to moderate asthmatic patients, using doses of budesonide ranging from 200 to 800 microg per day. There was no significant difference between daily dosing once or twice for all the clinical outcome variables, including withdrawals due to asthma, for which the odds ratio was 1.0 (95% confidence interval, 0.65-1.52). CONCLUSIONS: In mild to moderate asthma a once-daily budesonide regimen has a similar efficacy to a twice-daily regimen in doses up to 800 microg per day. A once-daily regimen has potential advantages in terms of patient compliance and satisfaction, when used in clinical practice.     

Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis

OBJECTIVE: To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals. METHODS: MSU crystal-induced neutrophil migration was studied in the murine air-pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme-linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright-Giemsa staining of cytospins. RESULTS: MSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti-S100A8 and anti-S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout. CONCLUSION: S100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.     

Low-molecular-weight heparins in ischemic heart disease

PURPOSE OF REVIEW: The objective of this review was to summarize the recent developments regarding the use of low-molecular-weight heparins in the management of acute coronary syndromes. RECENT FINDINGS: In the setting of unstable angina and non-ST-elevation myocardial infarction, enoxaparin is superior to unfractionated heparin in reducing death, myocardial infarction, and recurrent ischemia both in the short-term and to 1 year. However, this does not necessarily imply a class effect of low-molecular-weight heparins in general. When combined with glycoprotein IIb/IIIa inhibitors, enoxaparin appears to be effective and safe even for patients treated according to an early invasive strategy. In patients receiving fibrinolytics for ST-elevation myocardial infarction, low-molecular-weight heparins are as effective as unfractionated heparin in maintaining patency of the infarct-related artery and in reducing the composite endpoint of death and reinfarction. However, serious bleeding is more common, especially among the elderly, and the optimal dosing regimen in ST-elevation myocardial infarction remains to be defined. SUMMARY: Low-molecular-weight heparins are safe and effective in the management of unstable angina and non-ST-elevation myocardial infarction, with or without concurrent administration of glycoprotein IIb/IIIa inhibitors. Ongoing studies will clarify the role of low-molecular-weight heparins as adjunctive therapy for fibrinolysis.     

Prognostic value of exercise tests in male veterans with chronic coronary artery disease

PURPOSE: The authors evaluate the prognostic value of treadmill testing in a large consecutive series of patients with chronic coronary artery disease. Exercise testing is widely performed, but analyses of the prognostic value of test results have largely concentrated on patients referred for the diagnosis of coronary artery disease, patients after an acute coronary event or procedure, or patients with congestive heart failure. METHODS: All patients referred for evaluation at two university-affiliated Veterans Affairs Medical Centers who underwent exercise treadmill tests for clinical indications between 1987 and 2000 were determined to be dead or alive using the Social Security Death Index after a mean 5.8-year follow-up. Patients without established heart disease and those with congestive heart failure were excluded, leaving the target population of those with a history myocardial infarction or coronary intervention. Clinical and exercise test variables were collected prospectively according to standard definitions; testing and data management were performed in a standardized fashion using a computer-assisted protocol. All-cause mortality was used as the endpoint for follow-up. Standard survival analysis was performed including Kaplan Meier curves and the Cox Hazard Model. RESULTS: Of the 1,473 patients with coronary artery disease who had exercise testing, 273 (19%) patients had a revascularization procedure (Revascularization group); 813 (55%) had a history of myocardial infarction, diagnostic Q waves (MI group), or both; and 387 (26%) had a history of myocardial infarction or Q wave and revascularization (Combined group). Mean age of the patients was 61.8 +/- 9 years. A total of 401 deaths occurred during a mean follow-up of 5.8 years with an annual mortality rate of 4.5%. Only two variables, age and maximal exercise capacity, were independently and statistically associated with time to death in all three groups and were the strongest predictors of all cause mortality. CONCLUSION: A simple score based on METs, age, and history of myocardial infarction or diagnostic Q waves can stratify prognosis in patients with chronic coronary artery disease. The score enabled the identification of a group at low risk (32% of the cohort) with an annual mortality rate of 2%, a group at intermediate risk (42% of the cohort) with an annual mortality rate of about 4%, and a group at high risk (26% of the cohort) with an average annual mortality rate of approximately 7%.     

A Randomized Controlled Trial of High-Intensity Exercise and Executive Functioning in Cognitively Normal Older Adults

BackgroundThere is a paucity of interventional research that systematically assesses the role of exercise intensity and cardiorespiratory fitness, and their relationship with executive function in older adults. To address this limitation, we have examined the effect of a systematically manipulated exercise intervention on executive function.MethodsNinety-nine cognitively normal participants (age = 69.10 ± 5.2 years; n = 54 female) were randomized into either a high-intensity cycle-based exercise, moderate-intensity cycle-based exercise, or no-intervention control group. All participants underwent neuropsychological testing and fitness assessment at baseline (preintervention), 6-month follow-up (postintervention), and 12-month postintervention. Executive function was measured comprehensively, including measures of each subdomain: Shifting, Updating/ Working Memory, Inhibition, Verbal Generativity, and Nonverbal Reasoning. Cardiorespiratory fitness was measured by analysis of peak aerobic capacity; VO₂peak.ResultsFirst, the exercise intervention was found to increase cardiorespiratory fitness (VO₂peak) in the intervention groups, in comparison to the control group (F =10.40, p≤0.01). However, the authors failed to find mean differences in executive function scores between the high-intensity, moderate intensity, or inactive control group. On the basis of change scores, cardiorespiratory fitness was found to associate positively with the executive function (EF) subdomains of Updating/Working Memory (β = 0.37, p = 0.01, r = 0.34) and Verbal Generativity (β = 0.30, p = 0.03, r = 0.28) for intervention, but not control participants.ConclusionAt the aggregate level, the authors failed to find evidence that 6-months of high-intensity aerobic exercise improves EF in older adults. However, it remains possible that individual differences in experimentally induced changes in cardiorespiratory fitness may be associated with changes in Updating/ Working Memory and Verbal Generativity.     

Deep Brain Stimulation,Self and Relational Autonomy

Neuroethics - Questions about the nature of self and self-consciousness are closely aligned with questions about the nature of autonomy. These concepts have deep roots in traditional philosophical...     

Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus

Alphaviruses, such as chikungunya virus and Ross River virus (RRV), are associated with outbreaks of infectious rheumatic disease in humans worldwide. Using an established mouse model of disease that mimics RRV disease in humans, we showed that macrophage-derived factors are critical in the development of striated muscle and joint tissue damage. Histologic analyses of muscle and ankle joint tissues demonstrated a substantial reduction in inflammatory infiltrates in infected mice depleted of macrophages (i.e., "macrophage-depleted mice"). Levels of the proinflammatory factors tumor necrosis factor-alpha, interferon-gamma, and macrophage chemoattractant protein-1 were also dramatically reduced in tissue samples obtained from infected macrophage-depleted mice, compared with samples obtained from infected mice without macrophage depletion. These factors were also detected in the synovial fluid of patients with RRV-induced polyarthritis. Neutralization of these factors reduced the severity of disease in mice, whereas blocking nuclear factor kappaB by treatment with sulfasalazine ameliorated RRV inflammatory disease and tissue damage. To our knowledge, these findings are the first to demonstrate that macrophage-derived products play important roles in the development of arthritis and myositis triggered by alphavirus infection.