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.     

Visceral leishmaniasis: current status of control,diagnosis, and treatment,and a proposed research and development agenda

Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.     

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%.     

Central administration of corticotropin-releasing hormone alters downstream movement in an artificial stream in juvenile chinook salmon (Oncorhynchus tshawytscha)

We evaluated the effect of corticotropin-releasing hormone (CRH) on spatial distribution and downstream movement in an artificial stream in juvenile Chinook salmon (Oncorhynchus tshawytscha) during the period when the fish were able to tolerate seawater. An intracerebroventricular (ICV) injection of CRH (500 ng) to hatchery fish significantly increased the proportion of fish that were distributed downstream of a mid-stream release site. A second group of hatchery fish were given ICV injections of saline (control) or CRH (500 ng) and released near the top of the stream. The time taken to enter a trap at the lower end of the stream was recorded. In all cases the groups given CRH had a higher proportion of fish that did not enter the trap within 60 min of release. However, in those fish that did enter the trap, treatment with CRH increased the speed of downstream movement to this point relative to control fish. Wild sub-yearling Chinook salmon were captured during their downstream migration to the estuary and given ICV injections of saline or CRH (500 ng) either 2, 3, or 7 days after transport from the river. As with hatchery fish, a significantly higher proportion of wild fish that were administered CRH did not enter the trap at the lower end of the stream. The mean time of passage for control fish decreased on each successive day (day 2 > day 3 > day 7). In contrast, the mean passage time of the wild fish that were given CRH was relatively constant through time, and was only significantly faster than control fish on day 2. The current study provides evidence that CRH alters the downstream movement of juvenile Chinook in a simulated stream environment, and produces behavioral effects similar to those of juvenile salmonids that are stressed during their downstream migration.     

Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes.

AIMS: To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress. METHODS: Serum PEDF levels were measured by ELISA in a cross-sectional study of 123 Type 1 diabetic patients (71 without and 52 with microvascular complications) and 31 non-diabetic control subjects. PEDF associations with complication status, pulse-wave analysis and biochemical results were explored. RESULTS: PEDF levels [geometric mean (95% CI)] were increased in patients with complications 8.2 (7.0-9.6) microg/ml, vs. complication-free patients [5.3 (4.7-6.0) microg/ml, P < 0.001] and control subjects [5.3 (4.6-6.1) microg/ml, P < 0.001; anova between three groups, P < 0.001], but did not differ significantly between control subjects and complication-free patients (P > 0.05). In diabetes, PEDF levels correlated (all P < 0.001) with systolic blood pressure (r = 0.317), pulse pressure (r = 0.337), small artery elasticity (r = -0.269), glycated haemoglobin (r = 0.245), body mass index (r = 0.362), renal dysfunction [including serum creatinine (r = 0.491), cystatin C (r = 0.500)], triglycerides (r = 0.367), and inflammation [including log(e)C-reactive protein (CRP; r = 0.329), and soluble vascular cell adhesion molecule-1 (r = 0.363)]. Age, blood urea nitrogen, systolic blood pressure, pulse pressure and log(e)CRP correlated with PEDF levels in control subjects (all P < 0.04). PEDF levels were not significantly correlated with measures of oxidative stress: isoprostanes, oxidized low-density lipoprotein or paraoxonase-1 activity. On stepwise linear regression analysis (all subjects), independent determinants of PEDF levels were renal function, triglycerides, inflammation, small artery elasticity and age (r(2) = 0.427). CONCLUSIONS: In Type 1 diabetes, serum PEDF levels are associated with microvascular complications, poor vascular health, hyperglycaemia, adiposity and inflammation.     

Predictors of onset and progression of knee pain in adults living in the community. A prospective study

OBJECTIVE: To investigate determinants of the onset and progression of knee pain in a population-based sample of people aged > or = 50 yrs. METHODS: Prospective cohort study of 2982 people registered with three general practices in North Staffordshire, UK. Using questionnaire surveys at baseline and 3 yrs, demographic, knee-related and general health factors were assessed for their relationship with onset of new knee pain, and progression from non-severe to severe knee pain. RESULTS: Response rates were 77% (baseline) and 75% (follow-up). Baseline factors significantly associated with onset of knee pain were knee injury [odds ratio (OR) 1.6, 95% CI 1.2, 2.2], depression (OR 1.4, 95% CI 1.1, 1.8), widespread pain (OR 1.5, 95% CI 1.1, 1.9 compared with no pain) and younger age. Onset of severe knee pain was associated most strongly with obesity (OR 2.9, 95% CI 1.7, 5.1) and physical limitations (OR 2.5, 95% CI 1.5, 4.1), and with widespread pain, older age, female gender and comorbidity. The strongest independent predictors of progression from non-severe to severe knee pain were chronicity (OR 3.1, 95% CI 2.1, 4.6), previous use of health care (OR 2.2, 95% CI 1.5, 3.3) and obesity (OR 2.1, 95% CI 1.2, 3.6). CONCLUSION: In addition to a focus on obesity, there is potential for primary prevention of knee pain by tackling knee injuries and treating depression. Other factors are likely to determine whether the knee pain then progresses. An area for future research is the ineffectiveness of current health care in halting or reversing progression of knee pain at a population level.     

High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency

We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri–immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient’s CD4⁺ αβ T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4⁺ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4⁺ αβ T lymphocytes.