A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400-800 microg/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period. As primary efficacy variable, eosinophil cationic protein (ECP) in induced sputum as direct measurement of bronchial inflammation was assessed before and after treatment. To assure a baseline level of inflammation, an ECP concentration above 100 microg/L was required. Sputum eosinophil count, concentration of exhaled nitric oxide, urinary excretion of eosinophil protein X, and quality-of-life items were considered as secondary outcome variables. After treatment with montelukast, ECP in sputum was significantly reduced (montelukast: median -975 microg/L [5 to 95% confidence interval: -4295 to 583 microg/L]; placebo: 561 microg/L [-1335 to 3320 microg/L]; p < 0.01) and the quality-of-life score had significantly improved (p < 0.05) compared with placebo. Partly explained by low baseline levels, no statistically significant change in concentration of exhaled nitric oxide (p > 0.05), urinary excretion of eosinophil protein X (p > 0.05), or eosinophil count (p > 0.05) was found. In conclusion, add-on treatment with montelukast can suppress sputum ECP in children with steroid-dependent asthma, while at the same time an improvement in quality of life items occurs.     

Q fever: still a mysterious disease

Sir, In the concluding paragraph of his editorial,¹ Dr Raoult makesa statement about the dangers of false-positive PCR assays arisingfrom DNA contamination during the detection of Coxiella burnetii.The caution references a study² from our Q fever Research Group.The general reader is likely to conclude that the artifactsmentioned by Raoult invalidate our observations. We urge thereader to study the actualities of     

The European Smoking Prevention Framework Approach (EFSA): an example of integral prevention

A smoking prevention project in six European countries (European Smoking prevention Framework Approach) was developed, featuring activities for adolescents, schools and parents, including out-of-school activities. Consensus meetings resulted in agreement between the countries on goals, objectives and theoretical methods. Countries' specific objectives were also included. National diversities required country-specific methods to realize the goals and objectives. The community intervention trial was used as the research design. Since interventions took place at the community level, communities or regions were allocated at random to the experimental or control conditions. Complete randomization was achieved in four countries. At baseline, smoking prevalence among 23 125 adolescents at the start of the project was 5.6% for regular smoking and 4.0% for daily smoking. Smoking prevalence rates were higher among girls than boys in all countries as far as weekly smoking was concerned. Process evaluations revealed that the project's ambitions were high, but were limited by various constraints including time and delays in receiving funds. Future smoking prevention projects should aim to identify the effective components within the social influence approach as well as within broader approaches and on reaching sustained effects.     

Cancer incidence among 10,211 airline pilots: a Nordic study

BACKGROUND: Commercial airline pilots are exposed to cosmic radiation and other potentially carcinogenic elements during work and leisure activities. HYPOTHESIS: Work-related factors affect cancer pattern of the pilots. METHODS: A cohort of 10,051 male and 160 female airline pilots from Denmark, Finland, Iceland, Norway, and Sweden was followed for cancer incidence through the national cancer registries. There were 177,000 person-years at follow-up, 51,000 of them accumulated after 20 yr since the time of first employment. Standardized incidence ratios (SIRs) were defined as ratios of observed over expected numbers of cases based on national cancer incidence rates. Dose-response analyses were done with Poisson regression method. RESULTS: Among male pilots, there were 466 cases of cancer diagnosed vs. 456 expected. The only significantly increased SIRs concerned skin cancer: melanoma 2.3 (95% CI 1.7-3.0), squamous cell cancer 2.1 (1.7-2.8), and basal cell carcinoma 2.5 (1.9-3.2). The relative risk of skin cancers increased with the time since first employment, the number of flight hours, and the estimated radiation dose. There was an increase in the relative risk of prostate cancer with increasing number of flight hours in long-distance aircraft (p trend 0.01). No increased incidence was found for acute myeloid leukemia or brain cancer which were of interest a priori based on earlier studies. CONCLUSIONS: This large study, based on reliable cancer incidence data, showed an increased incidence of skin cancer. It did not indicate a marked increase in cancer risk attributable to cosmic radiation although some influence of cosmic radiation on skin cancer cannot be entirely excluded.     

Potent activity of soluble B7RP-1-Fc in therapy of murine tumors in syngeneic hosts

We have characterized a receptor:ligand pair, ICOS:B7RP-1, that is structurally and functionally related to CD28:B7.1/2. We reported previously that B7RP-1 costimulates T cell proliferation and immune responses (Yoshinaga et al., Nature 1999;402:827-32; Guo et al., J Immunol 2001;166:5578-84; Yoshinaga et al., Int Immunol 2000;12:1439-47). We report that B7RP-1-Fc causes rejection or growth inhibition of Meth A, SA-1 and EMT6 tumors in syngeneic mice. Established Meth A tumors were rejected effectively with a single dose of B7RP-1-Fc, however, the treatment was less effective on larger tumors. Mice that rejected Meth A tumors previously by Day 30, also rejected a subsequent Meth A challenge on Day 60, without additional B7RP-1-Fc treatment, indicating a long-lived memory response. Tumor cells believed to be less immunogenic, such as P815 and EL-4 cells, were less responsive to this treatment. The EL-4 responsiveness to the B7RP-1-Fc treatment was enhanced, however, by pre-treatment of the mice with cyclophosphamide. As expected, T cells appeared to be targeted by B7RP-1-Fc treatment. Thus, the administration of soluble B7RP-1-Fc may have therapeutic value in generating or enhancing anti-tumor activity in a clinical setting.     

Peptide-targeted PEG-liposomes in anti-angiogenic therapy

Peptides with the RGD amino acid sequence show affinity for the alpha(v)beta(3) integrin, an integrin which is over-expressed on angiogenic endothelium and involved in cell adhesion. A peptide with the sequence ATWLPPR has been demonstrated to show affinity for the vascular endothelial growth factor (VEGF) receptor, a receptor involved in the proliferation of endothelial cells. By coupling these peptides to liposomes, these liposomes can serve as a site-specific drug delivery system to tumor endothelial cells in order to inhibit angiogenesis. In the present study we demonstrate that the coupling of cyclic RGD-peptides or ATWLPPR-peptides to the surface of PEG-liposomes results in binding of these liposomes to endothelial cells in vitro. Subsequent studies with RGD-peptide targeted liposomes in vivo also demonstrate specific binding to the tumor endothelium.     

SK channels and the varieties of slow after-hyperpolarizations in neurons

Action potentials and associated Ca2+ influx can be followed by slow after-hyperpolarizations (sAHPs) caused by a voltage-insensitive, Ca2+-dependent K+ current. Slow AHPs are a widespread phenomenon in mammalian (including human) neurons and are present in both peripheral and central nervous systems. Although, the molecular identity of ion channels responsible for common membrane potential mechanisms has been largely determined, the nature of the channels that underlie the sAHPs in neurons, both in the brain and in the periphery, remains unresolved. This short review discusses why there is no clear molecular candidate for sAHPs.     

Pathways of removal of free DNA vector ends in normal and DNA-PKcs-deficient SCID mouse hepatocytes transduced with rAAV vectors

Elucidation of the mechanisms of transformation of single-stranded (ss) recombinant adeno-associated virus (rAAV) vector genomes into a variety of stable double-stranded (ds) forms is key to a complete understanding of rAAV vector transduction in vivo. Ds monomer genome formation and cellular ds DNA break (DSB) repair pathways that remove free vector ends toxic to cells, presumably play a central role in this process. By delivering rAAV and naked ds linear DNA vectors into livers of DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-deficient severe combined immunodeficiency (SCID) and wild-type mice, we demonstrate the presence of three major pathways for free ds vector end removal: (1) DNA-PKcs-dependent self-circularization, (2) DNA-PKcs-independent self-circularization, and (3) DNA-PKcs-independent concatemerization. By using the DNA-PKcs-independent pathways, mouse hepatocytes efficiently removed free ds rAAV vector ends even in the absence of DNA-PKcs. Our studies suggest a hierarchical organization of these processes; self-circularization is the preferred pathway over concatemerization, although the former has a limited capacity to remove free vector ends. These studies shed new light on the molecular mechanisms of rAAV vector transduction in vivo.     

Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes

BACKGROUND: Postprandial lipemia is important in the development of coronary artery disease because of elevated postprandial triacylglycerol-rich plasma lipoproteins and suppressed HDL-cholesterol concentrations. We showed in healthy subjects a possible association between postprandial lipid metabolism and the responses of the duodenal incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide after meals rich in saturated and monounsaturated fatty acids (oleic acid), respectively. OBJECTIVE: The objective was to compare the postprandial responses (8 h) of glucose, insulin, fatty acids, triacylglycerol, gastric inhibitory polypeptide, and GLP-1 to saturated- and monounsaturated-rich test meals. DESIGN: Twelve overweight patients with type 2 diabetes ingested 3 meals randomly: an energy-free soup with 50 g carbohydrate (control meal), the control meal plus 100 g butter, and the control meal plus 80 g olive oil. Triacylglycerol responses were measured in total plasma and in a chylomicron-rich and a chylomicron-poor fraction. RESULTS: No significant differences in the glucose, insulin, or fatty acid responses to the 2 fat-rich meals were seen. The plasma triacylglycerol and chylomicron triacylglycerol responses were highest after the butter meal. HDL-cholesterol concentrations decreased significantly after the butter meal but did not change significantly after the olive oil meal. GLP-1 responses were highest after the olive oil meal. CONCLUSIONS: Olive oil induced lower triacylglycerol concentrations and higher HDL-cholesterol concentrations than did butter, without eliciting significant changes in glucose, insulin, or fatty acids. Furthermore, olive oil induced higher concentrations of GLP-1, which may indicate a relation between fatty acid composition, incretin responses, and triacylglycerol metabolism postprandially in patients with type 2 diabetes.