Wheeze in preschool children and its relation with doctor diagnosed asthma.

OBJECTIVE--To describe the characteristics of wheeze and its relation with doctor diagnosed asthma in children aged 5 years and under. DESIGN--Questionnaire survey of population based random sample of children registered on Leicestershire Health Authority's child health index for immunisation; questionnaire completed by parents. SUBJECTS--1650 white children born in 1985 to 1989 who were surveyed in 1990. MAIN OUTCOME MEASURES--Age distribution, severity, precipitants, seasonal characteristics, and diurnal variation of wheeze, family history of asthma/atopy, and their association(s) with doctor diagnosed asthma. RESULTS--There were 1422 replies (86.2%). Two hundred and twenty two (15.6%) were reported to have wheezed and of these 121 (8.6%) had formally been diagnosed as having asthma. More than 80% of the former had recurrences of wheeze and 40% (72) had three or more episodes in the preceding 12 months. Age, number of episodes per year, the severity of shortness of breath with attacks, and precipitants other than colds were the major factors determining the probability that a wheezy child will be diagnosed as having asthma. The data also suggest that despite the strong association of symptom based criteria with the label asthma, asthma was not diagnosed by these same severity criteria in one quarter of cases. CONCLUSIONS--Clinical and physiological follow up studies of children identified as asthmatic by the above criteria during the preschool years should validate or refute the predictive value of these measures of wheeze severity.     

Hepatitis C virus (HCV) genotypes in the Caribbean island of Martinique: evidence for a large radiation of HCV-2 and for a recent introduction from Europe of HCV-4

Molecular epidemiological studies of hepatitis C virus (HCV) in the Caribbean may help to specify the origin and spread of HCV infection. Indeed, the Caribbean population is intermixed from European and African origins and geographically close to the American continent. We characterized HCV genotypes in the Caribbean island of Martinique. HCV genotypes were analyzed by sequencing or reverse hybridization in the 5' noncoding region (5'NC) in 250 HCV-monoinfected and 85 HCV-human immunodeficiency virus (HIV)-coinfected patients. In addition, sequencing in the nonstructural 5B (NS5B) gene was required to determine the subtype or to perform phylogenetic analysis in selected samples. Genotypes 1 to 6 were found, respectively, in 84.4, 6.8, 5.2, 2.8, 0.4, and 0.4% of 250 HCV-monoinfected patients and in 71.7, 7.1, 15.3, 5.9, 0, and 0% of 85 HCV-HIV-coinfected patients. HCV-1b was found in 66.4% of the HCV-monoinfected patients and was associated with blood transfusion, whereas HCV-1a was detected in 41.2% of the HCV-HIV-coinfected patients and was associated with intravenous drug use (IVDU). The HCV-3 strains belonged to subtype 3a and were linked to IVDU. Phylogenetic analyses were focused on HCV-2 and HCV-4, which are common in Africa. Two opposite patterns were evidenced. NS5B sequences from 19 HCV-2 isolates were affiliated with many different subtypes described either in Europe or in West Africa, suggesting an ancient radiation. In contrast, seven of the nine HCV-4 NS5B sequences ranged within HCV-4a and HCV-4d clusters spreading in continental France by the IVDU route. Epidemiological data demonstrate the recent introduction of HCV-4a and -4d subtypes into the Caribbean.     

Developmental defects in zebrafish for classification of EGF pathway inhibitors

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway.     

Abnormal Coronary Anatomy in Patients with Transposition of the Great Arteries and Atrial Switch: A Predictor of Serious Cardiac Adverse Events?

Sudden cardiac death and heart failure are well known long-term complications after atrial switch for D-transposition of the great arteries (D-TGA). Right systemic ventricular dysfunction is common and myocardial ischemia has been implicated as a putative mechanism for sudden death, with coronary anomalies prevalent in 30% of cases. We sought to assess an association between adverse events and coronary anomalies in patients with D-TGA and atrial switch surgery. An observational study was conducted in 3 tertiary centers (Montreal Heart Institute, Canada, Nationwide Children’s hospital, Chicago, USA and Hopital cardiologique Louis Pradel de Lyon, France). Adults with D-TGA and atrial switch surgery qualified for inclusion if they had a major adverse cardiovascular event (MACE), i.e., ventricular arrhythmia, sudden cardiac death, heart failure, cardiac transplantation, or cardiovascular death. The prevalence of coronary anomalies was compared to historical controls. Forty-five patients were included. Twenty-one (46.7%) patients experienced a ventricular arrhythmia and 35 (77.8%) suffered from symptomatic heart failure and/or severe right ventricular dysfunction. Twelve patients (26.7%) had congenitally abnormal coronary arteries. There was no difference in the prevalence of coronary anomalies between the cohort with a MACE and a pooled population of 647 historical controls with D-TGA (28.7%, p = 0.89). In conclusion, the prevalence of congenital coronary anomalies is not higher in patients with D-TGA and atrial switch surgery who had adverse cardiovascular events. It could be hypothesized that ischemic complications in this patient population are more likely to be related to a supply-demand mismatch of the distal microvasculature rather than proximal coronary anomalies.     

Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum

Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. The potency, selectivity, and predicted safety of PMO conjugates make this approach attractive for the development of a unique class of target-specific antimalarials and for large-scale functional analysis of the malarial genome.