Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators

BACKGROUND: The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12-14 hours. However, the precise role of formoterol in the maintenance treatment of asthma is still under debate. A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma. METHODS: In a multicentre double blind, placebo controlled, parallel group study 239 subjects with mild to moderate asthma were randomly assigned to treatment with either inhaled formoterol 24 micrograms twice daily (n = 125) or placebo (n = 114) during eight months. The study consisted of a four week run in period, a 24 week treatment period, and a four week washout period. All subjects were using regular inhaled corticosteroids (100-3200 micrograms daily) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief. The study was performed in 10 outpatient clinics in Canada, and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherlands. Twice daily self-reported peak expiratory flow (PEF) measurements, symptom scores, and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures. Spirometric values were measured at entry, at the start of treatment, after four, 12 and 24 weeks of treatment, and after four weeks washout. RESULTS: One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo. Baseline FEV1 was 67.1% predicted and mean bronchodilator reversibility was 26%. The mean total asthma symptom score was 3.6 (maximum possible 21). A significant decrease in symptoms in favour of formoterol (difference from placebo -0.64, 95% CI -0.04 to -1.23, p = 0.04) was observed. Compared with placebo, morning PEF increased (difference from placebo 28 l/min, 95% CI 18.3 to 37.7, p = 0.0001) and the use of short acting beta 1 agonists decreased (daytime difference from placebo -1.1 inhalation, 95% CI -1.4 to -0.7, p = 0.0001) in the formoterol group. PEF returned to baseline following discontinuation of formoterol, as did asthma symptom scores. Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study (58 and 55 courses, respectively). CONCLUSIONS: Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF, and decreasing the use of rescue beta 2 agonists. There was no apparent loss of asthma control during 24 weeks of treatment with formoterol.


     

Hemorrhagic and nonhemorrhagic brain lesions: evaluation with 0.35-T fast MR imaging

Two fast magnetic resonance (MR) imaging techniques, advanced Fourier and partial-flip imaging, were used at 0.35 T to examine 21 patients with suspected intracranial lesions; the results were quantitatively compared with a conventional spin-echo study. Both of the fast MR techniques yielded a fourfold reduction in imaging time per section. The advanced Fourier sequence showed contrast that was identical to the conventional spin-echo study with signal-to-noise ratios of 58% and 57% for the first and second echoes, respectively. The partial-flip sequence showed a contrast of 109% and 57% for lesions versus substantia alba, and 107% and 78% for substantia grisea versus substantia alba relative to the first and second echoes of the conventional spin-echo study. The partial-flip sequence was particularly sensitive to magnetic susceptibility; this produced artifacts that may undermine the usefulness of partial flip for routine screening in certain parts of the brain. However, this susceptibility significantly improved the detection of intracranial hemorrhage when compared with the spin-echo sequence, particularly when combined with phase mapping of the partial-flip study.     

Relation between respiratory symptoms, pulmonary function and peak flow variability in adults.

BACKGROUND--A study was carried out to determine whether subjects with respiratory symptoms are more likely to have impaired lung function or increased airway lability, and to quantify these relationships in a population of adults. METHODS--Data were collected from 511 participants (aged 20-70 years) from the Dutch part of the European Community Respiratory Health Survey (ECRHS). The symptoms analysed were: wheeze, dyspnoea > or = grade 3, nocturnal dyspnoea, cough and phlegm, and history of allergy. Lung function was measured by peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1). PEF variability was used as an index for bronchial lability. RESULTS--Both FEV1 and PEF were decreased with increasing numbers of symptoms. Subjects with one symptom had an increased risk of having an FEV1 value of < 70% (OR = 4.2) and this risk increased with an increasing number of symptoms. Subjects with three or more symptoms had an increased risk of having a PEF value of < 70%, a diurnal variation in PEF of > 10% (both OR = 4.4), and an increased risk of high between day variation (OR = 6.6). CONCLUSIONS--Subject-reported symptoms are related to impaired lung function and to increased variability of peak flow.     

Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group.

BACKGROUND--Despite effective treatments, the morbidity and mortality of obstructive airways disease (asthma and COPD) remains high. Home monitoring of peak expiratory flow (PEF) is increasingly being advocated as an aid to better management of obstructive airways disease. The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups. METHODS--Patients aged 18-60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were randomised to receive, in addition to a beta 2 agonist, either an inhaled corticosteroid (BA+CS), an anticholinergic (BA+AC), or a placebo (BA+PL). One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up. RESULTS--Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained: the mean (SE) increase in morning PEF was 51 (8) l/min in the BA+CS group compared with no change in the other two groups. Similarly, afternoon PEF increased by 22 (7) l/min. Diurnal variation in PEF (amplitude %mean) decreased from 18.0% to 10.2% in the first three months of treatment with BA+CS. Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative (median rho-0.40) but with a large scatter. Relations between diurnal variation in PEF and changes in symptom scores, FEV1, and bronchodilator response were even weaker. CONCLUSIONS--In patients with moderately severe obstructive airways disease, PEF rates and variation are greatly improved by inhaled corticosteroids. Since the relation of diurnal PEF variation with PC20, symptoms, FEV1, and bronchodilator response were all weak, these markers of disease severity may all provide different information on the actual disease state. PEF measurements should be used in addition to the other markers but not instead of them.     

Office-based laryngeal laser surgery: a review of 443 cases using three wavelengths.

BACKGROUND: Unsedated office-based laser surgery (UOLS) of the larynx and trachea has significantly improved the treatment options for patients with laryngotracheal pathology including recurrent respiratory papillomas, granulomas, leukoplakia, and polypoid degeneration. UOLS delivered by flexible endoscopes has dramatically impacted office-based surgery by reducing the time, costs, and morbidity of surgery. OBJECTIVES: To review our experience with 443 laryngotracheal cases treated by UOLS. METHODS: The laser logbooks at the Center for Voice and Swallowing Disorders were reviewed for UOLS, and the medical and laryngological histories were detailed, as were the treatment modalities, frequencies, and complications. RESULTS: Of the 443 cases, 406 were performed with the pulsed-dye laser, 10 with the carbon-dioxide laser, and 27 with the thulium: yttrium-aluminum-garnet laser. There were no significant complications in this series. A review of indications and wavelength selection criteria is presented. CONCLUSION: Unsedated, office-based, upper aerodigestive tract laser surgery appears to be a safe and effective treatment option for many patients with laryngotracheal pathology.     

Monitoring serum CEA in women with primary breast tumours positive for oestrogen receptor and with spread to lymph nodes.

Serum carcinoembryonic antigen concentrations (serum CEA) in 80 patients with primary breast cancer were measured preoperatively, one month after operation, and thereafter serially every third month. These data were related to histological and morphometric features of the primary breast carcinoma and the lymph node metastases and to clinical follow up data. Analysis of the serum CEA values showed significant correlations with size of tumour, the presence of lymph node metastases, oestrogen receptor, and occurrence of distant metastases. Furthermore, the results indicated that serial determination of serum CEA in the first two years after operation may be useful in monitoring for the occurrence of distant metastases in patients with metastatic spread to lymph nodes and with large (greater than or equal to 2 cm) primary breast tumours positive for oestrogen receptor. In agreement with other studies, however, it was found that the predictive value of serum CEA concentrations in general is weak and costs may prohibit the implementation of the routine assessment of CEA concentrations.     

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.     

Genome-wide search for atopy susceptibility genes in Dutch families with asthma

BACKGROUND: Atopy is a phenotype associated with asthma that has a heritable component. However, the role of atopysusceptibility genes in the development and expression of asthma and allergic disorders is not understood. OBJECTIVE: We sought to study the familial aggregation and co-occurrence of atopic phenotypes within family members of patients with asthma and to identify chromosomal regions that may contain genes that regulate different atopic phenotypes. METHODS: In 200 families (n = 1174) ascertained through a proband with asthma, genome-wide screen and linkage analysis was performed for the following atopic phenotypes: (1) specific IgE to common aeroallergens (Phadiatop assay); (2) specific IgE to Der p 1; (3) positive skin test responses to house dust mite; (4) positive skin test responses to 1 or more of 16 allergens; and (5) peripheral blood eosinophils. Results were compared with the linkage results for total serum IgE levels. RESULTS: There was clear familial aggregation of atopy. A high total serum IgE level in combination with a positive Phadiatop result or a normal total IgE level in combination with a negative Phadiatop result was found in 56.1% of the probands and 66.9% of the offspring. Several chromosomal regions that showed evidence for linkage to an atopic phenotype (ie, 2q, 6p, 7q, and 13q) also showed evidence of linkage with total serum IgE (Xu et al. Am J Hum Genet 2000;67:1163-73). Specific regions of interest for atopic traits were also detected on chromosomes 11q, 17q, and 22q. CONCLUSIONS: Atopic phenotypes show familial aggregation, although family members may differ in expression of atopy. Specific chromosomal regions appear to be important in susceptibility to different phenotypes of atopic responsiveness.     

Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy

The Bethlem myopathy is a rare autosomal dominant proximal myopathy characterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the majority of families linked to 21q22.3 and one large family linked to 2q37, implicating the three type VI collagen subunit genes, COL6A1 (chromosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes. Mutations of the invariant glycine residues in the triple-helical domain-coding region of COL6A1 and COL6A2 have been reported previously in the chromosome 21-linked families. We report here the identification of a G-->A mutation in the N-terminal globular domain-coding region of COL6A3 in a large American pedigree (19 affected, 12 unaffected), leading to the substitution of glycine by glutamic acid in the N2 motif, which is homologous to the type A domains of the von Willebrand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrelated Caucasian control chromosomes. Thus mutations in either the triple-helical domain or the globular domain of type VI collagen appear to cause Bethlem myopathy.