Significance of connective tissue disease features in idiopathic interstitial pneumonia.

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

Elevated nocturnal desaturation index predicts mortality in interstitial lung disease.

BACKGROUND: Nocturnal desaturation may contribute to long-term pulmonary vascular stress in interstitial lung disease (ILD). We study the prevalence, severity and prognostic utility of nocturnal desaturation across ILD. METHODS: ILD patients with overnight oximetry (June 2006-August 2008) were reviewed (n = 134). Significant nocturnal desaturation was considered as > 10% of sleep with SpO2 < 90%. Desaturation index (DI) was defined as the number of desaturation events > 4%/hr. Covariates, including indices of nocturnal desaturation, were evaluated against mortality. RESULTS: Nocturnal desaturation was present in 49 (37%) patients. 31% of patients had pulmonary hypertension (PH) on echocardiography. Increased DI was associated with higher mortality independent of age, gender and BMI (HR 1.04; 95% CI 1.00, 1.06; p = 0.009). In separate models, DI and a) elevated brain natriuretic peptide (BNP; HR 1.04; 95% CI 1.00, 1.08; p = 0.04); b) moderate-severe PH on echocardiography (HR 3.15; 95% CI 1.24, 8.00; p = 0.02); and c) daytime resting SpO2 (HR 0.92; 95% CI 0.85, 0.99; p = 0.04) independently predicted mortality following adjustment for age, gender and BMI. CONCLUSION: Nocturnal desaturation is common and may be severe in ILD. Elevated nocturnal DI predicts higher mortality across ILD, independent of other vascular parameters. This finding may have important implications for the pathogenesis of PH in IPF.

Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis.

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of "marginal" changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated. In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D( L,CO)) trends at 6 months were categorised as "significant" (FVC >10%; D(L,CO) >15%) or "marginal" (FVC 5-10%; D(L,CO) 7.5-15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality. In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54-5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19-4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19-4.60; p = 0.01). Marginal changes in D(L,CO) in IPF and marginal changes in FVC and D (L,CO) in fibrotic NSIP did not provide useful prognostic information. Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.

Use of intravenous cyclophosphamide in known or suspected, advanced non-specific interstitial pneumonia.

BACKGROUND: In severe, progressive interstitial lung disease (ILD), specific diagnosis is often difficult, and treatment therefore empirical. An effective, rapidly acting, well-tolerated therapy is desirable. This study reviews the tolerability and efficacy of i.v. cyclophosphamide in known or suspected non-specific interstitial pneumonia (NSIP) following the introduction of an i.v. cyclophosphamide protocol. METHODS: Records of 54 patients with biopsy-proven (n = 7) or suspected NSIP, based on clinico-radiological consensus (n = 47), receiving i.v. cyclophosphamide over 2004-6 were reviewed (excluding systemic sclerosis). Lung-function trends over six months were evaluated, and comparative analysis of paired pulmonary-function before and after the start of therapy was performed. RESULTS: IV cyclophosphamide was well tolerated, with two withdrawals from therapy, and four deaths, not directly related to treatment. IV cyclophosphamide was associated with disease stability at six-months. Despite having severe, progressive disease, patients receiving i.v. cyclophosphamide had stable lung function at six months. A greater therapeutic response was associated with coexistent HRCT abnormalities indicative of organizing pneumonia. In 22 patients with paired pulmonary-function tests, pulmonary function trends were significantly improved (p = 0.03) and change in DLco differed significantly (p < 0.0001), following cyclophosphamide treatment. CONCLUSION: In the empirical treatment of advanced, rapidly progressive known or suspected NSIP, i.v. cyclophosphamide is a well tolerated, rapidly acting immunosuppressant, associated with improvement or stability in most cases.

Pulmonary lymphatic vessel morphology: a review.

Our understanding of lymphatic vessels has been advanced by the recent identification of relatively specific lymphatic endothelium markers, including Prox-1, VEGFR3, podoplanin and LYVE-1. The use of lymphatic markers has led to the observation that, contrary to previous assumptions, human lymphatic vessels extend deep inside the pulmonary lobule, either in association with bronchioles, intralobular arterioles or small pulmonary veins. Pulmonary lymphatic vessels may thus be classified into pleural, interlobular (in interlobular septa) and intralobular. Intralobular lymphatic vessels may be further subdivided in: bronchovascular (associated with a bronchovascular bundle), perivascular (associated with a blood vessel), peribronchiolar (associated with a bronchiole), and interalveolar (in interalveolar septa). Most of the intralobular lymphatic vessels are in close contact with a blood vessel, either alone or within a bronchovascular bundle. A minority is associated with a bronchiole, and small lymphatics are occasionally present even in interalveolar septa, seemingly independent of blood vessels or bronchioles. The lymphatics of the interlobular septa often contain valves, are usually associated with the pulmonary veins, and connect with the pleural lymphatics. The large lymphatics associated with bronchovascular bundles have similar characteristics to pleural and interlobular lymphatics and may be considered conducting vessels. The numerous small perivascular lymphatics and the few peribronchiolar ones that are found inside the lobule are probably the absorbing compartment of the lung responsible for maintaining the alveolar interstitium relatively dry in order to provide a minimal thickness of the air-blood barrier and thus optimize gas diffusion. These lymphatic populations could be differentially involved in the pathogenesis of diseases preferentially involving distinct lung compartments.

Interstitial lung disease in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterised by fibrosis of the skin and internal organs, autoimmune abnormalities and widespread vasculopathy. A degree of interstitial lung involvement is present in the majority of patients, although clinically significant lung fibrosis is present in approximately a third. Autoantibodies are significant clinical markers; anti-topoisomerase is tightly linked to lung fibrosis, whereas anti-centromere antibodies are protective. Further evaluation of markers of progression of lung fibrosis, such as markers of epithelial permeability, will be crucial in clinical management. The clinical course of SSc-associated interstitial lung disease is highly variable, with stability observed in a significant proportion of patients. Therefore, the decision of whether to treat is a challenging one, and should be based on evaluation of disease severity (on the basis of CT extent and lung function) and longitudinal disease behaviour. Two recently published placebo controlled randomized trials have shown a significant, if small, effect of cyclophosphamide on preventing FVC decline. However, because of the significant toxicity of cyclophosphamide, the assessment of alternative, less toxic, immunosuppressive agents for the long-term management of SSc-associated interstitial lung disease is needed.

Short-acting beta 2 agonists for stable COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterised by progressive airflow limitation that is at best partially reversible. Despite the lack of reversibility patients with stable often report symptomatic improvement with short-acting beta-2 bronchodilator medication. OBJECTIVES: To determine the clinical effectiveness and assess the adverse effects of regular treatment with short-acting beta-2 agonists bronchodilators in patients with stable COPD. SEARCH STRATEGY: A search was carried out using the Cochrane Airways Group database. In addition, reference lists of review articles and retrieved studies were searched for other potentially relevant citations. SELECTION CRITERIA: Randomised controlled trials of at least one week in duration that compared treatment with inhaled short-acting beta-2 agonists delivered by metered dose inhaler or nebuliser with placebo in patients with stable COPD. DATA COLLECTION AND ANALYSIS: Data extraction and study quality assessment were performed independently by two reviewers. Where further or missing data was required, authors of studies were contacted. The data were analysed using the Cochrane Review Manager 4.0.4. MAIN RESULTS: Thirteen studies were included. All used a cross-over design and were of high quality. Post-bronchilator spirometry performed at the end of the study period showed a significant increase in FEV1 compared to placebo; weighted mean difference (WMD) =0.14 L; 95% Confidence Interval (CI) 0.04 to 0.25. This effect was only seen in studies in which the drug was delivered by metered dose inhaler. Post-bronchodilator morning and evening PEFR were significantly better during active treatment than during placebo; WMD=29.2 L/min; 95%CI 0.3 to 58.1 & WMD = 36.8 L/min; 95%CI: 2.6 to 70.9 respectively. A significant improvement in daily breathlessness score was observed during treatment with beta-2 agonist when compared to placebo; standardised mean difference (SMD) =1.33; 95%CI: 1.0 to 1.65. There was no improvement in exercise performance. The risk of dropping out of the study (ie treatment failure) when on treatment with placebo was almost twice that of patients on treatment with beta-2 agonists; Relative Risk =0.49; 95%CI 0.33-0.73). Patients preferred beta-2 agonist therapy more frequently than placebo; Odds Ratio = 9.04; 95%CI 4.6 to 17.61). No studies reported serious side effects during treatment with inhaled beta-agonists, but none were of sufficient size or length to allow any meaningful information on long-term occurrence of side effects. REVIEWER'S CONCLUSIONS: Short-acting beta-2 agonists delivered by metered dose inhaler on a regular basis improve lung function. Breathlessness but not exercise performance are also improved. There are insufficient data to provide reliable information on long-term adverse effects. Use of these drugs as first line agents for symptomatic treatment of COPD is supported by this review.

Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic condition characterised by progressive airflow limitation that is at most partially reversible. Despite the lack of reversibility patients often report symptomatic improvement with short-acting beta-2 bronchodilator medication. Short-acting beta-2 bronchodilators are used in the management of both stable and acute exacerbations of COPD. OBJECTIVES: To determine the clinical effectiveness and assess the adverse effects of regular treatment with short-acting beta-2 agonists bronchodilators in patients with stable COPD. SEARCH STRATEGY: A search was carried out using the Cochrane Airways Group database. In addition, the reference lists of review articles and the randomised controlled trials (RCTs) retrieved in full text were searched for other potentially relevant citations. SELECTION CRITERIA: RCTs of at least one week in duration comparing treatment with inhaled short-acting beta-2 agonists with placebo in patients with stable COPD. DATA COLLECTION AND ANALYSIS: Data extraction and study quality assessment was performed independently by two reviewers. Where further or missing data was required, authors of studies were contacted. The data was analysed using the Cochrane Review Manager 4.1. MAIN RESULTS: Thirteen studies were included in this review. All studies used a crossover design and were of high quality. Spirometry performed at the end of the study period and after the administration of treatment (post-bronchodilator) showed a slight but significant increase in FEV1 and FVC when compared to placebo (WMD=0.14 L; 95%CI=0.04,0.25 & WMD=0.30 L; 95%CI=0.02,0.58, respectively). In addition, both morning and evening PEFR were significantly better during active treatment than during placebo (WMD=29.17 L/min; 95%CI=0.25,58.09 & WMD=36.75 L/min; 95%CI=2.56,70.94, respectively). A significant improvement in daily breathlessness score was observed during treatment with beta-2 agonist when compared to placebo (SMD=1.33; 95%CI=1.0,1.65). The risk of dropping out of the study (treatment failure) when on treatment with placebo was almost twice that of patients on treatment with beta-2 agonists (RR=0.49; 95%CI=0.33,0.73). Patients preferred beta-2 agonists almost 10 times more frequently to placebo (OR=9.04; 95%CI=4.64,17.61). One study that used a validated questionnaire for 'quality of life' assessment, found highly significant improvements in the scores for dyspnoea (p=0.003) and fatigue (p=0.0003) during treatment with salbutamol. No studies reported serious side effects during treatment with inhaled beta-agonists. However, none of the studies were of sufficient length or size in order to allow any meaningful information on long-term occurrence of side effects. REVIEWER'S CONCLUSIONS: Use of short-acting beta-2 agonists on a regular basis for at least seven days in stable COPD is associated with improvements in post bronchodilator lung function and a decrease in breathlessness. Patients are far more likely to prefer treatment with beta-2 agonists than placebo, and less likely to drop out from such treatment. None of the studies included in this review reported sufficient data or were of sufficient length or size in order to provide reliable information on adverse effects. Therefore large scale, parallel, longer term studies would be needed to investigate the effect of treatment with regular inhaled beta-2 agonists on mortality, disease progression and side effects. Newer, long acting bronchodilators (including long-acting beta-2 agonists) are currently available and they may be more practical and/or effective in these patients. However, this review indicates that treatment with these older, inexpensive drugs is beneficial in patients with COPD.

Clinical, laboratory and radiological findings in pulmonary fibrosis with and without connective tissue disease.

Uncertainty exists over whether to consider "lone" idiopathic pulmonary fibrosis (LIPF) and pulmonary fibrosis associated with connective tissue disorders (PFCTD) as significantly different entities. We retrospectively analysed data collected at the time of first diagnosis in 17 patients with LIPF and in 14 patients with PFCTD and compared survival in the two groups. At first evaluation, the time from onset of respiratory symptoms, spirometric volumes and the diffusing capacity for carbon monoxide were not significantly different between the two groups. However, arterial oxygen tension was significantly lower in LIPF than in PFCTD (63 +/- 3 vs 88 +/- 3 mmHg, p < 0.001). The radiological profusion scores relative to the upper and middle lung fields were significantly higher in LIPF than in PFCTD (upper regions: 6.9 +/- 0.6 vs 3.4 +/- 0.6, p < 0.005 - middle regions: 7.1 +/- 0.5 vs 4.8 +/- 0.7, p < 0.025), whereas the scores relative to the lower fields were similar (7.4 +/- 0.4 in LIPF and 8.4 +/- 0.6 in PFCTD). Survival since onset of respiratory symptoms was significantly better in the PFCTD than in LIPF patients, with a hazard ratio of 4.16 (95% CI 1.12-15.58, p=0.034). Thus, in our series of patients, those with LIPF had a more severe disease than those with PFCTD as shown by the higher frequency of hypoxaemia, the more diffuse pulmonary involvement demonstrated by the chest X-ray and the decreased survival.

Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis.

Sarcoidosis is a heterogeneous disorder, both phenotypically and genetically. Two independent studies have recently shown that a functional polymorphism within butyrophilin-like 2 (BTNL2) gene predisposes to sarcoidosis independently of the human leukocyte antigen (HLA)-DRB1 alleles. However, in both studies, data analysis was not stratified by Löfgren's syndrome, a clinically and genetically distinct sarcoidosis subset. BTNL2, potentially encoding an immune coreceptor, is adjacent and in linkage disequilibrium (LD) with HLA-DRB1. We investigated six BTNL2 variants, including the functional rs2076530 (G > A), as well as HLA-DRB1 alleles, by sequence-specific primers-polymerase chain reaction, in 288 patients and 446 controls from two European countries. In the patient group as a whole, the HLA-DRB1*14 [odds ratio (OR) = 3.1, P(c) = 0.0003], DRB1*12 (OR = 2.5, P(c) = 0.003), and BTNL2 rs2076530 A allele (OR = 1.49, P(c) = 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Löfgren's syndrome and after adjusting for HLA-DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P = 0.23). By contrast, both HLA-DRB1*14 and DRB1*12 remained strongly significant (OR = 3.60, P < 0.0001 and OR = 3.03, P = 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non-Löfgren sarcoidosis after adjusting for HLA-DRB1 alleles (OR 0.37, P = 0.016). In summary, HLA-DRB1*14, DRB1*12, and BTNL2 haplotype 4--but not rs2076530 A--are associated with non-Löfgren sarcoidosis. However, the tight LD across the HLA complex makes it difficult to identify the precise location of the susceptibility locus/i. Larger sample sets from different ethnic groups, finer mapping, and more robust LD analyses across the HLA region are needed.

A polymorphism in the promoter region of the CD86 (B7.2) gene is associated with systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease of unknown aetiology characterized by fibrosis of the skin and internal organs, vascular abnormalities and humoral autoimmunity. Strong T-cell-dependent autoantibody and HLA associations are found in SSc subsets. The co-stimulatory molecule, CD86, expressed by antigen-presenting cells, plays a crucial role in priming naïve lymphocytes. We hypothesized that SSc, or one of the disease subsets, could be associated with single-nucleotide polymorphisms of the CD86 gene. Using sequence specific primer-polymerase chain reaction (SSP-PCR) methodology, we assessed four CD86 polymorphisms in 221 patients with SSc and 227 healthy control subjects from the UK. Haplotypes were constructed by inference and confirmed using PHASE algorithm. We found a strong association between SSc and a specific haplotype (haplotype 5), which was more prevalent in patients than in controls (29% vs 15%, OR = 2.3, chi(2) = 12, P = 0.0005). This association could be attributed to the novel -3479 promoter polymorphism; a significant difference was observed in the distribution of the CD86 -3479 G allele in patients with SSc compared to controls (43.7% vs. 32.4%, OR = 1.7, chi(2) = 12.1, P = 0.0005). TRANSFAC analyses suggest that the CD86-3479T allele contains putative GATA and TBP sites, whereas G allele does not. We assessed the relative DNA protein-binding activity of the -3479 polymorphism in vitro using electromobility gel shift assays (EMSA), which showed that the -3479G allele has less binding affinity compared to the T allele for nuclear proteins. These findings highlight the importance of co-stimulatory pathways in SSc pathogenesis.

Single-nucleotide polymorphisms in the SPARC gene are not associated with susceptibility to scleroderma.

OBJECTIVE: SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that modulates cell-cell and cell-extracellular matrix interactions. SPARC expression is restricted mainly to sites of tissue remodelling and wound repair, and is prominent in fibrotic disorders. Single-nucleotide polymorphisms (SNPs) in the SPARC gene are reportedly linked to scleroderma in four ethnic groups: Choctaw Indians, Caucasians, African Americans and Mexican Americans. We set out to reproduce and to positionally clone these disease associations in a set of UK Caucasian scleroderma patients and ethnically matched controls. METHODS: One hundred and twenty-one scleroderma subjects and 200 controls were genotyped by polymerase chain reaction with sequence-specific primers differing only in the 3' nucleotide corresponding to each allele of the biallelic SNPs. Scleroderma patients were analysed against controls and on the basis of their fibrosing alveolitis status as judged by high-resolution computed tomography evaluation and the extent of cutaneous involvement. RESULTS: Eight biallelic SNPs were genotyped: three from the last untranslated exon, which had been described previously, and an additional five novel SNPs: two in the promoter region, one in exon three and two in the 3' untranslated region. Six major haplotypes were constructed across all eight SNP positions. No significant differences in genotype, allele or haplotype frequency were observed between scleroderma and controls or within scleroderma subgroups. CONCLUSIONS: SNPs in the SPARC gene are not associated with susceptibility to scleroderma. This research adds to the genetic knowledge of the SPARC gene by identifying five novel SNPs spanning the whole gene and inserting these within the context of clearly defined haplotypes.

Multimedia presentation of lung sounds as a learning aid for medical students.

New educational technologies might help to compensate for the decrease in time and emphasis dedicated to physical examination in medical training. This may, in particular, be applicable for improving the skills in auscultation of the chest. We investigated whether a multimedia presentation of acoustic and graphic characteristics of lung sounds could improve the learning of pulmonary auscultation by medical students, in comparison with conventional teaching methods. We studied 48 medical students without clinical experience, who had received conventional formal teaching on chest examination. Chest auscultation skills were evaluated using an inaccuracy score for the student's auscultation report on three patients, selected according to a standardized procedure. After a baseline evaluation, 27 students in groups of 5-10, participated in a multimedia seminar on lung sounds during which digitized lung sounds were played and the corresponding time-expanded waveform and frequency spectrum were commented on and displayed on a computer. The remaining 21 students received conventional bedside training, acting as control group. The following week, all the students underwent a second evaluation of chest auscultation skills. No differences in the inaccuracy score were observed between the two groups in the preliminary test. However, in the second postintervention assessment, the inaccuracy score of the students who had followed the seminar (11.2 +/- 1.3 points) was significantly lower than that of the controls (16.6 +/- 1.6 points). The answers to a feedback questionnaire confirmed that the great majority of the students found the association of the acoustic signals with their visual image to be useful for learning and understanding lung sounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Host-vector system for integration of recombinant DNA into chromosomes of transformable and nontransformable streptococci.

We describe a genetic system in which transformation of Streptococcus pneumoniae and Streptococcus sanguis was used to insert recombinant DNA into the conjugative chromosomal element omega (cat tetM) 6001 (omega 6001). The element containing the recombinant DNA was then transferred by conjugation to the chromosome of transformable and nontransformable streptococci. When Escherichia coli plasmid pDP36 was used as donor in transformation, it was capable of inserting 5.9 kilobases of heterologous DNA into the chromosome of competent streptococcal strains carrying omega 6001; the transformants were scored for erythromycin resistance. Genetic analysis showed that in a fraction of the erythromycin-resistant transformants the integration via flanking homology of the heterologous DNA caused inactivation of the tetM gene of omega 6001. By analyzing the stability of the resistance markers, we found that stable integration of heterologous DNA was achieved only in the erythromycin-resistant, tetracycline-sensitive transformants. It was possible to detect conjugal transfer of the heterologous sequences from stable transformants to strains of S. pneumoniae, S. sanguis, Streptococcus pyogenes, and Streptococcus faecalis. The omega 6001-pDP36 host-vector system opens new possibilities for gene transfer in streptococci. By this method cloned streptococcal DNA (possibly mutagenized in vitro) can be returned to the original host, greatly facilitating complementation tests and fine physiological studies.

Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group.

Wheezing in childhood is not a single disorder and different wheezing-associated respiratory illnesses have been recently described. We investigated the association between wheezing conditions and familial, pre-, peri-, and postnatal risk factors. We studied 16,333 children, 6 to 7 yr old, enrolled in a population-based study. Standardized questionnaires were filled in by parents. A total of 1,221 children had transient early wheezing, 671 had persistent wheezing, 918 had late-onset wheezing, and 13,523 never had wheezing or asthma (control group). Maternal asthma or chronic obstructive airway disease were significantly (p < 0.0001) more associated with persistent wheezing than with transient early and late-onset wheezing. The same pattern was observed for exposure to maternal smoke during pregnancy. Having a mother > 35 yr old was protective against transient early wheezing (odds ratio [OR]: 0.68, 95% confidence intervals [95% CI]: 0.53 to 0.86). Breast feeding >/= 6 mo was slightly protective against transient early wheezing (OR: 0.82, 95% CI: 0.68 to 0.97), whereas it was a moderate risk factor for late-onset wheezing (OR: 1.22, 95% CI: 0.99 to 1.50). On the contrary, having siblings and attending a day care center were both risk factors for transient early wheezing (OR: 1.41 [95% CI: 1.21 to 1.64] and 1.70 [95% CI: 1.48 to 1.96], respectively) and protective factors against wheezing of late onset (OR: 0.83 [95% CI: 0.70 to 0.97] and 0.72 [95% CI: 0.59 to 0.88]). There was a stronger (p < 0.0001) positive association between personal history of eczema or allergic rhinitis and persistent and late-onset wheezing than transient early wheezing. Our findings suggest a different contribution of risk factors to wheezing conditions in childhood.

Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis.

OBJECTIVE: To search for single-nucleotide polymorphisms in the interleukin-8 (IL-8) and IL-8 receptor CXCR-1 and CXCR-2 genes, and to compare their distribution among patients with systemic sclerosis (SSc) with fibrosing alveolitis (FASSc) or without fibrosing alveolitis (NFASSc), or patients with cryptogenic fibrosing alveolitis (CFA), and normal healthy subjects. METHODS: Fifty control subjects were screened for potential polymorphisms by using polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3' end. The novel polymorphisms were subsequently examined in British Caucasian subjects, including 194 healthy controls, 71 patients with CFA, and 128 patients with SSc who were further subdivided into 78 FASSc patients and 50 NFASSc patients. RESULTS: Three novel biallelic polymorphisms were identified in the IL-8 gene (all in noncoding areas of the gene), 1 was found in the CXCR-1 gene (resulting in a conservative amino acid change), and 3 were observed in the CXCR-2 gene, of which the first resulted in a silent codon change and the others were in the 3' untranslated area of exon 3. Compared with controls, a significant increase in the frequency of the CXCR-2 +785 CC homozygote and of the CXCR-2 +1208 TT homozygote was found in the SSc patients (37% versus 22% [P = 0.01] and 33% versus 17% [P = 0.003], respectively). A subgroup analysis revealed this association to be significant both in the FASSc patients and in the NFASSc patients. CONCLUSION: This report describes an association between SSc and 2 polymorphisms occurring close to each other in the CXCR-2 gene. This finding and its functional significance need to be confirmed and analyzed in future studies.

Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children. SIDRIA Collaborative Group, Italy (Italian Studies on Respiratory Disorders in Children and the Environment).

BACKGROUND: A beneficial effect of fresh fruit consumption on lung function has been observed in several studies. The epidemiological evidence of the effect on respiratory symptoms and asthma is limited. The consumption of fruit rich in vitamin C was examined in relation to wheezing and other respiratory symptoms in cross sectional and follow up studies of Italian children. METHODS: Standardised respiratory questionnaires were filled in by parents of 18 737 children aged 6-7 years living in eight areas of Northern and Central Italy. The winter intake of citrus fruit and kiwi fruit by the children was categorised as less than once per week, 1-2 per week, 3-4 per week, and 5-7 per week. A subset of 4104 children from two areas was reinvestigated after one year using a second parental questionnaire to record the occurrence of wheezing symptoms over the intervening period. RESULTS: In the cross sectional analysis, after controlling for several confounders (sex, study area, paternal education, household density, maternal smoking, paternal smoking, dampness or mould in the child's bedroom, parental asthma), intake of citrus fruit or kiwi fruit was a highly significant protective factor for wheeze in the last 12 months (odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.55 to 0.78, for those eating fruit 5-7 times per week compared with less than once per week), shortness of breath with wheeze (OR = 0.68, 95% CI 0.56 to 0.84), severe wheeze (OR = 0.59, 95% CI 0.40 to 0.85), nocturnal cough (OR = 0.73, 95% CI 0.65 to 0.83), chronic cough (OR = 0.75, 95% CI 0.65 to 0.88), and non-coryzal rhinitis (OR = 0.72, 95% CI 0.63 to 0.83). In the follow up study fruit intake recorded at baseline was a strong and independent predictor of all symptoms investigated except non-coryzal rhinitis. In most cases the protective effect was evident even among children whose intake of fruit was only 1-2 times per week and no clear dose-response relationship was found. The effect was stronger (although not significantly so (p = 0.13)) in subjects with a history of asthma; those eating fresh fruit at least once a week experienced a lower one year occurrence of wheeze (29. 3%) than those eating fruit less than once per week (47.1%) (OR = 0. 46, 95% CI 0.27 to 0.81). CONCLUSIONS: Although the effect of other dietary components cannot be excluded, it is concluded that the consumption of fruit rich in vitamin C, even at a low level of intake, may reduce wheezing symptoms in childhood, especially among already susceptible individuals.