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A propos d'une observation: en cas d'insuffisance ventilatoire l'administration d'oxygene par voie nasale peut amener des concentrations d'oxygene exagerees dans l'air inhale. Le masque est preferable

Whole genome scan analyses have revealed that chromosomal region 3p21−24, which contains a gene cluster of CC chemokine receptors such as CCR3, is possibly linked to asthma. Because CCR3 ligands play a pivotal role in the selective recruitment and activation of inflammatory cells in the asthmatic airway, the authors examined whether there is any association between asthma and the CCR3 gene polymorphisms. Three polymorphisms were identified using the single stranded conformational polymorphism method in Japanese (Asian) and British (Caucasian) subjects; one silent mutation T51C and two missense mutations G824A and T971C. These polymorphisms were examined in 391 Japanese subjects (210 asthmatics and 181 nonasthmatic controls) and 234 British subjects (142 asthmatics and 92 nonasthmatic controls). Asthma diagnosis was based on episodic symptoms, documented wheeze, and the presence of reversible airflow limitation. CCR3 T51C demonstrated a significant association with the diagnosis of asthma in the British population (odds ratio 2.35, p

The beta subunit of high affinity immunoglobulin E (IgE) receptor (FcepsilonRIbeta) and the Clara cell derived inflammatory molecule, CC16 have been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic association study was performed with an intragenic microsatellite repeat of CC16 gene on chromosome 11q12-13 in relation to atopic and non-atopic asthma. Whereas variants of FcepsilonRIbeta at chromosome 11q13 show association with atopy and asthma, no significant association was found between asthma and CC16 genotypes irrespective of atopic status. These data support the candidacy of FcepsilonRIbeta rather than CC16 for the atopic asthma locus on chromosome 11q.

Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.

Genetically distinct forms of Pneumocystis carinii infect several mammalian hosts. We report the amplification of P. carinii DNA from samples of two infected thoroughbred foal lungs by using primers designed from the sequence of a P. carinii mitochondrial rRNA gene; these primers also prime the amplification of P. carinii DNA from other hosts. The nucleotide sequence of part of the mitochondrial rRNA gene amplified from P. carinii infecting one of the foals was determined and found to be distinct from that of published rat-, rabbit-, ferret-, and human-derived P. carinii sequences.

Pneumocystis carinii causes life-threatening pneumonia in T-lymphocyte-immunodeficient subjects in transplant and oncology units or with acquired immune deficiency syndrome (AIDS). Recent DNA homology studies show P. carinii to be a fungus. To investigate the biology and epidemiology of this parasite further, we elected to determine for it a more precise taxonomic assignment within the fungal kingdom. We screened a wide range of organisms representing the major orders of fungi using DNA amplification and subsequently sequenced a portion of the mitochondrial gene encoding the large subunit ribosomal RNA. Our data show that the opportunistic pulmonary pathogen P. carinii is closely related to the ustomycetous red yeast fungi, a group which includes organisms that are extensively distributed throughout the environment and which release many widely dispersed airborne spores.

In this issue of Thorax there are two articles which add to the observations on an inverse link between mycobacterial exposure and atopic disorder, and to the larger story that certain microbial exposures in early childhood may play a key part in limiting immune dysregulation. Von Mutius and colleagues report increasing tuberculosis notification rates associated with a stepwise decrease in symptoms of asthma and rhinoconjunctivitis in an international ecological study,1 while Omenaas et al found no relationship between IgE levels and tuberculin responses in Norwegian adults vaccinated with BCG at 14 years of age.2 One potential explanation for the promotion of clinical tolerance to allergens by certain microbial exposures may be framed within two related immunological concepts. Firstly, adaptive immune responses may be broadly categorised into two antagonistic subtypes (Th1 and Th2), each with its own set of molecular mediators or cytokines.3-5 Secondly, the type of T helper (Th) adaptive response to one antigen may influence the type of Th response to a quite independent antigen through modification of the cytokine profile of the immune milieu.6-8 In atopy there is over-reactivity of Th2 immune mechanisms involving the cytokines interleukin (IL)-4, IL-5 and IL-3, which leads to IgE production and eosinophilic mucosal inflammation in response to many antigens. Atopic or allergic responses to inhaled antigen or allergen such as those from house dust particles are a potent factor in the causation of asthma.6 9 10 Such vigorous Th2 immune responses are naturally seen in certain helminthic infections when they provide an important element of protective immunity.11-13What then is their origin, in dysregulated form, in atopy? Heterogeneous genetic factors are important because genetic variants at a number of chromosomal locations are linked to high IgE levels or asthma.14 Variants in the Th2 cytokine signalling …

Summary A 6.8 kjlobase fragment of mJtochondrial DNA from Pneumocystis carinii encodes for apocytochrome b, NADH dehydrogenase subunits 1, 2, 3, and 6, cytochrome oxidase subunit II, and the small subunit of ribosomal RNA. Comparative sequence analysis with a series of organisms representative of the fungal and protozoan groups shows that R carinii has, consistently, an average similarity of 60% with the fungi but only 20% with the protozoa. The data indicate homology with the fungi for this opportunistic pathogen.

The beta subunit of high affinity immunoglobulin E (IgE) receptor (FcepsilonRIbeta) and the Clara cell derived inflammatory molecule, CC16 have been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic association study was performed with an intragenic microsatellite repeat of CC16 gene on chromosome 11q12-13 in relation to atopic and non-atopic asthma. Whereas variants of FcepsilonRIbeta at chromosome 11q13 show association with atopy and asthma, no significant association was found between asthma and CC16 genotypes irrespective of atopic status. These data support the candidacy of FcepsilonRIbeta rather than CC16 for the atopic asthma locus on chromosome 11q.

Three HIV positive subjects presented with symptoms and radiographic changes suggestive of Pneumocystis carinii pneumonia. Methenamine silver staining of bronchoscopic alveolar lavage (BAL) fluid was negative (from one sample in one patient and two samples in the other two patients). Open lung biopsy was performed because of uncertain clinical progress and diagnosis; all three patients were found to have multiple pulmonary granulomata encasing numerous P carinii organisms. DNA amplification, using P carinii specific oligonucleotides, was performed on stored bronchoscopic BAL samples. P carinii specific amplification product was detected by ethidium bromide staining after electrophoretic separation on agarose gel in one case, and by the more sensitive technique of oligohybridisation in all three cases. In granulomatous P carinii pneumonia organisms are rarely identified in bronchoscopic alveolar lavage samples using histochemical staining, but are detectable by DNA amplification, although not at levels which can be readily distinguished from low, subclinical infection.

The IL-4RA locus encodes for the alpha chain of the IL-4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL-4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs). One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL-4 receptor alpha chain. The distribution of haplotypes 50-478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels100 U mL-1 than in those with IgE levels100 U mL-1. Furthermore, the distribution of haplotype 50-551 shows a weak association with IgE levels that is lacking for 478-551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.

Asthma is a complex syndrome in which bronchial inflammation and smooth muscle hyperactivity lead to labile airflow obstruction. The commonest form of asthma is that due to atopy, which is an immune disorder where production of IgE to inhaled antigens leads to bronchial mucosal inflammation. The ultimate origins of asthma are interactive environmental and genetic factors. The genetics is acknowledged to be heterogeneous, and one chromosomal region of interest and controversy has been 11q13. To clarify the nature of the chromosome 11q13 effect in atopy and asthma, we conducted a genetic association study in subjects with marked atopic asthma and matched controls, which incorporated the study of 13 genetic variants over a distance of 10-12 cM and which took account of detailed immune and clinical phenotyping. Association with high IgE levels was limited to the interval flanked by D11S1335 and CD20 in a 0.8-Mb interval and was greatest for variants of Fc epsilonRIbeta and HTm4; these variants also associated with asthma (recurrent wheeze with labile airflow obstruction and need for regular inhaler treatment). At the more telomeric marker, D11S480, variants associated with asthma, but not with high IgE levels. The data might support the possibility of multiple loci relevant to atopic asthma on chromosome 11q13.

BACKGROUND—Atopy is of complex origins but the recent rise in atopic diseases in westernised communities points to the action of important environmental effects. One candidate mechanism is the changing pattern of microbial exposure in childhood. This epidemiological study investigated the relationship between childhood infections and subsequent atopic disease, taking into account a range of social and medical variables. METHODS—A total of 1934 subjects representing a retrospective 1975-84 birth group at a family doctor practice in Oxfordshire were studied. Public health and practice records were reviewed; temporal records were made of all diagnoses of infections and their treatments, all immunisations, and diagnoses of asthma, hay fever and eczema; maternal atopy and a number of other variables were documented. RESULTS—Logistic regression analysis identified three statistically significant predictors of subsequent atopic disease: maternal atopy (1.97, 95% CI 1.46 to 2.66, p

The gene encoding Clara cell-derived inflammatory molecule CC16 has been cited as a candidate gene for atopic asthma on chromosome 11q13. A genetic association study was performed with variants of the CC16 gene on chromosome 11q13 in relation to asthma in British (n=275) and Japanese (n=300) populations. No significant association was found between asthma and CC16 genotypes, irrespective of atopic status in these two populations. These data suggest that CC16 might not be the major locus for asthma on 11q13.

BACKGROUND: Fc epsilon RI plays a central role in atopy, thus genetic variants of Fc epsilon RI-beta may alter receptor function to enhance atopic responses and may manifest as a more severe atopic phenotype and more symptomatic atopic disease. The immunological and clinical features of atopy in children with and without the Leu 181 variant of Fc epsilon RI-beta were compared. METHODS: Sixty British nuclear families, including 10 families with the Fc epsilon RI-beta variant Leu 181, recruited via a young proband with atopic asthma were analysed for atopic parameters including total IgE, specific IgE, and clinical atopic disorder. RESULTS: Compared with other children (combined atopic and non-atopic subjects), maternally inherited Leu 181 was associated with increased levels of total IgE (odds ratio (OR) 4.82, 95% confidence interval (CI) 1.02 to 27.66, p < 0.01) and a positive IgE response to grass pollen allergen (OR 7.45, 95% CI 1.56 to 35.52, p < 0.005) but not wheeze (OR 1.97, 95% CI 0.56 to 7.69), asthma (OR 2.25, 95% CI 0.65 to 7.85), or required medications (OR 0.95, 95% CI 0.29 to 3.14). There were trends for each atopic parameter to be more marked in atopic children with maternally inherited Leu 181 than in atopic children without Leu 181. Children with maternal Leu 181 had significantly raised eosinophils but there was no difference in basophil levels compared with other atopic children. CONCLUSIONS: The Leu 181 variant of Fc epsilon RI-beta, or another identified variant in linkage disequilibrium, may promote the development of atopy.

Human immune responses are heterogeneous and may involve antagonism between T helper (TH) lymphocyte subsets and their cytokines. Atopy is characterized by immediate immunoglobulin E (IgE)-mediated hypersensitivity to agents such as dust mites and pollen, and it underlies the increasingly prevalent disorder asthma. Among Japanese schoolchildren, there was a strong inverse association between delayed hypersensitivity toMycobacterium tuberculosisand atopy. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward TH1 type. Exposure and response toM. tuberculosismay, by modification of immune profiles, inhibit atopic disorder.

SUMMARY: The arom gene, encoding a single polypeptide that catalyses five consecutive steps of the pre-chorismate aromatic amino acid biosynthetic pathway, has been cloned from the opportunistic pathogen Pneumocystis carinii. There is a single open reading frame of 4788 bp which includes an intron of 45 bp that does not introduce a stop codon into the sequence. Thus, the derived amino acid sequence consists of 1581 residues, which is highly homologous to all fungal AROM proteins studied to date. These data support the view that P. carinii is a fungus and imply that its aromatic amino acid biosynthesis is conventionally organized.

We have undertaken a double blind placebo controlled study of the effect of nasal beclomethasone on the tendency to wheeze in 20 unselected hay fever sufferers, half with a history of previous seasonal wheezing. We found no difference between either bronchial hyperresponsiveness, as measured by methacholine challenge, home-monitored PEFR, nor recorded wheeze nor cough between treated and placebo groups although the numbers were small. All were allowed the antihistamine cetirizine hydrochloride 10 mg daily. Eighteen out of the 19 patients had either bronchial hyperresponsiveness (PD20 methacholine < 8 mumol or a > 2 doubling dose change in their PD20 during the pollen season). We have shown a significant positive correlation between a hay fever score (HFS) (created by taking the sum of the home scored; nasal discharge, nasal blockage, eye irritation, sneeze and antihistamine use) and peak seasonal specific IgE to mixed grass pollen (Spearman correlation coefficient 0.5 P < 0.02). There was also a positive correlation between the rise in specific IgE from pre to peak season and the HFS, correlation coefficient 0.6 P = 0.03).

A genetic association study was performed with coding variants of Fc epsilon RI beta in relation to atopic and non-atopic asthma in a Japanese population (n = 400). A coding variant of Gly237Glu in exon 7 of Fc epsilon RI beta gene showed association with atopic asthma (OR = 3.00, chi 2 = 5.10, p mean + 3 SD, OR = 8.56, chi 2 = 46.2, p < 0.0001), but not any allergen specific IgE. However, Leu181lle, another variant of Fc epsilon RI beta related to atopy in British and Australian populations, was not found in this Japanese population. These results suggest that variants of Fc epsilon RI beta may be an important genetic cause of the atopic asthma.

Thirty pulmonary infiltrates in 26 patients were investigated by bronchoalveolar lavage. Sixteen of the patients were on therapeutic immunosuppression for renal disease or transplant and 10 had leukaemia, lymphoma, or allied conditions. A rapid specific diagnosis was made in 21 (70%) episodes by cytological examination of the fluid and in 28 (93%) by a combination of cytology and microbiology. No complications from haemorrhage or pneumothorax ensued. Pneumonia due to Pneumocystis carinii was the most common diagnosis (27%), but opportunistic infections from cytomegalovirus, candida, aspergillus, zygomycetes, and acid fast bacilli were also identified by cytology. Two episodes were caused by occult pulmonary haemorrhage and five patients had malignant infiltration of the lung from leukaemia, myeloma, Hodgkin's disease, and lymphoplasmacytoid lymphoma. In two of these there was also evidence of infection. In seven cases with non-diagnostic cytology infections due to Staphylococcus aureus, Pseudomonas aeruginosa, pneumococcus, micrococcus, and Aspergillus fumigatus were identified on culture. In two patients (7%) no specific diagnosis was established by lavage: one had serological evidence of legionella infection and the second had P aeruginosa septicaemia. Twelve (75%) of the renal patients and six (60%) of those with leukaemia, lymphoma, and allied conditions recovered.

Mutagenicity and cytotoxicity are basic cellular effects of cigarette smoke which underlie the development of lung cancer and chronic obstructive airways disease. This study reports that, on a weight-for-weight basis, cigarette smoke condensates from low, middle and high tar cigarettes produce similar mutagenic effects detected by induced sister chromatid exchanges and similar cytotoxic effects detected by vital dye exclusion in human leucocytes. These findings, taken with the strong evidence that smokers extract more smoke from lower tar cigarettes to compensate for low nicotine yields, suggest that the health dangers associated with smoking these "safer" products are underestimated.

Neither propranolol (80 mg) nor metoprolol (100 mg) give orally to eight normal subjects altered mean ventilatory responses to carbon dioxide or to moderate graded exercise. Incremental doses of the drugs to totals of 320 mg propranolol and 400 mg metoprolol also did not effect these ventilatory responses. Both drugs markedly decreased the heart rate response to exercise. Neither propranolol nor metoprolol are likely to cause CO2 retention by an effect on the ventilatory responses to inhaled carbon dioxide or to exercise.

Epidemiological studies have firmly established that cigarette smoking causes almost all cases of anaplastic and squamous cell bronchial carcinomas. It is equally well known, however, that many smokers do not develop lung cancer and, although the amount of tobacco smoked is undoubtedly, the dominant risk factor, it seems possible that other factors may also be involved. There is increasing evidence to support Boveri's old hypothesis that somatic mutation is an important event in the development of cancer and we have recently shown that cigarette smoke condensate (CSC) produces many dose-related lesions in the cellular DNA of cultured human lymphocytes as measured by sister chromatid exchange (SCE) induction. Cytogenetic studies had previously shown an increase in chromosomal aberrations in blood lymphocytes of heavy smokers relative to non-smokers, but little or no increase in SCEs. We have now measured basal and CSC-induced SCE rates in lymphocytes from different individuals and report that smokers have higher rates than non-smokers and that smokers with untreated lung cancer have consistently higher rates than their matched heavy smoking controls. These results are in keeping with the somatic mutational hypothesis and the epidemiological evidence, but also raise questions related to difficulties in smoking dosimetry and to possible variation among different individuals' responses to a common insult.

There is increasing evidence that elastase may mediate pulmonary damage in emphysema and also that the release of intracellular elastase by cigarette smoke is necessarily associated with cell death. We report consistent and significant variation in response of lymphocytes from different individuals to the cytotoxic effect of cigarette smoke condensate in vitro. This variation which occurred at levels of cigarette smoke likely to be encountered in vivo and which was independent of the age, sex, or smoking habits of the subjects, may be relevant in determining the risk of developing emphysema amongst smokers.

THE carcinogenicity of tobacco tars and smoke in laboratory animals1,2 together with epidemiological evidence from man have clearly suggested that smoking causes most lung cancer3–5. However, other interpretations of the epidemiological evidence have been proposed6 and the carcinogens known to occur in cigarette smoke are present in only minute quantities7. There is increasing evidence that one prerequisite in the initiation of malignant transformation is an alteration in cellular DNA, and the findings that most carcinogens react with DNA8, that this reaction necessarily precedes transformation9 and that most carcinogens are mutagens10, support the importance of somatic mutation. Two types of visible chromosome changes that result from DNA damage are gross aberrations and symmetrical sister chromatid exchanges (SCE)11,12, and the induction of SCEs provides a very sensitive indicator of mutagen/carcinogen exposure at concentrations below those which normally result in the production of chromosomal aberrations13,14. Cytogenetic studies15,16 have shown an increase in chromosomal aberrations in blood lymphocytes of heavy smokers relative to non-smokers, but little17 or no16,18 increase in SCEs. Furthermore, products mutagenic to bacteria have been isolated from the urine of inhaling smokers19, and also smokers have a higher incidence of sperm abnormalities than non-smokers20. These studies imply that there may be higher levels of mutagens in body cells and fluids of smokers than in those of non-smokers, but little is known about the reaction of cigarette smoke with the DNA of exposed human cells, and even less about the possible mutagenic effects. Here we report that exposure of human lymphocytes to small quantities of tobacco smoke condensate leads to the formation of many DNA lesions that result in sister chromatid exchanges.