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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

Atopy is the state of allergy to common environmental antigens. Genetic and environmental factors promote the disorder. The impressive rise in prevalence, mainly centred on socio-economically developed communities around the world, emphasizes the potent action of environmental factors in moulding this immune disorder which is characterized by inadequately restrained Th-2 immune mechanisms and IgE production. Reversing the epidemiological trend depends on our identifying the major environmental inputs and acting against these. As yet, the nature of these environmental factors remains to be clarified. Candidate factors include changes in diet, chemical air pollution and microbial exposures in developed countries. This article limits its scope to changing microbial exposures as a potential mechanism. (a) It records epidemiological data that have associated atopic status with less natural exposure to pathogens, parasites and commensal micro-organisms, but with more exposure to certain antibiotics and public health immunizations in early life. (b) It records studies in mice that support the concept that certain microbial exposures can inhibit experimental allergy. (c) It considers potential immune mechanisms for such an action, including the possibility that certain natural infections promote immune regulatory processes that can restrain atopy. It is concluded that the hypothesis that changing patterns of microbial exposure may have promoted the rise in atopy is viable, and that exciting possibilities for reversing the rise of atopy may be derived from further studies.

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.

1. Atopy is a genetically heterogeneous disorder, but there is now strong evidence that one important locus is on chromosome 11q13. FcεRI-β at that location has been identified as a candidate gene and variants have been associated with atopy in population studies. 2. No information is available on the functional consequences of any of these variants, and defining this may prove difficult because of the complexity of the atopy phenotype and because FcεRIβ is expressed on a range of cells with different functions, including basophils, mast cells, eosinophils and antigen-presenting Langerhan's cells. 3. We have conducted a qualitative study of mast cell and basophil histamine release in nine atopic individuals with Ile-181→Leu mutation of FcεRIβ, and ten unrelated similarly atopic individuals without Ile-181→Leu mutation. There were non-significant trends for Ile-181→Leu-positive atopic subjects to produce wheal responses at lower allergen challenge in skin prick tests, and to release more histamine from basophils following in vitro allergen challenge. 4. The data do not provide decisive evidence of functional differences between atopic subjects with Ile-181→Leu and other atopic individuals; more discriminating functional experiments are required.

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.

The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of Fc epsilon RI-beta, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q.

Summary The results of testing for linkage between atopy and the chromosome 11 marker D11S97 is shown for all the 723 subjects genotyped by us up to January 1992. Lod score estimations were confounded by the high population prevalence of atopy, maternal inheritance of atopy at the 11q locus, genetic heterogeneity, and excess of atopy in families not ascertained through a single proband. Affected sib-pair analysis shows evidence for linkage which is not dependent on the definition of atopy or model specification. We suggest that presentation of sib-pair data will be suitable for meta-analysis of the different studies of genetic linkage and atopy.

DNA amplification of specific sequences and subsequent oligonucleotide hybridization were used to search for Pneumocystis carinii in post-mortem lung samplings from non-immunosuppressed individuals ranging from 15 to 70 years of age. No P. carinii-specific DNA was detected in 45 DNA amplification reactions from 15 lungs.

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 …

Twenty-five atopic children under 11 years of age were studied, using skin and RAST tests, for their specific IgE response to four species of pyroglyphid house dust mites, Dermatophagoides pteronyssinus, D. farinae, D. microceras and Euroglyphus maynei. All of the children were sensitive to D. pteronyssinus, 20 (80%) of these children were also sensitive to D. farinae and D. microceras, and 16 of the latter (64%) were also sensitive to E. maynei. Dust samples from various sites in the homes of the children revealed D. pteronyssinus in all homes studied but no D. farinae or D. microceras. E. maynei, although identified, was not present in significant numbers in any site. A control group of 20 atopic children of similar age who were not sensitive to house dust mite allergens had a similar exposure to the four mite species. These results suggest that factors in addition to mite exposure are important in the development of specific IgE responses to house dust mites.

Summary Background Atopy is a common syndrome underlying asthma, rhinitis, and eczema, and is characterised by high immunoglobulin E (IgE) responses to common antigens. IgE and mast-cell chymase (MCC–a serine protease secreted by skin mast cells) have a key role in atopic or allergic inflammation of the skin. The gene for MCC is located within a cluster of genes for cellular proteases on chromosome 14q11·2. We aimed to identify variants of MCC and another gene within this complex, and assess whether there is a genetic association between variants of MCC and atopic disorders–particularly eczema. Methods We randomly selected 100 controls and recruited patients-100 in each group–with atopic asthma, non-atopic asthma, atopic rhinitis, and atopic eczema. PCR amplification was used to test genomic DNA for an association between allelic polymorphisms in MCC and a flanking gene (CGL1, for the cathepsin-G-like protein) on chromosome 14q11 and asthma, rhinitis, and eczema. Findings We found a significant association between a BstXI polymorphism in MCC and eczema (odds ratio 2 17 [95% CM 21-3 88], p=0 009), but no association with atopic asthma, rhinitis, or non-atopic asthma. There was no association between an MboII polymorphism in CGL1 and any of the atopic disorders. Interpretation These findings suggest that variants of MCC may be one source of genetic risk for eczema.

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.

We recently described a protective effect of the low molecular weight protein tyrosine phosphatase (LMPTP) BC genotype, associated with the highest total enzymatic activity, against high serum IgE levels both in the English and the Italian populations. Here we test the hypothesis of a role of LMPTP in the negative modulation of IL-4 signal transduction checking for genetic interaction between interleukin-4 receptor alpha chain (IL-4RA) genetic polymorphisms and LMPTP polymorphism in the predisposition to high total IgE levels in the English population. We find a significant interaction between LMPTP polymorphism and the intracellular Gln/Arg polymorphism in position 551 of IL-4RA. Our data support the hypothesis of a direct or indirect biochemical interaction between LMPTP and IL-4RA resulting in different modulation of IL-4 signal transduction among joint genotypes.

Two studies were performed to compare the sensitivity of DNA amplification with immunofluorescence for the detection of Pneumocystis carinii in asymptomatic normal and immunosuppressed subjects receiving no anti-Pneumocystis chemoprophylaxis. In the first study, immunofluorescence and silver stains were used to examine 12 induced sputa and 12 bronchoalveolar lavage specimens from 24 normal control subjects; induced sputa from 20 renal transplant recipients; and induced sputa from 11 patients with fibrosing alveolitis. All specimens were negative for P carinii using both stains, apart from one renal patient in whom 2 P carinii cysts were seen by immunofluorescence alone. In the second study, DNA amplification and immunofluorescence were used to examine induced sputa from 3 groups of 10 control, renal, and heart/lung transplant recipients. All 30 specimens were negative for P carinii by immunofluorescence. However, 3 renal and 2 heart/lung patients were positive for P carinii by DNA amplification alone. One of these patients developed P carinii pneumonia 6 weeks after sputum induction. DNA amplification is a more sensitive technique than immunofluorescence for detecting P carinii. P carinii colonization occurs in asymptomatic organ transplant recipients, but not in normal individuals.

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.

Pneumocystis carinii pneumonia is a major complication of T-lymphocyte immune deficiency. Restriction of the disease to the alveolar spaces and failure to culture R. carinii has hindered simple diagnostic methods. We have developed a specific DNA amplification method for P. carinii and shown diagnostic sensitivity and specificity exceeding 95% for pneumocystis pneumonia when applied to bronchoscopic lavage and hypertonic saline induced sputum. We here report application of DNA amplification to simple oropharyngeal samples in 31 HIV-positive patients with respiratory illness. P. carinii-specific DNA was detected in 10 of 18 (56%) patients with pneumocystis pneumonia by ethidium bromide stained gels and 14 of 18 (78%) patients by the more sensitive technique of oligoblotting. P. carinii DNA was not detected in samples from 13 patients with other respiratory diagnoses. An oropharyngeal sample offers a simple specimen for detecting P. carinii by DNA amplification; refinements of technique and calibration may allow its development for accurate diagnostic and epidemiological work.

Atopy, a common familial syndrome underlying allergic asthma and rhinitis, is characterised by sustained immunoglobulin E (IgE) responses to common allergens. We have previously shown genetic linkage of atopy to the chromosome 11q13 marker D11S97 (pms51) through maternally derived alleles, but no likely candidate genes were known to lie near this marker. We have analysed maternally derived alleles from 155 sibling-pairs affected by atopy to seek evidence of linkage between the gene predisposing to atopy and other markers on chromosome 11q13. We found that the beta subunit of the high-affinity receptor for IgE (Fc epsilon RI-beta) also lies on chromosome 11q13, and that it is in close genetic linkage with the gene for atopy. The known roles of Fc epsilon RI in antigen-induced mast-cell degranulation and in the release of cytokines that enhance IgE production make the gene for its beta subunit a candidate for the chromosome 11 atopy locus.

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).

Atopy is a common familial state underlying allergic asthma and rhinitis. Lately, we have assigned a gene for atopy to chromosome 11q by linkage to the marker D11S97. Since previous studies have suggested that the risk of atopy is higher for children of atopic mothers than for those of atopic fathers, we sought differences between maternal and paternal patterns of transmission at the 11q13 locus among pairs of siblings in families affected by atopy. When we defined atopy as the presence of a positive skinprick test (greater than or equal to 2 mm) to any of a panel of common allergens, a higher than normal concentration of total serum IgE, or a positive radioallergosorbent test for a specific IgE, we found that 125 (62%) of the sibling-pairs affected by atopy shared the maternal 11q13 allele and 78 (38%) did not. This distribution differs significantly from the expected 50/50 distribution (p = 0.001). Of paternally derived alleles, 83 (46%) were shared and 96 (54%) were not (not significantly different from 50/50). The result was similar whatever definition of atopy was used and with other genetic markers on 11q. These findings show that transmission of atopy at the chromosome 11q locus is detectable only through the maternal line. The pattern of inheritance is consistent either with paternal genomic imprinting or with maternal modification of developing immune responses.

We have developed a highly specific and sensitive technique for the detection of Pneumocystis carinii DNA using DNA amplification by the polymerase chain reaction (PCR). PCR products are detected by agarose gel electrophoresis and Southern hybridization to an oligonucleotide probe. Here we report the calibration of parasite numbers with amplification and hybridization signals and show that we can detect P. carinii to a lower limit of one to two organisms. The quantification of this diagnostic technique allows us to establish the number of organisms in a clinical sample which correspond to pneumocystis pneumonia or to sub-clinical pulmonary colonization.

Pairwise analysis of siblings from 21 families showed that house dust mite (HDM) sensitive children were exposed to higher concentrations of Der p I allergen in their mattress (P = 0.005) and bedding (P = 0.04), but not bedroom floor (P = 0.33), than their atopic sibling who was not sensitive to HDM antigens. There was no difference in the exposure to HDM numbers/100 mg of dust in the mattress (P = 0.61) or bedroom floors (P = 0.09). In contrast, pairwise analysis of siblings from 15 families showed that HDM sensitive children were not exposed to significantly different concentrations of Der p I in the mattress (P = 0.96), bedding (P = 0.11) or bedroom floor (P = 0.70) nor HDM numbers/100 mg of dust in the mattress (P = 0.12) and bedroom floor (P = 0.98) than their non-atopic siblings. These findings were identical when absolute allergen load was compared in these pairs. Genetic linkage studies in these families suggest the tendency to atopic IgE responses is conferred by a putative atopy locus on chromosome 11q. These results together suggest that differences in allergen levels in beds, among siblings with a comparable genetic tendency to atopy, play a significant role in determining the development of HDM allergy.

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.

DNA amplification and silver staining were used to identify Pneumocystis carinii in bronchoscopic lavage and induced sputum samples during 51 episodes of respiratory illness in 47 subjects with H IV infection. In 20 episodes, in which the clinical diagnosis was pneumocystis pneumonia (PCP), silver stain was positive in 14 lavage samples (70%) and 7 sputum samples (35%), whereas DNA amplification was positive in 19 lavage samples (95%) and 18 sputum samples (90%). DNA amplification was positive in only 1 of 31 patients without PCP (PCP developed in this patient within 10 weeks). DNA amplification on induced sputum offers a powerful technique for diagnosis of PCP.

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.

Four of five patients with AIDS and pulmonary infection had syncopal reactions as a result of fine-needle aspiration of the lung; in one patient the reaction was fatal. Subsequently, in one of these patients and four further patients with AIDS or human immunodeficiency virus (HIV) infection, the autonomic nervous system proved to be abnormal. This preliminary evidence suggests HIV infection may be associated with an autonomic neuropathy, which may expose these patients to particular risk after invasive procedures.

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 familial occurrence of atopy, defined by skin prick test responses and serum immunoglobulin-E (IgE) titres to common inhaled allergens, was studied in 239 members of 40 nuclear and 3 extended families. 90% of the atopic children in the nuclear families had at least one demonstrably atopic parent. In each extended family, atopy was vertically transmitted, and 31 of 47 (66%) offspring of marriages between atopic and unaffected parents were atopic. Of the designated atopic subjects, 83% admitted to symptoms suggesting atopic disease but only 30% regarded themselves as having any such disorder. It is suggested that atopy, the propensity to produce IgE in response to common, usually inhaled, allergens, is inherited as an autosomal dominant character but that its clincal expression depends on interaction with other factors.

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.