Genetic polymorphism of MUC7: allele frequencies and association with asthma.

MUC7 encodes a small salivary mucin, previously called MG2, a glycoprotein with a putative role in facilitating the clearance of oral bacteria. The central domain of this glycoprotein was previously shown to comprise five or six tandemly repeated units of 23 amino-acids which carry most of the O-linked glycans. The polymorphism of these two allelic forms (MUC7*5 or MUC7*6) has been confirmed in this study in which we have analysed a large cohort of subjects (n = 375) of various ethnic origins. We have also identified a novel rare allele with eight tandem repeats (MUC7*8). MUC7*6 was the most common allele (0.78-0.95) in all the populations tested. The tandem repeat arrays of 22 MUC7*5 alleles and 34 MUC7*6 alleles were sequenced. No sequence differences were detected in any of the MUC7*6 alleles. Twenty-one MUC7*5 alleles sequenced lacked the 4th tandem repeat (structure TR12356), while one showed the structure TR12127. The structure of the MUC7*8 allele was TR12343456. Because of the known role of MUC7 in bacterial binding, and thus its potential involvement in susceptibility to chest disease we also tested MUC7 in our previously described series of Northern European atopic individuals with and without associated asthma. The MUC7*5 allele was rarer in the atopic asthmatics than in the atopic non-asthmatics (P = 0.014, OR for no asthma in atopic individuals 3.13, CI 1.01-6.10), and the difference in frequency between all asthmatics and all non-asthmatics was statistically significant (P = 0.009) while there was no difference between atopy and non-atopy (P = 0.199). In this study we also report the electrophoretic analysis of the MUC7 glycoprotein in saliva from individuals of different MUC7 genotype.

Polymorphism of human mucin genes in chest disease: possible significance of MUC2.

Most of the genes that encode epithelial mucins are highly polymorphic due to variations in the length of domains of tandemly repeated (TR) coding sequence, the part of the apomucin that is heavily glycosylated. We report here for the first time a difference in the distribution of MUC TR length alleles in chest disease. We examined the distribution of the length alleles of those MUC genes whose expression we have confirmed in the bronchial tree in an age- and sex-matched series of 50 pairs of atopic patients with and without asthma. There was no significant difference in the distribution of alleles of MUC1, MUC4, MUC5AC, and MUC5B. MUC2, however, showed a highly significant difference in distribution. The atopic, nonasthmatic individuals showed an allele distribution that was very different from all our other patient and control groups, this group showing a longer mean allele length. The observations suggest that longer MUC2 alleles may help protect atopic individuals from developing asthma, though the effect may be due to a linked gene. The biological significance of this variation with respect to susceptibility to asthma will merit further investigation, and it will also be important to substantiate this finding on an independent data set.

Pulmonary complications of HIV disease: 10 year retrospective evaluation of yields from bronchoalveolar lavage, 1983-93.

BACKGROUND: Pulmonary disease is a major contributor to morbidity and mortality in patients with HIV infection and AIDS. The aim of this study was to describe bronchoscopic findings and the spectrum of pulmonary pathogens in HIV seropositive patients undergoing investigation of respiratory disease over a 10 year period in a major UK referral centre. METHODS: Recruitment was procedure based with data being captured when bronchoscopy was clinically indicated. Data were evaluated from 580 HIV seropositive patients (559 men, age 13-65 years) over a 10 year period from June 1983 to March 1993. RESULTS: A total of 947 bronchoscopies was performed. The most frequent pulmonary pathogen isolated from bronchoalveolar lavage (BAL) fluid in 44% of all bronchoscopies was Pneumocystis carinii. Of all patients studied, 324 (55%) had at least one cytologically confirmed episode of P carinii pneumonia; this was AIDS defining in 219 (38%) of patients who underwent bronchoscopy. Between 1987 and 1993 the overall diagnostic yield from BAL fluid was 76%; 25% of all bronchoscopies yielded positive microbiological results, the most frequent isolates being Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas spp, and Haemophilus influenzae. Mycobacteria were identified in 8% of patients; M tuberculosis was the most common being identified in 3% of lavage samples and in 4% of patients. No drug-resistant M tuberculosis was found. Viral isolates (mainly cytomegalovirus) were identified in up to 31% of BAL fluid samples. Endobronchial Kaposi's sarcoma was seen in 15% of patients at bronchoscopy. CONCLUSIONS: Of the 1956 newly diagnosed HIV seropositive patients receiving clinical care at St Mary's Hospital over this period, approximately 30% underwent bronchoscopy. Diagnostic rates for P carinii pneumonia, endobronchial Kaposi's sarcoma, and bacterial and mycobacterial infection have remained largely constant since 1989. Bronchoalveolar lavage produces high diagnostic yields generally, and P carinii pneumonia remains a common cause of pulmonary disease in these patients.

Bronchopulmonary Kaposi's sarcoma in patients with AIDS.

BACKGROUND: Kaposi's sarcoma is the most common secondary neoplasm to complicate HIV infection and may cause pulmonary disease. METHODS: A prospective study was carried out in 140 consecutive patients who were HIV seropositive and required bronchoscopy for new respiratory symptoms of at least two weeks' duration, with either a chest radiographic abnormality or abnormality of pulmonary function. The patients were classified into those with single local endobronchial lesions of Kaposi's sarcoma or generalised widespread lesions. Before bronchoscopy all patients had routine simple pulmonary function tests and chest radiography. RESULTS: Thirty nine (21%) patients had evidence of cutaneous Kaposi's sarcoma. Nineteen of the 39 were found to have endobronchial Kaposi's sarcoma lesions at bronchoscopy, but none of those who did not have cutaneous Kaposi's sarcoma. Respiratory symptoms of cough and breathlessness and radiographic abnormalities were attributed to Kaposi's sarcoma in this group, except in four patients who had concomitant pneumocystis pneumonia. Eight patients had local endobronchial Kaposi's sarcoma lesions and 11 had extensive lesions. Patients with extensive lesions had more widespread radiographic abnormalities; four of the patients with local endobronchial lesions had normal chest radiographs. All patients had reduced transfer factor for carbon monoxide and transfer coefficient, whereas patients with extensive endobronchial lesions also had reductions in forced expiratory volume in one second and forced vital capacity. Median survival (with palliative chemotherapy with vincristine and bleomycin) was only seven months. In three patients who needed further diagnostic bronchoscopy endobronchial lesions had regressed while they were having chemotherapy. CONCLUSIONS: This study suggests that endobronchial Kaposi's sarcoma is a relatively common finding in patients with AIDS and is particularly common in patients with cutaneous Kaposi's sarcoma who present with respiratory illness. Endobronchial Kaposi's sarcoma causes respiratory disease and abnormalities of pulmonary function. Pulmonary Kaposi's sarcoma should be considered as a possible cause for respiratory illness in any patient with cutaneous Kaposi's sarcoma.

Pulmonary function in human immunodeficiency virus infection. A prospective 18-month study of serial lung function in 474 patients.

To investigate the development of a reduced DLCO in patients with HIV-related disease, we studied 474 HIV-seropositive patients and performed serial lung function measurements over 18 months. The mean values of DLCO at presentation were lower in patients with more advanced HIV disease compared with asymptomatic HIV-seropositive patients (DLCO 88% of predicted). When compared with the DLCO in asymptomatic HIV-seropositive patients, the DLCO had reduced values in patients with persistent generalized lymphadenopathy (PGL) (82% of predicted, p less than 0.05), acquired deficiency syndrome-related complex (ARC) (73% predicted, p less than 0.001), nonpulmonary Kaposi's sarcoma (KS) (72% of predicted, p less than 0.001), nonpulmonary complications of AIDS excluding KS (73% of predicted, p less than 0.001), pulmonary KS (63% of predicted, p less than 0.001), pulmonary mycobacterial infection (68% of predicted, p less than 0.05), pyogenic infection (70%, p less than 0.05), acute Pneumocystis carinii pneumonia (PCP; 49%, p less than 0.001), and following recovery from PCP (71%, p less than 0.001). Serial lung function measurements over 18 months revealed no change in DLCO within any patient group, and in particular there was no tendency for a gradual decline. Clinical deterioration due to the development of PCP was associated with a reduction in DLCO. Conversely, in patients recovering from PCP, there was a partial improvement in DLCO over 3 months. Zidovudine (AZT) use did not affect DLCO within any diagnostic group or the recovery in DLCO following PCP. However, cigarette smoking was associated with further reductions in DLCO in all patient groups and with an impaired recovery of DLCO following acute PCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Empirically treated Pneumocystis carinii pneumonia in London, 1983-1989.

For 227 episodes of Pneumocystis carinii pneumonia (PCP) treated at St Mary's between 1983 and 1989, factors predictive of fatal outcome were age, haemoglobin levels, peripheral lymphocyte count and alveolar-arterial oxygen gradient. Case fatality for the 47 empirically-treated episodes was significantly higher compared with the 180 cytologically proven episodes (55% vs 18%, chi 2 = 25.7, P less than 0.0001). Case fatality for episodes which could not be bronchoscoped was significantly higher compared with bronchoscopy negative cases (66% vs 25%, chi 2 = 4.5, P less than 0.05). Predictive factors for fatal outcome differed significantly for cases which could not be bronchoscoped and cytologically proven cases: haemoglobin level (10.7 g/dl vs 12.0 g/dl, P less than 0.001), lymphocyte count (0.64 x 10(9)/l vs 0.87 x 10(9)/l, P = 0.05) and oxygen gradient (77.7 mmHg vs 58.9 mmHg, P less than 0.02). Such differences were not observed between bronchoscopy negative and cytologically proven cases. Case fatality decreased significantly over time (b = -0.39, SE = 0.14, P less than 0.05). Total and non-fatal first time episodes displayed an inverse relationship between oxygen gradient and time (r = -0.22, P less than 0.006 and r = -0.24, P less than 0.01, respectively). Mean oxygen gradient of fatal episodes for sequential years increased significantly from 73 mmHg in 1983 to 102 mmHg in 1989 (r = 0.92, P less than 0.01). This suggests that medical intervention as well as presentation with less severe disease both contributed to improved case fatality over time.

Improved outcome of Pneumocystis carinii pneumonia in AIDS patients: a multifactorial treatment effect.

Factors determining the outcome of an episode of Pneumocystis carinii pneumonia (PCP) in 149 AIDS patients treated at St Mary's Hospital were identified and their importance on improved survival evaluated between 1984 and 1989. The proportion of fatal episodes of PCP decreased over time. Fatal compared with nonfatal episodes had lower mean alveolar-arterial oxygen gradient (82.5 mmHg vs 53.8 mmHg, P less than 0.001), mean haemoglobin level (11.2 g/dl vs 12.1 g/dl, P = 0.01), mean lymphocyte count (0.68 x 10(9)/l vs 0.92 x 10(9)/l, P = 0.05) and more coinfections (31% vs 5%, P less than 0.001). Over time, the most significant change which occurred was a reduction in alveolar-arterial oxygen gradient at time of first presentation with PCP (r = -0.37, P less than 0.001). Mean alveolar-arterial oxygen gradient declined from 79.9 mmHg in 1984 to 45.3 mmHg in 1989 (r = -0.88, P = 0.02), independently of zidovudine therapy or PCP prophylaxis. Patients were being treated at an earlier stage in their disease course as indicated by their reduced alveolar arterial oxygen gradient. This is due either to earlier patient presentation, earlier medical diagnosis or both. The widespread introduction of zidovudine and PCP prophylaxis may further contribute to improve morbidity and mortality patterns in the future.

Effect of HIV-1 and cytomegalovirus in bronchoalveolar lavage cells on the transfer factor for lung carbon monoxide in AIDS patients.

Abnormalities in pulmonary function tests have been observed in AIDS patients with pulmonary disease. In this study, the polymerase chain reaction (PCR) was used to determine if the reductions in transfer factor for lung carbon monoxide (TLCO) were due to the presence of HIV-1 or cytomegalovirus (CMV). HIV-1 was detected in cells from bronchoalveolar lavage (BAL) in 35 out of 60 (58%) of patients. The detection of HIV-1 had no significant effect on pulmonary function. CMV was detected in the BAL of 58% of patients in this study but CMV was the sole viral pathogen in the lung of only two out of 60 (3.3%) individuals. A significant reduction in TLCO was observed in individuals with PCP where CMV was also detected in the BAL. This study shows that reduction in TLCO in HIV-seropositive patients is not due to the presence of HIV-1 or CMV alone in BAL cells.

Tuberculosis in HIV infection.

PIP: Persons with AIDS (PWAs) are 100 times more likely to develop tuberculosis (TB) than the general population. The TB incidence rates in PWAs in the US range from 4-21%, especially among intravenous drug users and Haitians. In Florida, 60% of Haitian AIDS patients also had TB compared to 2.7% of non-Haitian AIDS patients. At a hospital in London, England, 25% of PWAs also had TB and 42% of all AIDS patients at this hospital were members of racial groups with a high prevalence of TB. In developed countries, reactivation of a latent TB infection is generally what occurs in AIDS patients. The absolute number of AIDS patients with TB in these countries is low and unlikely that it will spread to non-HIV seropositive patients. On the other hand, 30-60% of adults have been infected with Mycobacterium tuberculosis in central Africa and HIV seroprevalence is also high. So many AIDS patients here can develop TB through reactivation or exogenous primary infection. This situation significantly increases the risk of TB for HIV seronegative persons. In fact, TB is 1 of the most frequent opportunistic infections in PWAs in developing countries, such as central Africa. In patients at an early stage of HIV infection, TB manifests itself classically. The clinical presentation in patients in the late stages includes fever, weight loss, malaise, productive cough accompanied with labored breathing, an atypical chest radiograph, and extrapulmonary TB. This atypical pattern often results in delays of diagnosis and treatment. Many sputum samples do not test positive for M. tuberculosis therefore if a physician suspects TB, treatment should begin immediately. Some studies demonstrate that isoniazid prophylaxis substantially decreases the incidence of TB in HIV seropositive patients in Zambia. There is no conclusive evidence of the harm or effectiveness of the BCG vaccine in HIV children and adults.^ieng

Bone marrow macrophages and megakaryocytes express common acute lymphoblastic leukaemia antigen.

Common acute lymphoblastic leukaemia antigen (CALLA) was demonstrated on a proportion of bone marrow macrophages and megakaryocytes. CALLA was detected by two monoclonal antibodies (J5 & BA3) in a three-layer immunoalkaline phosphatase system applied to routine air-dried bone marrow smears. The J5 staining was confirmed by an indirect immunofluorescent method and the CALLA was shown to be at the surface of the macrophages and megakaryocytes by an indirect immunogold technique. The findings are discussed in relation to the known tissue distribution of CALLA and to the clinical use of anti-CALLA antibodies for bone marrow purging.

The differential effects of hydrocortisone on activation and tolerance induction in human T lymphocyte clones.

The in vitro effects of hydrocortisone on T cell activation and tolerance induction were investigated using human influenza virus immune T cell lines and clones. Hydrocortisone at 10(-9) to 10(-6) molar concentrations was able to inhibit the antigen induced but not the T cell growth factor (TCGF) mediated proliferative response of both the lines and clones. However, hydrocortisone was able to inhibit TCGF production by cloned T cells. The proliferative response of cloned T cells to intact influenza virus A/Texas/1/77 was more markedly inhibited by equivalent concentrations of hydrocortisone than was the response of that clone to a 24 amino acid sequence (p20) of the haemagglutinin molecule implying that hydrocortisone may also act at the level of antigen processing. Furthermore hydrocortisone was able neither to induce T cell tolerance alone nor to inhibit antigen specific tolerance induction. However, hydrocortisone did lower the antigen threshold for tolerance induction. The possible mechanisms of hydrocortisone activity in the modulation of T cell regulation in autoimmune disease are discussed.

Survey of antibiotic prescribing in a district general hospital. II. Lower respiratory tract infection.

A 28 day survey of all antibiotic prescriptions in a district general hospital included a brief interview with the prescriber of each prescription. One hundred and nineteen antibiotic courses were stated, by the prescriber, to be for the treatment of lower respiratory tract infection. By combining the prescriber's clinical evidence, laboratory data, and radiographic findings, an "index of infection" was produced for 94 patients. This index reflected features associated with bacterial infection of the lower respiratory tract and suggested that 49% of the antibiotic courses prescribed were justifiable, 11% were questionable, and 40% were unjustifiable. The choice of antibiotic was usually appropriate to the prescriber's diagnosis. Over 80% of the antibiotics used were of the penicillin group. Ampicillin, the single most frequently prescribed drug, accounted for 60% of the prescriptions. The frequency of diagnosis of chest infection increased with age. Almost 40% of patients over 81 years old who were admitted to hospital during the survey were prescribed antibiotics for chest infection. A higher proportion of older than of younger patients had low indices of infection.

Survey of antibiotic prescribing in a district general hospital. III. Urinary tract infection.

A 28 day survey of all antibiotic prescriptions in a district general hospital included a brief interview with the prescriber of each prescription. Fifty-nine antibiotic courses were stated by the prescriber to be for the treatment of urinary tract infection (UTI). Urine specimens from all patients treated for UTI were sent to the laboratory for bacteriological examination. 29 patients' treatment was started as the result of isolation of bacteria from the urine. 20 of the patients also had symptoms suggestive of UTI. 4 patients were treated solely because bacteria had been isolated from "routine" catheter stream urine specimens. 7 patients were treated for UTI despite the availability, at the time of prescription, of a laboratory report stating that bacteria had not been isolated from the urine. 19 patients' treatment was started before the results of bacteriological tests were available. By combining information about bacteriological examination of the urine specimens and clinical details recorded during the interview with the prescribed, it was considered that both initiation and continuation of antibiotic treatment was justified for 28/55 patients and that either initiation or continuation of treatment was unjustified for 27/55 patients.