[American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency].
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Documentation↗
Biomedical subjects
E Eden
Publications and source records attributed to E Eden.
Analysis and recognition of 5' UTR intron splice sites in human pre-mRNA.
Prediction of splice sites in non-coding regions of genes is one of the most challenging aspects of gene structure recognition. We perform a rigorous analysis of such splice sites embedded in human 5' untranslated regions (UTRs), and investigate correlations between this class of splice sites and other features found in the adjacent exons and introns. By restricting the training of neural network algorithms to 'pure' UTRs (not extending partially into protein coding regions), we for the first time investigate the predictive power of the splicing signal proper, in contrast to conventional splice site prediction, which typically relies on the change in sequence at the transition from protein coding to non-coding. By doing so, the algorithms were able to pick up subtler splicing signals that were otherwise masked by 'coding' noise, thus enhancing significantly the prediction of 5' UTR splice sites. For example, the non-coding splice site predicting networks pick up compositional and positional bias in the 3' ends of non-coding exons and 5' non-coding intron ends, where cytosine and guanine are over-represented. This compositional bias at the true UTR donor sites is also visible in the synaptic weights of the neural networks trained to identify UTR donor sites. Conventional splice site prediction methods perform poorly in UTRs because the reading frame pattern is absent. The NetUTR method presented here performs 2-3-fold better compared with NetGene2 and GenScan in 5' UTRs. We also tested the 5' UTR trained method on protein coding regions, and discovered, surprisingly, that it works quite well (although it cannot compete with NetGene2). This indicates that the local splicing pattern in UTRs and coding regions is largely the same. The NetUTR method is made publicly available at www.cbs.dtu.dk/services/NetUTR.
5' Untranslated Regions↗
Atopy, asthma, and emphysema in patients with severe alpha-1-antitrypysin deficiency.
Bronchial asthma is characterized by episodic airway obstruction and associated with wheezing, a bronchodilator response, an elevation in total serum IgE, and atopy. To determine whether asthma is more common in subjects with severe alpha 1-antitrypsin deficiency (alpha 1-ATD) and airway obstruction, we compared 38 patients who had this condition (Group 1) with 22 control patients with chronic obstructive pulmonary disease (COPD) (Group 2) and with five subjects with alpha 1-ATD and normal spirometry (Group 3). Subjects were evaluated with a symptom questionnaire, pulmonary function testing, intradermal allergen testing, and serum IgE measurement. Self-reported wheezing was a common symptom in all patient groups, but attacks of wheezing with dyspnea were significantly more common in Group 1. Of those patients with airway obstruction, more than 50% showed a bronchodilator response whether suffering from alpha 1-ATD or not. Atopy was more common in Group 1 than in Group 2 (48% versus 27%). Mean serum IgE for all groups was similar but significantly greater in patients with atopy. We estimated the prevalence of asthma in the study groups on the basis of the criteria of attacks of wheezing, reversible airway obstruction, atopy, and that increased IgE. The proportion of patients with asthma in Group 1 was significantly greater than that in Group 2 (22% versus 5%, p < 0.05). Our study shows that with control for the degree of airway obstruction, asthma, as defined, is more common in patients with alpha 1-ATD than in those without it. We suggest that a lack of alpha 1-AT in airways increases the propensity to develop asthma.
Adult↗
Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.
This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.
Adult↗
Uniform detection of HIV-1 in alveolar macrophages of pediatric but not adult AIDS patients.
Manifestations of pulmonary disease in pediatric AIDS patients differ from those in adults. To evaluate whether differences in the frequency of alveolar macrophage (AM) infection with human immunodeficiency virus type 1 (HIV-1) could account for these clinical distinctions, we undertook a comparative analysis of HIV-1 DNA in AMs from pediatric and adult AIDS patients by enzymatic amplification. A higher frequency of viral DNA detection in pediatric cases (100%) compared with adults (67%) was observed. The sensitivity of detection was 1 viral DNA copy per 4000 AMs; matched peripheral blood mononuclear cells from six of seven pediatric and eight of nine adult patients tested HIV-1 DNA positive. Adult but not pediatric patients exhibited a marked alveolar lymphocytosis, 32% mean lymphocyte count compared with 7.0%, respectively. These results suggest that the burden of HIV-1 in the lungs of pediatric AIDS patients is greater than that in adults.
Acquired Immunodeficiency Syndrome↗
Infection of macrophages with lymphotropic human immunodeficiency virus type 1 can be arrested after viral DNA synthesis.
Lymphotropic strains of human immunodeficiency virus type 1 (HIV-1), including HTLV-IIIB, replicate poorly in macrophages. We have shown previously that lymphotropic HIV-1 fuses equally well with T lymphocytes and macrophages (M. J. Potash, M. Zeira, Z.-B. Huang, T. Pearce, E. Eden, H. Gendelman, and D. J. Volsky, Virology 188:864-868, 1992), suggesting that events in the virus life cycle following virus-cell fusion limit virus replication. We report here that HIV-1 DNA is synthesized efficiently in either ADA or HTLV-IIIB infected alveolar macrophages or monocyte-derived macrophages within 24 h of virus infection, as observed by polymerase chain reaction for amplification of viral DNA sequences from the gag gene. Infection by a cloned lymphotropic HIV-1 strain, N1T-A, also leads to viral DNA synthesis. However, circular viral DNA was detected during strain ADA infection but not during HTLV-IIIB or N1T-A infection of monocyte-derived macrophages. These findings indicate that during replication of lymphotropic HIV-1 in macrophages, all steps of the virus life cycle up to and including reverse transcription take place and that defects in later events, including DNA migration to the nucleus, may account for the limited production of viral proteins.
DNA, Viral↗
Effect of corticosteroids on IL1 beta and TNF alpha release by alveolar macrophages from patients with AIDS and Pneumocystis carinii pneumonia.
The mechanisms by which corticosteroids (CCs) improve the outcome of AIDS patients with severe Pneumocystis carinii pneumonia (PCP) are unclear. We studied IL1 beta and TNF alpha release from alveolar macrophages (AMs) of patients receiving CCs for the treatment of PCP and also the effect of in vitro hydrocortisone on this release. Cytokine release from AMs of AIDS patients with pulmonary complications not receiving CCs (group 1) was compared with that from AM of those receiving CCs for PCP (group 2). The AMs of HIV-negative normal subjects (group 3) served as controls. All participants were nonsmokers or exsmokers. We found that lipopolysaccharide-stimulated AM from group 2 released significantly less interleukin-1 beta (IL1 beta) and tumor necrosis factor alpha (TNF alpha) than AM from group 1 and was similar to that from group 3. There was a significant positive correlation between the amount of TNF alpha and IL1 beta released. The presence of HC in the culture medium reduced in vitro IL1 beta and TNF alpha release from stimulated AM of the three groups. Thus, stimulated AMs from AIDS patients who receive CCs for treatment of PCP release significantly less IL1 beta and TNF alpha than AM from patients not receiving CCs. These findings suggest a mechanism by which CCs improve the outcome of AIDS patients with PCP.
AIDS-Related Opportunistic Infections↗
Virus-cell membrane fusion does not predict efficient infection of alveolar macrophages by human immunodeficiency virus type 1 (HIV-1).
Alveolar macrophages (AM) are the principal target cells for HIV-1 in lung tissue. To investigate the mechanisms of HIV-1 infection and efficient replication in these cells we isolated AM from 14 HIV-1 negative donors and exposed them to two virus isolates, either N1T, which replicates well in T lymphocytic and monocytic cell lines, or ADA, a monocytotropic virus. Membrane fluorescence dequenching assays demonstrated that HIV-1/N1T fuses efficiently with AM plasma membranes at neutral pH and that this interaction requires cellular CD4. Despite efficient fusion, AM from eight of 14 donors were not susceptible to productive infection with N1T. In contrast, ADA replicated in all AM populations tested. Soluble CD4 blocked infection of AM by either N1T or ADA, indicating that, like membrane fusion, entry of infectious virus requires an interaction with cellular CD4. Analysis of HIV-1 DNA accumulation in infected cells by enzymatic amplification revealed that productive infection by ADA correlated with a high HIV-1 DNA copy number and abortive infection by N1T was characterized by little or no stable cDNA. These studies suggest that the differences between the two HIV-1 strains studied in their ability to replicate in AM reside in phases of the virus life cycle that follow virus-cell fusion.
CD4 Antigens↗
Correlation of bronchoalveolar lavage findings to severity of Pneumocystis carinii pneumonia in AIDS. Evidence for the development of high-permeability pulmonary edema.
We correlated bronchoalveolar lavage findings with the clinical course and outcome of Pneumocystis pneumonia. Forty-eight patients with AIDS and a confirmed diagnosis of P carinii pneumonia were studied. Patients with additional pulmonary infections were excluded. On the basis of BAL findings, they were divided into those with a low neutrophil count (less than 5 percent) and those with a high neutrophil count (greater than or equal to 5 percent). Sixteen patients with AIDS but without PCP served as a control group. All BAL fluid samples from the control group showed a low neutrophil count. The group with PCP and a high neutrophil count had more severe respiratory compromise and greater morbidity than the group with PCP and a low neutrophil count. Mortality rate was not different. The group showing a high BALF neutrophil count also showed a higher BALF protein concentration, a higher ratio of BALF protein concentration to plasma protein concentration, and the presence of alpha 2-globulins compared with other groups. These findings suggest that increased alveolar-capillary permeability occurs during severe PCP.
Acquired Immunodeficiency Syndrome↗
Odontodysplasia: report of a case.
A case of generalized odontodysplasia in a nine year-5-month old male patient is presented. Clinical and radiological characteristics of this developmental anomaly and treatment is described. The distribution of affected teeth in all four quadrants suggests that genetic transmission or a somatic mutation may be the causative factor.
Child↗
A comparative study of some influencing factors of rampant or nursing caries in preschool children.
In this study, nutritional, socioeconomic and family characteristics of 71 children with rampant or nursing caries and 224 age-matched controls were studied on the basis of a questionnaire and a 3-day food intake diary completed by the parents. Oral examination was done and their weight and height measured. Most of the children with rampant or nursing caries had an unbalanced diet with high sugar content, while in the control group, most of the children had a balanced diet with a normal sugar content and regular brushing habits in comparison with the rampant caries group. Chi-square analysis, which was performed for balanced diet, sugar consumption and tooth brushing habits for both groups showed that there were highly significant differences. The rampant caries group was mostly from small families of middle and high socioeconomic groups. Infant feeding patterns of the children with rampant caries showed that most of them were breast-fed for less than 6 months or longer then 12 months. Their meals were usually sweetened in infancy and were given by nursing bottle and some had the habit of sucking a comforter dipped in honey or jam.
Bottle Feeding↗
Pulmonary Kaposi's sarcoma presenting as fulminant respiratory failure.
A 32-year-old black man, a homosexual patient with a history of lymphadenopathy, presented with diarrhea, weight loss, and a bilateral interstitial infiltrate. Within days after admission, the patient developed dyspnea with rapid progression to respiratory failure and a rapid increase of the infiltrate. An open-lung biopsy showed Kaposi's sarcoma. Treatment with chemotherapy reversed the respiratory failure.
Acquired Immunodeficiency Syndrome↗
Bronchoalveolar lavage via a modified stomach tube in intubated patients with the acquired immunodeficiency syndrome and diffuse pneumonia.
A simple non-bronchoscopic bronchoalveolar lavage method was used in 30 patients with the acquired immunodeficiency syndrome undergoing assisted ventilation for respiratory failure. A modified Argyle Levin stomach tube was passed via the endotracheal tube and lavage performed. The lavage was well tolerated and performed quickly and easily, required little training, and had a high degree of sensitivity (73%--a diagnosis in 22 of the 30 cases).
Acquired Immunodeficiency Syndrome↗
Effect of bronchoalveolar lavage fluid from patients with sarcoidosis or AIDS on interleukin 1 beta release from alveolar macrophages.
We studied the effect of concentrated surfactant-depleted BALF from 8 normal subjects, 13 patients with sarcoidosis, and 13 patients with AIDS on IL1 beta release by human AM. Adherent target AM were exposed to concentrated BALF in the presence or absence of LPS (1 microgram/ml) for two hours. Control AM were unexposed to BALF. After an additional 24-hour incubation, AM supernatants were collected and measured for IL1 beta by ELISA. No spontaneous IL1 beta release occurred from unstimulated AM. One of the sarcoid-BALF and three of the AIDS-BALF samples induced a small amount of IL1 beta release from unstimulated AM. In LPS-stimulated AM, exposure to normal BALF did not significantly alter IL1 beta release compared to unexposed AM. Exposure to sarcoid-BALF significantly increased the release of IL1 beta, while exposure to AIDS-BALF significantly reduced the IL1 beta level in the AM supernatants. The latter effect was related to the higher mortality induced by AIDS-BALF in AM. These data show that release of IL1 beta from LPS-stimulated AM is modified by a short exposure to a sample of alveolar fluid from patients with lung disease.
Acquired Immunodeficiency Syndrome↗
Interleukin 1 secretion from human alveolar macrophages in lung disease.
Interleukin 1 secretion from human alveolar macrophages was studied in patients with interstitial pulmonary fibrosis, sarcoidosis, and the acquired immunodeficiency syndrome with pneumonitis and compared to secretion from alveolar macrophages of normal volunteers. Macrophages lavaged from the lungs were stimulated with 10 micrograms/ml of lipopolysaccharide and cultured for 24 hr. In some cases macrophages were also stimulated with 1 microgram/ml lipopolysaccharide. After dialysis of the culture supernatants, interleukin 1 secretion was quantified by the thymocyte proliferation assay and probit analysis and expressed in terms of secretion from 1 million macrophages. Results showed that, on average, macrophages derived from patients secreted more interleukin 1 after stimulation with lipopolysaccharide compared to normal subjects. Mean secretion was significantly greater from macrophages of patients with acquired immunodeficiency syndrome and interstitial pulmonary fibrosis when stimulated with 10 micrograms/ml lipopolysaccharide. Of the 24 individuals studied, spontaneous interleukin 1 secretion was detected from unstimulated macrophages in only 1 patient and 1 normal volunteer. We conclude that alveolar macrophages lavaged from the lungs of patients with inflammatory lung disease have an increased capacity to secrete interleukin 1 on in vitro stimulation with lipopolysaccharide. Possible mechanisms for this increase are discussed.
Acquired Immunodeficiency Syndrome↗
Secretion of interleukin 1/leucocytic pyrogen from endotoxin-stimulated human alveolar macrophages is unaffected by indomethacin.
Human alveolar macrophages obtained from 7 normal volunteers and 7 patients with lung disease were stimulated with endotoxin (lipolysaccharide) to induce interleukin 1/leucocytic pyrogen (IL1/LP) secretion. Using the thymocyte assay we quantitated IL1/LP activity in macrophage supernatants obtained after 24 h. 10 micrograms/ml lipopolysaccharide stimulated alveolar macrophages to secrete significantly more IL1/LP activity than did 1 micrograms/ml. Apart from one patient with sarcoidosis, the presence of indomethacin did not significantly inhibit the quantity of IL1/LP secreted in response to LPS. We also demonstrated that the presence of indomethacin did not affect the response of thymocytes to IL1/LP. We conclude that the secretion of IL1/LP by human alveolar macrophages in response to endotoxin is not significantly reduced by the cyclooxygenase inhibitor indomethacin.
Animals↗
Interleukin-1 secretion by human alveolar macrophages stimulated with endotoxin is augmented by recombinant immune (gamma) interferon.
We investigated the role of the macrophage-activating factor gamma interferon (IFN) in the in vitro secretion of interleukin-1 (IL-1) from human alveolar macrophages. Macrophages were obtained from 6 normal volunteers and 5 patients by bronchoalveolar lavage. Macrophages were adhered to a plastic surface and then stimulated to secrete IL-1 with concentrations of endotoxin (LPS) ranging from 1 ng/ml to 10 micrograms/ml. Unstimulated macrophages served as a control. Recombinant gamma IFN was added to LPS-stimulated or unstimulated macrophage cultures in concentrations ranging from 0.25 to 1,000 U/ml. After 24 h of culture, supernatants were removed and IL-1 activity was measured by the thymocyte proliferation assay. Gamma IFN directly induced IL-1 secretion from macrophages of 2 of the subjects. In the presence of LPS, gamma IFN markedly augmented IL-1 secretion from macrophages of 10 of the 11 subjects. Gamma IFN could prime macrophages for increased response to LPS after 1 h of incubation. We conclude that gamma IFN provides a modulating signal for in vitro LPS-induced IL-1 secretion from alveolar macrophages and may enhance macrophage reactivity to inflammatory mediators in vivo.
Animals↗
Factor analysis of a self-concept instrument for older adults.
In this study, 235 community residents, ranging in age from 60 to 91 years, were administered a 31 scale semantic differential referring to the concept, "What I Really Am". The construct validity of similar self-concept instruments has been investigated through factor analysis, but the dimensionality of such scales with a gerontological population remains unresolved and hampers related research. Therefore, a principal factor solution was conducted and four factors accounting for 48.2% of the total variance were rotated to their varimax position. The first factor, representing 30.8% of the variance, suggested an Adjustment/Esteem factor. The second, accounting for an additional 7.5% of variance, represented an Achievement/Intellectual Capacity factor. Factor III appeared as an Emotional/Physical Stability factor (5.7%) and Factor IV, a Sociability/Congeniality factor (4.8%). The last two factors were extremely suggestive of Eysenck's personality dichotomy. Thus, the measure may reflect both stable personality dimensions as well as more reactive domains.
Aged↗