Genome-wide scan for adult onset primary open angle glaucoma.

Adult onset primary open angle glaucoma is a leading cause of blindness throughout the world. The disease results in an apoptotic death of retinal ganglion cells that is usually associated with an elevation of intraocular pressure. Familial aggregation of the disorder provides evidence for strong genetic influences that are likely to be the result of multiple susceptibility genes. A two-stage genome scan to identify the genomic locations of glaucoma susceptibility genes was performed using an initial pedigree set of 113 affected sibpairs and a second pedigree set of 69 affected sibpairs. Linkage analysis was performed using both model-dependent (lod score) and model-independent affected relative pair and sibpair methods. Twenty-five regions identified by the initial scan were further investigated using the second pedigree set. In the combined data analysis, regions located on chromosomes 2, 6, 9, 11, 14, 17 and 19 continued to produce model-dependent lod scores and/or an MLS >1.0, while five regions (2, 14, 17p, 17q and 19) produced an MLS >2. 0. Multipoint analysis using ASPEX also showed significant results on chromosomes 2, 14, 17p, 17q and 19. These results are an important step towards the identification of genes responsible for the genetic susceptibility to this blinding condition.

A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36.

OBJECTIVES: To demonstrate the inheritance of the pigment dispersion syndrome in 4 families and to determine the location of a gene responsible for this syndrome. PATIENTS: Fifty-four members of 4 families affected by the pigment dispersion syndrome and pigmentary glaucoma. All 4 families are white. Two of the pedigrees are of Irish descent, and 2 are of mixed western European descent that includes some Irish ancestry. INTERVENTIONS: Individuals from 4 pedigrees affected by the pigment dispersion syndrome and their spouses were clinically examined for evidence of the pigment dispersion syndrome. DNA samples from patients and appropriate family members were used for a genome screen using microsatellite repeat markers distributed throughout the human genome. Genotypes were used for linkage analysis to identify markers segregating with the disease trait. RESULTS: Twenty-eight patients showed clinical evidence of the pigment dispersion syndrome. Of these, 14 also had elevated intraocular pressures requiring medical or surgical treatment or both. Significant linkage was observed between the disease phenotype and markers located on the telomere of the long arm of human chromosome 7 (i.e., 7q35-q36). The maximum 2-point lod score (i.e., Zmax) for a single pedigree (i.e., PDS5) was 5.72 at theta = 0 for markers D7S2546 and D7S550. An analysis of affected recombinant individuals demonstrated that the responsible gene is located in a 10-centimorgan interval between markers D7S2462 and D7S2423. CONCLUSIONS: The pigment dispersion syndrome was found to be inherited as an autosomal dominant trait in 4 affected pedigrees. The gene responsible for the syndrome in these 4 families maps to the telomeric end of the long arm of chromosome 7 (i.e., 7q35-q36). Locating a gene responsible for this condition is the first step toward the isolation of the gene itself. Characterization of the responsible gene will help elucidate the pathophysiology of this disease and potentially will lead to new methods of diagnosis and treatment.

Lung sound nomenclature survey.

We report the terms used by 223 pulmonary physicians and 54 physicians in other specialties to describe eight recorded examples of lung sounds. The participants listened to the lung sounds at the 1988 American College of Chest Physicians annual convention and wrote "free form" answers. Pulmonary physicians used the terms "crackles" and "rales" with equal frequency to describe discontinuous adventitious lung sounds (ALS) and not at all to describe continuous ALS. Other physicians preferred the term "rales" in describing discontinuous ALS. The terms "wheeze" and "stridor" were used only in describing continuous ALS; however, the term "rhonchi" was frequently used to describe continuous and discontinuous ALS. The majority of participants recognized the normal breath sounds but not the pleural friction rub. Most did not use a qualifying adjective to describe ALS, and there was little agreement among those who did. The lung sound terminology used by physicians is not well standardized and the recommendations of the ATS/ACCP nomenclature subcommittee are not widely accepted.

Observer agreement, chest auscultation, and crackles in asbestos-exposed workers.

Investigators cite observer variability as a problem in using crackles to diagnose asbestosis. We measured agreement on the presence or absence of crackles noted during auscultation of 64 asbestos-exposed workers in order to clarify this question. There was 89 percent agreement between two observers who simultaneously examined subjects breathing from functional residual capacity (FRC). Kappa (kappa), a statistic accounting for chance agreement, was 0.73. Unanimous agreement between four observers who listened to tape recordings of the breath sounds was 81 percent (kappa = 0.69). When the subjects breathed from residual volume (RV) there was 78 percent (kappa = 0.53) and 67 percent (kappa = 0.60) agreement, respectively. Comparing direct to tape-playback auscultation, there was 90 percent (kappa = 0.77) and 84 percent (kappa = 0.58) intraobserver agreement when the subjects breathed from FRC and 90 percent (kappa = 0.79) and 75 percent (kappa = 0.39) when they breathed from RV. We conclude that observer variability is sufficiently low to allow trained observers to monitor asbestos-exposed workers for crackles directly and during tape-playback auscultation.

The prevalence and character of crackles (rales) in young women without significant lung disease.

Although some investigators have reported that crackles are present only in persons with lung disease, others say they also occur in normal persons. In order to clarify this difference of opinion, we determined the prevalence of crackles in 56 women without significant lung disease. The subjects ranged from 19 to 33 yr of age (mean, 21.3). They all had a FVC greater than 80% predicted and a FEV1/FVC ratio greater than 75%. None had a history of acute or chronic lung disease. During slow inspirations from residual volume, midinspiratory fine crackles were heard at the anterior bases in 35 of 56 subjects by a physician using an acoustic stethoscope, whereas a bioengineer using an 800 Hertz high pass filtered stethoscope heard crackles in 53 subjects. Crackles during tidal breathing were heard in 2 subjects. It is postulated that the crackles noted after expiration to residual volume are nonpathologic, and occur when basilar airways, which close at the end of a forced expiration, suddenly open during inspiration. Examination of the quality, timing, and anatomic distribution of the crackles in apparently normal subjects suggests that they can often be distinguished from those resulting from diseases such as bronchitis, interstitial fibrosis, and congestive heart failure.