Tissue heterogeneity of immunohistochemically detected estrogen receptor. Implications for image analysis quantification.

The increasingly popular immunohistochemical techniques for assay of the estrogen receptor (ER) allow localization of receptor positivity to specific cell populations. Heterogeneity of the ER in tumor cell populations may have important implications for analytic cell selection and for prognosis in ER-positive carcinomas. We studied 84 tissue blocks for level-to-level and geographic heterogeneity within level of the ER and cytokeratin by staining alternate serial sections for ER and cytokeratin. Distribution of ER and cytokeratin positivity was manually assessed. Homogenous positive staining was seen in 63 of 84 cases for ER and 71 of 84 cases for cytokeratin. Distinct geographic variability constant from level to level was seen in 7 cases for ER. In each of these cases, the cell populations stained uniformly for cytokeratin. Artifactual heterogeneity seemed to be uncommon for ER. Automated image analysis and manual ER estimation resulted in more positive cases than did the dextran-coated charcoal (DCC) technique. Interobserver correlation for the manual method seemed high, as did correlation between the manual method and image analysis. Because a majority of the immunohistochemical staining heterogeneity for ER seemed to be biologic, we believe it may mark carcinomas that are less responsive to tamoxifen and more likely to progress than would be predicted by more traditional methods of ER analysis.

Reliability of scoring respiratory disturbance indices and sleep staging.

STUDY OBJECTIVES: Unattended, home-based polysomnography (PSG) is increasingly used in both research and clinical settings as an alternative to traditional laboratory-based studies, although the reliability of the scoring of these studies has not been described. The purpose of this study is to describe the reliability of the PSG scoring in the Sleep Heart Health Study (SHHS), a multicenter study of the relation between sleep-disordered breathing measured by unattended, in-home PSG using a portable sleep monitor, and cardiovascular outcomes. DESIGN: The reliability of SHHS scorers was evaluated based on 20 randomly selected studies per scorer, assessing both interscorer and intrascorer reliability. RESULTS: Both inter- and intrascorer comparisons on epoch-by-epoch sleep staging showed excellent reliability (kappa statistics >0.80), with stage 1 having the greatest discrepancies in scoring and stage 3/4 being the most reliably discriminated. The arousal index (number of arousals per hour of sleep) was moderately reliable, with an intraclass correlation (ICC) of 0.54. The scorers were highly reliable on various respiratory disturbance indices (RDIs), which incorporate an associated oxygen desaturation in the definition of respiratory events (2% to 5%) with or without the additional use of associated EEG arousal in the definition of respiratory events (ICC>0.90). When RDI was defined without considering oxygen desaturation or arousals to define respiratory events, the RDI was moderately reliable (ICC=0.74). The additional use of associated EEG arousals, but not oxygen desaturation, in defining respiratory events did little to increase the reliability of the RDI measure (ICC=0.77). CONCLUSIONS: The SHHS achieved a high degree of intrascorer and interscorer reliability for the scoring of sleep stage and RDI in unattended in-home PSG studies.

Incidence and remission of habitual snoring over a 5- to 6-year period.

Habitual snoring is associated with an increased prevalence of hypertension, stroke, and ischemic heart disease. To determine factors that influence the incidence and remission of habitual snoring, we analyzed responses to successive self-administered questionnaires with questions pertaining to snoring in a group of subjects participating in the Tucson Epidemiologic Study of Obstructive Airways Disease. In this study, 1,476 subjects were surveyed 5.8 +/- 0.6 (SD) years apart. Among subjects who habitually snored on the initial survey, 58.2% snored persistently and 35.5% remitted on the ensuing survey. Among subjects who did not habitually snore in the initial survey, 10.5% developed it on the subsequent survey. In further analyses, we found that male sex, obesity, and respiratory symptoms were significant independent risk factors for development of habitual snoring. Age over 65 years, the absence of obesity, and the absence of respiratory symptoms were associated with remission of habitual snoring.

Methodological considerations of epidemiological diagnoses in respiratory diseases.

Since epidemiological research depends extensively on questionnaire responses, a comparison of such responses with a standardized medical evaluation was conducted. It was found that standardized questionnaires do well in comparison for certain kinds of information on chronic conditions. However, clinical evaluations will elicit more information, specifically of a milder nature. It was concluded that standardized epidemiological questionnaires are satisfactory for survey of chronic conditions.

Estimates of C. immitis infection by skin test reactivity in an endemic community.

This report is a comparison of two delayed hypersensitivity skin test reagents, coccidioidin and Spherulin, available for detection of prior infection by Coccidioides immitis. Coccidioidin proved to be a somewhat more sensitive reagent (33.4 per cent positive, vs 29.6 per cent for Spherulin). This difference persisted in the subjects when grouped by age, sex, exposure history, or history of coccidioidomycosis. Skin test reactivity to both reagents declined with age. Independent of exposure history coccidioidin detected 7.3 per cent of the subjects who were not detected by Spherulin; Spherulin detected prior infection in only 3.5 per cent of the subjects not detected by coccidioidin. These results differ from those of previously reported studies.

Ketoconazole treatment of nonprimary coccidioidomycosis. Evaluation of 60 patients during three years of study.

Sixty patients with coccidioidomycosis were treated with ketoconazole rather than with another antifungal agent, and their responses were evaluated in relation to the predominant site of involvement. For the three main groups, improvement occurred in 12 of 19 patients with chronic pulmonary infections, in 20 of 23 with soft tissue lesions and in six of 11 with skeletal involvement. Infections in soft tissues improved most rapidly (average of 34 days) and often with 200 mg per day, whereas pulmonary and skeletal infections improved more slowly (63 and 165 days, respectively), usually requiring 400 mg per day. Of 12 patients with response in whom therapy has been discontinued, seven have had relapses. Recurrence was apparent usually within the first month and after six months or less of treatment. Patients in remission had received ketoconazole for six to 17 months. Untoward drug effects included abdominal complaints (23 percent) and gynecomastia (8 percent). Therapy was discontinued in only three patients for side effects. Our findings support the use of ketoconazole in the treatment of certain forms of chronic coccidioidal infections.

The prevalence and incidence of asthma and asthma-like symptoms in a general population sample.

We have examined the prevalence of incidence of asthma and other wheezing syndromes in subjects in a longitudinal epidemiologic study. The point prevalence of asthma was 6.6%, with the highest rates occurring in children. Rates were also relatively high in older subjects, in most of whom "chronic bronchitis and/or emphysema" had been concomitantly diagnosed. Other wheezing was very common in this population sample; in most age groups, the point prevalence rates of some form of wheezing exceeded 30%. New asthma developed in 1.4% of the subjects who were followed over a period of approximately 4 yr. New attacks of shortness of breath with wheeze occurred in 10.3% of the subjects at risk over the same time period. The incidence of asthma was greatest in young children, was least in late adolescence, and increased again in early adult life. The incidence was 1.5 times greater in young boys than in young girls but was much greater in women older than 40 yr of age, perhaps reflecting the diagnostic biases of physicians. In subjects younger than 40 yr of age, onset of the disease was strongly associated with previously demonstrated allergy skin test reactivity. New disease in this age group occurred de novo, primarily within the first few years of life or during early adult life. Subjects in whom asthma developed after 40 yr of age usually had prior symptoms of chronic bronchial irritation and often had obvious spirometric abnormalities. The disease in these subjects was not associated with positive allergy skin test reactions. Because in these older subjects it does not appear possible to clearly distinguish "asthma" from "chronic bronchitis," the label "asthmatic bronchitis" appears to be a reasonable descriptive term for this syndrome.

The absence of a relationship between serum precipitins and pulmonary disease in a community.

To study the role of serum precipitins in respiratory illness in a community, sera obtained from 3,047 residents of Tucson, Ariz., were tested for the presence of precipitating antibody to a battery of antigens. Positive reactions were obtained in 54 subjects (1.8 percent), a lower incidence than has been reported previously. The majority of these subjects were older than 54 years of age, an age distribution significantly older than the entire sample (P less than 0.01). Pulmonary function among the subjects with positive precipitin reactions was not significantly different from that of the asymptomatic nonsmokers of the entire sample. None of the subjects who were lifelong residents of Arizona had serum precipitins to any of the thermophilic actinomycetes antigens which were used in the testing. These antigens have been found in association with extrinsic allergic alveolitis, most frequently among patients living in the north central United States and were derived from strains of Micropolyspora faeni, Thermoactinomycetes candidus and vulgaris. Each subject with precipitins to one or more of the tested antigens was matched by age, sex, and socioeconomic class with two subjects from the sample who had negative precipitin reactions. The groups did not differ in their prevalence of respiratory symptoms or abnormalities of pulmonary function. We conclude that the presence of precipitating serum antibodies among subjects in a community is not indicative of the presence of immunologic pulmonary disease but merely reflects previous exposure to the tested antigen. In addition, individuals whose sera contain precipitating antibody appear to have no increased tendency to develop other types of pulmonary disease.