The dominant temperature-sensitive lethal DTS7 of Drosophila melanogaster encodes an altered 20S proteasome beta-type subunit.

Proteasomes are multicatalytic complexes that function as the major proteolytic machinery in regulated protein degradation. The eukaryotic 20S proteasome proteolytic core structure comprises 14 different subunits: 7 alpha-type and 7 beta-type. DTS7 is a dominant temperature-sensitive (DTS) lethal mutation at 29 degrees that also acts as a recessive lethal at ambient temperatures. DTS7 maps to cytological position 71AB. Molecular characterization of DTS7 reveals that this is caused by a missense mutation in a beta-type subunit gene, beta2. A previously characterized DTS mutant, l(3)73Ai1, results from a missense mutation in another beta-type subunit gene, beta6. These two mutants share a very similar phenotype, show a strong allele-specific genetic interaction, and are rescued by the same extragenic suppressor, Su(DTS)-1. We propose that these mutants might act as "poison subunits," disrupting proteasome function in a dosage-dependent manner, and suggest how they may interact on the basis of the structure of the yeast 20S proteasome.

Variation in the use of do-not-resuscitate orders in patients with stroke.

OBJECTIVES: To identify sociodemographic and clinical characteristics associated with the use of do-not-resuscitate (DNR) orders in hospitalized patients with stroke. To examine whether the use of DNR orders varies across hospitals. METHODS: This observational cohort study used data collected for 13337 consecutive eligible patients with a primary diagnosis of stroke. These patients were discharged in 1991 through 1994 from 30 hospitals in a large metropolitan area. Study data were abstracted from patients' hospital records using standard forms. Admission severity of illness was measured using a validated multivariable model. Sociodemographic and clinical factors independently associated with the use of DNR orders were identified using stepwise logistic regression. RESULTS: Do-not-resuscitate orders were written for 2898 patients (22%). Patient characteristics independently (P < .01) associated with increased use of DNR orders included increasing age (odds ratio [OR], 1.06 per year); admission from a skilled nursing facility (OR, 2.44) or through the emergency department (OR, 1.49); cancer (OR, 2.73), intracerebral hemorrhage (OR, 2.12), coma (OR, 7.47), or lethargy or stupor on admission neurological assessment (OR, 3.38); and increasing admission severity (OR; 1.29 per decile). In contrast, African American race was associated with lower use of DNR orders (OR, 0.54). Although substantial variation in the use of DNR orders was observed across hospitals, with rates ranging from 12% to 32%, adjusting for the above patient characteristics eliminated much of this variation, including differences between major teaching and other hospitals and between hospitals with and without religious affiliations. CONCLUSIONS: In our community-based analysis of patients with stroke, the use of DNR orders was common and was strongly related to several patient characteristics. These factors explained much of the variation across hospitals. While our analysis did not account for differences in patient preferences for treatment, the differences we observed in the use of DNR orders across sociodemographic groups are suggestive of variations in care and may have important implications for the cost and quality of hospital care.

Patients perceived stigma associated with community-based directly observed therapy of tuberculosis in Uganda.

OBJECTIVE: To assess whether linkage of tuberculosis (TB) and HIV/AIDS increases the perception of stigma among TB patients on Community-Based Directly Observed Therapy (CB-DOT) compared to similar TB patients on self-administered therapy (SAT). DESIGN: A Cross-sectional study. SETTING: Kiboga (CB-DOT) and Mubende (SAT) districts, Uganda in 2000. SUBJECTS: One hundred and five tuberculosis patients on CB-DOT and 202 patients on SAT. One hundred and twenty one (39%) of these patients agreed to be tested for HIV. RESULTS: Patients on CB-DOT and patients on SAT were similar on most of the domains used to assess stigma associated with a TB diagnosis, except for the domain of TB diagnosis and general belief that TB and HIV/AIDS are linked. Patients on CB-DOT were more likely to believe that neighbours knew they had TB compared to patients on SAT (91% vs. 62%, p < 0.001), but the groups did not differ in their perception that neighbours thought they have HIV because of TB (46% vs. 46%, p = 0.954). HIV prevalence was similar in both groups. CONCLUSION: The study demonstrates that TB patients on CB-DOT did not differ from SAT patients in their perception of stigma as a result of TB. Therefore, HIV-related stigma may not limit wide implementation of CB-DOT in countries like Uganda.

Evolutionary conservation of a testes-specific proteasome subunit gene in Drosophila.

Proteasomes are large multisubunit particles that act as the proteolytic machinery for the ubiquitin-dependent proteolytic pathway. The core of this complex, the 20S proteasome, is made up of seven alpha-type and seven beta-type subunits, arranged in an (alpha1-alpha7)(beta1-beta7)(beta1-beta7)(alpha1-al pha7) configuration. Previous work had shown that there exist alternative isoforms of the Drosophila melanogaster alpha4-type subunit, encoded by two distinct genes, alpha4t1_dm and alpha4t2_dm, and that these are expressed exclusively in the germline of the testes. We sought to investigate the evolutionary conservation of this phenomenon by screening for orthologs of the alpha4-type gene family in the distantly related Drosophila species, D. virilis. We isolated the D. virilis orthologs of the somatically expressed gene, alpha4_dm, and the testes-specific gene, alpha4t2_dm. We failed to find an ortholog of the other testes-specific gene, alpha4t1_dm. The alpha4_dv gene maps to the X chromosome at 12A-C, its product shares 90% amino acid identity with alpha4_dm, and it is expressed at high levels in both males and females. The other gene, alpha4t_dv, encodes a protein most similar to the testes-specific alpha4t2_dm proteasome subunit (59% a.a. identity), and it maps to position 27 on chomosome 2. The expression of the alpha4t_dv gene is testes-specific, like that of alpha4t2_dm. The existence of testes-specific alpha4-type subunits in two widely diverged subgenera of Drosophila suggests that these subunit isoforms have important functional roles in spermatogenesis.

Personality changes in Alzheimer's disease.

How personality changes in Alzheimer's disease is not well understood. Accentuations of premorbid personality, systematic shifts in personality traits, and specific personality changes affecting subtypes of patients have been postulated. To investigate which of these alternatives occurs in Alzheimer's disease, caregivers were given a comprehensive personality inventory standardized for use by informants. Caregivers observed more neurotic, less extroverted, and less conscientious behavior. To a smaller extent, patients with Alzheimer's disease were reported as becoming less agreeable and less open. The changes in reports of neuroticism, extroversion, agreeableness, and openness suggested consistent systematic shifts across all patients. Patients with depressive features were reported to have been more neurotic; those with paranoid delusions were reported as having been more hostile. Premorbid personality traits may predispose to subsequent psychiatric symptoms in Alzheimer's disease.

Complex visual disturbances in Alzheimer's disease.

Although Alzheimer's disease (AD) involves visual association cortex, previous studies have not systematically investigated complex visual disturbances in AD. We examined 30 community-based AD patients, 13 (43%) of whom had complex visual complaints, and compared them with 30 controls on 7 types of complex visual tasks. Despite preserved visual acuity and color recognition, the AD patients were impaired in the visual evaluation of common objects, famous faces, spatial locations, and complex figures. In the AD patients, we found that all 30 had disturbances in figure-ground analysis; 17 (57%) had difficulties visually recognizing actual objects ("agnosia"); those with worse dementia disability had the most complex visual disturbances; and a subgroup (6) with Balint's syndrome performed the most poorly on the complex visual tasks. This study demonstrates that a range of complex visual disturbances are common in AD and suggests that they may result from the known neuropathology in the visual association cortex.

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

The relationship of clinical psychopathologic rating and cognitive factors to clinical dementia staging.

1. Sixty-six patients were assessed by one of three physicians employing CERAD assessment and were staged by CDR criteria. 2. The same day, trained raters completed the Brief Psychiatric Rating Scale, the Cornell Scale for Depression in Dementia and the Mini-mental State Examination. 3. Clinician's Global Rating of the CDR is strongly related to the Mini-mental State Examination Score. 4. The CDR is insensitive to mild psychopathology in this population.

Relationships among the variables age, weight, A/B behaviour, cholesterol, ways of coping and blood pressure levels.

This study investigated the interrelationship between serum cholesterol levels, coping responses, type A/B behaviour and blood pressure. A convenience sample of 191 working women completed a health history which included sociodemographic data and a 'Ways of Coping' checklist. In addition, they underwent a structured interview--for type A/B behaviour and were monitored every minute for blood pressure changes, before, during and after the interview. A stepwise regression revealed that four variables; age, weight, A/B type and cholesterol, explained 22% of variance in blood pressure levels. Further analysis showed that type B's used 'Seeking Social Support' significantly more than type A's.

Relative risk of untreated hypertension in type-A employed African American women.

The purpose of this study was to determine the relative risk of hypertension in African American women with type A behaviour pattern. Of the 305 employed African American women, 147 (48.2%) were classified as type A and 158 (51.8%) as type B. The logistic regression procedure was used to calculate the adjusted relative risk of having an elevated SBP by controlling for age, weight and cholesterol. We found that the adjusted relative risk of type A African American women having an elevated SBP and DBP was 9.06 and 2.26 times that of type B, respectively.

The factor structure of the Brief Psychiatric Rating Scale in Alzheimer's disease.

The factor structure of the Brief Psychiatric Rating Scale (BPRS) is well established with young psychiatric patients. A study by Overall and Beller showed, however, that its factor structure was different with geropsychiatric patients. Although the BPRS has been used in assessing the behavioral characteristics of patients with probable Alzheimer's disease (AD), its factor structure has not been established with these patients. The present study investigated the factor structure of the BPRS among patients with clinically diagnosed AD by (NINCDS/ADRDA) criteria. The scale had limited usefulness with outpatients with mild AD. The factor structure obtained was similar to that found with other patient groups, but a unique factor, including the items Tension and Uncooperativeness, probably reflects the behavioral and psychological agitation characteristic of some AD patients. We recommend caution be taken in generalizing data from younger psychiatric samples to older adult patients with dementia.

Assessment of behavioral and affective symptoms in Alzheimer's disease.

Noncognitive behavioral symptoms occurring during the prior week were studied in 34 Alzheimer's disease (AD) patients and 21 spousal control subjects via caregiver and patient interviews using the Behavioral Pathology in Alzheimer's Disease Rating Scale and the Cornell Scale for Depression in Dementia. Delusional or paranoid features were reported in 13 subjects (38%) and hallucinations in six (18%); patients with these psychoticlike symptoms had lower scores on the Folstein's Mini-Mental State Examination. Other behavioral symptoms reported in AD patients included anxiety (50%) and activity disturbances (44%). Six AD subjects (18%) and two controls (10%) showed mild to moderate symptoms of depression; AD subjects were more likely than controls to show behavioral signs and symptoms of depression, but the two groups did not differ in terms of mood-related, cyclical, or physical signs and symptoms.

Using telecomputing to provide information and support to caregivers of persons with dementia.

The Alzheimer's Disease Support Center (ADSC) is a telecomputing-based project designed to provide information and support to caregivers of persons with dementia. Inherent features of telecomputing make computer-mediated information and support systems like the ADSC a viable complement to existing efforts to meet caregivers' needs. This article outlines the rationale for the ADSC and describes its context, structure, content, and operation.

Burden and well-being: the same coin or related currency.

To examine whether caregiver burden and general well-being are opposite sides of the same coin or distinct constructs, we compared burden (in physical, mental, financial, and social domains) and well-being (in the same domains, but with separate objective and subjective measures). The domains of burden and well-being were examined first as correlates of one another, second as correlates of antecedents in the caregiving situation, and finally, as predictors of likelihood to institutionalize. We conclude that burden and well-being are not opposite sides of the same coin, but rather related currency, each useful for tapping unique facets of the caregiving experience.

Differences in the perceived well-being of wives and husbands caring for persons with Alzheimer's disease.

This study aimed to examine differences in subjective psychological well-being between husband and wife caregivers of persons with Alzheimer's disease in comparison to the psychological states of noncaregiver husbands and wives similar in age and ethnicity. The principal comparison of interest was whether differences between husband and wife caregivers were greater than those between comparison group husbands and wives. Significant interactions for six out of nine psychological measures indicate that gender-related differences between spouse caregivers were specifically associated with the caregiving role. Possible explanations for the discrepancy between husband and wife caregivers as well as practice implications are discussed.

A longitudinal study of the relationship between levels of depression among persons with Alzheimer's disease and levels of depression among their family caregivers.

The purpose of this study was to examine the effects, over time, of depressive symptoms in persons with Alzheimer's disease on depression in their family caregivers. In a sample of 353 patients and caregivers, multilevel longitudinal analysis was used to accommodate an observational design in which the number of observation points and the intervals between points varied across caregivers. The rate of change (increase) in caregiver depression was predicted by the rate of change (increase) in patient depressive symptoms and by increase in patient dependency in instrumental activities of daily living (ADLs). Acceleration of the increase in caregiver depression was predicted by acceleration in patient dependency in instrumental and basic ADLs but not by acceleration in patient depressive symptoms. These findings indicate the importance of measuring the rate and acceleration of change in patient characteristics in order to understand caregiver depression. They also support early interventions for caregivers.

Social management of Alzheimer's disease.

Focus on the biomedical aspects of AD in research and clinical care has resulted in the relative neglect of its psychological and social dimensions. An adequate clinical response to individuals diagnosed with AD must include attention to preserving continuity with the past and quality of life in the present. As AD is diagnosed earlier, care models that incorporate the experiences and perceptions of the diagnosed are not only feasible, but essential.

Effect of a music intervention on noise annoyance, heart rate, and blood pressure in cardiac surgery patients.

BACKGROUND: Exposure to noise in a critical care unit may trigger a response by the sympathetic nervous system, thereby increasing cardiovascular work in patients recovering from cardiac surgery. OBJECTIVE: To investigate the effects of a music intervention given twice on the first postoperative day on noise annoyance, heart rate, and arterial blood pressure in subjects with high (n = 22) and low (n = 18) sensitivity to noise. METHODS: A prospective, quasi-experimental, repeated-measures design was used. Based on results of power analysis, the sample size was 40. Subjects were recruited preoperatively, and their sensitivity to noise was assessed. On the first postoperative day, repeated-measures data were collected on levels of noise annoyance and physiological variables during 15 minutes of baseline and 15 minutes of music intervention on two occasions. Subjects completed a follow-up questionnaire regarding their perceptions of the noise in the critical care unit and the music intervention. RESULTS: Repeated-measures analysis of variance showed that subjects had lower levels of noise annoyance during music intervention than at baseline. Heart rate and systolic blood pressure decreased during the music intervention compared with baseline. Diastolic blood pressure decreased during the music intervention from baseline during time 2, but not time 1. Subjects with high baseline scores of noise sensitivity preoperatively had higher baseline levels of noise annoyance in the critical care unit the first postoperative day. Subjects rated the music intervention as highly enjoyable regardless of their baseline noise sensitivity or noise annoyance. CONCLUSION: Results of this study support the idea that noise annoyance is a highly individual phenomenon, influenced by a transaction of personal and environmental factors. Use of a music intervention with cardiac surgery patients during the first postoperative day decreased noise annoyance, heart rate, and systolic blood pressure, regardless of the subject's noise sensitivity.

Effects of educational attainment on the clinical expression of Alzheimer's disease: results from a research registry.

The "reserve" hypothesis suggests that education should affect the clinical expression of Alzheimer's disease (AD), but results from studies examining this idea are not consistent. In a single study, we evaluated the effects of educational attainment on three aspects of the clinical expression of AD: age at symptom onset, rate of cognitive decline, and survival. Subjects were 258 persons with mild- or moderate-stage Alzheimer's, drawn from our AD Research Registry. With statistical adjustment for confounding variables present in a clinic-based design, we found that higher educational attainment was associated with slightly earlier reports of symptom onset and a slower rate of cognitive decline on the Mini-Mental State Exam (MMSE). Education did not affect time of survival until death. We conclude that, for subjects in our sample, education had modest effects on aspects of the clinical expression of AD. These effects were not fully consistent with predictions derived from the "reserve" hypothesis.

Selection of dieldrin-resistant strains of Lucilia cuprina (Diptera: Calliphoridae) after ethyl methanesulfonate mutagenesis of a susceptible strain.

After ethyl methanesulfonate (EMS) mutagenesis of a susceptible strain (SWT), selective screening of Lucilia cuprina (Wiedemann) resulted in four strains that were resistant to the insecticide dieldrin. Concentrations used for selection were greater than LC99 of susceptible phenotypes. No resistant variants were screened from the standard laboratory strain (SWT) not treated with EMS. The resistance phenotypes of the four resistant strains were similar to each other and to that of a field-selected resistant strain. The genetic basis of resistance is monogenic in all strains and the data are consistent with the same locus, Rdl, determining resistance status in each strain. The Rdl locus maps to chromosome V, approximately 3.5 map units distal to the Sut locus. Dieldrin resistance may be caused by less effective blocking of insect neuronal GABA receptors by the chemical in resistant strains. The data indicate that the evolution of resistance to an insecticide in the field may be constrained by a limited number of genetical and biochemical options if a monogenic response is selected for and that the spontaneous mutation rate to the Rdl allele is less than 1 in 10(6) in the laboratory.