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Biomedical subjects

D A King

Publications and source records attributed to D A King.

At least 19 recordsLinked to original sources
PubMed2000

Structure of HAP1-PC7 bound to DNA: implications for DNA recognition and allosteric effects of DNA-binding on transcriptional activation.

HAP1 is a transcription factor in yeast whose DNA-binding domain has been implicated in directly affecting transcriptional activation. Two separate mutations in the DNA-binding domain, S63G (HAP1-PC7) and S63R (HAP1-18), retain wild-type binding affinity. However, HAP1-PC7 is transcriptionally silent while HAP1-18 shows highly elevated levels of transcription. We have determined the X-ray crystal structure of the DNA-binding domain of HAP1-PC7 bound to its DNA target, UAS(CYC7), and compared it to the previously solved HAP1-wt and HAP1-18 complexes to UAS(CYC7). Additionally, we have quantitatively compared the DNA-binding affinity and specificity of the HAP1-PC7, HAP1-18 and HAP1-wt DNA-binding domains. We show that, although the DNA-binding domains of these three proteins bind UAS(CYC7) with comparable affinity and specificity, the protein-DNA interactions are dramatically different between the three complexes. Conserved protein-DNA interactions are largely restricted to an internal DNA sequence that excludes one of the two conserved DNA half-sites of UAS(CYC7) suggesting a mode of recognition distinct from other HAP1 family members. Alternative protein-DNA interactions result in divergent DNA configurations between the three complexes. These results suggest that the differential transcriptional activities of the HAP1, HAP1-18 and HAP1-PC7 proteins are due, at least in part, to alternative protein-DNA contacts, and implies that HAP1-DNA interactions have direct allosteric effects on transcriptional activation.

Allosteric Regulation↗
PubMed2000

Cerebrovascular risk factors and 1-year depression outcome in older primary care patients.

OBJECTIVE: A model in which cerebrovascular disease contributes to the pathogenesis of depression in later life was the basis of the authors' hypothesis that cerebrovascular risk factors at intake are independently associated with depression at 1-year follow-up. METHOD: The subjects were 247 patients aged 60 years or older in primary care practices. The study measures were completed at intake and 1-year follow-up. Multiple regression techniques were used to determine the independent association of initial cerebrovascular risk factors with depressive symptoms and diagnoses at 1 year. RESULTS: The authors found that the severity of initial cumulative cerebrovascular risk factors was significantly independently associated with 1-year depressive symptoms and diagnoses, but not after also controlling for overall medical burden. CONCLUSIONS: The results lend some support to the cerebrovascular model of depression.

Age Factors↗
PubMed2000

A neuropsychological comparison of depressed suicide attempters and nonattempters.

The neuropsychological performance of 18 older inpatients with major depression who were admitted following a suicide attempt was compared with that of 29 older depressed inpatients who had never attempted suicide. There was an interactive effect of age and group on the Trail Making Test, part B, such that attempters showed greater performance declines with age. No other differences were detected between groups on a range of neuropsychological tasks. These findings are discussed in the context of the methodological limitations of previous studies and the need for future research to better elucidate the nature of the relationships between age, cognitive functioning, and suicidal behavior.

Age Factors↗
PubMed1999

Structure of HAP1-18-DNA implicates direct allosteric effect of protein-DNA interactions on transcriptional activation.

HAP1 is a yeast transcriptional activator that binds with equal affinity to the dissimilar upstream activation sequences UAS1 and UAS(CYC7), but activates transcription differentially when bound to each site. HAP1-18 harbors an amino acid change in the DNA binding domain. While binding UAS1 poorly, HAP1-18 binds UAS(CYC7) with wild-type properties and activates transcription at elevated levels relative to HAP1. We have determined the structure of HAP1-18-UAS(CYC7) and have compared it to HAP1-UAS(CYC7). Unexpectedly, the single amino acid substitution in HAP1-18 nucleates a significantly altered hydrogen bond interface between the protein and DNA resulting in DNA conformational changes and an ordering of one N-terminal arm of the protein dimer along the DNA minor groove. These observations, together with a large subset of transcriptionally defective mutations in the HAP1 DNA-binding domain that map to the HAP1-DNA interface, suggest that protein-DNA interactions may have direct allosteric effects on transcriptional activation.

Amino Acid Sequence↗
PubMed1999

Structure of a HAP1-DNA complex reveals dramatically asymmetric DNA binding by a homodimeric protein.

HAP1 is a member of a family of fungal transcription factors that contain a Zn2Cys6 binuclear cluster domain and bind as homodimers to sequences containing two DNA half sites. We have determined the 2.5 A crystal structure of HAP1 bound to a cognate upstream activation sequence from the CYC7 gene. The structure reveals that HAP1 is bound in a dramatically asymmetric manner to the DNA target. This asymmetry aligns the Zn2Cys6 domains in a tandem head-to-tail fashion to contact two DNA half sites, positions an N-terminal arm of one of the protein subunits to interact with the inter-half site base pairs in the DNA minor groove, and suggests a mechanism by which DNA-binding facilitates asymmetric dimerization by HAP1. Comparisons with the DNA complexes of the related GAL4, PPR1 and PUT3 proteins illustrate how a conserved protein domain can be reoriented to recognize DNA half sites of different polarities and how homodimeric proteins adopt dramatically asymmetric structures to recognize cognate DNA targets.

Amino Acid Sequence↗
PubMed1999

Psychiatric disorders in older primary care patients.

OBJECTIVE: Most older people with psychiatric disorders are never treated by mental health specialists, although they visit their primary care physicians regularly. There are no published studies describing the broad array of psychiatric disorders in such patients using validated diagnostic instruments. We therefore characterized Axis I psychiatric diagnoses among older patients seen in primary care. DESIGN: Survey of psychopathology using standardized diagnostic methods. SETTING: The private practices of three board-certified general internists, and a free-standing family medicine clinic. PARTICIPANTS: All patients aged 60 years or older who gave informed consent were eligible. MEASUREMENTS AND MAIN RESULTS: For the 224 subjects completing the study, psychiatric diagnoses were based on the Structured Clinical Interview for DSM-III-R. Point prevalence estimates used weighted averages based on the stratified sampling method. For the combined sites, 31.7% of the patients had at least one active psychiatric diagnosis. Prevalent current disorders included major depression (6.5%), minor depression (5.2%), dementia (5.0%), alcohol abuse or dependence (2. 3%), and psychotic disorders (2.0%). Dysthymic disorder and primary anxiety and somatoform disorders were less common and frequently comorbid with major depression. CONCLUSIONS: Mental disorders, particularly depression, are common among older persons seen in these primary care settings. Clinicians should be particularly vigilant about depression when evaluating older patients with anxiety or putative somatoform symptoms, given the relatively low prevalences of primary anxiety and somatoform disorders.

Aged↗
PubMed1999

Cerebrovascular risk factors and depression in older primary care patients: testing a vascular brain disease model of depression.

The authors examined whether cerebrovascular risk factors (CVRFs) are associated with depressive diagnoses and symptoms in 303 primary-care patients age >/=60 years, as would be consistent with a small-vessel brain disease model of later-life depression. CVRFs were not significantly independently associated with major, minor, or subsyndromal depression, late-onset major depression, or overall depressive symptom severity. These data did not support the notion that a small-vessel brain disease model of depression might apply to the majority of older persons with depressive symptoms and syndromes in primary-care settings. Future work should include longitudinal study with larger sample sizes.

Aged↗
PubMed1999

The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability.

OBJECTIVE: Existing diagnostic categories for depression may not encompass the majority of older people suffering clinically significant depressive symptoms. We have described the prevalence of subsyndromal depressive symptoms and tested the hypothesis that patients with subsyndromal depression have greater functional disability and general medical burden than nondepressed subjects but less than patients with diagnosable depressions. METHODS: Subjects were 224 patients, aged 60 years and older, recruited from private internal medicine offices or a family medicine clinic. Validated measures of psychopathology, medical burden, and functional status were used. The subsyndromal depression group was defined by a score of more than 10 on the Hamilton Rating Scale for Depression and by the absence of major or minor depressive disorder. Analyses included multiple regression techniques to determine the presence of group differences adjusted for demographic covariates. RESULTS: Subsyndromal depression was common (estimated point prevalence of 9.9% compared with 6.5% for major depression, 5.2% for minor depression, and .9% for dysthymic disorder), associated with functional disability and medical comorbidity to a degree similar to major or minor depression, and often treated with antidepressant medications. CONCLUSIONS: Although depressive conditions are common and are associated with considerable functional and medical morbidity in older primary care patients, many patients with clinically significant depressive symptoms are not captured by criteria-based syndromic diagnostic categories. Future work should include intervention studies of subsyndromally depressed older persons as well as attention to the course and biopsychosocial concomitants of diagnosable and subsyndromal depressions in this population.

Aged↗
PubMed1998

Cocaine and caffeine: conditioned place preference, locomotor activity, and additivity.

Conditioned place preference (CPP) was employed to clarify the reinforcing and locomotor stimulating effects of several doses of cocaine and caffeine (0.32, 1.0, 3.2, 5.6, and 10.0 mg/kg) and to explore the possibility of additive effects between the two drugs. Additionally, the hypothesis that the reinforcing effects of psychostimulants are mediated by the same systems that control psychostimulant-induced locomotor activity was examined by conducting correlational studies between drug-induced locomotor activity and time spent in the drug-conditioned compartments. Several doses of cocaine (1.0, 3.0, 5.6, 10.0 mg/kg), and caffeine (0.32, 1.0, 3.2, 5.6, 10.0) were found to condition place preference and stimulate locomotor activity. A combination of low doses (0.32 mg/kg) of each drug appeared to be additive. A positive relationship between locomotor activity observed during conditioning and time spent in the conditioned compartment during testing was found for cocaine but not caffeine or the low-dose combination of cocaine and caffeine.

Animals↗
PubMed1998

Quantitative and qualitative differences in the verbal learning performance of elderly depressives and healthy controls.

We compared the verbal learning and memory performance of 57 inpatients with unipolar major depression and 30 nondepressed control participants using the California Verbal Learning Test. The effect of age within this elderly sample was also examined, controlling for sex, educational attainment, and estimated level of intelligence. Except for verbal retention, the depressive had deficits in most aspects of performance, including cued and uncued recall and delayed recognition memory. As well, there were interactions between depression effects and age effects on some measures such that depressives' performance declined more rapidly with age than did the performance of controls. The results are discussed in the context of recent contradictory reports about the integrity of learning and memory functions in late-life depression. We conclude that there is consistent evidence, from this and other studies, that elderly depressed inpatients have significant deficits in a range of explicit verbal learning functions.

Adolescent↗
PubMed1998

Medical illness burden, trait neuroticism, and depression in older primary care patients.

OBJECTIVE: The authors tested the hypotheses that medical illness burden is independently associated with depression and that this association is moderated by neuroticism. METHOD: Multiple regression techniques were used to determine the independent associations of medical burden and neuroticism with depression in a group of 196 subjects, 60 years of age and older, recruited from primary care settings. RESULTS: Medical burden and neuroticism were independently associated with major depression, depressive symptoms, and psychiatric dysfunction. CONCLUSIONS: These findings support models in which medical disorders may contribute directly to depression. At the same time, the role of neuroticism in later-life depression warrants further study.

Aged↗
PubMed1998

Cerebrovascular risk factors and later-life major depression. Testing a small-vessel brain disease model.

The topic of vascular depression has received increasing prominence as a putative etiology of depression in later life. The authors examined one aspect of this model by comparing the burden of systemic cerebrovascular risk factors (CVRFs) in 130 psychiatric inpatients with major depression and 64 normal control (NC) subjects, all age > or = 50 years. Depressed subjects did not differ statistically from NCs on cumulative CVRF scores. Diabetes mellitus and atrial fibrillation were both associated with depression, but only atrial fibrillation retained an independent association after medical disability was statistically controlled. Among the depressed subjects, CVRF scores were not significantly associated with overall symptom severity, psychiatric disability, age at onset of depression, melancholic subtype, or psychotic depression. These data did not support the notion that a linear model of small-vessel disease might apply to the great majority of older inpatients with major depression.

Aged↗
PubMed1997

Screening for depression in elderly primary care patients. A comparison of the Center for Epidemiologic Studies-Depression Scale and the Geriatric Depression Scale.

BACKGROUND: Later-life depressive disorders are a major public health problem in primary care settings. A validated screening instrument might aid in the recognition of depression. However, available findings from younger patients may not generalize to older persons, and existing studies of screening instruments in older patient samples have suffered substantial methodological limitations. METHODS: One hundred thirty patients 60 years or older attending 3 primary care internists' practices participated in the study. Two screening scales were used: the Center for Epidemiologic Studies-Depression Scale (CES-D) and the Geriatric Depression Scale (GDS). The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. Third Edition, Revised, was used to establish "gold standard" diagnoses including major and minor depressive disorders. Receiver operating curve analysis was used to determine each scale's operating characteristics. RESULTS: Both the CES-D and the GDS had excellent properties in screening for major depression. The optimum cutoff point for the CES-D was 21, yielding a sensitivity of 92% and a specificity of 87%. The optimum cutoff point for the GDS was 10, yielding a sensitivity of 100% and a specificity of 84%. A shorter version of the GDS had a sensitivity of 92% and a specificity of 81% using a cutoff point of 5. All scales lost accuracy when used to detect minor depression or the presence of any depressive diagnosis. CONCLUSIONS: The CES-D and the GDS have excellent properties for use as screening instruments for major depression in older primary care patients. Because the GDS's yes or no format may ease administration, primary care clinicians should consider its routine use in their practices.

Aged↗
PubMed1997

Ruminative thinking in older inpatients with major depression.

Ruminative thinking, the tendency to dwell on particular ideas or themes, can be a prominent part of the phenomenology of major depression, but it rarely has been the focus of empirical research. We attempted to replicate (in adult psychiatric inpatients age > or = 50 years with DSM-III-R major depression) the previously published finding that ruminative thinking was associated with melancholia and with psychosis. In our sample, these associations were not present. In addition, we explored the relationships of ruminative thinking to specific areas of thought content (e.g., suicidal ideation, somatic worry), cognitive function and overall functional status; ruminative thinking was not associated with suicidal ideation, but was associated with greater somatic worry and with poorer functional status, although these associations were not independent of overall depressive severity. A substantial proportion of subjects were unable to complete the cognitive measures; ruminative thinking was independently associated with inability to complete these tasks. We conclude that ruminative thinking is a meaningful and common clinical phenomenon among severely depressed older inpatients. Further investigations in inpatients and other populations examining its relationships to other phenomenology, to course and outcome, and to putative underlying mechanisms of depression are warranted.

Adult↗
PubMed1995

Age of onset and medical illness in older depressed inpatients.

Age of onset of depressive episodes may serve as a useful marker of pathogenetic heterogeneity in late-life depression. Medical illness may play an important role in the pathogenesis of depression in the elderly, but its relationship to age of onset has not been carefully examined. We prospectively studied 110 older inpatients with DSM-III-R major depression. Using multiple regression techniques, we found that medical illness was not independently associated with age of onset. Independent predictors of older age of onset were age, male sex, absence of substance abuse history, and absence of melancholia. Our discussion reconsiders the usefulness of age of onset as a primary research variable for elucidating heterogeneity in late-life depression.

Activities of Daily Living↗
PubMed1995

Older age and the underreporting of depressive symptoms.

OBJECTIVE: To determine whether older age is associated with a decrease in self-reported depressive symptoms, independent of examiner-rated symptoms, in inpatients with major depression. DESIGN: Survey study. SETTING: Inpatient psychiatric units at a university medical center. PATIENTS: Eligible subjects were those over 20 years of age with a primary diagnosis of DSM-III-R major depression. Participation was sought from all subjects over 60 years of age and from every second or every third younger subject, depending on rater availability. Of 137 eligible subjects, 97 completed all study measures. MEASUREMENTS: The Beck Depression Inventory (BDI), as a measure of self-reported depressive symptoms, was the dependent variable. The Hamilton Rating Scale for Depression (Ham-D) was used to assess examiner-rated symptoms. MAIN RESULTS: Older age (P = .03) was associated negatively and examiner-rated depressive symptoms (P = .0001) were associated positively with BDI score. Other variables, including gender, education, age of depression onset, and medical illness burden, were not independently associated with BDI. Examination of depressive symptom subtotals (psychologic/affective vs. somatic/neurovegetative) revealed that only the self-reported psychologic/affective subtotal was significantly associated with age (P = .0018). CONCLUSIONS: Some older patients with clinically significant depression underreport their symptoms. When asking older patients about depressive symptoms, clinicians should view negative responses only within larger clinical contexts and should obtain information from other sources as needed. Similar concerns must temper interpretation of research that relies on subject self-report to study depression in late life.

Age Factors↗
PubMed1993

Depressive symptoms, medical illness, and functional status in depressed psychiatric inpatients.

OBJECTIVE: There is evidence that both psychiatric (especially affective) and medical illnesses contribute to physical disability. However, the differential contributions of specific psychiatric disorders and of medical pathology to functional status in psychiatric populations have not been studied. The authors therefore examined the contributions of depressive symptoms and medical illness to functional disability in depressed inpatients. METHOD: This prospective investigation included 109 psychiatric inpatients with DSM-III-R major depression. Regression techniques were used to examine the contribution of demographic variables (age, sex, education), depressive symptom severity (Hamilton Rating Scale for Depression score), psychiatric function (Global Assessment of Functioning Scale score), organ system pathology (Cumulative Illness Rating Scale score), and medical disability (Karnofsky Performance Status Scale score) to overall functional status (Instrumental Activities of Daily Living and Physical Self-Maintenance scores). These relationships were also examined in older and younger subgroups. RESULTS: Greater age, female sex, and illness factors all contributed to poorer functional status. Of the illness factors, psychiatric pathology contributed more to low functional status than did medical illness. The predictive power came specifically from the functionally based measures of psychiatric and medical illness; a quantitative measure of symptoms (Hamilton depression scale) or organ pathology (Cumulative Illness Rating Scale) did not significantly predict overall functional status. CONCLUSIONS: Clinicians and researchers should recognize that symptomatic and functional assessments tap related but different domains and that both psychiatric and medical illnesses contribute to overall disability.

Activities of Daily Living↗