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Biomedical subjects

E H Rubin

Publications and source records attributed to E H Rubin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning.

Camptothecins are a new class of anticancer drugs that target DNA topoisomerase I; current efforts are directed toward elucidating optimal combinations of these drugs with other antineoplastic agents. A rationale for the use of sequential therapy involving the combination of camptothecins with topoisomerase II-targeting drugs, such as etoposide, has arisen from observations of increased topoisomerase II protein levels in cell lines resistant to camptothecin. In an effort to understand potential mechanisms of resistance to this strategy, we developed a U-937 cell subline, denoted RERC, that is capable of surviving exposure to sequential topoisomerase poisoning. The RERC cells are 200-fold resistant to camptothecin, 8-fold resistant to etoposide, and 10-fold hypersensitive to cisplatin compared to the parental U-937 cells. Biochemical analyses indicate that the resistant phenotype involves alterations in both topoisomerase I and topoisomerase IIalpha. Topoisomerase I catalytic activity in the resistant cells is similar to that of the parental line but is resistant to camptothecin. Moreover, the resistant cells express a single mRNA species of topoisomerase I that codes for a mutation in codon 533. In addition, topoisomerase IIalpha protein levels are decreased 10-fold in the resistant line, coincident with a two-fold decrease in the expression of topoisomerase IIalpha mRNA. Collectively, these results indicate that resistance to sequential topoisomerase poisoning may involve a reduction in total cellular topoisomerase activity.

Antineoplastic Agents↗
PubMed1997

Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis.

Camptothecins are antineoplastic drugs that specifically target the enzyme DNA topoisomerase I. Prior work has identified a human topoisomerase I mutation, F361S, that confers resistance to camptothecin. We now demonstrate that substitutions in the 361-364 region can alter DNA cleavage/ligation by the enzyme. The defective catalysis exhibited by certain mutants likely relates to an impaired interaction with DNA, since these enzymes are more sensitive to the inhibitory effects of DNA binding ligands. Moreover, studies with peptides and fusion proteins suggest that the 361-364 region may bind DNA directly. The finding that the 361-364 region is involved in both enzyme catalysis and camptothecin resistance suggests that this region is part of the active site of human topoisomerase I and that camptothecin may interact with the enzyme at this site.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Current advances in Alzheimer's disease. A medical model paradigm for psychiatric education.

Psychiatrists have the expertise to play a major leadership role in the diagnosis and treatment of Alzheimer's disease. Psychiatry residents should be trained to recognize both the cognitive and noncognitive symptoms of this disease. Psychiatrists are in an excellent position to keep up with the rapidly expanding pharmacologic armamentarium to treat this devastating illness. Although such potentials are exciting, they undoubtedly will be complicated. Residency directors and departmental chairs should instill enthusiasm toward basic science advances and their clinical implications. Understanding the mechanisms underlying specific central nervous system illnesses should increase the likelihood of discovering the pathophysiology of others. The more psychiatrists and psychiatric residents become interested in these discoveries and the science underlying such progress in Alzheimer's disease, the better they will be able to keep up to date with progress in understanding other psychiatric disorders.

Aged↗
PubMed1996

Identification of a nucleolin binding site in human topoisomerase I.

DNA topoisomerase I (topo I) is involved in the regulation of DNA supercoiling, gene transcription, and rDNA recombination. However, little is known about interactions between topo I and other nuclear proteins. We used affinity chromatography with a topo I fusion protein to screen U-937 leukemic cell extracts and have identified nucleolin as a topo I-binding protein. Coimmunoprecipitation and other studies demonstrate that the interaction between topo I and nucleolin is direct. Furthermore, deletion analyses have identified the 166-210-amino acid region of topo I as sufficient for the interaction with nucleolin. Since nucleolin has been implicated in nuclear transport and in a variety of transcriptional processes, the interaction with topo I may relate to the cellular localization of topo I or to the known role of this topoisomerase in transcription.

Amino Acid Sequence↗
PubMed1996

Quality in residency training: toward a broader, multidimensional definition.

The authors propose a general definition of quality in residency train ing and describe a process for developing the definition. The definition and process go beyond the usual concerns with educational structures and processes and are customer-centered, outcomes-oriented, and consistent with views of quality widely applied in health care, manufacturing, and other businesses. The process begins by listing some of the more important customers of a training program--trainees, patients, funding agencies, health care employers, medical schools and teaching hospitals, and professional organizations--and then considers the needs of those customers. The result is a definition of quality in residency training that is multidimensional and includes aspects of residency training related to the clinical proficiency of trainees, socioeconomic dimensions of training, and ethical concerns. While some measures exist to put this multidimensional definition of quality into operation, much work will be needed to make it useful for the training of residents.

Health Services Needs and Demand↗
PubMed1996

Cerebral amyloid deposition and diffuse plaques in "normal" aging: Evidence for presymptomatic and very mild Alzheimer's disease.

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Aged↗
PubMed1995

Effects of alprazolam on glucose regulation in diabetes. Results of double-blind, placebo-controlled trial.

OBJECTIVE: To determine the effects of alprazolam on glucose regulation in anxious and nonanxious patients with poor glycemic control and establish whether regulatory benefits are related to anxiolytic effects of the medication. RESEARCH DESIGN AND METHODS: Fifty-eight patients with poor glycemic control, 16 (27.6%) of whom had a symptomatic generalized anxiety disorder, were entered into a randomized, double-blind, placebo-controlled, 8-week trial using alprazolam (up to 2 mg/day) as the active agent. Generalized anxiety disorder was determined in accordance with Diagnostic and Statistical Manual of Mental Disorders criteria, and anxiety symptoms were measured using the Hopkins Symptom Checklist. Glycated hemoglobin levels were used to determine glucose regulation. Compliance behavior was assessed using glucometers and medication monitors equipped with electronic memory. RESULTS: A statistically significant reduction in glycated hemoglobin level was observed in patients treated with alprazolam compared with those receiving placebo (-1.1 vs. -0.3%, P = 0.04). This treatment effect was not a function of differences in compliance behaviors. Anxiety symptoms decreased in both alprazolam- and placebo-treated patients with generalized anxiety disorder, but reduction in glycated hemoglobin level was not dependent on alleviation of anxiety. CONCLUSIONS: A short course of alprazolam improved glucose regulation in patients with a history of poor diabetes control. This effect was not directly related to concomitant changes in anxiety. Alprazolam treatment of anxious patients with poorly controlled diabetes may result in decreased anxiety and improved glucose regulation through independent mechanisms.

Adult↗
PubMed1994

Sex differences in the sensitivity of two self-report depression scales in older depressed inpatients.

Both the Geriatric Depression Scale (J. A. Yesavage et al., 1983) and the Beck Depression Inventory (A. T. Beck, A. J. Rush, B. F. Shaw, & G. Emery, 1979) were less effective in identifying depressed men than women in a sample of 191 geriatric psychiatric inpatients with major unipolar depression. From one quarter to one half of the men were missed cases, depending on the cutoff score used. Separate cutoff scores for older men and women on depression screening instruments may be appropriate.

Aged↗
PubMed1993

Influence of age on clinical and psychometric assessment of subjects with very mild or mild dementia of the Alzheimer type.

OBJECTIVE: The influence of age on performance on clinical and psychometric assessments is examined in groups of nondemented persons and individuals with either very mild or mild dementia of the Alzheimer type (DAT). DESIGN: Initial clinical and psychometric assessments of persons enrolled in longitudinal studies of DAT and nondemented control subjects. SETTING: Alzheimer's Disease Research Center at Washington University, St Louis, Mo. PARTICIPANTS: Volunteer samples of 108 people (44 men, 64 women) with mild DAT, 61 people (30 men, 31 women) with very mild DAT, and 122 healthy nondemented people (45 men, 77 women) were recruited between 1979 and 1991. Age ranged from 54 to 87 years. Persons with confounding medical, neurologic, or psychiatric disorders were excluded. Dementia severity was staged using the Clinical Dementia Rating scale. MAIN OUTCOME MEASURES: Five brief quantitative clinical tests included in the 90-minute clinician administered protocol, as well as 14 tests included in a 2-hour psychometric test battery. RESULTS: Dementia severity affected performance on all measurements. Age did not influence performance on clinical assessments. There was a significant interaction between age and dementia severity on 10 of 14 psychometric measures. In general, older nondemented individuals performed less well than younger nondemented individuals while older mildly demented persons performed about the same as, or slightly better than, their younger counterparts. CONCLUSIONS: Age does not affect performance on brief clinical assessment instruments. However, age affects psychometric performance differently in cognitively intact persons when compared with persons with DAT. As a result, psychometric differentiation between cognitively normal and demented individuals is more difficult in older populations.

Aged↗
PubMed1993

Psychopathology in younger versus older persons with very mild and mild dementia of the Alzheimer type.

OBJECTIVE: The psychopathology associated with early-onset dementia of the Alzheimer type was investigated by comparing the prevalence of psychiatric symptoms in younger subjects (mean age = 59 years) who had very mild or mild dementia with that in older adults (mean age = 72) whose dementia was of equivalent severity. METHOD: Nondemented comparison subjects and persons with very mild or mild dementia of the Alzheimer type were recruited to participate in longitudinal studies. All subjects met strict inclusion and exclusion criteria. Information pertaining to personality changes, affective symptoms, and psychotic symptoms was included in the 90-minute semistructured, physician-administered interview, which was used to assign a clinical dementia rating according to published guidelines. The younger group were age 64 or younger and consisted of 20 nondemented subjects, 11 subjects with very mild dementia, and 18 subjects with mild dementia. The older group, described previously, were 64-83 years old and consisted of 83 nondemented subjects, 41 persons with very mild dementia, and 68 subjects with mild dementia. RESULTS: The psychopathology in the younger subjects was similar to that in the older group. Personality changes occurred in over 80% of the younger persons with very mild illness. Psychotic symptoms were present in over 40% of the younger persons with mild illness but were rare in the group with very mild dementia. CONCLUSIONS: Similar patterns of psychopathology in younger and more elderly persons with dementia of the Alzheimer type support the suggestion that these changes are direct effects of the illness on the CNS. Increased attention to documenting these noncognitive symptoms and studying various treatments is urgently needed.

Age Factors↗
PubMed1992

Mild senile dementia of the Alzheimer type. 4. Evaluation of intervention.

The design of trials of interventions intended to slow or arrest the progression of senile dementia of the Alzheimer type must be based on analysis of the natural history of the disease. Using a random coefficients statistical model, we analyzed the natural history of senile dementia of the Alzheimer type in carefully defined subjects with mild disease (n = 68) for periods of up to 10 years. Subject performance was assessed longitudinally on batteries of clinical and psychometric measures. The characteristics of these measures were analyzed relevant to their utility as outcome measures for long-term trials in patients with senile dementia of the Alzheimer type. Estimates were made of sample sizes required to show arrest, and 50% or 25% slowing in the progression of mild disease. We suggest that a clinically relevant global measure, such as the Sum of Boxes of the Clinical Dementia Rating scale, and a performance-based clinical scale or psychometric measure would be appropriate in a 12- or 24-month trial enrolling subjects with mild senile dementia of the Alzheimer type.

Actuarial Analysis↗
PubMed1992

Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.

PURPOSE: We analyzed pretreatment characteristics of patients with postremission acute myeloid leukemia (AML) treated with high-dose cytarabine (HIDAC) during a recent Cancer and Leukemia Group B (CALGB) trial to determine risk factors associated with HIDAC neurotoxicity. PATIENTS AND METHODS: One hundred seventy-six patients received at least one course of HIDAC as part of a CALGB protocol designed to determine the optimal dose of cytarabine (ara-C) for postremission treatment of AML. HIDAC consisted of 3 g/m2 ara-C infused over 3 hours at 12-hour intervals on days 1, 3, and 5. The pretreatment characteristics of 170 patients were available for risk analyses. RESULTS: Eighteen patients (10%) experienced neurotoxicity. Univariate analyses demonstrated associations between the occurrence of neurotoxicity and elevated serum creatinine, age, and alkaline phosphatase (AP). Multivariate analysis showed that these variables were independent risk factors. These findings were used to construct a risk model with the following parameters: creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40 years, and AP greater than or equal to 3 x normal. Seventeen of 46 (37%) patients with two or more of these criteria developed neurotoxicity compared with one of 124 (1%) patients with one or none. The sensitivity and specificity of this model were 94% and 81%, respectively. CONCLUSION: We conclude that patients with two or more of the following parameters may be at increased risk for HIDAC neurotoxicity: (creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40, and AP greater than or equal to 3 x normal). However, this model should be confirmed by analysis of additional groups of patients treated with HIDAC.

Acute Disease↗
PubMed1991

The influence of major depression on clinical and psychometric assessment of senile dementia of the Alzheimer type.

OBJECTIVE: The performance on standard clinical and psychometric assessments of eight elderly individuals with major unipolar depression alone and seven with depression plus mild senile dementia of the Alzheimer type was compared with that of 41 nondepressed subjects suffering from very mild senile dementia of the Alzheimer type, 66 with mild senile dementia of the Alzheimer type, and 83 age-matched subjects without senile dementia. METHOD: Subjects with depression alone, depression plus mild senile dementia of the Alzheimer type, and very mild and mild senile dementia of the Alzheimer type met strict inclusionary and exclusionary criteria. A 90-minute semistructured interview, including several brief standardized clinical scales, was used to assign a Clinical Dementia Rating to each subject according to published guidelines, and each subject was given a 2-hour psychometric test battery. Data were analyzed by one-way multivariate analysis of variance to ascertain if there was an effect of group on clinical and psychometric test scores. RESULTS: The eight depressed subjects without concurrent dementia performed as well as the 83 nondepressed subjects without dementia on most clinical measures; however, their performance on most psychometric measures closely resembled that of the 41 nondepressed subjects with very mild dementia. The performance of the seven subjects with depression plus mild dementia was comparable to that of the 66 nondepressed subjects with mild dementia on most clinical and psychometric measures. CONCLUSIONS: Although depressed subjects performed as well as subjects without dementia on many clinical assessments, psychometric testing was not able to distinguish depressed subjects from those with very mild senile dementia of the Alzheimer type. This demonstrates the need for careful psychiatric evaluation before interpreting deficits on psychometric tests as indicating the presence of very mild senile dementia of the Alzheimer type.

Aged↗
PubMed1991

Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging.

We compare clinicopathologic data from 10 subjects identified in the very mild stage of senile dementia of the Alzheimer type with findings from similar studies in four cognitively normal subjects. We based the diagnosis of very mild dementia in the 10 subjects on informant reports and the judgment of experienced clinicians. Deficits of some psychometric measures of memory, language, and speeded psychomotor performance were observed for these subjects. The histologic markers of Alzheimer's disease, including neurofibrillary tangles and both the "diffuse" and classic subtypes of senile plaques, were present in the neocortex in all 10 subjects but essentially were absent in the four controls. These findings indicate that even "questionable" dementia can be diagnostic for Alzheimer's disease. Furthermore, because truly normal aging may be unaccompanied by neocortical senile plaques and neurofibrillary tangles, the presence of these lesions should suggest the possibility of clinically undetected Alzheimer's disease.

Activities of Daily Living↗
PubMed1991

Clinical diagnosis and course of Alzheimer's disease.

Alzheimer's disease can be accurately diagnosed by clinical methods alone in about 90% of cases. The adoption of uniform diagnostic criteria and assessment procedures, such as those developed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), will likely improve the characterization of the disease across a variety of clinical settings. In general, Alzheimer's disease is a relentlessly progressive disorder; however, it also is clinically heterogeneous. This is underscored by its diverse cognitive deficits, neurologic features, behavioral pathology, and rates of progression.

Alzheimer Disease↗
PubMed1990

Mild senile dementia of the Alzheimer type: 3. Longitudinal and cross-sectional assessment.

Sixty-six subjects diagnosed by validated criteria as having senile dementia of the Alzheimer type (SDAT) were assessed with clinical measures commonly used to study dementia. The severity of the SDAT was mild in 24, moderate in 24, and severe in 18. The data from these three groups in a cross-sectional study were compared with results in our earlier study of 43 subjects enrolled with mild SDAT and followed longitudinally. We concluded that the cross-sectional method underestimates the severity of progression as indicated by some of the clinical measures. Additionally, the 24 new subjects with mild SDAT were assessed longitudinally. This replication study confirmed our earlier conclusions that four of six clinical measures showed similar patterns over time and were useful throughout the study, global measures being more informative than brief individual measures with ceiling or floor effects.

Aged↗