A combinatorial mechanism for determining the specificity of E2F activation and repression.

Various studies have detailed the role of E2F proteins in both transcription activation and repression. Further study has shown that distinct promoter elements, but comprising the same E2F-recognition motif, confer positive or negative E2F control and that this reflects binding of either activator or repressor E2F proteins, respectively. We now show that the specificity of binding of an activator or repressor E2F protein is determined by adjacent sequences that bind a cooperating transcription factor. We propose that the functional E2F element is a module comprising not only the E2F-binding site but also the adjacent site for the cooperating transcription factor.

An ethnographic, controlled study of the use of a computer-based histology atlas during a laboratory course.

OBJECTIVE: To evaluate the use and effect of a computer-based histology atlas during required laboratory sessions in a medical school histology course. DESIGN: Ethnographic observation of students' interactions in a factorial, controlled setting. MEASUREMENTS: Ethnographer's observations; student and instructor self-report survey after each laboratory session with items rated from 1 (least) to 7 (best); microscope practicum scores at the end of the course. RESULTS: Between groups assigned the atlas and those not, the ethnographer found qualitative differences in the semantic categories used by students in communicating with each other and with the faculty. Differences were also found in the quality of the interactions and in the learning styles used with and without the computer present in the laboratory. The most interactive learning style was achieved when a pair of students shared a computer and a microscope. Practicum grades did not change with respect to historical controls. Students assigned the atlas, compared with those not assigned, reported higher overall satisfaction (a difference in score of 0.1, P = 0.003) and perceived their fellow students to be more helpful (a difference of 0.11, P = 0.035). They rated the usefulness of the microscope lower (a difference of 0.23, P<0.001). CONCLUSION: A computer-based histology atlas induces qualitative changes in the histology laboratory environment. Most students and faculty reacted positively. The authors did not measure the impact on learning, but they found that there are aspects of using the atlas that instructors must manipulate to make learning optimal. Ethnographic techniques can be helpful in delineating the context and defining what the interventions might be.

Risk factors for nonelective hospital readmissions.

We previously reported a predictive model that identified potentially modifiable risk factors for nonelective readmission to a county hospital. The objectives of this study were to determine if those risk factors were generalizable to a different population. We found that the previously reported risk factors were generalizable, and other potentially modifiable risk factors were identified in this population of veterans. However, further research is needed to establish whether or not the risk factors can be modified and whether or not modification improves outcomes.

Polychaetoid is required to restrict segregation of sensory organ precursors from proneural clusters in Drosophila.

Reduction of wild-type activity of the polychaetoid (pyd) gene results in formation of extra mechanosensory bristles on the head and notum of adult Drosophila. Loss of pyd function results in decreased ability to restrict sensory organ precursor (SOP) formation to a single cell per proneural cluster. Although the initial proneural cluster pattern of achaete expression is not altered in pyd mutants, extra cells within proneural clusters express the high levels of achaete characteristic of SOPs. This observation suggests that pyd+ functions as a negative regulator of achaete-scute complex expression within the proneural cluster. Synergistic interactions between pyd and Notch, Delta and extramacrochaetae mutations support this model. We also demonstrate that pyd is required for normal eye development.

An intervention on discharge polypharmacy.

OBJECTIVE: To determine if providing a way to cancel pre-admission prescriptions would reduce the number of active drug prescriptions (RXs) at discharge. DESIGN: A randomized non-blinded clinical trial. SETTING: Inpatient acute medical service of a university affiliated Veterans Administration medical center. PARTICIPANTS: Twelve medicine ward teams were randomized to control and intervention groups. Patients controlled had been discharged from these teams during 12 weeks and were receiving outpatient medications from this facility at hospital admission; control = 180, intervention = 168. INTERVENTION: At discharge, intervention teams used a computer-generated drug list to cancel or renew previous outpatient RXs or to prescribe new medications. Control teams could not cancel outpatient drugs and wrote all medications on individual prescriptions. MEASUREMENTS: The difference between admission and discharge RXs. RESULTS: There were no significant differences in patients' age, sex, race, Charlson Index (CI), or LOS between patient groups at discharge. The intervention group had fewer RXs on admission (5.4 vs 6.2, P < .05) and at discharge was not significantly different (2.9 vs 2.9, P = .87) from the control group. CONCLUSIONS: Providing a method for canceling pre-admission medications did not reduce the number of RXs at discharge. Further research is needed to evaluate the appropriateness of the large increase in RXs from admission to discharge for patients in acute hospital settings.

Some techniques for the analysis of work sampling data.

Work sampling is an observational technique that produces counts representing the number of times that an individual has been observed performing each of several tasks. These data are collected using either systematic or random times of observation, and typically exhibit correlation between repeated observations on the same individual, with the degree of correlation being a function of the amount of time elapsed between measurements. Using several recently developed statistical techniques, we illustrate how it is possible to carry out analyses of these nominal outcomes that account for the correlation between repeated outcomes. We use description of a work sampling study to motivate the techniques and we compare empirically results from analyses based on several different underlying assumptions.

Screening for social and environmental problems in a VA primary care setting.

Social workers are in an ideal position to identify and treat social and environmental problems early in the continuum of care. Information on these problems will facilitate informed decision making on the development and reallocation of resources to better meet patients needs. This study assessed the social and environmental problems of 132 patients seen in a primary care clinic at a university-affiliated Veterans Affairs (VA) medical center. The most prevalent social problems were financial difficulties, personal stress, family problems, legal concerns, and employment concerns. When asked, nearly one-third of all respondents requested social work services or information about services related to their problems. The findings suggest a clear need for social work interventions in VA primary care clinics that focus on both psychosocial problems.

Collaborative QI in community-based long term care.

BACKGROUND: In a statewide demonstration project funded by The Robert Wood Johnson Foundation, the state of Indiana, vendors, clients and Indiana University researchers began working together in 1992 to use quality improvement (QI) techniques to improve the delivery of community-based long term care services. QI STRATEGIES: These collaborators, working with state Area Agencies on Aging (AAAs) case managers, are implementing two strategies--Normative Treatment Planning (NTP), which standardizes the clinical assessment of client needs and the prescription of services by case managers, and the Client Feedback System (CFS), a systematic method for obtaining feedback from long term care clients on the quality of in-home services. CURRENT STATUS: This community-based long term care project has been implemented in AAAs throughout the state of Indiana. In January 1995 the state's 16 AAAs were randomly assigned to four experimental or control groups to assess the project's effectiveness. In the interim, clients are surveyed by telephone every six months to evaluate their satisfaction with services and clinical needs. LESSONS LEARNED: The experience suggests several lessons: (1) build on existing and successful activities; (2) involve a wide range of participants, not just innovators; (3) obtain buy-in from trade and professional associations that represent program participants; (4) turn national attention given to the program into an asset; (5) conduct separate data collection to evaluate an intervention's success; (6) visit the field often; (7) pay as much attention to program implementation as to development; and (8) provide ongoing, informal educational opportunities for the field. SUMMARY AND CONCLUSIONS: This project has resulted in significant movement toward a shared quality improvement vocabulary, information system, and a shared vision of high-quality home care.

Primary care physician productivity: the physician factor.

OBJECTIVES: To model physician productivity as a function of clinic (support system) characteristics and physician characteristics and to model the time a physician spends with the patient as a function of patient characteristics. DESIGN: Observational study. SETTING: A general medicine clinic of a university-affiliated Veterans Affairs medical center. PATIENTS: A cohort of 2,520 patients having 2,721 consecutive outpatient visits to 56 physicians. MAIN OUTCOME MEASURES: Physician productivity defined as patients seen/physician/hour and time (minutes) spent with the patient. RESULTS: Physicians saw a mean (+/- SD) of 1.62 +/- 0.68 patients/hour. Clinic characteristics explained 8.2% of the variability of session-specific physician productivity. Controlling for clinic characteristics, a factor representing the physician explained an additional 55.4%. A model for overall physician productivity, using physician characteristics, explained 84.9% of the variance, and time spent with the patient was an important predictor. Modeling physician time with patients, patient characteristics accounted for only 7% of the variability. Controlling for patient characteristics, the individual physician again provided the greatest explanatory power, an additional 22.8% of the variability. CONCLUSIONS: Physicians' practice patterns, rather than clinic or patient characteristics, may account for most of the variation in physician productivity. Given the magnitude of the influence of individual practice patterns, interventions to increase productivity need to consider methods to affect physician behavior.

A case manager intervention to reduce readmissions.

BACKGROUND: Acute hospitalizations represent substantial financial liability to closed health care systems. Among hospitalized patients, those with repeated admissions are high-cost users. Most managed care plans employ case management to control hospital use. This technique attempts to detect and fulfill unmet medical and social needs, intensify postdischarge care, identify and mobilize effective community services, and enhance primary care access. Despite the popularity of case management to control hospital use, few trials have examined its efficacy. METHODS: We conducted a randomized controlled trial of an intervention of case managers at a university-affiliated Veterans Affairs medical center. Six hundred sixty-eight patients aged 45 years or older who were discharged from the general medicine inpatient service, who had access to a telephone, and who received primary care at the hospital's clinics were randomized to the intervention (N = 333) and control (N = 335) groups. Within 24 hours of discharge, case managers mailed educational materials and access information to intervention patients, and within 5 days they called to review and resolve unmet needs, early warning signs, barriers to keeping appointments, and any readmissions. Case managers contacted intervention patients if they made no visits for 30 days. This resulted in a total of 6260 patient-case manager contacts. Control and intervention patients were followed up for 12 months. RESULTS: Intervention patients had more frequent visits per patient per month to the general medicine clinic (0.30 +/- 0.23 vs 0.26 +/- 0.22, P = .008), but we detected no significant differences between groups in nonelective readmissions, readmission days, or total readmissions. CONCLUSIONS: Frequent contacts for education, care, and accessibility by case managers using protocols were ineffective in reducing nonelective readmissions.

The effect of antibodies to subunit V of cytochrome oxidase on cyanide inhibition of electron transfer.

Binding of antibodies raised against subunit V of mammalian cytochrome oxidase to the intact membranous enzyme is redox-sensitive, suggesting the existence of 'open' and 'closed' protein conformers (Freedman, J.A., Cooper, C.E., Leece, B., Nicholls, P. and Chan, S.H.P. (1988) Biochem. Cell Biol. 66, 1210-1217). Similar open and closed states for the oxygen-reacting site have been proposed to explain cyanide binding kinetics (Jensen, P., Wilson, M.T., Aasa, R. and Malmström, B.G. (1984) Biochem. J. 224, 829-837). We therefore examined cyanide inhibition of oxidase activity polarographically and spectrophotometrically using soluble oxidase preincubated with and without anti-subunit V or non-immune rabbit gamma-globulin. The subunit-specific antibody decreased the cyanide 'on' rate and essentially eliminated the rapid phase of cyanide binding. We conclude that (i), bound antibody blocks HCN binding; (ii), antibody and HCN probably bind to the same conformation of the oxidase and (iii), the 'open'-'closed' conformation change that modulates binding of HCN may be similar to that which modulates antibody binding. The results are consistent with some reciprocating models of electron transfer and energy transduction by the oxidase (cf., Wikström, M.K.F., Krab, K. and Saraste, M. (1981) Cytochrome Oxidase: A Synthesis).

Replication of the multidimensionality of activities of daily living.

We attempted to replicate the three-dimensional factor structure of a previously proposed ADL scale and demonstrate an association between the advanced ADL dimension and cognitive function. Data used in these analyses were baseline assessments of health and functional status of hospitalized patients enrolled in a randomized controlled trial of case managers as a means of reducing health care utilization. We submitted 14 items from the OARS to a two-stage process of principal components factor analysis. Four significant dimensions emerged that were remarkably similar to the advanced, basic, and household ADL dimensions reported by Wolinsky and Johnson (1991). In this sample of hospitalized patients, however, incontinence emerged as a weak fourth dimension. Multiple regression of SPMSQ mental status examination scores on these ADL dimensions demonstrates the association between cognitive function and the advanced ADL dimension. These data confirm that the underlying structure of ADLs consists of at least three separate dimensions, one of which is aligned with cognitive capacity.

Research in social work practice: benefits of and obstacles to implementation in the Department of Veterans Affairs.

Although research is an important part of social work practice in health care, there is little systematic information that sheds light on research productivity, the benefits of conducting research, or the obstacles that must be overcome. This article represents the viewpoints of nearly all the directors of social services departments in the largest multihospital system in the United States, the Department of Veterans Affairs. The organizational characteristics of hospitals and the attitudes of the directors about research were important correlates of research productivity. Although lack of time, resources, and interest were cited as common obstacles, more than one-third of the departments were conducting or involved in at least one study. Information about the research efforts of other social services departments was considered an important resource, particularly for departments with no ongoing studies. The implications of these findings for social work research in health care are discussed.

Cytochrome c oxidase: structure, function, and membrane topology of the polypeptide subunits.

Mitochondrial cytochrome c oxidase and its bacterial homologs catalyze electron transfer and proton translocation reactions across membranes. The eukaryotic enzyme complex consists of a large number of polypeptide subunits. Three of the subunits (I, II, and III) are mitochondrially encoded while the remaining 6 (yeast) to 10 (bovine) are nuclear encoded. Antibody and chemical-labelling experiments suggest that subunits I-III and most (but not all) of the nuclear-encoded subunits span the inner mitochondrial membrane. Subunits I and II are the catalytic core of the enzyme. Subunit I contains haem a, haem a3 and CuB, while subunit II contains CuA and the cytochrome c binding site. Subunit III and most of the nuclear subunits are essential for the assembly of a functional catalytic enzyme. Some nuclear subunits are present as isozymes, although little functional difference has yet been detected between enzyme complexes composed of different isozymes. Therefore, any additional role attributed to the nuclear-encoded subunits beyond that of enzyme assembly must be tentative. We suggest that enough evidence exists to support the idea that modification of the larger nuclear subunits (IV, V, and possibly VI) can effect enzyme turnover in vitro. Whether this is a physiological control mechanism remains to be seen.

Two monoclonal antibody lines directed against subunit IV of cytochrome oxidase: a study of opposite effects.

Two monoclonal lines of antibodies were isolated with specificities against the amino half of Subunit IV of beef heart cytochrome oxidase. The lines had nonoverlapping epitopes. Both bound to the matrix face of membranous oxidase, neither bound to the cytoplasmic face. One line (QA4/C4) stimulated electron transfer in soluble or membranous oxidase, while the other (QA4) inhibited that activity by both oxidase preparations. These effects on electron transfer activity were not altered by the inclusion or omission of detergent. ATP depressed the binding of either antibody to either soluble or membranous oxidase. In the absence of ATP, QA4/C4 stimulated electron transfer only in the high affinity phase of cytochrome c oxidation (with decreased KM and increased Vmax), causing slight inhibition in the low affinity phase (with decreased KM). In the presence of ATP, QA4/C4 abolished the high affinity phase, but did not alter the ATP influence on the low affinity phase. In the absence of ATP, antibodies of line QA4 abolished the low affinity phase, leaving a high affinity phase similar to that induced by ATP. In the presence of ATP, QA4 abolished the high affinity phase, leaving a low affinity phase similar to that seen with ATP alone. This behavior is consistent with the dissection of two catalytic sites for cytochrome c and more than one ATP affector site.

Effects of subunit V antibodies on the topology of the subunit and the activity of beef heart cytochrome-c oxidase.

Redox-sensitive epitopes on subunit V of beef heart cytochrome-c oxidase were demonstrated previously using polyclonal subunit-specific antibodies raised in rabbits. The antibodies only slightly inhibited electron transfer, and the accessibility of their epitopes depended on the presence of a membrane and on the redox state of the oxidase. The present paper describes additional preparations of antibodies raised against subunit V. These antibodies have an even higher subunit specificity, they are more than three times as inhibitory against electron transfer, and their binding does not require a membrane. Moreover, the redox-sensitive nature of their binding to detergent-dispersed oxidase is sensitive to the method of its isolation. We discuss inferences that can be drawn from a detailed quantitative comparison of the interactions of the two antibody preparations with the antigen in different environments. The techniques used in the comparison can be used to examine other perturbants of the oxidase as to their effects on specific segments of the enzyme.