Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies.

Accurate DNA replication and repair is essential for proper development, growth and tumor-free survival in all multicellular organisms. A key requirement for the maintenance of genomic integrity is the availability of adequate and balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Notably, dNTP pool alterations lead to genomic instability and have been linked to multiple human diseases, including mitochondrial disorders, susceptibility to viral infection and cancer. In this review, we discuss how a key regulator of dNTP biosynthesis in mammals, the enzyme ribonucleotide reductase (RNR), impacts cancer susceptibility and serves as a target for anti-cancer therapies. Because RNR-regulated dNTP production can influence DNA replication fidelity while also supporting genome-protecting DNA repair, RNR has complex and stage-specific roles in carcinogenesis. Nevertheless, cancer cells are dependent on RNR for de novo dNTP biosynthesis. Therefore, elevated RNR expression is a characteristic of many cancers, and an array of mechanistically distinct RNR inhibitors serve as effective agents for cancer treatment. The dNTP metabolism machinery, including RNR, has been exploited for therapeutic benefit for decades and remains an important target for cancer drug development.

Inhibitory effects on mushroom tyrosinase by flavones from the stem barks of Morus lhou (S.) Koidz.

Five flavones displaying tyrosinase inhibitory activity were isolated from the stem barks of Morus lhou (S.) Koidz., a cultivated edible plant. The isolated compounds were identified as mormin (1), cyclomorusin (2), morusin (3), kuwanon C (4), and norartocarpetin (5). Mormin (1) was characterized as a new flavone possesing a 3-hydroxymethyl-2-butenyl at C-3. The inhibitory potencies of these flavonoids toward monophenolase activity of mushroom tyrosinase were investigated. The IC50 values of compounds 1-5 for monophenolase activity were determined to be 0.088, 0.092, 0.250, 0.135 mM, and 1.2 microM, respectively. Mormin (1), cyclomorusin (2), kuwanon C (4) and norartocarpetin (5) exhibited competitive inhibition characteristics. Interestingly norartocarpetin (5) showed a time-dependent inhibition against oxidation of L-tyrosine: it also operated under the enzyme isomerization model (k5 = 0.8424 min(-1), k6 = 0.0576 min(-1), K(app)(i) = 1.354 microM).

Quantitative trait loci for callus initiation and totipotency in maize (Zea mays L.).

Induction of embryogenic callus in culture is an important step in plant transformation procedures, but response is genotype specific and the genetics of the trait are not well understood. Quantitative trait loci (QTL) were mapped in a set of 126 recombinant inbred lines (RILs) of inbred H99 (high Type I callus response) by inbred Mo17 (low Type I callus response) that were evaluated over two years for Type I callus response. QTL were observed in a total of eleven bins on eight chromosomes, including eight QTL with main effects and three epistatic interactions. Many of the QTL were mapped to the same or bordering chromosomal bins as candidate genes for abscisic acid metabolism, indicating a possible role for the hormone in the induction of embryogenic callus, as has previously been indicated in microspore embryo induction. Further examinations of allelic variability for known candidate genes located near the observed QTL could be useful for expanding the understanding of the genetic basis of induction embryogenic callus. The QTL observed herein could also be used in a marker assisted selection (MAS) program to improve the response of agronomically useful inbreds, but only if the resources required for MAS are lower than those required for phenotypic selection.

Does the valve regulated release of urine from the bladder decrease encrustation and blockage of indwelling catheters by crystalline proteus mirabilis biofilms?

PURPOSE: We tested whether valve regulated, intermittent flow of urine from catheterized bladders decreases catheter encrustation. MATERIALS AND METHODS: Laboratory models of the catheterized bladder were infected with Proteus mirabilis. Urine was allowed to drain continuously through the catheters or regulated by valves to drain intermittently at predetermined intervals. The time that catheters required to become blocked was recorded and encrustation was visualized by scanning electron microscopy. RESULTS: When a manual valve was used to drain urine from the bladder at 2-hour intervals 4 times during the day, catheters required significantly longer to become blocked than those on continuous drainage (mean 62.6 vs 35.9 hours, p = 0.039). A similar 1.7-fold increase occurred when urine was drained at 4-hour intervals 3 times daily. Experiments with an automatic valve in which urine was released at 2 or 4-hour intervals through the day and night also showed a significant increase in mean time to blockage compared with continuous drainage (p = 0.001). Scanning electron microscopy confirmed that crystalline biofilm was less extensive on valve regulated catheters. CONCLUSIONS: Valve regulated, intermittent flow of urine through catheters increases the time that catheters require to become blocked with crystalline biofilm. The most beneficial effect was recorded when urine was released from the bladder at 4-hour intervals throughout the day and night by an automatic valve.

Clinical practice guidelines: when the tool becomes the rule.

This work provides a critical examination of the use of clinical practice guidelines to measure individual performance. The problems inherent in using a measure of central tendency derived from a distribution of individual performances are addressed, as is the translation of the collectively determined guidelines into a measurement instrument. It is suggested that every process on the distribution of processes used to determine the guideline must be considered equally legitimate representations of the process in question. It is further suggested that to accept as a standard of quality, a particular process simply because there is a minimum of variation between providers, is to ignore the importance of the linkage between process and outcome. The importance of an independent measure of quality based on outcomes is further emphasized by highlighting the tautological nature of analyses that include an input measure, such as nursing hours, in both the dependent variable and the list of independent variables. It is recommended that individual performance be evaluated within the tolerances of the distribution from which they were derived and not be held to some measure of central tendency of that distribution. The alternative is to use the measure of central tendency with plus or minus limits such as one, or more, standard deviations.

The relationship of impending death and age category to treatment intensity in the elderly.

The purpose of this study was to isolate and quantify the age-related treatment intensity differential in elderly clients (n = 278) with functional disability in one managed care setting. For those who died during the study, treatment intensity changes for the last year and month of life were examined. The subjects were categorized into four age groups: 75-79 years; 80-84 years; 85-89 years and 90 + years, and a treatment intensity index was calculated for each group using a ratio of actual to expected costs. Indices of overall costs and cost per day for all clients, and also indices for the year and month prior to death for the deceased clients were calculated. The results clearly show that for all clients, the oldest age group was treated less intensively than the youngest age group. For the deceased clients, the older age group was treated less intensively than the youngest age group in the last year and month of life but, for all age groups, the intensity of treatment increased during the last month of life.

What price an additional day of life? A cost-effectiveness study of case management.

OBJECTIVE: To examine the costs and benefits of a case-management program for an elderly, functionally impaired population in a managed care setting. STUDY DESIGN: A post hoc, cost-effectiveness study of case management. SUBJECTS AND METHODS: As part of a larger study, 317 elderly, functionally impaired clients were randomly assigned to a case-managed or regular-care group. During the 2-year study period, 34 clients in the case-managed and 43 clients in the regular-care group died. A post hoc analysis of the difference in average total cost per person, death rates, and average number of days of exposure per person were assessed to determine the cost per life saved and cost per additional day of life. RESULTS: Although the average costs for the case-managed group were greater than the costs for the regular-care group, clients in the case-managed group lived an average of 106 days longer. The cost per additional day of life was $40. The difference in death rates was so small that, by extrapolation, the cost per life saved was over $42 million. CONCLUSION: Although the case-management program was more costly when viewed from a purely fiscal perspective, it may very well be considered a success when its benefits are evaluated. The case-management program improved quality and was associated with prolonged life at a cost of $40 per day of additional life. Additional research involving other patient populations, study settings, and case-management models is warranted.

Defining the utility of clinically acceptable variations in evidence-based practice guidelines for evaluation of quality improvement activities.

This study examines the utility of systematically accounting for acceptable physician variations in guideline application. The results argue against assuming that even seemingly noncontentious guideline protocol offer a threshold of variation similar to conventional Continuous Quality Improvement (CQI) assessment standards. Findings also suggest that health service organizations can derive greater benefits from expending the resources necessary to standardize guidelines if compliance with both the medical review criteria, and the guidelines as originally constructed, is monitored as part of the evaluation activity.

The relationship between self-assessed health status, mortality, service use, and cost in a managed care setting.

This article explores the extent to which Self-Assessed Health Status (SAH) can contribute to the development of capitation and premium rates by predicting mortality, service use, and service cost in an elderly population in a managed care setting. Those who rated their health as poor were three times as likely to die, and service use and cost were positively associated with those who rated their health as poor. Performance indices based on the ratio of actual-to-expected cost within each SAH category suggest a more aggressive treatment of those who rated their health as poor.

Case management and the cost of care in the last month of life: evidence from one managed care setting.

Elderly, functionally disabled enrollees in a managed care organization were randomly assigned to case management or regular care. The service use and cost of care for the last month life for the case managed deceased is compared with that of the regular care group. The results suggest that contrary to general expectation, the managed care clients experienced greater use and costs of care in the last month of life.

Using collectively-derived standards to evaluate individual performance: a cautionary note on clinical practice guidelines.

The purpose of this work is to demonstrate the problem of evaluating an individual physician's performance relative to practice guidelines which have typically been derived from group consensus or some measure of central tendency. It is argued that when evaluated against a set of criteria derived at the macro-level, an individual physician's performance may justifiably vary due to the patient characteristics or the evolving process of care. It is also argued that it is not necessarily true that costs are reduced when practice variation is reduced. The results indicate that there are cost reduction in areas not targeted by the guidelines, suggesting a possible 'spillover effect' due to the increased vigilance in monitoring provider performance. The results also provide some evidence of increased costs following a reduction in variation. Caution should be exercised when evaluating individual physician performance relative to guidelines established at the aggregate level. Acceptable individual physician performance should be judged within the upper and lower boundaries of the implicit distribution of physicians' performances from which the established guidelines generated.

Case management of the elderly in a health maintenance organization: the implications for program administration under managed care.

Kaiser Permanente initiated a two-year demonstration ambulatory case management program in its Ohio region to evaluate five outcomes: perceived health status, functional status, and satisfaction with care, service use, and service costs. Expected results were not consistently obtained for the five outcome measures. Treatment group members did not, however, experience the functional status impairments or decline in health status perceptions reported by the control group during the study period. The unexpected finding that costs were not affected may be attributed to the type of case management intervention used in the demonstration program. This study is broadly applicable to managed care settings facing the challenge of developing programs to minimize the risk for bearing the costs of the Medicare beneficiaries' overall health when all services are not covered. Managed care administrators should be favorably disposed to implementing a case management model with the potential for affecting functional status, the most significant predictor of expensive continuing care for this cohort of Medicare beneficiaries, while working to develop more effective protocols and resource control strategies.

Utilization of hospital services by the elderly: geriatric crisis in one Canadian single payer system.

As the number and proportion of elderly persons in the Canadian population increase, utilization of health services by the elderly becomes a growing concern for health service insurers, financial managers and policy makers, as well as for care providers. The purpose of this paper is to present the results of a study to analyse the use of hospital services by the elderly in Alberta since the introduction of a universal single payer health care insurance system in 1970. The study period coincides with the implementation of publicly-financed comprehensive medical and hospital insurance programmes for all Alberta residents, making it possible to perform historical and population-based utilization analyses. Thus the data used for the study included all hospital discharge abstracts generated by all Alberta hospitals from 1971 to 1991. Trends in hospital service utilization by the elderly in terms of total number of separations, patient-days, and per case measures such as average length of stay as well as per capita utilization rates were reviewed to identify utilization patterns over the study period. Further, relative per capita utilization measures, in comparison with the base year (1971), age group 15-44, male, metropolitan residents, were derived and historical trends identified. A series of regression analyses were carried out to estimate the effects of age, sex and origin on utilization rates. In addition, for the period of 1984-1991, Diagnosis Related Groups (DRG) case weights were used to measure per capita and per case rates and to analyse historical relative utilization rates over the 8-year period. In general, there has been a significant decline in hospital utilization by Albertans under the publicly-financed single payer system, but utilization rates for elderly have remained high, resulting in high relative utilization rates in comparison with other age groups. It was also noted that per capita utilization rates for rural residents were substantially higher than urban residents. It appears that these higher utilization rates by the elderly and rural residents in combination with tight bed and financial control by the government have been causing significant bed shortage problems for non-elderly elective patients in urban areas.

The relationship between resource constraints and physician problem solving. Implications for improving the process of care.

OBJECTIVES: Research suggests that physicians will engage in more vigilant problem-solving under conditions of resource constraints than under conditions of resource slack. Increased vigilance related to physicians' clinical strategies enhances care by disposing physicians toward more optimal care choices. The authors examine whether pressures for clinical resource constraints encourage increased and sustained vigilance in problem-solving among cardiologists treating acute myocardial infarction. METHODS: The physician problem-solving process is reconstructed from the medical records of all eligible cases of acute myocardial infarction treated by the physician sample set over a 6-year period. The sample period encompasses phases of both resource slack and resource constraints. The Herfindahl index is used to measure the relative amount of vigilant problem-solving activity exhibited in each of five major tactical areas of the physician care strategies in each year of the study. RESULTS: The results support the hypothesis that resource constraints initially promote a shift to increased vigilance in physician problem-solving. Only one of the five major tactical areas, however, is characterized by sustained vigilance over time. The other areas are, instead, associated with a substantial reduction in vigilant activity after the initial peak period. CONCLUSIONS: The results suggest that resource constraints do set the stage for improved clinical decision-making. Sustained vigilance, however, appears to apply only to those portions of the care strategy for which the physician can draw a clear link between optimizing clinical activity and reducing resource consumption. For those portions of the care strategy for which the physician cannot establish a clear link, ongoing pressures to conserve resources results in reduced vigilance and a potential reduction in quality of clinical decision-making.

An atypical T-cell lymphosarcoma in a calf with bovine immunodeficiency-like virus infection.

An 11-month-old Holstein calf experimentally infected with bovine immunodeficiency-like virus (BIV) developed T-cell lymphosarcoma 5 months postinoculation, concurrent with progressive monocytosis. Tumors were found in the thymus, multiple lymph nodes, and brain. Tumor cells were CD2+, CD4-, CD8-T cells. Infectious BIV could be recovered from splenic tissue and blood mononuclear cells. Bovine leukemia virus was not present. Because this calf was part of an ongoing experiment on the pathogenesis of BIV infection, immune function data were also available both before and after lymphosarcoma developed. Neutrophil and monocyte function were normal, but lymphocyte blastogenesis was enhanced before the development of lymphosarcoma. Follicular hyperplasia in lymphoid tissues was also seen. This case raises the possibility that BIV infection may cause or be associated with some cases of atypical T-cell lymphosarcoma, without evidence of immune suppression at the time of tumor onset.

Quality of life improvement in patents with osteoarthritis: the potential for office-based assessment.

OBJECTIVE: This study presents the initial findings from our evaluation of the Nottingham Health Profile, a short and simple quality of life instrument, to determine its ease and robustness as a routine office tool for evaluating changes in the quality of life for arthritis patients undergoing joint replacement. METHODS: Thirty-five patients awaiting total joint replacement surgery were asked to complete the Nottingham Health Profile at their pre-operative clinic. A post-joint replacement evaluation profile, with a self-addressed stamped envelope, was mailed to each participant 3-4 months post-surgery. The profile was self-administered on both occasions. RESULT: The follow-up response rate was 69%. The t-test for the paired difference of related populations was used to determine pre-test and post-test changes. Significant improvement was found in the profile's 6 subscales, with energy, pain, and physical mobility significant at the 0.001 level, emotion and social isolation significant at the 0.005 level, and sleep significant at the 0.05 level. The before and after comparison of the profile's global self-assessment of health was not significant. CONCLUSION: Preliminary findings suggest that the Nottingham Health Profile is a useful office tool for the routine assessment of intervention-related changes in quality of life. The instrument was easy to self-administer and was associated with a mail return response rate consistent with other investigations using the profile. Even with a small sample size, the profile rendered data consistent with large-scale research evaluations of changes in quality of life for joint replacement patients. The finding that patients' global health status measures did not change despite improvements in quality of life subscales indicates that the instrument reliably netted out the quality of life benefits of the arthritis-related intervention from the patients' total burden of illness.

Variation in outpatient procedure rates in Canadian teaching hospitals.

OBJECTIVE: To determine the variation in the rate at which specific procedures are performed on an outpatient basis in Canadian teaching hospitals. DESIGN: An index of outpatient activity was developed using the ratio of expected-to-actual performance, with the expected performance representing empirical, exogenous criteria. SETTING: Canadian teaching hospitals. RESULTS: The index indicated whether the hospital, or group of hospitals, of interest is equally, more, or less active than the comparison group. The results show that Canadian teaching hospitals were 3% less active than Canadian nonteaching hospitals and Alberta teaching hospitals were 22% less active than all Canadian teaching hospitals. Individual teaching hospitals in Alberta were 21% more, 40% less, 9% less, 44% less, 8% less, 39% less, 20% less, and 2% less active than all other Alberta teaching hospitals. CONCLUSIONS: If variation in the use of less costly treatment modalities represents variation in quality as in Donabedian's unifying model, the results show considerable variation in quality across the generally accepted leaders in the medical care field. By comparing teaching hospitals with other teaching hospitals the difference in the patient severity level is minimized. The decision regarding the delivery modality represents only one decision in the complex decision matrix faced by physicians in the treatment episode. Given the considerable variation demonstrated in this study, the task of developing protocol, standards, or guidelines in order to reduce variation over the total treatment episode will be enormous.

Profitable and unprofitable DRGs: the implications for access.

Given a choice, hospitals would prefer to admit a patient with the potential to contribute to an accounting profit and prefer not to admit a patient with the potential to contribute to an accounting loss. It is suggested that if all hospitals found the same DRGs to be unprofitable, access to inpatient care would be denied those patient types. A set of 509 hospitals was stratified according to bedsize, Medicare load, type of control, teaching status and geographic location. The 10 most and 10 least profitable DRGs were identified for each hospital category and a Spearman's rank order correlation was used to determine the similarity or dissimilarity across hospital category. The results indicate that the more alike hospitals are in terms of bedsize, Medicare load and teaching status, the more alike are the DRGs that are determined to be unprofitable (or profitable). Conversely, the less alike they were on these characteristics, the less alike were the unprofitable (or profitable) DRGs. There were no differences evident when the hospitals were classified according to type of control or geographic location. These results are generally encouraging in terms of potential access but disturbing in terms of possible further financial threat to rural hospitals.