Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis.

Aurora B kinase is an integral regulator of cytokinesis, as it stabilizes the intercellular canal within the midbody to ensure proper chromosomal segregation during cell division. Here we identified that the ubiquitin E3 ligase complex SCF(FBXL2) mediates Aurora B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis. Three molecular acceptor sites (K¹°², K¹°³ and K²°7) within Aurora B protein were identified as important sites for its ubiquitination. A triple Lys mutant of Aurora B (K¹°²/¹°³/(²°7R)) exhibited optimal resistance to SCF(FBXL2)-directed polyubiquitination, and overexpression of this variant resulted in a significant delay in anaphase onset, resulting in apoptosis. A unique small molecule F-box/LRR-repeat protein 2 (FBXL2) activator, BC-1258, stabilized and increased levels of FBXL2 protein that promoted Aurora B degradation, resulting in tetraploidy, mitotic arrest and apoptosis of tumorigenic cells, and profoundly inhibiting tumor formation in athymic nude mice. These findings uncover a new proteolytic mechanism targeting a key regulator of cell replication that may serve as a basis for chemotherapeutic intervention in neoplasia.

F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest.

Dysregulated behavior of cell cycle proteins and their control by ubiquitin E3 ligases is an emerging theme in human lung cancer. Here, we identified and characterized the activity of a novel F-box protein, termed FBXL2, belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family. Ectopically expressed FBXL2 triggered G2/M-phase arrest, induced chromosomal anomalies and increased apoptosis of transformed lung epithelia by mediating polyubiquitination and degradation of the mitotic regulator, cyclin D3. Unlike other F-box proteins that target phosphodegrons within substrates, FBXL2 uniquely recognizes a canonical calmodulin (CaM)-binding motif within cyclin D3 to facilitate its polyubiquitination. CaM bound and protected cyclin D3 from FBXL2 by direct intermolecular competition with the F-box protein for access within this motif. The chemotherapeutic agent vinorelbine increased apoptosis of human lung carcinoma cells by inducing FBXL2 expression and cyclin D3 degradation, an effect accentuated by CaM knockdown. Depletion of endogenous FBXL2 stabilized cyclin D3 levels, accelerated cancer cell growth and increased cell viability after vinorelbine treatment. Last, ectopic expression of FBXL2 significantly inhibited the growth and migration of tumorogenic cells and tumor formation in athymic nude mice. These observations implicate SCF(FBXL2) as an indispensible regulator of mitosis that serves as a tumor suppressor.

The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine.

BACKGROUND: The administration of the diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine and measles, mumps, and rubella (MMR) vaccine has been associated with adverse neurologic events, including seizures. We studied the relation between these vaccinations and the risk of a first seizure, subsequent seizures, and neurodevelopmental disability in children. METHODS: This cohort study was conducted at four large health maintenance organizations and included reviews of the medical records of children with seizures. We calculated the relative risks of febrile and nonfebrile seizures among 679,942 children after 340,386 vaccinations with DTP vaccine, 137,457 vaccinations with MMR vaccine, or no recent vaccination. Children who had febrile seizures after vaccination were followed to identify the risk of subsequent seizures and other neurologic disabilities. RESULTS: Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination (adjusted relative risk, 5.70; 95 percent confidence interval, 1.98 to 16.42). Receipt of MMR vaccine was associated with an increased risk of febrile seizures 8 to 14 days after vaccination (relative risk, 2.83; 95 percent confidence interval, 1.44 to 5.55). Neither vaccination was associated with an increased risk of nonfebrile seizures. Analyses of automated data alone gave results similar to the analyses of the data from medical-record reviews. The number of febrile seizures attributable to the administration of DTP and MMR vaccines was estimated to be 6 to 9 and 25 to 34 per 100,000 children, respectively. As compared with other children with febrile seizures that were not associated with vaccination, the children who had febrile seizures after vaccination were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities. CONCLUSIONS: There are significantly elevated risks of febrile seizures on the day of receipt of DTP vaccine and 8 to 14 days after the receipt of MMR vaccine, but these risks do not appear to be associated with any long-term, adverse consequences.

The Houston Vision Assessment Test (HVAT): an assessment of validity. The Cataract Outcome Study Group.

PURPOSE: Cataract surgery is one of the most successful procedures in medicine, and outcome is typically measured by a single factor - improvement in visual acuity. Health-related functional outcome testing, which quantifies the patient's self-reported perception of impairment, can be integrated with objective clinical findings. Based on the patient's self-assessed lifestyle impairment, the physician and patient together can make an informed decision on the treatment that is most likely to benefit the patient. METHOD: A functional outcome test (the Houston Vision Assessment Test - HVAT, copyrighted 1990, 1992) was evaluated in a cataract population of 149 patients from seven study centers. Test results were correlated with objective ophthalmic endpoints. The HVAT divides an estimated total impairment into subcomponents of Visual Impairment (correctable by cataract surgery) and non-visual Physical Impairments (co-morbidities not affected by cataract surgery). RESULTS: In this prospective study, the average Visual Impairment score improved by 19 points (65%) following cataract extraction (the mean HVAT Visual Impairment score was 29 points before surgery and 10 points at 5 months post-surgery, a change of 65%). Physical Impairment remained unchanged by surgery. Visual acuity was a poor predictor of Visual Impairment. CONCLUSIONS: The HVAT has 11 simple questions. It may be self-administered and is available on the Internet: http://www.DHAC.com. The physician may err if his decision in favor of cataract surgery is based only on visual acuity. The HVAT has the potential to guide the decision-making process between patient and physician.

Balancing accountability and improvement: a case study from Massachusetts.

BACKGROUND: The Massachusetts Health Quality Partnership (MHQP), a coalition of health care providers and insurers, and business and government organizations, conducted a voluntary statewide survey about patients' experiences with inpatient care at Massachusetts hospitals in 1998, and made the results public. METHODS: MHQP contracted with The Picker Institute (Boston) to conduct the statewide survey about seven dimensions of care for adult medical, surgical, and maternity patients at 58 hospitals across Massachusetts. The communications strategy for public report release was designed to promote fair reporting by the news media and emphasize the improvement goals of performance measurement above evaluation. Along with critical agreements on report design, trial surveys, advertising, and commitments from coalition members about the use of survey results, these measures sought to drive out fear of participation and unfair evaluation. RESULTS: Statewide news media coverage reflected the project's communications goals. Editorial praise for the report was widespread. The project stimulated numerous hospital quality improvement efforts and focused hospital leaders on the need to improve patients' experiences with hospital care. All participating hospitals voluntarily renewed their enrollment for a third survey and public report cycle, and new hospitals joined the project. DISCUSSION: Voluntary public release of performance information by health care providers is possible when the risks, motivations, rewards, and penalties of measurement and public reporting are understood and carefully managed. The goals of public accountability reporting will be realized sooner when it is wedded to the spirit of continuous quality improvement and when providers are engaged as partners at every step of the measurement and reporting process.

Emerging and reemerging infectious diseases: a multidisciplinary perspective.

Predictions that infectious diseases would be eliminated as a major threat to human health have been shattered by emerging and reemerging infections, among them acquired immunodeficiency syndrome (AIDS), hemorrhagic fevers, marked increases in infections caused by antimicrobial-resistant bacteria, and the resurgence of tuberculosis and malaria. Understanding the dynamics of emerging and reemerging infections is critical to efforts to reduce the morbidity and mortality of such infections, to establish policy related to preparedness for infectious threats, and for decisions on where to use limited resources in the fight against infections. In order to offer a multidisciplinary perspective, 23 infectious disease specialists, epidemiologists, geneticists, microbiologists, and population biologists participated in an open forum at Emory University on emerging and reemerging infectious diseases. As summarized below, the group addressed questions about the definition, the identification, the factors responsible for, and multidisciplinary approaches to emerging and reemerging infections.

Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team.

OBJECTIVE: To fill the large "gaps and limitations" in current scientific knowledge of rare vaccine adverse events identified in recent reviews of the Institute of Medicine. METHODS: Computerized information on immunization, medical outcomes, and potential confounders on more than 500 000 children 0 to 6 years of age is linked annually at several health maintenance organizations to create a large cohort for multiple epidemiologic studies of vaccine safety. RESULTS: Analysis of 3 years of follow-up data shows that 549 488 doses of diphtheria-tetanus-pertussis (DTP) and 310 618 doses of measles-mumps-rubella (MMR) vaccines have been administered to children in the study cohort. Analyses for associations between vaccines and 34 medical outcomes are underway. Screening of automated data shows that seizures are associated with receipt of DTP on the same day (relative risk [RR], 2.1; 95% confidence interval [CI], 1.1 to 4.0) and 8 to 14 days after receipt of MMR (RR, 3.0; 95% CI, 2.1 to 4.2). The diversity of vaccination exposures in this large cohort permits us to show that an apparent association of seizures 8 to 14 days after Haemophilus influenzae type b vaccine (RR, 1.6; 95% CI, 1.2 to 2.1) was attributable to confounding by simultaneous MMR vaccination; the association disappears with appropriate adjustment (RR, 1.0; 95% CI, 0.7 to 1.4). CONCLUSION: Preliminary design, data collection, and analytic capability of the Vaccine Safety Datalink project has been validated by replication of previous known associations between seizures and DTP and MMR vaccines. The diversity in vaccine administration schedules permits potential disentangling of effects of simultaneous and combined vaccinations. The project provides a model of public health-managed care collaborations in addition to an excellent infrastructure for safety and other studies of vaccines.

Risk of hospitalization because of aseptic meningitis after measles-mumps-rubella vaccination in one- to two-year-old children: an analysis of the Vaccine Safety Datalink (VSD) Project.

OBJECTIVE: To assess the level of increased risk, if any, of hospitalizations for aseptic meningitis after Jeryl-Lynn mumps strain measles-mumps-rubella (MMR) vaccine in the Vaccine Safety Datalink population. STUDY DESIGN: A possible increased risk of aseptic meningitis 8 to 14 days after receipt of MMR was observed in a preliminary screening analysis of automated data from the Vaccine Safety Datalink (VSD) project Year 2 analysis. To further evaluate this association a retrospective 10-year matched case-control study was undertaken in the four health maintenance organizations (HMOs) in the VSD project. Cases ascertained from a broad scan of the automated data were validated against a standard case definition. Two controls matched on age, sex, HMO and HMO membership were assigned per case. RESULTS: The VSD project involves the cooperative collection of automated vaccination and medical outcome data from four large HMOs that currently have 500,000 children younger than 7 years of age under surveillance. Review of automated screening results from the first 2 years of data revealed a possible increased risk of aseptic meningitis 0 to 14 days after MMR with a relative risk of 3.61 (95% confidence interval, 1.0 to 13.1) although the total number of cases was small. Although the automated data had suggested a possible association of aseptic meningitis with MMR containing the Jeryl-Lynn strain of mumps, review of validated hospitalized cases during the observation period did not reveal evidence of an increased risk of aseptic meningitis after MMR containing the Jeryl-Lynn strain of mumps (odds ratio < 1.0 for all analyses). CONCLUSION: Although it is recognized that hospitalized cases represent a minority of the total cases of aseptic meningitis, it is reassuring that in this evaluation no increased risk of aseptic meningitis after MMR vaccine was found.

Human neurobehavioral research methods: impact of subject variables.

Behavioral tests are used in work site and community research to detect and characterize the effects of neurotoxic chemical exposures in human populations, but the influence of subject variables on test performance has not been well studied in normal adult populations. This research sought to evaluate the impact of two variables, education and cultural group, on 18 widely used tests of neurotoxic insult. Behavioral tests from the two consensus neurotoxicity test batteries (established by the World Health Organization and the U.S. Agency for Toxic Substances and Disease Registry) were administered to 715 people aged 26-45 with 0-18 years of education, drawn from European descent United States majority, American Indian, African American, and Latin American populations. Education, cultural group, age, and gender affected the outcome of behavioral tests as revealed by ANOVA, MANOVA, and multiple regression techniques. Education, followed by cultural group, accounted for the most variance in the tests studied. More importantly, years of education and cultural group had 13-25% shared variance on the cognitive tests and highly significant interactions derived from ANOVA tests. This suggests that these factors should be controlled in the design of a study rather than in the statistical analysis. Because these factors can mimic a neurotoxic insult, failure to adequately control and analyze them could lead to inaccurate conclusions about the association between poor performance and neurotoxic insult.

Ureteral obstruction in a patient with Burkitt's lymphoma and AIDS.

Burkitt's lymphoma presenting as an intrinsic ureteral mass is rare. We report on an immunocompromised patient with hydronephrosis secondary to direct involvement of the ureter by this non-Hodgkin's lymphoma. This case illustrates one of the manifestations of AIDS and the treatment of this manifestation. The relationship of AIDS and its sequela to the genitourinary system is discussed.

Extracorporeal membrane oxygenation in the neonate.

ECMO is a modified heart-lung bypass system for treatment of moribund neonates. The techniques are described. Our experience with 19 patients reveals a survival rate of 79 percent. In the future, with advances in technology, ECMO may become less invisible and extended to a larger population of newborns.

Assessing hospital nursing staff retention and turnover. A life table approach.

This research applied the life table technique to nursing personnel data in two types of hospitals to illustrate how administrators can examine patterns of continued employment. Although a large proportion of nurses were short-stay employees, the teaching hospital was found to have a higher retention rate than the community hospital corporation. The retention patterns are examined by personal and professional characteristics, as well as by reason for termination. Implications of our findings are discussed with respect to policy concerns related to hiring, retention, productivity, and staff development.

National trends in coverage and utilization of mental health, alcohol, and substance abuse services within managed health care systems.

This study reports the results of a 1986 national survey of mental health, alcohol, and substance abuse services within health maintenance organizations in the United States. Ninety-seven percent of responding health maintenance organizations (HMOs) offered mental health service coverage and two-thirds of responding HMOs offered alcohol and substance abuse service coverage. Annual mean mental health hospitalization was 36.90 days per 1,000 members and annual mean ambulatory mental health utilization was 0.29 physician encounters per member.

Medical technology assessment: adequate questions, appropriate methods, valuable answers.

Medical Technology Assessment begins with carefully posing the appropriate questions to be examined. Specification of the critical assessment provides the framework for the design to provide the answers. This paper addresses the Technology Assessment process as a sequence of the above steps. The practical requisites of the diversity of questions, the economic, and study design considerations generated are addressed in a systems analysis model of input-process-outcome. Applications and the relative merits of such design consideration are discussed and illustrated. The questions related to medical technologies may come from different groups of people directly or indirectly interested, and having active or passive relationship to a given technology. There are 4 basic issues from which the detailed questions derive. These are the issues of need, effectiveness, safety and cost. The timing of asking questions in the life-cycle of a technology and the adequacy of the answers determines the choice of methods, the extent of an evaluation and the quality of the responses. The reliability, external validity, generalizability, and the clarity of conclusions are the characteristics of a practical and valuable assessment.

The aims and methods of technology assessment.

Technology Assessment (T.A.) is viewed as a dynamic process. The paper emphasizes the basic aims of T.A. as an assessment and synthesis process. Specific areas of system analysis and the tracking of technology are presented with respect to T.A. priorities, stage of development, and the collateral use of the basic techniques of quantitative analysis in the context of community health. An information system, in conjunction with the role of new approaches to T.A. such as Meta-Analysis are discussed. Several examples from the literature are presented by way of illustration.

Effects of ultrasound on ultrastructure of human testes.

Studies to detect ultrastructural changes in testicular tissues after a fifteen-minute exposure to ultrasonic waves were done in 10 men undergoing bilateral orchiectomies for prostatic carcinoma. Examination of Sertoli cells and germ cells in different stages of differentiation failed to reveal significant differences between exposed and control testes.

Paratesticular desmoid tumor.

A primary intrascrotal mass clinically mimicking a testicular tumor was found to be a desmoid tumor originating from the spermatic cord. To our knowledge, this is the first reported case of a paratesticular desmoid tumor.