Racial and ethnic disparities in utilization of total knee arthroplasty among older women.

OBJECTIVE: To evaluate racial and ethnic disparities in utilization of total knee arthroplasty (TKA) in relation to demographic, health, and socioeconomic status variables. DESIGN: Prospective study of 102,767 Women's Health Initiative postmenopausal women initially aged 50-79, examining utilization rates of primary TKA between non-Hispanic Black/African American, non-Hispanic White, and Hispanic/Latina women (hereafter referred to as Black, White, and Hispanic). A total of 8,942 Black, 3,405 Hispanic, and 90,420 White women with linked Medicare claims data were followed until time of TKA, death, or transition from fee-for-service coverage. Absolute disparities were determined using utilization rates by racial/ethnic group and relative disparities quantified using multivariable hazards models in adjusting for age, arthritis, joint pain, mobility disability, body mass index, number of comorbidities, income, education, neighborhood socioeconomic status (SES), and geographic region. RESULTS: TKA utilization was higher among White women (10.7/1,000 person-years) compared to Black (8.5/1,000 person-years) and Hispanic women (7.6/1,000 person-years). Among women with health indicators for TKA including diagnosis of arthritis, moderate to severe joint pain, and mobility disability, Black and Hispanic women were significantly less likely to undergo TKA after adjusting for age [Black: HR (95% confidence interval) = 0.70 (0.63-0.79); Hispanic: HR = 0.58 (0.44-0.77)]. Adjustment for SES modestly attenuated the measured disparity, but significant differences remained [Black: HR = 0.75 (0.67-0.89); Hispanic: HR = 0.65 (0.47-0.89)]. CONCLUSIONS: Compared to White women, Black and Hispanic women were significantly less likely to undergo TKA after considering need and appropriateness for TKA and SES. Further investigation into personal-level and provider-level factors that may explain these disparities is warranted.

Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines.

OBJECTIVE: Lapatinib (Tykerb, GW572016), a potent inhibitor of the catalytic activities of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (ErbB2), inhibits population growth of selected EGFR and HER2 overexpressing cell lines. Previous studies with a small number of cell lines suggest a correlation between overexpression of EGFR and/or HER2 and sensitivity to growth inhibition by lapatinib; however, the precise determinants of lapatinib selectivity for tumour and/or other cells remain unclear. MATERIALS AND METHODS: To clarify the determinants of its selectivity in cultured cells, lapatinib-induced cell population growth inhibition and relative EGFR and HER2 protein expression were quantified in 61 different human tumour cell lines from 12 tumour types, two oncogene transformed human cell lines and two normal human cell cultures. Using statistical tools to analyse the data, a model describing the relationship between lapatinib IC(50) (the response variable) and EGFR and HER2 expression and tissue type (explanatory variables) was derived. CONCLUSION: The results suggest that simultaneous consideration of EGFR and HER2 expression, as well as tissue type yields the best determinant of lapatinib selectivity in cultured cells.

Prevalence, expenditures, utilization, and payment for persons with MS in insured populations.

OBJECTIVE: To determine the prevalence, expenditures, and utilization of enrollees with MS relative to all enrollees in privately insured, Medicare, and Medicaid populations. METHODS: The authors used insurer administrative billing data to identify persons with MS, their insured medical expenditures and utilization, and benchmark general insured population expenditures and utilization. Three samples of insurer billing data were analyzed: nationally representative samples for the privately insured (1994 through 1995) and Medicare (1996 though 1997) populations, and Medicaid data for disabled (1991 through 1996) populations from six states. RESULTS: Using 2 years of diagnoses on claims, the prevalence of MS in the privately insured population was 24 per 10,000, 36 per 10,000 in the Medicare population, and 71 per 10,000 in the Medicaid disabled population. Annual insured expenditures were $7,677 per privately insured enrollee with MS vs $2,394 for all privately insured enrollees, $13,048 per Medicare beneficiary with MS compared with $6,006 for all Medicare beneficiaries, and $7,352 per Medicaid disabled recipient with MS vs $4,088 per disabled recipient without MS. Home health expenditures were very high for Medicare beneficiaries with MS and nursing facility expenditures were very high for Medicaid disabled recipients with MS. A small proportion of enrollees with MS accounted for most expenditures. CONCLUSIONS: Insured enrollees with MS are two to three times more expensive than average insured enrollees. If the premiums that employers or governments pay health insurers and the capitation amounts that insurers pay health care providers do not account for these higher costs, a disincentive is created for the enrollment and care of persons with MS.

The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.

The Medicaid Rx model: pharmacy-based risk adjustment for public programs.

BACKGROUND: Risk adjustment models typically use diagnoses from claims or encounter records to assess illness severity. However, concerns about the availability and reliability of diagnostic data raise the potential for alternative methods of risk adjustment. Here, we explore the use of pharmacy data as an alternative or complement to diagnostic data in risk adjustment. OBJECTIVES: To develop and test a pharmacy-based risk adjustment model for SSI and TANF Medicaid populations. RESEARCH DESIGN: Pharmacological review combined with empirical evaluation. We developed the Medicaid Rx model, a system that classifies a subset of the National Drug Codes into categories that can be used for risk-assessment and risk-adjusted payment. SUBJECTS: Subjects consisted of 362,370 persons with disability and 1.5 million AFDC and TANF beneficiaries in California, Colorado, Georgia, and Tennessee during 1990-1999. MEASURES: We compare pharmacy and diagnostic classification for three chronic diseases. We also compare R2 statistics and use simulated health plans to evaluate the performance of alternative models. RESULTS: Pharmacy and diagnostic classification vary in their ability to identify specific chronic disease. Using simulated plans, diagnostic models are better at predicting expenditures than are pharmacy-based models for disabled Medicaid beneficiaries, although the models perform similarly for TANF Medicaid beneficiaries. Models that combine diagnostic and pharmacy data have superior overall performance. CONCLUSIONS: The performance of risk adjustment models using a combination of pharmacy and diagnostic data are superior to that of models using either data source alone, particularly among TANF beneficiaries. Concerns regarding variations in prescribing patterns and the incentives that may follow from linking payment to pharmacy use warrant further research.

Expression and purification of active recombinant ATM protein from transiently transfected mammalian cells.

The gene mutated in the human disease ataxia telangiectasia (AT), termed ATM, encodes a large protein kinase involved in DNA repair and cell cycle control. Biochemical characterization of ATM function has been somewhat difficult because of its large size (approximately 370 kDa) and relatively low level of expression in several systems. The majority of studies have used immunoprecipitated ATM or purified ATM obtained through relatively complex procedures. Here, we describe an efficient method for the expression and purification of FLAG-epitope-tagged recombinant human ATM protein (F-ATM). This method utilizes the expression of F-ATM in transiently transfected 293T cells followed by anti-FLAG-agarose affinity chromatography. The transfection procedure has been optimized for large (225-cm(2)) culture flasks and F-ATM can be purified to near homogeneity as judged by SDS-PAGE. This procedure yields approximately 1 microg of catalytically active F-ATM protein/225-cm(2) flask that can be used for biochemical studies.

The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo.

The epidermal growth factor receptor (EGFR) and ErbB-2 transmembrane tyrosine kinases are currently being targeted by various mechanisms in the treatment of cancer. GW2016 is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively. This report describes the efficacy in cell growth assays of GW2016 on human tumor cell lines overexpressing either EGFR or ErbB-2: HN5 (head and neck), A-431 (vulva), BT474 (breast), CaLu-3 (lung), and N87 (gastric). Normal human foreskin fibroblasts, nontumorigenic epithelial cells (HB4a), and nonoverexpressing tumor cells (MCF-7 and T47D) were tested as negative controls. After 3 days of compound exposure, average IC50 values for growth inhibition in the EGFR- and ErbB-2-overexpressing tumor cell lines were < 0.16 microM. The average selectivity for the tumor cells versus the human foreskin fibroblast cell line was 100-fold. Inhibition of EGFR and ErbB-2 receptor autophosphorylation and phosphorylation of the downstream modulator, AKT, was verified by Western blot analysis in the BT474 and HN5 cell lines. As a measure of cytotoxicity versus growth arrest, the HN5 and BT474 cells were assessed in an outgrowth assay after a transient exposure to GW2016. The cells were treated for 3 days in five concentrations of GW2016, and cell growth was monitored for an additional 12 days after removal of the compound. In each of these tumor cell lines, concentrations of GW2016 were reached where outgrowth did not occur. Furthermore, growth arrest and cell death were observed in parallel experiments, as determined by bromodeoxyuridine incorporation and propidium iodide staining. GW2016 treatment inhibited tumor xenograft growth of the HN5 and BT474 cells in a dose-responsive manner at 30 and 100 mg/kg orally, twice daily, with complete inhibition of tumor growth at the higher dose. Together, these results indicate that GW2016 achieves excellent potency on tumor cells with selectivity for tumor versus normal cells and suggest that GW2016 has value as a therapy for patients with tumors overexpressing either EGFR or ErbB-2.

Monoclonal antibodies generated against recombinant ATM support kinase activity.

We report on the rapid generation of two monoclonal antibodies, ATM A16.35 and ATM D16.11, that bind to the kinase domain of mutated ataxia telangiectasia (ATM). These antibodies were generated against E. coli-expressed recombinant protein using the RIMMS strategy. We show that ATM A16.35 binds ATM by Western blot analysis, and ATM D16.11 forms immune complexes with native ATM in immunoprecipitations without neutralizing kinase activity.

The Ras/p120 GTPase-activating protein (GAP) interaction is regulated by the p120 GAP pleckstrin homology domain.

Pleckstrin homology domains are structurally conserved functional domains that can undergo both protein/protein and protein/lipid interactions. Pleckstrin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including many that interact with Ras superfamily members, such as p120 GAP. The pleckstrin homology domain of p120 GAP is located in the NH(2)-terminal, noncatalytic region of p120 GAP. Overexpression of the noncatalytic domains of p120 GAP may modulate Ras signal transduction pathways. Here, we demonstrate that expression of the isolated pleckstrin homology domain of p120 GAP specifically inhibits Ras-mediated signaling and transformation but not normal cellular growth. Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interaction. Thus, we suggest that the pleckstrin homology domain of p120 GAP may specifically regulate the interaction of Ras with p120 GAP via competitive intra-molecular binding.

Impact of ethics consultations in the intensive care setting: a randomized, controlled trial.

OBJECTIVE: To determine the following: a) whether ethics consultations in the intensive care setting reduce nonbeneficial treatments, defined as days in the intensive care unit (ICU) and treatments delivered to those patients who ultimately fail to survive to hospital discharge; and b) whether physicians, nurses, social workers, and patients/families agree that ethics consultations in the ICU are beneficial in addressing treatment conflicts. DESIGN: Prospective, randomized, controlled trial of ethics consultations. SETTING: Medical and pediatric ICUs in a university medical center. PATIENTS: Seventy-four patients in whom value-based treatment conflicts arose during the course of treatment. INTERVENTIONS: The patients were randomly assigned to an intervention (ethics consultation offered) or nonintervention (ethics consultation not offered) arm of the trial. MEASUREMENTS: Medical data and ICU hospital days were compared between the intervention and control groups before and after the randomization. Likert scale and commentary responses were recorded to structured and open-ended interviews with the responsible physicians, nurses, social workers, and families of patients assigned to the intervention arm within 1 month after the patient's death or hospital discharge. Interviewees were asked whether ethics consultations helped with the following: a) to identify ethical issues; b) to analyze ethical issues; c) to resolve ethical issues; d) to educate about ethical issues; and e) to present personal views. MAIN RESULTS: There were no differences in overall mortality between the control patients and patients receiving ethics consultations. However, ethics consultations were associated with reductions in ICU hospital days and life-sustaining treatments in those patients who ultimately failed to survive to discharge. Also, ethics consultations were regarded favorably by most participants. CONCLUSIONS: Ethics consultations seem to be useful in resolving conflicts that may be inappropriately prolonging futile or unwanted treatments and are perceived to be beneficial.

Improving health-based payment for Medicaid beneficiaries: CDPS.

This article describes the Chronic Illness and Disability Payment System (CDPS), a diagnostic classification system that Medicaid programs can use to make health-based capitated payments for TANF and disabled Medicaid beneficiaries. The authors describe the diversity of diagnoses and different burdens of illness among disabled and AFDC Medicaid beneficiaries. Claims from seven States are analyzed, and payment weights are provided that States can use when adjusting HMO payments. The authors also compare the taxonomy and statistical performance of CDPS to other leading diagnostic classification systems and find that the new model performs better in a number of respects.

A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis.

We have tested a new ligand for peroxisome proliferator-activated receptor-gamma, GW7845, as an inhibitor of experimental mammary carcinogenesis, using the classic rat model with nitrosomethylurea as carcinogen. Rats were first treated with a single dose of nitrosomethylurea (50 mg/kg body weight, i.p.). Starting 1 week later, they were fed GW7845, at either 60 or 30 mg/kg of diet, for 2 months. This agent significantly reduced tumor incidence, tumor number, and tumor weight at both doses. This is the first report of the use of a ligand for peroxisome proliferator-activated receptor-gamma to prevent experimental breast cancer.

Intimate partner violence against women: do victims cost health plans more?

BACKGROUND: Previous studies of intimate partner violence have not compared the health care costs of female victims with those of a general female population. METHODS: Our study is an analysis of the computerized cost data for 126 identified victims of intimate partner violence in a large health plan in Minneapolis and St. Paul, Minnesota, in 1994. Data were compared with a random sample of 1007 general female enrollees (aged 18 to 64 years) who used health care services in the same year. RESULTS: We found that an annual difference of $1775 more was spent for victims of intimate partner violence than on a random sample of general female enrollees. Regression analyses found that victims of intimate partner violence were significantly younger and had more hospitalizations, general clinic use, mental health services use, and out-of-plan referrals. Use of emergency room services was the same across groups. CONCLUSIONS: Women who were victims of intimate partner violence cost this health plan approximately 92% more than a random sample of general female enrollees. Contrary to the findings of other studies, use of emergency room services was not a driving factor in the higher costs. Findings of significantly higher mental health service use are supported by other studies.

Explaining the decline in health insurance coverage, 1979-1995.

The decline in health insurance coverage among workers from 1979 to 1995 can be accounted for almost entirely by the fact that per capita health care spending rose much more rapidly than personal income during this time period. We simulate health insurance coverage levels for 1996-2005 under alternative assumptions concerning the rate of growth of spending. We conclude that reduction in spending growth creates measurable increases in health insurance coverage for low-income workers and that the rapid increase in health care spending over the past fifteen years has created a large pool of low-income workers for whom health insurance is unaffordable.

Defective potassium currents in ataxia telangiectasia fibroblasts.

Similarities exist between the progressive cerebellar ataxia in ataxia telangiectasia (AT) patients and a number of neurodegenerative diseases in both mouse and man involving specific mutations in ion channels and/or ion channel activity. These relationships led us to investigate the possibility of defective ion channel activity in AT cells. We examined changes in the membrane potential of AT fibroblasts in response to extracellular cation addition and found that the ability of AT fibroblasts to depolarize in response to increasing concentrations of extracellular K+ is significantly reduced when compared with control fibroblasts. Electrophysiological measurements performed with a number of AT cell lines, as well as two matched sets of primary AT fibroblast cultures, reveal that outward rectifier K+ currents are largely absent in AT fibroblasts in comparison with control cells. These K+ current defects can be corrected in AT fibroblasts transfected with the full-length ATM cDNA. These data implicate, for the first time, a role for ATM in the regulation of K+ channel activity and membrane potential.

Potent dipeptide inhibitors of the pp60c-src SH2 domain.

The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.

The formation of a covalent complex between a dipeptide ligand and the src SH2 domain.

The X-ray crystal structure of the src SH2 domain revealed the presence of a thiol residue (Cys 188) located proximal to the phosphotyrosine portion of a dipeptide ligand. An aldehyde bearing ligand (1) was designed to position an electrophilic carbonyl group in the vicinity of the thiol. X-ray crystallographic and NMR examination of the complex formed between (1) and the src SH2 domain revealed a hemithioacetal formed by addition of the thiol to the aldehyde group with an additional stabilizing hydrogen bond between the acetal hydroxyl and a backbone carbonyl.