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.

Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

The effect of age on fitness among female firefighters.

BACKGROUND: The physical demands of firefighting require both cardiovascular and muscular fitness, which both decline with age. While much has been published on age-related changes among male firefighters (FFs), data on female FFs are lacking. AIMS: To describe cardiorespiratory fitness (CRF) and muscular fitness in a sample of female career FFs ranging in age from 25 to 60 years and determine whether ageing affects their achievement of the current recommended professional CRF standards of 12 metabolic equivalents (METs). METHODS: Data were collected on female FFs over an 11-year period. A cross-sectional analysis using one-way analysis of variance with Bonferroni post hoc comparisons was used to compare age groups. RESULTS: There were 96 study participants. Maximum METs was significantly higher (P < 0.01) in the 25- to 34-year age group (14.6 ± 2.1) compared with the 35-44 age group (12.9 ± 2.0 METs) and the 45-54 age group (12.2 ± 1.8 METs, P < 0.001). While the mean values of all measured age groups met or exceeded the 12-MET profession standard, as many as one-third of FFs <45 years of age and 43% of FFs >45 years of age fell below the benchmark of 12 METs. Muscular fitness as measured by maximum number of push-ups, sit-ups and back endurance was not significantly different between age groups. CONCLUSIONS: Fire departments should recognize and take steps to ensure all female FFs maintain CRF and muscular fitness throughout their careers.

A multistate framework for the analysis of subsequent injury in sport (M-FASIS).

Physical activity is beneficial for many aspects of health but is associated with a risk of injury. Studies that assess causal risk factors of injury and reinjury provide valuable information to help develop and improve injury prevention programs. However, the underlying assumptions of analytical approaches often used to estimate causal factors in injury and subsequent injury research are often violated. This means that ineffective or even harmful interventions could be proposed because the underlying analyses produced unreliable or invalid causal effect estimates. We describe an adapted version of the multistate framework [multistate framework for the analysis of subsequent injury in sport (M-FASIS)] that makes investigator choices more transparent with respect to outcome and healing time. In addition, M-FASIS incorporates all previous sport injury analytical frameworks and accounts for injuries or conditions that heal or do not heal to 100%, acute and overuse injuries, illnesses, and competing event outcomes.

The role of SHIP1 in macrophage programming and activation.

The SHIP1 (SH2-containing inositol-5'-phosphatase 1) acts as a negative regulator of proliferation, survival and end cell activation in haemopoietic cells. It does so, at least in part, by translocating to membranes after extracellular stimulation and hydrolysing the phosphoinositide 3-kinase-generated second messenger, PtdIns(3,4,5)P(3) to PtdIns(3,4)P(2). SHIP1(-/-) mice have, as a result, an increased number of neutrophils and monocyte/macrophages because their progenitors display enhanced survival and proliferation. These mice also suffer from osteoporosis because of an increased number of hyperactive osteoclasts and a significant neutrophil infiltration of the lungs. Interestingly, SHIP1(-/-) mice do not display endotoxin tolerance and we have found that lipopolysaccharide-induced endotoxin tolerance is contingent on up-regulating SHIP1, through the production of autocrine-acting transforming growth factor-beta, in bone-marrow-derived macrophages and mast cells. Intriguingly, unlike bone-marrow-derived macrophages, SHIP1(-/-) peritoneal and alveolar macrophages produce 10-fold less NO than wild-type macrophages because these in vivo-generated macrophages have very high arginase I levels and this enzyme competes with inducible nitric oxide synthase for the substrate L-arginine. It is probable that, in the face of chronically increased PtdIns(3,4,5)P(3) levels in their myeloid progenitors, SHIP1(-/-) mice display a skewed development away from M1 (killer) macrophages (which have high inducible nitric oxide synthase levels and produce NO to kill microorganisms and tumour cells), towards M2 (healing) macrophages (which have high arginase levels and produce ornithine to promote host-cell growth and collagen formation). This skewing probably occurs to avoid septic shock and suggests that the phosphoinositide 3-kinase pathway plays a critical role in programming macrophages.

The role of SHIP in cytokine-induced signaling.

The phosphatidylinositol (PI)-3 kinase (PI3K) pathway plays a central role in regulating many biological processes via the generation of the key second messenger PI-3,4,5-trisphosphate (PI-3,4,5-P3). This membrane-associated phospholipid, which is rapidly, albeit transiently, synthesized from PI-4,5-P2 by PI3K in response to a diverse array of extracellular stimuli, attracts pleckstrin homology (PH) domain-containing proteins to membranes to mediate its many effects. To ensure that the activation of this pathway is appropriately suppressed/terminated, the ubiquitously expressed tumor suppressor PTEN hydrolyzes PI-3,4,5-P3 back to PI-4,5-P2 while the 145-kDa hemopoietic-restricted SH2-containing inositol 5'- phosphatase, SHIP (also known as SHIP1), the 104-kDa stem cell-restricted SHIP (sSHIP) and the more widely expressed 150-kDa SHIP2 hydrolyze PI-3,4,5-P3 to PI-3,4-P2. In this review we will concentrate on the properties of the three SHIPs, with special emphasis being placed on the role that SHIP plays in cytokine-induced signaling.

Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages.

The haemopoietic-restricted Src homology 2-containing inositol 5'-phosphatase (SHIP) acts as a negative regulator of myeloid cell proliferation, survival and end-cell activation. It does so, at least in part, by hydrolysing the phosphoinositide 3-kinase (PI3K)-generated second messenger, PtdIns(3,4,5) P (3) (PI-3,4,5-P(3)) to PtdIns(3,4) P (2). As a result, the myeloid progenitors in SHIP-knockout mice display enhanced survival and proliferation and the mice have increased numbers of neutrophils and monocytes/macrophages. Interestingly, although SHIP is not required for mast cell or macrophage development, it restrains their differentiation since progenitors from SHIP(-/-) mice differentiate into mature mast cells and macrophages significantly faster than their wild-type counterparts. This could suggest that elevated PI-3,4,5-P(3) levels accelerate myeloid differentiation. In bone-marrow-derived mast cells, SHIP prevents degranulation by IgE alone, restrains IgE-antigen-induced degranulation and limits the production of inflammatory cytokines. On the other hand, in peritoneal macrophages, SHIP is a positive regulator of NO production, since SHIP(-/-) peritoneal macrophages produce 5-10-fold less NO than their wild-type counterparts, even though they show greater lipopolysaccharide/interferon-gamma-induced nuclear factor kappa B activation and more rapid inducible NO synthase (iNOS) generation. This is a result of 10-fold higher levels of arginase I in the SHIP(-/-) macrophages, which redirects the iNOS substrate, L-arginine, from NO to ornithine production. This suggests that the chronically elevated PI-3,4,5-P(3) levels in SHIP(-/-) mice may convert M1 (killing) macrophages, which produce NO to kill micro-organisms and tumour cells, into M2 (healing) macrophages, which produce ornithine to promote host cell growth and fibrosis.

High school cross country running injuries: a longitudinal study.

OBJECTIVE: To determine the incidence rate of injury among high school cross country runners over a 15-year period. DESIGN: Prospective-longitudinal. SETTING: Twenty-three high schools in western Washington State under the surveillance of the University of Washington Athletic Health Care System between 1979-1994. PARTICIPANTS: One hundred and ninety-nine cross country teams. MAIN OUTCOME MEASURE: Injuries resulting from running in a cross country practice or meet. RESULTS: There were 1,622 injuries for an overall injury rate of 13.1/1,000 athletic exposures (AEs), i.e., participation of a runner in a practice or meet. Girls had a significantly higher overall injury rate (16.7/1,000 AEs) than boys (10.9/1,000 AEs) (p < 0.0001). Girls also had significantly higher injury rates than boys for both initial (p < 0.0001) and subsequent injuries (p < 0.0001), especially those at the same body location (p = 0.0001). This difference in risk estimates was consistent over a 15-year period. Nearly three-fourths of the injuries resulted in < or =4 days of disability. Overall, higher rates of initial injuries were reported during practices (9.2/1,000 AEs) than in meets (7.8/1,000 AEs) (p = 0.04). Shin injuries had the highest overall rates of new injury (1.9/1,000 AEs) and reinjury at the same body location (53.9/1,000 AEs). Girls had significantly higher initial injury rates than boys for shin (p < 0.0001), hip. and foot injuries (p < 0.01), and higher reinjury rates for knee. calf, and foot injuries, respectively (p < 0.05). CONCLUSION: The results of this study suggest that girl cross country runners are at higher risk of injury and reinjury than boy cross country runners.

Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein.

The Grb2 and Shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. To assess the role of these molecules in mammary epithelial development and tumorigenesis, we have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial cell-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mammary tumors were rarely observed in these strains. To explore the potential role of these adapter proteins in mammary tumorigenesis, mice coexpressing either Shc or Grb2 and a mutant form of polyomavirus middle T (PyV mT) antigen in the mammary epithelium were generated. Coexpression of either Shc or Grb2 with the mutant PyV mT antigen resulted in a dramatic acceleration of mammary tumorigenesis compared to parental mutant PyV mT strain. The increased rate of tumor formation observed in these mice was correlated with activation of the epidermal growth factor receptor family and mitogen-activated protein kinase pathway. These observations suggest that elevated levels of the Grb2 or Shc adapter protein can accelerate mammary tumor progression by sensitizing the mammary epithelial cell to growth factor receptor signaling.

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.

Managed health care: a concept not understood by rural Oklahomans.

OBJECTIVE: The purpose of the study was to find out what people in rural Oklahoma know and understand about managed care. METHODS: A fourteen-statement survey instrument was developed. A panel of managed care professionals were asked to participate to provide a "standard" to compare the responses of the general public. The survey was administered to the general public in five rural communities and to recipients of the Oklahoma AHEC Newsletter. RESULTS: Overall, the panel tended to agree and created an industry profile useful in comparison to the responses of the general public: (1) 55-65% of the respondents answered I Don't Know or Neither Agree nor Disagree to statements using the term "managed care" and only 15-20% of the public respondents answered I Don't Know to statements not including the term, "managed care." (2) 25-30% of the general public answered in accordance with the managed care panel. (3) Over 50% of the public respondents Agreed that changes are necessary in the health sector. CONCLUSIONS: The results of this survey suggest that rural Oklahomans are uninformed about the concept of managed care and need to become better informed.

The risk of diabetes in a subsequent pregnancy associated with prior history of gestational diabetes or macrosomic infant.

Prior studies suggest that diagnosis of gestational diabetes is associated with increased risk for development of gestational diabetes in future pregnancies, and with subsequent onset of established diabetes. The magnitudes of these risks have not been measured. Using linked birth certificate data from Washington State it is possible to identify all women with two or more births occurring during 1984-91. All women with gestational diabetes (n=1375) or with established diabetes (n=220), during their pregnancy for the second or greater birth were identified, and a control group consisting of women whose second or greater birth was not complicated by either condition was randomly selected (n=6380). Data from the birth certificate, for the previous birth, were compared in order to estimate the risks of developing gestational or established diabetes in a subsequent pregnancy among women with prior gestational diabetes relative to women without gestational diabetes. The age-adjusted risk of developing gestational diabetes in the pregnancy for the subsequent birth associated with prior gestational diabetes was 23.2 (95% (confidence interval) CI = 17.2-31.2); the risk of having developed established diabetes by the time of the subsequent birth was 55.5 (95% CI = 34.4-89.4). Women who had a macrosomic infant (>4000 gm) in the prior birth were also at increased risk for developing gestational diabetes (odds ratio OR = 3.3, 95% CI = 2.9-3.8) or established diabetes (OR = 5.8, 95% CI = 4.0-8.5). When data were restricted to patients with only one prior birth, to patients with early prenatal care, to delivery at facilities with long-established protocols for diagnosing gestational diabetes, or to more recent years, the risk estimates remained similarly elevated. The 23-fold increased risk of gestational diabetes associated with having gestational diabetes indicated on the birth certificate of a woman's previous baby, although not unexpected, is still remarkable and reinforces the importance of careful monitoring of women with this history. Although changes in how screening is conducted may account for some of the elevation in risk, our results stayed consistently elevated even when restrictions were made within the data to control for this. The fact that there was a 56-fold increased risk of having developed established diabetes by the time of the subsequent birth on record, associated with prior gestational diabetes, and a 6-fold increased risk associated with a macrosomic infant, supports the idea that these may be early steps in the development of established diabetes, and identifies a group that may benefit from close monitoring and possible intervention.

Prevalence of corporal punishment among students in Washington State schools.

OBJECTIVES: To determine the prevalence of corporal punishment in Washington State and the factors associated with its use in Washington elementary and secondary schools. DESIGN: Cross-sectional mail survey performed during the summer of 1992. SETTING: All elementary and secondary schools in the state of Washington. RESULTS: One thousand eighteen schools (47%) responded to the survey, of which 80% were publicly funded and 63% were located in urban areas. The study sample closely resembled the profile of all schools in the state. Almost 11% of participating schools permitted corporal punishment at the time of the survey and 3.2% reported its actual use during the 1991-1992 school year, resulting in an estimated prevalence of 7.2 incidents per 1000 students per year. Sixteen percent of corporal punishment actions occurred in schools not permitting its use. Ninety percent of public schools relied on district policy regarding corporal punishment. School characteristics associated with the use of corporal punishment included rural location (crude odds ratio, 2.2; 95% confidence interval, 1.5 to 3.4), enrollment of less than 500 students (crude odds ratio, 1.7; 95% confidence interval, 1.1 to 2.7), and kindergarten to eighth-grade or kindergarten to 12th-grade enrollment (crude odds ratio, 2.5; 95% confidence interval, 1.6 to 3.9). CONCLUSIONS: The lack of a statewide ban on school corporal punishment at the time of this survey was associated with the continued use of corporal punishment against children in districts that continued to permit it. School policies against corporal punishment were associated with much lower prevalence. Continued efforts are needed to enact and enforce laws in the remaining states that have not yet banned corporal punishment.

Correlates of change in walking for exercise: an exploratory analysis.

This study was designed to identify correlates of change in walking for exercise. Respondents to a random sample mailed exercise survey were asked to complete a follow-up questionnaire 24 months after the first. Responses were obtained from 1,739 adults, reflecting an 86.6% return rate. Nonrespondents did not differ from respondents for baseline level of walking for exercise. Respondents overrepresented Caucasian and middle to high education (or income) adults. Residualized measures of change in walking for exercise served as the dependent variable, adjusted for baseline walking. Similarly, key independent variables, subject to change over time, were included after residualization. At both baseline and 24 months follow-up, adults walked for exercise an average of just under 1 hour per week, and 23.5% of the initially active adults ceased walking for exercise at 2 years. Multiple regression analyses explained more variance in walking for exercise among women than men. Change in dynamic variables such as friend's support and vigorous physical activity accounted for most of the explained variance. Results suggest that dynamic variables may need to be sustained to maintain walking for exercise. The limited explained variance suggests that more precise measures and additional determinants of walking for exercise need to be identified.

Reliability and validity of self-reported physical activity in Latinos.

The reliability and validity of six self-report physical activity measures were assessed in Latino adults. Validity was assessed by caltrac activity monitors, 'significant others', and construct analyses. Vigorous activity measures had higher reliability and validity (e.g. r > 0.40, P < 0.05) than moderate intensity measures. Though measures varied in their validity, the use of standard physical activity measures with Latinos was supported, and recommendations for specific measures were provided.