Publications

BACKGROUND

Although inflammation is a core element of atherogenesis and plasma levels of fibrinogen (FGB), homocysteine, and intercellular adhesion molecule-1 (ICAM-1) differ by race/ethnicity, little is known about the role of genetic polymorphisms in the FGB, methylenetetrahydrofolate reductase (MTHFR), and ICAM-1 genes in determining plasma levels of these biomarkers. We examined the relationship between specific polymorphisms in the FGB, homocysteine, and ICAM-1 genes and their respective inflammatory biomarker concentrations at baseline in women from different race/ethnic groups.

METHODS

We genotyped specific polymorphisms in FGB (-455G>A/rs1800790), MTHFR (677C>T/rs1801133), and ICAM-1 (Lys56Met/rs5491 and Gly241Arg/rs1799969) at baseline and evaluated their relationship with respective inflammatory biomarker levels in 25,565 white, 476 African-American (black), 277 Hispanic, and 370 Asian women participating in the Women's Genome Health Study.

RESULTS

Overall, the minor allele frequencies for -455G>A were similar among white, Hispanic, and Asian women (17.2%-21.9%) but significantly lower in black women (6.6%, P < .001). The minor allele was associated with elevated FGB levels only in whites and Asians. After adjustment for age, body mass index, smoking, postmenopausal status, diabetes, hormone replacement therapy use, hypertension, and education, black women had the highest FGB levels compared to other race/ethnic groups. The minor allele frequency of the MTHFR 677C>T polymorphism was lowest in blacks (blacks 12.1%, whites 33.1%, Hispanics 39.0%, Asians 24.0%), and the T allele was only significantly associated with homocysteine levels in white women. Among whites, Hispanics, and Asians, the Lys56Met polymorphism was rare compared to the frequency in blacks (P < .001). Neither the Lys56Met nor Gly241Arg polymorphisms were common in Asians. Nonetheless, both polymorphisms were generally associated with lower ICAM-1 levels; the lowest levels were observed in black women.

CONCLUSION

We found significant associations between certain candidate genetic polymorphisms and baseline plasma levels of FGB, homocysteine, and ICAM-1 in women from various race/ethnic groups. The present investigation is hypothesis generating and suggests genetic determination of differential concentrations of these atherosclerosis-related inflammatory biomarkers differ among various race/ethnic groups.

Cross-sectional analyses were conducted to evaluate the effects of exposure to highway traffic on pulmonary function in Fresno, California. Traffic and spirometry data were available for 214 children (enrollment ages six to 11 years). Multiple linear regression was used to evaluate the relations between pulmonary function and traffic parameters. Heavy-duty vehicle count was used as a surrogate measure for diesel-related exposures. Pulmonary function was non-significantly associated with longer distance-to-road and non-significantly associated with higher traffic intensity. Evaluation of effect modification by FEF(25-75)/FVC (a measure of intrinsic airway size) showed that all pulmonary function measures of flow were significantly inversely related to a traffic metric that incorporates traffic intensity and roadway proximity. The results indicate that residence proximity to highway traffic is associated with lower pulmonary function among children with asthma, and smaller airway size is an important modifier of the effect of traffic exposure on pulmonary function and a marker of increased susceptibility.

Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of Ag receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep orthologue Lyp, confers susceptibility to multiple human autoimmune diseases in the context of complex genetic backgrounds. However, the functional significance of the R620W risk allele is not clear. We report that misexpression of wild-type or R620W Pep/Lyp in Jurkat cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph. It has been shown previously that although Pep-deficient mice on the B6 background have hyperresponsive memory T cells, autoimmunity does not develop. Mice containing a point mutation in the CD45 juxtamembrane wedge domain (E613R) develop a B cell-driven, lupus-like disease on the mixed 129/B6 background, but not on the B6 background. We studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the nonautoimmune B6 background to understand how complex susceptibility loci might interact in autoimmunity. In this study we report that double mutant mice develop a lupus-like disease as well as lymphadenopathy, polyclonal lymphocyte activation, and accelerated memory T cell formation. Following Ag receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyperresponsive CD45 E613R B cells, whereas peripheral T cells respond like Pep(-/-) T cells. These studies suggest that Pep(-/-) T cells in the context of a susceptible microenvironment can drive hyperresponsive CD45 E613R B cells to break tolerance.

Professional medical associations (PMAs) play an essential role in defining and advancing health care standards. Their conferences, continuing medical education courses, practice guidelines, definitions of ethical norms, and public advocacy positions carry great weight with physicians and the public. Because many PMAs receive extensive funding from pharmaceutical and device companies, it is crucial that their guidelines manage both real and perceived conflict of interests. Any threat to the integrity of PMAs must be thoroughly and effectively resolved. Current PMA policies, however, are not uniform and often lack stringency. To address this situation, the authors first identified and analyzed conflicts of interest that may affect the activities, leadership, and members of PMAs. The authors then went on to formulate guidelines, both short-term and long-term, to prevent the appearance or reality of undue industry influence. The recommendations are rigorous and would require many PMAs to transform their mode of operation and perhaps, to forgo valuable activities. To maintain integrity, sacrifice may be required. Nevertheless, these changes are in the best interest of the PMAs, the profession, their members, and the larger society.

Histone deacetylases (HDAC) may have a prominent role in the development of cancer and the response to anticancer therapy. However, the therapeutic relevance and tissue specificity of individual HDAC enzymes remain largely unknown. HDAC inhibitors may function as sensitizing agents to chemotherapies that target DNA through their effects on chromatin structure and plasticity. Here, we report a new role for HDAC2 as a regulator of chromatin compaction status and the mediator of HDAC inhibitor-induced sensitization to chemotherapy. The selective depletion of HDAC2 by small interfering RNA led to reduced expression of heterochromatin maintenance proteins and morphologic changes indicative of chromatin decondensation. Furthermore, depletion of HDAC2 but not HDAC1 or HDAC6 was sufficient to sensitize breast cancer cells to topoisomerase inhibitor-induced apoptosis. The levels of HDAC2 expression appear to correlate with the degree of HDAC inhibitor-induced histone acetylation in a surrogate tissue in patients. These data suggest that HDAC2 may be a relevant pharmacologic and biological target for combination therapy involving drugs that target DNA.

CONTEXT

The Leapfrog Hospital Survey allows hospitals to self-report the steps they have taken toward implementing the Safe Practices for Better Healthcare endorsed by the National Quality Forum. The Leapfrog Group currently ranks hospital performance on the safe practices initiative by quartiles and presents this information to the public on its Web site. It is unknown how well a hospital's resulting Safe Practices Score (SPS) correlates with outcomes such as inpatient mortality.

OBJECTIVE

To determine the relationship between hospitals' SPSs and risk-adjusted inpatient mortality rates.

DESIGN, SETTING, AND PARTICIPANTS

Observational analysis of discharge data for all urban US hospitals completing the 2006 safe practices initiative and identifiable in the Nationwide Inpatient Sample. Leapfrog provided an SPS for each hospital as well as 3 alternative scores based on shorter versions of the original survey. Hierarchical logistic regression was used to determine the relationship between quartiles of SPS and risk-adjusted inpatient mortality, after adjusting for hospital discharge volume and teaching status. Subgroup analyses were performed using data from patients older than 65 years and patients with 5% or greater expected mortality risk.

MAIN OUTCOME MEASURES

Inpatient risk-adjusted mortality by quartiles of survey score.

RESULTS

Of 1075 hospitals completing the 2006 Safe Practices Survey, 155 (14%) were identifiable in the National Inpatient Sample (1,772,064 discharges). Raw observed mortality in the primary sample was 2.09%. Fully adjusted mortality rates by quartile of SPS, from lowest to highest, were 1.97% (95% confidence interval [CI], 1.78%-2.18%), 2.04% (95% CI, 1.84%-2.25%), 1.96% (95% CI, 1.77%-2.16%), and 2.00% (95% CI, 1.80%-2.22%) (P = .99 for linear trend). Results were similar in the subgroup analyses. None of the 3 alternative survey scores was associated with risk-adjusted inpatient mortality, although P values for linear trends were lower (.80, .20, and .11).

CONCLUSION

In this sample of hospitals that completed the 2006 Safe Practices Survey, survey scores were not significantly associated with risk-adjusted inpatient mortality.

BACKGROUND

Adherence to inhaled anti-inflammatory therapy and self-management skills are essential parts of the asthma treatment plan to improve asthma control and prevent exacerbations. Whether self-management education improves long-term medication adherence is less clear.

OBJECTIVE

A 24-week prospective, randomized controlled trial was performed to study the effect of self-management education on long-term adherence to inhaled corticosteroid (ICS) therapy and markers of asthma control.

METHODS

After stabilization on ICS medication during a run-in phase, 95 adults with moderate-to-severe asthma were recruited from a large metropolitan community, and 84 were randomized to individualized self-management education, including self-monitoring of symptoms and peak flow or usual care with self-monitoring alone. The key components of the 30-minute intervention were asthma information, assessment, and correction of inhaler technique; an individualized action plan based on self-monitoring data; and environmental control strategies for relevant allergen and irritant exposures. The intervention was personalized based on pulmonary function, allergen skin test reactivity, and inhaler technique and reinforced at 2-week intervals.

RESULTS

Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a 9-fold greater odds of more than 60% adherence to the prescribed dose compared with control subjects at the end of the intervention (P = .02) and maintained a 3-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (P = .006), nighttime awakenings decreased (P = .03), and inhaled beta-agonist use decreased (P = .01) in intervention participants compared with control subjects.

CONCLUSION

Our results show that individualized asthma self-management education attenuates the usual decrease in medication adherence and improves clinical markers of asthma control.