Variability in bioreactivity linked to changes in size and zeta potential of diesel exhaust particles in human immune cells.

Acting as fuel combustion catalysts to increase fuel economy, cerium dioxide (ceria, CeO2) nanoparticles have been used in Europe as diesel fuel additives (Envirox™). We attempted to examine the effects of particles emitted from a diesel engine burning either diesel (diesel exhaust particles, DEP) or diesel doped with various concentrations of CeO2 (DEP-Env) on innate immune responses in THP-1 and primary human peripheral blood mononuclear cells (PBMC). Batches of DEP and DEP-Env were obtained on three separate occasions using identical collection and extraction protocols with the aim of determining the reproducibility of particles generated at different times. However, we observed significant differences in size and surface charge (zeta potential) of the DEP and DEP-Env across the three batches. We also observed that exposure of THP-1 cells and PBMC to identical concentrations of DEP and DEP-Env from the three batches resulted in statistically significant differences in bioreactivity as determined by IL-1ß, TNF-α, IL-6, IFN-γ, and IL-12p40 mRNA (by qRT-PCR) and protein expression (by ELISPOT assays). Importantly, bioreactivity was noted in very tight ranges of DEP size (60 to 120 nm) and zeta potential (-37 to -41 mV). Thus, these physical properties of DEP and DEP-Env were found to be the primary determinants of the bioreactivity measured in this study. Our findings also point to the potential risk of over- or under- estimation of expected bioreactivity effects (and by inference of public health risks) from bulk DEP use without taking into account potential batch-to-batch variations in physical (and possibly chemical) properties.

Black Medicaid beneficiaries experience breast cancer treatment delays more frequently than whites.

OBJECTIVE: Delays in treatment initiation may contribute to the poorer breast cancer survival among Black women compared with Whites. Lower socioeconomic status and lack of access to care are other reasons for the observed disparities. We, therefore, examined racial differences in treatment delays for early breast cancer in a similarly insured population of Medicaid beneficiaries. DESIGN AND SETTING: A retrospective cohort study using linked New Jersey Cancer Registry and Medicaid Research files using logistic regression models. PATIENTS: 237 Black and 485 White women aged 20-64 years diagnosed with early breast cancer between 1997 and 2001. MAIN OUTCOME MEASURE: Delays in treatment initiation. RESULTS: Blacks experience adjuvant chemotherapy delays more often than Whites. Black women had two-fold odds (95% confidence interval, 1.04, 4.38) of > or = 3 months delay in adjuvant chemotherapy than Whites. Blacks were also more likely to experience radiation treatment delays but this finding was not statistically significant (odds ratio 1.72, 95% CI .79, 3.77). No racial differences were observed for surgical and hormonal treatment delays. CONCLUSION: Blacks experienced delays in initiating adjuvant chemotherapy more frequently than Whites. These differences were observed even in a population with similar socioeconomic status and insurance access, suggesting that cultural and psychosocial factors may contribute to the observed differences.

Suppression of the NF-κB pathway by diesel exhaust particles impairs human antimycobacterial immunity.

Epidemiological studies suggest that chronic exposure to air pollution increases susceptibility to respiratory infections, including tuberculosis in humans. A possible link between particulate air pollutant exposure and antimycobacterial immunity has not been explored in human primary immune cells. We hypothesized that exposure to diesel exhaust particles (DEP), a major component of urban fine particulate matter, suppresses antimycobacterial human immune effector cell functions by modulating TLR-signaling pathways and NF-κB activation. We show that DEP and H37Ra, an avirulent laboratory strain of Mycobacterium tuberculosis, were both taken up by the same peripheral human blood monocytes. To examine the effects of DEP on M. tuberculosis-induced production of cytokines, PBMC were stimulated with DEP and M. tuberculosis or purified protein derivative. The production of M. tuberculosis and purified protein derivative-induced IFN-γ, TNF-α, IL-1ß, and IL-6 was reduced in a DEP dose-dependent manner. In contrast, the production of anti-inflammatory IL-10 remained unchanged. Furthermore, DEP stimulation prior to M. tuberculosis infection altered the expression of TLR3, -4, -7, and -10 mRNAs and of a subset of M. tuberculosis-induced host genes including inhibition of expression of many NF-κB (e.g., CSF3, IFNG, IFNA, IFNB, IL1A, IL6, and NFKBIA) and IFN regulatory factor (e.g., IFNG, IFNA1, IFNB1, and CXCL10) pathway target genes. We propose that DEP downregulate M. tuberculosis-induced host gene expression via MyD88-dependent (IL6, IL1A, and PTGS2) as well as MyD88-independent (IFNA, IFNB) pathways. Prestimulation of PBMC with DEP suppressed the expression of proinflammatory mediators upon M. tuberculosis infection, inducing a hyporesponsive cellular state. Therefore, DEP alters crucial components of antimycobacterial host immune responses, providing a possible mechanism by which air pollutants alter antimicrobial immunity.

Biochemical and morphological consequences of human α-synuclein expression in a mouse α-synuclein null background.

A consensus about the functions of human wild-type or mutated α-synuclein (αSYN) is lacking. Both forms of αSYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild-type αSYN (hwαSYN) or a doubly mutated (A30P*A53T) αSYN (hm(2) αSYN) in a C57Bl/6J line spontaneously deleted in mouse αSYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human αSYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) αSYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hwαSYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) αSYN transgene. These observations suggest that mutations in αSYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between hαSYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model.

Using Learning Teams for Reflective Adaptation (ULTRA): insights from a team-based change management strategy in primary care.

PURPOSE: The Using Learning Teams for Reflective Adaptation (ULTRA) study used facilitated reflective adaptive process (RAP) teams to enhance communication and decision making in hopes of improving adherence to multiple clinical guidelines; however, the study failed to show significant clinical improvements. The purpose of this study was to examine qualitative data from 25 intervention practices to understand how they engaged in a team-based collaborative change management strategy and the types of issues they addressed. METHODS: We analyzed field notes and interviews from a multimethod practice assessment, as well as field notes and audio-taped recordings from RAP meetings, using an iterative group process and an immersion-crystallization approach. RESULTS: Despite a history of not meeting regularly, 18 of 25 practices successfully convened improvement teams. There was evidence of improved practice-wide communication in 12 of these practices. At follow-up, 8 practices continued RAP meetings and found the process valuable in problem solving and decision making. Seven practices failed to engage in RAP primarily because of key leaders dominating the meeting agenda or staff members hesitating to speak up in meetings. Although the number of improvement targets varied considerably, most RAP teams targeted patient care-related issues or practice-level organizational improvement issues. Not a single practice focused on adherence to clinical care guidelines. CONCLUSION: Primary care practices can successfully engage in facilitated team meetings; however, leaders must be engaged in the process. Additional strategies are needed to engage practice leaders, particularly physicians, and to target issues related to guideline adherence.

Features of the Chronic Care Model (CCM) associated with behavioral counseling and diabetes care in community primary care.

BACKGROUND: The Chronic Care Model (CCM) was developed to improve chronic disease care, but it may also inform delivery of other types of preventive care. Using hierarchical analyses of service delivery to patients, we explored associations of CCM implementation with diabetes care and counseling for diet or weight loss and physical activity in community-based primary care offices. METHODS: Secondary analysis focused on baseline data from 25 practices (with an average of 4 physicians per practice) participating in an intervention trial targeting improved colorectal cancer screening rates. This intervention made no reference to the CCM. CCM implementation was measured through staff and clinical management surveys and was associated with patient care indicators (chart audits and patient questionnaires). RESULTS: Overall, practices had low levels of CCM implementation. However, higher levels of CCM implementation were associated with better diabetes assessment and treatment of patients (P = .009 and .015, respectively), particularly among practices open to "innovation." Physical activity counseling for obese and, particularly, overweight patients was strongly associated with CCM implementation (P = .0017), particularly among practices open to "innovation"; however, this association did not hold for overweight and obese patients with diabetes. CONCLUSIONS: Very modest levels of CCM implementation in unsupported primary care practices are associated with improved care for patients with diabetes and higher rates of behavioral counseling. Incremental incorporation of CCM components is an option, especially for community practices with stretched resources and with cultures of "innovativeness."

Intraclass correlation estimates for cancer screening outcomes: estimates and applications in the design of group-randomized cancer screening studies.

BACKGROUND: Screening has become one of our best tools for early detection and prevention of cancer. The group-randomized trial is the most rigorous experimental design for evaluating multilevel interventions. However, identifying the proper sample size for a group-randomized trial requires reliable estimates of intraclass correlation (ICC) for screening outcomes, which are not available to researchers. We present crude and adjusted ICC estimates for cancer screening outcomes for various levels of aggregation (physician, clinic, and county) and provide an example of how these ICC estimates may be used in the design of a future trial. METHODS: Investigators working in the area of cancer screening were contacted and asked to provide crude and adjusted ICC estimates using the analysis of variance method estimator. RESULTS: Of the 29 investigators identified, estimates were obtained from 10 investigators who had relevant data. ICC estimates were calculated from 13 different studies, with more than half of the studies collecting information on colorectal screening. In the majority of cases, ICC estimates could be adjusted for age, education, and other demographic characteristics, leading to a reduction in the ICC. ICC estimates varied considerably by cancer site and level of aggregation of the groups. CONCLUSIONS: Previously, only two articles had published ICCs for cancer screening outcomes. We have complied more than 130 crude and adjusted ICC estimates covering breast, cervical, colon, and prostate screening and have detailed them by level of aggregation, screening measure, and study characteristics. We have also demonstrated their use in planning a future trial and the need for the evaluation of the proposed interval estimator for binary outcomes under conditions typically seen in GRTs.

Toxicokinetics and toxicodynamics of paraquat accumulation in mouse brain.

Paraquat (PQ) is a potential human neurotoxicant and is used in models of oxidative stress. We determined the toxicokinetics (TK) and toxicodynamics (TD) of PQ in adult mouse brain following repeated or prolonged PQ exposure. PQ accumulated in different brain regions and reached a plateau after approximately 18 i.p. (10 mg/kg) doses and resulted in modest morbidity and mortality unpredictably associated with dose interval and number. PQ had divergent effects on horizontal locomotor behavior depending on the number of doses. PQ decreased striatal dopamine levels after the 18th to 36th i.p. dose (10 mg/kg) and reduced the striatal level of tyrosine hydroxylase. Drinking water exposure to PQ (0.03- 0.05 mg/ml) did not result in any mortality and resulted in concentration and time dependent levels in the brain. The brain half-life of PQ varied with mouse strain. PQ accumulates and may saturate a site in mouse brain resulting in complex PQ level and duration-related consequences. These findings should alter our risk assessment of this compound and demonstrate a useful, but complex dynamic model for understanding the consequences of PQ in the brain.

Modelling effectiveness of internally heterogeneous organizations in the presence of survey non-response: an application to the ULTRA study.

Levels of turbulence and uncertainty in family medicine practices participating in the ULTRA study are measured via a survey from heterogeneous viewpoints within each practice, including clinicians, nursing staff and office staff. In order to examine the effect of the average practice 'chaos' score on screening provided to patients, the analysis needed to account for large amounts of missing survey responses. Patterns of missing data included portions of missing responses within a job group (e.g. one out of three clinicians) to missing responses from whole subgroups within a practice (e.g. all three clinicians) to a whole practice of missing survey responses (e.g. all clinicians, nursing staff and office staff). The expectation-maximization (EM) algorithm, using a hierarchical model for covariate information, is used to handle the missing data. It was found that the varied patterns of missingness of survey responses among the heterogeneous subgroups within the practices had large effects on estimated effects of practice chaos on patient care.

Hyperlipidemia guideline adherence and association with patient gender.

BACKGROUND: Gender disparities in cardiovascular disease (CVD) management have become increasingly apparent in recent years. Previous research has focused on inpatient disparities, but little is known about how patient gender affects assessment, treatment, and management of patients for hyperlipidemia and cardiovascular risk in primary care settings. Patients with coronary artery disease (CAD) and hyperlipidemia are at high risk for cardiovascular and cerebrovascular morbidity. We sought to examine the effect of patient gender on assessment, treatment, and target maintenance of hyperlipidemia among patients with CAD in a primary care setting. METHODS: Chart abstraction was done for 715 patients with CAD in 55 family practices in New Jersey and eastern Pennsylvania as part of the Using Learning Teams for Reflective Adaptation (ULTRA) project. Hyperlipidemia assessment, treatment, and target adherence scores were determined for those at-risk patients based on National Heart, Lung, and Blood Institute (NHLBI) recommended National Cholesterol Education Program (NCEP) ATP III guidelines. Generalized linear models were used to determine the association of hyperlipidemia guideline adherence with patient gender, using comorbidities and age as confounders. RESULTS: After controlling for comorbidities and age, women were less likely to be assessed for lipids (p = 0.0462). There was no difference in treatment (p = 0.1074) or target laboratory values (p = 0.3949). CONCLUSIONS: Women with CAD are less often assessed for lipids than men in primary care practices. More intensive efforts may be necessary to educate physicians and patients about cardiovascular risk for women.

Estimates, power and sample size calculations for two-sample ordinal outcomes under before-after study designs.

Sample size calculations are given for comparing two groups of subjects, typically referring to active and non-active intervention groups, on an ordinal outcome in experiments where the subjects are measured before and after intervention. These calculations apply to log-odds models with random intercepts, treatment, time and treatment-by-time interaction terms, the latter being the term of interest. The assumed forms of the odds ratios are flexible, allowing for proportional odds, adjacent categories, or other conditional models for ordinal responses. Simulations studies show that, for given sample sizes, the nominal and actual powers of the proposed test are similar.