Expelled from the mountain top?

In 1968, Martin Luther King Jr. professed, "We've got some difficult days ahead. But it really doesn't matter with me now, because I've been to the mountaintop…. And I've seen the Promised Land." Sadly, 55 years later, the United States may have future difficult days regarding fair access to higher education for peoples of diverse demographic backgrounds. Given the Supreme Court's conservative majority, all signs point to a decision that will make achieving racial diversity at all, especially at highly selective universities, impossible.

Musculoskeletal pain stakeholder engagement and partnership development: determining patient-centered research priorities.

BACKGROUND: Musculoskeletal (MSK) pain is a global public health problem with increased societal burden. Increased attention has focused toward patient and other stakeholder perspectives when determining future MSK pain research priorities, however infrastructure and capacity building within the community are needed for individuals and organizations to participate in patient-centered outcomes research. The purpose of this manuscript is to describe our collaborative experiences with several MSK pain stakeholders and processes to identify a top priority research topic. METHODS: Lunch meetings and formalized workshops were used to develop infrastructure for engaging patients and other stakeholders with early capacity building for partners to identify MSK pain research ideas based on their personal experiences. Additional capacity building and engagement through literature searching further prepared partners to contribute informed decisions about MSK pain research topics and subsequent selection of an important research question. RESULTS: Several key deliverables (e.g., Governance Document, Communication Plan) were developed and completed over the course of this project to provide partnership structure. Other key deliverables included a list of preliminary comparative effectiveness research ideas (n = 8) and selection of shared decision making for MSK pain as the top priority research topic with patient partners identifying pain self-efficacy as an important outcome domain. CONCLUSIONS: Our patient partners provided the catalyst for identifying shared decision making as a high priority research topic based on a wide spectrum of stakeholder perspectives and unique experiences. Patient partners were primarily identified using a single rehabilitation health system and clinician partners were heavily weighted by physical therapists which may have introduced selection bias.

A communications tool to recruit policymakers to a CBPR partnership for childhood obesity prevention.

The purpose of this paper is to describe a process and technical requirements for the development of a video and related communications strategy that CBPR partnerships can use to recruit policymakers to participatory research. Policymakers play a critical role in social change agendas, yet are often difficult to engage for a variety of reasons, including limited availability and multiple, competing demands and constituencies. This paper draws on the experience of the Healthy Jacksonville Childhood Obesity Prevention Coalition, a 10-year-old partnership with a large membership and strong community roots in Duval County, Florida. The objectives of the communications strategy were to engage local and state policymakers in policy change that would positively affect childhood obesity prevention; educate policymakers about the social determinants of health, particularly those related to childhood obesity; and to do so in a way that elicited champions for the coalition's goals.

Whistleblowing in the pharmaceutical industry in the United States, England, Canada, and Australia.

Fraud and abuse in the spending of public monies plague governments around the world. In the United States the False Claims Act encourages whistleblowing by private individuals to expose evidence of fraud. They are rewarded for their efforts with monetary compensation and protection from retaliation. Such is not the case in Canada, England, and Australia. Although some recent legislation has increased the protections afforded to whistleblowers, they are still likely to be viewed more as disloyal employees than courageous public servants, and there is little incentive to risk their jobs and reputation. Qui tam laws provide a police force of thousands in the effort to reduce rampant fraud, waste, and abuse, and would be an asset in any health-care system where pubic health policy requires conservation of resources.

Changes in circulating satiety hormones in obese children: a randomized controlled physical activity-based intervention study.

The aims of this study are to examine in children: (i) obesity-related alterations in satiety factors such as leptin, ghrelin, and obestatin; (ii) the link between satiety factors and cardiometabolic risk factors; and (iii) the impact of a physical activity-based lifestyle intervention on the levels of these satiety factors in the obese. We studied a total of 21 adolescents (BMI percentile, 99.0 +/- 0.6 for 15 obese and 56.2 +/- 1.1 for 6 lean). The obese subjects underwent a 3-month randomized controlled physical activity-based lifestyle intervention. Leptin, soluble leptin receptor (sOB-R), ghrelin, and obestatin levels were determined as the primary outcome measures. Other markers of cardiometabolic disease such as inflammation and insulin resistance were also determined. Body composition was measured by dual-energy X-ray absorptiometry. The concentrations of ghrelin, obestatin, and sOB-R were significantly lower in the obese children compared to the lean controls, whereas that of leptin was higher (all P < 0.05). Although intervention led to a net increase in obestatin (P < 0.01) and no change in ghrelin levels, the balance between ghrelin and obestatin (ratio of ghrelin to obestatin, G/O) decreased (P < 0.02). Intervention reduced leptin and increased sOB-R (P < 0.01 for both). Significant associations between satiety factors and other cardiometabolic risk factors were also observed. Taken together, alterations in the levels of satiety factors are evident early in the clinical course of obesity, but physical activity-based lifestyle intervention either prevented their continued increase or normalized their levels. These beneficial effects appear to aid in the maintenance of body weight and reduction in cardiovascular risk.

Immunoendocrine response to cycling following ingestion of caffeine and carbohydrate.

PURPOSE: This study investigated the effect of caffeine consumed with and without carbohydrate (CHO) on immunoendocrine responses after exercise. METHODS: On four occasions, 12 recreational male cyclists cycled for 2 h at 65% V O2max. Sixty minutes before exercise, participants ingested 6 mg.kg(-1) body mass of caffeine (CAF) or placebo (PLA), then during exercise they consumed a 6% CHO or placebo (PLA) drink, providing CAF/CHO, PLA/CHO, CAF/PLA, and PLA/PLA conditions. RESULTS: f-MLP-stimulated neutrophil oxidative burst responses were significantly higher after exercise on CAF/CHO and PLA/CHO (both P<0.05) than PLA/PLA when expressed as a percentage of baseline value. The response on CAF/PLA tended to be higher than PLA/PLA at this point (P=0.056). No significant differences between CAF/CHO, PLA/CHO, and CAF/PLA were observed after exercise; however, only PLA/CHO showed no significant postexercise decline. Coingestion of CAF/CHO significantly attenuated epinephrine (P<0.05) and IL-6 (P<0.05) responses that occurred after ingestion of CAF alone (CAF/PLA) and significantly attenuated the transient alterations in circulating leukocyte (P<0.05) and neutrophil (P<0.01) counts. Plasma cortisol concentration was significantly lower on PLA/CHO than CAF/PLA and PLA/PLA after exercise (P<0.05). Perceived exertion during exercise was significantly lower on CAF/CHO than the other three trials (P<0.05). CONCLUSION: Taken together, this suggests that coingestion of caffeine and CHO has greater influence on immunoendocrine responses than neutrophil functional responses to prolonged exercise.

Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations.

Genes involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. To determine if common single nucleotide polymorphisms (SNPs) in beta(1)-adrenergic receptor (ADRB1), beta(2)-adrenergic receptor (ADRB2), beta(3)-adrenergic receptor (ADRB3), and alpha(2)-adrenergic receptor (ADRA2A) genes associate with obesity and metabolic alterations, we recruited 74 healthy African American and 161 white men and women (age, 18-49 years) to participate in this case-control genetic association study. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. Associations between genotype and body mass index (BMI), percentage of body fat (by measuring skinfold thickness in 7 different sites), fasting (12-hour) plasma glucose, insulin, potassium concentrations, glycated hemoglobin, and insulin resistance (homeostasis model assessment [HOMA(IR)] score) were performed. Among whites, the ADRB1 Arg389-->Gly variant associated with insulin concentrations and HOMA(IR): mean +/- SD values for insulin and HOMA(IR) in Arg389 homozygotes and carriers of the Gly were 10 +/- 7.0 and 12 +/- 9.4 micro IU/mL (P = .02) and 2.1 +/- 1.7 and 2.6 +/- 2.2 (P = .057), respectively. Systolic blood pressure was higher in whites for carriers of the ADBR1 Ser49 compared to Gly49 homozygotes (124 +/- 12.6 vs 119 +/- 11.3 mm Hg, respectively; P = .02). Subsequent analysis revealed that these associations were attributable to a higher BMI among obese participants. The ADRA2A G1780A SNP associated with BMI and percentage of body fat in African Americans (P = .05). Interactions were detected between ADRA2A C-1291G and ADRB2 Gln27-->Glu variants for obesity in African Americans and between ADRA2A C-1291G SNP and ADBR1 haplotype for obesity in whites. We conclude that common SNPs in adrenergic receptor genes may be important susceptibility loci for obesity and related alterations. Because of the limited size of our populations, our results should be interpreted with caution and should be replicated in larger populations.

Comparison of three strategies for preventing hypothermia in critically injured casualties during aeromedical evacuation.

Critically injured patients are at risk for hypothermia. This study determined the efficacy of three hypothermia prevention strategies: the ChillBuster warming blanket, ChillBuster with a reflective blanket, and two wool blankets. A quasi-experimental design was used to compare changes in core temperature. Following resuscitation from hypovolemic shock, 20 swine were assigned to one of the three interventions, placed in an environmental chamber set to reproduce in-flight conditions onboard a military cargo aircraft (50 degrees F/airspeed 0.2 m/s), and monitored for 6 hours. A repeated measures analysis of variance and least-squared difference post hoc were performed. The ChillBuster/reflective blanket group was significantly warmer than the ChillBuster only group and the wool blanket group (p < 0.01). After 6 hours of cold exposure, the ChillBuster/reflective blanket group remained warm while the ChillBuster only and wool blanket groups developed mild hypothermia. Combined use of a warming blanket and reflective blanket was effective in preventing hypothermia over 6 hours and is feasible in a deployed military environment.

Physician-diagnosed asthma and acute chest syndrome: associations with NOS polymorphisms.

The main objectives of this paper were to test the hypothesis that polymorphisms in NOS1 and NOS3 genes associate with ACS in SCD patients and to characterize the association between physician-diagnosed asthma and acute chest syndrome (ACS). Case-control study of sickle cell disease patients >or=5 years old with ACS (cases; n=86) and those without ACS (controls; n=48) was carried out. Associations between ACS and the AAT repeat in intron 13 (formerly intron 20) of the NOS1, and with NOS3 T-786C polymorphism were explored. Physician-diagnosed asthma was determined by chart review, patient- or parent (guardian)-reported asthma, and drug use. Eighty five percent of participants with asthma had at least one episode of ACS compared to 14.6% of controls: adjusted odds ratio (OR) (95%CI) 5.46 (2.20,13.5), P= or<0.0001. Asthma correlated with the number of episodes of ACS (P<0.001). NOS1 AAT repeat polymorphism associated with the risk of ACS (P=0.001) in patients without physician-diagnosed asthma. No associations were found between the genotype of the NOS3 T-786C SNP and ACS. Physician-diagnosed asthma is a major risk factor for ACS. NOS1 AAT repeat polymorphism may contribute to physician-diagnosed asthma.

The C523A beta2 adrenergic receptor polymorphism associates with markers of asthma severity in African Americans.

Our goal was to explore associations between ss2 adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively (p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans.

Patterns of asthma symptoms and perceptions of harm from seasonal atmospheric events in rural Western Montana.

To characterize the frequency of and relationship between self-reported asthma symptoms and physician-diagnosed asthma, identify seasons associated with heightened symptoms, and describe the influence of seasonal atmospheric events and ambient environmental factors on asthma symptoms and perceptions of harm, a seven-county region of Western Montana was surveyed, utilizing a two-stage sampling method. Respondents were queried concerning asthma-related history, symptoms, and environmental concerns. Of 2,790 respondents, 12% reported physician-diagnosed asthma. Eighteen percent reported one or more and 9% reported two or more asthma-related symptoms. Over 70% of asthmatics reported worsened asthma symptoms during wildland-fire smoke exposure. Of those reporting summer as the season they experienced the greatest breathing problems, 81% reported breathing problems from wildland-fire smoke (p < 0.01). Of those reporting worsened symptoms in fall or winter, 61% reported breathing problems during winter inversions (p < 0.001).

Influence of leukotriene pathway polymorphisms on response to montelukast in asthma.

RATIONALE: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. OBJECTIVE: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. METHODS: Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, chi(2) and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. MEASUREMENTS: Outcomes were asthma exacerbation rate and changes in FEV(1) compared with baseline. RESULTS: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV(1) (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. CONCLUSIONS: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.

Influence of sex and beta2 adrenergic receptor haplotype on resting and terbutaline-stimulated whole body lipolysis.

beta 2 adrenergic receptors ( beta 2 ARs) are important mediators of lipolysis. The beta 2 AR gene is highly polymorphic. To determine the contribution of beta 2 AR polymorphisms to variability in whole body lipolysis, we compared basal and terbutaline-stimulated lipolytic rates (Ra) using tracer techniques in 14 healthy, non-obese males (n=7) and females (n=7) who were homozygous for Cys-19/Arg16/Gln27 or Arg-19/Gly16/Glu27 haplotypes. Fasting (overnight) Ra values were higher in females compared to males. Mean+/-SD Ra, Ra/body weight, Ra/fat free mass, Ra/fat, and Ra/energy expenditure rates in males and females were 155+/-46 vs 311+/-111 micromol/min (P=.007); 2.0+/-0.61 vs 5.2+/-2.3 micromol/(min kg) (P=.006); 2.5+/-0.75 vs 7.8+/-3.4 micromol/(min kg) (P=.003); 10+/-3.7 vs 17+/-7.4 micromol/(min kg) (P=.09); and 144+/-45.5 vs 392+/-111 micromol/d (P=.0001), respectively. Mean+/-SD basal glycerol concentrations were higher in females compared to males: 62+/-5.6 vs 36+/-17 micromol/L (P=.003). Basal glycerol concentrations and Ra values were similar by beta2 AR haplotype. Basal glucose and insulin concentrations tended to be higher in males compared to females and were similar by haplotype. Terbutaline-stimulated changes in glycerol concentrations were variable and are not related to either sex or haplotype. We conclude that compared to haplotype, sex is a more important determinant of basal lipolysis after a 12-hour fast in healthy, non-obese individuals.

Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons.

Recent studies have begun to focus on the signals that regulate axonal protein synthesis and the functional significance of localized protein synthesis. However, identification of proteins that are synthesized in mammalian axons has been mainly based on predictions. Here, we used axons purified from cultures of injury-conditioned adult dorsal root ganglion (DRG) neurons and proteomics methodology to identify axonally synthesized proteins. Reverse transcription (RT)-PCR from axonal preparations was used to confirm that the mRNA for each identified protein extended into the DRG axons. Proteins and the encoding mRNAs for the cytoskeletal proteins beta-actin, peripherin, vimentin, gamma-tropomyosin 3, and cofilin 1 were present in the axonal preparations. In addition to the cytoskeletal elements, several heat shock proteins (HSP27, HSP60, HSP70, grp75, alphaB crystallin), resident endoplasmic reticulum (ER) proteins (calreticulin, grp78/BiP, ERp29), proteins associated with neurodegenerative diseases (ubiquitin C-terminal hydrolase L1, rat ortholog of human DJ-1/Park7, gamma-synuclein, superoxide dismutase 1), anti-oxidant proteins (peroxiredoxins 1 and 6), and metabolic proteins (e.g., phosphoglycerate kinase 1 (PGK 1), alpha enolase, aldolase C/Zebrin II) were included among the axonally synthesized proteins. Detection of the mRNAs encoding each of the axonally synthesized proteins identified by mass spectrometry in the axonal compartment indicates that the DRG axons have the potential to synthesize a complex population of proteins. Local treatment of the DRG axons with NGF or BDNF increased levels of cytoskeletal mRNAs into the axonal compartment by twofold to fivefold but had no effect on levels of the other axonal mRNAs studied. Neurotrophins selectively increased transport of beta-actin, peripherin, and vimentin mRNAs from the cell body into the axons rather than changing transcription or mRNA survival in the axonal compartment.

Modeling the metabolic effects of terbutaline in beta2-adrenergic receptor diplotypes.

OBJECTIVE: Our objective was to determine whether beta(2)-adrenergic receptor polymorphisms influence terbutaline-stimulated changes in glucose, insulin, and potassium concentrations in healthy adults. METHODS: Seven healthy adults homozygous for the Arg-19/Gly16/Glu27 haplotype (RGE) and seven homozygous for the Cys-19/Arg16/Gln27 haplotype (CRQ) volunteered to receive a 1-hour infusion of terbutaline (0.01 mg/kg). A 2-compartment pharmacokinetic model was fitted to the terbutaline concentrations. Concentrations of glucose and insulin were fitted simultaneously by use of a coupled feedback indirect response model. An indirect response model was also fitted to the plasma potassium concentration versus time data. The -2 log-likelihood ratio test was used to determine whether estimates of the covariates of diplotype and sex improved the model fittings. RESULTS: Demographic variables, anthropometric characteristics, and pharmacokinetics did not differ by diplotype. The coupled feedback model fitted the glucose and insulin concentration data well with excellent precision. Terbutaline stimulated production of glucose (S(1)) to a greater extent in RGE compared with CRQ diplotypes, as follows: S(1) = 0.039 +/- 0.007 (mean +/- SD) versus 0.0276 +/- 0.01, respectively (P <.05, -2 log-likelihood criterion). The baseline values, disposition rate constants for glucose (k(out1)) and insulin (k(out2)), production rate of insulin (S(2)), feedback effect of insulin on glucose (S(3)), and pharmacodynamic parameters for potassium did not differ by diplotype or sex. CONCLUSIONS: The beta(2) receptor diplotype influences receptor-stimulated glucose production in healthy, nonobese individuals, which is consistent with beta(2) receptor-mediated hepatic glycogenolysis. Future metabolic studies of this system should consider beta(2) receptor genetic variants.

Growth factor regulation of human growth plate chondrocyte proliferation in vitro.

Linear growth occurs as the result of growth plate chondrocytes undergoing proliferative and hypertrophic phases. Paracrine feedback loops that regulate the entry of chondrocytes into the hypertrophic phase have been shown and similar pathways likely exist for the proliferative phase. Human long-bone growth plate chondrocytes were cultured in vitro. The proliferative effects of a variety of factors were determined by [3H]thymidine uptake and the gene expression profile of these cells was determined by DNA microarray analysis. Serum, insulin-like growth factor (IGF)-I and -II, transforming growth factor-beta (TGF-beta, fibroblast growth factor (FGF)-1, -2, and -18, and platelet-derived growth factor (PDGF)-BB were potent stimulators of proliferation. FGF-10, testosterone, and bone morphogenetic proteins (BMP)-2, -4, and -6 inhibited proliferation. Microarray analysis showed that the genes for multiple members of the IGF-I, TGF-beta, FGF, and BMP pathways were expressed, suggesting the presence of autocrine/paracrine pathways that regulate the proliferative phase of growth plate-mediated growth.

Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease.

Most of the energy requirement for cell growth, differentiation, and development is met by the mitochondria in the form of ATP produced by the process of oxidative phosphorylation. Human mitochondrial DNA encodes a total of 13 proteins, all of which are essential for oxidative phosphorylation. The mRNAs for these proteins are translated on mitochondrial ribosomes. Recently, the genes for human mitochondrial ribosomal proteins (MRPs) have been identified. In this review, we summarize their refined chromosomal location. It is well known that mutations in the mitochondrial translation system, i.e., ribosomal RNA and transfer RNA cause various pathologies. In this review, we suggest possible associations between clinical conditions and MRPs based on coincidence of genetic map data and chromosomal location. These MRPs may be candidate genes for the clinical condition or may act as modifiers of existing known gene mutations (mt-tRNA, mt-rRNA, etc.).

Effect of montelukast on time-course of exhaled nitric oxide in asthma: influence of LTC4 synthase A(-444)C polymorphism.

Leukotrienes (LT) mediate inflammation in asthma. The fraction of exhaled nitric oxide (FE(NO)) is thought to be a sensitive and reproducible method for assessing airway inflammation in asthmatics and the anti-inflammatory effects of drugs. A number of factors are known to contribute to intrapatient variation in FE(NO) which can confound interpretation. The aims of this study were to characterize the time-course of FE(NO), determine the effect of montelukast on the time-course of FE(NO), and evaluate the influence of the LTC(4) synthase A(-444)C polymorphism on montelukast-evoked changes in FE(NO). Following a 2-week run-in, 7 males and 5 females with asthma, 10-16 years old, received 5 or 10 mg of montelukast or an identical placebo at bedtime for 7 days in double-blind, crossover fashion, followed by a 7-day washout. FE(NO)was quantified every 30 min for 3 or 6 hr at baseline and on days 1, 2, 3, and 7 of treatment. A time-averaged value for FE(NO) was calculated (FE(NO)*), and % changes in FE(NO)* relative to baseline vs. time following placebo and montelukast were compared. The genotype of the A(-444)C polymorphism was determined by PCR and RFLP. FE(NO) varied markedly as a function of time in each patient. Time-averaged values of FE(NO) (FE(NO)*) during placebo and montelukast treatment were similar. Montelukast significantly reduced the slope of the % change in FE(NO)* vs. time curve in heterozygotes (n = 4), but not in A/A homozygotes (n = 8). These data suggest that heterozygotes respond better to montelukast compared to A/A homozygotes, at least with respect to changes in FE(NO). We conclude that assessment of inflammation or the anti-inflammatory effects of drugs in asthma based on single determinations of FE(NO) can be misleading. We further conclude that the A(-444)C polymorphism in the LTC(4) synthase gene probably contributes to interpatient variability in montelukast-evoked changes in FE(NO)* and warrants further study.