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1.  Src and Caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer 
Cancer research  2010;71(3):832-841.
In bladder cancer, increased Caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and, RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using transwells and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration and metastasis, while, Cav-1 overexpression or Src depletion increased the migration of non-metastatic RT4 cells. Biochemical studies indicated Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses while Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles appears warranted.
PMCID: PMC4306590  PMID: 21148751
Caveolin-1; Src; Rho A; Rho C; metastasis; bladder neoplasms
Recent research has attempted to clarify the contributions of several mutational processes, such as substitutions or homologous recombination. Simplistic, tractable protein models, which determine the compact native structure phenotype from the sequence genotype, are well-suited to such studies. In this paper, we use a lattice-protein model to examine the effects of point mutation and homologous recombination on evolving populations of proteins. We find that while the majority of mutation and recombination events are neutral or deleterious, recombination is far more likely to be beneficial. This results in a faster increase in fitness during evolution, although the final fitness level is not significantly changed. This transient advantage provides an evolutionary advantage to subpopulations that undergo recombination, allowing fixation of recombination to occur in the population.
PMCID: PMC4249953  PMID: 25473139
homologous protein recombination; introns; lattice-protein
3.  DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA 
Breast cancer research and treatment  2013;141(3):10.1007/s10549-013-2703-y.
Breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Attenuation of breast cancer metastasis to bone and associated osteolysis by fish oil (FO), rich in EPA and DHA, has been demonstrated previously. However, it was not known whether EPA and DHA differentially or similarly affect breast cancer bone metastasis and associated osteolysis. In vitro culture of parental and luciferase gene encoded MDA-MB-231 human breast cancer cell lines treated with EPA and DHA revealed that DHA inhibits proliferation and invasion of breast cancer cells more potently than EPA. Intra-cardiac injection of parental and luciferase gene encoded MDA-MB-231 cells to athymic NCr nu/nu mice demonstrated that DHA treated mice had significantly less breast cancer cell burden in bone, and also significantly less osteolytic lesions than EPA treated mice. In vivo cell migration assay as measured by luciferase intensity revealed that DHA attenuated cell migration specifically to the bone. Moreover, the DHA treated group showed reduced levels of CD44 and TRAP positive area in bone compared to EPA treated group. Breast cancer cell burden and osteolytic lesions were also examined in intra-tibially breast cancer cell injected mice and found less breast cancer cell growth and associated osteolysis in DHA treated mice as compared to EPA treated mice. Finally, doxorubicin resistant MCF-7 (MCF-7dox) human breast cancer cell line was used to examine if DHA can improve sensitization of MCF-7dox cells to doxorubicin. DHA improved the inhibitory effect of doxorubicin on proliferation and invasion of MCF-7dox cells. Interestingly, drug resistance gene P-gp was also down-regulated in DHA plus doxorubicin treated cells. In conclusion, DHA attenuates breast cancer bone metastasis and associated osteolysis more potently than EPA, possibly by inhibiting migration of breast cancer cell to the bone as well as by inhibiting osteoclastic bone resorption.
PMCID: PMC3839302  PMID: 24062211
Breast cancer; bone metastasis; omega-3 fatty acids; docosahexaenoic acid; osteolysis
4.  Walking and running produce similar reductions in cause-specific disease mortality in hypertensives 
Hypertension  2013;62(3):485-491.
To test prospectively in hypertensives whether moderate and vigorous exercise produce equivalent reductions in mortality, Cox-proportional hazard analyses were applied to energy expenditure (metabolic equivalents hours/day, METh/d) in 6,973 walkers and 3,907 runners who used hypertensive medications at baseline. 1121 died during 10.2-year follow-up: 695 cardiovascular disease (CVD, ICD10 I00-99, 465 underlying cause, 230 contributing cause), 124 cerebrovascular disease, 353 ischemic heart disease (ICD10 I20-25, 257 underlying, 96 contributing), 122 heart failure (ICD10 I50, 24 underlying, 98 contributing), and 260 dysrhythmias (ICD10 I46-49, 24 underlying, 236 contributing). Relative to <1.07 METh/d, running or walking 1.8-3.6 METh/d produced significantly lower all-cause (29% reduction, 95%CI: 17% to 39%, P=0.0001), CVD (34% reduction, 95%CI: 20% to 46%, P=0.0001), cerebrovascular disease (55% reduction, 95%CI: 27% to 73%, P=0.001), dysrhythmia (47% reduction, 95%CI: 27% to 62%, P=0.0001), and heart failure mortality (51% reduction, 95%CI: 21% to 70%, P=0.003), as did ≥3.6 METh/d with all-cause (22% reduction, 95%CI: 6% to 35%, P=0.005), CVD (36% reduction, 95%CI: 19% to 50%, P=0.0002), cerebrovascular disease (47% reduction, 95%CI: 6% to 71%, P=0.03), and dysrhythmia mortality (43% reduction, 95%CI: 16% to 62%, P=0.004). Diabetes and chronic kidney disease mortality also decreased significantly with METh/d. All results remained significant when BMI adjusted. Merely meeting guideline levels (1.07 to 1.8 METh/d) did not significantly reduced mortality. The dose-response was significantly nonlinear for all endpoints except diabetes, and cerebrovascular and chronic kidney disease. Results did not differ between running and walking. Thus, walking and running produce similar reductions in mortality in hypertensives.
PMCID: PMC4090350  PMID: 23940195
Hypertension; Exercise; Cardiovascular diseases; Diabetes Mellitus; Type 2; Renal Insufficiency; chronic
5.  Beyond Punnett Squares: Student Word Association and Explanations of Phenotypic Variation through an Integrative Quantitative Genetics Unit Investigating Anthocyanin Inheritance and Expression in Brassica rapa Fast Plants 
CBE Life Sciences Education  2014;13(3):410-424.
This study explores shifts in student word association and explanations of phenotypic variation through an integrative quantitative genetics unit using Brassica rapa Fast Plants.
Genetics instruction in introductory biology is often confined to Mendelian genetics and avoids the complexities of variation in quantitative traits. Given the driving question “What determines variation in phenotype (Pv)? (Pv=Genotypic variation Gv + environmental variation Ev),” we developed a 4-wk unit for an inquiry-based laboratory course focused on the inheritance and expression of a quantitative trait in varying environments. We utilized Brassica rapa Fast Plants as a model organism to study variation in the phenotype anthocyanin pigment intensity. As an initial curriculum assessment, we used free word association to examine students’ cognitive structures before and after the unit and explanations in students’ final research posters with particular focus on variation (Pv = Gv + Ev). Comparison of pre- and postunit word frequency revealed a shift in words and a pattern of co-occurring concepts indicative of change in cognitive structure, with particular focus on “variation” as a proposed threshold concept and primary goal for students’ explanations. Given review of 53 posters, we found ∼50% of students capable of intermediate to high-level explanations combining both Gv and Ev influence on expression of anthocyanin intensity (Pv). While far from “plug and play,” this conceptually rich, inquiry-based unit holds promise for effective integration of quantitative and Mendelian genetics.
PMCID: PMC4152203  PMID: 25185225
6.  Localized Flux Maxima of Arsenic, Lead, and Iron around Root Apices in Flooded Lowland Rice 
Environmental Science & Technology  2014;48(15):8498-8506.
In wetland-adapted plants, such as rice, it is typically root apexes, sites of rapid entry for water/nutrients, where radial oxygen losses (ROLs) are highest. Nutrient/toxic metal uptake therefore largely occurs through oxidized zones and pH microgradients. However, the processes controlling the acquisition of trace elements in rice have been difficult to explore experimentally because of a lack of techniques for simultaneously measuring labile trace elements and O2/pH. Here, we use new diffusive gradients in thin films (DGT)/planar optode sandwich sensors deployed in situ on rice roots to demonstrate a new geochemical niche of greatly enhanced As, Pb, and Fe(II) mobilization into solution immediately adjacent to the root tips characterized by O2 enrichment and low pH. Fe(II) mobilization was congruent to that of the peripheral edge of the aerobic root zone, demonstrating that the Fe(II) mobilization maximum only developed in a narrow O2 range as the oxidation front penetrates the reducing soil. The Fe flux to the DGT resin at the root apexes was 3-fold higher than the anaerobic bulk soil and 27 times greater than the aerobic rooting zone. These results provide new evidence for the importance of coupled diffusion and oxidation of Fe in modulating trace metal solubilization, dispersion, and plant uptake.
PMCID: PMC4124062  PMID: 24967508
7.  The development and evaluation of a five-language multi-perspective standardised measure: clinical decision-making involvement and satisfaction (CDIS) 
The aim of this study was to develop and evaluate a brief quantitative five-language measure of involvement and satisfaction in clinical decision-making (CDIS) – with versions for patients (CDIS-P) and staff (CDIS-S) – for use in mental health services.
An English CDIS was developed by reviewing existing measures, focus groups, semistructured interviews and piloting. Translations into Danish, German, Hungarian and Italian followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force principles of good practice for translation and cultural adaptation. Psychometricevaluation involved testing the measure in secondary mental health services in Aalborg, Debrecen, London, Naples, Ulm and Zurich.
After appraising 14 measures, the Control Preference Scale and Satisfaction With Decision-making English-language scales were modified and evaluated in interviews (n = 9), focus groups (n = 22) and piloting (n = 16). Translations were validated through focus groups (n = 38) and piloting (n = 61). A total of 443 service users and 403 paired staff completed CDIS. The Satisfaction sub-scale had internal consistency of 0.89 (0.86-0.89 after item-level deletion) for staff and 0.90 (0.87-0.90) for service users, both continuous and categorical (utility) versions were associated with symptomatology and both staff-rated and service userrated therapeutic alliance (showing convergent validity), and not with social disability (showing divergent validity), and satisfaction predicted staff-rated (OR 2.43, 95%CI 1.54- 3.83 continuous, OR 5.77, 95%CI 1.90-17.53 utility) and service user-rated (OR 2.21, 95%CI 1.51-3.23 continuous, OR 3.13, 95%CI 1.10-8.94 utility) decision implementation two months later. The Involvement sub-scale had appropriate distribution and no floor or ceiling effects, was associated with stage of recovery, functioning and quality of life (staff only) (showing convergent validity), and not with symptomatology or social disability (showing divergent validity), and staff-rated passive involvement by the service user predicted implementation (OR 3.55, 95%CI 1.53-8.24). Relationships remained after adjusting for clustering by staff.
CDIS demonstrates adequate internal consistency, no evidence of item redundancy, appropriate distribution, and face, content, convergent, divergent and predictive validity. It can be recommended for research and clinical use. CDIS-P and CDIS-S in all 3 five languages can be downloaded at
Trial registration
PMCID: PMC4115477  PMID: 25066212
Clinical decision-making; Involvement; Satisfaction; Mental health; Psychometric; Translation; Patient reported outcome measure; Recovery
8.  Increases in Weight and Body Size Increase the Odds for Hypertension During 7 Years of Follow-up 
Obesity (Silver Spring, Md.)  2008;16(11):2541-2548.
Changes in BMI and body size were compared to incident hypertension in 24,550 men and 10,111 women followed prospectively as part of the National Runners’ Health Study to test whether long-term weight change affects hypertension risk. Incident hypertensions were reported by 2,143 men and 430 women during (mean ± s.d.) 7.8 ± 1.8 and 7.5 ± 2.0 years of follow-up, respectively. Despite being active, men’s and women’s BMI increased 1.15 ± 1.70 and 0.95 ± 1.89 kg/m2, respectively, and their waist circumferences increased 2.97 ± 5.02 and 3.29 ± 6.67cm, respectively. Compared to those whose BMI declined, those who gained ≥2.4kg/m2 had an odds ratio (95% confidence interval) of 1.68 (1.45, 1.94) for becoming hypertensive if male and 1.42 (1.05, 1.92) if female. Men whose waist circumference increased ≥ 6cm had an odds ratio of 1.22 (1.01, 1.47) for becoming hypertensive compared to those whose waists decreased. In both sexes, the odds for hypertension were significantly related to BMI at follow-up when adjusted for baseline BMI, but generally not to baseline BMI when adjusted for follow-up BMI. In the subset whose weights remained relatively unchanged during follow-up (±0.4kg/m2), each kg/m2 increment in average BMI was associated with an odds ratio for becoming hypertensive of 1.19 (1.14, 1.24) in men and 1.11 (1.02, 1.20) in women. Thus, even among lean, physically active individuals: (i) weight gain increases hypertension risk; (ii) higher body weight increases the hypertension risk in a dose-dependent manner in the absence of any weight change; and (iii) there is no advantage carried forward to having been previously lean.
PMCID: PMC4108283  PMID: 18756262
9.  Prospective Epidemiological Cohort Study of Reduced Risk for Incident Cataract with Vigorous Physical Activity and Cardiorespiratory Fitness during a 7-Year Follow-up 
To test whether greater vigorous physical activity (kilometers per week run) and greater cardiorespiratory fitness (10-km race performance in meters per second) reduce the incidence of clinically diagnosed cataract.
Prospective cohort study of self-reported clinical diagnosis of cataract in nondiabetic, nonvegetarian, and nonsmoking male (n = 29,025) and female runners (n = 11,967).
Incident cataracts were reported by 733 (2.53%) men and 179 (1.50%) women during (mean ± SE) 7.74 ± 0.01 and 7.42 ± 0.02 years of follow-up, respectively. The risk for incident cataract increased with BMI, such that the risk in men > 27.5 kg/m2 was 88% larger than in men <20 kg/m2. Men’s cataract risk declined significantly in relation to running distance (P = 0.01), even when adjusted for BMI. Men who ran ≥64 km/wk had 35% lower risk for cataract than those reporting <16 km/wk (28% lower risk when adjusted for BMI). In addition, men with greater cardiorespiratory fitness were at significantly less risk for development of cataract than were the least fit men. This result was not accounted for by adjustment for running distance or BMI. Compared with the least fit men, those who ran faster than 4.75 m/s had 50% lower risk for incident cataract (43% lower when adjusted for km/wk and BMI).
These data suggest that the men’s cataract risk decreased in association with lower BMI, greater physical activity, and greater cardiorespiratory fitness, the latter being statistically independent of both BMI and physical activity. The study limitations include the absence of confirmation of the clinical diagnosis and the lack of specificity of the type of cataract.
PMCID: PMC4108287  PMID: 18408175
10.  Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men 
Physical activity and cardiorespiratory fitness are not currently recognized as factors related to preventing gout, nor are risk factors for gout in physically active men well understood.
The objective was to identify risk factors for gout in ostensibly healthy, vigorously active men.
Incident self-reported gout was compared with baseline diet, body mass index (BMI; in kg/m2), physical activity (in km/d run), and cardiorespiratory fitness (in m/s during 10-km footrace) prospectively in 28 990 male runners.
Men (N=228; 0.79%) self-reported incident gout during 7.74 y of follow-up. The risk of gout increased with higher alcohol intake [per 10 g/d; relative risk (RR): 1.19; 95% CI: 1.12 to 1.26; P<0.0001], meat consumption (per servings/d; RR: 1.45; 95% CI: 1.06 to 1.92; P=0.002), and BMI (RR: 1.19; 95% CI: 1.15 to 1.23; P<0.0001) and declined with greater fruit intake (per pieces/d; RR: 0.73; 95% CI: 0.62 to 0.84; P<0.0001), running distance (per km/d; RR: 0.92; 95% CI: 0.88 to 0.97; P<0.001), and fitness (per m/s; RR: 0.55; 95% CI: 0.41 to 0.75; P<0.0001). The RR per 10 g alcohol/d consumed as wine (1.27; P=0.002), beer (1.19; P<0.0001), and mixed drinks (1.13; P=0.18) was not significantly different from each other. Men who consumed >15 g alcohol/d had 93% greater risk than abstainers, and men who averaged >2 pieces fruit/d had 50% less risk than those who ate <0.5 fruit/d. Risk of gout was 16-fold greater for BMI>27.5 than <20. Compared with the least active or fit men, those who ran ≥8 km/d or >4.0 m/s had 50% and 65% lower risk of gout, respectively. Lower BMI contributed to the risk reductions associated with distance run and fitness.
These findings, based on male runners, suggest that the risk of gout is lower in men who are more physically active, maintain ideal body weight, and consume diets enriched in fruit and limited in meat and alcohol.
PMCID: PMC4090353  PMID: 18469274
11.  Prospective Study of Incident Age-Related Macular Degeneration in Relation to Vigorous Physical Activity during a 7-Year Follow-up 
To test whether the risk of age-related macular degeneration (AMD) decreases with vigorous physical activity.
This was a prospective study of self-reported clinically diagnosed macular degeneration in male (n=29,532) and female (n=12,176) runners followed prospectively for 7.7 years. Survival analyses of incident AMD versus average running distance (kilometers per day), cardiorespiratory fitness (10-km footrace performance), body mass index (BMI), cigarette use, and diet at baseline.
The 110 men and 42 women reporting incident AMD were older than those unaffected (mean ± SE: 54.81 ± 0.97 vs. 44.86 ± 0.06 years), and the men were significantly more likely to have once smoked cigarettes (50.6 vs. 41.2%, P = 0.04 when adjusted for age). Age-and sex-adjusted AMD risk was greater in the men and women who consumed more meat (3.17 ± 0.20 vs. 2.55 ± 0.02 servings/wk) and less fruit (9.41 ± 0.70 vs. 10.92 ± 0.05 pieces/wk). The men and women reporting incident AMD ran for exercise significantly less than those who remained unaffected, when adjustment was made for age and sex (4.57 ± 0.30 vs. 5.34 ± 0.02 km/d, P ≤ 0.01). When adjusted for age, sex, diet, and smoking history, the relative risk for AMD decreased 10% per km/d increment in running distance. Moreover, compared with the men and women who averaged less than 2 km/d, those averaging 2 to 4 km/d had 19% lower adjusted risk, and those averaging ≥4 km/d had 42% to 54% lower adjusted AMD risk.
Higher doses of vigorous exercise (running) are associated with lower incident AMD risk independent of weight, cardiorespiratory fitness, and cigarette use. Limitations of the analyses include the select nature of the sample and reliance on self-report of both running history and clinically diagnosed AMD.
PMCID: PMC4090325  PMID: 18566466
12.  Effects of Running and Walking on Osteoarthritis and Hip Replacement Risk 
Running and other strenuous sports activities are purported to increase osteoarthritis (OA) risk, more so than walking and less-strenuous activities. Analyses were therefore performed to test whether running, walking, and other exercise affect OA and hip replacement risk, and to assess BMI’s role in mediating these relationships.
Proportional hazards analyses of patients’ report of having physician-diagnosed OA and hip replacement vs. exercise energy expenditure (metabolic equivalents, METs).
74,752 runners reported 2004 OA and 259 hip replacements during 7.1-year follow-up, while the 14,625 walkers reported 695 OA and 114 hip replacements over 5.7 years. Compared to running <1.8 METhr/d, the risks for OA and hip replacement decreased: 1) 18.1% (P=0.01) and 35.1% (P=0.03), respectively, for 1.8 to 3.6 METhr/d run; 2) 16.1% (P=0.03) and 50.4% (P=0.002), respectively, for 3.6 to 5.4 METhr/d run; and 3) 15.6% (P=0.02) and 38.5% (P=0.01), respectively, for ≥5.4 METhr/d run, suggesting that the risk reduction mostly occurred by 1.8 METhr/d. Baseline BMI was strongly associated with both OA (5.0% increase per kg/m2, P=2x10−8) and hip replacement risks (9.8% increase per kg/m2, P=4.8x10−5), and adjustment for BMI substantially diminished the risk reduction from running ≥1.8 METhr/d for OA (from 16.5%, P=0.01 to 8.6%, P=0.21) and hip replacement (from 40.4%, P=0.005 to 28.5%, P=0.07). The reductions in OA and hip replacement risk by exceeding 1.8 METhr/d did not differ significantly between runners and walkers. Other (non-running) exercise increased the risk of OA by 2.4% (P=0.009) and hip replacement by 5.0% per METhr/d (P=0.02), independent of BMI.
Whereas other exercise increased OA and hip replacement risk, running significantly reduced their risk due, in part, to running’s association with lower BMI.
PMCID: PMC3756679  PMID: 23377837
Prevention; exercise; epidemiology; cohort study
13.  Incident hypercholesterolemia in relation to changes in vigorous physical activity 
Test whether changes in vigorous exercise affect the risk for hypercholesterolemia.
Incident physician-diagnosed hypercholesterolemia was compared in recreational runners whose weekly distances run increased > 0.5 km/day (4034 men, 1897 women), remained constant (±0.5 km/d; 4685 men, 1904 women), or decreased > 0.5 km/d (15,678 men, 6224 women) during 7.8 yr of prospective follow-up.
Relative to those whose distance was maintained or reduced, the odds ratio (OR) (95% confidence interval) for hypercholesterolemia for those whose running increased was significantly less than 1 for men {OR: 0.82 (0.72–0.93), P = 0.0006}, women {OR: 0.71 (0.54–0.92), P = 0.01}, and men and women combined adjusted for sex {OR: 0.80 (0.72–0.89), P < 0.0001}. The significance of the odds ratios was somewhat diminished when adjusted for baseline and follow-up BMI in men {OR: 0.89 (0.79–1.01), P = 0.06}, women {OR: 0.71 (0.54–0.92), P = 0.08}, and the adjusted sexes combined {OR: 0.88 (0.79–0.98), P = 0.02}. When average distance run {i.e., (baseline + follow-up) / 2} was compared with incident hypercholesterolemia in the 6589 runners whose distance remained constant, each kilometer-per-day increment in average running distance was associated with an odds ratio significantly less than 1 in men {OR: 0.90 (0.86–0.93)}, women {OR: 0.91 (0.84–0.98)}, and the adjusted sexes combined {OR: 0.90 (0.87–0.93)}, which was also attributable in part to BMI in men {OR: 0.94 (0.90–0.97), P = 0.0005}, women {OR: 0.96 (0.89–1.04), P = 0.35}, and the adjusted sexes combined {OR: 0.94 (0.91–0.97), P = 0.0003}.
The odds for hypercholesterolemia: 1) decrease in runners who increase their running mileage and 2) decline in association with the higher dose of vigorous activity even in the absence of any change in exercise. These effects are associated in part to the runners’ BMI.
PMCID: PMC4073642  PMID: 19092705
high cholesterol; prevention; running; epidemiology
14.  Greater Weight Loss from Running than Walking during 6.2-yr Prospective Follow-up 
Test whether equivalent changes in moderate (walking) and vigorous exercise (running) produce equivalent weight loss under free-living, non-experimental conditions.
Regression analyses of changes (Δ) in BMI vs. exercise energy expenditure (ΔMETh/d, 1 metabolic equivalent or MET=3.5 ml O2•kg−1•min−1) from survey questionnaires completed at baseline and 6.2 years thereafter in 15,237 walkers and 32,216 runners.
At baseline, walkers spent less energy walking than runners spent running (mean±SD males: 2.22±1.65 vs. 5.31±3.12, females: 2.15±1.63 vs. 4.76±3.03 METh/d) and walkers were significantly heavier than runners (males: 26.63±4.04 vs. 24.09±2.58, females: 25.44±5.14 vs. 21.61±2.49 kg/m2). During follow-up, energy expenditure declined less for walking in walkers than for running in runners (males: −0.19±1.92 vs. −1.27±2.87, females: −0.30±1.93 vs. −1.28±2.85 METh/d). ΔBMI was inversely related to both ΔMETh/d run and ΔMETh/d walked, but more strongly to ΔMETh/d run than walked in men, and in heavier women. Specifically, the regression coefficient for ΔBMI vs. ΔMETh/d was significantly more negative for running than walking in men in the 1st quartile (differences in slope±SE: −0.06±0.03, P=0.01), 2nd quartile (−0.10±0.03, P=0.001), 3rd quartile (−0.17±0.03, P<10−8) and 4th quartile of BMI (−0.14±0.03, P<10−4) and in the 4th BMI quartile of women (−0.32±0.04 kg/m2 per METh/d, P<10−17). This represented 90% greater weight loss per METh/d run than walked in the 4th BMI quartile for both sexes. Age-related weight gain was attenuated by running in both sexes (P<10−6), and by walking in women (P=0.005).
Although ΔBMI was significantly associated with both ΔMETh/d run and walked, the ΔBMI was significantly greater for Δrunning than Δwalking.
PMCID: PMC4067491  PMID: 23190592
Obesity; prevention; epidemiology; overweight
15.  Walking vs running for hypertension, cholesterol, & diabetes risk reduction 
To test whether equivalent energy expenditure by moderate-intensity (e.g., walking) and vigorous-intensity exercise (e.g., running) provides equivalent health benefits.
Methods and Results
We used the National Runners’ (n=33,060) and Walkers’ (n=15,945) Health Study cohorts to examine the effect of differences in exercise mode and thereby exercise intensity on coronary heart disease (CHD) risk factors. Baseline expenditure (METhr/d) was compared to self-reported, physician-diagnosed incident hypertension, hypercholesterolemia, diabetes and CHD during 6.2 years follow-up. Running significantly decreased the risks for incident hypertension by 4.2% (P<10-7), hypercholesterolemia by 4.3% (P<10-14), diabetes by 12.1% (P<10-5), and CHD by 4.5% per METh/d run (P=0.05). The corresponding reductions for walking were 7.2% (P<10-6), 7.0% (P<10-8), 12.3% (P<10-4), and 9.3% (P=0.01). Relative to <1.8 METh/d, the risk reductions for 1.8 to 3.6, 3.6 to 5.4, 5.4 to 7.2, and ≥ 7.2 METh/d were: 1) 10.1%, 17.7%, 25.1% and 34.9% from running and 14.0%, 23.8%, 21.8% and 38.3% from walking for hypercholesterolemia; 2) 19.7%, 19.4%, 26.8% and 39.8% from running and 14.7%, 19.1%, 23.6% and 13.3% from walking for hypertension; 3) 43.5%, 44.1%, 47.7% and 68.2% from running and 34.1%, 44.2%, and 23.6% from walking for diabetes (too few cases for diabetes for walking >5.4 METh/d). The risk reductions were not significantly greater for running than walking for diabetes (P=0.94) or CHD (P=0.26), and only marginally greater for walking than running for hypertension (P=0.06) and hypercholesterolemia (P=0.04).
Equivalent energy expenditures by moderate (walking) and vigorous (running) exercise produced similar risk reductions for hypertension, hypercholesterolemia, diabetes, and CHD, but there is limited statistical power to evaluate CHD conclusively.
PMCID: PMC4067492  PMID: 23559628
16.  Walking and running are associated with similar reductions in cataract risk 
Habitual running has been associated with reduced risk of cataract development in one prospective study. The purpose of the current analyses is to provide further evidence of this potentially important benefit of vigorous exercise, and to test whether moderate exercise (e.g., walking) provides a significant and equivalent reduction in cataract risk as vigorous exercise (e.g. running).
Cox proportional hazard analyses of self-reported, physician-diagnosed incident cataracts vs. baseline energy expenditure (metabolic equivalents or METs) in 32,610 runners and 14,917 walkers during 6.2-year follow-up. Results are reported as hazard ratios (HR), percent risk reductions (100*(HR-1)), and 95% confidence intervals (95%CI).
Runners and walkers reported 733 and 1,074 incident cataracts during follow-up, respectively. When adjusted for sex, race, age, education, smoking, and intakes of meat, fruit and alcohol, lower cataract risk was significantly associated with both running (HR=0.960 per METh/d, 95%CI 0.935 to 0.986) and walking (HR=0.918 per METh/d, 95%CI: 0.881 to 0.956,), with no significant difference in the per METh/d risk reduction between running and walking, or between men and women. Compared to running or walking at or below guideline levels (≤1.8 METh/d), incident cataract risk was significantly lower for running or walking 1.8 to 3.6 (16.4% lower, 95%CI: 6.4% to 25.3%), 3.6 to 5.4 (19.0% lower, 95%CI: 5.6% to 30.4%), 5.4 to 7.2 (26.2% lower, 95%CI: 11.2% to 38.7%), 7.2 to 9.0 (34.1% lower, 95%CI: 10.0% to 51.2%), and ≥9 METh/d (41.6% lower, 95%CI: 19.8% to 57.4%).
Moderate (walking) and vigorous (running) exercise were both significantly associated with lower cataract risk, and their effects similar. Cataract risk appears to decrease linearly with increasing exercise energy expenditure through 9 METh/d.
PMCID: PMC3757559  PMID: 23274600
Vision; prevention; epidemiology; exercise
17.  Concentrated fish oil (Lovaza®) extends lifespan and attenuates kidney disease in lupus-prone short-lived (NZBxNZW)F1 mice 
A growing number of reports indicate that anti-inflammatory actions of fish oil (FO) are beneficial against systemic lupus erythematosus (SLE). However, the majority of pre-clinical studies were performed using 5–20% FO, which is higher than the clinically relevant dose for lupus patients. The present study was performed in order to determine the effective low dose of FDA-approved concentrated FO (Lovaza®) compared to the commonly used FO-18/12 (18-Eicosapentaenoic acid [EPA]/12-Docosahexaenoic acid [DHA]). We examined the dose-dependent response of Lovaza® (1% and 4%) on an SLE mouse strain (NZB×NZW)F1 and compared the same with 1% and 4% placebo, as well as 4% FO-18/12, maintaining standard chow as the control. Results show for the first time that 1% Lovaza® extends maximal lifespan (517 d) and 4% Lovaza® significantly extends both the median (502 d) and maximal (600 d) life span of (NZB×NZW)F1 mice. In contrast, FO-18/12 extends only median lifespan (410 d) compared to standard chow diet (301 d). Additionally, 4% Lovaza® significantly decreased anti-dsDNA antibodies, reduced glomerulonephritis and attenuated lipopolysaccharide-induced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in splenocytes compared to placebo. 4% Lovaza® was also shown to reduce the expression of inflammatory cytokines, including IL-1β, IL-6 and TNF-α, while increasing renal anti-oxidant enzymes in comparison to placebo. Notably, NFκB activation and p65 nuclear translocation were lowered by 4% Lovaza® compared to placebo. These data indicate that 1% Lovaza® is beneficial, but 4% Lovaza® is more effective in suppressing glomerulonephritis and extending life span of SLE-prone short-lived mice, possibly via reducing inflammation signaling and modulating oxidative stress.
PMCID: PMC3970264  PMID: 23918873
Fish oil; inflammation; kidney disease; lifespan; lupus; survival
18.  Anticipated and experienced discrimination amongst people with schizophrenia, bipolar disorder and major depressive disorder: a cross sectional study 
BMC Psychiatry  2014;14:157.
The unfair treatment of individuals with severe mental illness has been linked to poorer physical and mental health outcomes. Additionally, anticipation of discrimination may lead some individuals to avoid participation in particular life areas, leading to greater isolation and social marginalisation. This study aimed to establish the levels and clinical and socio-demographic associations of anticipated and experienced discrimination amongst those diagnosed with a schizophrenia and comparator severe mental illnesses (bipolar and major depressive disorders).
This study was a cross-sectional analysis of anticipated and experienced discrimination from 202 individuals in South London (47% with schizophrenia, 32% with depression and 20% with bipolar disorder).
93% of the sample anticipated discrimination and 87% of participants had experienced discrimination in at least one area of life in the previous year. There was a significant association between the anticipation and the experience of discrimination. Higher levels of experienced discrimination were reported by those of a mixed ethnicity, and those with higher levels of education. Women anticipated more discrimination than men. Neither diagnosis nor levels of functioning were associated with the extent of discrimination. Clinical symptoms of anxiety, depression and suspiciousness were associated with more experienced and anticipated discrimination respectively.
The unfair treatment of individuals with severe mental illnesses remains unacceptably common. Population level interventions are needed to reduce levels of discrimination and to safeguard individuals. Interventions are also required to assist those with severe mental illness to reduce internalised stigma and social avoidance.
PMCID: PMC4045950  PMID: 24885144
Schizophrenia; Depression; Bipolar; Discrimination; Gender; Ethnicity; Stigma
19.  Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors 
Journal of Medicinal Chemistry  2014;57(6):2813-2819.
A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.
PMCID: PMC4010551  PMID: 24592914
20.  Effectiveness of a community-based intervention for people with schizophrenia and their caregivers in India (COPSI): a randomised controlled trial 
Lancet  2014;383(9926):1385-1394.
Observational evidence suggests that community-based services for people with schizophrenia can be successfully provided by community health workers, when supervised by specialists, in low-income and middle-income countries. We did the COmmunity care for People with Schizophrenia in India (COPSI) trial to compare the effectiveness of a collaborative community-based care intervention with standard facility-based care.
We did a multicentre, parallel-group, randomised controlled trial at three sites in India between Jan 1, 2009 and Dec 31, 2010. Patients aged 16–60 years with a primary diagnosis of schizophrenia according to the tenth edition of the International Classification of Diseases, Diagnostic Criteria for Research (ICD-10-DCR) were randomly assigned (2:1), via a computer-generated randomisation list with block sizes of three, six, or nine, to receive either collaborative community-based care plus facility-based care or facility-based care alone. Randomisation was stratified by study site. Outcome assessors were masked to group allocation. The primary outcome was a change in symptoms and disabilities over 12 months, as measured by the positive and negative syndrome scale (PANSS) and the Indian disability evaluation and assessment scale (IDEAS). Analysis was by modified intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 56877013.
187 participants were randomised to the collaborative community-based care plus facility-based care group and 95 were randomised to the facility-based care alone group; 253 (90%) participants completed follow-up to month 12. At 12 months, total PANSS and IDEAS scores were lower in patients in the intervention group than in those in the control group (PANSS adjusted mean difference −3·75, 95% CI −7·92 to 0·42; p=0·08; IDEAS −0·95, −1·68 to −0·23; p=0·01). However, no difference was shown in the proportion of participants who had a reduction of more than 20% in overall symptoms (PANSS 85 [51%] in the intervention group vs 44 [51%] in the control group; p=0·89; IDEAS 75 [48%] vs 28 [35%]). We noted a significant reduction in symptom and disability outcomes at the rural Tamil Nadu site (−9·29, −15·41 to −3·17; p=0·003). Two patients (one in each group) died by suicide during the study, and two patients died because of complications of a road traffic accident and pre-existing cardiac disease. 18 (73%) patients (17 in the intervention group) were admitted to hospital during the course of the trial, of whom seven were admitted because of physical health problems, such as acute gastritis and vomiting, road accident, high fever, or cardiovascular disease.
The collaborative community-based care plus facility-based care intervention is modestly more effective than facility-based care, especially for reducing disability and symptoms of psychosis. Our results show that the study intervention is best implemented as an initial service in settings where services are scarce, for example in rural areas.
Wellcome Trust.
PMCID: PMC4255067  PMID: 24612754
21.  The challenge of change in acute mental health services: measuring staff perceptions of barriers to change and their relationship to job status and satisfaction using a new measure (VOCALISE) 
Health services are subject to frequent changes, yet there has been insufficient research to address how staff working within these services perceive the climate for implementation. Staff perceptions, particularly of barriers to change, may affect successful implementation and the resultant quality of care. This study measures staff perceptions of barriers to change in acute mental healthcare. We identify whether occupational status and job satisfaction are related to these perceptions, as this might indicate a target for intervention that could aid successful implementation. As there were no available instruments capturing staff perceptions of barriers to change, we created a new measure (VOCALISE) to assess this construct.
All nursing staff from acute in-patient settings in one large London mental health trust were eligible. Using a participatory method, a nurse researcher interviewed 32 staff to explore perceptions of barriers to change. This generated a measure through thematic analyses and staff feedback (N = 6). Psychometric testing was undertaken according to standard guidelines for measure development (N = 40, 42, 275). Random effects models were used to explore the associations between VOCALISE, occupational status, and job satisfaction (N = 125).
VOCALISE was easy to understand and complete, and showed acceptable reliability and validity. The factor analysis revealed three underlying constructs: ‘confidence,’ ‘de-motivation’ and ‘powerlessness.’ Staff with negative perceptions of barriers to change held more junior positions, and had poorer job satisfaction. Qualitatively, nursing assistants expressed a greater sense of organisational unfairness in response to change.
VOCALISE can be used to explore staff perceptions of implementation climate and to assess how staff attitudes shape the successful outcomes of planned changes. Negative perceptions were linked with poor job satisfaction and to those occupying more junior roles, indicating a negative climate for implementation in those groups. Staff from these groups may therefore need special attention prior to implementing changes in mental health settings.
PMCID: PMC4016533  PMID: 24555496
Perception; Measures; Organisational change; Mental health; Nursing
22.  Low HDL3 reduces the odds of men surviving to age 85 during 53-year follow-up 
To identify high-density lipoprotein (HDL) subfractions associated with longevity in men.
Fifty-three-year prospective follow-up of Gofman’s Livermore Cohort between 1954 and 2008.
Lawrence Livermore National Laboratory.
One thousand one hundred forty-four men who consented to the study, had analytic ultracentrifuge measurements of lipoprotein subfractions at baseline, and were old enough at baseline to have survived to age 85 during follow-up.
Survival was determined according to participant contact, Social Security Death Index, and National Death Index.
Three hundred ninety men survived to 85 years old (34.1%). Survivors were less likely than nonsurvivors to be in the lowest HDL3 (% (standard error) 18.5% (2.0%) vs 27.3% (1.6%), P < .001) and HDL2 (22.1% (2.1%) vs 27.7% (1.6%), P = 0.04) quartiles. Logistic regression analyses showed that the lowest HDL3 quartile significantly predicted shorter longevity (P = 0.002), whereas the linear increases per mg/dL of HDL3 did not (P = 0.38), suggesting a risk threshold proximal to the 25th percentile. Men who were above the 25th HDL3 percentile had 70% greater odds of surviving until age 85 than those below this level, which persisted when adjusted for HDL2, very low-density lipoprotein (LDL), and standard risk factors. Proportional hazard analyses of survival before age 85 showed that being in the lowest HDL3 quartile increased age-adjusted cancer risk by 39% (P = 0.05) and noncancer risk by 23% (P = 0.04) when adjusted for other risk factors. Survivors also smoked less (mean ± SD 0.31 ± 0.48 vs 0.57 ± 0.56 packs/d, P < .001), had lower systolic (118.36 ± 11.08 vs 122.81 ± 13.55 mmHg, P < .001) and diastolic (70.61 ± 8.59 vs 73.14 ± 9.22 mmHg, P < .001) blood pressures and lower LDL mass (359.55 ± 80.42 vs 374.37 ± 86.10 mg/dL, P = 0.009) and total cholesterol concentrations (229.51 ± 43.21 vs 235.89 ± 45.40 mg/dL, P = 0.04) than nonsurvivors.
Low HDL3 reduces the odds of extended survival in men, independent of HDL2, other lipoproteins, and standard risk factors.
PMCID: PMC3926864  PMID: 22329432
23.  The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis*  
The Journal of Biological Chemistry  2013;289(7):4244-4261.
Background: Sar1 mediates the onward transport of ER cargo.
Results: Sar1B promotes VLDL secretion, whereas Sar1A antagonizes this activity, and a deficit of both reduces cholesterol biosynthesis.
Conclusion: Sar1B independently of and through its lipoprotein secretion function promotes the expression of genes regulating cholesterol biosynthesis.
Significance: Sar1B-mediated transport activities contribute to both the functional integrity of the ER membrane and blood cholesterol levels.
Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.
PMCID: PMC3924288  PMID: 24338480
Apolipoproteins; Cholesterol Regulation; Endoplasmic Reticulum (ER); Lipoprotein Secretion; Transcriptomics
24.  Breast Cancer Mortality vs. Exercise and Breast Size in Runners and Walkers 
PLoS ONE  2013;8(12):e80616.
Identify predictors of breast cancer mortality in women who exercised below (<7.5 metabolic equivalent hours/week, MET-hours/wk), at (7.5 to 12.5 MET-hours/wk), or above (≥12.5 MET-hours/wk) recommended levels.
Cox proportional hazard analyses of baseline pre-diagnosis MET-hours/wk vs. breast cancer mortality adjusted for follow-up age, race, baseline menopause, and estrogen and oral contraceptive use in 79,124 women (32,872 walkers, 46,252 runners) from the National Walkers' and Runners' Health Studies.
One-hundred eleven women (57 walkers, 54 runners) died from breast cancer during the 11-year follow-up. The decline in mortality in women who exercised ≥7.5 MET-hours/wk was not different for walking and running (P = 0.34), so running and walking energy expenditures were combined. The risk for breast cancer mortality was 41.5% lower for ≥7.5 vs. <7.5 MET-hours/wk (HR: 0.585, 95%CI: 0.382 to 0.924, P = 0.02), which persisted when adjusted for BMI (HR: 0.584, 95%CI: 0.368 to 0.956, P = 0.03). Other than age and menopause, baseline bra cup size was the strongest predictor of breast cancer mortality, i.e., 57.9% risk increase per cup size when adjusted for MET-hours/wk and the other covariates (HR: 1.579, 95%CI: 1.268 to 1.966, P<0.0001), and 70.4% greater when further adjusted for BMI (HR: 1.704, 95%CI: 1.344 to 2.156, P = 10−5). Breast cancer mortality was 4.0-fold greater (HR: 3.980, 95%CI: 1.894 to 9.412, P = 0.0001) for C-cup, and 4.7-fold greater (HR: 4.668, 95%CI: 1.963 to 11.980, P = 0.0004) for ≥D-cup vs. A-cup when adjusted for BMI and other covariates. Adjustment for cup size and BMI did not eliminate the association between breast cancer mortality and ≥7.5 MET-hour/wk walked or run (HR: 0.615, 95%CI: 0.389 to 1.004, P = 0.05).
Breast cancer mortality decreased in association with both meeting the exercise recommendations and smaller breast volume.
PMCID: PMC3857169  PMID: 24349006
25.  Inadequate Exercise as a Risk Factor for Sepsis Mortality 
PLoS ONE  2013;8(12):e79344.
Test whether inadequate exercise is related to sepsis mortality.
Research Design and Methods
Mortality surveillance of an epidemiological cohort of 155,484 National Walkers' and Runners' Health Study participants residing in the United States. Deaths were monitored for an average of 11.6-years using the National Death index through December 31, 2008. Cox proportional hazard analyses were used to compare sepsis mortality (ICD-10 A40-41) to inadequate exercise (<1.07 METh/d run or walked) as measured on their baseline questionnaires. Deaths occurring within one year of the baseline survey were excluded.
Sepsis was the underlying cause in 54 deaths (sepsisunderlying) and a contributing cause in 184 deaths (sepsiscontributing), or 238 total sepsis-related deaths (sepsistotal). Inadequate exercise was associated with 2.24-fold increased risk for sepsisunderlying (95%CI: 1.21 to 4.07-fold, P = 0.01), 2.11-fold increased risk for sepsiscontributing (95%CI: 1.51- to 2.92-fold, P<10−4), and 2.13-fold increased risk for sepsistotal (95%CI: 1.59- to 2.84-fold, P<10−6) when adjusted for age, sex, race, and cohort. The risk increase did not differ significantly between runners and walkers, by sex, or by age. Sepsistotal risk was greater in diabetics (P = 10−5), cancer survivors (P = 0.0001), and heart attack survivors (P = 0.003) and increased with waist circumference (P = 0.0004). The sepsistotal risk associated with inadequate exercise persisted when further adjusted for diabetes, prior cancer, prior heart attack and waist circumference, and when excluding deaths with cancer, or cardiovascular, respiratory, or genitourinary disease as the underlying cause. Inadequate exercise also increased sepsistotal risk in 2163 baseline diabetics (4.78-fold, 95%CI: 2.1- to 13.8-fold, P = 0.0001) when adjusted, which was significantly greater (P = 0.03) than the adjusted risk increase in non-diabetics (1.80-fold, 95%CI: 1.30- to 2.46-fold, P = 0.0006).
Inadequate exercise is a risk factor for sepsis mortality, particular in diabetics.
PMCID: PMC3850902  PMID: 24324580

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