Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy.

Synovial inflammation is a central feature of osteoarthritis (OA), elicited when local regulatory macrophages (M2-like) become overwhelmed, activating an inflammatory response (M1-like). Bone marrow mononuclear cells (BMNC) are a source of naïve macrophages capable of reducing joint inflammation and producing molecules essential for cartilage metabolism. This study investigated the response of BMNC to normal (SF) and inflamed synovial fluid (ISF). Equine BMNC cultured in autologous SF or ISF (n = 8 horses) developed into macrophage-rich cultures with phenotypes similar to cells native to normal SF and became more confluent in ISF (~100%) than SF (~25%). BMNC cultured in SF or ISF were neither M1- nor M2-like, but exhibited aspects of both phenotypes and a regulatory immune response, characterized by increasing counts of IL-10+ macrophages, decreasing IL-1ß concentrations and progressively increasing IL-10 and IGF-1 concentrations. Changes were more marked in ISF and suggest that homeostatic mechanisms were preserved over time and were potentially favored by progressive cell proliferation. Collectively, our data suggest that intra-articular BMNC could increase synovial macrophage counts, potentiating the macrophage- and IL-10-associated mechanisms of joint homeostasis lost during the progression of OA, preserving the production of cytokines involved in tissue repair (PGE2 , IL-10) generally impaired by frequently used corticosteroids.

Autologous bone marrow mononuclear cells modulate joint homeostasis in an equine in vivo model of synovitis.

Osteoarthritis (OA) is characterized by macrophage-driven synovitis. Macrophages promote synovial health but become inflammatory when their regulatory functions are overwhelmed. Bone marrow mononuclear cells (BMNCs) are a rich source of macrophage progenitors used for treating chronic inflammation and produce essential molecules for cartilage metabolism. This study investigated the response to autologous BMNC injection in normal and inflamed joints. Synovitis was induced in both radiocarpal joints of 6 horses. After 8 h, 1 inflamed radiocarpal and 1 normal tarsocrural joint received BMNC injection. Contralateral joints were injected with saline. Synovial fluid was collected at 24, 96, and 144 h for cytology, cytokine quantification, and flow cytometry. At 144 h, horses were euthanatized, joints were evaluated, and synovium was harvested for histology and immunohistochemistry. Four days after BMNC treatment, inflamed joints had 24% higher macrophage counts with 10% more IL-10+ cells than saline-treated controls. BMNC-treated joints showed gross and analytical improvements in synovial fluid and synovial membrane, with increasing regulatory macrophages and synovial fluid IL-10 concentrations compared with saline-treated controls. BMNC-treated joints were comparable to healthy joints histologically, which remained abnormal in saline-treated controls. Autologous BMNCs are readily available, regulate synovitis through macrophage-associated effects, and can benefit thousands of patients with OA.-Menarim, B. C., Gillis, K. H., Oliver, A., Mason, C., Ngo, Y., Werre, S. R., Barrett, S. H., Luo, X., Byron, C. R., Dahlgren, L. A. Autologous bone marrow mononuclear cells modulate joint homeostasis in an equine in vivo model of synovitis.

Eating behaviors and weight loss outcomes in a 12-month randomized trial of diet and/or exercise intervention in postmenopausal women.

BACKGROUND: Certain eating behaviors are common among women with obesity. Whether these behaviors influence outcomes in weight loss programs, and whether such programs affect eating behaviors, is unclear. METHODS: Our aim was to examine the effect of baseline eating behaviors on intervention adherence and weight among postmenopausal women with overweight or obesity, and to assess intervention effects on eating behaviors. Four hundred and 39 women (BMI ≥25 kg/m2) were randomized to 12 months of: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 225 mins/week ('exercise'; n = 117); iii) combined dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle change control (n = 87). At baseline and 12 months, restrained eating, uncontrolled eating, emotional eating and binge eating were measured by questionnaire; weight and body composition were assessed. The mean change in eating behavior scores and weight between baseline and 12 months in the diet, exercise, and diet + exercise arms were each compared to controls using the generalized estimating equation (GEE) modification of linear regression adjusted for age, baseline BMI, and race/ethnicity. RESULTS: Baseline restrained eating was positively associated with change in total calories and calories from fat during the dietary intervention but not with other measures of adherence. Higher baseline restrained eating was associated with greater 12-month reductions in weight, waist circumference, body fat and lean mass. Women randomized to dietary intervention had significant reductions in binge eating (- 23.7%, p = 0.005 vs. control), uncontrolled eating (- 24.3%, p < 0.001 vs. control), and emotional eating (- 31.7%, p < 0.001 vs. control) scores, and a significant increase in restrained eating (+ 60.6%, p < 0.001 vs. control); women randomized to diet + exercise reported less uncontrolled eating (- 26.0%, p < 0.001 vs. control) and emotional eating (- 22.0%, p = 0.004 vs. control), and increased restrained eating (+ 41.4%, p < 0.001 vs. control). Women randomized to exercise alone had no significant change in eating behavior scores compared to controls. CONCLUSIONS: A dietary weight loss intervention helped women modify eating behaviors. Future research should investigate optimal behavioral weight loss interventions for women with both disordered eating and obesity. TRIAL REGISTRATION: NCT00470119 (https://clinicaltrials.gov). Retrospectively registered May 7, 2007.

Adoption and Implementation of Evidence-Based Colorectal Cancer Screening Interventions Among Cancer Control Program Grantees, 2009-2015.

PURPOSE AND OBJECTIVES: Colorectal cancer (CRC) is the second-leading cause of cancer death in the United States. Although effective CRC screening tests exist, CRC screening is underused. Use of evidence-based interventions (EBIs) to increase CRC screening could save many lives. The Colorectal Cancer Control Program (CRCCP) of the Centers for Disease Control and Prevention (CDC) provides a unique opportunity to study EBI adoption, implementation, and maintenance. We assessed 1) the number of grantees implementing 5 EBIs during 2011 through 2015, 2) grantees' perceived ease of implementing each EBI, and 3) grantees' reasons for stopping EBI implementation. INTERVENTION APPROACH: CDC funded 25 states and 4 tribal entities to participate in the CRCCP. Grantees used CRCCP funds to 1) provide CRC screening to individuals who were uninsured and low-income, and 2) promote CRC screening at the population level. One component of the CRC screening promotion effort was implementing 1 or more of 5 EBIs to increase CRC screening rates. EVALUATION METHODS: We surveyed CRCCP grantees about EBI implementation with an online survey in 2011, 2012, 2013, and 2015. We conducted descriptive analyses of closed-ended items and coded open-text responses for themes related to barriers and facilitators to EBI implementation. RESULTS: Most grantees implemented small media (≥25) or client reminders (≥21) or both all program years. Although few grantees reported implementation of EBIs such as reducing structural barriers (n = 14) and provider reminders (n = 9) in 2011, implementation of these EBIs increased over time. Implementation of provider assessment and feedback increased over time, but was reported by the fewest grantees (n = 17) in 2015. Reasons for discontinuing EBIs included funding ending, competing priorities, or limited staff capacity. IMPLICATIONS FOR PUBLIC HEALTH: CRCCP grantees implemented EBIs across all years studied, yet implementation varied by EBI and did not get easier with time. Our findings can inform long-term planning for EBIs with state and tribal public health institutions and their partners.

Repletion of vitamin D associated with deterioration of sleep quality among postmenopausal women.

Reduced health-related quality of life (HRQOL), depressive symptoms and poor sleep quality are important health issues among postmenopausal women and may be associated with low vitamin D status. Overweight postmenopausal women, with serum 25-hydroxyvitamin D [25(OH)D] 10-32ng/m, were recruited in Seattle, WA (2010-2012) and randomly assigned to 12months of weight loss +2000IU oral vitamin D3/day or weight loss+daily placebo. The weight-loss program included a reduced-calorie diet and 225min/week of moderate-to-vigorous aerobic activity. Eight subscales of HRQOL were assessed by the MOS 36-Item Short-Form Health Survey. Depressive symptoms were assessed using the Brief Symptom Inventory-18, and sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Mean 12-month changes in HRQOL, depressive symptoms and sleep quality were compared between groups (intent-to-treat) using generalized estimating equations. Compared to placebo, women receiving vitamin D did not experience any significant change in depressive symptoms (p=0.78), HRQOL subscales (all p>0.05), or overall sleep quality (p=0.21). However, a greater magnitude of change in serum 25(OH)D was associated with an increased need to take medications to sleep (ptrend=0.01) and overall worse sleep quality (ptrend<0.01). Women who became vitamin D replete (≥32ng/mL) also showed a deterioration in total PSQI sleep quality score compared to women who remained <32ng/mL despite supplementation, even after adjusting for relevant covariates (Non-Replete: -5.7% vs. Replete: +6.2%, p<0.01). Vitamin D supplementation of 2000IU/d may result in overall worse sleep quality for postmenopausal women with low circulating vitamin D undergoing weight loss.

The effects of separate and combined dietary weight loss and exercise on fasting ghrelin concentrations in overweight and obese women: a randomized controlled trial.

OBJECTIVE: Compensatory metabolic changes that accompany weight loss, for example, increased ghrelin, contribute to weight regain and difficulty in long-term weight loss maintenance; however, the separate effects of long-term caloric restriction and exercise on total circulating ghrelin in humans are unknown. DESIGN: A 12-month randomized controlled trial comparing: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week ('exercise'; n = 117); iii) dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle-change control (n = 87). PARTICIPANTS: 439 overweight or obese postmenopausal women (50-75 y). MEASUREMENTS: Fasting total serum ghrelin was measured by radioimmunoassay at baseline and 12 months. Fasting serum leptin, adiponectin and insulin were also measured. RESULTS: Fasting total ghrelin significantly increased in the diet + exercise arm (+7·4%, P = 0·008) but not in either the diet (+6·5%, P = 0·07) or exercise (+1·0%, P = 0·53) arms compared with control. Greater weight loss was associated with increased ghrelin concentrations, regardless of intervention. Neither baseline ghrelin nor body composition modified the intervention effects on changes in total ghrelin. The 12-month change in total ghrelin was inversely associated with changes in leptin, insulin and insulin resistance, and positively associated with change in adiponectin. CONCLUSIONS: Greater weight loss, achieved through a reduced calorie diet or exercise, is associated with increased total ghrelin concentrations in overweight or obese postmenopausal women.

Assessment of training and technical assistance needs of Colorectal Cancer Control Program Grantees in the U.S.

BACKGROUND: Practitioners often require training and technical assistance to build their capacity to select, adapt, and implement evidence-based interventions (EBIs). The CDC Colorectal Cancer Control Program (CRCCP) aims to promote CRC screening to increase population-level screening. This study identified the training and technical assistance (TA) needs and preferences for training related to the implementation of EBIs among CRCCP grantees. METHODS: Twenty-nine CRCCP grantees completed an online survey about their screening activities, training and technical assistance in 2012. They rated desire for training on various evidence-based strategies to increase cancer screening, evidence-based competencies, and program management topics. They also reported preferences for training formats and facilitators and barriers to trainings. RESULTS: Many CRCCP grantees expressed the need for training with regards to specific EBIs, especially system-level and provider-directed EBIs to promote CRC screening. Grantees rated these EBIs as more difficult to implement than client-oriented EBIs. Grantees also reported a moderate need for training regarding finding EBIs, assessing organizational capacity, implementing selected EBIs, and conducting process and outcome evaluations. Other desired training topics reported with higher frequency were partnership development and data collection/evaluation. Grantees preferred training formats that were interactive such as on-site trainings, webinars or expert consultants. CONCLUSIONS: Public health organizations need greater supports for adopting evidence-based interventions, working with organizational-level change, partnership development and data management. Future capacity building efforts for the adoption of EBIs should focus on systems or provider level interventions and key processes for health promotion and should be delivered in a variety of ways to assist local organizations in cancer prevention and control.

Process evaluation of a regional public health model to reduce chronic disease through policy and systems changes, Washington State, 2010-2014.

INTRODUCTION: Although the regionalization of public health systems has been well documented in the case of emergency preparedness, there is little literature on the application of regional approaches to other aspects of public health. From 2011 through 2014 the Washington State Department of Health implemented a Community Transformation Grant to support community-level policy and systems changes to decrease chronic disease risk factors and increase access to clinical preventive services. The Department of Health implemented the grant through a regional model, grouping 32 of the state's 35 local health jurisdictions into 5 regions. Our process evaluation identifies the challenges and facilitators to Community Transformation Grant planning and implementation. METHODS: We conducted 34 key informant interviews with people directly involved in the implementation of the Community Transformation Grant. We interviewed state and local partners, including representatives from each region, the Department of Health, external consultants, and regional partners. We collected data from October 2013 through July 2014. RESULTS: Challenges for planning, building, and implementing a regional model for chronic disease prevention included stakeholder buy-in, regional geography, and communication; facilitators included shared regional history and infrastructure, strong leadership, collaborative relationships, shared vision and goals, sufficient funding, and direct technical assistance and training. CONCLUSION: Lessons learned in Washington State provide a foundation for other states interested in using a regional approach to reduce chronic disease risk. Policy and systems changes require adequate time, funding, and staffing. States and funders should work closely with local leaders to address these challenges and facilitators.

Weight and metabolic effects of dietary weight loss and exercise interventions in postmenopausal antidepressant medication users and non-users: a randomized controlled trial.

OBJECTIVE: Antidepressants may attenuate the effects of diet and exercise programs. We compared adherence and changes in body measures and biomarkers of glucose metabolism and inflammation between antidepressant users and non-users in a 12-month randomized controlled trial. METHODS: Overweight or obese, postmenopausal women were assigned to: diet (10% weight loss goal, N=118); moderate-to-vigorous aerobic exercise (225 min/week, N=117); diet+exercise (N=117); and control (N=87) in Seattle, WA 2005-2009. Women using antidepressants at baseline were classified as users (N=109). ANCOVA and generalized estimating equation approaches, respectively, were used to compare adherence (exercise amount, diet session attendance, and changes in percent calorie intake from fat, cardiopulmonary fitness, and pedometer steps) and changes in body measures (weight, waist and percent body fat) and serum biomarkers (glucose, insulin, homeostasis assessment-insulin resistance, and high-sensitivity C-reactive protein) between users and non-users. An interaction term (intervention×antidepressant use) tested effect modification. RESULTS: There were no differences in adherence except that diet session attendance was lower among users in the diet+exercise group (P<0.05 vs. non-users). Changes in body measures and serum biomarkers did not differ by antidepressant use (Pinteraction>0.05). CONCLUSION: Dietary weight loss and exercise improved body measures and biomarkers of glucose metabolism and inflammation independent of antidepressant use.

Supporting the Health of Low Socioeconomic Status Employees: Qualitative Perspectives From Employees and Large Companies.

OBJECTIVE: The aim of this study was to identify alignments between wellness offerings low socioeconomic status (SES) employees need and those large companies can provide. METHODS: Focus groups (employees); telephone interviews (large companies). Employees were low-SES, insured through their employers, and employed by large Washington State companies. Focus groups covered perceived barriers to healthy behaviors at work and potential support from companies. Interviews focused on priorities for employee health and challenges reaching low-SES employees. RESULTS: Seventy-seven employees participated in eight focus groups; 12 companies completed interviews. Employees identified facilitators and barriers to healthier work environments; companies expressed care for employees, concerns about employee obesity, and reluctance to discuss SES. CONCLUSION: Our findings combine low-SES employee and large company perspectives and indicate three ways workplaces could most effectively support low-SES employee health: create healthier workplace food environments; prioritize onsite physical activity facilities; use clearer health communications.

Musculoskeletal fitness and weight gain in Canada.

BACKGROUND: Obesity is a growing health issue in Canada, and identifying the determinants of weight gain is important for the development of appropriate prevention strategies. PURPOSE: To quantify the association between musculoskeletal fitness (MSF) and subsequent weight gain and development of obesity. METHODS: The sample included 606 participants (20-69 yr; 291 men, 315 women) from the Physical Activity Longitudinal Study (PALS), a follow-up of participants from the 1981 Canadian Fitness Survey. Standardized assessments of height, weight, MSF (push-ups, sit-ups, grip strength, and trunk flexibility), and cardiorespiratory fitness were made at baseline (1981). Follow-up data on self-reported height and weight and body mass index (BMI) were collected by survey in 2002-2004. Logistic regression was used to predict obesity and weight gain of > or = 10 kg between 1981 and 2002-2004. RESULTS: During the 20-yr follow-up, the prevalence of obesity (BMI > or = 30 kg.m(-2)) increased from 3.1 to 15.2%, reflecting a mean weight gain of 7.4 kg (men: 6.7 kg; women: 8.1 kg). Further, independent of age, sex, baseline BMI, physical activity, cardiorespiratory fitness, smoking, alcohol consumption, and income, low MSF was associated with significantly higher odds of having gained at least 10 kg during follow-up (OR: 1.78, 95% CI: 1.14-2.79). CONCLUSIONS: The results indicate that MSF is a significant predictor of weight gain during a 20-yr period. Promoting participation in activities that enhance MSF may be beneficial in attenuating age-related weight gain and in preventing obesity among Canadians.

Prevention Research Center Collaborations With State Departments of Health: Washington State.

State health departments and Prevention Research Centers (PRCs) have complementary mandates and expertise important to improving population health. State health departments manage and administer numerous programs with broad population reach. PRCs bridge dissemination and implementation research and public health practice to improve health programming and outcomes. This paper describes the 15-year partnership between the Washington State Department of Health and the PRC at the University of Washington. Through this partnership, the Washington State Department of Health increases their research and evaluation capacity by working with the University of Washington PRC, and the University of Washington PRC receives opportunities to apply evidence in a variety of practice settings, expand the reach of their research-tested programs to new populations, and form new partnerships. The partnership focused initially on improving colorectal cancer screening rates through increased dissemination and implementation of evidence-based interventions. The partnership scope has grown to include small cancer screening projects in worksites and healthcare systems, Washington's Colorectal Cancer Control Program, breast and cervical cancer screening, hypertension control, and worksite health promotion. The partnership yields three main types of outcomes that strengthen practice and science: (1) findings from each major assessment or evaluation activity, published in the peer-reviewed literature when possible; (2) use of the findings to improve public health practice and impact; and (3) training opportunities for employees of local and state health departments and public health students. PRCs, health departments, and the populations they serve have much to gain from this type of partnership.

Gene expression in breast and adipose tissue after 12 months of weight loss and vitamin D supplementation in postmenopausal women.

Adipose tissue is involved in the etiology of postmenopausal breast cancer, possibly through increased sex steroid hormone production, inflammation, and altered adipokines. Vitamin D may affect these pathways but its effect on gene expression in different tissues has not been examined. Within a double-blind, 12-month placebo-controlled randomized trial, we compared 2000 IU/day oral vitamin D3 supplementation (N = 39) vs. placebo (N = 40) on the expression of 5 genes in breast and adipose tissue in overweight/obese postmenopausal women (50-75 years). All participants had serum 25-hydroxyvitamin D (25(OH)D) levels ≥ 10-<32 ng/mL ("insufficient") and concurrently completed a behavioral weight loss program. Random periareolar fine needle aspiration (RPFNA) and abdominal subcutaneous adipose tissue biopsies were performed at baseline and 12 months. Changes in expression of aromatase (CYP19A1), peroxisome proliferator-activated receptor gamma (PPARG), adiponectin (ADIPOQ), monocyte-chemoattractant protein 1 (MCP-1), and vitamin D receptor (VDR) were analyzed by qRT-PCR. Compared to placebo, 2000 IU vitamin D did not show significant effects on gene expression in breast or adipose tissue. Replete women (i.e., 25(OH)D ≥ 32 ng/mL; N = 17) showed a small decrease in MCP-1 expression compared to an increase among women who remained 'insufficient' despite supplementation (N = 12) (Replete:-1.6% vs. Non-replete: 61.2%, p = 0.015) in breast, but not adipose tissue. No statistically significant differences in gene expression were detected according to degree of weight loss. Vitamin D repletion during weight loss may have different effects on gene expression in breast and adipose tissue. Further research on the localized effects of vitamin D is needed to determine its effect on breast cancer risk.

Effects of Vitamin D3 Supplementation on Lean Mass, Muscle Strength, and Bone Mineral Density During Weight Loss: A Double-Blind Randomized Controlled Trial.

OBJECTIVES: To compare the effects of 12 months of vitamin D3 supplementation with that placebo on lean mass, bone mineral density (BMD), and muscle strength in overweight or obese postmenopausal women completing a structured weight-loss program. DESIGN: Double-blind, placebo-controlled randomized clinical trial. SETTING: Fred Hutchinson Cancer Research Center, Seattle, Washington. PARTICIPANTS: Postmenopausal women aged 50 to 75 with a body mass index (BMI) of 25 kg/m(2) or greater and a serum 25-hydroxyvitamin D (25(OH)D) concentration between 10.0 and 32.0 ng/mL (insufficient) (N = 218). INTERVENTION: Oral vitamin D3 2,000 IU/d or placebo in combination with a lifestyle-based weight loss intervention consisting of a reduction of 500 kcal to 1,000 kcal per day and 225 min/wk of moderate- to vigorous-intensity aerobic exercise. MEASUREMENTS: Serum 25(OH)D, body composition, and muscle strength were measured before randomization (baseline) and at 12 months. Mean changes of the groups were compared (intention to treat) using generalized estimating equations. RESULTS: Change in 25(OH)D was significantly different between the vitamin D and placebo groups at 12 months (13.6 ng/mL vs -1.3 ng/mL, P < .001), but no differences in change in lean mass (-0.8 kg vs -1.1 kg, P = .53) or BMD of the spine (-0.01 g/cm(2) vs 0.0 g/cm(2) , P = .82) or right femoral neck (both -0.01 g/cm(2) , P = .49) were detected between the groups. Leg strength decreased in the vitamin D group but not in the placebo group (-2.6 pounds vs 1.8 pounds, P = .03). In women randomized to vitamin D, achieving repletion (25(OH)D ≥ 32 ng/mL) did not alter results. CONCLUSION: Vitamin D3 supplementation during weight-loss decreased leg strength but did not alter changes in lean mass or BMD in postmenopausal women with vitamin D insufficiency.

Effects of vitamin D supplementation during weight loss on sex hormones in postmenopausal women.

OBJECTIVE: The aim of the study was to compare the effects of vitamin D3 supplementation versus placebo on serum sex hormones in postmenopausal women completing a 12-month diet + exercise weight loss program. METHODS: Two hundred eighteen overweight or obese women (50-75 y) with serum 25-hydroxyvitamin D at least 10 to less than 32 ng/mL ("insufficient") were randomized to either weight loss + 2,000 IU/day oral vitamin D3, or to weight loss + daily placebo. Serum sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone were measured by radioimmunoassay before randomization and at 12 months. Mean changes were compared between groups (intent-to-treat) using generalized estimating equations. RESULTS: The 12-month changes in sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone did not differ between groups (all P > 0.05). However, a greater increase in serum 25-hydroxyvitamin D was associated with a greater increase in sex hormone-binding globulin (Ptrend = 0.01), and larger decreases in free and bioavailable estradiol (Ptrend = 0.04, Ptrend = 0.03, respectively). In post-hoc analyses, we compared women randomized to vitamin D whose serum 25-hydroxyvitamin D remained insufficient (n = 38), to women who became replete (25-hydroxyvitamin D ≥32 ng/mL; n = 53). Replete women showed greater reductions in bioavailable estradiol (-1.8 vs -0.7 pg/mL), free testosterone (-0.8 vs -0.3 pg/mL), and bioavailable testosterone (-1.8 vs -0.6 ng/dL), and a greater increase in sex hormone-binding globulin (10.6 vs 4.7 nmol/L) (all P < 0.05), even after adjusting for differences in total 12-month weight loss. CONCLUSIONS: Overall, 12-month changes in sex hormone did not differ between groups. However, vitamin D repletion was associated with greater reductions in sex hormones during weight loss, with a possible dose-dependent effect. Future studies should test higher doses and target circulating 25-hydroxyvitamin D levels when measuring such effects.

Effect of Vitamin D3 Supplementation in Combination with Weight Loss on Inflammatory Biomarkers in Postmenopausal Women: A Randomized Controlled Trial.

Obesity and vitamin D deficiency are associated with risk for several cancers, possibly through inflammation and adipokine-related pathways. Two hundred and eighteen postmenopausal women with BMI > 25 kg/m(2) and low serum 25-hydroxyvitamin D (25(OH)D; ≥10-<32 ng/mL), were randomized to 12 months of either (i) weight-loss intervention + 2000 IU/day oral vitamin D3 or (ii) weight-loss intervention + daily placebo. Serum adiponectin, leptin, TNFα, IL6, IL1ß, IL8, and IL10, were measured by immunoassay, and a composite inflammatory biomarker score calculated. Using generalized estimating equations, mean changes in outcomes were compared between arms (intent-to-treat), adjusted for possible confounders. Analyses were also stratified by weight-loss (gained/no weight-loss; <5%; 5% to 10%; ≥10%). At 12 months, there were no significant differences in analyte changes between arms. In stratified analyses, participants randomized to vitamin D3 who lost 5% to 10% of baseline weight, versus participants who gained weight/had no weight-loss, had significantly greater decreases in levels of IL6 compared with those randomized to placebo: absolute change -0.75 pg/mL (-17.2%), placebo versus -1.77 pg/mL (-37.3%), vitamin D, P = 0.004. Similar but attenuated results were observed for participants who lost ≥10% of baseline weight: -0.41 pg/mL (-13.6%), placebo versus -0.67 pg/mL (-17.3%), vitamin D, P = 0.02. Effects of vitamin D3 supplementation on levels of IL1ß were inconsistent when stratified by weight loss. There were no intervention effects on IL10, TNFα, IL8, the composite score, adiponectin, or leptin, when stratified by weight-loss. In conclusion, vitamin D3 supplementation in combination with weight-loss of at least 5% of baseline weight was associated with significant reductions in levels of IL6.

No effect of caloric restriction or exercise on radiation repair capacity.

INTRODUCTION: Maintenance of normal weight and higher levels of physical activity are associated with a reduced risk of several types of cancer. Because genomic instability is regarded as a hallmark of cancer development, one proposed mechanism is improvement of DNA repair function. We investigated links between dietary weight loss, exercise, and strand break rejoining in an ancillary study to a randomized-controlled trial. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized to the following: a) reduced calorie weight loss diet ("diet," n = 118), b) moderate- to vigorous-intensity aerobic exercise ("exercise," n = 117), c) a combination ("diet + exercise," n = 117), or d) control (n = 87). The reduced calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 min of moderate to vigorous aerobic activity 5 d·wk for 12 months. DNA repair capacity was measured in a subset of 226 women at baseline and 12 months from cryopreserved peripheral mononuclear cells using the comet assay. Anthropometric and body composition measures were performed at baseline and 12 months. RESULTS: DNA repair capacity did not change significantly with any of the 12-month interventions compared with control; there were also no significant changes when stratified by changes in body composition or aerobic fitness (V˙O2max). At baseline, DNA repair capacity was positively associated with weight, body mass index, and fat mass (r = 0.20, P = 0.003; r = 0.19, P = 0.004; r = 0.13, P = 0.04, respectively) and inversely with lean body mass (r = -0.14, P = 0.04). CONCLUSION: In conclusion, DNA repair capacity in cryopreserved PBMCs (Comet Assay) did not change with dietary weight loss or exercise interventions in postmenopausal women within a period of 12 months. Other assays that capture different facets of DNA repair function may be needed.

Vitamin D3 supplementation during weight loss: a double-blind randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with obesity; whether repletion supports weight loss and changes obesity-related biomarkers is unknown. OBJECTIVE: We compared 12 mo of vitamin D3 supplementation with placebo on weight, body composition, insulin, and C-reactive protein (CRP) in postmenopausal women in a weight-loss intervention. DESIGN: A total of 218 overweight/obese women (50-75 y of age) with serum 25-hydroxyvitamin D [25(OH)D] ≥10 ng/mL but <32 ng/mL were randomly assigned to weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo. The weight-loss intervention included a reduced-calorie diet (10% weight loss goal) and 225 min/wk of moderate-to-vigorous aerobic activity. Mean 12-mo changes in weight, body composition, serum insulin, CRP, and 25(OH)D were compared between groups (intent-to-treat) by using generalized estimating equations. RESULTS: A total of 86% of participants completed the 12-mo measurements. The mean (95% CI) change in 25(OH)D was 13.6 (11.6, 15.4) ng/mL in the vitamin D3 arm compared with -1.3 (-2.6, -0.3) ng/mL in the placebo arm (P < 0.0001). Changes in weight [-7.1 (-8.7, -5.7) compared with -7.4 (-8.1, -5.4) kg], body mass index (in kg/m(2): both -2.8), waist circumference [-4.9 (-6.7, -2.9) compared with -4.5 (-5.6, -2.6) cm], percentage body fat [-4.1 (-4.9, -2.9) compared with -3.5 (-4.5, -2.5)], trunk fat [-4.1 (-4.7, -3.0) compared with -3.7 (-4.3, -2.9) kg], insulin [-2.5 (-3.4, -1.7) compared with -2.4 (-3.3, -1.4) µU/mL], and CRP [-0.9 (-1.2, -0.6) compared with -0.79 (-0.9, -0.4) mg/L] [corrected] were similar between groups (all P > 0.05). Compared with women who achieved 25(OH)D <32 ng/mL, women randomly assigned to vitamin D who became replete (ie, 25(OH)D ≥32 ng/mL) lost more weight [-8.8 (-11.1, -6.9) compared with -5.6 (-7.2, -5.0) kg; P = 0.05], waist circumference [-6.6 (-9.3, -4.3) compared with -2.5 (-4.6, -2.0) cm; P = 0.02], and percentage body fat [-4.7 (-6.1, -3.5) compared with -2.6 (-3.9, -2.2); P = 0.04]. Among women with complete pill counts (97% adherence), the mean decrease in CRP was 1.18 mg/mL (46%) in the vitamin D arm compared with 0.46 mg/mL (25%) in the placebo arm (P = 0.03). CONCLUSIONS: Vitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements. This trial was registered at clinicaltrials.gov as NCT01240213.

Long-term physical activity trends in breast cancer survivors.

BACKGROUND: Physical activity is associated with reduced mortality and higher quality of life in breast cancer survivors; however, limited data on the prevalence of activity and long-term trends after diagnosis are available. METHODS: A multiethnic cohort of 631 women (18-64 years) with stage 0 to IIIA breast cancer was followed for 10 years. Recreational aerobic activity (MET-h/wk) was ascertained for the year before diagnosis (baseline), 24 months, 5 years, and 10 years after enrollment. Women were classified according to U.S. physical activity guidelines (≥150 min/wk moderate or ≥75 min/wk vigorous activity). The OR for meeting guidelines at 5 and 10 years according to baseline factors was estimated using logistic regression. The change in MET-h/wk was predicted using linear regression. RESULTS: Prediagnosis, 34% of women met physical activity guidelines; 34.0%, 39.5%, and 21.4% met guidelines at 24 months, 5 years, and 10 years after enrollment, respectively. Less than 8% of survivors met guidelines at all follow-up periods. Over 10 years, recreational aerobic activity decreased by a mean ± SD of 4.3 ± 16.2 MET-h/wk. Meeting guidelines pre-diagnosis was strongly associated with meeting guidelines at 5 years [OR (95% confidence interval; CI): 2.76 (1.85-4.1)] and 10 years [OR (95% CI): 3.35 (2.13-5.28)]. No other demographic or prognostic factors were significantly associated with the 10-year change in MET-h/wk. CONCLUSION: The vast majority of early breast cancer survivors do not meet national exercise recommendations 10 years postdiagnosis. IMPACT: Physical activity levels are low in breast cancer survivors across the 10 years postdiagnosis; nonetheless, the predictors of activity in this population remain poorly understood.

Effects of dietary weight loss and exercise on insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in postmenopausal women: a randomized controlled trial.

High levels of insulin-like growth factor (IGF)-I may increase the risk of common cancers in humans. We hypothesized that weight loss induced by diet and/or exercise would reduce IGF-I in postmenopausal women. Four hundred and thirty nine overweight or obese [body mass index (BMI) ≥ 25 kg/m(2)] women (50-75 years) were randomly assigned to: (i) exercise (N = 117), (ii) dietary weight loss (N = 118), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 minutes/day, 5 days/week of moderate-to-vigorous intensity activity. Fasting serum IGF-I and IGF-binding protein (IGFBP)-3 were measured at baseline and 12 months by radioimmunoassay. Higher baseline BMI was associated with lower IGF-I and IGF-I/IGFBP-3 molar ratio. Although no significant changes in either IGF-I or IGFBP-3 were detected in any intervention arm compared with control, the IGF-I/IGFBP-3 ratio increased significantly in the diet (+5.0%, P < 0.01) and diet + exercise (+5.4%, P < 0.01) groups compared with control. Greater weight loss was positively associated with change in both IGF-I (P(trend) = 0.017) and IGF-I/IGFBP-3 ratio (P(trend) < 0.001) in the diet group, but inversely with change in IGFBP-3 in the diet + exercise group (P(trend) = 0.01). No consistent interaction effects with baseline BMI were detected. Modified IGF-I bioavailability is unlikely to be a mechanism through which caloric restriction reduces cancer risk in postmenopausal women.