eScholarship@UMMS

Syndicate content
Recent documents in eScholarship@UMMS
Updated: 1 hour 40 min ago

Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations

Mon, 02/10/2014 - 12:55pm

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts.

Salicylate prevents virus-induced type 1 diabetes in the BBDR rat

Mon, 02/10/2014 - 12:55pm

Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR) rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV) and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist) develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1beta, IL-6, IFN-gamma, IL-12, and haptoglobin (an acute phase protein) in KRV+pIC treated rats. Significant elevations of IL-1beta and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1beta, IL-6, IFN-gamma and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus-induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes.

KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance

Mon, 02/10/2014 - 12:55pm

Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1alpha expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.

Toll-like receptor induced pro-interleukin-1beta and interleukin-6 in monocytes are lower in healthy infants compared to adults

Mon, 02/10/2014 - 12:55pm

Infants have long been known to have higher infectious diseases morbidity and mortality and suboptimal vaccination responses compared to older children and adults. A variety of differences in innate and adaptive immune responses have been described between these two groups. We compared Toll-like receptor (TLR)-induced production of pro-interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha between 2-month-old infants and adults. TLR 7/8-induced production of pro-IL-1beta and IL-6 in monocytes was lower in 2-month-old infants compared to adults. There was no difference in TLR 7/8-induced production of TNF-alpha. Lower TLR-induced production of pro-IL-1beta and IL-6 in innate immune cells during early infancy likely contributes to suboptimal vaccine responses and infectious diseases susceptibility.

E-Science as a Catalyst for Transformational Change in University Research Libraries: A Dissertation

Fri, 02/07/2014 - 11:21am

Changes in how research is conducted, from the growth of e-science to the emergence of big data, have lead to new opportunities for librarians to become involved in the creation and management of research data, at the same time the duties and responsibilities of university libraries continue to evolve. This study examines those roles related to e-science while exploring the concept of transformational change and leadership issues in bringing about such a change. Using the framework established by Levy and Merry for first- and second-order change, four case studies of libraries whose institutions are members in the Association of Research Libraries (ARL) are developed. The case studies highlight why the libraries became involved in e-science, the role librarians are assuming related to data management education and policy, and the provision of e-science programs and services. Each case study documents the structural and programmatic changes that have occurred in a library to provide e-science services and programs, the future changes library leaders are working to implement, and the change management process used by managerial leaders to bringing about, and permanently embed those changes into the library culture. Themes such as vision, team leadership, the role of library

Roundtable Discussion and Final Comments

Fri, 02/07/2014 - 10:38am

Roundtable discussion of: Berkowitz B. Studying the outcomes of community-based coalitions. Am J Community Psychol. 2001 Apr;29(2):213-27

Physicians' responses to financial incentives. Evidence from a for-profit ambulatory care center

Fri, 02/07/2014 - 10:04am

Health Stop is a major chain of ambulatory care centers operating for profit. Until 1985 its physicians were paid a flat hourly wage. In the middle of that year, a new compensation plan was instituted to provide doctors with financial incentives to increase revenues. Physicians could earn bonuses the size of which depended on the gross incomes they generated individually. We compared the practice patterns of 15 doctors, each employed full time at a different Health Stop center in the Boston area, in the same winter months before and after the start of the new arrangement. During the periods compared, the physicians increased the number of laboratory tests performed per patient visit by 23 percent and the number of x-ray films per visit by 16 percent. The total charges per month, adjusted for inflation, grew 20 percent, mostly as a result of a 12 percent increase in the average number of patient visits per month. The wages of the seven physicians who regularly earned the bonus rose 19 percent. We conclude that substantial monetary incentives based on individual performance may induce a group of physicians to increase the intensity of their practice, even though not all of them benefit from the incentives.

Carrying out the Medicine/Public Health Initiative: the roles of preventive medicine and community-responsive care

Fri, 02/07/2014 - 10:04am

Leaders in medicine and public health, recognizing the inherent interdependency of these fields, established the Medicine/Public Health Initiative in the mid-1990s as "an evolving forum in which representatives of both sectors can explore their mutual interests in improving health and [can] define collaborative mechanisms to achieve that goal." The Initiative's participants developed six goals that they and others in medicine and public health across the nation should implement: engage the community; change the education process; create joint research efforts by clinical, public health, and preventive medicine investigators; develop a shared view of illness between medicine and public health; work together to provide health care; and work jointly to develop health care assessment measures. The authors describe the six goals in depth and explain the important combined roles of clinically-oriented preventive medicine and community-oriented preventive medicine--as practiced in a model of health care delivery called community-oriented primary care (COPC)--in implementing the Initiative's goals. They then report recent efforts, including two in Boston and Dallas, to merge medicine and public health, and state that academic health centers, which are in the process of reshaping themselves, can help themselves as well as the public by embracing their key role in the effort to integrate medicine and public health. In particular, they can expand and strengthen existing training programs in preventive medicine and COPC or add these programs to their curricula.

Primary prevention for resettled refugees from Burma: where to begin?

Fri, 02/07/2014 - 10:03am

Developing effective primary prevention initiatives may help recently arrived refugees retain some of their own healthy cultural habits and reduce the tendency to adopt detrimental ones. This research explores recent arrivals' knowledge regarding eating behaviors, physical activity and sleep habits. Working collaboratively with community members, a healthy living curriculum was adapted and pilot tested in focus groups. A community-engaged approach to revising and implementing a health promotion tool was effective in beginning dialogue about primary prevention among a group of recently arrived refugees from Burma. Seven themes were identified as particularly relevant: food choices, living environment, health information, financial stress, mobility/transportation, social interaction and recreation, and hopes and dreams. Refugees desire more specific information about nutrition and exercise, and they find community health workers an effective medium for delivering this information. The outcomes of this study may inform future targeted interventions for health promotion with refugees from Burma.

Cognitive impairment and self-care in heart failure

Thu, 02/06/2014 - 12:52pm

BACKGROUND: Heart failure (HF) is a prevalent chronic disease in older adults that requires extensive self-care to prevent decompensation and hospitalization. Cognitive impairment may impact the ability to perform HF self-care activities. We examined the association between cognitive impairment and adherence to self-care in patients hospitalized for acute HF.

DESIGN: Prospective cohort study.

SETTING AND PARTICIPANTS: A total of 577 patients (mean age = 71 years, 44% female) hospitalized for HF at five medical centers in the United States and Canada.

MEASUREMENTS AND METHODS: Participants were interviewed for information on self-reported adherence to self-care using the European Heart Failure Self-care Behaviour Scale. We assessed cognitive impairment in three domains (memory, processing speed, and executive function) using standardized measures. Patients' demographic and clinical characteristics were obtained through medical record review. Multivariable linear regression was used to examine the association between cognitive impairment and self-care practices adjusting for demographic and clinical factors.

RESULTS: A total of 453 patients (79%) were impaired in at least one cognitive domain. Average adherence to self-care activities among patients with global cognitive impairment did not differ significantly from those without cognitive impairment (30.5 versus 29.6; 45-point scale). However, impaired memory was associated with lower self-care scores (P = 0.006) in multivariable models.

CONCLUSION: Cognitive impairment is highly prevalent among older patients hospitalized for HF. Memory impairment is associated with poorer adherence to self-care practices. Screening for memory impairment in patients with HF may help to identify patients at risk for poor self-care who may benefit from tailored disease management programs.

Culture, Behavior, and Health

Wed, 02/05/2014 - 11:50am

Chapter learning objectives: Understand cultural concepts and various mechanisms through which culture influences health and health behavior; apply major health behavior theories to culture and health; determine strategies to incorporate culture into research and health care.

Translational Research Phases in the Behavioral and Social Sciences: Adaptations from the Biomedical Sciences

Wed, 02/05/2014 - 11:50am

Chapter learning objectives: Define translational research and understand its importance to improve population health; compare and contrast translational research phases in biomedical research with behavioral and social sciences research; identify strategies to improve translational research in health behavior change interventions.

Weight gain prevention in the school worksite setting: Results of a multi-level cluster randomized trial

Tue, 02/04/2014 - 5:20pm

OBJECTIVE: To describe the effectiveness, reach and implementation of a weight gain prevention intervention among public school employees.

METHOD: A multi-level intervention was tested in a cluster randomized trial among 782 employees in 12 central Massachusetts public high schools from 2009 to 2012. The intervention targeted the nutrition and physical activity environment and policies, the social environment and individual knowledge, attitudes and skills. The intervention was compared to a materials only condition. The primary outcome measures were change in weight and body mass index (BMI) at 24-month follow-up. Implementation of physical environment, policy and social environment strategies at the school and interpersonal levels, and intervention participation at the individual level were assessed.

RESULTS: At 24-month follow-up, there was a net change (difference of the difference) of -3.03 pounds (p=.04) and of -.48 BMI units (p=.05) between intervention and comparison conditions. The majority of intervention strategies were successfully implemented by all intervention schools, although establishing formal policies was challenging. Employee participation in programs targeting the physical and social environment was maintained over time.

CONCLUSION: This study supports that a multi-level intervention integrated within the organizational culture can be successfully implemented and prevent weight gain in public high school employees.

Development and validation of the Lifestyle Self-Efficacy Scale for Latinos with Diabetes (LSESLD)

Tue, 02/04/2014 - 5:20pm

OBJECTIVES: To develop and validate a self-efficacy measure of diabetes self-management, the Lifestyle Self-Efficacy Scale for Latinos with Diabetes (LSESLD), designed for low-income, Spanish-speaking Latinos with diabetes.

DESIGN: Quantitative and qualitative methods.

SETTING: Community health centers in central and western Massachusetts.

PARTICIPANTS: Low-income Latinos (N = 252) enrolled in a randomized diabetes self-management intervention trial.

MEASURES: Construct validity, internal consistency, sensitivity to change over time.

RESULTS: The LSESLD demonstrated good internal consistency (Cronbach's alpha = .85), reasonable construct validity (moderate, significant associations between the LSESLD and validated measures of diabetes knowledge, dietary intake, physical activity, blood glucose self-monitoring, and HbA1c values), and sensitivity to intervention-related changes over time.

CONCLUSION: The LSESLD is a reliable and valid research instrument assessing self-efficacy related to diabetes self-management among low-income, Spanish-speaking populations.

Middle school food environments and racial/ethnic differences in sugar-sweetened beverage consumption: findings from the Healthy Choices study

Tue, 02/04/2014 - 5:20pm

BACKGROUND: Prior studies have demonstrated disproportionate clustering of fast food outlets around schools.

PURPOSE: The purpose of this study is to determine if racial/ethnic differences in middle school student self-reported sugar-sweetened beverage (SSB) consumption is explained by differential distributions of food outlets surrounding their schools.

METHODS: Baseline (2005) data were analyzed from 18,281 middle school students in 47 Massachusetts schools participating in Healthy Choices, an obesity prevention program. Linear mixed effects models were used to examine the association of individual race/ethnicity and daily SSB consumption and the potential mediating effect of the density of food outlets (the number of fast food outlets and convenience stores in a 1500 m buffer area surrounding the school) on this association adjusting for individual and school demographics.

RESULTS: More SSB consumption was reported by students of all racial/ethnic minority groups compared to their White peers except Asians. The density of fast food restaurants and convenience stores was not associated with individual SSB consumption (beta=0.001, p=0.875) nor did it mediate the association of race/ethnicity and SSB consumption.

CONCLUSIONS: Racial and ethnic differences in SSB consumption among MA middle school students cannot be fully explained by the location of fast food restaurants and convenience stores.

Family physical activity and meal practices associated with disordered weight control behaviors in a multiethnic sample of middle-school youth

Tue, 02/04/2014 - 5:20pm

OBJECTIVE: Family practices around weight-related behaviors can shape children's development of disordered weight control behaviors (DWCB), such as vomiting, taking laxatives, or taking diet pills without a prescription. This study examined family meal and physical activity (PA) practices associated with DWCB among a multiethnic sample of youth.

METHODS: We assessed self-report data on frequency of family sit-down dinners, types of parental involvement in their children's PA, and DWCB are from 15,461 6th to 8th grade girls and boys in 47 middle schools participating in the Massachusetts Healthy Choices Study at baseline (2005).

RESULTS: Youth who had family sit-down dinners every day had lower odds of DWCB (girls: odds ratio [OR] 0.3; 95% confidence interval [CI] 0.2-0.5; boys: OR 0.6; 95% CI 0.4-0.9) than youth who never had family sit-down dinners. Similar effect estimates were found for youth who had family sit-down dinners most days. Parental provision of rides to and from a PA event was also found to be protective against DWCB among girls (OR 0.7; 95% CI 0.5-0.9). In contrast, parental participation in PA with their children was associated with increased risk for DWCB (girls: OR 1.4; 95% CI 1.0-1.8; boys: OR 1.9; 95% CI 1.4-2.4). These associations did not differ by race/ethnicity or weight status.

CONCLUSIONS: Programs emphasizing the importance of family meals may be beneficial in preventing DWCB in youth of all ethnicities. Further research is needed on how various methods of parental involvement in their children's PA are associated with DWCB. rights reserved.

Environmental factors associated with disordered weight-control behaviours among youth: a systematic review

Tue, 02/04/2014 - 5:20pm

OBJECTIVE: Environmental factors may be very important in the development of disordered weight-control behaviours (DWCB) among youth, yet no study to date has conducted a review that synthesizes these findings. The purpose of the present study was to systematically review existing literature on environmental influences on DWCB among youth and to identify conceptual and methodological gaps in the literature.

DESIGN: Systematic review.

SETTING: Studies were identified through a systematic search using PubMed, PsycINFO, Google Scholar and secondary references. Inclusion criteria included observational studies published in peer-reviewed journals from 1994 to 2012 that examined environmental exposure(s) associated with DWCB among youth.

SUBJECTS: Ninety-three studies, the majority of which utilized a cross-sectional design (75 %; n 70), were identified. Longitudinal studies' follow-up time ranged from 8 months to 10 years.

RESULTS: Parental, peer and media influences have been extensively studied as factors associated with DWCB among youth. Fewer studies have examined behavioural settings (i.e. homes, schools, neighbourhoods) or sectors of influence other than the media on DWCB. No studies utilized multilevel methods to parse out environmental influences on DWCB. Most studies (69 %, n 64) did not explicitly utilize a theory or model to guide the research.

CONCLUSIONS: Findings indicate that exploring a wider range of environmental influences on DWCB, specifically behavioural settings and sectors of influence, using diverse study samples and multilevel methodology is needed to advance the field and to inform the design of comprehensive prevention programmes that target DWCB and other weight-related behaviours.

The contribution of school environmental factors to individual and school variation in disordered weight control behaviors in a statewide sample of middle schools

Tue, 02/04/2014 - 5:20pm

We investigated the contribution of school environmental factors to individual and school variation in disordered weight control behaviors (DWCB). Analyses were based on self-report data gathered from 18,567 middle-school students in 2005 and publicly available data on school characteristics. We observed large differences across schools in percent of students engaging in DWCB in the past month, ranging from less than 1% of the student body to 12%. School-neighborhood poverty was associated with higher odds of DWCB in boys. Preventive strategies need to account for wide variability across schools and environmental factors that may contribute to DWCB in early adolescence.