Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.

Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.

Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans.

Alternations of redox metabolism have been associated with the extension of lifespan in roundworm Caenorhabditis elegans, caused by moderate mitochondrial dysfunction, although the underlying signalling cascades are largely unknown. Previously, we identified transcriptional factor Krüppel-like factor-1 (KLF-1) as the main regulator of cytoprotective longevity-assurance pathways in the C. elegans long-lived mitochondrial mutants. Here, we show that KLF-1 translocation to the nucleus and the activation of the signalling cascade is dependent on the mitochondria-derived hydrogen peroxide (H2O2) produced during late developmental phases where aerobic respiration and somatic mitochondrial biogenesis peak. We further show that mitochondrial-inducible superoxide dismutase-3 (SOD-3), together with voltage-dependent anion channel-1 (VDAC-1), is required for the life-promoting H2O2 signalling that is further regulated by peroxiredoxin-3 (PRDX-3). Increased H2O2 release in the cytoplasm activates the p38 MAPK signalling cascade that induces KLF-1 translocation to the nucleus and the activation of transcription of C. elegans longevity-promoting genes, including cytoprotective cytochrome P450 oxidases. Taken together, our results underline the importance of redox-regulated signalling as the key regulator of longevity-inducing pathways in C. elegans, and position precisely timed mitochondria-derived H2O2 in the middle of it.

Helping persons with multiple chronic conditions overcome barriers to self-management.

ABSTRACT: The prevalence of multiple chronic conditions is growing dramatically, which complicates day-to-day self-management for patients. This article describes the features of multiple chronic conditions, an updated chronic care model, barriers to self-management, and strategies NPs can use to reduce or eliminate barriers to self-management in adults with multiple chronic conditions.

A salvage pathway maintains highly functional respiratory complex I.

Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation of dysfunctional CI arising from the inactivation of the N-module subunits due to attrition caused by its constant activity under physiological conditions. This CI salvage pathway maintains highly functional CI through a favorable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. Our results also identify ClpXP activity as an unforeseen target for therapeutic interventions in the large group of mitochondrial diseases characterized by the CI instability.

KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants.

Most manipulations that extend lifespan also increase resistance to various stress factors and environmental cues in a range of animals from yeast to mammals. However, the underlying molecular mechanisms regulating stress resistance during aging are still largely unknown. Here we identify Krüppel-like factor 1 (KLF-1) as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage L3 to D1. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.

U.S. Preventive Services Task Force Methods to Communicate and Disseminate Clinical Preventive Services Recommendations.

The U.S. Preventive Services Task Force (USPSTF) issues evidence-based screening and prevention recommendations, and key to this task is dissemination and implementation of these recommendations. The Task Force has recommendations for more than 84 topics; each USPSTF Recommendation Statement includes a letter grade, a topline summary to guide clinician interpretation in practice, and a summary of gaps in evidence to help catalyze clinically relevant research. The USPSTF aims to update existing topics regularly and considers new topics to add each year. Clearly communicating and disseminating each recommendation is a critical task to ensure maximum benefit from use of the recommendations. The primary USPSTF audience is primary care clinicians. Over time, other audiences have become interested in the USPSTF and these entities have broad and diverse needs, necessitating a range of communication platforms and approaches. This includes engagement with and input from topic experts, primary care and federal partners, and the public to help shape the development of the recommendations. It also includes engagement of partners to disseminate USPSTF recommendations to help ensure that the primary care workforce remains up-to-date on USPSTF recommendations. This paper outlines the approaches used by the USPSTF to both solicit input (e.g., public comment periods), as well as to facilitate dissemination of its recommendations to help improve the health of all Americans (e.g., web-based and mobile application tools, journal publications, and annual reports to Congress).

Screening for Impaired Visual Acuity in Older Adults: US Preventive Services Task Force Recommendation Statement.

DESCRIPTION: Update of the US Preventive Services Task Force (USPSTF) recommendation on screening for impaired visual acuity in older adults. METHODS: The USPSTF reviewed the evidence on screening for visual acuity impairment associated with uncorrected refractive error, cataracts, and age-related macular degeneration among adults 65 years or older in the primary care setting; the benefits and harms of screening; the accuracy of screening; and the benefits and harms of treatment of early vision impairment due to uncorrected refractive error, cataracts, and age-related macular degeneration. POPULATION: This recommendation applies to asymptomatic adults 65 years or older who do not present to their primary care clinician with vision problems. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in older adults. (I statement).

Screening for Autism Spectrum Disorder in Young Children: US Preventive Services Task Force Recommendation Statement.

DESCRIPTION: New US Preventive Services Task Force (USPSTF) recommendation on screening for autism spectrum disorder (ASD) in young children. METHODS: The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of brief, formal screening instruments for ASD administered during routine primary care visits and the benefits and potential harms of early behavioral treatment for young children identified with ASD through screening. POPULATION: This recommendation applies to children aged 18 to 30 months who have not been diagnosed with ASD or developmental delay and for whom no concerns of ASD have been raised by parents, other caregivers, or health care professionals. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children for whom no concerns of ASD have been raised by their parents or a clinician. (I statement).

Screening for Depression in Adults: US Preventive Services Task Force Recommendation Statement.

DESCRIPTION: Update of the 2009 US Preventive Services Task Force (USPSTF) recommendation on screening for depression in adults. METHODS: The USPSTF reviewed the evidence on the benefits and harms of screening for depression in adult populations, including older adults and pregnant and postpartum women; the accuracy of depression screening instruments; and the benefits and harms of depression treatment in these populations. POPULATION: This recommendation applies to adults 18 years and older. RECOMMENDATION: The USPSTF recommends screening for depression in the general adult population, including pregnant and postpartum women. Screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. (B recommendation).

Evaluating Feasible and Referable Behavioral Counseling Interventions.

The U.S. Preventive Services Task Force (USPTF) recognizes that behaviors have a major impact on health and well-being. Currently, the USPSTF has 11 behavioral counseling intervention (BCI) recommendations. These BCIs can be delivered in a primary care setting or patients can be referred to other clinical or community programs. Unfortunately, many recommended BCIs are infrequently and ineffectually delivered, suggesting that more evidence is needed to understand which BCIs are feasible and referable. In response, the USPSTF convened an expert forum in 2013 to inform the evaluation of BCI feasibility. This manuscript reports on findings from the forum and proposes that researchers use several frameworks to help clinicians and the USPSTF evaluate which BCIs work under usual conditions. A key recommendation for BCI researchers is to use frameworks whose components can support dissemination and implementation efforts. These frameworks include the Template for Intervention Description and Replication (TIDieR), which helps describe the essential components of an intervention, and pragmatic frameworks like Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) or Pragmatic-Explanatory Continuum Indicator Summary (PRECIS), which help to report study design elements and outcomes. These frameworks can both guide the design of more-feasible BCIs and produce clearer feasibility evidence. Critical evidence gaps include a better understanding of which patients will benefit from a BCI, how flexible interventions can be without compromising effectiveness, required clinician expertise, necessary intervention intensity and follow-up, impact of patient and clinician intervention adherence, optimal conditions for BCI delivery, and how new care models will influence BCI feasibility.

A demonstration of peer support for Ugandan adults with type 2 diabetes.

BACKGROUND: By 2030, 80% of people with diabetes will be living in developing countries. PURPOSE: The purpose of this pre-post quasi-experimental study was to test the feasibility of a peer intervention to improve the following: (1) diabetes self-care behaviors, (2) glycemic control, (3) social support and emotional well-being, (4) linkages to health care providers, and (5) to assess the sustainability of the intervention 18 months later. METHOD: Participants were adults with type 2 diabetes who resided in rural Uganda. Participants (n = 46) attended a 1-day diabetes education program and agreed to make weekly contacts over 4 months with each other by phone or in person to assist with daily management, provide social and emotional support, and encourage appropriate contact with health care providers. RESULTS: Results indicated improvement in glycosylated hemoglobin (A1C), diastolic blood pressure, and eating behaviors. CONCLUSIONS: A short-term peer support program was a feasible intervention to improve diabetes care in rural Uganda. Participants were successfully recruited and retained, and they experienced positive behavioral and physiologic outcomes. Elements of the intervention were sustained 18 months after the intervention.

Succinate dehydrogenase upregulation destabilize complex I and limits the lifespan of gas-1 mutant.

Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity. We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor -1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPR(mt)). The major difference that we detected between mutants of different longevity, is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation.

Forced sexual experiences as risk factor for self-reported HIV infection among southern African lesbian and bisexual women.

Even though women who have sex with women are usually understood to be at no or very low risk for HIV infection, we explored whether lesbian and bisexual women in a geographical area with high HIV prevalence (Southern Africa) get tested for HIV and whether, among those women who get tested, there are women who live with HIV/AIDS. The study was conducted in collaboration with community-based organizations in Botswana, Namibia, South Africa and Zimbabwe. Data were collected via written surveys of women who in the preceding year had had sex with a woman (18 years and older; N = 591). Most participating women identified as lesbian and black. Almost half of the women (47.2%) reported ever having had consensual heterosexual sex. Engagement in transactional sex (lifetime) was reported by 18.6% of all women. Forced sex by men or women was reported by 31.1% of all women. A large proportion of the women reported to ever have been tested for HIV (78.3%); number of lifetime female and male partners was independently associated with having been tested; women who had engaged in transactional sex with women only or with women and men were less likely to have been tested. Self-reported HIV prevalence among tested women who knew their serostatus was 9.6%. Besides age, the sole independent predictor of a positive serostatus was having experienced forced sex by men, by women, or by both men and women. Study findings indicate that despite the image of invulnerability, HIV/AIDS is a reality for lesbian and bisexual women in Southern Africa. Surprisingly, it is not sex with men per se, but rather forced sex that is the important risk factor for self-reported HIV infection among the participating women. HIV/AIDS policy should also address the needs of lesbian, bisexual and other women who have sex with women.

Evaluation of a Web-based malaria risk reduction game for study abroad students.

OBJECTIVE: Compare feedback strategies in 3 versions of an educational game. PARTICIPANTS: Study abroad students (N = 482) participated by playing the game and completing pregame/postgame surveys January-March 2010. METHODS: This study employed an experimental design. Primary outcome measures were knowledge gain, player satisfaction, and risk perception. RESULTS: One-third had previously traveled to a malaria-risk region, and two thirds planned to do so. Baseline malaria knowledge was low. Postgame knowledge and risk perception were significantly higher than pregame, irrespective of past travel status. The group that automatically received explanatory feedback following game decisions scored higher for mean knowledge gain, without differences in player satisfaction. CONCLUSIONS: The challenges of designing a feedback strategy to support Web-based learning make these results highly relevant to health educators developing interactive multimedia interventions. The increasing number of students traveling to higher-risk destinations demands attention. Both malaria-naive and malaria-experienced students would benefit from this approach to travel health education.

Helping patients with chronic conditions overcome barriers to self-care.

This article provides an overview of barriers to self-care, patients' perceptions and understanding of their chronic illness, interviewing techniques, and approaches nurse practitioners can use to reduce or eliminate barriers to self-care in adults with chronic conditions.

Peer support for self-management of diabetes improved outcomes in international settings.

Self-management of diabetes is essential to reducing the risks of associated disabilities. But effective self-management is often short-lived. Peers can provide the kind of ongoing support that is needed for sustained self-management of diabetes. In this context, peers are nonprofessionals who have diabetes or close familiarity with its management. Key functions of effective peer support include assistance in daily management, social and emotional support, linkage to clinical care, and ongoing availability of support. Using these four functions as a template of peer support, project teams in Cameroon, South Africa, Thailand, and Uganda developed and then evaluated peer support interventions for adults with diabetes. Our initial assessment found improvements in symptom management, diet, blood pressure, body mass index, and blood sugar levels for many of those taking part in the programs. For policy makers, the broader message is that by emphasizing the four key peer support functions, diabetes management programs can be successfully introduced across varied cultural settings and within diverse health systems.

Development of a malaria knowledge test for student travelers.

This paper describes a malaria knowledge test (MKT) developed to evaluate a web-based game for students who increasingly travel to malaria-risk regions of the world. The 18-item MKT was structured according to the dimensions of the self-regulation model (SRM) to measure the accuracy of students' beliefs about malaria. An experimental design was used to compare three game versions. Students (N=482) participated in 2010 by completing a pre-test, playing a Web-based game simulating student travel to malaria-endemic destinations, and completing a post-test. Study data support the validity and reliability of the MKT for the evaluation of malaria education interventions and for student self-assessment. Use of the MKT to evaluate an educational game about malaria revealed a strong overall learning effect and discrimination by game version, travel experience, and SRM dimension. This 5-min test may also be adapted for educational outreach purposes among health care providers globally, residents of malaria-endemic regions, and other high risk travel groups (e.g., elderly, chronic health conditions, pregnant, or returning to malaria-endemic regions to visit friends/relatives).

Predictors of low-income, obese mothers' use of healthful weight management behaviors.

OBJECTIVE: To examine the influence of personal and environmental factors on healthful weight management behaviors mediated through self-efficacy among low-income obese mothers. DESIGN: Cross-sectional design. SETTING: Special Supplemental Nutrition Program for Women, Infants, and Children in Wisconsin. PARTICIPANTS: Two hundred eighty-four obese mothers aged 18-34 years. MAIN OUTCOME MEASURES: Personal factors (eg, eating low-fat/low-calorie food for weight management), environmental factors, self-efficacy, and weight management behaviors. Data were collected via self-administered written questionnaires. ANALYSIS: Latent class cluster analysis and structural logistic regression. RESULTS: Women who perceived more importance of eating low-fat/low-calorie food for weight management were more likely to practice multiple behavioral strategies to manage their weight (odds ratio = 0.37) than women who perceived less importance of eating low-fat/low-calorie food for weight management. Women who reported higher positive mood self-efficacy were more likely (odds ratio = 1.63) to practice multiple strategies to manage their weight than women who reported lower positive mood self-efficacy. Environmental factors did not predict use of multiple healthful weight management behaviors. No mediation effect was found. CONCLUSIONS AND IMPLICATIONS: Stressing the importance of food choices and reinforcing learners' self-confidence to make healthful choices at parties and celebrations may be helpful ways to address common barriers to healthful weight management.

Insights on conducting research in low-resource settings: examples from Vietnam and Uganda.

This commentary describes key observations and strategies, based on the author's experiences in Vietnam and Uganda, for tailoring evidence-based behavioral medicine research in low-resource settings.

Perspectives on healthy behaviors among low-income Latino and non-Latino adults in two rural counties.

OBJECTIVES: Rural populations and individuals with low incomes are less likely than the general population to achieve recommended levels of physical activity and fruit and vegetable consumption. The purpose of this study was to describe the perspectives of low-income adults in 2 rural Wisconsin counties on the factors that influence physical activity and healthy eating. DESIGN AND SAMPLE: A qualitative descriptive study was conducted using 4 focus groups: 2 in English and 2 in Spanish. A convenience sample (N=20) was recruited. MEASURES: Focus group questions and data analysis were based on an ecological framework. A team of 3 researchers performed content analysis of focus group transcripts. RESULTS: Participants reported individual, social, and community influences on health behaviors. Individual barriers included lack of motivation and lack of knowledge. Participants described the importance of family, friends, and the community social climate for health behaviors. Latinos emphasized the need for resources such as community gardens and public spaces for physical activity, while non-Latinos recommended community education related to healthy eating. CONCLUSIONS: The results suggest that relevant health promotion strategies in rural, low-income populations include multilevel approaches, the development of schools as health promotion resources, and strategies to build social connections among community residents.