Parkinson's Disease in Relation to Pesticide Exposure and Nuclear Encoded Mitochondrial Complex I Gene Variants

Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with ∼ 2-fold risk variation in an Australian case-control sample. We further characterized this sample of 306 cases and 321 controls to determine the mutual information contained in the 22 SNPs and, additionally, level of pesticide exposure: five distinct risk sets were identified using grade-of-membership analysis. Of these, one was robust to pesticide exposure (I), three were vulnerable (II, III, IV), and another (V) denoted low risk for unexposed persons. Risk for individual subjects varied > 16-fold according to level of membership in the vulnerable groups. We conclude that inherited variation in mitochondrial complex I genes and pesticide exposure together modulate risk for PD

Challenges to generating political prioritization for adolescent sexual and reproductive health in Kenya: A qualitative study.

BackgroundDespite the high burden of adverse adolescent sexual and reproductive health (SRH) outcomes, it has remained a low political priority in Kenya. We examined factors that have shaped the lack of current political prioritization of adolescent SRH service provision.MethodsWe used the Shiffman and Smith policy framework consisting of four categories-actor power, ideas, political contexts, and issue characteristics-to analyse factors that have shaped political prioritization of adolescent SRH. We undertook semi-structured interviews with 14 members of adolescent SRH networks between February and April 2019 at the national level and conducted thematic analysis of the interviews.FindingsSeveral factors hinder the attainment of political priority for adolescent SRH in Kenya. On actor power, the adolescent SRH community was diverse and united in adoption of international norms and policies, but lacked policy entrepreneurs to provide strong leadership, and policy windows were often missed. Regarding ideas, community members lacked consensus on a cohesive public positioning of the problem. On issue characteristics, the perception of adolescents as lacking political power made politicians reluctant to act on the existing data on the severity of adolescent SRH. There was also a lack of consensus on the nature of interventions to be implemented. Pertaining to political contexts, sectoral funding by donors and government treasury brought about tension within the different government ministries resulting in siloed approaches, lack of coordination and overall inefficiency. However, the SRH community has several strengths that augur well for future political support. These include the diverse multi-sectoral background of its members, commitment to improving adolescent SRH, and the potential to link with other health priorities such as maternal health and HIV/AIDS.ConclusionIn order to increase political attention to adolescent SRH in Kenya, there is an urgent need for policy actors to: 1) create a more cohesive community of advocates across sectors, 2) develop a clearer public positioning of adolescent SRH, 3) agree on a set of precise approaches that will resonate with the political system, and 4) identify and nurture policy entrepreneurs to facilitate the coupling of adolescent SRH with potential solutions when windows of opportunity arise

Maternal separation with early weaning: a novel mouse model of early life neglect

<p>Abstract</p> <p>Background</p> <p>Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse.</p> <p>Results</p> <p>In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect.</p> <p>Conclusions</p> <p>These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.</p

Ariel - Volume 9 Number 4

Executive Editor Emily Wofford Business Manager Fredric Jay Matlin University News John Patrick Welch World News George Robert Coar Editorials Editor Steve Levine Features Mark Rubin Brad Feldstein Sports Editor EIi Saleeby Circulation Victor Onufreiczuk Lee Wugofski Graphics and Art Steve Hulkower Commons Editor Brenda Peterso

Combining experiment and energy landscapes to explore anaerobic heme breakdown in multifunctional hemoproteins

To survive, many pathogens extract heme from their host organism and break down the porphyrin scaffold to sequester the Fe2+ ion via a heme oxygenase. Recent studies have revealed that certain pathogens can anaerobically degrade heme. Our own research has shown that one such pathway proceeds via NADH-dependent heme degradation, which has been identified in a family of hemoproteins from a range of bacteria. HemS, from Yersinia enterocolitica, is the main focus of this work, along with HmuS (Yersinia pestis), ChuS (Escherichia coli) and ShuS (Shigella dysenteriae). We combine experiments, Energy Landscape Theory, and a bioinformatic investigation to place these homologues within a wider phylogenetic context. A subset of these hemoproteins are known to bind certain DNA promoter regions, suggesting not only that they can catalytically degrade heme, but that they are also involved in transcriptional modulation responding to heme flux. Many of the bacterial species responsible for these hemoproteins (including those that produce HemS, ChuS and ShuS) are known to specifically target oxygen-depleted regions of the gastrointestinal tract. A deeper understanding of anaerobic heme breakdown processes exploited by these pathogens could therefore prove useful in the development of future strategies for disease prevention

Education and Levels of Salivary Cortisol Over the Day in US Adults

Background - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to be an important pathway linking socioeconomic position and chronic disease. Purpose - This paper tests the association between education and the diurnal rhythm of salivary control. Methods - Up to 8 measures of cortisol (mean of 5.38 per respondent) over two days were obtained from 311 respondents aged 18-70, drawn from 2001-2002 Chicago Community Adult Health Study. Multi-level models with linear splines were used to estimate waking level, rates of cortisol decline, and area-under-the-curve over the day, by categories of education. Results - Lower education (0-11 years) was associated with lower waking levels of cortisol, but not the rate of decline of cortisol, resulting in a higher area-under-the-curve for more educated respondents throughout the day. Conclusions - This study found evidence of lower cortisol exposure among individuals with less education and thus does not support the hypothesis that less education is associated with chronic over-exposure to cortisol

Education and Levels of Salivary Cortisol Over the Day in US Adults

Background - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to be an important pathway linking socioeconomic position and chronic disease. Purpose - This paper tests the association between education and the diurnal rhythm of salivary control. Methods - Up to 8 measures of cortisol (mean of 5.38 per respondent) over two days were obtained from 311 respondents aged 18-70, drawn from 2001-2002 Chicago Community Adult Health Study. Multi-level models with linear splines were used to estimate waking level, rates of cortisol decline, and area-under-the-curve over the day, by categories of education. Results - Lower education (0-11 years) was associated with lower waking levels of cortisol, but not the rate of decline of cortisol, resulting in a higher area-under-the-curve for more educated respondents throughout the day. Conclusions - This study found evidence of lower cortisol exposure among individuals with less education and thus does not support the hypothesis that less education is associated with chronic over-exposure to cortisol

Bone Nanomechanical Properties and Relationship to Bone Turnover and Architecture in Patients With Atypical Femur Fractures: A Prospective Nested Case-Control Study

Atypical femur fractures (AFFs) are well-established serious complication of long-term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case-control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue-level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty-two full-thickness transiliac bone biopsies were obtained from age- and sex-matched patients on long-term bisphosphonate therapy with (n = 16) and without an AFF (n = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface-based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non-AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non-AFF groups or between cortical and cancellous bone of non-AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non-AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long-term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF