The Use of Low-Calorie Sweeteners by Children: Implications for Weight Management123

The rise in pediatric obesity since the 1970s has been well established in the United States and is becoming a major concern worldwide. As a potential means to help slow the obesity epidemic, low-calorie sweeteners (LCS) have gained attention as dietary tools to assist in adherence to weight loss plans or prevention of excess weight gain. Observational studies tend to show positive correlations between LCS consumption and weight gain in children and adolescents. Although the data are intriguing, these epidemiologic studies do not establish that LCS cause weight gain, because there are likely many lifestyle and genetic differences between children and families who choose to consume LCS and those who do not. Short-term randomized controlled trials have shown LCS use to be BMI neutral or to have modest weight-reducing effects in overweight and obese adolescents. The long-term effects of LCS in children and adolescents are unknown. Some compelling research is currently underway and may provide needed insight into the potential role of LCS in weight management. The paucity of data regarding the effects of LCS use in children and adolescents creates challenges in decision-making for health care providers and parents

Dead Time, Pileup, and Accurate Gamma-Ray Spectrometry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58611/1/R&R.pd

The half-life of 76 As

In the course of making high-accuracy measurements of arsenic, we found that the most recently published and compiled half-life of 76 As did not agree with our data as well as the earlier accepted value. To redetermine this parameter, 76 As sources were measured on four Ge gamma detector systems, and an exponential function was fitted to the decay data by two different nonlinear least-squares methods. We obtained T 1/2 = 1.09379 days with a standard uncertainty of 0.00045 days. This result is 1.5% higher than the most recent value, but is in agreement with the older, less precise, consensus value.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43130/1/10967_2004_Article_5117002.pd

Differential α4(+)/(-)β2 Agonist-Binding Site Contributions To α4β2 Nicotinic Acetylcholine Receptor Function Within And Between Isoforms

Two α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) isoforms exist with (α4)2(β2)3 and (α4)2(β2)3 subunit stoichiometries and high versus low agonist sensitivities (HS and LS), respectively. Both isoforms contain a pair of α4(+)/(-)β2 agonist- binding sites. The LS isoform also contains a unique α4(+)/(-)α4 site with lower agonist affinity than the α4(+)/(-)β2 sites. However, the relative roles of the conserved α4(+)/(-)β2 agonist-binding sites in and between the isoforms have not been studied. We used a fully linked subunit concatemeric nAChR approach to express pure populations of HS or LS isoform α4β2∗-nAChR. This approach also allowed us to mutate individual subunit interfaces, or combinations thereof, on each isoform background. We used this approach to systematically mutate a triplet of β2 subunit (-)-face E-loop residues to their non-conserved α4 subunit counterparts or vice versa (β2HQT and α4VFL, respectively). Mutant-nAChR constructs (and unmodified controls) were expressed in Xenopus oocytes. Acetylcholine concentration-response curves and maximum function were measured using two-electrode voltage clamp electrophysiology. Surface expression was measured with 125I-mAb 295 binding and was used to define function/nAChR. If the α4(+)/(-)β2 sites contribute equally to function, making identical β2HQT substitutions at either site should produce similar functional outcomes. Instead, highly differential outcomes within the HS isoform, and between the two isoforms, were observed. In contrast, α4VFL mutation effects were very similar in all positions of both isoforms. Our results indicate that the identity of subunits neighboring the otherwise equivalent α4(+)/(-)β2 agonist sites modifies their contributions to nAChR activation and that E-loop residues are an important contributor to this neighbor effect

The Unique a4(1)/(2)a4 Agonist Binding Site in (a4) 3 (b2) 2 Subtype Nicotinic Acetylcholine Receptors Permits Differential Agonist Desensitization Pharmacology versus the (a4) 2 (b2) 3 Subtype s

ABSTRACT Selected nicotinic agonists were used to activate and desensitize high-sensitivity (HS) (a4) 2 (b2) 3 ) or low-sensitivity (LS) (a4) 3 (b2) 2 ) isoforms of human a4b2-nicotinic acetylcholine receptors (nAChRs). Function was assessed using 86 Rb 1 efflux in a stably transfected SH-EP1-ha4b2 human epithelial cell line, and twoelectrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing concatenated pentameric HS or LS a4b2-nAChR constructs (HSP and LSP). Unlike previously studied agonists, desensitization by the highly selective agonists A-85380 [3-(2(S)-azetidinylmethoxy)pyridine] and sazetidine-A (Saz-A) preferentially reduced a4b2-nAChR HS-phase versus LS-phase responses. The concatenated-nAChR experiments confirmed that approximately 20% of LS-isoform acetylcholine-induced function occurs in an HS-like phase, which is abolished by Saz-A preincubation. Six mutant LSPs were generated, each targeting a conserved agonist binding residue within the LS-isoform-only a4(1)/(2)a4 interface agonist binding site. Every mutation reduced the percentage of LS-phase function, demonstrating that this site underpins LS-phase function. Oocyte-surface expression of the HSP and each of the LSP constructs was statistically indistinguishable, as measured using b2-subunit-specific [ 125 I]mAb295 labeling. However, maximum function is approximately five times greater on a "per-receptor" basis for unmodified LSP versus HSP a4b2-nAChRs. Thus, recruitment of the a4(1)/(2)a4 site at higher agonist concentrations appears to augment otherwisesimilar function mediated by the pair of a4(1)/(2)b2 sites shared by both isoforms. These studies elucidate the receptor-level differences underlying the differential pharmacology of the two a4b2-nAChR isoforms, and demonstrate that HS versus LS a4b2-nAChR activity can be selectively manipulated using pharmacological approaches. Since a4b2 nAChRs are the predominant neuronal subtype, these discoveries likely have significant functional implications, and may provide important insights for drug discovery and development

Food Consumption and its Impact on Cardiovascular Disease: Importance of Solutions Focused on the Globalized Food System A Report From the Workshop Convened by the World Heart Federation

Major scholars in the field, based on a 3-day consensus, created an in-depth review of current knowledge on the role of diet in CVD, the changing global food system and global dietary patterns, and potential policy solutions. Evidence from different countries, age/race/ethnicity/socioeconomic groups suggest the health effects studies of foods, macronutrients, and dietary patterns on CVD appear to be far more consistent though regional knowledge gaps are highlighted. There are large gaps in knowledge about the association of macronutrients to CVD in low- and middle-income countries (LMIC), particularly linked with dietary patterns are reviewed. Our understanding of foods and macronutrients in relationship to CVD is broadly clear; however major gaps exist both in dietary pattern research and ways to change diets and food systems. Based on the current evidence, the traditional Mediterranean-type diet, including plant foods/emphasizing plant protein sources, provides a well-tested healthy dietary pattern to reduce CV

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

A community-based participatory approach to planning child and youth health services in north west British Columbia : finding common ground

A growing recognition of the need for participatory health services research requires multiple stakeholder collaboration between researchers, clinical service providers, managerial and policy decision-makers, and the public. Recent Canadian provincial and federal reports support the need for participatory inquiry, yet little is being done in practice. This thesis explores a community-based participatory research process for planning child and youth health services and proposes methods to close the gap between research and practice. The study took place in the North West Health Service Delivery Area of British Columbia. This large geographic region represents over one-quarter of the provincial land mass, yet is home to <90,000 people. Approximately 30% are children and youth 19 years of age and under. Approximately 22% of the residents are Aboriginal. A participatory research approach was used with a mixed methods design. The priority component was qualitative. Qualitative data were collected and integrated through a unique sequence of methods, including semi-structured interviews, focus groups, and a search conference. Qualitative data were analyzed using a constructivist grounded theory method. The nested component was quantitative. Quantitative data were accessed from a provincial health services utilization database. Geographic information systems (GIS) software was used as a tool to map selected data, which was incorporated into the search conference. Three general conceptual categories emerged from the data: perceptivity about, emotivity generated by, and inclusivity in, the health system. Two core conceptual categories emerged: boundaries and boundary objects. Three knowledge boundaries were introduced: syntactic, semantic, and pragmatic, building upon and supporting empirical research on innovation and technology development. This study proposes a fourth knowledge boundary: phronetic. The characteristics of boundary objects occupying this phronetic boundary are fluid, real-time, participatory, and collaborative in locally-situated, multi-stakeholder, boundary-crossing settings. These boundary objects facilitate the melding of knowledge and action in ways that are relevant to stakeholders in their local realities. A conceptual framework is proposed to guide and unify participatory research and planning processes. This research is expected to lead to more effective multi-stakeholder, community-based approaches to the planning and development of network models for child and youth health services.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat