Paclitaxel Succinate Analogs: Anionic Introduction as a Strategy to Impart Blood Brain Barrier Permeability

A focused library of TX-67 (C10 hemi-succinate) analogs have been prepared including regioisomeric, functional group, and one-carbon homologs. These were prepared to investigate TX-67’s lack of interaction with P-glycoprotein (Pgp). Tubulin stabilization ability, cytotoxicity, and Pgp interactions were evaluated. All carboxylic acid analogs had no apparent interactions with Pgp whereas the ester variants of the same compounds displayed characteristics of Pgp substrates. Furthermore, it is demonstrated that hydrogen-bonding properties were significant with respect to Pgp interactions. This anionic introduction strategy may allow for delivery of paclitaxel into the CNS as well as establishing a new method for delivery of other, non-CNS permeable drugs

Associations of American Indian Children\u27s Screen-Time Behavior With Parental Television Behavior, Parental Perceptions of Children\u27s Screen Time, and Media-Related Resources in the Home

Introduction: American Indian children have high rates of overweight and obesity, which may be partially attributable to screen-time behavior. Young children\u27s screen-time behavior is strongly influenced by their environment and their parents\u27 behavior. We explored whether parental television watching time, parental perceptions of children\u27s screen time, and media-related resources in the home are related to scree time (ie, television, DVD/video, video game, and computer use) among Oglala Lakota youth residing on or near the Pine Ridge Reservation in South Dakota. Methods: We collected baseline data from 431 child and parent/caregiver pairs who participated in Bright Start, a group-randomized, controlled, school-based obesity prevention trial to reduce excess weight gain. Controlling for demographic characteristics, we used linear regression analysis to assess associations between children\u27s screen time and parental television watching time, parental perceptions of children\u27s screen time, and availability of media-related household resources. Results: The most parsimonious model for explaining children screen time included the children\u27s sex, parental body mass index, parental television watching time, how often the child watched television after school or in the evening, parental perception that the child spent too much time playing video games, how often the parent limited the child\u27s television time, and the presence of a VCR/DVD player or video game player in the home (F7,367 = 14.67; P \u3c .001; adjusted R2 = .37). The presence of a television in the bedroom did not contribute significantly to the model. Conclusion: Changes in parental television watching time, parental influence over children\u27s screen-time behavior, and availability of media-related resources in the home could decrease screen time and may be used as a strategy for reducing overweight and obesity in American Indian children

ITGB5 and AGFG1 variants are associated with severity of airway responsiveness

Background: Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity. Methods: A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects. Results: The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1. Conclusions: Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings

Why nature matters: A systematic review of intrinsic, instrumental, and relational values

\ua9 2023 The Author(s). Published by Oxford University Press on behalf of the American Institute of Biological Sciences. In this article, we present results from a literature review of intrinsic, instrumental, and relational values of nature conducted for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, as part of the Methodological Assessment of the Diverse Values and Valuations of Nature. We identify the most frequently recurring meanings in the heterogeneous use of different value types and their association with worldviews and other key concepts. From frequent uses, we determine a core meaning for each value type, which is sufficiently inclusive to serve as an umbrella over different understandings in the literature and specific enough to help highlight its difference from the other types of values. Finally, we discuss convergences, overlapping areas, and fuzzy boundaries between different value types to facilitate dialogue, reduce misunderstandings, and improve the methods for valuation of nature\u27s contributions to people, including ecosystem services, to inform policy and direct future research

Height, adiposity and body fat distribution and breast density in young women

INTRODUCTION: Breast density is one of the strongest risk factors for breast cancer, but determinants of breast density in young women remain largely unknown. METHOD: Associations of height, adiposity and body fat distribution with percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) were evaluated in a cross-sectional study of 174 healthy women, 25-29 years old. Adiposity and body fat distribution were measured by anthropometry and dual-energy x-ray absorptiometry (DXA), while %DBV and ADBV were measured by magnetic resonance imaging (MRI). Associations were evaluated using linear mixed effects models. All tests of statistical significance are 2-sided. RESULTS: Height was significantly positively associated with %DBV but not ADBV; for each standard deviation (SD) increase in height, %DBV increased by 18.7% in adjusted models. In contrast, all measures of adiposity and body fat distribution were significantly inversely associated with %DBV; a SD increase in body mass index (BMI), percent fat mass, waist circumference and the android:gynoid fat mass ratio (A:G ratio) each was associated significantly with a 44.4% - 47.0% decrease in %DBV after adjustment for childhood BMI and other covariates. Although associations were weaker than for %DBV, all measures of adiposity and body fat distribution also were significantly inversely associated with ADBV before adjustment for childhood BMI. However, after adjustment for childhood BMI only the DXA measures percent fat mass and A:G ratio remained significant; a SD increase in each was associated with a 13.8% - 19.6% decrease in ADBV . In mutually adjusted analysis, percent fat mass and the A:G ratio remained significantly inversely associated with %DBV, but only the A:G ratio was significantly associated with ADBV; a SD increase in A:G ratio was associated with a 18.5% decrease in ADBV. CONCLUSIONS: Total adiposity and body fat distribution are independently inversely associated with %DBV, whereas in mutually adjusted analysis only body fat distribution (A:G ratio) remained significantly inversely associated with ADBV in young women. Research is needed to identify biological mechanisms underlying these associations

Summer effects on body mass index (BMI) gain and growth patterns of American Indian children from kindergarten to first grade: a prospective study

<p>Abstract</p> <p>Background</p> <p>Overweight and obesity are highly prevalent among American Indian children, especially those living on reservations. There is little scientific evidence about the effects of summer vacation on obesity development in children. The purpose of this study was to investigate the effects of summer vacation between kindergarten and first grade on growth in height, weight, and body mass index (BMI) for a sample of American Indian children.</p> <p>Methods</p> <p>Children had their height and weight measured in four rounds of data collection (yielded three intervals: kindergarten, summer vacation, and first grade) as part of a school-based obesity prevention trial (Bright Start) in a Northern Plains Indian Reservation. Demographic variables were collected at baseline from parent surveys. Growth velocities (Z-score units/year) for BMI, weight, and height were estimated and compared for each interval using generalized linear mixed models.</p> <p>Results</p> <p>The children were taller and heavier than median of same age counterparts. Height Z-scores were positively associated with increasing weight status category. The mean weight velocity during summer was significantly less than during the school year. More rapid growth velocity in height during summer than during school year was observed. Obese children gained less adjusted-BMI in the first grade after gaining more than their counterparts during the previous two intervals. No statistically significant interval effects were found for height and BMI velocities.</p> <p>Conclusions</p> <p>There was no indication of a significant summer effect on children's BMI. Rather than seasonal or school-related patterns, the predominant pattern indicated by weight-Z and BMI-Z velocities might be related to age or maturation.</p> <p>Trial registration</p> <p>Bright Start: Obesity Prevention in American Indian Children Clinical Trial Govt ID# <a href="http://www.clinicaltrials.gov/ct2/show/NCT00123032">NCT00123032</a></p

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes

<p>Abstract</p> <p>Background</p> <p>Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.</p> <p>Methods</p> <p>rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.</p> <p>Results</p> <p>Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV₁and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.</p> <p>Conclusion</p> <p>Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.</p

Ethnic variation in validity of the estimated obesity prevalence using self-reported weight and height measurements

<p>Abstract</p> <p>Background</p> <p>We examined ethnic differences between levels of body mass index (BMI) based on self-reported and measured body height and weight and the validity of self-reports used to estimate the prevalence of obesity (BMI≥30 kg/m²) in Turkish, Moroccan, and Dutch people in the Netherlands. Furthermore, we investigated whether BMI levels and the prevalence of obesity in Turkish and Moroccan people with incomplete self-reports (missing height or weight) differ from those with complete self-reports.</p> <p>Methods</p> <p>Data on self-reported and measured height and weight were collected in a population-based survey among 441 Dutch, 414 Turks and 344 Moroccans aged 18 to 69 years in Amsterdam, the Netherlands in 2004. BMI and obesity were calculated from self-reported and measured height and weight.</p> <p>Results</p> <p>The difference between measured and estimated BMI was larger in Turkish and Moroccan women than in Dutch women, which was explained by the higher BMI of the Turkish and Moroccan women. In men we found no ethnic differences between measured and estimated BMI. Sensitivity to detect obesity was low and specificity was high. In participants with available self-reported and measured height and weight, self-reports produced a similar underestimation of the obesity prevalence in all ethnic groups. However, many obese Turkish and Moroccan women had incomplete self-reports, missing height or weight, resulting in an additional underestimation of the prevalence of obesity. Among men (all ethnicities) and Dutch women, the availability of height or weight by self-report did not differ between obese and non obese participants.</p> <p>Conclusions</p> <p>BMI based on self-reports is underestimated more by Turkish and Moroccan women than Dutch women, which is explained by the higher BMI of Turkish and Moroccan women. Further, in women, ethnic differences in the estimation of obesity prevalence based on self-reports do exist and are due to incomplete self-reports in obese Turkish and Moroccan women. In men, ethnicity is not associated with discrepancies between levels of BMI and obesity prevalence based on measurements and self-reports. Hence, our results indicate that using measurements to accurately determine levels of BMI and obesity prevalence in public health research seems even more important in Turkish and Moroccan migrant women than in other populations.</p