Combining data on the bioavailability of midazolam and physiologically‐based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny

Pediatric physiologically‐based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature. A pediatric PBPK model was then used to assess six different ontogeny models in predicting bioavailability from preterm neonates to adults. The average fold error ranged from 0.7 to 1.38, with the rank order of least to most biased model being No Ontogeny < Upreti = Johnson < Goelen < Chen < Kiss. The absolute average fold error ranged from 1.17 to 1.64 with the rank order of most to least precise being Johnson > Upreti > No Ontogeny > Goelen > Kiss > Chen. The optimal ontogeny model is difficult to discern when considering the possible influence of CYP3A5 and other population variability; however, this study suggests that from term neonates and older a faster onset Johnson model with a lower fraction at birth may be close to this. For inclusion in other PBPK models, independent verification will be needed to confirm these results. Further research is needed in this area both in terms of age‐related changes in midazolam and similar drug bioavailability and intestinal CYP3A4 ontogeny

Combining data on the bioavailability of midazolam and physiologically‐based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny

Pediatric physiologically‐based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature. A pediatric PBPK model was then used to assess six different ontogeny models in predicting bioavailability from preterm neonates to adults. The average fold error ranged from 0.7 to 1.38, with the rank order of least to most biased model being No Ontogeny < Upreti = Johnson < Goelen < Chen < Kiss. The absolute average fold error ranged from 1.17 to 1.64 with the rank order of most to least precise being Johnson > Upreti > No Ontogeny > Goelen > Kiss > Chen. The optimal ontogeny model is difficult to discern when considering the possible influence of CYP3A5 and other population variability; however, this study suggests that from term neonates and older a faster onset Johnson model with a lower fraction at birth may be close to this. For inclusion in other PBPK models, independent verification will be needed to confirm these results. Further research is needed in this area both in terms of age‐related changes in midazolam and similar drug bioavailability and intestinal CYP3A4 ontogeny

Combining data on the bioavailability of midazolam and physiologically‐based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny

Pediatric physiologically‐based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature. A pediatric PBPK model was then used to assess six different ontogeny models in predicting bioavailability from preterm neonates to adults. The average fold error ranged from 0.7 to 1.38, with the rank order of least to most biased model being No Ontogeny Upreti > No Ontogeny > Goelen > Kiss > Chen. The optimal ontogeny model is difficult to discern when considering the possible influence of CYP3A5 and other population variability; however, this study suggests that from term neonates and older a faster onset Johnson model with a lower fraction at birth may be close to this. For inclusion in other PBPK models, independent verification will be needed to confirm these results. Further research is needed in this area both in terms of age‐related changes in midazolam and similar drug bioavailability and intestinal CYP3A4 ontogeny

Quantification of drug metabolising enzymes and transporter proteins in the paediatric duodenum via LC-MS/MS proteomics using a QconCAT technique

Characterising the small intestine absorptive membrane is essential to enable prediction of the systemic exposure of oral formulations. In particular, the ontogeny of key intestinal Drug Metabolising Enzymes and Transporter (DMET) proteins involved in drug disposition needs to be elucidated to allow for accurate prediction of the PK profile of drugs in the paediatric cohort. Using pinch biopsies from the paediatric duodenum (n = 36; aged 11 months to 15 years), the abundance of 21 DMET proteins and two enterocyte markers were quantified via LC-MS/MS. An established LCMS nanoflow method was translated to enable analysis on a microflow LC system, and a new stable-isotope-labelled QconCAT standard developed to enable quantification of these proteins. Villin-1 was used to standardise abundancy values. The observed abundancies and ontogeny profiles, agreed with adult LC-MS/MS-based data, and historic paediatric data obtained via western blotting. A linear trend with age was observed for duodenal CYP3A4 and CES2 only. As this work quantified peptides on a pinch biopsy coupled with a microflow method, future studies using a wider population range are very feasible. Furthermore, this DMET ontogeny data can be used to inform paediatric PBPK modelling and to enhance the understanding of oral drug absorption and gut bioavailability in paediatric populations

Influence of the Environment on Participation in Social Roles for Young Adults with Down Syndrome

Background: The concept of disability is now understood as a result of the interaction between the individual, features related to impairment, and the physical and social environment. It is important to understand these environmental influences and how they affect social participation. The purpose of this study is to describe the social participation of young adults with Down syndrome and examine its relationship with the physical and social environment. Methods: Families ascertained from the Down syndrome ‘Needs Opinion Wishes’ database completed questionnaires during 2011. The questionnaires contained two parts, young person characteristics and family characteristics. Young adults’ social participation was measured using the Assessment of Life Habits (LIFE-H) and the influences of environmental factors were measured by the Measure of the Quality of the Environment (MQE). The analysis involved descriptive statistics and linear and logistic regression. Results: Overall, participation in daily activities was higher (mean 6.45) than in social roles (mean 5.17) (range 0 to 9). When the physical and/or social environment was reported as a facilitator, compared to being no influence or a barrier, participation in social roles was greater (coef 0.89, 95%CI 0.28, 1.52, coef 0.83, 95%CI 0.17, 1.49, respectively). The relationships between participation and both the physical (coef 0.60, 95% CI -0.40, 1.24) and social (coef 0.20, 95%CI -0.47, 0.87) environments were reduced when age, gender, behavior and functioning in ADL were taken into account. Conclusion: We found that young adults’ participation in social roles was influenced more by the physical environment than by the social environment, providing a potentially modifiable avenue for intervention

The response of the maize nitrate transport system to nitrogen demand and supply across the lifecycle

The definitive version is available at www.newphytologist.comAn understanding of nitrate (NO3-) uptake throughout the lifecycle of plants, and how this process responds to nitrogen (N) availability, is an important step towards the development of plants with improved nitrogen use efficiency (NUE). NO3- uptake capacity and transcript levels of putative high- and low-affinity NO3- transporters (NRTs) were profiled across the lifecycle of dwarf maize (Zea mays) plants grown at reduced and adequate NO3-. Plants showed major changes in high-affinity NO3- uptake capacity across the lifecycle, which varied with changing relative growth rates of roots and shoots. Transcript abundances of putative high-affinity NRTs (predominantly ZmNRT2.1 and ZmNRT2.2) were correlated with two distinct peaks in high-affinity root NO3- uptake capacity and also N availability. The reduction in NO3- supply during the lifecycle led to a dramatic increase in NO3- uptake capacity, which preceded changes in transcript levels of NRTs, suggesting a model with short-term post-translational regulation and longer term transcriptional regulation of NO3- uptake capacity. These observations offer new insight into the control of NO3- uptake by both plant developmental processes and N availability, and identify key control points that may be targeted by future plant improvement programmes to enhance N uptake relative to availability and/or demand.Trevor Garnett, Vanessa Conn, Darren Plett, Simon Conn, Juergen Zanghellini, Nenah Mackenzie, Akiko Enju, Karen Francis, Luke Holtham, Ute Roessner, Berin Boughton, Antony Bacic, Neil Shirley, Antoni Rafalski, Kanwarpal Dhugga, Mark Tester, and Brent N. Kaise

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

Sample and data collection were funded by Cancer Research UK. Analysis was funded by Breast Cancer Now, the Rosetrees Trust, Guys & St Thomas’ Charity (CanHelp) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London

Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity

Emerging Strategies for Healthy Urban Governance

Urban health promotion is not simply a matter of the right interventions, or even the necessary resources. Urban (and indeed global) health depends to an important extent on governance, the institutions and processes through which societies manage the course of events. This paper describes the concept of governance, distinguishing between reforms aimed at improving how government works and innovations that more fundamentally reinvent governance by developing new institutions and processes of local stakeholder control. The paper highlights strategies urban governors can use to maximize their influence on the national and international decisions that structure urban life. It concludes with some observations on the limitations of local governance strategies and the importance of establishing a “virtuous circuit” of governance through which urban dwellers play a greater role in the formation and implementation of policy at the national and global levels

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications