The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone

Dependence on heroin and other opioids represents a considerable problem worldwide. There is a continual need to improve therapy and/ or find more efficacious alternatives if these issues are to be addressed. The most commonly implemented pharmacological therapy in treating said dependencies is methadone; however its success is the subject of ongoing debate. Certain plasma proteins including alpha1-acid glycoprotein (AGP) bind to drugs which causes inactivation and, if low enough, may prevent a therapeutic effect being attained. The hepatic synthesis of AGP increases two- to five-fold during numerous physiological and pathophysiological conditions, becoming the most prevalent acute phase protein in the blood. Additionally, the structure of the sugar chains (glycans) attached to the surface of underlying polypeptide backbones can differ, potentially altering the functions performed. AGP was isolated from blood samples obtained from patients undergoing various stages and types of opioid-replacement therapy and from heparinised blood samples provided by the Blood Transfusion Service. Structural analysis of the glycans was undertaken primarily through the use of high pH anion-exchange chromatography (HPAEC) and intrinsic fluorescence used as a measure of drug binding. The composition of glycans attached to the polypeptide backbone of AGP isolated from patient samples was found to markedly differ from that of a ‘normal' healthy population. Levels of galactose and N-acetyl-glucosamine were amplified in all methadone treatment groups which suggested increased branching of glycans; this was supported by HPAEC analysis of complete glycan chains. Binding of methadone to all isolated AGP samples was elevated at the highest drug concentrations tested; however the degree of quenching appeared to be greater in patients. Therefore, the glycoforms expressed by AGP appear to be associated with the subsequent binding of the glycoprotein to methadone. It is possible that altered glycosylation could increase affinity for the drug, reducing its bioactive concentration to below that required to produce the pharmacological effect. Currently, the doses of methadone used in opioid replacement therapy are primarily influenced by the expression of physical symptoms, however this preliminary study has indicated that determination of the level and glycoform expression of AGP may offer potential use when determining the most effective therapy and dosage regimen.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone

Dependence on heroin and other opioids represents a considerable problem worldwide. There is a continual need to improve therapy and/ or find more efficacious alternatives if these issues are to be addressed. The most commonly implemented pharmacological therapy in treating said dependencies is methadone; however its success is the subject of ongoing debate. Certain plasma proteins including alpha1-acid glycoprotein (AGP) bind to drugs which causes inactivation and, if low enough, may prevent a therapeutic effect being attained. The hepatic synthesis of AGP increases two- to five-fold during numerous physiological and pathophysiological conditions, becoming the most prevalent acute phase protein in the blood. Additionally, the structure of the sugar chains (glycans) attached to the surface of underlying polypeptide backbones can differ, potentially altering the functions performed. AGP was isolated from blood samples obtained from patients undergoing various stages and types of opioid-replacement therapy and from heparinised blood samples provided by the Blood Transfusion Service. Structural analysis of the glycans was undertaken primarily through the use of high pH anion-exchange chromatography (HPAEC) and intrinsic fluorescence used as a measure of drug binding. The composition of glycans attached to the polypeptide backbone of AGP isolated from patient samples was found to markedly differ from that of a ‘normal' healthy population. Levels of galactose and N-acetyl-glucosamine were amplified in all methadone treatment groups which suggested increased branching of glycans; this was supported by HPAEC analysis of complete glycan chains. Binding of methadone to all isolated AGP samples was elevated at the highest drug concentrations tested; however the degree of quenching appeared to be greater in patients. Therefore, the glycoforms expressed by AGP appear to be associated with the subsequent binding of the glycoprotein to methadone. It is possible that altered glycosylation could increase affinity for the drug, reducing its bioactive concentration to below that required to produce the pharmacological effect. Currently, the doses of methadone used in opioid replacement therapy are primarily influenced by the expression of physical symptoms, however this preliminary study has indicated that determination of the level and glycoform expression of AGP may offer potential use when determining the most effective therapy and dosage regimen.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone.

Dependence on heroin and other opioids represents a considerable problem worldwide. There is a continual need to improve therapy and/ or find more efficacious alternatives if these issues are to be addressed. The most commonly implemented pharmacological therapy in treating said dependencies is methadone; however its success is the subject of ongoing debate. Certain plasma proteins including alpha1-acid glycoprotein (AGP) bind to drugs which causes inactivation and, if low enough, may prevent a therapeutic effect being attained. The hepatic synthesis of AGP increases two- to five-fold during numerous physiological and pathophysiological conditions, becoming the most prevalent acute phase protein in the blood. Additionally, the structure of the sugar chains (glycans) attached to the surface of underlying polypeptide backbones can differ, potentially altering the functions performed. AGP was isolated from blood samples obtained from patients undergoing various stages and types of opioid-replacement therapy and from heparinised blood samples provided by the Blood Transfusion Service. Structural analysis of the glycans was undertaken primarily through the use of high pH anion-exchange chromatography (HPAEC) and intrinsic fluorescence used as a measure of drug binding. The composition of glycans attached to the polypeptide backbone of AGP isolated from patient samples was found to markedly differ from that of a ‘normal’ healthy population. Levels of galactose and N-acetyl-glucosamine were amplified in all methadone treatment groups which suggested increased branching of glycans; this was supported by HPAEC analysis of complete glycan chains. Binding of methadone to all isolated AGP samples was elevated at the highest drug concentrations tested; however the degree of quenching appeared to be greater in patients. Therefore, the glycoforms expressed by AGP appear to be associated with the subsequent binding of the glycoprotein to methadone. It is possible that altered glycosylation could increase affinity for the drug, reducing its bioactive concentration to below that required to produce the pharmacological effect. Currently, the doses of methadone used in opioid replacement therapy are primarily influenced by the expression of physical symptoms, however this preliminary study has indicated that determination of the level and glycoform expression of AGP may offer potential use when determining the most effective therapy and dosage regimen

Validation of a health-related quality of life instrument for primary ciliary dyskinesia (QOL-PCD)

Background: Quality of life (QOL)-primary ciliary dyskinesia (PCD) is the first disease-specific, health-related QOL instrument for PCD. Psychometric validation of QOL-PCD assesses the performance of this measure in adults, including its reliability, validity and responsiveness to change. Methods: Seventy-two adults (mean (range) age: 33 years (18–79 years); mean (range) FEV1% predicted: 68 (26–115)) with PCD completed the 49-item QOL-PCD and generic QOL measures: Short-Form 36 Health Survey, Sino-Nasal Outcome Test 20 (SNOT-20) and St George Respiratory Questionnaire (SGRQ)-C. Thirty-five participants repeated QOL-PCD 10–14 days later to measure stability or reproducibility of the measure. Results: Multitrait analysis was used to evaluate how the items loaded on 10 hypothesised scales: physical, emotional, role and social functioning, treatment burden, vitality, health perceptions, upper respiratory symptoms, lower respiratory symptoms and ears and hearing symptoms. This analysis of item-to-total correlations led to 9 items being dropped; the validated measure now comprises 40 items. Each scale had excellent internal consistency (Cronbach's α: 0.74 to 0.94). Two-week test–retest demonstrated stability for all scales (intraclass coefficients 0.73 to 0.96). Significant correlations were obtained between QOL-PCD scores and age and FEV1. Strong relationships were also found between QOL-PCD scales and similar constructs on generic questionnaires, for example, lower respiratory symptoms and SGRQ-C (r=0.72, p<0.001), while weak correlations were found between measures of different constructs. Conclusions: QOL-PCD has demonstrated good internal consistency, test–retest reliability, convergent and divergent validity. QOL-PCD offers a promising tool for evaluating new therapies and for measuring symptoms, functioning and QOL during routine care

River Restoration to Achieve a Stage 0 Condition: Summary of a Workshop Held November 5-6, 2020

Restoration to achieve Stage 0 is a valley-scale, process-based (hydrologic, geologic and biological) approach that aims to reestablish stream depositional environments to maximize longitudinal, lateral, and vertical connectivity at base flows and facilitate development of dynamic, self-formed and self-sustaining wetland-stream complexes. The term Stage 0 originally described complex multi-channel conditions and wider floodplains that evidence suggests were common when Euro-Americans arrived. Stage 0 is one stage in a 9-stage stream channel evolution model. Stage 0 is now also more broadly used to describe stream restoration projects aimed at changing the current condition and future evolution of incised, single-channel streams to achieve those multi-channel and wider floodplain conditions. The Stage 0 approach has generated excitement among restoration practitioners and researchers. It is seen as an action on a scale commensurate with past impacts; potentially capable of putting streams and their floodplains on a trajectory to recovery that is sustainable with minimal future intervention. Projects that reset the valley surface elevation may include the transfer of large amounts of sediment into incised channels from adjacent terraces using heavy machinery, and placement of logs and boulders to create structure across the resulting floodplain. Recreating expanded, complex and resilient stream and floodplain habitats over the longer term may involve considerable short-term disturbance of existing stream environments. Because some of these streams currently support sensitive populations of focal or endangered species (most notably salmonids) projects designed to achieve a Stage 0 condition have raised some questions and concerns among land managers and regulators charged with recovering those species. The approach is relatively new, so there are also questions regarding terminology, implementation and monitoring approaches, and appropriate sites and scale for these projects. In this science and policy context, a Stage 0 Stream Restoration Workshop was held on November 5-6, 2020 with the goal to bring together practitioners, researchers, regulators and other stakeholders to discuss current topics and data gaps related to implementing and monitoring restoration projects intended to achieve a Stage 0 condition. The online workshop included expert presentations, questions and discussions during plenary sessions, and smaller breakout groups. This document summarizes the workshop proceedings

A quality-of-life measure for adults with primary ciliary dyskinesia: QOL-PCD

Primary ciliary dyskinesia (PCD) is characterised by chronic suppurative lung disease, rhino-sinusitis, hearing impairment and sub-fertility. We have developed the first multidimensional measure to assess health-related quality of life (HRQoL) in adults with PCD (QOL-PCD). Following a literature review and expert panel meeting, open-ended interviews with patients investigated the impact of PCD on HRQoL in the UK and North America (n=21). Transcripts were content analysed to derive saturation matrices. Items were rated for relevance by patients (n=49). Saturation matrices, relevance scores, literature review, evaluation of existing measures, and expert opinion contributed to development of a preliminary questionnaire. The questionnaire was refined following cognitive interviews (n=18). Open-ended interviews identified a spectrum of issues unique to adults with PCD. Saturation matrices confirmed comprehensive coverage of content. QOL-PCD includes 48 items covering the following seven domains: Physical Functioning, Emotional Functioning, Treatment Burden, Respiratory and Sinus Symptoms, Ears and Hearing, Social Functioning, and Vitality and Health Perceptions. Cognitive testing confirmed that content was comprehensive and the items were well-understood by respondents. Content validity and cognitive testing supported the items and structure. QOL-PCD has been translated into other languages and is awaiting psychometric testing

Investigating the State of Play of Geobim Across Europe

In both the Geographic Information (Geo) and Building Information Modelling (BIM) domains, it is widely acknowledged that the integration of data from both domains is beneficial and a crucial step in facing the multi-disciplinary challenges of our built environment. The result of this integration – which can broadly be termed GeoBIM – could answer questions such as identifying an appropriate Heating, Ventilation and Air Conditioning system for a building based on room usage, outside air temperature, solar exposure and traffic pollution or validating whether a proposed built asset meets relevant planning constraints. Developing a coherent approach to GeoBIM integration requires consensus between multiple stakeholders from both the Geo and the BIM side and at an international level. This multi-country and multi-stakeholder approach is the topic of a 2-year EuroSDR project on GeoBIM integration that started in November 2017. The general aim of the project is to detail both the needs and the issues of GeoBIM integration, studied from use cases as well as from existing experiences in the participating countries and to develop initial solutions accordingly. This paper reports initial results – it identifies strong potential for GeoBIM but also rather fragmented activity, with no national level focus. It also notes that research (both in industry and academia) primarily focuses on standards, interoperability and data integration or exchange. Based on these findings – and with a focus on existing work and topics of interest to NMCAs – the next phase of the work will develop more detailed case studies for Asset Management and Urban Planning