The emerging role of metabolomics in the development of biomarkers for pulmonary hypertension and other cardiovascular diseases (2013 Grover Conference series)

Abstract The functional and prognostic significance of pulmonary hypertension (PH) is well established, yet our understanding of circulating peptides and metabolites that might mark or contribute to various forms of PH remains limited. Metabolites are the end result of all the regulatory complexity present in a cell, tissue, or organism and therefore serve as the most proximal reporters of the body’s response to a disease process or drug therapy. This review presents the rationale, methodology, and preliminary findings from studies that apply comprehensive metabolite profiling to gain knowledge of new circulating markers of PH

Impact of Chain Architecture on the Thickness Dependence of Physical Aging Rate of Thin Polystyrene Films

The dynamics of polymer thin films have been demonstrated to be significantly altered from the bulk, but the origins of such differences are not well defined. In this work, we seek to understand the differences in the structural dynamics (or physical aging) of polystyrene (PS) through branching and other well defined architectures (comb and centipede). The aging dynamics of ultrathin films (\u3c 30 nm) differ from relatively thick films (100-150nm) with linear PS thin films aging more rapidly than the relatively “bulk-like” thick films. Ellipsometric measurements are used to characterize the physical aging rate of the films. The change in film thickness and refractive index as the films are held below the glass transition temperature (Tg) provides a simple measure of the physical aging. In this study, four different architectures (linear, comb, 4 arm star, and centipede) will be investigated. For each PS architecture, the aging rate will be determined for film thickness ranging from 10nm to 100nm over aging temperatures from 65C to 95C. Preliminary investigation shows that the branching of the PS will decrease the aging rate

Application of Metabolomics to Cardiovascular Biomarker and Pathway Discovery

Emerging technologies based on mass spectrometry and nuclear magnetic resonance enable the monitoring of hundreds of metabolites from tissues or body fluids, that is, “metabolomics.” Because metabolites change rapidly in response to physiologic perturbations, they represent proximal reporters of disease phenotypes. The profiling of low molecular weight biochemicals, including lipids, sugars, nucleotides, organic acids, and amino acids, that serve as substrates and products in metabolic pathways is particularly relevant to cardiovascular diseases. In addition to serving as disease biomarkers, circulating metabolites may participate in previously unanticipated roles as regulatory signals with hormone-like functions. Cellular metabolic pathways are highly conserved among species, facilitating complementary functional studies in model organisms to provide insight into metabolic changes identified in humans. Although metabolic profiling technologies and methods of pattern recognition and data reduction remain under development, the coupling of metabolomics with other functional genomic approaches promises to extend our ability to elucidate biological pathways and discover biomarkers of human disease

Report on a collecting trip of the British Myriapod Group to Hungary in 1994

During a collecting trip participated jointly by the members of the British Myriapod Group and by Hungarian experts in 1994, 34 species of millipedes, 14 of centipedes, 8 of woodlice and 73 of spiders were recorded from Hungary. Two records of the millipede species Boreoiulus tenuis (Bigler, 1913) and Styrioiulus styricus (Verhoeff, 1896) were new to the fauna of Hungary

Counterfactual reasoning and knowledge of possibilities

Williamson has argued against scepticism concerning our metaphysically modal knowledge, by arguing that standard patterns of suppositional reasoning to counterfactual conclusions provide reliable sources of correct ascriptions of possibility and necessity. The paper argues that, while Williamson’s claims relating to necessity may well be right, he has not provided adequate reasons for thinking that the familiar modes of counterfactual reasoning to which he points generalise to provide a decent route to ascriptions of possibility. The paper also explores another path to ascriptions of possibility that may be extracted from Williamson’s ideas, before briefly considering the general status of counterfactual reasoning in relation to our knowledge of possibilities

Cardiovascular Functional Changes in Chronic Kidney Disease:Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain

Indecomposable K1K_1 classes on a Surface and Membrane Integrals

Let $X$ be a projective algebraic surface. We recall the $K$-group $K_{1,\mathrm{ind}}^{(2)}(X)$ of indecomposables and provide evidence that membrane integrals are sufficient to detect these indecomposable classes

The Joy Project

Community Development for Social Change provides a comprehensive introduction to the theory and practice of community development and associated activities and discusses best practice from global experience and links that to the UK context. The book integrates the realities of practice to key underpinning theories, human rights, values and a commitment to promoting social justice. A range of practice models are described and analysed, including UK models, popular education and community organising as well as a range of practice issues that need to be understood by community development workers. For example, strategies to promote individual and community empowerment, challenging discrimination, building and sustaining groups, and critical reflection on practice. Finally, a range of case studies from the UK and overseas illustrates good practice in diverse contexts. These case studies are analysed with reference to the values of community development, the promotion of social justice and the underpinning theories. It is an essential text for those on community development courses as well as for a range of workers, including local government, national and local voluntary agencies, and community based organisations

Adolescent Self-Consent for Biomedical HIV Prevention Research: Implications for Institutional Review Board Approval and Implementation

Purpose The Adolescent Medicine Trials Network Protocol 113 (ATN113) is an open-label, multisite demonstration project and Phase II safety study of human immunodeficiency virus (HIV) preexposure prophylaxis with 15- to 17-year-old young men who have sex with men that requires adolescent consent for participation. The purpose of this study was to examine factors related to the process by which Institutional Review Boards (IRBs) and researchers made decisions regarding whether to approve and implement ATN113 so as to inform future biomedical HIV prevention research with high-risk adolescent populations. Methods Participants included 17 researchers at 13 sites in 12 states considering ATN113 implementation. Qualitative descriptive methods were used. Data sources included interviews and documents generated during the initiation process. Results A common process for initiating ATN113 emerged, and informants described how they identified and addressed practical, ethical, and legal challenges that arose. Informants described the process as responding to the protocol, preparing for IRB submission, abstaining from or proceeding with submission, responding to IRB concerns, and reacting to the outcomes. A complex array of factors impacting approval and implementation were identified, and ATN113 was ultimately implemented in seven of 13 sites. Informants also reflected on lessons learned that may help inform future biomedical HIV prevention research with high-risk adolescent populations. Conclusions The results illustrate factors for consideration in determining whether to implement such trials, demonstrate that such protocols have the potential to be approved, and highlight a need for clearer standards regarding biomedical HIV prevention research with high-risk adolescent populations