Ischaemic preconditioning in exercise and disease: One size fits all?

Ischaemia reperfusion injury (IR-injury) occurs when blood supply to a certain area of the body is blocked, and is subsequently followed by reperfusion. During the period of ischaemia, tissue is damaged as a result of lack of oxygen. Rapid reperfusion is mandatory, but unfortunately causes damage in addition to the damage induced by ischaemia alone. While a prolonged period of ischaemia is harmful to the bodily tissue, short periods of ischaemia interspersed with short bouts of reperfusion have protective effects. This mechanism is called ischaemic preconditioning (IPC). In this thesis, the impact of co-morbidity and age on IR-injury and IPC are explored. Moreover, the possible role of IPC to enhance exercise performance is investigated. Finally an attempt is made to understand the interchangeable effects of IPC and exercise performance in the prevention of IR-injury. Using the brachial artery endothelial function as a surrogate marker, first the consequences of IR-injury in both young and older individuals on endothelial function were studied. It was also assessed whether IPC could prevent endothelial IR-injury. It was found that endothelial function in both groups declined, when IR-injury was not preceded with IPC. However, when IPC was applied prior to IR-injury, a protective effect was detected in young subjects, but not in older participants. In chapter 5, this study was repeated in patients with heart failure, as they are at an increased risk for IR-injury. While in both groups a significant decline in endothelial function was observed, a much larger decline was established in the heart failure group. Moreover, IPC failed to protect against endothelial dysfunction in heart failure patients after IR-injury. The third study presented in this thesis, focused on the question whether exercise performance enhancement during a 5-km time trial was comparable when IPC on the upper legs was applied immediately before the time trial versus 24 hours (24-IPC) prior to exercise. Interestingly, a significant and strong correlation was found in finish time between acute IPC and 24-IPC, suggesting comparable effects of IPC and 24-IPC on exercise performance. In a follow-up study, it was determined whether local IPC applied on the upper arm, or remote IPC applied on the legs, would lead to an improved maximum incremental arm crank exercise test in individuals with a complete spinal cord lesion. The main finding was that upper arm IPC led to an increased performance enhancement, whilst remote IPC (stimulus below the lesion) did not lead to any significant differences. These studies help to inform the best or most practical application of IPC in daily life situations. Some previous work has suggested that exercise may resemble some of the effects of IPC. More specifically, acute exercise might possess the same protective effects against ischaemia-reperfusion injury as IPC. Therefore, in young healthy individuals it was studied, whether an acute bout of endurance or interval exercise is able to protect against brachial endothelial IR-injury. It was established that interval exercise prevented endothelial dysfunction after an IR stimulus, while no protective effect of endurance exercise was found. It was concluded that interval exercise, but not endurance exercise, prevented endothelial dysfunction after an ischaemic period. In conclusion, this thesis provides further evidence for the protective effects of (remote) IPC, both on the prevention of endothelial IR-injury as well as improvement in exercise performance. However, effects may depend on the protocol and population studied

Prospects for observing ultracompact binaries with space-based gravitational wave interferometers and optical telescopes.

Space-based gravitational wave interferometers are sensitive to the galactic population of ultra-compact binaries. An important subset of the ultra-compact binary popula- tion are those stars that can be individually resolved by both gravitational wave in- terferometers and electromagnetic telescopes. The aim of this paper is to quantify the multi-messenger potential of space-based interferometers with arm-lengths between 1 and 5 Gm. The Fisher Information Matrix is used to estimate the number of binaries from a model of the Milky Way which are localized on the sky by the gravitational wave detector to within 1 and 10 deg2 and bright enough to be detected by a magni- tude limited survey. We find, depending on the choice of GW detector characteristics, limiting magnitude, and observing strategy, that up to several hundred gravitational wave sources could be detected in electromagnetic follow-up observations

Drug therapy for chronic heart failure due to left ventricular systolic dysfunction : a scientific review : I. Introduction

Heart failure is a complex syndrome resulting from cardiac changes, structural or functional, that cause pump failure and consequently diminished cardiac output. Drug therapy improves patients' prognosis and, based on good-quality evidence, is safe and cost-effective. There are several drug classes that can be used in left ventricular dysfunction, so it may be useful to discuss their stratification and prioritization for clinical practice. This is the first of a series of papers that will present and discuss the most valid, important and applicable evidence on drug therapy in chronic heart failure due to left ventricular systolic dysfunction. We will not discuss acute heart failure (or decompensation of chronic heart failure) or non-pharmacologic treatments (implantable cardioverter-defibrillators, cardiac resynchronization therapy, heart transplantation, anti-platelet therapy, etc.).A insuficiência cardíaca define-se como uma síndrome complexa resultante de alterações cardíacas estruturais ou funcionais, que têm como consequência a diminuição da função de bomba do coração e, por consequência, o respectivo volume de ejecção. A terapêutica farmacológica melhora o prognóstico destes doentes e, baseado em evidência de boa qualidade, é segura e apresenta uma boa relação de custo-eficácia. Existem várias classes de medicamentos que podem ser utilizados em doentes com disfunção do ventrículo esquerdo, pelo que é útil uma discussão detalhada de cada uma delas, com estratificação e prioritização do seu uso prático. Este é o primeiro de uma série de artigos que têm como objectivo principal apresentar e discutir a evidência mais válida, importante e aplicável sobre a utilização de fármacos na insuficiência cardíaca crónica por disfunção sistólica do ventrículo esquerdo. Não se irá discutir quer a insuficiência cardíaca aguda - ou crónica agudizada - quer outros tratamentos que não os farmacológicos (por exemplo os desfibrilhadores implantáveis, técnicas de ressincronização, transplante cardíaco, anti-agregação plaquetária, etc.).info:eu-repo/semantics/publishedVersio

Deconvolution of bulk blood eQTL effects into immune cell subpopulations

BACKGROUND: Expression quantitative trait loci (eQTL) studies are used to interpret the function of disease-associated genetic risk factors. To date, most eQTL analyses have been conducted in bulk tissues, such as whole blood and tissue biopsies, which are likely to mask the cell type-context of the eQTL regulatory effects. Although this context can be investigated by generating transcriptional profiles from purified cell subpopulations, current methods to do this are labor-intensive and expensive. We introduce a new method, Decon2, as a framework for estimating cell proportions using expression profiles from bulk blood samples (Decon-cell) followed by deconvolution of cell type eQTLs (Decon-eQTL). RESULTS: The estimated cell proportions from Decon-cell agree with experimental measurements across cohorts (R ≥ 0.77). Using Decon-cell, we could predict the proportions of 34 circulating cell types for 3194 samples from a population-based cohort. Next, we identified 16,362 whole-blood eQTLs and deconvoluted cell type interaction (CTi) eQTLs using the predicted cell proportions from Decon-cell. CTi eQTLs show excellent allelic directional concordance with eQTL (≥ 96-100%) and chromatin mark QTL (≥87-92%) studies that used either purified cell subpopulations or single-cell RNA-seq, outperforming the conventional interaction effect. CONCLUSIONS: Decon2 provides a method to detect cell type interaction effects from bulk blood eQTLs that is useful for pinpointing the most relevant cell type for a given complex disease. Decon2 is available as an R package and Java application (https://github.com/molgenis/systemsgenetics/tree/master/Decon2) and as a web tool (www.molgenis.org/deconvolution)