Cardiovascular development of the preterm infant

The numbers of preterm births and cardiovascular deaths are increasing in most countries. The causes of both developments are multiple and apparently not related to each other. However, preterm birth might provide an increasing contribution to the burden of cardiovascular morbidity and mortality, since epidemiological evidence is growing that cardiovascular disease risk factors such as hypertension, ischemic heart disease and cerebrovascular events are linked to preterm birth. Despite this, most of the underlying mechanisms remain unknown. The overall concept of this thesis was to seek evidence for a perinatal origin of the changes seen in adults who were born preterm, regarding both vascular and cardiac function. For this purpose, we performed a longitudinal observational study, investigating diameter and intimamedia thickness of the aorta and carotid artery, and analyzing cardiac function during the first six months after preterm birth. In addition to well-established ultrasound methods, we applied innovative technology such as speckle-tracking echocardiography, since advances in myocardial imaging have facilitated the echocardiographic examination of preterm infants and even the detection of subclinical functional impairment. In preterm born infants, we found significant alterations of the development of the vascular and cardiac systems. The arteries we examined became significantly narrower and the intima-media thickened in relation to vessel diameter when they were compared to healthy infants born at term. In addition, we found significant differences in the left ventricular systolic and diastolic function, suggesting that myocardial remodeling may occur as an adaptive process of premature exposure towards the extra-uterine circulation. Early changes in the cardiovascular development of the preterm infant may persist and have long-term implications. In fact, adults born preterm exhibit similar alterations in cardiovascular structure and function to those found in our studies. As it is not currently possible to prevent preterm births or influence the developmental changes described in this thesis, we will meet more children and adolescents with remodeled vessels and hearts in the future. Further research on the underlying mechanisms is warranted. In addition, early and continued follow-up will be required if we are to determine the long-term and clinical significance, and to improve cardiovascular health in the growing population of individuals born preterm

Dysregulated cytokine and oxidative response in hyperglycolytic monocytes in obesity

Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood. Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors. Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention

Prognostic impact of fractional flow reserve measurements in patients with acute coronary syndromes: a subanalysis of the FLORIDA study

Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes (ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (p = 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%, p = 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%, p = 0.47) and revascularization (9.9 vs. 12.1%, p = 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS

Progressive adaptation in physical activity and neuromuscular performance during 520d confinement

To understand whether prolonged confinement results in reductions in physical activity and adaptation in the musculoskeletal system, six subjects were measured during 520 d isolation in the Mars500 study. We tested the hypothesis that physical activity reduces in prolonged confinement and that this would be associated with decrements of neuromuscular performance. Physical activity, as measured by average acceleration of the body\u27s center of mass ("activity temperature") using the actibelt® device, decreased progressively over the course of isolation (p<0.00001). Concurrently, countermovement jump power and single-leg hop force decreased during isolation (p<0.001) whilst grip force did not change (p≥0.14). Similar to other models of inactivity, greater decrements of neuromuscular performance occurred in the lower-limb than in the upper-limb. Subject motivational state increased non-significantly (p = 0.20) during isolation, suggesting reductions in lower-limb neuromuscular performance were unrelated to motivation. Overall, we conclude that prolonged confinement is a form of physical inactivity and is associated with adaptation in the neuromuscular system

Recommendations for neonatologist performed echocardiography in Europe: Consensus Statement endorsed by European Society for Paediatric Research (ESPR) and European Society for Neonatology (ESN)

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Vascular Tissue Engineering: Effects of Integrating Collagen into a PCL Based Nanofiber Material

The engineering of vascular grafts is a growing field in regenerative medicine. Although numerous attempts have been made, the current vascular grafts made of polyurethane (PU), Dacron®, or Teflon® still display unsatisfying results. Electrospinning of biopolymers and native proteins has been in the focus of research to imitate the extracellular matrix (ECM) of vessels to produce a small caliber, off-the-shelf tissue engineered vascular graft (TEVG) as a substitute for poorly performing PU, Dacron, or Teflon prostheses. Blended poly-ε-caprolactone (PCL)/collagen grafts have shown promising results regarding biomechanical and cell supporting features. In order to find a suitable PCL/collagen blend, we fabricated plane electrospun PCL scaffolds using various collagen type I concentrations ranging from 5% to 75%. We analyzed biocompatibility and morphological aspects in vitro. Our results show beneficial features of collagen I integration regarding cell viability and functionality, but also adverse effects like the loss of a confluent monolayer at high concentrations of collagen. Furthermore, electrospun PCL scaffolds containing 25% collagen I seem to be ideal for engineering vascular grafts

Two Lysines in the Forkhead Domain of Foxp3 Are Key to T Regulatory Cell Function

Background: The forkhead box transcription factor, Foxp3, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. The carboxyl-terminal forkhead (FKH) domain is required for the nuclear localization and DNA binding of Foxp3. We assessed how individual FKH lysines contribute to the functions of Foxp3 in Treg cells. Methodology/Principal Findings: We found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function in vivo and in vitro. These lysine mutations did not affect the level of expression of Foxp3 but inhibited IL-2 promoter remodeling and had important and differing effects on Treg-associated gene expression. Conclusions/Significance: These data point to complex effects of post-translational modifications at individual lysines within the Foxp3 FKH domain that affect Treg function. Modulation of these events using small molecule inhibitors ma