Origins of Metabolic Signals

Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC- derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen- independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue

Blood viscosity in microvessels: Experiment and theory

The apparent viscosity of blood flowing through narrow glass tubes decreases strongly with decreasing tube diameter over the range from about 300 μm to about 10 μm. This phenomenon, known as the Fåhraeus-Lindqvist effect, occurs because blood is a concentrated suspension of deformable red blood cells with a typical dimension of about 8 μm. Most of the resistance to blood flow through the circulatory system resides in microvessels with diameters in this range. Apparent viscosity of blood in microvessels in vivo has been found to be significantly higher than in glass tubes with corresponding diameters. Here we review experimental observations of blood’s apparent viscosity in vitro and in vivo, and progress towards a quantitative theoretical understanding of the mechanisms involved

Betriebsräte und 'Andere Vertretungsorgane': Verbreitung und Kontext betrieblicher Beschäftigtenvertretungen in der deutschen Privatwirtschaft

"Über die Verbreitung und Kontextbedingungen von Betriebsräten und betriebsverfassungsrechtlich nicht abgesicherten 'Anderen Vertretungsorganen' (AVOs) liegen nur wenige durch empirische Breitenerhebungen gesicherte Informationen vor. Der Beitrag untersucht diese Aspekte auf Basis einer für Deutschland repräsentativen Erhebung von rund 3.200 Betrieben der Privatwirtschaft. Mit Hilfe theoretischer Vorüberlegungen werden mögliche Einflussfaktoren in verschiedenen Konzepten der Industrial Relations- und Organisationsforschung verortet und systematisiert. Die Untersuchung zeigt, dass jeweils unterschiedliche Kontextfaktoren die Betriebrats- und AVO-Existenz erklären: Während Betriebsräte vor allem Ausdruck von Betriebsgrößen- und Branchendifferenzen, betrieblichen Entwicklungspfaden und berufskulturellen Orientierungen der Beschäftigten sind, stehen AVOs in engem Zusammenhang mit der Beteiligungsstrategie des Managements und betriebskulturellen Faktoren." (Autorenreferat)"There is little empirically validated knowledge about the coverage and contextual factors of workplace level employee representation - works councils (WC) and other representation bodies (ORBs) which are not legally based on the German Works Constitution Act. This article analyses both aspects by exploiting a representative survey data of approximately 3.200 workplaces in the German private sector. Coverage and contextual factors of employee representation structures are examined from the perspective of various theoretical models derived from industrial relations and organisational research. The article concludes that contextual factors differ considerably between WCs and ORBs: While the incidence of WCs depends mainly on firm size, industry, path dependence and employee related factors, the existence of ORBs is first of all related to the participation strategy of management and aspects of company culture." (author's abstract

Kollektive Interessenregulierung in der 'betriebsratsfreien Zone': typische Formen 'Anderer Vertretungsorgane'

"Kollektive betriebliche Interessenregulierung findet in vielen privatwirtschaftlichen Betrieben in Form sog. 'Anderer Vertretungsorgane' (AVOs) statt. Diese Interessenvertretung 'jenseits des Betriebsrats' erlangt in jüngerer Zeit vermehrt Beachtung in der Arbeits- und Industriesoziologie. Die empirische Forschung fokussierte dabei einerseits auf die Interessenregulierungsstrukturen in Sektoren mit hochqualifizierter Beschäftigung wie der New Economy, anderseits wurden mit Hilfe von Breitenerhebungen Fragen der Verbreitung, Kontextbedingungen und internen Strukturen dieser Gremien untersucht. Kaum systematische Beachtung fand dabei die Tatsache, dass AVOs keine homogene Gruppe von Interessenvertretungsorganen darstellen. Der Beitrag analysiert daher unterschiedliche Typen 'Anderer Vertretungsorgane'." (Autorenreferat)"In many private German companies, collective interest representation at plant-level is carried out through so-called 'alternative representation bodies'. This form of employee representation outside the legal system of Works Councils has been attracting attention in industrial relations research in recent years. Some empirical studies have focussed on patterns of interest regulation in sectors of qualified labor and the 'New Economy'; other research has used survey methods to analyze the distribution, contextual factors, and internal structures of alternative representation bodies. Until now, the diversity of form and function of these bodies has not been sufficiently recognized. In this respect, they are unlike works councils which are founded and act according to the Works Constitution Act (Betriebsverfassungsgesetz) - an exclusive model of interest representation. This article analyses different types of alternative representation bodies." (author's abstract

The medical profession, industry and continuing medical education:finding the balance that's right for patients

Provision and participation in formal external continuing medical education (CME) is costly. Employer or state support of CME is the exception rather than the rule. The medical industry has supported both providers and consumers of educational activities, leading to concerns of commercial bias. Recent medical industry initiatives in Europe to improve the transparency of the relationship between industry and the profession, including the field of medical education, have had the paradoxical effect of the industry playing an increasingly direct role in the provision of physician education. Funding of medical professional society annual congresses has been directly and indirectly jeopardized. Acknowledging that there are areas of cooperation in the field of education between the medical profession and the medical industry from which both can benefit, we argue that medical education requires an objective approach that the primary fiduciary duty of medical industry companies precludes. Medical professional societies, as not-for-profit organizations whose core mission is the development and promotion of best practice, are best placed to guide and deliver medical education to their members. (C) 2019 Published by Elsevier Inc

Linking complement C3 and B cells in nasal polyposis

Nasal polyposis often is characterized by a persistent inflammation of the sinonasal mucosa, disease recurrence after medical or surgical intervention, and asthma comorbidity. Dysregulated complement activation may contribute to immunologic alterations and disease. To date, there is only scattered knowledge on the source and regulation of the central complement factors in the pathogenesis of nasal polyps. Here, we aim to study complement signatures, especially the C3-C3aR axis, and focus on cellular sources and targets in nasal polyps. Expression of complement factors, including C3, C5, and the anaphylatoxin receptors, was analyzed in nasal polyp tissue samples, the corresponding inferior turbinates, and healthy controls using transcriptomic methods and protein measurements. Distinct patterns of complement expression were found in nasal polyps compared to controls, characterized by an increased C3 activation and an increase in C3aR-bearing cells. In contrast, no difference was shown for epithelial-dependent C3 production. Besides low intracellular C3-expression levels for lymphocytes in general, we could identify an enlarged B lymphocyte population in nasal polyps displaying high amounts of intracellular C3. Our data suggest a prominent role for the C3-C3aR-axis in nasal polyps and, for the first time, describe a B cell population containing high levels of intracellular C3, suggesting a new role of B cells in the maintenance of the inflammation by complement

Model-based inference from microvascular measurements: Combining experimental measurements and model predictions using a Bayesian probabilistic approach

Objective: In vivo imaging of the microcirculation and network-oriented modeling have emerged as powerful means of studying microvascular function and understanding its physiological significance. Network-oriented modeling may provide the means of summarizing vast amounts of data produced by high-throughput imaging techniques in terms of key, physiological indices. To estimate such indices with sufficient certainty, however, network-oriented analysis must be robust to the inevitable presence of uncertainty due to measurement errors as well as model errors. Methods: We propose the Bayesian probabilistic data analysis framework as a means of integrating experimental measurements and network model simulations into a combined and statistically coherent analysis. The framework naturally handles noisy measurements and provides posterior distributions of model parameters as well as physiological indices associated with uncertainty. Results: We applied the analysis framework to experimental data from three rat mesentery networks and one mouse brain cortex network. We inferred distributions for more than 500 unknown pressure and hematocrit boundary conditions. Model predictions were consistent with previous analyses, and remained robust when measurements were omitted from model calibration. Conclusion: Our Bayesian probabilistic approach may be suitable for optimizing data acquisition and for analyzing and reporting large data sets acquired as part of microvascular imaging studies

Coalescent angiogenesis—evidence for a novel concept of vascular network maturation

Angiogenesis describes the formation of new blood vessels from pre-existing vascular structures. While the most studied mode of angiogenesis is vascular sprouting, specific conditions or organs favor intussusception, i.e., the division or splitting of an existing vessel, as preferential mode of new vessel formation. In the present study, sustained (33-h) intravital microscopy of the vasculature in the chick chorioallantoic membrane (CAM) led to the hypothesis of a novel non-sprouting mode for vessel generation, which we termed "coalescent angiogenesis." In this process, preferential flow pathways evolve from isotropic capillary meshes enclosing tissue islands. These preferential flow pathways progressively enlarge by coalescence of capillaries and elimination of internal tissue pillars, in a process that is the reverse of intussusception. Concomitantly, less perfused segments regress. In this way, an initially mesh-like capillary network is remodeled into a tree structure, while conserving vascular wall components and maintaining blood flow. Coalescent angiogenesis, thus, describes the remodeling of an initial, hemodynamically inefficient mesh structure, into a hierarchical tree structure that provides efficient convective transport, allowing for the rapid expansion of the vasculature with maintained blood supply and function during development

Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors?: Position Paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology

Cardiovascular disease (CVD) is the leading cause of death in women, and knowledge of the clinical consequences of atherosclerosis and CVD in women has grown tremendously over the past 20 years. Research efforts have increased and many reports on various aspects of ischaemic heart disease (IHD) in women have been published highlighting sex differences in pathophysiology, presentation, and treatment of IHD. Data, however, remain limited. A description of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward. In this report, we identify gaps in existing literature and make recommendations for future research. Women largely share similar cardiovascular risk factors for IHD with men; however, women with suspected or confirmed IHD have less coronary atherosclerosis than men, even though they are older and have more cardiovascular risk factors than men. Coronary endothelial dysfunction and microvascular disease have been proposed as important determinants in the aetiology and prognosis of IHD in women, but research is limited on whether sex differences in these mechanisms truly exist. Differences in the epidemiology of IHD between women and men remain largely unexplained, as we are still unable to explain why women are protected towards IHD until older age compared with men. Eventually, a better understanding of these processes and mechanisms may improve the prevention and the clinical management of IHD in wome

Structural Adaptation and Heterogeneity of Normal and Tumor Microvascular Networks

Relative to normal tissues, tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Here, computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Topology, vascular diameter, length, and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and the random variability of vascular responses were altered to simulate ‘normal’ and ‘tumor’ adaptation modes. The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points (d3var) and deficit of oxygen delivery relative to demand (O2def). In the tumor, d3var and O2def were higher (0.404 and 0.182) than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with ‘normal’ parameters gave low values (0.288 and 0.099). Conversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with ‘tumor’ parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including strongly reduced responses to conducted stimuli