Mechanisms of failure and outcome of secondary surgical interventions after thoracic endovascular aortic repair (TEVAR)

We evaluated mechanisms of failure and outcome of secondary surgical interventions after thoracic endovascular aortic repair (TEVAR).

The Interface Between Morphology and Action Planning: a Comparison of Two Species of New World Monkeys

Recent research with several species of nonhuman primates suggests sophisticated motor-planning abilities observed in human adults may be ubiquitous among primates. However, there is considerable variability in the extent to which these abilities are expressed across primate species. In the present experiment, we explore whether the variability in the expression of anticipatory motor-planning abilities may be attributed to cognitive differences (such as tool use abilities) or whether they may be due to the consequences of morphological differences (such as being able to deploy a precision grasp). We compared two species of New World monkeys that differ in their tool use abilities and manual dexterity: squirrel monkeys, Saimiri sciureus (less dexterous with little evidence for tool use) and tufted capuchins, Sapajus apella (more dexterous and known tool users). The monkeys were presented with baited cups in an untrained food extraction task. Consistent with the morphological constraint hypothesis, squirrel monkeys frequently showed second-order motor planning by inverting their grasp when picking up an inverted cup, while capuchins frequently deployed canonical upright grasping postures. Findings suggest that the lack of ability for precision grasping may elicit more consistent second-order motor planning, as the squirrel monkeys (and other species that have shown a high rate of second-order planning) have fewer means of compensating for inefficient initial postures. Thus, the interface between morphology and motor planning likely represents an important factor for understanding both the ontogenetic and phylogenetic origins of sophisticated motor-planning abilities. (C) 2013 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.

Novel insights into mechanisms of food allergy and allergic airway inflammation using experimental mouse models

Over the last decades, considerable efforts have been undertaken in the development of animal models mimicking the pathogenesis of allergic diseases occurring in humans. The mouse has rapidly emerged as the animal model of choice, due to considerations of handling and costs and, importantly, due to the availability of a large and increasing arsenal of genetically modified mouse strains and molecular tools facilitating the analysis of complex disease models. Here, we review latest developments in allergy research that have arisen from in vivo experimentation in the mouse, with a focus on models of food allergy and allergic asthma, which constitute major health problems with increasing incidence in industrialized countries. We highlight recent novel findings and controversies in the field, most of which were obtained through the use of gene-deficient or germ-free mice, and discuss new potential therapeutic approaches that have emerged from animal studies and that aim at attenuating allergic reactions in human patients.

[Complement--a phylogenetically old system as a new player in the development of atherosclerosis]

Atherosclerotic diseases such as coronary artery disease and ischaemic stroke are caused by chronic inflammation in arterial vessel walls. The complement system is part of the innate immune system. It is involved in many processes contributing to onset and development of atherosclerotic plaques up to the final stage of acute thrombotic events. This is due to its prominent role in inflammatory processes. In addition, there is increasing evidence that interactions between complement and coagulation provide a link between inflammation and thrombosis. On the other hand, the complement system also has an atheroprotective function through the clearance of apoptotic material. The knowledge of these complex mechanisms will become increasingly important, also for clinicians, since it may lead to novel therapeutic and diagnostic options. Therapies targeting the complement system have the potential to reduce tissue damage caused by acute ischaemic events. Whether early anti-inflammatory and anti-complement therapy may be able to prevent atherosclerosis, remains a hot topic for research.

New developments in the area of factor XIII

To cite this article: Schroeder V, Kohler HP. New developments in the area of factor XIII. J Thromb Haemost 2013; 11: 234-44. Summary.  Coagulation factor (F)XIII is best known for its role in fibrin stabilization and cross-linking of antifibrinolytic proteins to the fibrin clot. From patients with congenital FXIII deficiency, it is known that FXIII also has important functions in wound healing and maintaining pregnancy. Over the last decade more and more research groups with different backgrounds have studied FXIII and have unveiled putative novel functions for FXIII. FXIII, with its unique role as a transglutaminase among the other serine protease coagulation factors, is now recognized as a multifunctional protein involved in regulatory mechanisms and construction and repair processes beyond hemostasis with possible implications in many areas of medicine. The aim of this review was to give an overview of exciting novel findings and to highlight the remarkable diversity of functions attributed to FXIII. Of course, more research into the underlying mechanisms and (patho-)physiological relevance of the many described functions of FXIII is needed. It will be exciting to observe future developments in this area and to see if and how these interesting findings may be translated into clinical practice in the future.

Endemic pemphigus foliaceus: towards understanding autoimmune mechanisms of disease development

Fogo selvagem is an endemic form of pemphigus foliaceus (EPF) found in Brazil. Environmental and genetic factors are thought to contribute to the disease, which is associated with pathogenic IgG4 autoantibodies against the desmosomal cadherin desmoglein 1. In this issue, as an additional framework to understand autoimmune mechanisms in EPF, Flores et al. have investigated whether fogo selvagem patients and healthy individuals from endemic areas develop autoantibody responses against other desmosomal cadherins and E-cadherin.

Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone

Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50 µM, respectively. The cellular ATP content started to decrease at 20 µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidation at 10 µM and amiodarone at 20 µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.

Huntington's disease: new aspects on phenotype and genotype

Huntington's disease typically presents with involuntary movements, cognitive decline and behavioural abnormalities; however, new data show a greater spectrum and more complexity in the mode of presentation than previously appreciated. On one hand efforts are under way to better assess all aspects of the evolving phenotype over the course of the disease, on the other hand large cohorts have been prospectively followed-up and similar efforts are now being started in China. In this communication, we briefly review the most salient findings from the last couple of years. The recently established large cohorts allow the performance of accurate studies examining correlation of genetic polymorphisms with specific aspects of the phenotype thus allowing for some mechanistic insight into the causes of phenotypic variation. While Huntington's disease is the most frequent hereditary cause of chorea, other disorders with similar clinical phenotypes, including neuroacanthocytosis, are now better known, including a better understanding of the primary cause as well as the pathophysiology at the molecular level. Studies on the mechanisms of disease in these different disorders may shed light on the respective pathomechanisms and may open new approaches to a better understanding and additional treatment options for choreatiform neurodegenerative disorders.

A New Symbiosis: Municipalities, Private Contractors and Non-Governmental Organisations for the Provision of Local Public Services"

This project considered the second stage of transforming local administration and public service management to reflect democratic forms of government. In Hungary in the second half of the 1990s more and more public functions delegated to local governments have been handed over to the private or civil sectors. This has led to a relative decrease of municipal functions but not of local governments' responsibilities, requiring them to change their orientation and approach to their work so as to be effective in their new roles of managing these processes rather than traditional bureaucratic administration. Horvath analysed the Anglo-Saxon, French and German models of self-government, identifying the differing aspects emphasised in increasing the private sector's role in the provision of public services, and the influence that this process has on the system of public administration. He then highlighted linkages between actors and local governments in Hungary, concluding that the next necessary step is to develop institutional mechanisms, financial incentives and managerial practices to utilise the full potential of this process. Equally important is the need for conscious avoidance of restrictive barriers and unintended consequences, and for local governments to confront the social conflicts that have emerged in parallel with privatisation. A further aspect considered was a widening of the role of functional governance at local level in the field of human services. A number of different special purpose bodies have been set up in Hungary, but the results of their work are unclear and Horvath feels that this institutionalisation of symbiosis is not the right path in Hungary today. He believes that the change from local government to local governance will require the formulation of specific public policy, the relevance of which can be proven by processes supported with actions.

The strategies of the Theileria parasite: a new twist in host-pathogen interactions

Theileria parasites infect and transform cells of the ruminant immune system. Continuous proliferation and survival of Theileria-transformed cells involves the well-orchestrated activation of several host-cell signalling pathways. Constitutive NF-kappa B (nuclear factor kappa B) activation is accomplished by recruiting the IKK (I kappa B kinase) complex, a central regulator of NF-kappa B pathways, to the surface of the transforming schizont, where it becomes permanently activated. Constitutive activation of the PI-3K-PKB [phosphoinositide 3-kinase-(Akt) protein kinase B] pathway is likely to be indirect and is essential for continuous proliferation. Theileria-transformed T cells express a range of anti-apoptotic proteins that can be expected to provide protection against apoptosis induced by death receptors, as well as cellular control mechanisms that are mobilised to eliminate cells that entered a cycle of uncontrolled proliferation.

Mechanisms of airway obliteration after lung transplantation

Post-transplant bronchiolitis obliterans, also called bronchiolitis obliterans syndrome, affects up to 50-60% of patients who survive 5 yr after surgery according to its clinical definition, which is based on the degree of obstructive airway disease. Alloimmune-independent and -dependent mechanisms produce injuries and inflammation of epithelial cells and subepithelial structures, leading to aberrant tissue repair. The triggering of innate immunity by various infections or chemical injuries after, for example, gastroesophageal reflux, may lead to the release of danger signals that are able to activate dendritic cells, a crucial link with adaptive immunity. Inflammation can also increase the expression and display of major histocompatibility alloantigens and thus favor the initiation of rejection episodes. These phenomena may be limited in time and location or may be protracted. Reducing the risk of alloimmune-independent factors may be as important as treating acute episodes of lung rejection. Excessive immunosuppression may be deleterious by increasing the risk of infection, thereby triggering innate and adaptive immunity. New potential therapeutic targets are emerging from the research performed on leukotriene receptors, chemokine receptors, and growth factors. Neutralizing these molecules reduces the initial mononuclear and polynuclear infiltrates or the subsequent fibroproliferative process and the neovascular changes, feeding this process.

Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

Central hypersensitivity in chronic pain: mechanisms and clinical implications

The available literature consistently shows increased pain sensitivity after sensory stimulation of healthy tissues in patients who have various chronic pain conditions. This indicates a state of hypersensitivity of the CNS that amplifies the nociceptive input arising from damaged tissues. Experimental data indicate that central hypersensitivity is probably induced primarily by nociceptive input arising from a diseased tissue. In patients, imbalance of descending modulatory systems connected with psychologic distress may play a role. There is experimental support in animal studies for the persistence of central hypersensitivity after complete resolution of tissue damage. This is particularly true for neuropathic pain conditions, whereby potentially irreversible plasticity changes of the CNS have been documented in animal studies. Whether such changes are present in musculoskeletal pain states is at present uncertain. Despite the likely importance of central hypersensitivity in the pathophysiology of chronic pain, this mechanism should not be used to justify the lack of understanding on the anatomic origin of the pain complaints in several pain syndromes, which is mostly due to limitations of the available diagnostic tools. Treatment strategies for central hypersensitivity in patients have been investigated mostly in neuropathic pain states. Possible therapy modalities for central hypersensitivity in chronic pain of musculoskeletal origin are largely unexplored. The limited evidence available and everyday practice show, at best, modest efficacy of the available treatment modalities for central hypersensitivity. The gap between basic knowledge and clinical benefits remains large and should stimulate further intensive research.