1,394 research outputs found

    Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic Cardiomyopathy

    Get PDF
    Objective: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes mellitus. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy. Research Design and Methods: We utilized B1 receptor knockout mice and investiged cardiac inflammation, fibrosis and oxidative stress after induction of streptozotocin (STZ)-induced diabetes mellitus. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. Results: B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the MAP kinase p38, less oxidative stress as well as normalized cardiac inflammation, shown by fewer invading cells and, no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the pro-fibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor. Conclusion: These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy

    The myocardium and its fibrous matrix working in concert as a spatially netted mesh: a critical review of the purported tertiary structure of the ventricular mass

    Get PDF
    With the increasing interest now paid to volume reduction surgery, in which the cardiac surgeon is required to resect the ventricular myocardium to an extent unenvisaged in the previous century, it is imperative that we develop as precise knowledge as is possible of the basic structure of the ventricular myocardial mass and its functional correlates. This is the most important in the light of the adoption by some cardiac surgeons of an unvalidated model which hypothesises that the entire myocardial mass can be unravelled to produce one continuous band. It is our opinion that this model, and the phylogenetic and functional correlates derived from it, is incompatible with current concepts of cardiac structure and cardiodynamics. Furthermore, the proponents of the continuous myocardial band have made no effort to demonstrate perceived deficiencies with current concepts, nor have they performed any histological studies to validate their model. Clinical results using modifications of radius reduction surgery based on the concept of the continuous myocardial band show that the procedure essentially becomes ineffective. As we show in this review, if we understand the situation correctly, it was the erstwhile intention of the promoters of the continuous band to elucidate the basic mechanism of diastolic ventricular dilation. Their attempts, however, are doomed to failure, as is any attempt to conceptualise the myocardial mass on the basis of a tertiary structure, because of the underlying three-dimensional netting of the myocardial aggregates and the supporting fibrous tissue to form the myocardial syncytium. Thus, the ventricular myocardium is arranged in the form of a modified blood vessel rather than a skeletal muscle. If an analogy is required with skeletal muscle, then the ventricular myocardium possesses the freedom of motion, and the ability for shaping and conformational self-controlling that is better seen in the tongue. It is part of this ability that contributes to the rapid end-systolic ventricular dilation. Histologic investigations reveal that the fibrous content of the three-dimensional mesh is relatively inhomogeneous through the ventricular walls, particularly when the myocardium is diseased. The regional capacity to control systolic mural thickening, therefore, varies throughout the walls of the ventricular components. The existence of the spatially netted structure of the ventricular mass, therefore, must invalidate any attempt to conceptualise the ventricular myocardium as a tertiary arrangement of individual myocardial bands or tract

    Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia

    Get PDF
    BACKGROUND: Thyroid dysfunction is a well-known adverse effect of first-generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function. METHODS: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients. RESULTS: Overall, 33 of 73 (45%) had one or more thyroid function test abnormalities during follow-up. Hypothyroidism or hyperthyroidism were found in 18 of 73 (25%) and 21 of 73 (29%) cases after a median of 6 and 22 weeks, respectively. In most patients (29 of 39, 74%) thyroid dysfunction was transient without clinical symptoms. Therapy of hypo-/hyperthyroidism was required in three patients. Thyroid dysfunction never resulted in the discontinuation of TKI therapy. Under treatment with imatinib, nilotinib, and dasatinib, thyroid abnormalities were detected in 25%, 55%, and 70%, respectively. Four of 55 patients (7%) treated with nilotinib had evidence for an autoimmune thyroiditis (antibody positive in 3 of 4 patients) with an episode of hyperthyroidism preceding hypothyroidism. CONCLUSIONS: Thyroid dysfunction is a common adverse event with second-generation TKI therapy in patients with Ph-positive chronic myeloid leukemia. Although the mechanism is still unclear, the high frequency of thyroid abnormalities, including autoimmune thyroiditis, warrants regular and long-term monitoring of thyroid function in these patients

    Tube Models for Rubber-Elastic Systems

    Full text link
    In the first part of the paper we show that the constraining potentials introduced to mimic entanglement effects in Edwards' tube model and Flory's constrained junction model are diagonal in the generalized Rouse modes of the corresponding phantom network. As a consequence, both models can formally be solved exactly for arbitrary connectivity using the recently introduced constrained mode model. In the second part, we solve a double tube model for the confinement of long paths in polymer networks which is partially due to crosslinking and partially due to entanglements. Our model describes a non-trivial crossover between the Warner-Edwards and the Heinrich-Straube tube models. We present results for the macroscopic elastic properties as well as for the microscopic deformations including structure factors.Comment: 15 pages, 8 figures, Macromolecules in pres

    On the nature of surface roughness with application to contact mechanics, sealing, rubber friction and adhesion

    Full text link
    Surface roughness has a huge impact on many important phenomena. The most important property of rough surfaces is the surface roughness power spectrum C(q). We present surface roughness power spectra of many surfaces of practical importance, obtained from the surface height profile measured using optical methods and the Atomic Force Microscope. We show how the power spectrum determines the contact area between two solids. We also present applications to sealing, rubber friction and adhesion for rough surfaces, where the power spectrum enters as an important input.Comment: Topical review; 82 pages, 61 figures; Format: Latex (iopart). Some figures are in Postscript Level

    Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis

    Get PDF
    Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis

    Overcoming the Challenges Associated with Image-based Mapping of Small Bodies in Preparation for the OSIRIS-REx Mission to (101955) Bennu

    Get PDF
    The OSIRIS-REx Asteroid Sample Return Mission is the third mission in NASA's New Frontiers Program and is the first U.S. mission to return samples from an asteroid to Earth. The most important decision ahead of the OSIRIS-REx team is the selection of a prime sample-site on the surface of asteroid (101955) Bennu. Mission success hinges on identifying a site that is safe and has regolith that can readily be ingested by the spacecraft's sampling mechanism. To inform this mission-critical decision, the surface of Bennu is mapped using the OSIRIS-REx Camera Suite and the images are used to develop several foundational data products. Acquiring the necessary inputs to these data products requires observational strategies that are defined specifically to overcome the challenges associated with mapping a small irregular body. We present these strategies in the context of assessing candidate sample-sites at Bennu according to a framework of decisions regarding the relative safety, sampleability, and scientific value across the asteroid's surface. To create data products that aid these assessments, we describe the best practices developed by the OSIRIS-REx team for image-based mapping of irregular small bodies. We emphasize the importance of using 3D shape models and the ability to work in body-fixed rectangular coordinates when dealing with planetary surfaces that cannot be uniquely addressed by body-fixed latitude and longitude.Comment: 31 pages, 10 figures, 2 table

    An MPEG-7 scheme for semantic content modelling and filtering of digital video

    Get PDF
    Abstract Part 5 of the MPEG-7 standard specifies Multimedia Description Schemes (MDS); that is, the format multimedia content models should conform to in order to ensure interoperability across multiple platforms and applications. However, the standard does not specify how the content or the associated model may be filtered. This paper proposes an MPEG-7 scheme which can be deployed for digital video content modelling and filtering. The proposed scheme, COSMOS-7, produces rich and multi-faceted semantic content models and supports a content-based filtering approach that only analyses content relating directly to the preferred content requirements of the user. We present details of the scheme, front-end systems used for content modelling and filtering and experiences with a number of users
    corecore