α2C-Adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy

Aims The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic α2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human α2C-adrenoceptor gene (α2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). Methods and results We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% β-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the α2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). Conclusion α2C-Adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guideline

Relatório de Estágio

O presente documento surge como um culminar do percurso formativo da Prática Educativa Supervisionada, em contexto de Educação Pré-Escolar e Ensino do 1.º Ciclo do Ensino Básico, onde serão explicitados referentes teóricos e legais, mobilizando conhecimentos científicos, pedagógicos e didáticos, por meio a articular a teoria e a prática desenvolvida. Salienta-se a importância concebida a todo este processo, que emergiu da metodologia de investigação-ação, uma vez que possibilitou o desenvolvimento de práticas pedagógicas refletidas a partir da observação e reflexão contínua dos contextos educativos, através das grelhas de observação e diários de formação, e que impulsionou a análise das ações desenvolvidas de forma crítica e analítica. Neste sentido, e tendo em conta os desafios da atualidade que o docente tem vindo a ultrapassar para transformar os paradigmas educacionais, urge a necessidade de formar profissionais com uma nova visão abrangente no que se refere a uma perspetiva socioconstrutivista. O perfil duplo de docente abrange o desenvolvimento de profissionais que devem formar cidadão ativos na sociedade, fornecendo-lhes durante o percurso escolar, ferramentas e competências essenciais para a vida. Destaca-se, ainda, um trabalho colaborativo desenvolvido ao longo deste processo e que permitiu o crescimento a nível pessoal e profissional.This research paper results from a formative path in Supervised Educational Practice, carried out within the scope of the Master in Pre-School Education and Teaching of the 1st Cycle of the Basic Education. In this study, theoretical and legal references are explained, assembling scientific, pedagogical, and didactic knowledge to connect theory and practice. The importance of this entire process, which emerged from the action research methodology, is highlighted as it enabled the development of pedagogical practices. The study focus on the observation and continuous analysis of the educational context, through the use of observation grids and training diaries, which enhanced the analysis of the actions developed critically and analytically. In this sense and considering the current challenges that the teacher faces to transform educational paradigms, there is an urgent need to train professionals with a new comprehensive vision concerning a socio-constructivist perspective. The dual teacher profile encompasses the development of professionals who must train active citizens in society, providing them with essential tools and skills for life during their school career. It is also noteworthy the collaborative work developed throughout this process, which allowed personal and professional growth

Seismic performance of existing hollow reinforced concrete bridge columns

Highway bridges can be considered as crucial civil structures for economic and social progress of urban areas. The damages to highway bridges due to earthquake events may have dramatic impact on the interested area, with or without life threatening consequences, since bridges are essential for relief operations. For these reasons, the assessment of seismic performance of existing bridge structures is a paramount issue, especially in those countries, such as Italy, where most of existing bridges was constructed before the advancement in earthquake engineering principles and seismic design codes. Several major earthquakes occurred throughout the world highlighted the seismic vulnerability of the bridge piers, due to obsolete design. If, for ordinary shaped reinforced concrete (RC) bridge columns the seismic assessment issue can be considered as almost solved, due to several analytical assessment formulations available in literature, and adopted by codes, the same cannot be said for columns with hollow-core cross section, despite their widespread use. None of the current codes addresses specialized attention to RC hollow core members, and only quite recently, attention has been paid to experimental cyclic response of hollow columns. Some critical issues for hollow RC columns are related to the assessment of their shear capacity, special focusing on degradation mechanisms, and the high shear deformation characterizing the seismic response of such elements. In the above outlined contest, a contribution in the seismic assessment of hollow bridges piers is provided by the present work: the investigation of cyclic lateral response of RC existing bridge piers with hollow rectangular and hollow circular cross-section is performed. Special attention has been focused on failure mode prediction and shear capacity assessment. A critical review of the state-of-the-art and of the theoretical background is firstly carried out: the review process has been focused on the past experimental and analytical research on seismic performance of hollow reinforced concrete bridge piers, both for hollow rectangular and hollow circular cross sections. The experimental campaign, conducted at Laboratory of the Department of Structures for Engineering and Architecture, University of Naples “Federico II”, is presented. The experimental program comprised tests on six reduced-scale RC bridge piers with hollow cross-section (four rectangular shaped and two circular shaped). The specimens were ad hoc designed in order to be representative of the existing bridge columns typical of the Italian transport infrastructures realized before 1980, by using a scaling factor equal to 1:4. The construction procedure is detailed, too. All the tests were performed in quasi-static way by applying increasing horizontal displacement cycles with constant axial load (equal to 5% of the axial compressive capacity) until collapse. The monitoring system is accurately explained: it was composed of two sub-systems, one used for global measures (forces and displacement), and the other to deeply investigate about local deformation. Experimental results for both hollow rectangular and hollow circular specimens are reported: for each specimen the results in terms of lateral load versus drift are shown and the evolution of observed damage with increasing displacement is described and related to the lateral load-drift response. An experimental analysis of deformability contributions to the top displacement is performed, mainly in order to better understand the relevance of taking into account shear deformations for bridge piers assessment. The energy dissipation capacity is also analyzed, evaluating the equivalent damping ratio and its evolution with ductility. For hollow rectangular specimens, the global response is modelled through a three-component numerical model, in which flexure, shear and bar slip are considered separately. The main goal of the numerical analysis is to reproduce the experimental deformability contributions. The last part of the work focuses on the definition of proper shear strength models for both hollow rectangular and hollow circular cross sections, and the definition of a deformability capacity model for hollow rectangular cross section. To this aim, two different experimental databases are collected and critically analyzed. The effectiveness in shear capacity and failure mode prediction of main existing shear capacity models is investigated, by applying these models to the database columns. Based on the obtained results, some modifications to existing shear strength models are discussed and proposed in order to improve their reliability for hollow columns. Finally, a new drift capacity model is developed and proposed to assess drift at shear failure of hollow rectangular columns

Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice

Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan’s Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage

Cardiovascular characterization of Angiotensin II AT2-receptor- and adrenergic receptor-knockout-mice

Die Deletion des AT2-Rezeptors (AT2-KO) führt zu erhöhter Blutdruckempfindlichkeit und vaskulärer Hypertrophie durch Aktivitätszunahhme der P70S6-Kinase. Die Vasodilatation von Blutgefäßen wird maßgeblich durch beta1-adrenerge Rezeptoren vermittelt. Die Deletion von alpha2-adrenergen Rezeptoren (alpha2-KO) führt zur Entwicklung einer Herzinsuffizienz nach Aortenstenose. Der Mortalitätanstieg ist mit erhöhten Plasmanoradrenalin-Spiegeln (a2A-KO), bzw. Plasmaadrenalin-Spiegeln (a2C-KO) assoziiert.The deletion of AT2-receptors causes increased blood-pressure sensitivity and vascular hypertrophy by increased P70S6-Kinase activity. Vasodilation is mainly mediated by beta1-adrenoceptors. The deletion of alpha2-adrenoceptors leads to heart failure after aortic banding. The increased mortality is associated with elevated plasma levels of norepinephrine (a2A-KO) or epinephrine (a2C-KO)

Anwendbarkeit von QUIKS bei stationär konservativ behandelten Tumorpatienten

Background!#!Quality improvement in conservative pain management (QUIKS), a module for nonoperative patients in the QUIPS project was tested on a cohort of tumor patients regarding its applicability.!##!Material and methods!#!Conservatively treated inpatients at the University Hospital of Würzburg (UKW) were prospectively surveyed on the quality of pain management using the QUIKS outcome questionnaire (AZ 129/17, Ethics Committee at UKW). Information on therapy and demographics was taken from the hospital's internal documentation system.!##!Results!#!During the data collection period 100 conservatively treated inhouse tumor patients from different hospitals were included. Of the patients 74% required assistance in answering the questionnaire. Functional limitations or pain treatment-related side effects were present in 77% of the patients; the average pain level was 6 on the numerical rating scale. The most commonly reported type of pain was back pain and headache. Of the patients 18% received pain therapy with opioids and 26% with nonopioids, adjustment was made in 5% with opioids and in 44% with nonopioids and pain medicine specialists were consulted in 9% of cases.!##!Conclusion!#!The application of the questionnaire was well accepted by the patients but required a high level of assistance in completing it. A high level of pain was observed during the hospital stay and the adjustment of pain therapy or the involvement of pain medicine specialists was rare. The interpretation of statements regarding the quality of tumor pain may be limited as other (pre-existing) pain entities, such as nontumor-associated pain or chronic tumor pain could not be clearly delineated

AT2 receptor activation regulates myocardial eNOS expression via the calcineurin-NF-AT pathway.

The role of AT2-receptors has recently been subject of considerable debate. We investigated the influence of AT2-stimulation/inhibition on myocardial endothelial NO-synthase (eNOS, NOS-III) promoter activity and eNOS protein expression. Stimulation of rat cardiomyocytes with angiotensin II (AngII) increased eNOS protein expression 3.3-fold. This was blocked by Cyclosporin A (CsA). Inhibition of the AT1-receptor did not reduce AngII-mediated eNOS protein expression, whereas AT2 stimulation increased it 2.4-fold and AT2 inhibition suppressed it. The modulatory effects of the AT2-receptor on eNOS expression was confirmed in mice with a genetic deletion of the AT2-receptor (AT2-KO). In gel shift assays two putative NF-AT sites in a 1.6 kb eNOS promoter fragment showed NF-AT binding and a supershift by NF-AT2(-c1)-specific antibodies. Stimulation of transfected cells with AngII or specific AT2-receptor agonists resulted in a significant increase in eNOS promoter activity, which was blocked by CsA, MCIP1, and mutation of an upstream NF-AT site. CONCLUSION: 1) AngII-stimulation of the myocardium, both in vivo and in vitro, is accompanied by increased expression of eNOS. 2) This effect is mediated by the calcineurin pathway and is induced by the AT2-receptor. 3) These results define a calcineurin/NF-AT/eNOS pathway as downstream effector of AT2-receptor activation in the myocardium

PCR primers for microsatellite loci in a Madagascan waterbird, the Sakalava Rail (Amaurornis olivieri)

We isolated 76 microsatellite loci from the Sakalava rail (Amaurornis olivieri) genome. These were tested in 30 individuals from six sites (in three regions) across the species’ range in Madagascar. Thirty-four of the 76 loci produced unambiguous polymorphic markers, with mean H e = 0.544 (range 0.0678–0.885), mean H o = 0.430 (range 0.0400–0.767) and mean N a = 4.59 (range 2–10). In addition, we tested all primers for amplification in the Wood rail, Canirallus kioloides (N = 3) and the Bemaraha rail, Canirallus sp. nov (N = 3). Twelve of the loci produced successful amplification with eight loci showing polymorphism