9,872 research outputs found

    Die akute Appendizitis im Kindes- und Jugendalter: neue diagnostische Verfahren für die prätherapeutische Differenzierung histopathologischer Entitäten zur Unterstützung konservativer Therapiestrategien

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    Hintergrund der hier zusammengefassten Studien war die aktuelle Datenlage, die dafür spricht, dass es sich bei der klinisch unkomplizierten, histopathologisch phlegmonösen und der klinisch komplizierten, histopathologisch gangränösen Appendizitis um unabhängige Entitäten handelt. Diese können unterschiedlichen Therapieoptionen (konservativ vs. operativ) zugeführt werden. Vor diesem Hintergrund war es ein Ziel der Arbeiten zu untersuchen, wie die Formen der akuten Appendizitis im Kindes- und Jugendalter bereits prätherapeutisch unterschieden werden können. Sowohl in der Labordiagnostik (P1 und P2) als auch im Ultraschall (P3) lassen sich Unterschiede zwischen Patient*innen mit unkomplizierter, phlegmonöser und komplizierter (gangränöser und perforierender) Appendizitis aufzeigen. Hierdurch allein kann allerdings aufgrund unzureichender Trennschärfe noch keine ausreichende Entscheidungssicherheit erreicht werden. Mit Verfahren der künstlichen Intelligenz auf Untersucher-unabhängige diagnostische Parameter (P4) konnte die Vorhersagegenauigkeit der akuten Appendizitis weiter gesteigert werden. Interessante Ergebnisse bezüglich der unterschiedlichen Pathomechanismen der beiden inflammatorischen Entitäten ergaben sich durch eine differenzielle Genexpressionsanalyse (P5). In einer Proof-of-Concept-Studie wurden zuvor beschriebene Methoden der künstlichen Intelligenz auf die Genexpressionsdaten angewandt (P6). Hierdurch konnte im Modell eine grundsätzliche Differenzierbarkeit der Entitäten durch die Anwendung der neuen Methode aufgezeigt werden. Ein mittelfristiges Ziel ist es, eine Biomarkersignatur zu definieren, die ihre Aussagekraft durch einen Computeralgorithmus hat. Hierdurch soll eine schnelle Therapieentscheidung ermöglicht werden. Im Idealfall sollte diese Biomarkersignatur sicher, objektiv und einfach zu bestimmen sein sowie eine höhere diagnostische Sicherheit als die bisherige Diagnostik mittels Anamnese, Untersuchung, Laboranalyse und Ultraschall bieten. Langfristiges Ziel von Folgestudien ist die Identifizierung einer Biomarkersignatur mit der bestmöglichen Vorhersagekraft. Hinsichtlich der routinemäßigen klinischen Diagnostik ist die Anwendung von Point-of-Care Devices auf PCR-Basis denkbar. Hier könnte eine limitierte Anzahl von Primern für eine Biomarkersignatur mit hoher Vorhersagekraft zum Einsatz kommen. Der dadurch ermittelte Biomarker würde seine Aussagekraft durch einen einfach anzuwendenden Computeralgorithmus erhalten. Die Kombination aus Genexpressionsanalyse mit Methoden der künstlichen Intelligenz kann somit die Grundlage für ein neues diagnostisches Instrument zur sicheren Unterscheidung unterschiedlicher Appendizitisentitäten darstellen

    Examples of works to practice staccato technique in clarinet instrument

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    Klarnetin staccato tekniğini güçlendirme aşamaları eser çalışmalarıyla uygulanmıştır. Staccato geçişlerini hızlandıracak ritim ve nüans çalışmalarına yer verilmiştir. Çalışmanın en önemli amacı sadece staccato çalışması değil parmak-dilin eş zamanlı uyumunun hassasiyeti üzerinde de durulmasıdır. Staccato çalışmalarını daha verimli hale getirmek için eser çalışmasının içinde etüt çalışmasına da yer verilmiştir. Çalışmaların üzerinde titizlikle durulması staccato çalışmasının ilham verici etkisi ile müzikal kimliğe yeni bir boyut kazandırmıştır. Sekiz özgün eser çalışmasının her aşaması anlatılmıştır. Her aşamanın bir sonraki performans ve tekniği güçlendirmesi esas alınmıştır. Bu çalışmada staccato tekniğinin hangi alanlarda kullanıldığı, nasıl sonuçlar elde edildiği bilgisine yer verilmiştir. Notaların parmak ve dil uyumu ile nasıl şekilleneceği ve nasıl bir çalışma disiplini içinde gerçekleşeceği planlanmıştır. Kamış-nota-diyafram-parmak-dil-nüans ve disiplin kavramlarının staccato tekniğinde ayrılmaz bir bütün olduğu saptanmıştır. Araştırmada literatür taraması yapılarak staccato ile ilgili çalışmalar taranmıştır. Tarama sonucunda klarnet tekniğin de kullanılan staccato eser çalışmasının az olduğu tespit edilmiştir. Metot taramasında da etüt çalışmasının daha çok olduğu saptanmıştır. Böylelikle klarnetin staccato tekniğini hızlandırma ve güçlendirme çalışmaları sunulmuştur. Staccato etüt çalışmaları yapılırken, araya eser çalışmasının girmesi beyni rahatlattığı ve istekliliği daha arttırdığı gözlemlenmiştir. Staccato çalışmasını yaparken doğru bir kamış seçimi üzerinde de durulmuştur. Staccato tekniğini doğru çalışmak için doğru bir kamışın dil hızını arttırdığı saptanmıştır. Doğru bir kamış seçimi kamıştan rahat ses çıkmasına bağlıdır. Kamış, dil atma gücünü vermiyorsa daha doğru bir kamış seçiminin yapılması gerekliliği vurgulanmıştır. Staccato çalışmalarında baştan sona bir eseri yorumlamak zor olabilir. Bu açıdan çalışma, verilen müzikal nüanslara uymanın, dil atış performansını rahatlattığını ortaya koymuştur. Gelecek nesillere edinilen bilgi ve birikimlerin aktarılması ve geliştirici olması teşvik edilmiştir. Çıkacak eserlerin nasıl çözüleceği, staccato tekniğinin nasıl üstesinden gelinebileceği anlatılmıştır. Staccato tekniğinin daha kısa sürede çözüme kavuşturulması amaç edinilmiştir. Parmakların yerlerini öğrettiğimiz kadar belleğimize de çalışmaların kaydedilmesi önemlidir. Gösterilen azmin ve sabrın sonucu olarak ortaya çıkan yapıt başarıyı daha da yukarı seviyelere çıkaracaktır

    Genetic considerations in cerebral small vessel diseases

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    Cerebral small vessel disease (CSVD) encompasses a broad clinical spectrum united by pathology of the small vessels of the brain. CSVD is commonly identified using brain magnetic resonance imaging with well characterized markers including covert infarcts, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. The pathophysiology of CSVD is complex involving genetic determinants, environmental factors, and their interactions. While the role of vascular risk factors in CSVD is well known and its management is pivotal in mitigating the clinical effects, recent research has identified novel genetic factors involved in CSVD. Delineating genetic determinants can promote the understanding of the disease and suggest effective treatments and preventive measures of CSVD at the individual level. Here we review CSVD focusing on recent advances in the genetics of CSVD. The knowledge gained has advanced understanding of the pathophysiology of CSVD, offered promising early results that may improve subtype identification of small vessel strokes, has led to additional identification of mendelian forms of small vessel strokes, and is getting closer to influencing clinical care through pharmacogenetic studies

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 β chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IκB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de referência para doentes com estenose aórtica e visa a eliminação da sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica. Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os mecanismos biológicos subjacentes a uma remodelagem reversa incompleta ainda não são claros. Além disso, não dispomos de ferramentas de prognóstico definitivos nem de terapias auxiliares para melhorar a condição dos pacientes indicados para substituição da válvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica para a caracterização, respetivamente, do miocárdio e do líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas desreguladas foram detetadas. As análises de anotação de genes, de enriquecimento de vias celulares e discriminativa corroboram um cenário de aumento da expressão de genes pro-hipertróficos e de síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos apontou para a cadeia β do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma, sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição dos pacientes indicados para intervenção. Em particular, a avaliação funcional de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver força (tensão ativa). Este estudo levanta várias hipóteses na investigação da remodelagem reversa. No futuro, estudos de ganho e/ou perda de função realizados em cardiomiócitos isolados ou em modelos animais de banding-debanding da aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos encontrados. Além disso, estudos clínicos em coortes de maior dimensão trarão conclusões definitivas quanto ao valor de prognóstico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    Mathematical models to evaluate the impact of increasing serotype coverage in pneumococcal conjugate vaccines

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    Of over 100 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumo- coccal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. This thesis has four aims. First, to explore the limitations and assumptions of published pneu- mococcal models and the implications for future vaccine formulation and policy. Second, to conduct a trend analysis assembling all the available evidence for serotype replacement in Europe, North America and Australia to characterise invasive pneumococcal disease (IPD) caused by vaccine-type (VT) and non-vaccine-types (NVT) serotypes. The motivation behind this is to assess the patterns of relative abundance in IPD cases pre- and post-vaccination, to examine country-level differences in relation to the vaccines employed over time since introduction, and to assess the growth of the replacement serotypes in comparison with the serotypes targeted by the vaccine. The third aim is to use a Bayesian framework to estimate serotype-specific invasiveness, i.e. the rate of invasive disease given carriage. This is useful for dynamic transmission modelling, as transmission is through carriage but a majority of serotype-specific pneumococcal data lies in active disease surveillance. This is also helpful to address whether serotype replacement reflects serotypes that are more invasive or whether serotypes in a specific location are equally more invasive than in other locations. Finally, the last aim of this thesis is to estimate the epidemiological and economic impact of increas- ing serotype coverage in PCVs using a dynamic transmission model. Together, the results highlight that though there are key parameter uncertainties that merit further exploration, divergence in serotype replacement and inconsistencies in invasiveness on a country-level may make a universal PCV suboptimal.Open Acces

    TOWARDS AN UNDERSTANDING OF EFFORTFUL FUNDRAISING EXPERIENCES: USING INTERPRETATIVE PHENOMENOLOGICAL ANALYSIS IN FUNDRAISING RESEARCH

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    Physical-activity oriented community fundraising has experienced an exponential growth in popularity over the past 15 years. The aim of this study was to explore the value of effortful fundraising experiences, from the point of view of participants, and explore the impact that these experiences have on people’s lives. This study used an IPA approach to interview 23 individuals, recognising the role of participants as proxy (nonprofessional) fundraisers for charitable organisations, and the unique organisation donor dynamic that this creates. It also bought together relevant psychological theory related to physical activity fundraising experiences (through a narrative literature review) and used primary interview data to substantiate these. Effortful fundraising experiences are examined in detail to understand their significance to participants, and how such experiences influence their connection with a charity or cause. This was done with an idiographic focus at first, before examining convergences and divergences across the sample. This study found that effortful fundraising experiences can have a profound positive impact upon community fundraisers in both the short and the long term. Additionally, it found that these experiences can be opportunities for charitable organisations to create lasting meaningful relationships with participants, and foster mutually beneficial lifetime relationships with them. Further research is needed to test specific psychological theory in this context, including self-esteem theory, self determination theory, and the martyrdom effect (among others)

    Epilepsy Mortality: Leading Causes of Death, Co-morbidities, Cardiovascular Risk and Prevention

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    a reuptake inhibitor selectively prevents seizure-induced sudden death in the DBA/1 mouse model of sudden unexpected ... Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by ..
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