Uncomplicated community-acquired pneumonia in immunocompetent children

A pneumonia é uma das principais causas de mortalidade em crianças fora do período neonatal. Sua prevalência tem diminuído nos últimos anos principalmente devido à implementação de vacinas contra S. pneumoniae e H. influenzae tipo b. Os principais patógenos causadores variam conforme a faixa etária, sendo o pneumococo um agente prevalente em crianças a partir dos 2 meses de idade. Não há sintomas específicos e sinais radiológicos patognomônicos de pneumonia. Quadros iniciais podem apresentar radiografia de tórax normal e a presença de alterações não diferencia causas bacterianas de virais. Exames de imagem devem ser realizados em pacientes hospitalizados, sendo dispensáveis para pacientes atendidos ambulatorialmente. Outros exames de imagem têm surgido como opção para auxílio diagnóstico, como ecografia torácica e ressonância magnética pulmonar. Assim como os exames de imagem, os exames laboratoriais devem se restringir ao ambiente hospitalar e seu resultado deve ser interpretado dentro do contexto clínico e de demais exames complementares. O isolamento do agente etiológico é útil no manejo terapêutico, para garantir o uso correto de antibioticoterapia, reduzindo as taxas de resistência bacteriana. Entretanto, a sensibilidade destes exames continua baixa, sendo necessário iniciar tratamento conforme o germe mais prevalente para a faixa etária e conforme o estado vacinal do paciente. Os principais antimicrobianos utilizados em ambiente hospitalar e ambulatorial são penicilina e amoxicilina, respectivamente. Em caso de suspeita de pneumonia atípica, deve-se fazer uso de macrolídeos.Pneumonia is one of the leading causes of mortality in children outside the neonatal period. Its prevalence has been reduced in recent years mainly due to the implementation of vaccines against S. pneumoniae and H. influenzae type b. The main causative pathogens vary according to the age group, with pneumococcus being a prevalent agent in children from 2 months of age. There are no specific symptoms and radiological pathognomonic signs of pneumonia. Initial chest radiographs may appear normal and the presence of changes does not differentiate between bacterial and viral causes. Images should be performed in hospitalized patients and is not necessary for outpatients. Other imaging studies have emerged as an option for diagnostic assistance, such as thoracic ultrasonography and pulmonary magnetic resonance imaging. Laboratory tests should be restricted to inpatients and the result should be interpreted within the clinical context and other complementary tests. Isolation of the etiologic agent is useful for correct therapeutic management and to reduce bacterial resistance rates. However, the sensitivity of these tests remains low and it is necessary to start treatment according to the most prevalent bacteria, according to the age group and the vaccination state. The most frequent antimicrobial agents used in inpatient and outpatient settings are penicillin and amoxicillin. In case of suspicion of atypical pneumonia, macrolides should be used

Strategieoptionen zur Realisierung einer 100%igen Biofütterung bei Monogastriern im ökologischen Landbau

Die Umstellung auf 100%ige Biofütterung innerhalb der nächsten drei Jahre stellt eine große Herausforderung in der Monogastrierfütterung dar. Die in diesem Dossier vorgestellten Lösungsoptionen sind hinsichtlich ihrer Implementierungsmöglichkeit sehr unterschiedlich zu bewerten: Manche Optionen, wie beispielsweise die bakterielle Aminosäureherstellung, setzen noch erhebliche Forschungsarbeiten voraus, andere, wie die Verfütterung von bestimmten Silagen, sind bereits bewerte Praxis bei der Fütterung von Wiederkäuern, müssen allerdings erst noch auf Monogastrier angepasst werden. Während für die bakterielle Aminosäureherstellung entsprechende Bakterienstämme in ihrer Leistungsfähigkeit optimiert und geeignete Biosubstrate gefunden werden müssen, müssen bei der Silagebereitung und -verfütterung vor allem noch verbesserte technische Lösungen gefunden und installiert werden, damit das darin vorhandene Potenzial zur Entfaltung kommt

Corrigendum to "Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization" [Neoplasia volume 27 (2022) pp. 100784/Number C]

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered “undruggable”. An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression. Keywords: EWS-FLI1; Ewing sarcoma; Fimepinostat; HDACi; Protein stabilit

Risks of pyrrolizidine alkaloids in tea and herbal infusions

Pyrrolizidinalkaloide (PA) sind sekundäre Pflanzeninhaltsstoffe, die von einer Vielzahl von Pflanzen gebildet werden und u. a. zur Abwehr von Fraßfeinden dienen. Toxikologisch bedeutsam sind die PA, die eine Doppelbindung in 1,2-Position aufweisen. Diese können zu gesundheitlichen Schäden bei Mensch und Tier führen, wobei die Leber das Hauptzielorgan darstellt. Neben den bekannten hepatotoxischen Effekten können 1,2-ungesättigte PA auch die DNA schädigen und krebserzeugend wirken. Die Verbindungen gelangen in erster Linie über Wild- und Beikräuter in die Lebensmittelkette. In der im Jahr 2016 durch das Bundes­institut für Risikobewertung (BfR) veröffentlichten Bewertung stellte der Verzehr von kontaminiertem Tee und Kräutertee die wesentliche Expositionsquelle für die Bevölkerung gegenüber 1,2-ungesättigten PA in Deutschland dar; aber auch andere Lebensmittel können zur Aufnahme beitragen. In der vorliegenden Arbeit, in der ausschließlich Tee und Kräutertee berücksichtigt werden, zeigt sich, dass die Gehalte an 1,2-ungesättigten PA in dieser Lebensmittelgruppe im Vergleich zu 2016 deutlich gesunken sind. Dennoch kann es insbesondere bei Personen, die langfristig hohe Mengen Kräutertee bzw. Rooibostee verzehren, auch gegenwärtig noch zu Aufnahmemengen kommen, die in einem Margin of Exposure von unter 10.000 resultieren, weshalb es auch weiterhin angezeigt scheint, Maßnahmen zur Senkung der Gehalte durchzuführen.Pyrrolizidine alkaloids (PA) are secondary plant metabolites which are produced by a large number of plants, e. g. to ward off herbivores. PA with a double bond in the 1,2-position are of toxicological relevance. These derivatives can cause adverse health effects in humans and animals, with the liver being the major target organ. Besides the known hepatotoxic effects, 1,2-unsaturated PA may also damage DNA and may be carcinogenic. The occurrence of these compounds in foods is primarily caused by contamination with wild herbs. In the assessment published in 2016 by the German Federal Institute for Risk Assessment (BfR), consumption of contaminated tea and herbal tea was the main source of exposure for the population to 1.2-unsaturated PA in Germany; however, other foods can also contribute to intake. The present study, which focuses exclusively on tea and herbal tea, shows that levels of 1,2-unsaturated PA in this food group have decreased significantly compared to 2016. Nevertheless, persons who consume high amounts of herbal tea or rooibos tea in the long term may still be exposed to intakes that result in a margin of exposure of less than 10,000, which is why it still seems appropriate to implement measures to reduce the levels

QUALICOPC, a multi-country study evaluating quality, costs and equity in primary care

Contains fulltext : 96249.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: The QUALICOPC (Quality and Costs of Primary Care in Europe) study aims to evaluate the performance of primary care systems in Europe in terms of quality, equity and costs. The study will provide an answer to the question what strong primary care systems entail and which effects primary care systems have on the performance of health care systems. QUALICOPC is funded by the European Commission under the "Seventh Framework Programme". In this article the background and design of the QUALICOPC study is described. METHODS/DESIGN: QUALICOPC started in 2010 and will run until 2013. Data will be collected in 31 European countries (27 EU countries, Iceland, Norway, Switzerland and Turkey) and in Australia, Israel and New Zealand. This study uses a three level approach of data collection: the system, practice and patient. Surveys will be held among general practitioners (GPs) and their patients, providing evidence at the process and outcome level of primary care. These surveys aim to gain insight in the professional behaviour of GPs and the expectations and actions of their patients. An important aspect of this study is that each patient's questionnaire can be linked to their own GP's questionnaire. To gather data at the structure or national level, the study will use existing data sources such as the System of Health Accounts and the Primary Health Care Activity Monitor Europe (PHAMEU) database. Analyses of the data will be performed using multilevel models. DISCUSSION: By its design, in which different data sources are combined for comprehensive analyses, QUALICOPC will advance the state of the art in primary care research and contribute to the discussion on the merit of strengthening primary care systems and to evidence based health policy development

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target

The higher level of organization of the oxidative phosphorylation system: mitochondrial supercomplexes

The organization of the oxidative phosphorylation (OXPHOS) system within the inner mitochondrial membrane appears to be far more complicated than previously thought. In particular, the individual protein complexes of the OXPHOS system (complexes I to V) were found to specifically interact forming defined supramolecular structures. Blue-native polyacrylamide gel electrophoresis and single particle electron microscopy proved to be especially valuable in studying the so-called “respiratory supercomplexes”? Based on these procedures, increasing evidence was presented supporting a “solid state” organization of the OXPHOS system. Here, we summarize results on the formation, organisation and function of the various types of mitochondrial OXPHOS supercomplexes