Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response

Objective: We investigated the metabolic, hemodynamic, and inflammatory responses of pharmacological and physical therapies aimed at reducing body temperature in febrile critically ill patients. Design and setting: Open-label, randomized trial in a surgical ICU in a tertiary university hospital. Patients: Thirty analgosedated, mechanically ventilated patients with a temperature of 38.5°C or higher were randomized to receive either intravenous metamizol, intravenous propacetamol, or external cooling. Measurements and results: Body temperature and metabolic and hemodynamic variables were recorded at baseline and during the following 4h. Cytokine concentrations were assessed before and 4 and 12h after the initiation of antipyresis. Body temperature decreased significantly in all treatment groups. For a 1°C temperature decrease, the energy expenditure index increased by 5% with external cooling and decreased by 7% and 8% in the metamizol and propacetamol groups, respectively. Metamizol induced a significant decrease in mean arterial pressure and urine output compared to baseline and to the other two groups. C-reactive protein increased over time, but compared to the other groups it was significantly lower in patients receiving metamizol after 4h. Cytokine concentrations were not different among the three groups or over time, although interleukin 6 tended to decrease over time in the metamizol group. Conclusions: Metamizol, propacetamol, and external cooling equally reduced temperature. Considering the undesirable hemodynamic effects, metamizol should not be considered the first antipyretic choice in unstable patients. Propacetamol or external cooling should be preferred, although the latter should be avoided in patients unlikely to tolerate the increased metabolic demand induced by external coolin

Inhaled nitric oxide for high-altitude pulmonary edema

BACKGROUND. Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. When administered by inhalation, nitric oxide, an endothelium-derived relaxing factor, attenuates the pulmonary vasoconstriction produced by short-term hypoxia. METHODS. We studied the effects of inhaled nitric oxide on pulmonary-artery pressure and arterial oxygenation in 18 mountaineers prone to high-altitude pulmonary edema and 18 mountaineers resistant to this condition in a high altitude laboratory (altitude, 4559 m). We also obtained lung-perfusion scans before and during nitric oxide inhalation to gain further insight into the mechanism of action of nitric oxide. RESULTS. In the high-altitude laboratory, subjects prone to high-altitude pulmonary edema had more pronounced pulmonary hypertension and hypoxemia than subjects resistant to high-altitude pulmonary edema. Arterial oxygen saturation was inversely related to the severity of pulmonary hypertension (r=-0.50, P=0.002). In subjects prone to high-altitude pulmonary edema, the inhalation of nitric oxide (40 ppm for 15 minutes) produced a decrease in mean (+/-SD) systolic pulmonary-artery pressure that was three times larger than the decrease in subjects resistant to such edema (25.9+/-8.9 vs. 8.7+/-4.8 mm Hg, P<0.001). Inhaled nitric oxide improved arterial oxygenation in the 10 subjects who had radiographic evidence of pulmonary edema (arterial oxygen saturation increased from 67+/-10 to 73+/-12 percent, P=0.047), whereas it worsened oxygenation in subjects resistant to high-altitude pulmonary edema. The nitric oxide-induced improvement in arterial oxygenation in subjects with high-altitude pulmonary edema was accompanied by a shift in blood flow in the lung away from edematous segments and toward nonedematous segments. CONCLUSIONS. The inhalation of nitric oxide improves arterial oxygenation in high-altitude pulmonary edema, and this beneficial effect may be related to its favorable action on the distribution of blood flow in the lungs. A defect in nitric nitric oxide synthesis may contribute to high-altitude pulmonary edema

Über das erfolgreiche Scheitern einer europäischen Verfassung

O pozytywnych skutkach upadku Konstytucji EuopejskiejÜber das erfolgreiche Scheitern einer europäischen Verfassun

Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling

Objective The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment. Design We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny. Results Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids. Conclusions Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.This study was funded by the Deutsche Forschungsgemeinschaft (DFG, K.L. 2544/1-1 and 1-2), the Forschungskern SyStaR to AK, BIU (Böhringer Ingelheim Ulm to AK), the Fritz-Thyssen Foundation (Az. 10.15.2.040), the German Cancer Aid (111879) and the Else-Kröner-Fresenius-Stiftung (2011_A200). AK is indebted to the Baden-Württemberg Stiftung for the financial support of this research project by the Eliteprogramme for Postdocs. AK is also an Else-Kröner-Fresenius Memorial Fellow. LP is supported by a research fellowship of the Else-Kröner-Fresenius-Stiftung. MH was supported by the International Graduate School in Molecular Medicine and the Bausteinprogramme (L.SBN. 110), Ulm University. MM is supported by a grant of Ulm University (Baustein for Senior Clinician Scientists). IGC is funded by the Interdisciplinary Center for Clinical Research (IZKF Aachen) and Start Program, RWTH Aachen University Medical School, Aachen, German

Distributional (Single) Index Models

A Distributional (Single) Index Model (DIM) is a semi-parametric model for distributional regression, that is, estimation of conditional distributions given covariates. The method is a combination of classical single index models for the estimation of the conditional mean of a response given covariates, and isotonic distributional regression. The model for the index is parametric, whereas the conditional distributions are estimated non-parametrically under a stochastic ordering constraint. We show consistency of our estimators and apply them to a highly challenging data set on the length of stay (LoS) of patients in intensive care units. We use the model to provide skillful and calibrated probabilistic predictions for the LoS of individual patients, that outperform the available methods in the literature

Beschreibung von Weidesystemen rinderhaltender Betriebe in der Schweiz

Die Weidehaltung ist zwar die ursprünglichste Form der Rinderhaltung, aber es ist nicht bekannt, welche Weidesysteme in der Schweizer Landwirtschaft bevorzugt umgesetzt werden und auf welchen Grundlagen Entscheide zur Weidebewirtschaftung getroffen werden. Anhand eines Fragebogens wurden die Kenngrössen der Weidewirtschaft sowie die Grundlagen der Bewirtschaftungsentscheidungen für 15 Milch- oder Mastviehbetriebe in der Deutschschweiz erfasst. Die Betriebe unterschieden sich in Bezug auf die Lage, ihre Grösse und die Erfahrung der Betriebsleitenden stark voneinander. Das verbreitetste Weidesystem war die Umtriebsweide. Sie wurde auf sämtlichen Mutterkuhbetrieben und bei den meisten Kälber- und Rinderherden angewendet. Von den Milchviehbetrieben setzten 6 von 10 auf die Umtriebsweide, während 3 Betriebe eine Portionenweide hatten. Nur ein Betrieb wendete für seine Milchvieh- und Rinderherden je eine Standweide an. Bei der Wahl des Weidesystems waren der Verlauf der Parzellengrenzen, das saubere Abfressen sowie eine Minimierung des Aufwands die entscheidenden Kriterien. Beim Weidemanagement gab es grosse Unter-schiede. Während bei Milchvieh die Besatzzeit meist 2 bis 5 Tage dauerte und danach maximal 1 Monat Ruhezeit folgte, war dieser Rhythmus bei Mutterkühen langsamer. Die Besatzzeit dauerte auf den meisten Betrieben 6 bis 15 Tage mit einer anschliessenden Ruhezeit von bis zu 2 Monaten. Bei Jungtieren waren die Besatz- und Ruhezeiten sehr unterschiedlich und es gab weniger Nutzungen pro Jahr als bei adulten Tieren. Auch die Besatzdichte war bei Kälber- und Rinderweiden rund fünfmal tiefer als bei Milch- und Mutterkühen.Although grazing is the most original form of cattle farming, it is not known which stocking methods are preferred in Swiss agriculture and according to which criteria management decisions are made. A questionnaire was used to record the characteristics of pasture management for 15 dairy or beef cattle farms in the German-speaking part of Switzerland. The farms differed in terms of location, size and experience of the farm managers. The most common grazing system was rotational stocking. It was used on all suckler cow herds and on most young cattle herds. 6 out of 10 dairy farms used rotational grazing, while 3 had strip grazing. Only one farm applied continuous stocking for both dairy and beef herds. Decisive criteria for the stocking method were the course of the paddock boundaries, clean grazing and minimisation of effort. The farms differed a lot in terms of their pasture management. While stocking periods for dairy cows usually lasted 2 to 5 days followed by a maximum rest period of 1 month, this rhythm was slower for suckler cows. Their rearing usually lasted 6 to 15 days with a subsequent rest period of up to 2 months on most farms. For young animals, the stocking and resting periods were very different and there were fewer stocking cycles per year than for adult animals. Stocking rates were about five times lower on young cattle pastures than on dairy and suckler cows

Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN), and intraductal papillary mucinous neoplasm (IPMN) is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized

The Impact of Bioactive Lipids on Cardiovascular Development

Lysophospholipids comprise a group of bioactive molecules with multiple biological functions. The cardinal members of this signalling molecule group are sphingosylphosphorylcholine (SPC), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) which are, at least in part, homologous to each other. Bioactive lipids usually act via G-protein coupled receptors (GPCRs), but can also function as direct intracellular messengers. Recently, it became evident that bioactive lipids play a role during cellular differentiation development. SPC induces mesodermal differentiation of mouse ES cells and differentiation of promyelocytic leukemia cells, by a mechanism being critically dependent on MEK-ERK signalling. LPA stimulates the clonal expansion of neurospheres from neural stem/progenitor cells and induces c-fos via activation of mitogen- and stress-activated protein kinase 1 (MSK1) in ES cells. S1P acts on hematopoietic progenitor cells as a chemotactic factor and has also been found to be critical for cardiac and skeletal muscle regeneration. Furthermore, S1P promotes cardiogenesis and similarly activates Erk signalling in mouse ES cells. Interestingly, S1P may also act to maintain human stem cell pluripotency. Both LPA and S1P positively regulate the proliferative capacity of murine ES cells. In this paper we will focus on the differential and developmental impact of lysophospholipids on cardiovascular development

The Potential of iPS Cells in Synucleinopathy Research

α-synuclein is a protein involved in the pathogenesis of several so-called synucleinopathies including Parkinson's disease. A variety of models have been so far assessed. Human induced pluripotent stem cells provide a patient- and disease-specific model for in vitro studies, pharmacotoxicological screens, and hope for future cell-based therapies. Initial experimental procedures include the harvest of patients' material for the reprogramming process, the investigation of the patients genetic background in the cultured cells, and the evaluation of disease-relevant factors/proteins under various cell culture conditions