Untersuchungen zur Optimierung der Irrigation bei der percutanen Harnsteinentfernung

Die PCNL und insbesondere die Mini-PCNL mit ihren effektiven „Ausspüleffekt“ haben sich weltweit als Standardverfahren in der percutanen Harnsteinsanierung etabliert. Die Miniaturisierung des PCNL Systems hat zu niedrigerem Blutverlust, schnellerer Genesung und besserer postoperativer Schmerzkontrolle bei erhaltener hoher SFR geführt. Als Konsequenz der Miniaturisierung entsteht ein erhöhter intrarenaler Druck und die OP-Zeit verlängert sich. Das führt zu erhöhter Spülflüssigkeitsaufnahme und folgend zur Septikämie, Azidose, Hypokaliämie und Volumenüberlastung des Herz-Kreislauf-Systems. Ziel dieser Arbeit ist, anhand der erhobenen experimentellen Ergebnissen die instrumentenbedingte Irrigation weitestmöglich zu optimieren, so dass eine effektive Harnsteinausspülung bei niedrigen intrarenalen Drücken und schmalen Amplatzschäften möglich ist. In den vorliegenden Studien konnte eine wegweisende Aussage zur Rolle der Geometrie der einzelnen PCNL Komponenten nicht getroffen werden. Ob der intrarenale Druck in der Harnsteinentfernung eine Bedeutung hat, wurde nicht hinter-fragt. Es gibt spärliche Informationen zum Einfluss des Volumenstroms auf die Harnsteinausspülung. Der Funktionsmechanismus des sog. Ausspüleffektes ist noch nicht vollständig verstanden. Mithilfe einer starren Messkammer erfolgte an zwei Nephroskopen und am Assortiment in Länge und Durchmesser verschiedener Amplatzschäfte die Erfassung von Volumenstrom (ml/min) und Kammerdruck (cmH2O) im Bezug zum Amplatzschaft und Nephroskop. Der Einfluss des Volumenstroms und des Kammerdrucks auf die Harnsteinausspülung wurde an standardisierten artifiziellen Steinen recherchiert und den vorhandenen Amplatzschäften. Zur Untersuchung des Ausspüleffektes erfolgte die Spülstromdarstellung mittels Toluidinblau im PVC-Röhrchen und der Messkammer sowie Erhebung der Druckverteilung in modifizierten Amplatzschäften mit separater Druckmessmöglichkeit und der Messkammer. Für beide Nephroskope konnte gezeigt werden, dass der Volumenstrom bei zunehmendem Durchmesser und abnehmender Länge des Amplatzschaftes steigt und der Kammerdruck fällt. Die Verwendung zu breiter Amplatzschäfte im Bezug zum Nephroskop zieht keine wesentliche Verbesserung der Spülkonditionen mit sich. Die wichtigsten Variablen innerhalb eines PCNL Systems, die für den intrarenalen Druck und den endgültigen Volumenstrom verantwortlich sind, sind folgend: der Volumenstrom über das Nephroskop, die Amplatzschaftdurchmesser und die Amplatzschaftlänge. Die intrarenale Druckerhöhung hat keinen positiven Einfluss auf das Ausspülen von Harnsteindesintegraten im Gegensatz zum Volumenstrom. Aus-schlaggebend für den Ausspüleffekt ist die Druckgradientkraft und die mit ihr verbundene Schleppkraft des Volumenstroms

Wielohormonalna niedoczynność przysadki u pacjenta z klinicznym rozpoznaniem zespołu Chitayat-Hall

We report an 8-year-old proband with severe motor and intellectual disability presenting a variety of dysmorphic features such as microcephaly, prominent glabella (ridged metopic suture) and congenital distal limb contractures. As well as panhypopituitary insufficiency, brain defects, e.g. agenesis of corpus callosum, colpocephaly, and pachygyria as well as strabismus and tracheo-laryngeal hypoplasia, were diagnosed. Genetic examination revealed a normal karyotype and excluded Wolf-Hirschhorn syndrome and subtelomeric deletions. Chitayat-Hall syndrome was diagnosed based on clinical traits. (Pol J Endocrinol 2010; 61 (3): 318-321)W pracy przedstawiono opis przypadku chorobowego 8-letniej dziewczynki z głębokim opóźnieniem rozwoju psychoruchowego i intelektualnego, prezentującego szereg różnych cech dysmorficznych, takich jak: małogłowie, wydatna gładzizna oraz wrodzone przykurcze dystalnych części kończyn. Ponadto u dziecka rozpoznano wielohormonalną niedoczynność przysadki, wady mózgowia, takie jak: agenezja ciała modzelowatego, nadmiernie szerokie zakręty mózgu oraz kolpocefalia, a także zez, wiotkość krtani i tchawicy. W wykonanych badaniach genetycznych wykazano prawidłowy kariotyp żeński, wykluczono zespół Wolfa-Hirschhorna oraz delecje subtelomerowe, ponadto w porównawczej hybrydyzacji genomowej (CGH) nie wykazano nieprawidłowości. Na podstawie całości obrazu klinicznego postawiono u pacjentki rozpoznanie zespołu Chitayat-Hall. (Endokrynol Pol 2010; 61 (3): 318-321

Enzymatic Metabolism of Ergosterol by Cytochrome P450scc to Biologically Active 17α,24-Dihydroxyergosterol

SummaryWe demonstrate the metabolism of ergosterol by cytochrome P450scc in either a reconstituted system or isolated adrenal mitochondria. The major reaction product was identified as 17α,24-dihydroxyergosterol. Purified P450scc also generated hydroxyergosterol as a minor product, which is probably an intermediate in the synthesis of 17α,24-dihydroxyergosterol. In contrast to cholesterol and 7-dehydrocholesterol, cleavage of the ergosterol side chain was not observed. NMR analysis clearly located one hydroxyl group to C24, with evidence that the second hydroxyl group is at C17. 17α,24-Dihydroxyergosterol inhibited cell proliferation of HaCaT keratinocytes and melanoma cells. Thus, in comparison with cholesterol and 7-dehydrocholesterol, the 24-methyl group and the C22-C23 double bond of ergosterol prevent side chain cleavage by P450scc and change the enzyme’s hydroxylase activity from C22 and C20, to C24 and C17, generating bioactive product

Stakeholder perspectives to improve risk management in European farming systems

The challenges faced by agricultural systems call for an advance in risk management (RM) assessments. This research identifies and discusses potential improvements to RM across 11 European Union (EU) farming systems (FS). The paper proposes a comprehensive, participatory approach that accounts for multi-stakeholder perspectives relying on 11 focus groups for brainstorming and gathering suggestions to improve RM. Data analysis is based on content analysis and coding of suggested improvements, and their assessment through the lenses of main challenges faced, farms’ flexibility, and dependence on subsidies. First, the results show that necessary improvements differ depending on whether they have their origin in sudden shocks or long-term pressures. Second, farm dependence on direct payments determines a stronger need to improve financial instruments, whereas farm flexibility suggests a need for more accessible and tailored tools for low-flexibility FS, and increased know-what and know-how for high-flexibility FS. Third, our findings indicate a potential for extending stakeholder involvement in RM to new or unconventional roles. Underlying specific improvements, the paper suggests and discusses three main avenues to improve RM as a whole: i) a developed learning and knowledge network; ii) new forms of collaboration; and iii) integrated financial and policy instruments

EACVI survey on investigations and imaging modalities in chronic coronary syndromes

AIMS The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey to evaluate current practice for the assessment and management of patients with suspected and confirmed chronic coronary syndromes. METHODS AND RESULTS One-hundred and ten imaging centres from 37 countries across the world responded to the survey. Most non-invasive investigations for coronary artery disease were widely available, except cardiovascular magnetic resonance (available 40% centres). Coronary computed tomography angiography (CCTA) and nuclear scans were reported by a multi-disciplinary team in only a quarter of centres. In the initial assessment of patients presenting with chest pain, only 32% of respondents indicated that they rely on pre-test probability for selecting the optimal imaging test while 31% proceed directly to CCTA. In patients with established coronary artery disease and recurrent chest pain, respondents opted for stress echocardiography (27%) and nuclear stress perfusion scans (26%). In asymptomatic patients with coronary artery disease and an obstructive (>70%) right coronary artery stenosis, 58% of respondents were happy to pursue medical therapy without further testing or intervention. This proportion fell to 29% with left anterior descending artery stenosis and 1% with left main stem obstruction. In asymptomatic patients with evidence of moderate-to-severe myocardial ischaemia (15%), only 18% of respondents would continue medical therapy without further investigation. CONCLUSION Despite guidelines recommendations pre-test probability is used to assess patients with suspected coronary artery in a minority of centres, one-third of centres moving directly to CCTA. Clinicians remain reticent to pursue a strategy of optimal medical therapy without further investigation or intervention in patients with controlled symptoms but obstructive coronary artery stenoses or myocardial ischaemia

EACVI survey on investigations and imaging modalities in chronic coronary syndromes

Aims The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey to evaluate current practice for the assessment and management of patients with suspected and confirmed chronic coronary syndromes.Methods and results One-hundred and ten imaging centres from 37 countries across the world responded to the survey. Most non-invasive investigations for coronary artery disease were widely available, except cardiovascular magnetic resonance (available 40% centres). Coronary computed tomography angiography (CCTA) and nuclear scans were reported by a multi-disciplinary team in only a quarter of centres. In the initial assessment of patients presenting with chest pain, only 32% of respondents indicated that they rely on pre-test probability for selecting the optimal imaging test while 31% proceed directly to CCTA. In patients with established coronary artery disease and recurrent chest pain, respondents opted for stress echocardiography (27%) and nuclear stress perfusion scans (26%). In asymptomatic patients with coronary artery disease and an obstructive (>70%) right coronary artery stenosis, 58% of respondents were happy to pursue medical therapy without further testing or intervention. This proportion fell to 29% with left anterior descending artery stenosis and 1% with left main stem obstruction. In asymptomatic patients with evidence of moderate-to-severe myocardial ischaemia (15%), only 18% of respondents would continue medical therapy without further investigation.Conclusion Despite guidelines recommendations pre-test probability is used to assess patients with suspected coronary artery in a minority of centres, one-third of centres moving directly to CCTA. Clinicians remain reticent to pursue a strategy of optimal medical therapy without further investigation or intervention in patients with controlled symptoms but obstructive coronary artery stenoses or myocardial ischaemia.</p

Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway

16 pages, 10 figures, supplementary information https://doi.org/10.1038/s41467-023-39051-x.-- Data availability: The diffraction data and coordinates of the p38α complexes bound to NC-p38i compounds have been deposited in the Protein Data Bank under accession codes 7PVU, 7Z6I and 7Z9T. We have also used the following PDB structures: 4LOO, 1A9U, 3COI, 7N8T, 2ZOQ, 1PME, 3GC9, 1CM8, 4UX9. Source data are provided with this paperp38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathwayThis work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (MICINN, PID2019-109521RB-I00 and PID2021-122478NB-I00), the BioMedTec program of IRB-Fundació La Caixa, the European Research Council (Proof of Concept p38_InTh-825763), AGAUR (2016 LLAV 00043 and 2019 PROD 00138 supported by FEDER, and 2017 SGR-557, 2017 SGR-50, 2021 SGR-909, and 2021 SGR-866), BBVA Foundation, and the European Union’s Horizon 2020 research and innovation program (euCanSHare 825903 and BioExcel-3 101093290). L.G. and B.B. were funded by predoctoral contracts from MICINN (BES-2016-077122) and the Marie Skłodowska-Curie COFUND action of IRB Barcelona and the PREBIST Predoc Programme (PREBIST_754558), respectively. F.C. is a Ramon y Cajal Fellow (RYC2019-026768-I). Access to ALBA was granted through the BAG proposals 2018092972 and 2020094472. We gratefully acknowledge institutional funding from IRB Barcelona, the CERCA Programme of the Catalan Government, and the MICINN through the Centres of Excellence Severo Ochoa award. M.J.M. and A.R.N. are supported by the Institució Catalana de Recerca i Estudis Avancats (ICREA)With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec