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"text": "\n169750\nThe "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies" (SPRINTT) randomized controlled trial: Case finding, screening and characteristics of eligible participants.\n\nMarzetti, E\n\nCesari, M\n\nCalvani, R\n\nMsihid, J\n\nTosato, M\n\nRodriguez-Mañas, L\n\nLattanzio, F\n\nCherubini, A\n\nBejuit, R\n\nDi Bari, M\n\nMaggio, M\n\nVellas, B\n\nDantoine, T\n\nCruz-Jentoft, AJ\n\nSieber, CC\n\nFreiberger, E\n\nSkalska, A\n\nGrodzicki, T\n\nSinclair, AJ\n\nTopinkova, E\n\nRýznarová, I\n\nStrandberg, T\n\nSchols, AMWJ\n\nSchols, JMGA\n\nRoller-Wirnsberger, R\n\nJónsson, PV\n\nRamel, A\n\nDel Signore, S\n\nPahor, M\n\nRoubenoff, R\n\nBernabei, R\n\nLandi, F\n\nSPRINTT Consortium\n\nBeiträge in Fachzeitschriften\nISI:000449275300006\n30261246.0\n10.1016/j.exger.2018.09.017\nNone\nThe ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT)" randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention in the prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describe the procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. We also illustrate the main demographic and clinical characteristics of eligible screenees.\n The identification of PF&S was based on the co-occurrence of three defining elements: (1) reduced physical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) low muscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3) absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT was advertised through a variety of means. Site-specific case finding strategies were developed to accommodate the variability across centers in catchment area characteristics and access to the target population. A quick "participant profiling" questionnaire was devised to facilitate PF&S case finding.\n During approximately 22 months, 12, 58 prescreening interviews were completed in 17 SPRINTT sites resulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participating in the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidity burden. In most centers, project advertisement through mass media was the most rewarding case finding strategy.\n PF&S case finding in the community is a challenging, but feasible task. Although largely autonomous in daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity. This subset of the older population is therefore at high risk for disability and other negative health-related events. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass communication methods.\n Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.\n\nRoller-Wirnsberger, Regina\n\n\n"
},
{
"text": "\n186181\nAberrant repair initiated by the adenine-DNA glycosylase does not play a role in UV-induced mutagenesis in <i>Escherichia coli</i>.\n\nZutterling, C\n\nMursalimov, A\n\nTalhaoui, I\n\nKoshenov, Z\n\nAkishev, Z\n\nBissenbaev, AK\n\nMazon, G\n\nGeacintov, NE\n\nGasparutto, D\n\nGroisman, R\n\nZharkov, DO\n\nMatkarimov, BT\n\nSaparbaev, M\n\nBeiträge in Fachzeitschriften\nISI:000452460800003\n30568855.0\n10.7717/peerj.6029\nPMC6286661\nDNA repair is essential to counteract damage to DNA induced by endo- and exogenous factors, to maintain genome stability. However, challenges to the faithful discrimination between damaged and non-damaged DNA strands do exist, such as mismatched pairs between two regular bases resulting from spontaneous deamination of 5-methylcytosine or DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved the mismatch-specific DNA glycosylases that can recognize and remove regular DNA bases in the mismatched DNA duplexes. The Escherichia coli adenine-DNA glycosylase (MutY/MicA) protects cells against oxidative stress-induced mutagenesis by removing adenine which is mispaired with 7, -dihydro-8-oxoguanine (8oxoG) in the base excision repair pathway. However, MutY does not discriminate between template and newly synthesized DNA strands. Therefore the ability to remove A from 8oxoG•A mispair, which is generated via misincorporation of an 8-oxo-2'-deoxyguanosine-5'-triphosphate precursor during DNA replication and in which A is the template base, can induce A•T→C•G transversions. Furthermore, it has been demonstrated that human MUTYH, homologous to the bacterial MutY, might be involved in the aberrant processing of ultraviolet (UV) induced DNA damage.\n Here, we investigated the role of MutY in UV-induced mutagenesis in E. coli. MutY was probed on DNA duplexes containing cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproduct (6-4PP). UV irradiation of E. coli induces Save Our Souls (SOS) response characterized by increased production of DNA repair enzymes and mutagenesis. To study the role of MutY in vivo, the mutation frequencies to rifampicin-resistant (RifR) after UV irradiation of wild type and mutant E. coli strains were measured.\n We demonstrated that MutY does not excise Adenine when it is paired with CPD and 6-4PP adducts in duplex DNA. At the same time, MutY excises Adenine in A•G and A•8oxoG mispairs. Interestingly, E. coli mutY strains, which have elevated spontaneous mutation rate, exhibited low mutational induction after UV exposure as compared to MutY-proficient strains. However, sequence analysis of RifR mutants revealed that the frequencies of C→T transitions dramatically increased after UV irradiation in both MutY-proficient and -deficient E. coli strains.\n These findings indicate that the bacterial MutY is not involved in the aberrant DNA repair of UV-induced DNA damage.\n\nKoshenov, Zhanat\n\n\n"
},
{
"text": "\n187137\nThe sarcopenia and physical frailty in older people: multi-component treatment strategies (SPRINTT) project: description and feasibility of a nutrition intervention in community-dwelling older Europeans.\n\nJyväkorpi, SK\n\nRamel, A\n\nStrandberg, TE\n\nPiotrowicz, K\n\nBłaszczyk-Bębenek, E\n\nUrtamo, A\n\nRempe, HM\n\nGeirsdóttir, Ó\n\nVágnerová, T\n\nBillot, M\n\nLarreur, A\n\nSavera, G\n\nSoriano, G\n\nPicauron, C\n\nTagliaferri, S\n\nSanchez-Puelles, C\n\nCadenas, VS\n\nPerl, A\n\nTirrel, L\n\nÖhman, H\n\nWeling-Scheepers, C\n\nAmbrosi, S\n\nCostantini, A\n\nPavelková, K\n\nKlimkova, M\n\nFreiberger, E\n\nJonsson, PV\n\nMarzetti, E\n\nPitkälä, KH\n\nLandi, F\n\nCalvani, R\n\nSPRINTT consortium\n\nBeiträge in Fachzeitschriften\nISI:000617838500002\n33583000.0\n10.1007/s41999-020-00438-4\nPMC7990826\nThe "Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies" (SPRINTT) project sponsored a multi-center randomized controlled trial (RCT) with the objective to determine the effect of physical activity and nutrition intervention for prevention of mobility disability in community-dwelling frail older Europeans. We describe here the design and feasibility of the SPRINTT nutrition intervention, including techniques used by nutrition interventionists to identify those at risk of malnutrition and to carry out the nutrition intervention.\n SPRINTT RCT recruited older adults (≥ 70 years) from 11 European countries. Eligible participants (n = 1517) had functional limitations measured with Short Physical Performance Battery (SPPB score 3-9) and low muscle mass as determined by DXA scans, but were able to walk 400 m without assistance within 15 min. Participants were followed up for up to 3 years. The nutrition intervention was carried out mainly by individual nutrition counseling. Nutrition goals included achieving a daily protein intake of 1.0-1.2 g/kg body weight, energy intake of 25-30 kcal/kg of body weight/day, and serum vitamin D concentration ≥ 75 mmol/L. Survey on the method strategies and feasibility of the nutrition intervention was sent to all nutrition interventionists of the 16 SPRINTT study sites.\n Nutrition interventionists from all study sites responded to the survey. All responders found that the SPRINTT nutrition intervention was feasible for the target population, and it was well received by the majority. The identification of participants at nutritional risk was accomplished by combining information from interviews, questionnaires, clinical and laboratory data. Although the nutrition intervention was mainly carried out using individual nutritional counselling, other assisting methods were used as appropriate.\n The SPRINTT nutrition intervention was feasible and able to adapt flexibly to varying needs of this heterogeneous population. The procedures adopted to identify older adults at risk of malnutrition and to design the appropriate intervention may serve as a model to deliver nutrition intervention for community-dwelling older people with mobility limitations.\n\nPerl, Annemarie\n\nRoller-Wirnsberger, Regina\n\n\n"
},
{
"text": "\n111110\nNo improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.\n\nThiel, U\n\nWawer, A\n\nWolf, P\n\nBadoglio, M\n\nSantucci, A\n\nKlingebiel, T\n\nBasu, O\n\nBorkhardt, A\n\nLaws, HJ\n\nKodera, Y\n\nYoshimi, A\n\nPeters, C\n\nLadenstein, R\n\nPession, A\n\nPrete, A\n\nUrban, EC\n\nSchwinger, W\n\nBordigoni, P\n\nSalmon, A\n\nDiaz, MA\n\nAfanasyev, B\n\nLisukov, I\n\nMorozova, E\n\nToren, A\n\nBielorai, B\n\nKorsakas, J\n\nFagioli, F\n\nCaselli, D\n\nEhninger, G\n\nGruhn, B\n\nDirksen, U\n\nAbdel-Rahman, F\n\nAglietta, M\n\nMastrodicasa, E\n\nTorrent, M\n\nCorradini, P\n\nDemeocq, F\n\nDini, G\n\nDreger, P\n\nEyrich, M\n\nGozdzik, J\n\nGuilhot, F\n\nHoller, E\n\nKoscielniak, E\n\nMessina, C\n\nNachbaur, D\n\nSabbatini, R\n\nOldani, E\n\nOttinger, H\n\nOzsahin, H\n\nSchots, R\n\nSiena, S\n\nStein, J\n\nSufliarska, S\n\nUnal, A\n\nUssowicz, M\n\nSchneider, P\n\nWoessmann, W\n\nJürgens, H\n\nBregni, M\n\nBurdach, S\n\non behalf of the Solid Tumor Working Party (STWP) and the Pediatric Disease Working Party (PDWP) of the European Group for Blood and Marrow Transplantation (EBMT), the Asia Pacific Blood and Marrow Transplantation (APBMT), the Pediatric Registry for Stem Cell Transplantations (PRST)\n\nthe MetaEICESS Study Group\n\nBeiträge in Fachzeitschriften\nISI:000292048500019\n21245159.0\n10.1093/annonc/mdq703\nNone\nBackground: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. Patients and methods: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. Results: Median overall survival was 7.9 months [+/- 1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (+/- 1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). Conclusions: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.\n\nSchwinger, Wolfgang\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n184070\nA 10 year comparative study of caesarean deliveries using the Robson 10 group classification system in a university hospital in Austria.\n\nBracic, T\n\nPfniß, I\n\nTaumberger, N\n\nKutllovci-Hasani, K\n\nUlrich, D\n\nSchöll, W\n\nReif, P\n\nBeiträge in Fachzeitschriften\nISI:000585918300007\n33064735.0\n10.1371/journal.pone.0240475\nPMC7567372\nThe Robson ten group classification system is used as a global standard for assessing, monitoring and comparing caesarean delivery (CD) rates within and between maternity services. Our objective was to compare the changes of CD rates at our institution between the years 2008-2010 and 2017-2019 using the Robson ten group classification system.\n Data was collected retrospectively and all women were classified using the obstetric concepts and parameters described in the Robson ten group classification system.\n During 2008-2010 7, 32 deliveries were performed, increasing to 9, 90 in 2017-2019. The CD rate also increased from 29.1% to 32.2% (p<.05) during this 10 year period. In both observed periods group 5 (single cephalic multiparous women at term with a previous CD) was the largest contributor to the overall CD rate accounting for 20.2% of all CD during 2008-2010 and increasing to 26.9% in 2017-2019 (p<.001). The overall size of group 5 also increased from 8.3% to 11.6% (p<.001). Furthermore, an increase in CD rate in group 7 (multiparous women with a single breech pregnancy, including women with a uterine scar) from 92.9% to 98.2% (p = .752) could be observed. In group 8 (women with multiple pregnancies, including women with a uterine scar) a slight shift towards vaginal delivery (VD) can be reported with CD rates decreasing from 82% to 79.2% (p = .784). There was no observed difference with CD rates in group 1 although the group size decreased from 29.4% in 2008-2010 to 24.2% in 2017-2019 (p<.001). The CD rate in group 10 experienced a slight elevation, in 2008-2010 46.2% were delivered per CD and in 2017-2019 48.8% (p = .553). The overall size of group 10 decreased, contributing 8.9% in 2008-2010 and 8% in 2017-2019 (p<.05) to the overall birthrate.\n The biggest contributors to the CD rate in our hospital remain multiparous women at term with a previous CD. The CD rates, as well as the overall size of this group, keep rising, resulting in a need to establish more effective ways to motivate women with one previous CD towards vaginal birth after caesarean delivery (VBAC). Furthermore, the CD rate in preterm deliveries is increasing and approaching 50%. This illustrates the need to discuss whether CD is the appropriate mode of delivery in half of the preterm infants.\n\nBracic, Taja\n\nGold ehem Ulrich, Daniela\n\nKutllovci Hasani, Kaltrina\n\nPfniß, Isabella\n\nReif, Philipp\n\nSchöll, Wolfgang\n\nTaumberger, Nadja\n\n\n"
},
{
"text": "\n160193\nMultitarget Quantitative PCR Improves Detection and Predicts Cultivability of the Pathogen Burkholderia pseudomallei.\n\nGohler, A\n\nTrung, TT\n\nHopf, V\n\nKohler, C\n\nHartleib, J\n\nWuthiekanun, V\n\nPeacock, SJ\n\nLimmathurotsakul, D\n\nTuanyok, A\n\nSteinmetz, I\n\n\n\nBeiträge in Fachzeitschriften\nISI:000398771200011\n28188208.0\n10.1128/AEM.03212-16\nPMC5377509\nBurkholderia pseudomallei\nis present in the environment in many parts of the world and causes the often-fatal disease melioidosis. The sensitive detection and quantification ofB. pseudomalleiin the environment are a prerequisite for assessing the risk of infection. We recently reported the direct detection ofB. pseudomalleiin soil samples using a quantitative PCR (qPCR) targeting a single type three secretion system 1 (TTSS1) gene. Here, we extend the qPCR-based analysis ofB. pseudomalleiin soil by validating novel qPCR gene targets selected from a comparative genomic analysis. Two hundred soil samples from two rice paddies in northeast Thailand were evaluated, of which 47% (94/200) wereB. pseudomalleiculture positive. The TTSS1 qPCR and two novel qPCR assays that targeted open reading frames (ORFs) BPSS0087 and BPSS0745 exhibited detection rates of 76.5% (153/200), 34.5% (69/200), and 74.5% (150/200), respectively. The combination of TTSS1 and BPSS0745 qPCR increased the detection rate to 90% (180/200). Combining the results of the three qPCR assays and the BPSS1187 nested PCR previously published, all 200 samples were positive by at least one PCR assay. Samples positive by either TTSS1 (n= 153) or BPSS0745 (n= 150) qPCR were more likely to be direct-culture positive, with odds ratios of 4.0 (95% confidence interval [CI], 1.7 to 9.5;P< 0.001) and 9.0 (95% CI, 3.1 to 26.4;P< 0.001), respectively. HighB. pseudomalleigenome equivalents correlated with high CFU counts by culture. In conclusion, multitarget qPCR improved theB. pseudomalleidetection rate in soil samples and predicted culture positivity. This approach has the potential for use as a sensitive environmental screening method forB. pseudomalleiIMPORTANCEThe worldwide environmental distribution of the soil bacteriumBurkholderia pseudomalleiremains to be determined. So far, most environmental studies have relied on culture-based approaches to detect this pathogen. Since current culture methods are laborious, are time consuming, and have limited sensitivity, culture-independent and more sensitive methods are needed. In this study, we show that aB. pseudomallei-specific qPCR approach can detect significantly higher numbers ofB. pseudomallei-positive soil samples from areas where it is endemic compared with that from culture. The use of multiple independentB. pseudomallei-specific qPCR targets further increased the detection rate ofB. pseudomalleicompared with that from single targets. Samples with a high molecularB. pseudomalleiload were more likely to be culture positive. We conclude that our quantitative multitarget approach might be useful in defining areas where there is a risk ofB. pseudomalleiinfections in different parts of the world.\n Copyright © 2017 American Society for Microbiology.\n\nSteinmetz, Ivo\n\n\n"
},
{
"text": "\n184018\nPathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B<sub>100</sub>-Reactive CD4<sup>+</sup> T-Regulatory Cells.\n\nWolf, D\n\nGerhardt, T\n\nWinkels, H\n\nMichel, NA\n\nPramod, AB\n\nGhosheh, Y\n\nBrunel, S\n\nBuscher, K\n\nMiller, J\n\nMcArdle, S\n\nBaas, L\n\nKobiyama, K\n\nVassallo, M\n\nEhinger, E\n\nDileepan, T\n\nAli, A\n\nSchell, M\n\nMikulski, Z\n\nSidler, D\n\nKimura, T\n\nSheng, X\n\nHorstmann, H\n\nHansen, S\n\nMitre, LS\n\nStachon, P\n\nHilgendorf, I\n\nGaddis, DE\n\nHedrick, C\n\nBenedict, CA\n\nPeters, B\n\nZirlik, A\n\nSette, A\n\nLey, K\n\nBeiträge in Fachzeitschriften\nISI:000576528800009\n32703007.0\n10.1161/CIRCULATIONAHA.119.042863\nPMC7515473\nThroughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4+ T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (TH1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4+ T cells with an atheroprotective, regulatory T cell (Treg) phenotype in healthy individuals. Yet, the function of apoB-reactive Tregs and their relationship with pathogenic TH1 cells remain unknown.\n To interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B978-993 (apoB+) at the single-cell level.\n We found that apoB+ T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a Treg-like transcriptome, although only 21% of all apoB+ T cells expressed the Treg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB+ T cells formed several clusters with mixed TH signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of TH1, T helper cell type 2 (TH2), and T helper cell type 17 (TH17), and of follicular-helper T cells. ApoB+ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic TH1/TH17-like cells with proinflammatory properties and only a residual Treg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed TH1/TH17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB+ Tregs in lineage tracing of hyperlipidemic Apoe-/- mice. In adoptive transfer experiments, converting apoB+ Tregs failed to protect from atherosclerosis.\n Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive Tregs as a novel cellular target in atherosclerosis.\n\nAnto Michel, Nathaly\n\nZirlik, Andreas\n\n\n"
},
{
"text": "\n184856\nCerebral small vessel disease genomics and its implications across the lifespan.\n\nSargurupremraj, M\n\nSuzuki, H\n\nJian, X\n\nSarnowski, C\n\nEvans, TE\n\nBis, JC\n\nEiriksdottir, G\n\nSakaue, S\n\nTerzikhan, N\n\nHabes, M\n\nZhao, W\n\nArmstrong, NJ\n\nHofer, E\n\nYanek, LR\n\nHagenaars, SP\n\nKumar, RB\n\nvan den Akker, EB\n\nMcWhirter, RE\n\nTrompet, S\n\nMishra, A\n\nSaba, Y\n\nSatizabal, CL\n\nBeaudet, G\n\nPetit, L\n\nTsuchida, A\n\nZago, L\n\nSchilling, S\n\nSigurdsson, S\n\nGottesman, RF\n\nLewis, CE\n\nAggarwal, NT\n\nLopez, OL\n\nSmith, JA\n\nValdés Hernández, MC\n\nvan der Grond, J\n\nWright, MJ\n\nKnol, MJ\n\nDörr, M\n\nThomson, RJ\n\nBordes, C\n\nLe Grand, Q\n\nDuperron, MG\n\nSmith, AV\n\nKnopman, DS\n\nSchreiner, PJ\n\nEvans, DA\n\nRotter, JI\n\nBeiser, AS\n\nManiega, SM\n\nBeekman, M\n\nTrollor, J\n\nStott, DJ\n\nVernooij, MW\n\nWittfeld, K\n\nNiessen, WJ\n\nSoumaré, A\n\nBoerwinkle, E\n\nSidney, S\n\nTurner, ST\n\nDavies, G\n\nThalamuthu, A\n\nVölker, U\n\nvan Buchem, MA\n\nBryan, RN\n\nDupuis, J\n\nBastin, ME\n\nAmes, D\n\nTeumer, A\n\nAmouyel, P\n\nKwok, JB\n\nBülow, R\n\nDeary, IJ\n\nSchofield, PR\n\nBrodaty, H\n\nJiang, J\n\nTabara, Y\n\nSetoh, K\n\nMiyamoto, S\n\nYoshida, K\n\nNagata, M\n\nKamatani, Y\n\nMatsuda, F\n\nPsaty, BM\n\nBennett, DA\n\nDe Jager, PL\n\nMosley, TH\n\nSachdev, PS\n\nSchmidt, R\n\nWarren, HR\n\nEvangelou, E\n\nTrégouët, DA\n\nInternational Network against Thrombosis (INVENT) Consortium\n\nInternational Headache Genomics Consortium (IHGC)\n\nIkram, MA\n\nWen, W\n\nDeCarli, C\n\nSrikanth, VK\n\nJukema, JW\n\nSlagboom, EP\n\nKardia, SLR\n\nOkada, Y\n\nMazoyer, B\n\nWardlaw, JM\n\nNyquist, PA\n\nMather, KA\n\nGrabe, HJ\n\nSchmidt, H\n\nVan Duijn, CM\n\nGudnason, V\n\nLongstreth, WT\n\nLauner, LJ\n\nLathrop, M\n\nSeshadri, S\n\nTzourio, C\n\nAdams, HH\n\nMatthews, PM\n\nFornage, M\n\nDebette, S\n\nBeiträge in Fachzeitschriften\nISI:000608838200004\n33293549.0\n10.1038/s41467-020-19111-2\nPMC7722866\nWhite matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50, 70 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1, 38 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.\n\nHofer, Edith\n\nSABA, Yasaman\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n122203\nFebrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.\n\nvan Baalen, A\n\nHäusler, M\n\nPlecko-Startinig, B\n\nStrautmanis, J\n\nVlaho, S\n\nGebhardt, B\n\nRohr, A\n\nAbicht, A\n\nKluger, G\n\nStephani, U\n\nProbst, C\n\nVincent, A\n\nBien, CG\n\nBeiträge in Fachzeitschriften\nISI:000308062500007\n22911482.0\n10.1055/s-0032-1323848\nNone\nFebrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1, 00, 00. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.\n Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.\n\nPlecko, Barbara\n\n\n"
},
{
"text": "\n157117\nC-FOS expression in the rat brain in response to substance P and neurokinin B.\n\nSpitznagel, H\n\nBaulmann, J\n\nBlume, A\n\nUnger, T\n\nCulman, J\n\nBeiträge in Fachzeitschriften\nISI:000171812300002\n11597586.0\n10.1016/S0006-8993(01)02858-X\nNone\nSubstance P, the principal neurokinin peptide in the mammalian brain and the natural ligand for the NK(1) tachykinin receptor, plays an integrative role in the regulation of cardiovascular, neuroendocrine and behavioural responses to stress. In rats, stimulation of periventricular NK(1) receptors in the forebrain induces a distinct pattern of cardiovascular responses which is accompanied by intense grooming behaviour. Ligands for NK(3) receptors induce a different pattern of cardiovascular and behavioural responses which comprises an increased release of vasopressin from the posterior pituitary and wet-dog shakes behaviour. To define the brain areas in the rat which respond to stimulation of forebrain NK(1) and NK(3) receptors and participate in the generation of these responses, the induction of c-Fos immunoreactivity was examined in brains following intracerebroventricular injections of substance P and neurokinin B in conscious rats. Stimulation of central NK(1) receptors by substance P (25, 100 and 500 pmol) injected into the lateral ventricle elicited grooming behaviour (face washing and hind limb grooming) and resulted in a marked c-Fos expression in the paraventricular, dorsomedial and parabrachial nuclei and in the medial thalamus. At 25 pmol, substance P did not significantly increase c-Fos expression, at 100 pmol, maximal c-Fos activation was induced in all four brain regions which responded to the peptide. Intracerebroventricular pretreatment of rats with the selective and high-affinity, non-peptide NK(1) receptor antagonist, RP 67580 (500 pmol), but not with its inactive enantiomer, RP 68651, completely abolished the behavioural response to substance P and reduced the substance P-induced c-Fos expression in all brain areas to nearly control levels. Intracerebroventricular injection of the natural ligand for NK(3) receptors, neurokinin B (500 pmol), elicited wet-dog shakes behaviour and activated c-Fos expression in localized regions of the forebrain including the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, paraventricular, supraoptic and anterior hypothalamic nuclei, medial thalamus and in the ventral tegmental area. These results demonstrate that the neurokinins, substance P and neurokinin B, induce specific and different patterns of c-Fos expression in distinct regions of the rat brain. Brain areas which selectively responded to substance P have been traditionally linked to the central regulation of cardiovascular and neuroendocrine reactions to stress or involved in the processing of nociceptive responses. On the other side, brain areas activated by neurokinin B are known to be involved in the central regulation of blood pressure, water and salt homeostasis or control of behaviour.\n\n\n"
},
{
"text": "\n168161\nMortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).\n\nBoeddha, NP\n\nSchlapbach, LJ\n\nDriessen, GJ\n\nHerberg, JA\n\nRivero-Calle, I\n\nCebey-López, M\n\nKlobassa, DS\n\nPhilipsen, R\n\nde Groot, R\n\nInwald, DP\n\nNadel, S\n\nPaulus, S\n\nPinnock, E\n\nSecka, F\n\nAnderson, ST\n\nAgbeko, RS\n\nBerger, C\n\nFink, CG\n\nCarrol, ED\n\nZenz, W\n\nLevin, M\n\nvan der Flier, M\n\nMartinón-Torres, F\n\nHazelzet, JA\n\nEmonts, M\n\nEUCLIDS consortium\n\nBeiträge in Fachzeitschriften\nISI:000434295200002\n29855385.0\n10.1186/s13054-018-2052-7\nPMC5984383\nSepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability.\n Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis.\n Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001).\n Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.\n\nKohlfürst, Daniela\n\nZenz, Werner\n\n\n"
},
{
"text": "\n176364\nDifferences in the quality of oral anticoagulation therapy with vitamin K antagonists in German GP practices - results of the cluster-randomized PICANT trial (Primary Care Management for Optimized Antithrombotic Treatment).\n\nMertens, C\n\nSiebenhofer, A\n\nBerghold, A\n\nPregartner, G\n\nUlrich, LR\n\nMergenthal, K\n\nKemperdick, B\n\nSchulz-Rothe, S\n\nRauck, S\n\nHarder, S\n\nGerlach, FM\n\nPetersen, JJ\n\nBeiträge in Fachzeitschriften\nISI:000478651900002\n31370840.0\n10.1186/s12913-019-4372-y\nPMC6676561\nIn Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K antagonists (VKAs). The quality of OAC in German GP practices, differences between various practices, and improvement potential through implementation of case management, have not yet been investigated satisfactorily. Based on results of a cluster-randomized controlled trial, we aimed to assess whether OAC quality can be improved, any variations between practices exist and determine practice- and patient-level factors.\n The PICANT trial (2012-2015) was performed in 52 GP practices in Hesse, Germany. Adult patients with long-term indication for OAC received best practice case management in the intervention group. International normalized ratio (INR) values were recorded from anticoagulation passes. The Rosendaal method was used to calculate Time in Therapeutic Range (TTR) at patient level, and mean pooling to obtain center-specific TTR (cTTR) at practice level. The quality of OAC was assessed by TTR and cTTR. Linear model analyses were used to investigate associations between practice-/ patient-level factors and TTR.\n Inclusion of 736 patients (49.6% intervention and 50.4% control patients); 690 (93.8%) received phenprocoumon. Within 24 months, the TTR was 75.1% (SD 17.6) in the intervention versus 74.3% (SD 17.8) in the control group (p = 0.670). The cTTR averaged 75.1% (SD 6.5, range: 60.4 to 86.7%) in the intervention versus 74.3% (SD 7.2, range: 52.7 to 85.7%) in the control group (p = 0.668). At practice level, the TTR was significantly lower in practices with a male physician and certification in quality management. At patient level, the TTR was significantly higher in patients with moderate to high compliance, in men, and in patients that performed self-management. The TTR was significantly lower in patients with certain comorbidities, and who were hospitalized.\n The intervention did not effectively improve OAC quality compared to routine care. Quality of INR control was generally good, but considerable variation existed between GP practices. The variability indicates optimization potential in some practices. The demonstrated association between patient-level factors and TTR highlights the importance of considering patient characteristics that may impede achieving high quality therapeutic outcomes.\n ISRCTN registry, ISRCTN41847489 , registered 27 February 2012.\n\nBerghold, Andrea\n\nPregartner, Gudrun\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n184244\nImpact of Altered Gastrocnemius Morphometrics and Fascicle Behavior on Walking Patterns in Children With Spastic Cerebral Palsy.\n\nHösl, M\n\nKruse, A\n\nTilp, M\n\nSvehlik, M\n\nBöhm, H\n\nZehentbauer, A\n\nArampatzis, A\n\nBeiträge in Fachzeitschriften\nISI:000584739300001\n33178029.0\n10.3389/fphys.2020.518134\nPMC7597072\nSpastic cerebral palsy (SCP) affects neural control, deteriorates muscle morphometrics, and may progressively impair functional walking ability. Upon passive testing, gastrocnemius medialis (GM) muscle bellies or fascicles are typically shorter, thinner, and less extensible. Relationships between muscle and gait parameters might help to understand gait pathology and pathogenesis of spastic muscles. The current aim was to link resting and dynamic GM morphometrics and contractile fascicle behavior (both excursion and velocity) during walking to determinants of gait. We explored the associations between gait variables and ultrasonography of the GM muscle belly captured during rest and during gait in children with SCP [n = 15, gross motor function classification system (GMFCS) levels I and II, age: 7-16 years] and age-matched healthy peers (n = 17). The SCP children's plantar flexors were 27% weaker. They walked 12% slower with more knee flexion produced 42% less peak ankle push-off power (all p < 0.05) and 7/15 landed on their forefoot. During the stance phase, fascicles in SCP on average operated on 9% shorter length (normalized to rest length) and displayed less and slower fascicle shortening (37 and 30.6%, respectively) during push-off (all p ≤ 0.024). Correlation analyses in SCP patients revealed that (1) longer-resting fascicles and thicker muscle bellies are positively correlated with walking speed and negatively to knee flexion (r = 0.60-0.69, p < 0.0127) but not to better ankle kinematics; (2) reduced muscle strength was associated with the extent of eccentric fascicle excursion (r = -0.57, p = 0.015); and (3) a shorter operating length of the fascicles was correlated with push-off power (r = -0.58, p = 0.013). Only in controls, a correlation (r = 0.61, p = 0.0054) between slower fascicle shortening velocity and push-off power was found. Our results indicate that a thicker gastrocnemius muscle belly and longer gastrocnemius muscle fascicles may be reasonable morphometric properties that should be targeted in interventions for individuals with SCP, since GM muscle atrophy may be related to decreases in walking speed and undesired knee flexion during gait. Furthermore, children with SCP and weaker gastrocnemius muscle may be more susceptible to chronic eccentric muscle overloading. The relationship between shorter operating length of the fascicles and push-off power may further support the idea of a compensation mechanism for the longer sarcomeres found in children with SCP. Nevertheless, more studies are needed to support our explorative findings.\n Copyright © 2020 Hösl, Kruse, Tilp, Svehlik, Böhm, Zehentbauer and Arampatzis.\n\n\n"
},
{
"text": "\n2481\nTachykinin inhibition of acid-induced gastric hyperaemia in the rat.\n\nHeinemann, A\n\nJocic, M\n\nHerzeg, G\n\nHolzer, P\n\nBeiträge in Fachzeitschriften\nISI:A1996VZ59600004\n8982497.0\n10.1111/j.1476-5381.1996.tb16068.x\nPMC1915790\n1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10, 27 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140, 33 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140, 33 but not MEN 10, 27 or ketotifen. 5. SR 140, 33, MEN 10, 27 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric mucosal vasoconstriction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8. These data show that NKA has two fundamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion through an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are mediated by different receptors. This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion.\n\nHeinemann, Akos\n\nHolzer, Peter\n\n\n"
},
{
"text": "\n70879\nLong-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus.\n\nHorvath, K\n\nJeitler, K\n\nBerghold, A\n\nEbrahim, SH\n\nGratzer, TW\n\nPlank, J\n\nKaiser, T\n\nPieber, TR\n\nSiebenhofer, A\n\nBeiträge in Fachzeitschriften\nISI:000245760200074\n17443605.0\n10.1002/14651858.CD005613.pub3\nNone\nBACKGROUND: Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. OBJECTIVES: To assess the effects of long-term treatment with long-acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. MAIN RESULTS: Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. AUTHORS' CONCLUSIONS: Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir.\n\nBerghold, Andrea\n\nHorvath, Karl\n\nJeitler, Klaus\n\nPieber, Thomas\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n71005\nDual regulation of cardiac Na+-K+ pumps and CFTR Cl- channels by protein kinases A and C.\n\nErlenkamp, S\n\nGlitsch, HG\n\nKockskämper, J\n\nBeiträge in Fachzeitschriften\nISI:000175781400028\n11976939.0\n10.1007/s00424-002-0802-4\nNone\nRegulation of Na+-K+ pump current (I(p)) and cystic fibrosis transmembrane conductance regulator (CFTR) Cl- current (I(CFTR)) by protein kinases A and C (PKA and PKC) was compared under identical experimental conditions by simultaneous measurement of the two currents in guinea-pig ventricular myocytes whole-cell voltage-clamped at 30-32 degrees C. Membrane current (I) was monitored at a holding potential (V) of -20 mV. I/ V relationships were obtained by hyperpolarizing voltage ramps. Phorbol 12, 3-dibutyrate (PDBu, 0.1-1 microM) and chelerythrine (10 microM) were used to stimulate and inhibit, respectively, PKC activity. PKA was stimulated by forskolin (4 microM) and inhibited by H-89 (50 microM). At -20 mV, stimulation of PKC by PDBu increased I(p) to 121-123% of control. Addition of chelerythrine completely reversed this effect. The PDBu-induced augmentation of I(p) was voltage dependent. The ratio I(p)(PDBu)/ I(p)(control) increased from 1.10 at -100 mV to ~1.35 at positive membrane potentials. Stimulation of PKA by forskolin also increased I(p) voltage dependently (128% of control at -20 mV). The effects of PKC and PKA stimulation on I(p) were additive. The maximum I(p) observed in the presence of PDBu and forskolin was 141% of control. Application of either H-89 or chelerythrine reversibly decreased I(p) by 40% and 24%, respectively, suggesting that basal PKA and PKC activities were involved in the regulation of I(p). In the presence of H-89, PDBu was unable to increase I(p). Likewise, pre-application of chelerythrine abolished the forskolin-induced augmentation of I(p). In contrast to I(p), I(CFTR) (measured simultaneously) was absent under basal conditions. Stimulation of PKA by forskolin activated a pronounced I(CFTR). Stimulation of PKC by PDBu, on the other hand, neither activated the Cl(-) current significantly nor increased I(CFTR) pre-activated by forskolin. Inhibition of PKC by chelerythrine, however, attenuated the PKA-mediated activation of I(CFTR). The results reveal a complex interplay between PKA and PKC in regulating cardiac I(p) and I(CFTR) with some similarities but also important differences. I(p) is increased voltage dependently and additively by stimulation of both kinases. The steady-state activity of each of the kinases is involved in the modulation of basal I(p) and obligatory for the augmentation of I(p) induced by stimulation of the other kinase. In contrast, there appears to be no basal I(CFTR). I(CFTR) is activated significantly only after stimulation of PKA. PKC activity, however, appears to facilitate this activation.\n\n\n"
},
{
"text": "\n108283\nMulticentric tumor manifestations of high grade gliomas: independent proliferation or hallmark of extensive disease?\n\nHefti, M\n\nvon Campe, G\n\nSchneider, C\n\nRoelcke, U\n\nLandolt, H\n\nBeiträge in Fachzeitschriften\nISI:000274665200007\n20175026.0\n10.1055/s-0029-1241190\nNone\nObjective: Improvements in microneurosurgical techniques, radiotherapy and chemotherapy for the treatment of high grade gliomas resulted in better local tumor control and longer progression-free survival. Multicentric (MC) lesions located distant from the initial resection area contribute to treatment failure in a growing number of patients. These MC lesions may develop within the course of the disease (metachronous) or may already be present at the time of first tumor manifestation (synchronous). To look for mechanisms and regular patterns behind MC glioma manifestations and to investigate whether they are "a second primary tumor" or the result of continuous diffuse glioblastoma cell invasion, we retrospectively analyzed the initial and all follow-up MR studies of our high grade glioma (HGG) patients. Patients and Methods: MR studies of 247 consecutive patients treated for HGG at a single institution were analyzed. MC tumor manifestation was defined as more than one gadolinium enhancing lesion within the brain on MRI without a connecting signal alteration in T2 sequences and/or without a connecting hypointense mass in T1 sequences. The minimal distance to define two solitary lesions was set at > 10 mm. According to these specifications 40 patients showed MC tumor manifestations in their MR studies on admission or during treatment of their disease. The MR studies of these cases were retrospectively analyzed for patterns in MC tumor manifestation and progression. Topographical specifications and delay in manifestation were used to explain possible pathways of development. Kaplan Meyer survival graphs for metachronous and synchronous MC disease were calculated. Results: 24 patients showed MC tumor manifestation at the time of admission. 16 cases developed MC manifestation within a follow-up period of 3-57 months. The location of all lesions could be categorized into one of three distinct patterns (white matter, subependymal, intraventricular). The patterns showed individual and location-specific time gaps to metachronous manifestation. Calculated from the time of first tumor diagnosis, the median survival was longer for patients with metachronous MC lesions (353 days, p < 0.05) compared to patients with synchronous MC lesions (110 days) or patients without multicentricity (234 days). Patients with metachronous lesions showed a similar survival (72 days) as patients with synchronous MC lesions (110 days) once they developed MC disease. Conclusion: The topographical patterns and temporal characteristics of MC disease suggest that all manifestations share common mechanisms such as an active migratory process. Our data therefore do not support the concept of an independent MC development of multiple gliomas.\n\nvon Campe, Gord\n\n\n"
},
{
"text": "\n146906\nEndoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.\n\nPimentel-Nunes, P\n\nDinis-Ribeiro, M\n\nPonchon, T\n\nRepici, A\n\nVieth, M\n\nDe Ceglie, A\n\nAmato, A\n\nBerr, F\n\nBhandari, P\n\nBialek, A\n\nConio, M\n\nHaringsma, J\n\nLangner, C\n\nMeisner, S\n\nMessmann, H\n\nMorino, M\n\nNeuhaus, H\n\nPiessevaux, H\n\nRugge, M\n\nSaunders, BP\n\nRobaszkiewicz, M\n\nSeewald, S\n\nKashin, S\n\nDumonceau, JM\n\nHassan, C\n\nDeprez, PH\n\nBeiträge in Fachzeitschriften\nISI:000360273400011\n26317585.0\n10.1055/s-0034-1392882\nNone\nThis Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence.\n 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barrett's esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).\n © Georg Thieme Verlag KG Stuttgart · New York.\n\nLangner, Cord\n\n\n"
},
{
"text": "\n183966\nImpaired kidney function is associated with lower quality of life among community-dwelling older adults : The screening for CKD among older people across Europe (SCOPE) study.\n\nArtzi-Medvedik, R\n\nKob, R\n\nFabbietti, P\n\nLattanzio, F\n\nCorsonello, A\n\nMelzer, Y\n\nRoller-Wirnsberger, R\n\nWirnsberger, G\n\nMattace-Raso, F\n\nTap, L\n\nGil, P\n\nMartinez, SL\n\nFormiga, F\n\nMoreno-González, R\n\nKostka, T\n\nGuligowska, A\n\nÄrnlöv, J\n\nCarlsson, AC\n\nFreiberger, E\n\nMelzer, I\n\nSCOPE investigators\n\nBeiträge in Fachzeitschriften\nISI:000576901000001\n33008306.0\n10.1186/s12877-020-01697-3\nPMC7530949\nQuality of life (QoL) refers to the physical, psychological, social and medical aspects of life that are influenced by health status and function. The purpose of this study was to measure the self-perceived health status among the elderly population across Europe in different stages of Chronic Kidney Disease (CKD).\n Our series consisted of 2255 community-dwelling older adults enrolled in the Screening for Chronic Kidney Disease (CKD) among Older People across Europe (SCOPE) study. All patients underwent a comprehensive geriatric assessment (CGA), including included demographics, clinical and physical assessment, number of medications taken, family arrangement, Geriatric Depression Scale (GDS), Cumulative Illness Rating Scale, History of falls, Lower urinary tract symptoms, and Short Physical Performance Battery (SPPB). Estimated glomerular filtration rate (eGFR) was calculated by Berlin Initiative Study (BIS) equation. Quality of life was assessed by Euro Qol questionnaire (Euro-Qol 5D) and EQ-Visual Analogue Scale (EQ-VAS). The association between CKD (eGFR < 60, < 45 ml or < 30 ml/min/1.73m2) and low EQoL-VAS was investigated by multivariable logistic regression models.\n CKD was found to be significantly associated with low EQoL-VAS in crude analysis (OR = 1.47, 95%CI = 1.16-1.85 for eGFR< 60; OR = 1.38, 95%CI = 1.08-1.77 for eGFR< 45; OR = 1.57, 95%CI = 1.01-2.44). Such association was no longer significant only when adjusting for SPPB (OR = 1.20, 95%CI = 0.93-1.56 for eGFR< 60; OR = 0.87, 95%CI = 0.64-1.18 for eGFR< 45; OR = 0.84, 95%CI = 0.50-1.42), CIRS and polypharmacy (OR = 1.16, 95%CI = 0.90-1.50 for eGFR< 60; OR = 0.86, 95%CI = 0.64-1.16 for eGFR< 45; OR = 1.11, 95%CI = 0.69-1.80) or diabetes, hypertension and chronic obstructive pulmonary disease (OR = 1.28, 95%CI = 0.99-1.64 for eGFR< 60; OR = 1.16, 95%CI = 0.88-1.52 for eGFR< 45; OR = 1.47, 95%CI = 0.92-2.34). The association between CKD and low EQoL-VAS was confirmed in all remaining multivariable models.\n CKD may significantly affect QoL in community-dwelling older adults. Physical performance, polypharmacy, diabetes, hypertension and COPD may affect such association, which suggests that the impact of CKD on QoL is likely multifactorial and partly mediated by co-occurrent conditions/risk factors.\n\nRoller-Wirnsberger, Regina\n\nWirnsberger, Gerhard\n\n\n"
},
{
"text": "\n161242\n15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics.\n\nKrenn, V\n\nPerino, G\n\nRüther, W\n\nKrenn, VT\n\nHuber, M\n\nHügle, T\n\nNajm, A\n\nMüller, S\n\nBoettner, F\n\nPessler, F\n\nWaldstein, W\n\nKriegsmann, J\n\nCasadonte, R\n\nHäupl, T\n\nWienert, S\n\nKrukemeyer, MG\n\nSesselmann, S\n\nSunitsch, S\n\nTikhilov, R\n\nMorawietz, L\n\nBeiträge in Fachzeitschriften\nISI:000407410300002\n28687159.0\n10.1016/j.prp.2017.05.005\nNone\nThe histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0-9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to≤4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of≥5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew's disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8-0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals).\n Copyright © 2017 Elsevier GmbH. All rights reserved.\n\nSunitsch, Sandra\n\n\n"
}
]
}