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"text": "\n6265\nIncidence of limb fracture across Europe: results from the European Prospective Osteoporosis Study (EPOS).\n\nIsmail, AA\n\nPye, SR\n\nCockerill, WC\n\nLunt, M\n\nSilman, AJ\n\nReeve, J\n\nBanzer, D\n\nBenevolenskaya, LI\n\nBhalla, A\n\nBruges Armas, J\n\nCannata, JB\n\nCooper, C\n\nDelmas, PD\n\nDequeker, J\n\nDilsen, G\n\nFalch, JA\n\nFelsch, B\n\nFelsenberg, D\n\nFinn, JD\n\nGennari, C\n\nHoszowski, K\n\nJajic, I\n\nJanott, J\n\nJohnell, O\n\nKanis, JA\n\nKragl, G\n\nLopez Vaz, A\n\nLorenc, R\n\nLyritis, G\n\nMarchand, F\n\nMasaryk, P\n\nMatthis, C\n\nMiazgowski, T\n\nNaves-Diaz, M\n\nPols, HA\n\nPoor, G\n\nRapado, A\n\nRaspe, HH\n\nReid, DM\n\nReisinger, W\n\nScheidt-Nave, C\n\nStepan, J\n\nTodd, C\n\nWeber, K\n\nWoolf, AD\n\nO'Neill, TW\n\nBeiträge in Fachzeitschriften\nISI:000176999400007\n12111017.0\n10.1007/s001980200074\nNone\nThe aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50-79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7.3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2.5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not 'other' limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions, though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n16750\nSystematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial.\n\nPanici, PB\n\nMaggioni, A\n\nHacker, N\n\nLandoni, F\n\nAckermann, S\n\nCampagnutta, E\n\nTamussino, K\n\nWinter, R\n\nPellegrino, A\n\nGreggi, S\n\nAngioli, R\n\nManci, N\n\nScambia, G\n\nDell'Anna, T\n\nFossati, R\n\nFloriani, I\n\nRossi, RS\n\nGrassi, R\n\nFavalli, G\n\nRaspagliesi, F\n\nGiannarelli, D\n\nMartella, L\n\nMangioni, C\n\nBeiträge in Fachzeitschriften\nISI:000228413200010\n15840878.0\n10.1093/jnci/dji102\nNone\nBACKGROUND: The role of systematic aortic and pelvic lymphadenectomy in patients with optimally debulked advanced ovarian cancer is unclear and has not been addressed by randomized studies. We conducted a randomized clinical trial to determine whether systematic aortic and pelvic lymphadenectomy improves progression-free and overall survival compared with resection of bulky nodes only. METHODS: From January 1991 through May 2003, 427 eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-C and IV epithelial ovarian carcinoma were randomly assigned to undergo systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes only (n = 211). Progression-free survival and overall survival were analyzed using a log-rank statistic and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: After a median follow-up of 68.4 months, 292 events (i.e., recurrences or deaths) were observed, and 202 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for first event was statistically significantly lower in the systematic lymphadenectomy arm (hazard ratio [HR] = .75, 95% confidence interval [CI] = 0.59 to 0.94; P = .01) than in the no-lymphadenectomy arm, corresponding to 5-year progression-free survival rates of 31.2 and 21.6% in the systematic lymphadenectomy and control arms, respectively (difference = 9.6%, 95% CI = 1.5% to 21.6%), and to median progression-free survival of 29.4 and 22.4 months, respectively (difference = 7 months, 95% CI = 1.0 to 14.4 months). The risk of death was similar in both arms (HR = 0.97, 95% CI = 0.74 to 1.29; P = .85), corresponding to 5-year overall survival rates of 48.5 and 47%, respectively (difference = 1.5%, 95% CI = -8.4% to 10.6%), and to median overall survival of 58.7 and 56.3 months, respectively (difference = 2.4 months, 95% CI = -11.8 to 21.0 months). Median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the systematic lymphadenectomy arm than in the no-lymphadenectomy arm (300 versus 210 minutes, P\n\nTamussino, Karl\n\n\n"
},
{
"text": "\n62084\nCellular accumulation of amiodarone and desethylamiodarone in cultured human cells. Consequences of drug accumulation on cellular lipid metabolism and plasma membrane properties of chronically exposed cells.\n\nHonegger, UE\n\nZuehlke, RD\n\nScuntaro, I\n\nSchaefer, MH\n\nToplak, H\n\nWiesmann, UN\n\nBeiträge in Fachzeitschriften\nISI:A1993KL50500010\n8382061.0\n10.1016/0006-2952(93)90070-D\nNone\nAmiodarone (AMIO), a potent antiarrhythmic drug, is clinically widely used despite its frequent side effects after chronic administration. These side effects coincide with an intralysosomal accumulation of AMIO and its main metabolite desethylamiodarone (DEA) and may be causally related to the drug-induced intracellular storage of phospholipids (PL). Kinetics of cellular uptake and release of radiolabelled AMIO and DEA were studied following single and multiple exposures of cultured human skin fibroblasts to 5 and 10 microM drug concentrations. AMIO and DEA were efficiently taken up into cultured cells. The rate of uptake was slower than that of other cationic amphiphilic drugs. The intracellular steady state concentrations were in the millimolar range suggesting a lysosomal trapping. Repetitive exposures of cultures resulted in a cumulative and partly saturable drug uptake. The accumulation of DEA was higher than that of AMIO throughout. AMIO and DEA previously taken up into the cells during a 2 hr exposure were completely released into the washing media, suggesting an exchangeable form of the accumulated drugs. Following repetitive exposures only part of the drugs was released. Under chasing conditions using washing media containing non-labelled AMIO and DEA respectively or ammonium chloride the release of the chronically accumulated 14C-labelled drugs was increased. This suggested a drug storage in the form of complexes in acidic compartments. Phospholipid (PL) content as well as individual PL fractions were changed in whole cells and in isolated plasma membranes. PL accumulation is assumed to occur by inhibition of PL degradation due to formation of non-degradable drug-PL complexes or by inhibition of phospholipase activities. Cellular PL accumulation seemed to interfere with PL recycling. Changes in PL composition of purified plasma membranes were in part complementary to the ones in whole cells. The alterations in membrane PL composition may explain the changes in membrane fluidity and the decrease in beta-adrenoceptor density and in isoproterenol-stimulated cAMP formation. The results obtained provide an explanation for the pharmacokinetic, and possibly for the pharmacodynamic and also toxicological behaviour of AMIO and DEA in vivo.\n\nToplak, Hermann\n\n\n"
},
{
"text": "\n65126\nFresh frozen plasma in the pediatric age group and in congenital coagulation factor deficiency\n\nMuntean, W\n\nBeiträge in Fachzeitschriften\nISI:000179356200006\nNone\n10.1016/S0049-3848(02)00149-4\nNone\nGenerally, the rules of good practice in transfusion medicine apply also to the pediatric age group. However, the frequency of specific diseases that might necessitate the administration of fresh frozen plasma (FFP) differs from that in adults. Physiologic differences to the later age exist in the neonatal period and in young infants, especially with respect to the hemostatic system, that must be recognized when considering administration of FFP. The plasma levels of many procoagulant factors and important anticoagulants are lower in neonates than in other age groups. Despite these findings, healthy neonates show no easy bruising, no increased bleeding during surgery, and excellent wound healing. The same discrepancy obtains between in vitro and clinical findings with primary hemostasis in neonates. The good primary hemostasis in neonates despite poor in vitro platelet function seems to be due mainly to a very high von Willebrand factor and the presence of more high-multimeric subunits of von Willebrand factor than later in life. We must assume that these particular plasma levels of procoagulant and anticoagulant proteins are essential for the correct function of neonatal hemostasis. Evidence that the hemostatic system of neonates works best with physiologic concentrations of procoagulants and anticoagulants can also be inferred from studies where the administration of clotting factor concentrates gave poor results. Since healthy neonates and young infants have excellent hemostasis, there is absolutely no indication to 'correct' these values to adult's norms prior to invasive procedures by administering FFP. Indications for FFP, met more frequently in the pediatric age group than later in life, are exchange transfusion and extracorporeal membrane oxygenation. Indications applying equally to adults are other extracorporeal life support systems, disseminated intravascular coagulation, hepatic coagulopathy, and 'complex unclear coagulopathies'. In congenital clotting factor deficiency, replacement therapy is much more easily administered using a highly specific concentrate. When FFP is used to raise the level of the congenitally deficient factor, the huge volume needed to reach sufficiently high plasma levels can frequently be a major problem. For this reason, FFP as a replacement therapy in congenital factor deficiency is only indicated when no specific concentrate is available, as is the case in factor V deficiency and factor XI deficiency. (C) 2002 Elsevier Science Ltd. All rights reserved.\n\nMuntean, Eugen\n\n\n"
},
{
"text": "\n116576\nSubclassification of pT3 Urothelial Carcinoma of the Renal Pelvicalyceal System is Associated With Recurrence-Free and Cancer-Specific Survival: Proposal for a Revision of the Current TNM Classification.\n\nShariat, SF\n\nZigeuner, R\n\nRink, M\n\nMargulis, V\n\nHansen, J\n\nKikuchi, E\n\nKassouf, W\n\nRaman, JD\n\nRemzi, M\n\nKoppie, TM\n\nBensalah, K\n\nGuo, CC\n\nMikami, S\n\nSircar, K\n\nNg, CK\n\nHaitel, A\n\nKabbani, W\n\nChun, FK\n\nWood, CG\n\nScherr, DS\n\nKarakiewicz, PI\n\nLangner, C\n\nBeiträge in Fachzeitschriften\nISI:000305841100019\n22285763.0\n10.1016/j.eururo.2012.01.019\nNone\nBackground: The clinical course of pT3 upper tract urothelial carcinoma (UTUC) is highly variable. Objectives: The aim of the current study was to validate the clinical and prognostic importance of pT3 subclassification in the renal pelvicalyceal system in a large international cohort of patients. Design, setting, and participants: From a multi-institutional international database, 858 renal pelvicalyceal tumors treated with radical nephroureterectomy (RNU) were systematically reevaluated by genitourinary pathologists. Category pT3 pelvic tumors were categorized as pT3a (infiltration of the renal parenchyma on a microscopic level only) versus pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue). Intervention: RNU. Measurements: Associations of pT3 subclassifications with clinicopathologic features were assessed with the chi-square test. Prognostic impact was assessed with the log-rank test and multivariable Cox regression analyses. Results and limitations: Of 858 patients with renal pelvicalyceal tumors, 266 (31%) had pT3 disease. Of these, 146 (54.9%) were classified as pT3a and 120 (45.1%) as pT3b. Compared with pT3a, pT3b cancers were associated with higher tumor grade, nodal disease, and tumor necrosis. Ten-year recurrence-free (pT3a 58% vs pT3b 38%; p < 0.001) and cancer-specific (pT3a 60% vs pT3b 39%; p = 0.002) survival rates were lower for patients with pT3b disease. In multivariable analyses, classification pT3b was an independent predictor of both disease recurrence (hazard ratio [HR]: 1.8, p = 0.003) and cancer-specific mortality (HR: 1.7; p = 0.02). The major limitation is the retrospective character of the study. Conclusions: Subclassification of pT3 renal pelvicalyceal UTUC helps identify patients who are at increased risk of disease progression and cancer-related death. Further research may help assess the value of subclassification and its inclusion in future editions of the American Joint Committee on Cancer-International Union Against Cancer TNM classification system. (C) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nLangner, Cord\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n135939\nBeta-blockade versus Buckberg blood-cardioplegia in coronary bypass operation.\n\nKuhn-Régnier, F\n\nNatour, E\n\nDhein, S\n\nDapunt, O\n\nGeissler, HJ\n\nLaRosé, K\n\nGörg, C\n\nMehlhorn, U\n\nBeiträge in Fachzeitschriften\nISI:000078959100013\n10077376.0\n10.1016/S1010-7940(98)00289-9\nNone\nContinuous perfusion of the coronary arteries with beta-blocker (esmolol)-enriched normothermic blood during cardiac surgery has been suggested as an alternative technique for myocardial protection. The aim of the present study was to compare the beta-blocker technique to Buckberg's blood cardioplegia during coronary artery bypass grafting (CABG).\n Sixty patients with coronary artery disease were randomly assigned to either the esmolol group (ES, n = 30) or the blood cardioplegia group (BC, n = 30). During aortic crossclamp ES patients received continuous normothermic coronary perfusion with esmolol-enriched blood. Hearts of the BC group were protected by antegrade cold blood cardioplegia according to Buckberg. We measured left ventricular (LV) contractility using TEE (fractional area of contraction, FAC) and hemodynamic parameters prior to cannulation for cardiopulmonary bypass (CPB), after decannulation, and 4 h postoperatively. Myocardial lactate release was measured prior to aortic cross-clamp, during cross-clamp, and after decannulation. LV biopsies for determination of heat-shock protein (HSP-70), actin pattern and intercellular adhesion-molecule (ICAM-I) as indicators for structural changes were collected prior CPB, at the end of the aortic cross-clamp period, and prior to weaning off CPB.\n There was no significant difference between both groups with respect to grafts and cross-clamp time. ES hearts did not release lactate during cross-clamp. In contrast, BC hearts released significant amounts of lactate. Post CPB FAC and hemodynamics under similar inotropic stimulation showed no difference between groups, whereas at 4 h post CPB measurements showed slightly better values in the ES group: cardiac index: ES: 2.9+/-0.1 (SEM) versus BC: 2.6+/-0.1 L/min per m2 (P < 0.05); FAC: ES: 55+/-3 versus BC: 48+/-3% (P < 0.05). HSP-70 and actin pattern showed no difference between groups; however, ICAM-I showed a significantly higher degree of structural changes in BC hearts: 18+/-2 versus ES: 11+/-1% (P < 0.05).\n Our data demonstrate that application of the beta-blocker technique during routine CABG was associated with slightly better functional recovery and less structural myocardial alteration as compared with intermittent cold blood cardioplegia, however, both techniques provided equivalent myocardial protection in terms of patient outcome. Future studies are required to investigate if myocardial ischemia minimization by use of the beta-blocker technique may be beneficial in compromized hearts.\n\n\n"
},
{
"text": "\n154986\nMolecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway.\n\nFröhlich, LF\n\nMrakovcic, M\n\nSmole, C\n\nZatloukal, K\n\nBeiträge in Fachzeitschriften\nISI:000382435700001\n27601937.0\n10.1186/s12935-016-0343-0\nPMC5011867\nRecent studies indicated that histone deacetylase inhibitors (HDACi), a class of anticancer agents, are in addition to their ability of apoptosis induction also capable of provoking autophagy. Promoted by the treatment of malignant uterine sarcoma cells with the HDACi suberoylanilide hydroxamic acid (SAHA), we previously demonstrated predominant dose-dependent activation of autophagy in ESS-1 cells, but prevalent induction of apoptosis in MES-SA cells.\n In order to extend our previous studies, SAHA-treated ESS-1 and MES-SA cells were monitored for protein expression to reveal differences in known markers of apoptosis explaining the different cytotoxic responses. Further analysis of the identified candidate protein included cell rescue experiments by gene transfer followed by subsequent screening of cells for induction of apoptosis and autophagy by immunoblotting, caspase activity as well as LC3 and MDC/PI staining. LDH release assays were performed to assess the amount of cell-mediated cytotoxicity.\n In our search for responsible autophagic regulatory genes upstream of mammalian target of rapamycin (mTOR), we now discovered that, in contrast to MES-SA cells, a TP53-637C>T nonsense mutation located in the transactivating domain of the oncogenic suppressor p53 causes loss of its protein and consequently reduced PUMA induction in ESS-1 cells. Upon re-introduction of wild-type TP53, SAHA-treated ESS-1 cells underwent immediate apoptotic cell death as supported by upregulation of PUMA and caspase-9 as well as by activation of caspases-3 and -7 and PARP-1 cleavage. Concurrent downregulation of autophagy was noticed by upregulated mTor and phospho-mTOR expression as well as monitoring autophagosome formation employing LC3 and MDC staining. Previously, cytoplasmic master regulatory activities of the oncogenic suppressor p53 in inhibiting autophagy and triggering apoptosis were unravelled. Accordingly, p53-deficiency could explain both, the previously documented apoptosis resistance and prevailing SAHA-induced autophagy in ESS-1 cells. Using MES-SA cells with RNAi-silenced p53 expression and several p53-deficient tumor cell lines undergoing SAHA-induced autophagy, we could generally validate our finding suggesting an inhibitory role for p53 in the autophagic pathway in response to SAHA treatment.\n Conclusively, these results could identify cytoplasmic p53 protein as a molecular switch that directly mediates the cytotoxic response of SAHA and thus open new therapeutic avenues.\n\nZatloukal, Kurt\n\n\n"
},
{
"text": "\n176727\nMatched-paired analysis of patients treated for invasive mucormycosis: standard treatment versus posaconazole new formulations (MoveOn).\n\nSalmanton-García, J\n\nSeidel, D\n\nKoehler, P\n\nMellinghoff, SC\n\nHerbrecht, R\n\nKlimko, N\n\nRáčil, Z\n\nFalces-Romero, I\n\nIngram, P\n\nBenítez-Peñuela, MÁ\n\nRodríguez, JY\n\nDesoubeaux, G\n\nBarać, A\n\nGarcía-Vidal, C\n\nHoenigl, M\n\nMehta, SR\n\nCheng, MP\n\nKlyasova, G\n\nHeinz, WJ\n\nIqbal, N\n\nKrause, R\n\nOstermann, H\n\nPenack, O\n\nSchalk, E\n\nSheppard, DC\n\nWillinger, B\n\nWisplinghoff, H\n\nVehreschild, JJ\n\nCornely, OA\n\nVehreschild, MJGT\n\nFungiScope® ECMM/ISHAM Working Group\n\nBeiträge in Fachzeitschriften\nISI:000498167700027\n31393591.0\n10.1093/jac/dkz344\nNone\nFirst-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability.\n Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment.\n We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction).\n Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp].\n Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.\n © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.\n\nHönigl, Martin\n\nKrause, Robert\n\n\n"
},
{
"text": "\n75685\nEffect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.\n\nCoersmeier, C\n\nWittenberg, HR\n\nAehringhaus, U\n\nDreyling, KW\n\nPeskar, BM\n\nBrune, K\n\nPeskar, BA\n\nBeiträge in Fachzeitschriften\nNone\n3092600.0\nNone\nNone\nThe effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.\n\nPeskar, Bernhard\n\n\n"
},
{
"text": "\n88026\nA microarray study on the effect of extracellular magnesium deprivation upon expression profiles of molecular pathways and biological processes in isolated human atrial myocardium\n\nGasser, S\n\nAblasser, K\n\nRoessl, U\n\nDellacher, A\n\nvon Lewinski, D\n\nMangge, H\n\nMachler, H\n\nTrantina, A\n\nTscheliessnigg, KH\n\nUdermann, H\n\nPorta, S\n\nFriehs, I\n\nScherr, E\n\nGasser, R\n\nBeiträge in Fachzeitschriften\nISI:000262448300001\nNone\nNone\nNone\nWhile we well understand that nutritional Mg2+-deprivation is lethal and caused numerous cellular dysfunctions ending up with myocardial cell necrosis, the effects of extracellular Mg2+-concentrations on molecular pathways and processes has not been studied as yet. Characterizing these Mg2+-dependent intracellular molecular pathways may well constitute a further step towards understanding the effects of magnesium on myocardial function as well as protection. Using molecular profiling technique, we look at over 20, 00 different gene expressions in the presence and absence of extracellular M-g2+, thus identifying the specific molecular signature of myocardial Mg2+-deprivation. This allows LIS to demonstrate its effects at the molecular level in resting human atrial myocardium. Using PANTHER software (Applied Biosystems) we assess up- and down-regulation of gene expression associated with biological processes and pathways. Myocardial gene expression after exposure of 30 minutes to Mg2+-free solution is massively altered compared to control experiments. We find a complex de-regulation of gene expression secondary to Mg2+ deficiency. It can be seen that gene expression associated with clusters of immunity and defence processes' protein metabolism and signal transduction as well as nucleoside, nucleotide and nucleic metabolism are significantly down-regulated. Similarly, biological processes involved in transcription, protein biosynthesis and cell communication, nucleoside, nucleotide and nucleic metabolism as well as signal transduction and protein metabolism are effected by Up-regulation. Clusters of pathways down-regulated by Mg2+ deficiency are: various signaling pathways, T-cell activation, apoptosis and angiogenesis. Clusters of up-regulated pathways are mainly different groups of signaling. In summary, experimental myocardial Mg2+-deprivation leads to complex changes in the expression profile of biological processes and molecular pathways. On the other hand, one can deduce from earlier observations that Mg2+, is well buffered and remains relatively uninfluenced by extracellular maneuvers. The interdependence of intracellular and extracellular Mg2+, however, appears once more difficult to understand. Further studies are certainly needed in order to firmly establish the mechanisms of extracellular Mg2+ influencing intracellular processes and pathways.\n\nAblasser, Klemens\n\nGasser, Robert\n\nMangge, Harald\n\nvon Lewinski, Dirk\n\n\n"
},
{
"text": "\n119612\nTwo-round rapid-cycle RT-PCR in single closed capillaries increases the sensitivity of HCV RNA detection and avoids amplicon carry-over.\n\nRatge, D\n\nScheiblhuber, B\n\nLandt, O\n\nBerg, J\n\nKnabbe, C\n\nBeiträge in Fachzeitschriften\nISI:000174670500002\n11856617.0\n10.1016/S1386-6532(01)00244-X\nNone\nBACKGROUND: For the detection of hepatitis C virus (HCV) specific nucleic acids the polymerase chain reaction (PCR) is widely used. Rapid-cycle PCR is performed in glass capillaries with the LightCycler instrument and allows PCR including product analysis to be performed within a closed system in about 1 h. Thus, rapid-cycle PCR appears especially suitable for routine diagnostic applications. However, the volume of the PCR vessel is restricted to about 20 microl, which may limit the sensitivity of the PCR. To increase its sensitivity two-round or nested primer PCR protocols have been developed. In rapid-cycle PCR first-round PCR products are usually collected from the capillaries by centrifugation, a procedure prone to cross-contamination. OBJECTIVES: Development of a two-round rapid-cycle reverse transcription-polymerase chain reaction (RT-PCR) in single closed LightCycler capillaries for the sensitive detection of HCV RNA in serum or plasma. STUDY DESIGN: A set of two pairs of nested primers was selected. The first-round RT-PCR reaction mixture was separated from the second-round PCR mixture by silicone oil. Reverse transcription followed by the first-round PCR was performed. Then, the second-round mixture was combined with first-round products by a centrifugation step followed by second round PCR during which fluorescence intensities were recorded and used for quantification. RESULTS: To establish the sensitivity of this novel assay a serial dilution of HCV reference standard was used. In plasma samples about 100 IU/ml HCV were consistently detected using the high pure viral RNA kit for nucleic acid purification. This detection limit was found to be about 20 fold increased compared with single-round RT-PCR and corresponded to 3.4 IU of HCV per capillary. Using a panel of HCV genotype standards the novel assay exhibited similar sensitivity for all HCV genotypes. The applicability for clinical routine testing was demonstrated by examining 156 clinical samples. CONCLUSION: Two-round RT-PCR with the LightCycler instrument using a single closed capillary throughout the procedure was found ideally suited for rapid (100 min), accurate and sensitive molecular diagnosis of active HCV infections. Since the capillaries remained closed during the procedure carry-over contamination was precluded.\n\n\n"
},
{
"text": "\n161083\nLow-Dose Paclitaxel-Coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: One-Year Results of the ILLUMENATE European Randomized Clinical Trial (Randomized Trial of a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon).\n\nSchroeder, H\n\nWerner, M\n\nMeyer, DR\n\nReimer, P\n\nKrüger, K\n\nJaff, MR\n\nBrodmann, M\n\nILLUMENATE EU RCT Investigators\n\nBeiträge in Fachzeitschriften\nISI:000402636700009\n28424223.0\n10.1161/CIRCULATIONAHA.116.026493\nPMC5459585\nNumerous studies have reported favorable outcomes using drug-coated balloons (DCBs) for treatment of symptomatic peripheral artery disease of the superficial femoral and popliteal arteries. However, the treatment effect compared with an uncoated balloon has differed greatly among the randomized trials, with better outcomes observed with higher-dose DCBs. This European trial was designed to assess the safety and effectiveness of a next-generation low-dose (2-µg/mm2 surface dose of paclitaxel) DCB.\n This was a prospective, randomized, multicenter, single-blinded trial. Patients were randomized (3:1) to treatment with a low-dose DCB or an uncoated percutaneous transluminal angioplasty (PTA) balloon. The primary safety end point was a composite of freedom from device- and procedure-related death through 30 days after the procedure and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months after the procedure. The primary effectiveness end point was primary patency at 12 months.\n Patients were randomized to treatment with a DCB (222 patients, 254 lesions) or uncoated PTA balloon (72 patients, 79 lesions) after successful predilatation. Mean lesion length was 7.2 and 7.1 cm, and 19.2% and 19.0% of lesions represented total occlusions, respectively. The primary safety end point was met, and superiority was demonstrated; freedom from a primary safety event was 94.1% (193 of 205) with DCB and 83.3% (50 of 60) with PTA, for a difference of 10.8% (95% confidence interval, 0.9%-23.0%). The primary effectiveness end point was met, and superiority of DCB over PTA was achieved (83.9% [188 of 224] versus 60.6% [40 of 66]; P<0.001). Outcomes with DCB were also superior to PTA per the Kaplan-Meier estimate for primary patency (89.0% versus 65.0% at 365 days; log-rank P<0.001) and for rates of clinically driven target lesion revascularization (5.9% versus 16.7%; P=0.014).\n Superiority with a low-dose DCB for femoropopliteal interventions was demonstrated over PTA for both the safety and effectiveness end points.\n URL: http://www.clinicaltrials.gov. Unique identifier: NCT01858363.\n © 2017 The Authors.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n166688\nAdrenomedullin for Risk Stratification of Emergency Patients With Nonspecific Complaints: An Interventional Multicenter Pilot Study.\n\nNickel, CH\n\nMessmer, AS\n\nGhanim, L\n\nIlsemann-Karakoumis, J\n\nGiersdorf, S\n\nHertel, S\n\nErnst, S\n\nGeigy, N\n\nBingisser, R\n\nBeiträge in Fachzeitschriften\nISI:000370520200019\n26735540.0\n10.1097/MD.0000000000002395\nPMC4706260\nPatients with nonspecific complaints (NSC) presenting to the emergency department (ED) are at risk of life-threatening conditions. New stress biomarkers such as the midregional portion of adrenomedullin (MR-proADM) promise to support decision-making. This study tested the following hypotheses: biomarker-assisted disposition of patients with NSC will not increase mortality. Second, discharge from the ED will increase if clinical risk assessment is combined with low MR-proADM levels. Third, inappropriate disposition to a lower level of care will decrease, if clinical assessment is combined with high MR-proADM levels, and fourth that this algorithm is feasible in the ED setting. Prospective, multicenter, randomized, controlled interventional feasibility study with a 30-day follow-up, including patients with NSC. Patients were randomly assigned to either the standard group (decision-making solely based on clinical assessment) or the Novum group (biomarker-assisted). Regarding disposition, patients were assigned to 1 of 3 risk classes: high-risk (admission to hospital), intermediate risk (community geriatric hospital), and low-risk patients (discharge). In the Novum group, in addition to clinical risk assessment, the information of the MR-proADM level was used. Unless there were overruling criteria, patients were transferred or discharged according to the risk assessment. Primary endpoint was 30-day mortality. Secondary endpoints were comparisons of patient disposition and related mortality rates, ED, and hospital length of stay and readmission. The final study cohort consisted of 398 patients (210 in the Standard group and 188 in the Novum group). Overruling, that is, disposition not according to the result of the proposed algorithm occurred in 51 cases. Baseline characteristics between Standard and Novum groups were similar. The mortality rate in the Novum group was 4.3%, as compared to the Standard group mortality of 6.2%, which was not significantly different (intention-to treat analysis). This was confirmed by the perprotocol analysis as well as by sensitivity analysis. For the secondary endpoints, no significant differences were detected. Biomarker-assisted disposition is safe in patients with NSC. Discharge rates did not increase. Feasibility could only partly be shown due to an unexpectedly high overruling rate. Inappropriate disposition to lower levels of care did not change. ClinicalTrials. gov Identifier: NCT00920491.\n\nSchweiger, Leyla\n\n\n"
},
{
"text": "\n174110\nPostural hemodynamic parameters in older persons have a seasonal dependency : A pilot study.\n\nTrozic, I\n\nPlatzer, D\n\nFazekas, F\n\nBondarenko, AI\n\nBrix, B\n\nRössler, A\n\nGoswami, N\n\nBeiträge in Fachzeitschriften\nISI:000519157900009\n30868225.0\n10.1007/s00391-019-01525-3\nPMC7066096\nIt is known that blood pressure regulation differs seasonally. It is unknown, however, how the cardiovascular system in patients with a stroke reacts to postural changes in different seasons. The aim was therefore to investigate how different temperatures in cold and warm seasons influence the reactions of haemodynamic mechanisms as well as heart rate variability during a sit-to-stand test in patients with stroke and a control group.\n Hemodynamic responses were assessed in both groups during a sit-to-stand test (5 min sitting followed by 5 min standing) beat to beat within two different seasons. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), heart rate (HR), stroke index (SI), cardiac index (CI) and heart rate variability (HRV) were continuously monitored.\n During the sitting baseline period delta values of DBP (+15.1 [Standard error (SE) 3.75] mmHg, p < 0.05) and MBP (+14.35 [SE 4.18] mmHg, p < 0.05) were significantly higher in colder months compared to warmer months whereas SI (-3.86 [SE 1.43] ml/beat/m2, p < 0.05) and CI (-0.4 [SE 0.11] l/min/m2, p < 0.05) were lower in colder months compared to warmer months in non-stroke participants. In patients with stroke during sitting, baseline period delta values of DBP (+19.92 [SE 8.03] mmHg, p < 0.05) and MBP (+19.29 [SE 8.6] mmHg, p < 0.05) were significantly higher in colder months compared to warmer months but SI (-5.43 [SE 1.96] ml/beat/m2, p < 0.05) was significantly lower in colder months compared to warmer months. After standing, there was a significant decrease in SBP in warmer months (-16.84 [SE 4.38] mmHg, p < 0.05) and a decrease in DBP in warmer months (-7.8 [SE 2.3] mmHg, p < 0.05) and colder months (-6.73 [SE 1.5] mmHg, p < 0.05) in non-stroke participants and a decrease in MBP in warmer months (-12.5 [SE 2.8] mmHg, p < 0.05) and colder months (-8.93 [SE 1.8] mmHg, p < 0.05) in non-stroke participants and in warmer months (-14.54 [SE 4.1] mmHg, p < 0.05) in patients with stroke.\n Elderly with and without stroke respond to orthostatic stress with a greater drop in blood pressure in the warmer seasons.\n\nBrix, Bianca\n\nFazekas, Franz\n\nGoswami, Nandu\n\nPlatzer, Dieter\n\nRössler, Andreas\n\n\n"
},
{
"text": "\n184784\nLong-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial.\n\nBuse, JB\n\nBode, BW\n\nMertens, A\n\nCho, YM\n\nChristiansen, E\n\nHertz, CL\n\nNielsen, MA\n\nPieber, TR\n\nPIONEER 7 investigators\n\nBeiträge in Fachzeitschriften\nISI:000600201600004\n33318068.0\n10.1136/bmjdrc-2020-001649\nPMC7737050\nThe PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.\n A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight.\n In the durability part, mean (SD) changes in HbA1c and body weight from week 0 were -1.5% (0.8) and -1.3% (1.0) and -2.8 kg (3.8) and -3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were -0.2% for oral semaglutide and 0.1% for sitagliptin (difference -0.3% (95% CI -0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were -2.4 kg and -0.9 kg (difference -1.5 kg (95% CI -2.8 to -0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.\n Long-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.\n NCT02849080.\n © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n\nPieber, Thomas\n\n\n"
},
{
"text": "\n186781\nDual-energy CT and ceramic or titanium prostheses material reduce CT artifacts and provide superior image quality of total knee arthroplasty.\n\nKasparek, MF\n\nTöpker, M\n\nLazar, M\n\nWeber, M\n\nKasparek, M\n\nMang, T\n\nApfaltrer, P\n\nKubista, B\n\nWindhager, R\n\nRingl, H\n\nBeiträge in Fachzeitschriften\nNone\n29881885.0\n10.1007/s00167-018-5001-8\nPMC6527539\nTo evaluate the influence of different scan parameters for single-energy CT and dual-energy CT, as well as the impact of different material used in a TKA prosthesis on image quality and the extent of metal artifacts.\n Eight pairs of TKA prostheses from different vendors were examined in a phantom set-up. Each pair consisted of a conventional CoCr prosthesis and the corresponding anti-allergic prosthesis (full titanium, ceramic, or ceramic-coated) from the same vendor. Nine different (seven dual-energy CT and two single-energy CT) scan protocols with different characteristics were used to determine the most suitable CT protocol for TKA imaging. Quantitative image analysis included assessment of blooming artifacts (metal implants appear thicker on CT than they are, given as virtual growth in mm in this paper) and streak artifacts (thick dark lines around metal). Qualitative image analysis was used to investigate the bone-prosthesis interface.\n The full titanium prosthesis and full ceramic knee showed significantly fewer blooming artifacts compared to the standard CoCr prosthesis (mean virtual growth 0.6-2.2 mm compared to 2.9-4.6 mm, p < 0.001). Dual-energy CT protocols showed less blooming (range 3.3-3.8 mm) compared to single-energy protocols (4.6-5.5 mm). The full titanium and full ceramic prostheses showed significantly fewer streak artifacts (mean standard deviation 77-86 Hounsfield unit (HU)) compared to the standard CoCr prosthesis (277-334 HU, p < 0.001). All dual-energy CT protocols had fewer metal streak artifacts (215-296 HU compared to single-energy CT protocols (392-497 HU)). Full titanium and ceramic prostheses were ranked superior with regard to the image quality at the bone/prosthesis interface compared to a standard CoCr prosthesis, and all dual-energy CT protocols were ranked better than single-energy protocols.\n Dual-energy CT and ceramic or titanium prostheses reduce CT artifacts and provide superior image quality of total knee arthroplasty at the bone/prosthesis interface. These findings support the use of dual-energy CT as a solid imaging base for clinical decision-making and the use of full-titanium or ceramic prostheses to allow for better CT visualization of the bone-prosthesis interface.\n\nApfaltrer, Paul\n\n\n"
},
{
"text": "\n53318\nPrimacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog.\n\nKim, SP\n\nEllmerer, M\n\nVan Citters, GW\n\nBergman, RN\n\nBeiträge in Fachzeitschriften\nISI:000185748500001\n14514627.0\n10.2337/diabetes.52.10.2453\nNone\nObesity is highly correlated with insulin resistance and the development of type 2 diabetes. Insulin resistance will result in a decrease in insulin's ability to stimulate glucose uptake into peripheral tissue and will suppress glucose production by the liver. However, the development of peripheral and hepatic insulin resistance relative to one another in the context of obesity-associated insulin resistance is not well understood. To examine this phenomena, we used the moderate fat-fed dog model, which has been shown to develop both subcutaneous and visceral adiposity and severe insulin resistance. Six normal dogs were fed an isocaloric diet with a modest increase in fat content for 12 weeks, and they were assessed at weeks 0, 6, and 12 for changes in insulin sensitivity and glucose turnover. By week 12 of the diet, there was a more than twofold increase in trunk adiposity as assessed by magnetic resonance imaging because of an accumulation in both subcutaneous and visceral fat depots with very little change in body weight. Fasting plasma insulin had increased by week 6 (150% of week 0) and remained increased up to week 12 of the study (170% of week 0). Surprisingly, there appeared to be no change in the rates of insulin-stimulated glucose uptake as measured by euglycemic-hyperinsulinemic clamps throughout the course of fat feeding. However, there was an increase in steady-state plasma insulin levels at weeks 6 and 12, indicating a moderate degree of peripheral insulin resistance. In contrast to the moderate defect seen in the periphery, there was a marked impairment in insulin's ability to suppress endogenous glucose production during the clamp such that by week 12 of the study, there was a complete inability of insulin to suppress glucose production. Our results indicate that a diet enriched with a moderate amount of fat results in the development of both subcutaneous and visceral adiposity, hyperinsulinemia, and a modest degree of peripheral insulin resistance. However, there is a complete inability of insulin to suppress hepatic glucose production during the clamp, suggesting that insulin resistance of the liver may be the primary defect in the development of insulin resistance associated with obesity.\n\n\n"
},
{
"text": "\n103964\nGenetic determinants of major blood lipids in Pakistanis compared with Europeans.\n\nSaleheen, D\n\nSoranzo, N\n\nRasheed, A\n\nScharnagl, H\n\nGwilliam, R\n\nAlexander, M\n\nInouye, M\n\nZaidi, M\n\nPotter, S\n\nHaycock, P\n\nBumpstead, S\n\nKaptoge, S\n\nDi Angelantonio, E\n\nSarwar, N\n\nHunt, SE\n\nSheikh, N\n\nShah, N\n\nSamuel, M\n\nHaider, SR\n\nMurtaza, M\n\nThompson, A\n\nGobin, R\n\nButterworth, A\n\nAhmad, U\n\nHakeem, A\n\nZaman, KS\n\nKundi, A\n\nYaqoob, Z\n\nCheema, LA\n\nQamar, N\n\nFaruqui, A\n\nMallick, NH\n\nAzhar, M\n\nSamad, A\n\nIshaq, M\n\nRasheed, SZ\n\nJooma, R\n\nNiazi, JH\n\nGardezi, AR\n\nMemon, NA\n\nGhaffar, A\n\nRehman, FU\n\nHoffmann, MM\n\nRenner, W\n\nKleber, ME\n\nGrammer, TB\n\nStephens, J\n\nAttwood, A\n\nKoch, K\n\nHussain, M\n\nKumar, K\n\nSaleem, A\n\nKumar, K\n\nDaood, MS\n\nGul, AA\n\nAbbas, S\n\nZafar, J\n\nShahid, F\n\nBhatti, SM\n\nAli, SS\n\nFahim, M\n\nSagoo, G\n\nBray, S\n\nMcGinnis, R\n\nDudbridge, F\n\nWinkelmann, BR\n\nBoehm, B\n\nThompson, S\n\nOuwehand, W\n\nMarz, W\n\nFrossard, P\n\nDanesh, J\n\nDeloukas, P\n\nBeiträge in Fachzeitschriften\nISI:000281006600007\n20570915.0\n10.1161/CIRCGENETICS.109.906180\nNone\nBackground-Evidence is sparse about the genetic determinants of major lipids in Pakistanis. Methods and Results-Variants (n = 45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P < 10(-13)), APOA5/ZNF259 (rs651821; P < 10(-13)) and GCKR (rs1260326; P < 10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P < 10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference < 10(-4)). Conclusions-Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans. (Circ Cardiovasc Genet. 2010;3:348-357.)\n\nMärz, Winfried\n\nRenner, Wilfried\n\nScharnagl, Hubert\n\n\n"
},
{
"text": "\n140739\nElevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis.\n\nSimon, Y\n\nKessler, SM\n\nGemperlein, K\n\nBohle, RM\n\nMüller, R\n\nHaybaeck, J\n\nKiemer, AK\n\nBeiträge in Fachzeitschriften\nISI:000346712800015\n25548482.0\n10.3748/wjg.v20.i47.17839\nPMC4273134\nTo characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.\n Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatography-mass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues.\n Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2) gene expression and increased iron deposition in transgenic animals.\n This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.\n\nHaybäck, Johannes\n\n\n"
},
{
"text": "\n144472\nErrors in administration of parenteral drugs in intensive care units: multinational prospective study.\n\nValentin, A\n\nCapuzzo, M\n\nGuidet, B\n\nMoreno, R\n\nMetnitz, B\n\nBauer, P\n\nMetnitz, P\n\nResearch Group on Quality Improvement of the European Society of Intensive Care Medicine (ESICM)\n\nSentinel Events Evaluation (SEE) Study Investigators\n\nBeiträge in Fachzeitschriften\nISI:000264205400001\n19282436.0\n10.1136/bmj.b814\nPMC2659290\nTo assess on a multinational level the frequency, characteristics, contributing factors, and preventive measures of administration errors in parenteral medication in intensive care units.\n Observational, prospective, 24 hour cross sectional study with self reporting by staff.\n 113 intensive care units in 27 countries.\n 1328 adults in intensive care.\n Number of errors; impact of errors; distribution of error characteristics; distribution of contributing and preventive factors.\n 861 errors affecting 441 patients were reported: 74.5 (95% confidence interval 69.5 to 79.4) events per 100 patient days. Three quarters of the errors were classified as errors of omission. Twelve patients (0.9% of the study population) experienced permanent harm or died because of medication errors at the administration stage. In a multiple logistic regression with patients as the unit of analysis, odds ratios for the occurrence of at least one parenteral medication error were raised for number of organ failures (odds ratio per increase of one organ failure: 1.19, 95% confidence interval 1.05 to 1.34); use of any intravenous medication (yes v no: 2.73, 1.39 to 5.36); number of parenteral administrations (per increase of one parenteral administration: 1.06, 1.04 to 1.08); typical interventions in patients in intensive care (yes v no: 1.50, 1.14 to 1.96); larger intensive care unit (per increase of one bed: 1.01, 1.00 to 1.02); number of patients per nurse (per increase of one patient: 1.30, 1.03 to 1.64); and occupancy rate (per 10% increase: 1.03, 1.00 to 1.05). Odds ratios for the occurrence of parenteral medication errors were decreased for presence of basic monitoring (yes v no: 0.19, 0.07 to 0.49); an existing critical incident reporting system (yes v no: 0.69, 0.53 to 0.90); an established routine of checks at nurses' shift change (yes v no: 0.68, 0.52 to 0.90); and an increased ratio of patient turnover to the size of the unit (per increase of one patient: 0.73, 0.57 to 0.93).\n Parenteral medication errors at the administration stage are common and a serious safety problem in intensive care units. With the increasing complexity of care in critically ill patients, organisational factors such as error reporting systems and routine checks can reduce the risk for such errors.\n\nMetnitz, Philipp\n\n\n"
}
]
}