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"text": "\n170263\nGM-CSF: a strong arteriogenic factor acting by amplification of monocyte function.\n\nBuschmann, IR\n\nHoefer, IE\n\nvan Royen, N\n\nKatzer, E\n\nBraun-Dulleaus, R\n\nHeil, M\n\nKostin, S\n\nBode, C\n\nSchaper, W\n\nBeiträge in Fachzeitschriften\nISI:000172885100011\n11730814.0\n10.1016/S0021-9150(01)00637-2\nNone\nWe investigated the role of the colony stimulating factor for monocytes (GM-CSF) to test the hypothesis whether prolongation of the monocyte's life cycle will support arteriogenesis (rapid growth of preexisting collateral arteries). This appeared logical in view of our discovery that circulating monocytes play an important part in the positive remodeling of small preexisting arterioles into arteries to compensate for arterial occlusions (arteriogenesis) and especially following our findings that MCP-1 markedly increases the speed of arteriogenesis. The continuous infusion of GM-CSF for 7 days into the proximal stump of the acutely occluded femoral artery of rabbits by osmotic minipump produced indeed a marked arteriogenic response as demonstrated by an increase (2-fold) in number and size of collateral arteries on postmortem angiograms and by the increase of maximal blood flow during vasodilation measured in vivo by blood pump perfusion of the hindquarter (5-fold). When GM-CSF and MCP-1 were simultaneously infused the effects on arteriogenesis were additive on angiograms as well as on conductance. GM-CSF was also able to widen the time window of MCP-1 activity: MCP-1 treatment alone was ineffective when given after the third week following occlusion. When administered together with GM-CSF about 80% of normal maximal conductance of the artery that was replaced by collaterals were achieved, a result that was not reached before by any other experimental treatment. Experiments with cells isolated from treated animals showed that monocyte apoptosis was markedly reduced. In addition we hypothesize that GM-CSF may aid in releasing pluripotent monocyte (stem-) cells from the bone marrow into the circulation. In contrast to MCP-1, GM-CSF showed no activity on monocyte transmigration through- and also no influence on monocyte adhesion to cultured endothelial cells. In conclusion we have discovered a new function of the hemopoietic stem cell factor GM-CSF, which is also a powerful arteriogenic peptide that acts via prolongation of the life cycle of monocytes/macrophages.\n\nBuschmann, Eva Elina\n\n\n"
},
{
"text": "\n174235\nDesign and rationale of a randomized noninferiority trial to evaluate the SurVeil drug-coated balloon in subjects with stenotic lesions of the femoropopliteal artery - the TRANSCEND study.\n\nElmariah, S\n\nAnsel, GM\n\nBrodmann, M\n\nDoros, G\n\nFuller, S\n\nGray, WA\n\nPinto, DS\n\nRosenfield, KA\n\nMauri, L\n\nBeiträge in Fachzeitschriften\nISI:000461306800011\n30685679.0\n10.1016/j.ahj.2018.12.012\nNone\nDrug-coated balloons (DCBs), developed to reduce restenosis after percutaneous intervention in peripheral arterial disease (PAD), have been shown to be safe and efficacious, particularly in treating PAD affecting the femoropopliteal segment. The SurVeil DCB uses an excipient intended to optimize both the uniformity and transfer of paclitaxel to the vessel wall, allowing for efficient drug loading and lower systemic exposure than currently available DCBs, Heretofore, clinical outcomes have not previously been compared to other DCBs.\n This prospective, multicenter, international, randomized, single-blind, trial will compare 1:1 the SurVeil DCB with the IN.PACT Admiral DCB for treatment of patients with Rutherford classification 2 to 4 due to femoral and/or popliteal arterial disease. The trial will randomize 446 subjects (with reference vessel diameter 4-7 mm and total lesion length ≤180 mm). Subjects will be followed for 60 months. The primary efficacy endpoint is 1 year primary patency, defined as composite freedom from clinically-driven target-lesion revascularization (TLR) and binary restenosis (core lab-adjudicated duplex ultrasound peak systolic velocity ratio ≥2.4, or ≥50% stenosis via angiography). The primary safety endpoint is composite freedom from device- and procedure-related death through 30 days and freedom from target limb major amputation and clinically-driven target vessel revascularization through 12 months. The primary analysis is a test of noninferiority of the SurVeil vs. IN.PACT Admiral on the primary efficacy and safety endpoints according to absolute deltas of 15.0% and 10.0%, respectively.\n The Randomized And Controlled Noninferiority Trial to Evaluate Safety and Clinical Efficacy of the SurVeil DCB in the Treatment of Subjects with Stenotic Lesions of the Femoropopliteal Artery Compared to the Medtronic IN.PACT Admiral (TRANSCEND) study will assess safety and efficacy of the SurVeil DCB relative to a commonly used DCB.\n Copyright © 2018 Elsevier Inc. All rights reserved.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n175373\nThe role of ventricular-arterial coupling in cardiac disease and heart failure: assessment, clinical implications and therapeutic interventions. A consensus document of the European Society of Cardiology Working Group on Aorta & Peripheral Vascular Diseases, European Association of Cardiovascular Imaging, and Heart Failure Association.\n\nIkonomidis, I\n\nAboyans, V\n\nBlacher, J\n\nBrodmann, M\n\nBrutsaert, DL\n\nChirinos, JA\n\nDe Carlo, M\n\nDelgado, V\n\nLancellotti, P\n\nLekakis, J\n\nMohty, D\n\nNihoyannopoulos, P\n\nParissis, J\n\nRizzoni, D\n\nRuschitzka, F\n\nSeferovic, P\n\nStabile, E\n\nTousoulis, D\n\nVinereanu, D\n\nVlachopoulos, C\n\nVlastos, D\n\nXaplanteris, P\n\nZimlichman, R\n\nMetra, M\n\nBeiträge in Fachzeitschriften\nISI:000468038100004\n30859669.0\n10.1002/ejhf.1436\nNone\nVentricular-arterial coupling (VAC) plays a major role in the physiology of cardiac and aortic mechanics, as well as in the pathophysiology of cardiac disease. VAC assessment possesses independent diagnostic and prognostic value and may be used to refine riskstratification and monitor therapeutic interventions. Traditionally, VAC is assessed by the non-invasive measurement of the ratio of arterial (Ea) to ventricular end-systolic elastance (Ees). With disease progression, both Ea and Ees may become abnormal and the Ea/Ees ratio may approximate its normal values. Therefore, the measurement of each component of this ratio or of novel more sensitive markers of myocardial (e.g. global longitudinal strain) and arterial function (e.g. pulse wave velocity) may better characterize VAC. In valvular heart disease, systemic arterial compliance and valvulo-arterial impedance have an established diagnostic and prognostic value and may monitor the effects of valve replacement on vascular and cardiac function. Treatment guided to improve VAC through improvement of both or each one of its components may delay incidence of heart failure and possibly improve prognosis in heart failure. In this consensus document, we describe the pathophysiology, the methods of assessment as well as the clinical implications of VAC in cardiac diseases and heart failure. Finally, we focus on interventions that may improve VAC and thus modify prognosis.\n © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n182187\nThe importance of maternal insulin resistance throughout pregnancy on neonatal adiposity.\n\nLima, RA\n\nDesoye, G\n\nSimmons, D\n\nDevlieger, R\n\nGaljaard, S\n\nCorcoy, R\n\nAdelantado, JM\n\nDunne, F\n\nHarreiter, J\n\nKautzky-Willer, A\n\nDamm, P\n\nMathiesen, ER\n\nJensen, DM\n\nAndersen, LT\n\nTanvig, M\n\nLapolla, A\n\nDalfra, MG\n\nBertolotto, A\n\nManta, U\n\nWender-Ozegowska, E\n\nZawiejska, A\n\nHill, DJ\n\nSnoek, FJ\n\nJelsma, JGM\n\nvan Poppel, M\n\nBeiträge in Fachzeitschriften\nISI:000529612000001\n32352590.0\n10.1111/ppe.12682\nPMC7891448\nAlthough previous studies evaluated the association of maternal health parameters with neonatal adiposity, little is known regarding the complexity of the relationships among different maternal health parameters throughout pregnancy and its impact on neonatal adiposity.\n To evaluate the direct and indirect associations between maternal insulin resistance during pregnancy, in women with obesity, and neonatal adiposity. In addition, associations between maternal fasting glucose, triglycerides (TG), non-esterified fatty acids (NEFA), and neonatal adiposity were also assessed.\n This is a longitudinal, secondary analysis of the DALI study, an international project conducted in nine European countries with pregnant women with obesity. Maternal insulin resistance (HOMA-IR), fasting glucose, TG, and NEFA were measured three times during pregnancy (<20, 24-28, and 35-37 weeks of gestation). Offspring neonatal adiposity was estimated by the sum of four skinfolds. Structural equation modelling was conducted to evaluate the direct and indirect relationships among the variables of interest.\n Data on 657 mother-infant pairs (50.7% boys) were analysed. Neonatal boys exhibited lower mean sum of skinfolds compared to girls (20.3 mm, 95% CI 19.7, 21.0 vs 21.5 mm, 95% CI 20.8, 22.2). In boys, maternal HOMA-IR at <20 weeks was directly associated with neonatal adiposity (β = 0.35 mm, 95% CI 0.01, 0.70). In girls, maternal HOMA-IR at 24-28 weeks was only indirectly associated with neonatal adiposity, which implies that this association was mediated via maternal HOMA-IR, glucose, triglycerides, and NEFA during pregnancy (β = 0.26 mm, 95% CI 0.08, 0.44).\n The timing of the role of maternal insulin resistance on neonatal adiposity depends on fetal sex. Although the association was time-dependent, maternal insulin resistance was associated with neonatal adiposity in both sexes.\n © 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.\n\nDesoye, Gernot\n\nVan Poppel, Mireille Nicoline Maria\n\n\n"
},
{
"text": "\n183764\nInternational Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E<sub>2</sub> Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions.\n\nNorel, X\n\nSugimoto, Y\n\nOzen, G\n\nAbdelazeem, H\n\nAmgoud, Y\n\nBouhadoun, A\n\nBassiouni, W\n\nGoepp, M\n\nMani, S\n\nManikpurage, HD\n\nSenbel, A\n\nLongrois, D\n\nHeinemann, A\n\nYao, C\n\nClapp, LH\n\nBeiträge in Fachzeitschriften\nISI:000590414000006\n32962984.0\n10.1124/pr.120.019331\nPMC7509579\nProstaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.\n Copyright © 2020 The Author(s).\n\nHeinemann, Akos\n\n\n"
},
{
"text": "\n1860\nOperations on patients deemed "unfit for operation and anaesthesia": what are the consequences?\n\nPrause, G\n\nRatzenhofer-Komenda, B\n\nSmolle-Juettner, F\n\nKrenn, H\n\nPojer, H\n\nToller, W\n\nVoit, H\n\nOffner, A\n\nSmolle, J\n\nBeiträge in Fachzeitschriften\nISI:000072336400007\n9542559.0\n10.1111/j.1399-6576.1998.tb04923.x\nNone\nThe decision "patient unfit for anaesthesia and operation" is likely to cause a delay of the scheduled operation. This retrospective evaluation was done: 1) to determine the correctness of preoperative tentative diagnoses of coexisting diseases making anaesthesia and operation excessively risky in relation to the physician's training status; 2) to examine the question of whether preoperative medical management modified according to the anaesthesiologist's suggestions had a positive impact on the perioperative course.\n The medical records of patients scheduled for elective non-cardiac surgery who were rated "unfit for operation and anaesthesia" were evaluated. The accuracy of the tentative diagnoses was examined for relation to the training status of the anaesthesiologists. The preoperative management was tested for its impact on postoperative outcome.\n During the observation period 16, 22 patients underwent preoperative anaesthesiological assessment; 1021 (6.3%) were initially considered to be unfit for operation and anaesthesia. The records of 807 patients were available for review. The accuracy of the tentative diagnoses was 70%, and was not significantly affected by the training status of the physicians (P = 0.022). Four hundred and seventeen patients were excluded from the second part of the investigation (discharged without operation, underwent operation using local anaesthesia or tentative diagnosis not confirmed). Three hundred and ninety patients were operated under general anaesthesia. Group I (n = 216) was managed according to the anaesthesiologist's suggestions and was found to have a significantly lower complication rate (18.1%) than group II (n = 174) in which the suggestions from the preoperative assessment were ignored (32.2%; P < 0.05). The perioperative mortality rate in group I was 2.3% compared with 5.2% in group II (n.s.; P > 0.05).\n We conclude that the anaesthesiology decision "patient unfit for operation and anaesthesia" has a high accuracy, independent of the anaesthesiologist's training status, and that preoperative medical management significantly reduces complications.\n\nPrause, Gerhard\n\nSmolle, Josef\n\nSmolle-Juettner, Freyja-Maria\n\nToller, Wolfgang\n\nVoit-Augustin, Henrika\n\n\n"
},
{
"text": "\n3151\nPreoperative treatment with recombinant human erythropoietin or predeposit of autologous blood in women undergoing primary hip replacement.\n\nGombotz, H\n\nGries, M\n\nSipurzynski, S\n\nFruhwald, S\n\nRehak, P\n\nBeiträge in Fachzeitschriften\nISI:000088028000013\n10903019.0\n10.1034%2Fj.1399-6576.2000.440613.x\nNone\nBACKGROUND: Controversy exists about the advantages of predeposit of autologous blood (PDAB), and whether more comfortable blood conservation regimens may yield comparable results. To test the hypothesis that preoperative treatment with recombinant human erythropoietin (rHuEPO) with or without acute concomitant normovolaemic haemodilution (ANHD) is as effective as PDAB in reducing allogeneic blood transfusions, we conducted a prospective randomised study in women undergoing primary hip replacement. METHODS: Sixty consecutive female patients scheduled for primary hip replacement and suitable for PDAB were randomly assigned to one of 3 groups. Group I (EPO) and II (ANHD) received 600 U/kg rHuEPO s.c. and 100 mg iron saccharate i.v. on day 14 and, if needed, on day 7 before surgery. Additionally, in group II acute normovolaemic haemodilution (ANHD) was implemented after induction of anaesthesia. In group III (PDAB) conventional PDAB up to 3 U, without volume replacement but with concomitant oral iron therapy, was performed starting 4 weeks before surgery. RESULTS: The blood conservation methods resulted in a comparable net gain of red cells in all 3 groups until the day of surgery. Because of the withdrawal of autologous blood, haemoglobin values before surgery were lower in the PDAB group than in the EPO and ANHD groups, and during surgery were lower in the PDAB and ANHD groups than in the rHuEPO-only group. Applying moderate ANHD in conjunction with preoperative rHuEPO treatment did not yield an incremental decrease in allogeneic transfusions. There was no difference between the groups in the number of patients who received allogeneic transfusions or in the total number of allogeneic units transfused. CONCLUSIONS: Withdrawal of autologous blood is associated with lower pre- and intraoperative haemoglobin levels when compared to preoperative augmentation of red cell mass using rHu-EPO. As a measure to reduce allogeneic transfusion requirements, preoperative treatment with rHuEPO may be as effective as standard predeposit of autologous blood in women undergoing primary hip replacement, but requires less preoperative time.\n\nFruhwald, Sonja\n\n\n"
},
{
"text": "\n5558\nNovel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers.\n\nVécsey-Semjén, B\n\nBecker, KF\n\nSinski, A\n\nBlennow, E\n\nVietor, I\n\nZatloukal, K\n\nBeug, H\n\nWagner, E\n\nHuber, LA\n\nBeiträge in Fachzeitschriften\nISI:000176625100006\n12096341.0\n10.1038/sj.onc.1205577\nNone\nA major obstacle to obtaining more detailed insights into the diversity of phenotypic and molecular changes occurring in colon cancer cells is the lack of low-passage colon cancer cell lines, which would still closely reflect the phenotype of the colon cancer cells in vivo. Here, we characterize eight novel, low passage number human colon carcinoma cell lines, originating from colorectal cancers extensively characterized in the clinics. All cell lines closely resemble the original tumors with respect to phenotype, markers and detectable genetic changes. Cell morphology and marker expression is highly variable, ranging from fully polarized cells correctly expressing all basolateral epithelial markers, to cells with mesenchymal characteristics and a complete loss of polarity due to delocalization or loss of junction complex proteins. The alterations in phenotype and epithelial marker expression correspond to changes already detectable in the primary tumor in vivo. Seven of the cell lines show chromosomal instability, while one cell line is characterized by microsatellite instability. p53 associated with K-ras mutations were detected in three cell lines. Hitherto non-described E-cadherin mutations were found at both alleles in one cell line whereas in another cell line the E-cadherin protein was down-regulated. A stabilizing beta-catenin mutation (S45F) appears in the same cell line that carried the mutated E-cadherin gene. Six cell lines carried APC mutations, which in five of the lines led to an activated beta-catenin/Tcf/LEF signaling pathway. In accordance with beta-catenin/Tcf/LEF activation, the cell lines show increased migration and invasiveness. Our results show that the characterized, low-passage cell lines mirror the diversity of the individual tumors from which they were derived. Through molecular analyses of these cell lines we demonstrate that tumorgenicity events are much more diverse in human colon cancer than expected, despite the common origin of the tumors from a small patient group with similar tumor grading and clinical prognosis.\n\nZatloukal, Kurt\n\n\n"
},
{
"text": "\n53019\nPredictive value of access blood flow and stenosis in detection of graft failure.\n\nWang, E\n\nSchneditz, D\n\nLevin, NW\n\nBeiträge in Fachzeitschriften\nISI:000165287400007\n11105801.0\nNone\nNone\nAIMS: Low access flow and the diagnosis of high degrees of venous stenosis have been recommended as indications for prophylactic angioplasty. However, recent studies have shown that prophylactic angioplasty for > 50% stenosis did not prolong graft patency, and that a single flow measurement may not accurately predict graft failure. In this study we compared the value of monthly measurement of access flow and of the maximal degree of stenosis in the detection of graft failure over a three-month period. METHODS: Thirty-nine hemodialysis patients with polytetrafluoroethylene (PTFE) grafts were evaluated by Doppler ultrasound at monthly intervals for three months. Graft failures were defined as thrombosis, or surgical and angioplastic revisions required because of the presence of access recirculation, and patients with graft failure were followed within the subsequent one-month periods of observation. RESULTS: Twelve graft failures occurred during the three-month period of observation. The risk for subsequent graft failure significantly increased at flows < 300 ml/min. Nine (20%) graft failures occurred with stenoses of 30 to 50%, and three (13%) with stenoses of> 50%. The grafts that failed in the second and the third study months had a 25.8% (380 +/- 62 vs. 287 +/- 190 ml/min, p < 0.05) and a 36.5% (393 +/- 142 vs. 226 +/- 41 ml/min, p < 0.05) decrease in access flow, respectively. There was no significant change in access flow for the grafts patent throughout the study (911 +/- 333, 794 +/- 302, and 919 +/383 ml/min, p = ns). No significant increases in maximal stenosis were found for the grafts that failed in the second month (44 +/- 6.1 vs. 48 +/- 15%, p = ns) and the third month (48 +/- 9 vs. 51 +/- 16%, p = ns). There were no significant changes in the maximum stenosis for the grafts patent throughout the three-month study periods (37 +/- 15, 3 +/- 11, and 44 +/- 15%, p = ns). CONCLUSIONS: Access flow is a more sensitive predictor of graft failure than stenosis. Examination of trend in decline of access flow is a more powerful indicator to detect graft dysfunction than an individual single flow value.\n\nSchneditz, Daniel\n\n\n"
},
{
"text": "\n63654\nDifferential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia.\n\nTinhofer, I\n\nMarschitz, I\n\nKos, M\n\nHenn, T\n\nEgle, A\n\nVillunger, A\n\nGreil, R\n\nBeiträge in Fachzeitschriften\nISI:000073797000033\n9596676.0\n10.1182/blood.V91.11.4273.411k25_4273_4281\nNone\nB-chronic lymphocytic leukemia (B-CLL) is characterized by cellular and humoral immune defects resulting in increased rates of infection and disturbed immune surveillance against cancer cells as well as by the expansion of slowly proliferating tumor cells. We found increased Fas receptor (FasR) expression in peripheral blood CD4+ and CD8+ cells of B-CLL patients compared with the equivalent cells of healthy donors. Although increased Fas receptor expression was significant in both T-lymphocytic subsets, only CD4+ cells from B-CLL patients underwent apoptosis after treatment with the agonistic Fas antibody CH11. In CD4+ cells of B-CLL patients, the Fas-sensitivity also correlated with a CD4+/CD8+ ratio below the lower threshold of healthy individuals (<1.0). By contrast, FasR expression in the CD19(+) fraction of B-CLL patients was downregulated compared with normal controls, and this was associated with an insensitivity to CH11-induced apoptosis. The B-CLL cell line EHEB as well as CD19(+) cells from B-CLL patients constitutively expressed Fas ligand (FasL). The FasL was functionally active, as the B-CLL cell line as well as T-cell-depleted CD19+ B-CLL fractions were able to kill target T-acute lymphatic leukemia (T-ALL) cells in vitro. This effect was inhibited by the antagonistic FasR-antibody ZB4, the neutralizing anti-FasL monoclonal antibody (MoAb) NOK-2 or by transfection of the caspase inhibitor crmA. These data point to the fact that expression of FasL on CD19(+) B-CLL cells, together with enhanced susceptibility of CD4+ T cells toward FasL-bearing effector cells, are causally linked to the relative reduction of CD4+ cells occurring during B-CLL progression. These findings could explain the inversion of the ratio of CD4+/CD8+ cell numbers, which may be causally linked to the immune deficiency observed in these patients and to the expansion of the neoplastic clone in B-CLL.\n\nMarschitz, Ingrid Christine\n\n\n"
},
{
"text": "\n123662\nEnhanced absorption of insulin aspart as the result of a dispersed injection strategy tested in a randomized trial in type 1 diabetic patients.\n\nMader, JK\n\nBirngruber, T\n\nKorsatko, S\n\nDeller, S\n\nKöhler, G\n\nBoysen, S\n\nAugustin, T\n\nMautner, SI\n\nSinner, F\n\nPieber, TR\n\nAP@home Consortium\n\nBeiträge in Fachzeitschriften\nISI:000316462400019\n23193211.0\n10.2337/dc12-1319\nPMC3609526\nWe investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo.\n Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide-negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration.\n The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1, 61 ± 469 vs. 1, 65 ± 527; P = 0.08).\n A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.\n\nDeller, Sigrid\n\nKöhler, Gerd\n\nKorsatko, Stefan\n\nMader, Julia\n\nMautner, Selma\n\nPieber, Thomas\n\nSinner, Frank Michael\n\n\n"
},
{
"text": "\n127446\nNovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality\n\nStupp, R\n\nWong, ET\n\nKanner, AA\n\nSteinberg, D\n\nEngelhard, H\n\nHeidecke, V\n\nKirson, ED\n\nTaillibert, S\n\nLiebermann, F\n\nDbaly, V\n\nRam, Z\n\nVillano, JL\n\nRainov, N\n\nWeinberg, U\n\nSchiff, D\n\nKunschner, L\n\nRaizer, J\n\nHonnorat, J\n\nSloan, A\n\nMalkin, M\n\nLandolfi, JC\n\nPayer, F\n\nMehdorn, M\n\nWeil, RJ\n\nPannullo, SC\n\nWestphal, M\n\nSmrcka, M\n\nChin, L\n\nKostron, H\n\nHofer, S\n\nBruce, J\n\nCosgrove, R\n\nPaleologous, N\n\nPalti, Y\n\nGutin, PH\n\nBeiträge in Fachzeitschriften\nISI:000307884900012\n22608262.0\n10.1016/j.ejca.2012.04.011\nNone\nPurpose: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. Methods: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24 h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. Results: Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n = 120) or active chemotherapy control (n = 117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p = 0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p = 0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p = 0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p = 0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. Conclusions: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF. (C) 2012 Elsevier Ltd. All rights reserved.\n\n\n"
},
{
"text": "\n130165\nQuality control of RNA preservation and extraction from paraffin-embedded tissue: implications for RT-PCR and microarray analysis.\n\nKashofer, K\n\nViertler, C\n\nPichler, M\n\nZatloukal, K\n\nBeiträge in Fachzeitschriften\nISI:000322633700081\n23936242.0\n10.1371/journal.pone.0070714\nPMC3729557\nAnalysis of RNA isolated from fixed and paraffin-embedded tissues is widely used in biomedical research and molecular pathological diagnostics. We have performed a comprehensive and systematic investigation of the impact of factors in the pre-analytical workflow, such as different fixatives, fixation time, RNA extraction method and storage of tissues in paraffin blocks, on several downstream reactions including complementary DNA (cDNA) synthesis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray hybridization. We compared the effects of routine formalin fixation with the non-crosslinking, alcohol-based Tissue Tek Xpress Molecular Fixative (TTXMF, Sakura Finetek), and cryopreservation as gold standard for molecular analyses. Formalin fixation introduced major changes into microarray gene expression data and led to marked gene-to-gene variations in delta-ct values of qRT-PCR. We found that qRT-PCR efficiency and gene-to-gene variations were mainly attributed to differences in the efficiency of cDNA synthesis as the most sensitive step. These differences could not be reliably detected by quality assessment of total RNA isolated from formalin-fixed tissues by electrophoresis or spectrophotometry. Although RNA from TTXMF fixed samples was as fragmented as RNA from formalin fixed samples, much higher cDNA yield and lower ct-values were obtained in qRT-PCR underlining the negative impact of crosslinking by formalin. In order to better estimate the impact of pre-analytical procedures such as fixation on the reliability of downstream analysis, we applied a qRT-PCR-based assay using amplicons of different length and an assay measuring the efficiency of cDNA generation. Together these two assays allowed better quality assessment of RNA extracted from fixed and paraffin-embedded tissues and should be used to supplement quality scores derived from automated electrophoresis. A better standardization of the pre-analytical workflow, application of additional quality controls and detailed sample information would markedly improve the comparability and reliability of molecular studies based on formalin-fixed and paraffin-embedded tissue samples.\n\nKashofer, Karl\n\nPichler, Martin\n\nViertler, Christian\n\nZatloukal, Kurt\n\n\n"
},
{
"text": "\n133524\nMaternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat.\n\nHochmeister, S\n\nPekar, T\n\nLindner, M\n\nKitic, M\n\nHaindl, M\n\nStorch, M\n\nFazekas, F\n\nLinington, C\n\nBeiträge in Fachzeitschriften\nISI:000330240500045\n24465550.0\n10.1371/journal.pone.0085393\nPMC3896359\nNeurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum.\n Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody.\n We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children.\n\nFazekas, Franz\n\nHaindl, Michaela\n\nHochmeister, Sonja\n\n\n"
},
{
"text": "\n142543\nMeasuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report.\n\nPavletic, SZ\n\nMartin, P\n\nLee, SJ\n\nMitchell, S\n\nJacobsohn, D\n\nCowen, EW\n\nTurner, ML\n\nAkpek, G\n\nGilman, A\n\nMcDonald, G\n\nSchubert, M\n\nBerger, A\n\nBross, P\n\nChien, JW\n\nCouriel, D\n\nDunn, JP\n\nFall-Dickson, J\n\nFarrell, A\n\nFlowers, ME\n\nGreinix, H\n\nHirschfeld, S\n\nGerber, L\n\nKim, S\n\nKnobler, R\n\nLachenbruch, PA\n\nMiller, FW\n\nMittleman, B\n\nPapadopoulos, E\n\nParsons, SK\n\nPrzepiorka, D\n\nRobinson, M\n\nWard, M\n\nReeve, B\n\nRider, LG\n\nShulman, H\n\nSchultz, KR\n\nWeisdorf, D\n\nVogelsang, GB\n\nResponse Criteria Working Group\n\nBeiträge in Fachzeitschriften\nISI:000236190600002\n16503494.0\n10.1016/j.bbmt.2006.01.008\nNone\nThe lack of standardized criteria for quantitative measurement of therapeutic response in clinical trials poses a major obstacle for the development of new agents in chronic graft-versus-host disease (GVHD). This consensus document was developed to address several objectives for response criteria to be used in chronic GVHD-related clinical trials. The proposed measures should be practical for use both by transplantation and nontransplantation medical providers, adaptable for use in adults and in children, and focused on the most important chronic GVHD manifestations. The measures should also give preference to quantitative, rather than semiquantitative, measures; capture information regarding signs, symptoms, and function separately from each other; and use validated scales whenever possible to demonstrate improved patient outcomes and meet requirements for regulatory approval of novel agents. Based on these criteria, we propose a set of measures to be considered for use in clinical trials, and forms for data collection are provided (). Measures should be made at 3-month intervals and whenever major changes are made in treatment. Provisional definitions of complete response, partial response, and progression are proposed for each organ and for overall outcomes. The proposed response criteria are based on current expert consensus opinion and are intended to improve consistency in the conduct and reporting of chronic GVHD trials, but their use remains to be demonstrated in practice.\n\nGreinix, Hildegard\n\n\n"
},
{
"text": "\n159134\nNeutrophil gelatinase-associated lipocalin levels are U-shaped in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study-Impact for mortality.\n\nWoitas, RP\n\nScharnagl, H\n\nKleber, ME\n\nDelgado, GE\n\nGrammer, TB\n\nPichler, M\n\nKrämer, BK\n\nMärz, W\n\nStojakovic, T\n\nBeiträge in Fachzeitschriften\nISI:000394424500040\n28207778.0\n10.1371/journal.pone.0171574\nPMC5312954\nNeutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein released by damaged renal tubular cells and mature neutrophils. It is elevated in kidney injury, but also in patients with coronary artery disease (CAD) and myocardial infarction. We investigated the prognostic value of NGAL for total and cardiovascular mortality in patients undergoing coronary angiography without history of renal insufficiency at inclusion into the study.\n The LURIC study is an ongoing prospective cohort study of patients referred for coronary angiography and is designed to evaluate determinants of cardiovascular health.\n NGAL was determined in plasma of 2997 persons (mean age: 62.7 years; 69.7% men) with a follow up for 10 years. 2358 patients suffered from CAD and 638 did not-these patients served as controls. Stable CAD was found in 1408 and unstable CAD in 950 patients. Death rate from cardiovascular events and all causes was highest in patients within the 4th quartile of NGAL (≥56 ng/ml, p<0.001 vs third quartile), even after adjustment for age and gender. According to multivariable-adjusted Cox analysis adjusting for well-known cardiovascular risk factors, as well as lipid lowering therapy, angiographic CAD, and C-reactive protein we found patients in the highest NGAL quartile being at increased risk for cardiovascular (hazard ratio (HR) 1.33, 95%CI 1.05-1.67, p = 0.016) and all cause mortality (HR 1.29 95%CI 1.07-1.55, p = 0.007) compared to those in the third quartile. The lowest risk was seen in the third quartile of NGAL (41-56 ng/ml) suggesting a U-shaped relationship between NGAL and mortality. Further adjustment for creatinine abrogated the predictive effect of NGAL. However, the 3rd and 4th quartiles of NGAL were significantly associated with higher neutrophil counts, which were associated with CAD, non-ST elevation and ST-elevation myocardial infarction (p<0.05).\n Plasma NGAL concentrations are mainly derived from neutrophils and do not predict mortality independent of renal function.\n\nMärz, Winfried\n\nPichler, Martin\n\nScharnagl, Hubert\n\n\n"
},
{
"text": "\n161868\nBiomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease.\n\nLindholm, D\n\nLindbäck, J\n\nArmstrong, PW\n\nBudaj, A\n\nCannon, CP\n\nGranger, CB\n\nHagström, E\n\nHeld, C\n\nKoenig, W\n\nÖstlund, O\n\nStewart, RAH\n\nSoffer, J\n\nWhite, HD\n\nde Winter, RJ\n\nSteg, PG\n\nSiegbahn, A\n\nKleber, ME\n\nDressel, A\n\nGrammer, TB\n\nMärz, W\n\nWallentin, L\n\nBeiträge in Fachzeitschriften\nISI:000407028500001\n28797349.0\n10.1016/j.jacc.2017.06.030\nNone\nCurrently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).\n This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.\n In a prospective, randomized trial cohort of 13, 64 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1, 47 patients in another study.\n During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This "ABC-CHD" model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.\n This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903).\n Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n168752\nTackling frailty and functional decline: Background of the action group A3 of the European innovation partnership for active and healthy ageing.\n\nCano, A\n\nDargent, G\n\nCarriazo, A\n\nLópez-Samaniego, L\n\nApostolo, J\n\nCampos, E\n\nHolland, C\n\nVarela-Nieto, I\n\nLuz Sánchez-Sánchez, M\n\nIllario, M\n\nIaccarino, G\n\nRoller, RE\n\nGoossens, E\n\nVollenbroek-Hutten, M\n\nPais, S\n\nSchena, F\n\nMusian, D\n\nAlvino, S\n\nMaggio, M\n\nLiotta, G\n\nUssai, S\n\nOrfila, F\n\nO'Caoimh, R\n\nPaul, C\n\nPazzi, S\n\nRomano, V\n\nObbia, P\n\nBeiträge in Fachzeitschriften\nISI:000441490400009\n30049350.0\n10.1016/j.maturitas.2018.06.009\nNone\nAgeing populations represent a challenge to the sustainability of current healthcare systems. The need to balance these demographic changes with gains in healthy life years and quality of life (QoL) constitutes an additional challenge. Aware of this, the European Commission (EC) launched the European Innovation Partnership on Active and Healthy Ageing (EIPonAHA) in 2012. The EIPonAHA is an interdisciplinary and cross-sector initiative involving more than 3000 partners with two specific objectives: to increase the healthy life expectancy of Europeans by two years by 2020, while increasing their QoL. The initiatives of the EIPonAHA have been organized according to six thematic action groups (AGs), with the A3 group targeting areas relating to the prevention of functional decline and frailty. In addition to the good practices of partners, there are several on-going collaborative works. The involvement of the EC includes support through an elaborated research programme in which the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) and the Directorate-General for Communications Networks, Content and Technology (DG CONNECT) are the main funding bodies. Screening approaches and preventive interventions constitute most of the initiatives within the A3 AG. Partners are distributed across five sub-groups according to good practices: i) cognitive decline, ii) food and nutrition, iii) physical activity, iv) caregivers, and v) frailty and functional decline. Regular updates of the progression of both good practices and collaborative works are presented in A3 AG meetings. The 2017 meeting in Valencia, Spain, showcased in this paper, provides an up-to-date overview of the current status of A3 activities.\n Copyright © 2018 Elsevier B.V. All rights reserved.\n\nRoller-Wirnsberger, Regina\n\n\n"
},
{
"text": "\n179163\nHDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction.\n\nWallner, M\n\nEaton, DM\n\nBerretta, RM\n\nLiesinger, L\n\nSchittmayer, M\n\nGindlhuber, J\n\nWu, J\n\nJeong, MY\n\nLin, YH\n\nBorghetti, G\n\nBaker, ST\n\nZhao, H\n\nPfleger, J\n\nBlass, S\n\nRainer, PP\n\nvon Lewinski, D\n\nBugger, H\n\nMohsin, S\n\nGraier, WF\n\nZirlik, A\n\nMcKinsey, TA\n\nBirner-Gruenberger, R\n\nWolfson, MR\n\nHouser, SR\n\nBeiträge in Fachzeitschriften\nISI:000507499600006\n31915304.0\n10.1126/scitranslmed.aay7205\nPMC7065257\nHeart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration-approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients.\n Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.\n\nBirner-Grünberger, Ruth\n\nBlass, Sandra\n\nBugger, Heiko Matthias\n\nGindlhuber, Jürgen\n\nGraier, Wolfgang\n\nLiesinger, Laura\n\nRainer, Peter\n\nSchittmayer-Schantl, Matthias\n\nvon Lewinski, Dirk\n\nWallner, Markus\n\nZirlik, Andreas\n\n\n"
},
{
"text": "\n181876\nLongitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm.\n\nCole, JH\n\nRaffel, J\n\nFriede, T\n\nEshaghi, A\n\nBrownlee, WJ\n\nChard, D\n\nDe Stefano, N\n\nEnzinger, C\n\nPirpamer, L\n\nFilippi, M\n\nGasperini, C\n\nRocca, MA\n\nRovira, A\n\nRuggieri, S\n\nSastre-Garriga, J\n\nStromillo, ML\n\nUitdehaag, BMJ\n\nVrenken, H\n\nBarkhof, F\n\nNicholas, R\n\nCiccarelli, O\n\nMAGNIMS study group\n\nBeiträge in Fachzeitschriften\nISI:000530530100001\n32285956.0\n10.1002/ana.25746\nNone\nDuring the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes.\n In a longitudinal, multicenter sample of 3, 65 magnetic resonance imaging (MRI) scans, in 1, 04 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured "brain-predicted age" using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored.\n Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001).\n The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, "brain-age" could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93-105.\n © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.\n\nEnzinger, Christian\n\nPirpamer, Lukas\n\n\n"
}
]
}