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Stolwijk J.A.,University of Regensburg | Hartmann C.,Universitaetsmedizin Mainz | Balani P.,Institute Of Bioengineering And Nanotechnology, Singapore | Albermann S.,Merck Serono GmbH | And 3 more authors.
Biosensors and Bioelectronics | Year: 2011

In this study adherent animal cells were grown to confluence on circular gold-film electrodes of 250μm diameter that had been deposited on the surface of a regular culture dish. The impedance of the cell-covered electrode was measured at designated frequencies to monitor the behavior of the cells with time. This approach is referred to as electric cell-substrate impedance sensing or short ECIS in the literature. The gold-film electrodes were also used to deliver well-defined AC voltage pulses of several volts amplitude and several hundred milliseconds duration to the adherent cells in order to achieve reversible membrane electroporation (in situ electroporation=ISE). Electroporation-assisted introduction of membrane impermeable molecules into the cytoplasm was studied by using FITC-labeled dextran molecules of different molecular weights. Probes as big as 2MDa were successfully loaded into the cells residing on the electrode surface. Time-resolved impedance measurements before and immediately after the electroporation pulse revealed the kinetics of membrane resealing as well as subsequent changes in cell morphology. Cells recovered from the electroporation pulse within less than 90min. When membrane-impermeable, bioactive compounds like N 3 - or bleomycin were introduced into the cells by in situ electroporation, concomitant ECIS readings sensitively reported on the associated response of the cells to these toxins as a function of time (ISE-ECIS). © 2011 Elsevier B.V.


Giannini E.H.,University of Cincinnati | Mehta A.B.,University College London | Hilz M.J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Hilz M.J.,New York University | And 12 more authors.
Molecular Genetics and Metabolism | Year: 2010

Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument's total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument's domains was estimated and the DS3's quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R2 = 0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts. © 2009 Elsevier Inc. All rights reserved.


Lynch T.J.,Smilow Cancer Hospital | Bondarenko I.,City Clinical Hospital | Luft A.,Leningrad Regional Clinical Hospital | Serwatowski P.,Oddzial Chemioterapii | And 7 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin. Patients and Methods: Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m 2) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≥ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety. Results: The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity. Conclusion: Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC. © 2012 by American Society of Clinical Oncology.


Vulcu S.,Saarland University | Eickele L.,Saarland University | Cinalli G.,Childrens Hospital | Wagner W.,Universitaetsmedizin Mainz | Oertel J.,Saarland University
Journal of Neurosurgery | Year: 2015

Object Endoscopic third ventriculostomy (ETV) is the procedure of choice in the treatment of obstructive hydrocephalus. The excellent clinical and radiological success rates are well known. Nevertheless, very few papers have addressed the very long term outcomes of the procedure in very large series. The authors present a large case series of 113 patients who underwent 126 ETVs, and they highlight the initial postoperative outcome after 3 months and long-term follow-up with an average of 7 years. Methods All patients who underwent ETV at the Department of Neurosurgery, Mainz University Hospital, between 1993 and 1999 were evaluated. Obstructive hydrocephalus was the causative pathology in all cases. Results The initial clinical success rate was 82% and decreased slightly to 78% during long-term follow-up. Longterm success was analyzed using Kaplan-Meier curves. Overall, ETV failed in 31 patients. These patients underwent a second ETV or shunt treatment. A positive impact on long-term success was seen for age older than 6 months, and for obstruction due to cysts or benign aqueductal stenosis. The complication rate was 9% with 5 intraoperative and 5 postoperative events. Conclusions The high clinical success rate in short-term and long-term follow-up confirms ETV's status as the gold standard for the treatment of obstructive hydrocephalus, especially for distinct pathologies. The patient's age and underlying pathology may influence the outcome. These factors should be considered carefully preoperatively by the surgeon. © AANS, 2015.


PubMed | Childrens Hospital, Saarland University and Universitaetsmedizin Mainz
Type: Journal Article | Journal: Journal of neurosurgery | Year: 2015

Endoscopic third ventriculostomy (ETV) is the procedure of choice in the treatment of obstructive hydrocephalus. The excellent clinical and radiological success rates are well known. Nevertheless, very few papers have addressed the very long term outcomes of the procedure in very large series. The authors present a large case series of 113 patients who underwent 126 ETVs, and they highlight the initial postoperative outcome after 3 months and long-term follow-up with an average of 7 years.All patients who underwent ETV at the Department of Neurosurgery, Mainz University Hospital, between 1993 and 1999 were evaluated. Obstructive hydrocephalus was the causative pathology in all cases.The initial clinical success rate was 82% and decreased slightly to 78% during long-term follow-up. Long-term success was analyzed using Kaplan-Meier curves. Overall, ETV failed in 31 patients. These patients underwent a second ETV or shunt treatment. A positive impact on long-term success was seen for age older than 6 months, and for obstruction due to cysts or benign aqueductal stenosis. The complication rate was 9% with 5 intraoperative and 5 postoperative events.The high clinical success rate in short-term and long-term follow-up confirms ETVs status as the gold standard for the treatment of obstructive hydrocephalus, especially for distinct pathologies. The patients age and underlying pathology may influence the outcome. These factors should be considered carefully preoperatively by the surgeon.


Doll H.,Witten/Herdecke University | Maegele M.,Witten/Herdecke University | Bohl J.,Universitaetsmedizin Mainz | Storkel S.,Witten/Herdecke University | And 7 more authors.
Journal of Neurotrauma | Year: 2010

Therapeutic hypothermia (TH) is still being explored as a therapeutic option after traumatic brain injury (TBI) but clinical data has not supported its efficacy. Experimental approaches were promising, but clinical data did not support its efficacy in the treatment of TBI. A novel approach of pharyngeal selective brain cooling (pSBC), recently introduced by our group, has been accompanied by superior neurofunctional, sensorimotor, and cognitive outcomes. This work is now extended by data on histomorphological and physical outcomes after pSBC in a model of experimental TBI. Male Sprague-Dawley rats were subjected to lateral fluid-percussion (LFP) brain injury, and randomized to the following experimental groups: (1) TBI with pSBC, (2) TBI without pSBC, and (3) sham animals. On day post-injury (DPI) 14, the animals were sacrificed and their brains were harvested for immunohistochemistry using the following antibodies: (1) glial fibrillary acidic protein (GFAP), (2) neurofilament (NF), and (3) synaptophysin (SY). In pSBC animals brain temperature was selectively lowered to 33 ± 0.5°C within 15 min post-injury, and maintained for 180 min after induction, while keeping rectal temperatures at physiological levels. Animals that had undergone pSBC showed a significantly faster recovery of body weight starting on DPI 3, and had gained substantially more weight than TBI-only animals on DPI 14 (p < 0.001), indicating superior physical recovery. Areas of cortical damage were significantly smaller in pSBC animals compared to TBI-only animals (p < 0.01). pSBC was associated with preservation of cortical tissue ipsilateral to the lesion, and superior physical recovery after experimental TBI. These results complement earlier reports in which pSBC was associated with superior neurofunctional and cognitive outcomes using the same experimental model. © Copyright 2010, Mary Ann Liebert, Inc.


PubMed | Sathya Kidney Center & Super Speciality Hospital, Council of Scientific and Industrial Research Center for Cellular and Molecular Biology, Sridevi Maternity & Nursing Home and Universitaetsmedizin Mainz
Type: Journal Article | Journal: Orthopaedic journal of sports medicine | Year: 2015

Articular cartilage (AC) injuries and malformations are commonly noticed because of trauma or age-related degeneration. Many methods have been adopted for replacing or repairing the damaged tissue. Currently available AC repair methods, in several cases, fail to yield good-quality long-lasting results, perhaps because the reconstructed tissue lacks the cellular and matrix properties seen in hyaline cartilage (HC).To reconstruct HC tissue from 2-dimensional (2D) and 3-dimensional (3D) cultures of AC-derived human chondrocytes that would specifically exhibit the cellular and biochemical properties of the deep layer of HC.Descriptive laboratory study.Two-dimensional cultures of human AC-derived chondrocytes were established in classical medium (CM) and newly defined medium (NDM) and maintained for a period of 6 weeks. These cells were suspended in 2 mm-thick collagen I gels, placed in 24-well culture inserts, and further cultured up to 30 days. Properties of chondrocytes, grown in 2D cultures and the reconstructed 3D cartilage tissue, were studied by optical and scanning electron microscopic techniques, immunohistochemistry, and cartilage-specific gene expression profiling by reverse transcription polymerase chain reaction and were compared with those of the deep layer of native human AC.Two-dimensional chondrocyte cultures grown in NDM, in comparison with those grown in CM, showed more chondrocyte-specific gene activity and matrix properties. The NDM-grown chondrocytes in 3D cultures also showed better reproduction of deep layer properties of HC, as confirmed by microscopic and gene expression analysis. The method used in this study can yield cartilage tissue up to approximately 1.6 cm in diameter and 2 mm in thickness that satisfies the very low cell density and matrix composition properties present in the deep layer of normal HC.This study presents a novel and reproducible method for long-term culture of AC-derived chondrocytes and reconstruction of cartilage tissue with properties similar to the deep layer of HC in vitro.The HC tissue obtained by the method described can be used to develop an implantable product for the replacement of damaged or malformed AC, especially in younger patients where the lesions are caused by trauma or mechanical stress.


Nanduri V.,Council of Scientific and Industrial Research Center for Cellular and Molecular Biology | Tattikota S.M.,Council of Scientific and Industrial Research Center for Cellular and Molecular Biology | Tattikota S.M.,Universitaetsmedizin Mainz | Avinash Raj T.,Council of Scientific and Industrial Research Center for Cellular and Molecular Biology | And 3 more authors.
Orthopaedic Journal of Sports Medicine | Year: 2014

Background: Articular cartilage (AC) injuries and malformations are commonly noticed because of trauma or age-related degeneration. Many methods have been adopted for replacing or repairing the damaged tissue. Currently available AC repair methods, in several cases, fail to yield good-quality long-lasting results, perhaps because the reconstructed tissue lacks the cellular and matrix properties seen in hyaline cartilage (HC). Purpose: To reconstruct HC tissue from 2-dimensional (2D) and 3-dimensional (3D) cultures of AC-derived human chondrocytes that would specifically exhibit the cellular and biochemical properties of the deep layer of HC. Study Design: Descriptive laboratory study. Methods: Two-dimensional cultures of human AC–derived chondrocytes were established in classical medium (CM) and newly defined medium (NDM) and maintained for a period of 6 weeks. These cells were suspended in 2 mm–thick collagen I gels, placed in 24-well culture inserts, and further cultured up to 30 days. Properties of chondrocytes, grown in 2D cultures and the reconstructed 3D cartilage tissue, were studied by optical and scanning electron microscopic techniques, immunohistochemistry, and cartilage-specific gene expression profiling by reverse transcription polymerase chain reaction and were compared with those of the deep layer of native human AC. Results: Two-dimensional chondrocyte cultures grown in NDM, in comparison with those grown in CM, showed more chondrocyte-specific gene activity and matrix properties. The NDM-grown chondrocytes in 3D cultures also showed better reproduction of deep layer properties of HC, as confirmed by microscopic and gene expression analysis. The method used in this study can yield cartilage tissue up to approximately 1.6 cm in diameter and 2 mm in thickness that satisfies the very low cell density and matrix composition properties present in the deep layer of normal HC. Conclusion: This study presents a novel and reproducible method for long-term culture of AC-derived chondrocytes and reconstruction of cartilage tissue with properties similar to the deep layer of HC in vitro. Clinical Relevance: The HC tissue obtained by the method described can be used to develop an implantable product for the replacement of damaged or malformed AC, especially in younger patients where the lesions are caused by trauma or mechanical stress. © The Author(s) 2014.


Heinemann M.K.,Universitaetsmedizin Mainz | Beyersdorf F.,University Hospital Freiburg
Thoracic and Cardiovascular Surgeon | Year: 2016

It is this Editorials intention to alert authors on what can and should easily be avoided when preparing a manuscript. Everybody is well aware that it is not the authors who are to blame primarily, but the world/system that we live in. One can hardly sum up the problem better than Charlotte Haug did recently in the New England Journal of Medicine: The problem is the perverse incentive system in scientific publishing. As long as authors are (mostly) rewarded for publishing many articles and editors are (mostly) rewarded for publishing them rapidly, new ways of gaming the traditional publication models will be invented more quickly than new control measures can be put in place.3 Scientific/medical editors have to deal with these and more unpleasant circumstances. Luckily, they are a relatively uniform cohort reaching for the same goals: to make their journal, and thus the world, just that little bit better. Amazingly often they succeed in doing so - rendering their work very worthwhile. A helpful precondition is mutual respect and appreciation despite having to survive in an increasingly competitive market.

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