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Aim: The aim of this study was to measure cortico-cortical connectivity in multiple sclerosis (MS) patients by TMS-evoked potential (TEP) latencies in EEG evoked by transcranial magnetic stimulation (TMS) of the hand area of the primary motor cortex of one hemisphere. TEPs were recorded on the stimulated- and at the homologue site in the non-stimulated contralateral hemisphere. Both interhemispheric directions were tested. Interhemispheric latencies of the two main reproducible TEPs, the positive component at 60 ms and the negative component at 100 ms (P60 and N100, respectively), were expected to be significantly prolonged in MS-patients compared to healthy volunteers.
Material and methods: The study compared interhemispheric propagation of P60 and N100 in groups of 12 patients with early-stage relapsing-remitting MS (RRMS) and 16 age- and gender-matched healthy controls. The study was approved by the Ethics Committee of the Medical Faculty of the Goethe-University of Frankfurt/Main and conformed to the latest revision of the Declaration of Helsinki of 2008. TEPs were recorded by means of EEG and their latencies were statistically evaluated in 10 channels around the stimulation site and in 10 corresponding electrodes in the non-stimulated contralateral hemisphere. Interhemispheric conduction time was calculated by the difference of TEP latency in non-stimulated vs. stimulated hemisphere.
Results: An ANOVA on interhemispheric conduction time showed a significant prolongation for the N100 from left to right hemisphere in MS compared to controls, while no group differences were found for the P60 and the N100 from right to left hemisphere.
Conclusion: The results provide first evidence that the N100 may constitute an interesting marker to measure interhemispheric conduction delays in early-stage RRMS. The specificity of the present finding and its relation to fiber tract pathology should be examined in further correlative analyses with diffusion tensor imaging and other structural MRI data.
Background: Exercise seems to minimize prostate cancer specific mortality risk and treatment related side effects like fatigue and incontinence. However the influence of physical activity on the immunological level remains uncertain. Even prostate cancer patients undergoing palliative treatment often have a relatively long life span compared to other cancer entities. To optimize exercise programs and their outcomes it is essential to investigate the underlying mechanisms. Further, it is important to discriminate between different exercise protocols and therapy regimes.
Methods/Design: The ProImmun study is a prospective multicenter patient preference randomized controlled trial investigating the influence of a 24 week endurance exercise program in 80–100 prostate cancer patients by comparing patients undergoing Antiandrogen therapy combined with exercise (AE), Antiandrogen therapy without exercise (A), Chemotherapy with exercise(CE) or Chemotherapy without exercise (C). The primary outcome of the study is a change in prostate cancer relevant cytokines and hormones (IL-6, MIF, IGF-1, Testosterone). Secondary endpoints are immune cell ratios, oxidative stress and antioxidative capacity levels, VO2 peak, fatigue and quality of life. Patients of the intervention group exercise five times per week, while two sessions are supervised. During the supervised sessions patients (AE and CE) exercise for 33 minutes on a bicycle ergometer at 70-75% of their VO2 peak. To assess long term effects and sustainability of the intervention two follow-up assessments are arranged 12 and 18 month after the intervention.
Discussion: The ProImmun study is the first trial which primarily investigates immunological effects of a six month endurance exercise program in prostate cancer patients during palliative care. Separating patients treated with Antiandrogen therapy from those who are additionally treated with Chemotherapy might allow a more specific view on the influence of endurance training interventions and the impact of different therapy protocols on the immune function.
Trial registration: German Clinical Trials Register: DRKS00004739
Poster presentation: 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)
Significant progress has been made over the last decade towards realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells, and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also continuously expanding cytotoxic cell lines such as NK-92 are being considered for adoptive cancer immunotherapy. High cytotoxicity of NK-92 has previously been shown against malignant cells of hematologic origin in preclinical studies, and general safety of infusion of NK-92 cells has been established in phase I clinical trials. To enhance their therapeutic utility, we genetically modified NK-92 cells to express chimeric antigen receptors (CAR) specific for tumor-associated surface antigens. Such CAR were composed of a tumor-specific scFv antibody fragment fused via hinge and transmembrane domains to intracellular signaling moieties such as CD3 zeta chain, or composite fusion molecules also containing a costimulatory protein domain in addition to CD3 zeta. For development towards clinical applications, here a codon-optimized second generation CAR was constructed that consists of an ErbB2-specific scFv antibody domain fused via a linker to a composite CD28-CD3 zeta signaling domain. GMP-compliant protocols for vector production, lentiviral transduction and expansion of a genetically modified NK-92 single cell clone (NK-92/5.28.z) were established. Functional analysis of NK-92/5.28.z cells revealed high and stable CAR expression, selective cytotoxicity against ErbB2-expressing but otherwise NK-resistant tumor cells of different origins in vitro, as well as homing to ErbB2-expressing tumors in vivo. Furthermore, antigen specificity and selective cytotoxicity of these cells were retained in vivo, resulting in antitumoral activity against subcutaneous and intracranial glioblastoma xenografts in NSG mice. Ongoing work now focuses on the development of these cells for adoptive immunotherapy of ErbB2-positive glioblastoma.
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
"PULS." – a blog-based online-magazine for students of medicine of the Goethe University Frankfurt
(2013)
In the context of nationwide protests 2009 also students of the faculty of medicine/dentistry at Goethe-University in Frankfurt demanded more transparency and communication. To satisfy these demands, a web 2.0-tool offered an innovative solution: A blog-based online-magazine for students and other faculty-members. The online-magazine "PULS." is realized with the share-ware blog-software (wordpress version 3.1.3) and is conceived and written by an online-journalist. "PULS." is available from https://newsmagazin.puls.med.uni-frankfurt.de/wp/. The articles are generated from own investigations and from ideas of different groups of the faculty– deanship, students and lecturers. A user-analysis is conducted with the open-source software Piwik and considers the data security. Additionally, every year an anonymous online-user-survey (Survey Monkey) is conducted. "PULS." is continuously online since 14.02.2010 and has published 806 articles (state: 27.11.2012) and has about 2400 readers monthly. The content focuses on the needs of Frankfurt medical students. The close cooperation with different groups of the faculty - deanship, students and lecturers - furthermore guarantees themes relevant to the academic faculty. "PULS." flanks complex projects and decisions with background-information and communicates them understandable. The user-evaluation shows a growing number of readers and a high acceptance for the online-magazine, its themes and its style. The web 2.0-tool "Blog" and the web-specific language comply with media habits of the main target group, the students of the faculty medicine/dentistry. Thus, "PULS." has proven as a suitable and strategic instrument. It pushes towards a higher transparency, more communication and a stronger identification of the students with their faculty.
"PULS." - Ein Blog als Online-Magazin für Medizinstudierende der Goethe-Universität Frankfurt
(2013)
Im Herbst 2009 forderten Studierende im Rahmen landesweiter Proteste auch am Fachbereich Medizin/Zahnmedizin der Goethe-Universität Frankfurt mehr Transparenz und Kommunikation zu Angelegenheiten ihres Studiums. Einen innovativen Lösungsansatz, um diesen Forderungen nachzukommen, bietet eines der Web 2.0 Werkzeuge: ein auf einer Blog-Software basierendes Online-Magazin für Studierende und andere Mitglieder des Fachbereichs.
Das öffentlich zugängliche Online-Magazin "PULS." (https://newsmagazin.puls.med.uni-frankfurt.de/wp/) wird mit einer freien Blog-Software (wordpress Version 3.1.3.) realisiert und von einer Online-Redakteurin konzipiert und geschrieben. Die Beiträge entstehen nach eigenen Recherchen sowie aus Anregungen und Gesprächen mit verschiedenen Personengruppen des Fachbereichs. Die datenschutzkonforme Auswertung der Zugriffe erfolgt über eine open-source Webanalyse-Software (Piwik). Zusätzlich werden jährlich mit dem Online-Umfrage-Tool Survey Monkey die Nutzer anonym befragt.
"PULS." ist seit dem 14.02.2010 ununterbrochen online und hat seitdem 806 Beiträge (Stand: 27.11.2012) publiziert und wird von ca. 2400 Besuchern monatlich gelesen. Das Themenspektrum ist zentriert auf die Anliegen der Frankfurter Medizin- und Zahnmedizinstudierenden. Die enge Zusammenarbeit mit verschiedenen Gruppierungen des Fachbereichs – Dekanat, Studierende und Lehrende – garantiert darüber hinaus ein fachbereichs-relevantes Themenspektrum. Das Online-Magazin begleitet komplexe Projekte und Entscheidungen mit Hintergrundinformationen und kommuniziert sie verständlich. Eine jährliche Nutzer-Evaluierung zeigt eine wachsende Leserzahl und eine sehr hohe Zustimmung für das Online-Magazin, seine Inhalte und seinen Stil. Das Web 2.0-Medium "Blog" und seine web-typische Sprache entsprechen dem Medienverhalten der Zielgruppe, d.h. den Studierenden des Fachbereichs Medizin.
"PULS." hat sich als ein geeignetes und strategisches Instrument erwiesen, um größere Transparenz, mehr Kommunikation und letztendlich eine stärkere Identifikation der Studierenden mit ihrem Fachbereich voranzutreiben.
Medizinstudium, Examina und die Berufstätigkeit sind stressig; belastbare Daten zum allgemeinen und spezifischen Stress während des Medizinstudiums liegen nur in geringem Ausmaß vor. Wir haben die Stressbelastung und Resilienz der Frankfurter Medizinstudenten in den Kohorten 1. vorklinisches Semester, 1. klinisches Semester und PJ-Eintritt erhoben (Trierer Inventar zum chronischen Stress TICS, altersnormierter Mittelwert = 50; Resilienz-Skala RS11, kein Optimum, hohe Werte weisen auf Resilienz hin); an der Studie nahmen jeweils mehr als 90% der entsprechenden Kohorte teil. Während zu Studienbeginn der Summenwert (altersnormierter T-Wert) bei 56% lag, fiel dieser im 1. klin. Semester auf 54%, und stieg zum PJ nur gering wieder an. Unter den Subskalen fiel auf, dass Überlastung, Überforderung und chronische Besorgnis parallel zum Gesamtscore abfielen, die Subskala Unzufriedenheit jedoch zunahm (1. vorklin. Semester 53%, 1. klin. Semester 55%, PJ 58%). Die höchsten Werte in der PJ-Gruppe fanden sich ebenfalls für die Subskalen soziale Überlastung, Mangel an sozialer Anerkennung und Soziale Spannungen. Niedrigere Stressskala-Werte zeigten sich nach dem Staatsexamen M1 in den Subskalen Überlastung, Erfolgsdruck, Überforderung, soziale Isolierung, chronische Besorgnis und dem Summenscore. Überraschenderweise fiel der Summenwert der Resilienz vom 1. vorklinischen und 1. klinischen Semester (80,7%) auf 76,7% vor dem PJ-Eintritt, dieser Abfall zeigte sich für alle 11 Einzelitems dieses Fragebogens in gleicher Weise. Während eine Abnahme der Belastungsabhängigen Skalen Überlastung und Überforderung nach dem Staatsexamen M1 erwartet worden war, überraschte die im Gruppenvergleich abnehmende Resilienz bei den Studenten vor dem Praktischen Jahr. Ebenso überraschend war die fast kontinuierliche Zunahme auf der Subskala Unzufriedenheit während des Studiums. Inwieweit diese Differenzen auf das Studium zurückzuführen sind oder auf eine überzufällige Häufung bei den Studienabbrechern, wird in einer prospektiven Fortführung dieser Studie untersucht.
Network or graph theory has become a popular tool to represent and analyze large-scale interaction patterns in the brain. To derive a functional network representation from experimentally recorded neural time series one has to identify the structure of the interactions between these time series. In neuroscience, this is often done by pairwise bivariate analysis because a fully multivariate treatment is typically not possible due to limited data and excessive computational cost. Furthermore, a true multivariate analysis would consist of the analysis of the combined effects, including information theoretic synergies and redundancies, of all possible subsets of network components. Since the number of these subsets is the power set of the network components, this leads to a combinatorial explosion (i.e. a problem that is computationally intractable). In contrast, a pairwise bivariate analysis of interactions is typically feasible but introduces the possibility of false detection of spurious interactions between network components, especially due to cascade and common drive effects. These spurious connections in a network representation may introduce a bias to subsequently computed graph theoretical measures (e.g. clustering coefficient or centrality) as these measures depend on the reliability of the graph representation from which they are computed. Strictly speaking, graph theoretical measures are meaningful only if the underlying graph structure can be guaranteed to consist of one type of connections only, i.e. connections in the graph are guaranteed to be non-spurious. ...
Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.
Background: Candida spp. are a frequent cause of nosocomial bloodstream infections worldwide.
Objective: To evaluate the use patterns and outcomes associated with intravenous (IV) fluconazole therapy in intensive care units in Spain and Germany.
Patients and methods: The research reported here was a prospective multicenter longitudinal observational study in adult intensive care unit patients receiving IV fluconazole. Demographic, microbiologic, therapy success, length of hospital stay, adverse event, and all-cause mortality data were collected at 14 sites in Spain and five in Germany, from February 2004 to November 2005.
Results: Patients (n = 303) received prophylaxis (n = 29), empiric therapy (n = 140), preemptive therapy (n = 85), or definitive therapy (n = 49). A total of 298 patients (98.4%) were treated with IV fluconazole as first-line therapy. The treating physicians judged therapy successful in 66% of prophylactic, 55% of empiric, 45% of preemptive, and 43% of definitive group patients. In the subgroup of 152 patients with proven and specified Candida infection only, 32% suffered from Candida specified as potentially resistant to IV fluconazole. The overall mortality rate was 42%.
Conclusion: Our study informs treatment decision makers that approximately 32% of the patients with microbiological results available suffered from Candida specified as potentially resistant to IV fluconazole, highlighting the importance of appropriate therapy.