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The E3 ubiquitin ligase MYCBP2 negatively regulates neuronal growth, synaptogenesis, and synaptic strength. More recently it was shown that MYCBP2 is also involved in receptor and ion channel internalization. We found that mice with a MYCBP2-deficiency in peripheral sensory neurons show prolonged thermal hyperalgesia. Loss of MYCBP2 constitutively activated p38 MAPK and increased expression of several proteins involved in receptor trafficking. Surprisingly, loss of MYCBP2 inhibited internalization of transient receptor potential vanilloid receptor 1 (TRPV1) and prevented desensitization of capsaicin-induced calcium increases. Lack of desensitization, TRPV internalization and prolonged hyperalgesia were reversed by inhibition of p38 MAPK. The effects were TRPV-specific, since neither mustard oil-induced desensitization nor behavioral responses to mechanical stimuli were affected. In summary, we show here for the first time that p38 MAPK activation can inhibit activity-induced ion channel internalization and that MYCBP2 regulates internalization of TRPV1 in peripheral sensory neurons as well as duration of thermal hyperalgesia through p38 MAPK.
Background: Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer.
Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer.
Methods: Acutely-ill, non-surgical patients ≥70 years with (n = 274) or without cancer (n = 2,965) received certoparin 3,000 UaXa o.d. or UFH 5,000 IU t.i.d. for 8-20 days.
Results: 1) Thromboembolic events in cancer patients (proximal DVT, symptomatic non-fatal PE and VTE-related death) occurred at 4.50% with certoparin and 6.03% with UFH (OR 0.73; 95% CI 0.23-2.39). Major bleeding was comparable and minor bleedings (0.75 vs. 5.67%) were nominally less frequent. 7.5% of certoparin and 12.8% of UFH treated patients experienced serious adverse events. 2) Thromboembolic event rates were comparable in patients with or without cancer (5.29 vs. 4.13%) as were bleeding complications. All cause death was increased in cancer (OR 2.68; 95%CI 1.22-5.86). 10.2% of patients with and 5.81% of those without cancer experienced serious adverse events (OR 1.85; 95% CI 1.21-2.81).
Conclusions: Certoparin 3,000 UaXa o.d. and 5,000 IU UFH t.i.d. were equally effective and safe with respect to bleeding complications in patients with cancer. There were no statistically significant differences in the risk of thromboembolic events in patients with or without cancer receiving adequate anticoagulation.
Trial Registration: clinicaltrials.gov, NCT00451412
Event-related potentials (ERPs) are widely used in basic neuroscience and in clinical diagnostic procedures. In contrast, neurophysiological insights from ERPs have been limited, as several different mechanisms lead to ERPs. Apart from stereotypically repeated responses (additive evoked responses), these mechanisms are asymmetric amplitude modulations and phase-resetting of ongoing oscillatory activity. Therefore, a method is needed that differentiates between these mechanisms and moreover quantifies the stability of a response. We propose a constrained subspace independent component analysis that exploits the multivariate information present in the all-to-all relationship of recordings over trials. Our method identifies additive evoked activity and quantifies its stability over trials. We evaluate identification performance for biologically plausible simulation data and two neurophysiological test cases: Local field potential (LFP) recordings from a visuo-motor-integration task in the awake behaving macaque and magnetoencephalography (MEG) recordings of steady-state visual evoked fields (SSVEFs). In the LFPs we find additive evoked response contributions in visual areas V2/4 but not in primary motor cortex A4, although visually triggered ERPs were also observed in area A4. MEG-SSVEFs were mainly created by additive evoked response contributions. Our results demonstrate that the identification of additive evoked response contributions is possible both in invasive and in non-invasive electrophysiological recordings.
IL-22 is an immunoregulatory cytokine displaying pathological functions in models of autoimmunity like experimental psoriasis. Understanding molecular mechanisms driving IL-22, together with knowledge on the capacity of current immunosuppressive drugs to target this process, may open an avenue to novel therapeutic options. Here, we sought to characterize regulation of human IL22 gene expression with focus on the established model of Jurkat T cells. Moreover, effects of the prototypic immunosuppressant cyclosporin A (CsA) were investigated. We report that IL-22 induction by TPA/A23187 (T/A) or αCD3 is inhibited by CsA or related FK506. Similar data were obtained with peripheral blood mononuclear cells or purified CD3(+) T cells. IL22 promoter analysis (-1074 to +156 bp) revealed a role of an NF-AT (-95/-91 nt) and a CREB (-194/-190 nt) binding site for gene induction. Indeed, binding of CREB and NF-ATc2, but not c-Rel, under the influence of T/A to those elements could be proven by ChIP. Because CsA has the capability to impair IκB kinase (IKK) complex activation, the IKKα/β inhibitor IKKVII was evaluated. IKKVII likewise reduced IL-22 induction in Jurkat cells and peripheral blood mononuclear cells. Interestingly, transfection of Jurkat cells with siRNA directed against IKKα impaired IL22 gene expression. Data presented suggest that NF-AT, CREB, and IKKα contribute to rapid IL22 gene induction. In particular the crucial role of NF-AT detected herein may form the basis of direct action of CsA on IL-22 expression by T cells, which may contribute to therapeutic efficacy of the drug in autoimmunity.
Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. Protective IL28B variations are strongly associated with on-treatment viral kinetics and approximately 2-fold increased sustained virologic response (SVR) rates in HCV genotype 1 and 4 patients. In HCV genotype 1 patients, IL28B variations were shown to be the strongest pre-treatment predictor of virologic response. In the treatment of HCV genotype 2 and 3 infected patients, IL28B variations play only a minor role. Preliminary data indicate that IL28B variations are also associated with treatment outcome of regimens, including directly acting antiviral (DAA) agents, though their impact seems to be attenuated compared to standard treatment. Here, we review these important findings and discuss possible implications for clinical decision making in the treatment of HCV infection.
Nosocomial infectious diseases (e.g. influenza, pertussis) are a threat particularly for immunocompromised and vulnerable patients. Although vaccination of healthcare workers (HCWs) constitutes the most convenient and effective means to prevent nosocomial transmissions, vaccine uptake among HCWs remains unacceptably low. Worldwide, numerous studies have demonstrated that nurses have lower vaccination rates than physicians and that there is a relationship between receipt of vaccination by HCWs and knowledge. Measures to improve vaccination rates need to be profession-sensitive as well as specific in their approach in order to achieve sustained success.
Herb induced liver injury (HILI) is a particular challenge that also applies to purported cases presumably caused by black cohosh (BC), an herb commonly used to treat menopausal symptoms. We analyzed and reviewed all published case reports and spontaneous reports of initially alleged BC hepatotoxicity regarding quality of case details and causality assessments. Shortcomings of data quality were more evident in spontaneous reports of regulatory agencies compared to published case reports, but assessments with the scale of CIOMS (Council for the International Organizations of Sciences) or its updated version revealed lack of causality for BC in all cases. The applied causality methods are structured, quantitative, and liver specific with clear preference over an ad hoc causality method or the liver unspecific Naranjo scale. Reviewing the case data and the reports dealing with quality specifications of herbal BC products, there is general lack of analysis with respect to authentication of BC in the BC products used by the patients. However, in one single regulatory study, there was a problem of BC authentication in the analysed BC products, and other reports addressed the question of impurities and adulterants in a few BC products. It is concluded that the use of BC may not exert an overt hepatotoxicity risk, but quality problems in a few BC products were evident that require additional regulatory quality specifications.
Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) κB is required for Smac mimetic– mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-κB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-κB by overexpression of the dominant-negative IκBα superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-κB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor α (TNFα) by the TNFα blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-κB–dependent, TNFα-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic–based combination protocols in the treatment of pancreatic cancer.
Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.
Die kutane Wundheilung hat die funktionelle Wiederherstellung der Gewebeintegrität nach Schädigung zum Ziel. Sie erfolgt im Sinne einer gesteuerten Kaskade von sequentiellen Ereignissen. Diese umfassen die Hämostase, die Inflammation, die Granulation, die Reepithelialisierung und das Remodeling. Die zugrundeliegenden Prozesse werden von einer Vielzahl proinflammatorischer Zytokine und Wachstumsfaktoren reguliert. Neben diesen Proteinmediatoren ist eine Beteiligung löslicher Kleinmoleküle, wie dem Stickstoffmonoxid (NO), für die Regulation der Wundheilung bekannt.
NO ist ein flüchtiges Radikal, welches enzymatisch durch die Isoformen der Stickstoffmonoxidsynthasen (NOS) aus der Aminosäure L-Arginin synthetisiert wird. NO entfaltet ein breites Spektrum physiologischer und pathophysiologischer Effekte. Dabei ist für die induzierbare NOS (iNOS) eine relevante Beteiligung an epithelialen Prozessen hinreichend dokumentiert. FRANK et al. [1998] konnten eine starke Induktion der iNOS während der kutanen Wundheilung sowie einen funktionellen Zusammenhang zu den NO-Wirkungen auf Keratinozyten zeigen, die in Verbindung mit der enzymatischen Funktion der iNOS stehen.
Eine gestörte kutane Wundheilung wurde auch für Mäuse mit Defizienz der endothelialen NOS (eNOS) beschrieben. Die Beteiligung der eNOS an der Wundheilung war bislang jedoch weitgehend unklar. Die vorliegende Arbeit hatte zum Ziel, die Expressionsmuster der eNOS im Wundheilungsverlauf in gesunden und diabetischen Mäusen aufzuzeigen.
In einem kutanen Wundheilungsmodell in Mäusen konnte die Expression von eNOS mRNA und Protein gezeigt werden. Die Expressionskinetik zeigte eine moderate Induktion der eNOS in den frühen Wundheilungsphasen. Diese ließ sich nicht mit einer endothelialen Expressionsänderung erklären, wie es Untersuchungen mit CD31 als pan-endothelialem Marker nahe legten.
Immunhistochemisch konnten Gefäßendothelien des Granulationsgewebes, Keratinozyten der Wundränder, das sich ausbildende Neo-Epithel und Haarfollikel als zusätzliche Quellen der eNOS Proteinexpression in Wunden identifiziert werden. Die eNOS Färbung zeigte sich dabei begrenzt auf die suprabasal gelegenen Keratinozyten der benannten Epithelien. Die Expression der eNOS in Keratinozyten konnte schließlich auch in kultivierten primären humanen Keratinozyten und HaCaT Keratinozyten auf mRNA-Ebene bestätigt werden.
Darüber hinaus zeigte sich ein funktioneller Zusammenhang zwischen eNOS Expression und epithelialer Proliferation: So bildeten eNOS-defiziente Mäuse deutlich reduzierte Wundrandepithelien aus, die durch eine verminderte Proliferation der Keratinozyten charakterisiert waren. Untersuchungen an diabetischen Mäusen (db/db) stützten diesen funktionellen Zusammenhang. In den Expressionskinetiken in diabetischen Tieren zeigte sich eine deutlich reduzierte Expression von eNOS mRNA und Protein vor allem in den späten Wundheilungsphasen.
In der vorliegenden Arbeit werden die zeitliche Expression der eNOS, die Detektion der eNOS in Wunden sowie deren Alteration in diabetischen Mäusen mit Bezug auf ihre funktionelle Bedeutung in der kutanen Wundheilung abschließend diskutiert.
Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim.
Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago.
Results: During hospitalization, the platelet count was measured above 330,000/μl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved.
Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.
Seroconversion rates following influenza vaccination in patients with hematologic malignancies after hematopoietic stem cell transplantation (HSCT) are known to be lower compared to healthy adults. The aim of our diagnostic study was to determine the rate of seroconversion after 1 or 2 doses of a novel split virion, inactivated, AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HSCT recipients (ClinicalTrials.gov Identifier: NCT01017172). Blood samples were taken before and 21 days after a first dose and 21 days after a second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer of ≤1:10 before and ≥1:40 after or ≥1:10 before and ≥4-fold increase in AB titer 21 days after vaccination. Seventeen patients (14 allogeneic, 3 autologous HSCT) received 1 dose and 11 of these patients 2 doses of the vaccine. The rate of seroconversion was 41.2% (95% confidence interval [CI] 18.4-67.1) after the first and 81.8% (95% CI 48.2-97.7) after the second dose. Patients who failed to seroconvert after 1 dose of the vaccine were more likely to receive any immunosuppressive agent (P = .003), but time elapsed after or type of HSCT, age, sex, or chronic graft-versus-host disease was not different when compared to patients with seroconversion. In patients with hematologic malignancies after HSCT the rate of seroconversion after a first dose of an adjuvanted H1N1 influenza A vaccine was poor, but increased after a second dose.
Das Buch "Qualitative Evaluation" zeigt Schritt für Schritt die Vorgehensweise und stellt damit in sehr anwendungsorientierter Form das Handwerkszeug für eine qualitative Evaluation zur Verfügung. So werden Lesende in die Lage versetzt, eine solche Evaluation auch bei geringen Vorkenntnissen durchzuführen, wobei damit das Risiko verbunden sein kann, dass bei der Interpretation der Befunde wichtige Voraussetzungen für das Gelingen einer qualitativen Studie wie Verwurzelung der Interpretation im tatsächlich aufgezeichneten Text vernachlässigt werden.
Osteoid osteoma is a benign bone tumor of undetermined etiology, composed of a central zone named nidus which is an atypical bone completely enclosed within a wellvascularized stroma and a peripheral sclerotic reaction zone. There are three types of radiographic features: cortical, medullary and subperiosteal. Forty-four patients with osteoid osteoma were studied retrospectively. In plain films, 35 patients presented as the cortical type, six cases were located in the medullary zone and three had subperiosteal osteoid osteoma. In all the cases, the nidus was visualized on computed tomography (CT) scan. The nidus was visible in four out of five patients who had also undergone magnetic resonance imaging (MRI). Double-density sign, seen on radionuclide bone scans was positive in all patients. MRI is more sensitive in the diagnosis of bone marrow and soft tissue abnormalities adjacent to the lesion, and in the nidus that is located closer to the medullary zone. On the other hand, CT is more specific when it comes to detecting the lesion’s nidus.
Während des Zellzykluses werden spezifische regulatorische Proteine, die Cycline exprimiert, die mit ihren spezifischen CDK (Cyclin Dependent Kinases) interagieren und sie hierdurch aktivieren. So interagiert in der frühen G1 Phase Cyclin D1 mit CDK4 und CDK6. Die D-Cyclin kontrollieren gemeinsam mit Cyclin E den G1 Restriktionspunkt. Rb wird durch diese D-Cycline und die assoziierten Kinasen CDK4/6 mehrfach phosphoryliert und kann nun Transkriptionsfaktoren wie E2F nicht mehr inhibieren und die nun freie E2F/ DP-Untereinheit ( = DNS-Bindungsprotein) kann Promotoraktivierung vermitteln und Gene aktivieren, die die S-Phase einleiten. Hiermit wird der Zelle der Fortschritt durch den Zellzyklus ermöglicht bis Rb gegen Ende des Zellzyklus durch Phosphatasen dephoshoryliert wird und die aus der Mitose hervorgegangenen Tochterzellen nach Ende der M-Phase erneut in der G1-Phase sind. CDK-Inhibitoren (CDKI) können diese Cyclin/CDK Komplexe in jeder Zellzyklusphase hemmen und Zellzyklusarrest auslösen. In der vorliegenden Arbeit sollte die Expression von Cyclin D1 und Retinoblastomgens immunhistochemisch untersucht werden. Es wurde versucht, mit der Avidin-Biotin-Enzymkomplexmethode die Proteinexpression des Retinoblastomgens mit einem monoklonalem Antikörper in Probeexzisionen von Mammakarzinomen der Jahre 1983 bis 1987 dazustellen, die in Paraffinum eingebettet waren. Trotz vielfacher Versuchswiederholungen gelang es nicht, eine Kernfärbung hervorzubringen, die wissenschaftlichem Standard genügte. Zum damaligen Zeitpunkt stand noch nicht viel know-how bezüglich der Kernfärbung mittels Antikörpern zur Verfügung. Vor allem nicht bei Präparaten, die bis zu 15 Jahre in Paraffinum eingebetet waren. Somit konnte eine verwertbare Kernfärbung der Gewebeschnitte, das Retinoblastomgen betreffend, nicht nachgewiesen werden und damit war es bedauerlicherweise auch nicht möglich, eine Korrelation zwischen Cyclin D1 und Retinoblastomgen im Mammakarzinom nachzuweisen. Bei der nun verbliebenen Analyse des Cyclin D1 wiesen von 198 Tumoren 10,6% (21 Präparate) eine positive Kernfärbung auf. Hierbei wurden die Präparate, die bei der lichtmikroskopischen Beurteilung der immunhistochemisch gefärbten Zellen einen Prozentsatz von 10% oder größer aufwiesen, wurden als positiv gewertet.13 von den 198 Tumoren zeigten eine Färbbarkeit zwischen 1%-10% auf und wurden per definitionem als negativ gewertet. Hieraus folgt, dass bei 164 Tumoren überhaupt keine Zellkernfärbung stattfand. Es zeigte sich, dass aufgrund der niedrigen positiven Fallzahlen nur schwer eine statische Signifikanz erreichbar sein würde. Das spiegelte unter anderem die Korrelation mit dem Menopausenstatus wieder, die einen p-Wert von 0,273 aufwies und sich hiermit einer statistischen Signifikanz entzog. Auch beim Vergleich von Cyclin D1 mit dem Ostrogen/Progesteron- Rezeptorstatus ist ein verwertbares Ergebnis nicht erreichbar (p=0,08) Eine prognostische Signifikanz des TNM-Stagings konnte bei T:p= 0,496; N:p=0,052 und M:p=0,720 nicht bestätigt werden. Zwar zeigte sich bei der Cyclin D1-Expression der Lymphknoten primär ein grenzwertig positiver Wert von p=0,047. Dieser wurde jedoch durch den kontrollierenden Fisher Exact-Test nicht bestätigt (p=0,052). Ebenfalls konnte keine signifikante Beziehung zum histologischen Tumortyp (p=0,553) und zum Differenzierungsgrad (p=0,575) nachgewiesen werden. Bei den Kaplan-Meier-Analysen in Bezug auf das rezidivfreie Intervall
(p=0,934), das metastasenfreie Intervall (p=0,386) sowie das krankheitsfreie Intervall (p=0,709), konnte kein signifikanter Parameter erhoben werden. Der Einfluss von Cyclin D1 auf das Gesamtüberleben spiegelt letztendlich auch keinen signifikanten Zusammenhang wider (p=0,830). Insgesamt zeigte sich bei keinem Parameter ein signifikanter Bezug. Dies ist wohl, wie auch bei der Versuchsreihe mit dem Retinoblastom, bei dem es ja zu überhaupt keiner verwertbaren Kernfärbung kam, auf das Alter der Probeexcisionen und der damals noch in Entwicklung befindlichen Verfahren zu erklären. Wobei hier nur gemutmaßt werden kann. Eine etablierte Methode jedoch, stand noch nicht zur Verfügung. In den letzten Jahren ist zunehmend wenig Augenmerk dem Gebiet der Cycline und des Retinoblastomgens, besonders im Hinblick auf das Mammakarzinom, gelegt worden. Vielleicht lässt sich mit den jetzigen etablierten Methoden eine Renaissance dieser interessanten Forschungsrichtung erwecken.
Jahresbericht 2010 / Fachbereich Medizin und Klinikum der Goethe-Universität Frankfurt am Main
(2011)
This case study evaluated the response of objective and subjective markers of overreaching to a highly demanding conditioning training mesocycle in elite tennis players to determine 1) whether players would become functionally or non-functionally overreached, and 2) to explore how coherently overreaching markers would respond. Performance, laboratory and cardiac autonomous activity markers were evaluated in three experienced male tennis professionals competing at top 30, top 100 and top 1000 level before and after their strength and conditioning training was increased by 120, 160 and 180%, respectively, for 30 days. Every week, subjective ratings of stress and recovery were evaluated by means of a questionnaire. After 74, 76 and 55 h of training, increases in V̇O2max (+8, +5 and +18%) and speed strength indices (+9, +23 and +5%) were observed in all players. Changes of maximal heart rate (-5, -6, +4 beats per minute), laboratory markers (e.g. insulin-like growth factor -26, -17, -9%; free testosterone to cortisol ratio -63, +2, -12%) and cardiac autonomous activity markers (heart rate variability -49, -64, -13%) were variable among the players. Improved performance provides evidence that overreaching was functional in all players. However, several overreaching markers were altered and these alterations were more pronounced in the two top 100 players. The response of overreaching indicators was not coherent.
Im Jahre 2004 sind am Universitätsklinikum Frankfurt zwei Patienten mit X-CGD gentherapeutisch behandelt worden. Nach einer initialen Phase mit Nachweis ausreichender Mengen Oxidase-positiver Zellen im Blut der Patienten und einer deutlichen klinischen Besserung vorbestehender Infektionsherde kam es zu einem Verlust der Transgenexpression durch epigenetische Veränderungen des viralen Promotors. Ferner entwickelte sich durch Insertionsmutagenese eine klonale Expansion in der Hämatopoese und schließlich ein myelodysplastisches Syndrom mit Monosomie 7 bei beiden Patienten. In der Zusammenschau mit anderen Gentherapiestudien zur X-CGD zeigt sich, dass bislang ein langanhaltendes Engraftment funktionierender genkorrigierter Zellen nur im Zusammenhang mit einer Insertionsmutagenese beobachtet wurde. Zukünftige gentherapeutische Strategien zur Behandlung der X-CGD müssen das Risiko einer Insertionsmutagenese minimieren und gleichzeitig die Effektivität des Engraftments genkorrigierter Zellen steigern. Dies soll durch den Einsatz von SIN-Vektoren sowie einer Intensivierung der Konditionierung der Patienten erreicht werden.
PURPOSE: This study investigates the distortion of geometry of catheters and anatomy in acquired U/S images, caused by utilizing various stand-off materials for covering a transrectal bi-planar ultrasound probe in HDR and LDR prostate brachytherapy, biopsy and other interventional procedures. Furthermore, an evaluation of currently established water-bath based quality assurance (QA) procedures is presented.
MATERIAL AND METHODS: Image acquisitions of an ultrasound QA setup were carried out at 5 MHz and 7 MHz. The U/S probe was covered by EA 4015 Silicone Standoff kit, or UA0059 Endocavity balloon filled either with water or one of the following: 40 ml of Endosgel(®), Instillagel(®), Ultraschall gel or Space OAR™ gel. The differences between images were recorded. Consequently, the dosimetric impact of the observed image distortion was investigated, using a tissue equivalent ultrasound prostate phantom - Model number 053 (CIRS Inc., Norfolk, VA, USA).
RESULTS: By using the EA 4015 Silicone Standoff kit in normal water with sound speed of 1525 m/s, a 3 mm needle shift was observed. The expansion of objects appeared in radial direction. The shift deforms also the PTV (prostate in our case) and other organs at risk (OARs) in the same way leading to overestimation of volume and underestimation of the dose. On the other hand, Instillagel(®) and Space OAR™ "shrinks" objects in an ultrasound image for 0.65 mm and 0.40 mm, respectively.
CONCLUSIONS: The use of EA 4015 Silicone Standoff kit for image acquisition, leads to erroneous contouring of PTV and OARs and reconstruction and placement of catheters, which results to incorrect dose calculation during prostate brachytherapy. Moreover, the reliability of QA procedures lies mostly in the right temperature of the water used for accurate simulation of real conditions of transrectal ultrasound imaging.
High grade gliomas, including anaplastic glioma WHO grade III and glioblastoma WHO IV (GBM), carry a dismal prognosis. Taking all nowadays-available therapeutics options, including radiation, chemotherapy and surgery, for GBM into consideration the prognosis after initial diagnosis is about 12 month. Despite this bad prognosis, researchers gained a tremendous insight into the molecular and genetic signatures of low and high grade gliomas. Several different subtypes of GBM were demonstrated with respect to their genetic background. These genetic alterations include p53 mutation in secondary GBMs and EGFR amplification in primary GBMs, respectively. Very recently, great excitement was raised after the discovery of IDH1 mutation in low-grade gliomas and secondary GBMs. This discovery is of great significance since it allows further categorizing of GBMs and is helpful in distinguishing low-grade gliomas from non-neoplastic adjacent brain tissue. Despite all this progress there is an urgent need for fresh additional therapeutic strategies. In addition to the identification of novel therapeutic regimens it is of utmost importance to gain an understanding about the molecular mechanisms on how GBMs manage to evade from almost any anti-cancer treatment regimen. In experimental models of glioblastoma there are a number of novel therapeutic regimens that exhibited promising results. These novel therapeutics include, but are not limited to: Apoptosis-based therapeutics (Tumor necrosis factor alpha related apoptosis inducing ligand, TRAIL), tyrosinkinase-inhibitors, Heat-shock-protein 90 (HSP90) inhibitors, polyphenols, novel drug combinations and intracranial application based strategies. This chapter will primarily review and focus on molecular mechanisms of resistance in GBM and rising new therapeutic venues for high-grade gliomas. High-grade gliomas are a group of primary heterogenous tumors of which glioblastoma World Health Organisation, WHO IV (GBM), is the most common one. Once the diagnosis of GBM is made, the average survival time is approximately 12-15 month (Hegi, Diserens et al., 2005). Treatment usually consists of temozolomide (commonly used chemotherapeutic drug for the treatment of GBM, TMZ), radiation (either alone or in combination with chemotherapeutics) and surgery (Hegi, Diserens et al., 2005)...
Application of the liposuction techniques and principles in specific body areas and pathologies
(2011)
The buttocks have been a symbol of attraction, sexuality and eroticism since ancient times and therefore, they have an important role in defining the posterior body contour. More and more people are talking about and understand the meaning and the role that buttocks play in modeling and physical beauty. The three dimensional gluteoplasty (3-DGP) is an innovative technique that allows us to change volume, shape and firmness, not only in the buttocks but also in the adjacent regions such as the thighs and trochanters, becoming an ideal tool to answer the frequent reasons of consultation of our patients about this particular area of the body: ...
There are many tools available that are used to evaluate a radiotherapy treatment plan, such as isodose distribution charts, dose volume histograms (DVH), maximum, minimum and mean doses of the dose distributions as well as DVH point dose constraints. All the already mentioned evaluation tools are dosimetric only without taking into account the radiobiological characteristics of tumors or OARs. It has been demonstrated that although competing treatment plans might have similar mean, maximum or minimum doses they may have significantly different clinical outcomes (Mavroidis et al. 2001). For performing a more complete treatment plan evaluation and comparison the complication-free tumor control probability (P+) and the biologically effective uniform dose (D ) have been proposed (Källman et al. 1992a, Mavroidis et al. 2000). The D concept denotes that any two dose distributions within a target or OAR are equivalent if they produce the same probability for tumor control or normal tissue complication, respectively (Mavroidis et al. 2001)...
Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
Electronic supplementary material: The online version of this article (doi:10.1007/s00702-011-0717-3) contains supplementary material, which is available to authorized users.
Event-related potential (ERP) data in monolingual German speakers have shown that sentential metric expectancy violations elicit a biphasic ERP pattern consisting of an anterior negativity and a posterior positivity (P600). This pattern is comparable to that elicited by syntactic violations. However, proficient French late learners of German do not detect violations of metric expectancy in German. They also show qualitatively and quantitatively different ERP responses to metric and syntactic violations. We followed up the questions whether (1) latter evidence results from a potential pitch cue insensitivity in speech segmentation in French speakers, or (2) if the result is founded in rhythmic language differences. Therefore, we tested Spanish late learners of German, as Spanish, contrary to French, uses pitch as a segmentation cue even though the basic segmentation unit is the same in French and Spanish (i.e., the syllable). We report ERP responses showing that Spanish L2 learners are sensitive to syntactic as well as metric violations in German sentences independent of attention to task in a P600 response. Overall, the behavioral performance resembles that of German native speakers. The current data suggest that Spanish L2 learners are able to extract metric units (trochee) in their L2 (German) even though their basic segmentation unit in Spanish is the syllable. In addition Spanish in contrast to French L2 learners of German are sensitive to syntactic violations indicating a tight link between syntactic and metric competence. This finding emphasizes the relevant role of metric cues not only in L2 prosodic but also in syntactic processing.
Temporal regularity allows predicting the temporal locus of future information thereby potentially facilitating cognitive processing. We applied event-related brain potentials (ERPs) to investigate how temporal regularity impacts pre-attentive and attentive processing of deviance in the auditory modality. Participants listened to sequences of sinusoidal tones differing exclusively in pitch. The inter-stimulus interval (ISI) in these sequences was manipulated to convey either isochronous or random temporal structure. In the pre-attentive session, deviance processing was unaffected by the regularity manipulation as evidenced in three event-related-potentials (ERPs): mismatch negativity (MMN), P3a, and reorienting negativity (RON). In the attentive session, the P3b was smaller for deviant tones embedded in irregular temporal structure, while the N2b component remained unaffected. These findings confirm that temporal regularity can reinforce cognitive mechanisms associated with the attentive processing of deviance. Furthermore, they provide evidence for the dynamic allocation of attention in time and dissociable pre-attentive and attention-dependent temporal processing mechanisms.
Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development
(2011)
Different molecular pathways involved in maintaining mitochondrial function are of fundamental importance to control cellular homeostasis. Mitochondrial i-AAA protease is part of such a surveillance system, and PaIAP is the putative ortholog in the fungal aging model Podospora anserina. Here, we investigate the role of PaIAP in aging and development. Deletion of the gene encoding PaIAP resulted in a specific phenotype. When incubated at 27°C, spore germination and fruiting body formation are not different from that of the corresponding wild-type strain. Unexpectedly, the lifespan of the deletion strain is strongly increased. In contrast, cultivation at an elevated temperature of 37°C leads to impairments in spore germination and fruiting body formation and to a reduced lifespan. The higher PaIAP abundance in wild-type strains of the fungus grown at elevated temperature and the phenotype of the deletion strain unmasks a temperature-related role of the protein. The protease appears to be part of a molecular system that has evolved to allow survival under changing temperatures, as they characteristically occur in nature.
AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization.
METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements.
RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively.
CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.
Anti-angiogenesis in hepatocellular carcinoma treatment : current evidence and future perspectives
(2011)
Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as “bridging” therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospecretrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.
Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder and manifests at old age. While many details of its pathogenesis remain to be elucidated, in particular the protein and mitochondrial quality control during stress responses have been implicated in monogenic PD variants. Especially the mitochondrial kinase PINK1 and the ubiquitin ligase PARKIN are known to cooperate in autophagy after mitochondrial damage. As autophagy is also induced by loss of trophic signaling and PINK1 gene expression is modulated after deprivation of cytokines, we analyzed to what extent trophic signals and starvation stress regulate PINK1 and PARKIN expression. Time course experiments with serum deprivation and nutrient starvation of human SH-SY5Y neuroblastoma cells and primary mouse neurons demonstrated phasic induction of PINK1 transcript up to twofold and PARKIN transcript levels up to sixfold. The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes. Analysis of primary mouse cells from PINK1-knockout mice indicated that PARKIN induction and lysosomal translocation occurred independent of PINK1. Suppression of the PI3K-Akt-mTOR signaling by pharmacological agents modulated PARKIN expression accordingly. In conclusion, this expression survey demonstrates that PARKIN and PINK1 are coregulated during starvation and suggest a role of both PD genes in response to trophic signals and starvation stress.
Platypnea orthodeoxia is a rare disorder characterized by dyspnea and arterial desaturation, exacerbated by the upright position and relieved when the subject is recumbent. We report the case of a 79-year old woman admitted to hospital with dyspnea who was thought to have restrictive ventilatory impairment due to osteoporosis and severe kyphosis. Interestingly, the dyspnea was aggravated in the upright position, whereas the symptoms improved in the supine position. Arterial blood gas analysis confirmed orthodeoxia. The lung function test showed only a mild obstructive and restrictive ventilation disorder. Echocardiography revealed a patent foramen ovale and an aneurysm of the atrial septum protruding into the left atrium, despite normal right atrial pressure. Transesophageal echocardiography showed a prominent Eustachian valve guiding a blood flow from the inferior vena cava directly onto the atrial septum, thereby pushing open the patent foramen ovale. Contrast-enhanced echocardiography confirmed a spontaneous right-to-left shunt through the patent foramen ovale. It was assumed that the platypnea-orthodeoxia was caused by a prominent Eustachian valve redirected to the patent foramen ovale as a result of severe osteoporosis with subsequent thoracic kyphosis and a change in the position of the entire heart. The patient underwent permanent transcatheter closure of the patent foramen ovale after hemodynamic assessment had confirmed a significant right-to-left shunt through it. After the procedure the arterial oxygen pressure increased significantly in the upright position and dyspnea improved.
Meeting Abstract : 82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. Freiburg i. Br., 01.-05.06.2011.
Ca. 3 Millionen Erwachsene in der Bundesrepublik Deutschland leiden unter Tinnitus, wobei eine bei jedem dieser Patienten zur Heilung führende Therapie bisher noch nicht existiert. Ansatzpunkt einer neuartigen Therapie ist die Wiederherstellung des normalen elektrischen Entladungsmusters im Hörnerv mittels elektrischer Stimulation. Hiermit berichten wir über unsere ersten Erfahrungen mit dem Tinnelec, einem Implantat mit einer einzelnen Stimulations-Elektrode die in der Rundfensternische platziert wird.
Zurzeit haben wir 4 einseitig ertaubten Patienten mit Tinnitus auf dem betroffenen Ohr jeweils ein Tinnelec-System implantiert. Die Dauer des Tinnitus betrug mindestens ein Jahr und gängige Tinnitus-Therapien wie z.B. Infusionstherapie waren erfolglos geblieben. Ein psychogener Tinnitus wurde ausgeschlossen. Der durch den Tinnitus verursachte Leidensdruck wurde anhand einer VAS Scala (Visuelle Analog Scala) und eines Tinnitus-Handicap-Inventory (THI) Fragebogens beurteilt. Die Reizapplikation betrug mind. 4 Stunden täglich. Als Stimulationsparameter wurde eine Reizmusterannäherung an den Tinnitus angestrebt.
Bei drei Patienten wurde unter der Stimulation der Tinnitus erträglicher, eine zeitweise komplette Unterdrückung des Tinnitus schon innerhalb der ersten Therapie-Wochen wurde jedoch nur in einem der Fälle berichtet. Diese Ergebnisse wurden auch durch das THI und VAS unterstützt.
Die Tinnelec-Implantation erscheint für Tinnitus Erfolg versprechend zu sein. Weitere Studien bei Tinnitus-Patienten ohne zusätzliche Hörbeeinträchtigung sind jedoch notwendig bis endgültige Schlussfolgerungen betreffend dieses Implantats gezogen werden können. In jedem Fall bleibt die Option einer Cochlea-Implantation im selben Ohr, nach Explantation des Tinnelec, bestehen.
Meeting Abstract : 10. Deutscher Kongress für Versorgungsforschung, 18. GAA-Jahrestagung. Deutsches Netzwerk Versorgungsforschung e. V. ; Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie e. V. 20.-22.10.2011, Köln
Hintergrund: Multimedikation als Folge von Multimorbidität ist ein zentrales Problem der Hausarztpraxis und erhöht das Risiko für unangemessene Arzneimittel-Verordnungen (VO). Um die Medikation bei älteren, multimorbiden Patienten zu optimieren und zu priorisieren, wurde eine computergestützte, durch Medizinische Fachangestellte (MFA) assistierte, komplexe Intervention (checklistengestütztes Vorbereitungsgespräch sowie Überprüfung eingenommener Medikamente durch MFA, Einsatz des web-basierten ArzneimittelinformationsDienstes AiD, spezifisches Arzt-Patienten-Gespräch) entwickelt und in einer 12-monatigen Pilotstudie auf Machbarkeit getestet. Ein auf 9 Items reduzierter MAI [1] wurde eingesetzt, um dessen Eignung als potentielles primäres Outcome der Hauptstudie zu prüfen.
Material und Methoden: In die Pilotstudie in 20 Hausarztpraxen mit Cluster-Randomisation auf Praxisebene in Kontrollgruppe (Regelversorgung b. empfohlenem Standard) vs. Interventionsgruppe (komplexe Intervention b. empfohlenem Standard) wurden 5 Pat./Praxis eingeschlossen (≥65 Jahre, ≥3 chron. Erkrankungen, ≥5 Dauermedikamente, MMSE ≥26, Lebenserwartung ≥6 Monate). Zur Bewertung des MAI wurden an Baseline (T0), 6 Wo. (T1) & 3 Mon. (T2) nach Intervention erhoben: VO, Diagnosen, Natrium, Kalium & Kreatinin i.S., Größe, Gewicht, Geschlecht, Cumulative Illness Rating Scale (CIRS) [2] durch die Hausarztpraxis; Symptome für unerwünschte Arzneimittelwirkungen im Patienten-Telefoninterview.
Für den MAI wurde die Angemessenheit jeder VO in den 9 Kategorien Indikation, Effektivität, Dosierung, korrekter & praktikabler Applikationsweg, Arzneimittelwechselwirkung, Drug-disease-Interaktion, Doppelverordnung, Anwendungsdauer 3-stufig bewertet (1 = korrekt - 3 = unkorrekt) und für die Auswertung auf Patientenebene summiert. Die Bewertung erfolgte ohne Kenntnis der Gruppenzugehörigkeit. Deskriptive Statistiken und Reliabilitätsanalysen, ungewichtete Auswertung und Gewichtung n. Bregnhoj [3].
Ergebnisse: Es wurden N=100 Patienten in die Studie eingeschlossen, im Mittel 76 Jahre (Standardabweichung, SD 6; Range, R: 64-93) , 52% Frauen, durchschnittlich 9 VO/Pat. (SD 2; R 4-16), mittlerer CIRS-Score 10 (SD 4; R 0-23). Basierend auf N=851 VO (100 Pat.) zu T0 betrug der Reliabilitätskoeffizient (RK, Cronbachs Alpha) der ungewichteten 9 Items 0,70. Items 1-5 wiesen akzeptable Trennschärfen auf (0,52-0,64), die der Items 6, 7 & 9 fielen mit 0,21-0,29 niedriger aus, die des Item 8 betrug 0,06. Auf der Basis der 9 gewichteten Items fiel die interne Konsistenz des MAI erwartet höher aus (0,75). Die Reliabilitätsanalysen auf VO-Ebene zeigten einen RK von 0,67 (ungewichtet) vs. 0,75 (gewichtet), die Trennschärfen waren vergleichbar. Zur Zwischenauswertung betrug der MAI (T1-T0) in der Interventionsgruppe (5 Praxen, 24 Pat.) -0,9 (SD 5,6), in der Kontrollgruppe (7 Praxen, 35 Pat.) -0,5 (SD 4,9); die Differenz zwischen beiden Gruppen Mi–Mk -0,4 [95% Konfidenzintervall: -3,4;2,6].
Schlussfolgerung: Der MAI ist als potentielles primäres Outcome in der Hauptstudie geeignet: wenige fehlende Werte, Darstellung von Unterschieden prä-post und zwischen den Gruppen, akzeptable interne Konsistenz. Der niedrige Trennschärfekoeffizient des Items 8 weist darauf hin, dass dieses Item nicht mit dem Gesamt-Skalenwert korreliert, auch die Items 6, 7 und 9 korrelieren wesentlich schwächer mit dem Gesamt-Skalenwert als die Items 1 bis 5. Eine Wichtung z.B. der Items 2, 5, 6 und 9 könnte erwogen werden, um den Fokus der Intervention in der Hauptzielgröße angemessen abzubilden.
Introduction: Encouraged by the change in licensing regulations the practical professional skills in Germany received a higher priority and are taught in medical schools therefore increasingly. This created the need to standardize the process more and more. On the initiative of the German skills labs the German Medical Association Committee for practical skills was established and developed a competency-based catalogue of learning objectives, whose origin and structure is described here.
Goal of the catalogue is to define the practical skills in undergraduate medical education and to give the medical schools a rational planning basis for the necessary resources to teach them.
Methods: Building on already existing German catalogues of learning objectives a multi-iterative process of condensation was performed, which corresponds to the development of S1 guidelines, in order to get a broad professional and political support.
Results: 289 different practical learning goals were identified and assigned to twelve different organ systems with three overlapping areas to other fields of expertise and one area of across organ system skills. They were three depths and three different chronological dimensions assigned and the objectives were matched with the Swiss and the Austrian equivalent.
Discussion: This consensus statement may provide the German faculties with a basis for planning the teaching of practical skills and is an important step towards a national standard of medical learning objectives.
Looking ahead: The consensus statement may have a formative effect on the medical schools to teach practical skills and plan the resources accordingly.
Einleitung: Angestoßen durch die Änderung der Approbationsordnung haben die berufspraktischen Kompetenzen in Deutschland eine höhere Priorität erhalten und werden in den medizinischen Fakultäten deswegen vermehrt vermittelt. Dadurch entstand die Notwendigkeit, den Prozess mehr und mehr zu standardisieren. Auf Initiative der deutschsprachigen Skills Labs wurde der GMA-Ausschuss für praktische Fertigkeiten gegründet, der einen kompetenzbasierten Lernzielkatalog entwickelte, dessen Entstehung und Struktur hier beschrieben wird. Ziel des Kataloges ist es, die praktischen Fertigkeiten im Medizinstudium zu definieren und damit den Fakultäten eine rationale Planungsgrundlage für die zur Vermittlung praktischer Fertigkeiten notwendigen Ressourcen zu geben.
Methodik: Aufbauend auf schon vorhandenen deutschsprachigen Lernzielkatalogen wurde mittels einem mehrfach iterativem Kondensationsprozesses, der der Erarbeitung von S1-Leitlinien entspricht, vorgegangen, um eine breite fachliche und politische Abstützung zu erhalten.
Ergebnisse: Es wurden 289 verschiedene praktische Lernziele identifiziert, die zwölf verschiedenen Organsystemen, drei Grenzbereichen zu anderen Kompetenzbereichen und einem Bereich mit organsystemübergreifenden Fertigkeiten zugeordnet. Sie wurden drei verschiedenen zeitlichen und drei verschiedenen Tiefendimensionen zugeordnet und mit dem Schweizer und dem Österreichischem Pendant abgeglichen.
Diskussion: Das vorliegende Konsensusstatement kann den deutschen Fakultäten eine Grundlage zur Planung der Vermittlung praktischer Fertigkeiten bieten und bildet einen wichtigen Schritt zu einem nationalen Standard medizinischer Lernziele.
Blick in die Zukunft: Das Konsensusstatement soll einen formativen Effekt auf die medizinischen Fakultäten haben, ihre praktischen Unterrichtsinhalte entsprechend zu vermitteln und die Ressourcen danach zu planen.
High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.
The aim of this study was to investigate the diagnostic power of CA 549, MSA and CA 15-3 in identifying breast cancer. The study included 232 patients of which 56 were healthy, 43 had benign breast cancer and 191 with other growths. The results were obtained using a specific immunoassay and using producers' cut offs. The following sensitivity and specificity of markers were found: CA 549 (sen.: 40%/spec.: 90%), MSA (sen.: 22%/spec.: 96%), and CA 15-3 (sen.: 33%/spec.: 86%). Ideal cut offs were defined with ROC curves. A significant correlation was found between CA 549, MSA, and CA 15-3. The combination of markers does not improve the clinical usefulness to identify only breast cancer. Serum tumor markers are abnormally elevated in patients with breast cancer. CA 549, MSA, CA 15-3 are useful clinical markers, good indicators of disease extent, and may have important prognostic value. This study demonstrates the role of the tumor markers in breast cancer.
Background. The aim of this study was to show the importance of the bone marker procollagen type 1 aminoterminal propeptide (P1NP) in detecting bone metastases in women suffering from breast cancer. We furthermore investigated to what degree P1NP is correlated to the degree of bone metastases, and if P1NP is increased in patients with metastases other than bone. Patients and Methods. We analyzed 80 serum samples of women (17 premenopausal/63 postmenopausal) with breast cancer. Therefore we used a specific immunoassay “ELECSYS 2010” by Roche Diagnostics. We divided our group of patients with regard to menopausal status, sites of metastases and number of bone metastases. Results. As a result we found higher concentrations of P1NP in women with radiologically confirmed bone metastases (median: 125.75 ng/mL) in comparison to the collective without bone involvement (median: 73.61 ng/mL). However, both groups showed values above the applied cutoff values of median 27.8 ng/mL for premenopausal women and median: 37.1 ng/mL for the postmenopausal group due to the fact that all patients had cancer. Furthermore higher P1NP concentrations were found in women with more than 5 sites of bone metastases (median: 183.9 ng/mL) than in patients with only one site of bone metastases (median: 37 ng/mL). Also patients with no bone involvement but other sites of metastases showed quite high P1NP concentrations (median: 73.61 ng/mL). Conclusion. The marker of bone turnover procollagen type 1 aminoterminal propeptide can be considered as a useful tool for estimating the extent of bone involvement and for the detection of bone metastases. P1NP cannot replace conventional methods for detecting bone metastases such as radiological methods but it can help clarify unclear radiological results. This study does not take into account the change of P1NP concentration during the course of therapy.
BACKGROUND: Exsanguinating hemorrhage is the major cause of death in patients with pelvic ring disruption.
AIMS: The aim of this study was to document outcomes after the stabilization of pelvic ring injuries by a C-clamp and control of hemorrhage by pelvic packing. Physiological parameters were tested as prognostic factors.
SETTING AND DESIGN: This was a retrospective study at a level I trauma center. The study period was from January 1996 to December 2007.
MATERIALS AND METHODS: Fifty patients with pelvic ring disruption and hemorrhagic shock were analyzed. The pelvic rings were fixed by a C-clamp, and patients with ongoing hemorrhage underwent laparotomy and extra- and/or intra-peritoneal pelvic packing. Clinical parameters (heart rate, mean arterial pressure) and physiological parameters (lactate levels, hemoglobin, hematocrit) were documented at admission and at different time points during the initial treatment (1, 2, 3, 4, 6, 8, and 12h after admission).
RESULTS: Within 12 h of admission, 16 patients died (nonsurvivors) due to hemorrhagic shock (n=13) or head injuries (n=3). In this group, 12 patients underwent laparotomy with pelvic packing. Thirty-four patients survived the first 12 h (early survivors) after fixation by a C-clamp and additional packing in 23 patients. Four of these patients died 12.3±7.1 days later due to multiple organ failure (n=3) or severe head injury (n=1). The blood lactate level at admission was significantly higher in the group of nonsurvivors (7.2±0.8 mmol/L) compared to the early survivors (4.3±0.5 mmol/L, P<0.05). While hemoglobin values improved within the first 2 h in nonsurvivors, lactate levels continued to increase.
CONCLUSION: Pelvic packing in addition to the C-clamp fixation effectively controls severe hemorrhage in patients with pelvic ring disruption. Early sequential measurements of blood lactate levels can be used to estimate the severity of shock and the response to the shock treatment.
The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model.
This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo.
Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3rNutlin10 μM, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin10 μM cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin10 μM cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin10 μM cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3rNutlin10 μM and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
Das Thema dieses Diskussionspapiers ist die Ökonomisierung des Sozialen. Methodisch handelt es sich um eine metatheoretische Analyse, der gleichzeitig theoretische wie empirische und normative Erkenntnisinteressen zugrunde liegen. Die vergleichende Analyse von Diskurspositionen über gesellschaftliche Transformationsprozesse zeigt dabei, dass sich die objektiven Anforderungsstrukturen und subjektiven Bewältigungsstrukturen im Umbruch befinden. Die drei ausgewählten Diskurspositionen werden dabei auf theoretische Fundierung, empirische Validierung und normative Implikationen hin untersucht. Die divergierenden theoretischen wie empirischen Bezüge bilden mit den normativ-politischen Positionen weitgehend kohärente Diskurspositionen. Der postpositivistische Theorienvergleich zeigt ein Bild sich theoretisch, empirisch und normativ ergänzender (wissenschaftlicher) Narrative, die belegen, dass die Sozialwissenschaf(en) nicht wertneutral berichten, sondern selbst politische Akteure sui generis sind und am Zeichnen des Bildes dessen, was sie untersuchen, aktiv partizipieren.
Plagiarismus in der Medizin wird im Ausland im letzten Jahrzehnt zunehmend erforscht,
nicht so in Deutschland. Prominente Plagiatsfälle auch außerhalb der Medizin stellen darüber
hinaus grundlegende Fragen an die Qualität von Wissenschaft. Plagiarismus und
unethisches Verhalten in der Wissenschaft werden in diesem Arbeitspapier im Kontext
des grundlegenden institutionell-organisatorischen Wandels des Wissenschafts- und
Hochschulsystems durch die Übertragung von Konzepten des New Public Management
(NPM) auf die Governance des Hochschul- und Wissenschaftssystems diskutiert. Möglichkeiten
und Grenzen verschiedener Strategien zum Umgang mit Plagiarismus werden
vorgestellt. Dabei wird insbesondere auf die Verwendung von Plagiats-Software eingegangen.
Die Verwendung einer Software-Lösung im Fachbereich Humanmedizin wird aus
verschiedenen Gründen kritisch eingeschätzt. Erste Ergebnisse aus einer empirischen
Studie zum Plagiarismus von Studierenden zeigen ebenfalls, dass der Prävention von
Plagiaten durch Aufklärung und Ausbildung mehr Beachtung geschenkt werden muss. Auf
Grundlage der theoretischen Überlegungen, Recherchen und der eigenen empirischen
Erhebungen werden Bausteine für einen systematischen Umgang mit Plagiarismus für die
Hochschulmedizin entwickelt.
Das vorliegende Diskussionspapier ist die erweiterte and aktualisierte Fassung des Kapitels „Neoliberalismus und Arzt-Patient-Beziehung“ meines Buches „Zur sozialen Anatomie des Gesundheitswesens. Neoliberalismus und Gesundheitspolitik in Deutschland“ (Frankfurt 2005). Es geht dabei um die Ökonomisierung bzw. Kommerzialisierung eines sozialen Bereiches, der davor lange Zeit verschont wurde. Der Einfluss von Markt und Wettbewerb auf die Arzt-Patient- Beziehung werden beschrieben und analysiert sowie auf daraus folgende wichtige Veränderungen hingewiesen. Dabei zeigt sich, dass der Patient zunehmend zum Kunden wird und der Arzt immer intensiver unternehmerisch zu denken hat. Der Ermessensspielraum für ärztliche Entscheidungen, von Indikationsstellungen und therapeutischen Interventionen, werden davon nicht unerheblich berührt. Daraus ergeben sich ethische Aspekte, die schon vor einigen Jahrzehnten von der „kritischen Medizin“ beklagt wurden. Gesundheit wird hier als Menschenrecht gesehen. Als Gegenmodell zur um sich greifenden Kommerzialisierung gelten neue Formen der Versorgung, die auf der Basis von Solidarität beruhen.