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Purpose: Metabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE).
Methods: 1H and 31P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (<median OS) survival time from BVZ-onset. Metabolite concentrations from tumor tissue and their ratios were compared to contralateral normal-appearing tissue (control).
Results: Before BVZ, 1H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by 31P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031).
Conclusion: An elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.
In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener’s principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.
Background: To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and ε-aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery.
Methods and Findings: We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively.
Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13–2.21), p<0.001 in the low (n = 14,297) and in the intermediate risk subgroup (1.42 (1.09–1.84), p<0.001; n = 14,427), respectively. Contrarily, in the subgroup of high risk patients (n = 4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67–1.58), p = 0.90).
Conclusion: Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.
The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.
Background: The students' perception of working conditions in hospitals hasn't been subject of research in Germany so far. However the perception plays an important role talking about the sustainability of working conditions. The iCept Study wants to examine the perception of medical students compared to the perception of practicing physicians.
Methods: The perception will be investigated with a redesigned questionnaire based upon two established and validated questionnaires. The two samples built for this study (students and physician) will be chosen from members of the labor union Marburger Bund. The iCept-Study is designed as an anonymized online-survey.
Discussion: The iCept-Study is thought to be the basis of ongoing further investigations regarding the perception of working conditions in hospitals. The results shall serve the facilitation of improving working conditions.
Im Rahmen einer prospektiven Kohortenstudie wurde in der vorliegenden Arbeit die Epidemiologie und Ätiologie von Fieber während chemotherapiebedingter Neutropenie bei Patienten mit hämatologischen Neoplasien untersucht. Das diagnostische und therapeutische Vorgehen wurde beschrieben und die Übereinstimmung mit den Vorgaben einer hausinternen Leitlinie wurde evaluiert und der Verbrauch an antimikrobiellen Substanzen dokumentiert. Febrile Episoden konnten in 74% der Neutropenieepisoden dokumentiert werden; in 51% der Neutropenieepisoden kam es zu persistierendem Fieber ≥ 3 Tage. Eine dem Fieber zugrunde liegende Infektion wurde in 55% der Chemotherapiezyklen (Neutropeniedauer Median 16 Tage) mittels klinischer, apparativer und mikrobiologischer Diagnostik gefunden. Die häufigsten infektiösen Komplikationen waren Enteritiden mit Nachweis von C. difficile (11%), Enteritiden ohne Nachweis von C. difficile (29%), Pneumonien mit pilztypischen Infiltraten (12%) und Pneumonien mit unspezifischen Infiltraten (11%), sowie mikrobiologisch bestätigte Septikämien (18%). Im Vergleich zu Angaben in der Literatur wurde FUO in der vorliegenden Untersuchung häufiger diagnostiziert (11,8 Tage pro 1000 Patiententage vs. 8,2 Tage pro 1000 Patiententage). Die Gesamtmortalität des Kollektivs lag bei 7%. Die häufigste Todesursache war der septische Schock (8 von 5 Patienten; 63%), welcher sich auf dem Boden einer gramnegativen Septikämie mit multiresistenten Keimen entwickelt hatte (3 von 5 Septikämien; 60%). Die Mortalitätsrate war ähnlich hoch wie im Literaturvergleich bei Studien mit akuten myeloischen Leukämien. Prognoserelevante Faktoren, welche im Rahmen der vorliegenden Studie evaluiert wurden, sind durch schwer therapierbare Grunderkrankungen hervorgerufene prolongierte Neutropeniezeiten, sowie infektiöse Komplikationen, vor allem bei Nachweis multiresistenter Erreger.
Die Compliance bezüglich des diagnostischen und therapeutischen Vorgehens bei persistierendem Fieber betrug in der vorliegenden Arbeit zwischen 47% und 82%. Die Compliance mit den in der Leitlinie vorgeschlagenen antimikrobiellen prophylaktischen und initialen empirischen Therapien lag zwischen 83% und 85%. Der Gesamtverbrauch an antibiotischen und antimykotischen Substanzen war in der vorliegenden Studie höher als im Literaturvergleich (1647 DDD vs. 1140 DDD und 650 DDD vs. 430 DDD). Dabei fällt insbesondere der hohe Verbrauch an Reservemedikamenten gegen grampositive Bakterien auf. Allerdings fehlen aktuelle Vergleichsdaten vergleichbarer Patientenkollektive.
Bezüglich der Optimierung der diagnostischen Maßnahmen ist vor allem die Erhöhung der Sensitivität der Bronchoalveolären Lavage bei Pilzinfektionen, rechtzeitig und regelmäßig durchgeführte Surveillanceabstriche bei febriler Neutropenie, sowie die Diskussion der diagnostischen Ergebnisse und des weiteren therapeutischen Vorgehens mit infektiologischen Experten zu fordern. Patienten mit persistierendem Fieber - vor allem bei positivem Blutkulturnachweis - sollten, aufgrund des positiven prädiktiven Wertes erregerpositiver Blutkulturen für die Notwendigkeit einer intensivmedizinischen Betreuung und einer erhöhten Mortalität, Anlass sein, diagnostische und therapeutische Maßnahmen zu verbessern. Ziel ist es, durch verstärkten Einsatz diagnostischer Maßnahmen und Diskussion mikrobiologischer Befunde im Einzelfall, Reservesubstanzen seltener einzusetzen, gegebenenfalls Breitspektrum-Antibiotika oder ihre Kombinationen zu deeskalieren und somit die Kolonisation mit resistenten Erregern positiv zu beeinflussen, sowie das Ansprechen auf antimikrobielle Therapien zu optimieren.
Die Teilnahme an multizentrischen Surveillancestudien zur Inzidenzerfassung wichtiger, eindeutig definierter neutropener nosokomialer Infektionen wie radiologisch detektierter Pneumonien, mikrobiologisch bestätigter Septikämien und C. difficilepositiver Enteritiden, sowie zur Generierung von Antiinfektivaverbrauchszahlen, könnte helfen, die Beratung und Entscheidungsfindung am Krankenbett zu unterstützen. Auch könnten in diesem Rahmen Zahlen generiert werden, welche bisher zum Vergleich fehlten.
Die vorliegende Arbeit versteht sich im Rahmen der Erfassung von Ätiologie, Diagnostik und antimikrobieller Therapien bei febriler Neutropenie als Teil eines solchen Surveillanceprogrammes und hat somit eine Grundlagen für zukünftige Datenerhebungen geliefert.
kurz und kn@pp news : Nr. 27
(2013)
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future.
Cataract surgery is one of the oldest and the most frequent outpatient clinic operations in medicine performed worldwide. The clouded human crystalline lens is replaced by an artificial intraocular lens implanted into the capsular bag. During the last six decades, cataract surgery has undergone rapid development from a traumatic, manual surgical procedure with implantation of a simple lens to a minimally invasive intervention increasingly assisted by high technology and a broad variety of implants customized for each patient’s individual requirements. This review discusses the major advances in this field and focuses on the main challenge remaining – the treatment of presbyopia. The demand for correction of presbyopia is increasing, reflecting the global growth of the ageing population. Pearls and pitfalls of currently applied methods to correct presbyopia and different approaches under investigation, both in lens implant technology and in surgical technology, are discussed.