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1993 stellte die Entdeckung winziger Stückchen von Ribonukleinsäuren, heute als microRNAs bekannt, die Wissenschaftler vor ein Rätsel. Erstmals beobachtet wurden sie in dem Fadenwurm C. elegans, einem einfachen, vergleichsweise leicht durchschaubaren Organismus. Was die Wissenschaftler verwirrte, war die Tatsache, dass diese microRNAs ganz offensichtlich nicht für Proteine kodierten. Welche Funktion haben sie dann? Inzwischen weiß man, dass sie eine wichtige Rolle bei der Genregulation spielen. Und das nicht nur im Fadenwurm: MicroRNAs sind evolutionär hoch konserviert, sie kommen auch in höheren Organismen vor. Im Menschen sind mehr als 1500 microRNAs beschrieben, und man geht davon aus, dass mindestens 30 Prozent der Gene direkt durch microRNAs reguliert werden. Das lässt sich auch für therapeutische Zwecke nutzen. In unserer Arbeitsgruppe erforschen wir insbesondere die Rolle der microRNAs bei Herz- und Gefäß-Erkrankungen.
Background: Acoustic Radiation Force Impulse (ARFI)-imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE).
Methods: ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules $5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging.
Results: One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy.
Conclusions: ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.
Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin.
Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.
Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05).
Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted.
Background: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).
Methods: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128).
Results: At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.
Conclusions: Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
Background: Despite limited effectiveness of short-term psychotherapy for chronic depression, there is a lack of trials of long-term psychotherapy. Our study is the first to determine the effectiveness of controlled long-term psychodynamic and cognitive-behavioral (CBT) treatments and to assess the effects of preferential vs. randomized assessment.
Methods/design: Patients are assigned to treatment according to their preference or randomized (if they have no clear preference). Up to 80 sessions of psychodynamic or psychoanalytically oriented treatments (PAT) or up to 60 sessions of CBT are offered during the first year in the study. After the first year, PAT can be continued according to the ‘naturalistic’ usual method of treating such patients within the system of German health care (normally from 240 up to 300 sessions over two to three years). CBT therapists may extend their treatment up to 80 sessions, but focus mainly maintenance and relapse prevention. We plan to recruit a total of 240 patients (60 per arm). A total of 11 assessments are conducted throughout treatment and up to three years after initiation of treatment. The primary outcome measures are the Quick Inventory of Depressive Symptoms (QIDS, independent clinician rating) and the Beck Depression Inventory (BDI) after the first year.
Discussion: We combine a naturalistic approach with randomized controlled trials(RCTs)to investigate how effectively chronic depression can be treated on an outpatient basis by the two forms of treatment reimbursed in the German healthcare system and we will determine the effects of treatment preference vs. randomization.
Hintergrund: In dieser prospektiven Studie wurden erstmals die Auswirkung der Lageveränderung von der Rücken- auf Bauchlagerung auf Hämodynamik und Säure-Basen-Haushalt unter Einlungenventilation bei Patienten untersucht, die sich einer elektiven endoskopischen Ösophagusresektion unterzogen.
Methodik: Insgesamt wurden 10 Patienten (Alter 63 ± 12 Jahre) der ASA-Klassen I-III eingeschlossen. Ausgeschlossen waren Patienten der ASA-Klasse IV-V und Patienten bei denen die Einlungenventilation aus technischen Gründen nicht durchführbar war. Aufgezeichnet wurden neben hämodynamischen Parametern (HF, MAD, ZVD, PAPmean, HI, SVRI) auch respiratorische Parameter (pH, BE, HCO3-, paCO2, paO2, SaO2, SgvO2).
Ergebnisse: Hämodynamik: Die Herzfrequenz stieg unter Einlungenventilation in Bauchlage signifikant gegenüber dem Ausgangswert an. Auch der ZVD stieg 30min nach Umlagerung vom Rücken in Bauchlage unter Einlungenventilation signifikant an. Der Herzindex lag unter Einlungenventilation in Bauchlage signifikant unter dem Endwert.
Säure-Basen-Haushalt: paCO2 und Standard-Bicarbonat (HCO3-) lagen sowohl vor als auch nach Umlagerung im Normbereich. Der pH und der base excess (BE) zeigten einen minimalen Abfall 15min. nach Lagerungsmanöver vom Rücken- in die Bauchlage. Der Sauerstoffpartialdruck (paO2) fiel signifikant um 50% im Vergleich zum Ausgangswert unter Einlungenventilation ab. Die gemischt-venöse Sättigung (SgvO2) fiel ebenfalls unter Einlungenventilation unter den Normbereich, während der Umlagerung vom Rücken auf den Bauch konnte ein Anstieg der SgvO2 um 1,5% verzeichnet werden. Nach Umlagerung traten keine signifikanten Veränderungen der Werte auf.
Schlussfolgerung: Die Ergebnisse der vorliegenden Untersuchung zeigen, dass laparoskopische Ösophagusresektionen mit Veränderungen der hämodynamischen und respiratorischen Parameter einhergehen, die klinische Relevanz war dabei in dem von uns untersuchten Kollektiv als gering anzusehen.
Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity.
Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed.
Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls.
Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma.
Das Buch ist in vier größere Teile aufgeteilt: Zunächst werden die wichtigsten Entwicklungen in der Frankfurter Universitätsmedizin bis zum Kriegsbeginn verfolgt (Allgemeines, Entrechtungen/Entlassungen, Berufungen, Kliniken und Institute). Anschließend wird die Universitätsmedizin im Krieg beschrieben (Allgemeines, Berufungen, Kliniken und Institute). Schließlich werden separat die schlimmsten Schandtaten und Verbrechen Frankfurter Universitätsmediziner (unter besonderer Berücksichtigung von Berner, Mengele und Hirt) und abschließend die (bescheidenen) oppositionellen Aktivitäten dargelegt