Ergebnisse zweier Operationsmethoden zur Behandlung der weiblichen Stressinkontinenz

Aufgabenstellung: Ziel der empirischen Studie war es, zwei Operationsmethoden zur Behandlung der weiblichen Stressinkontinenz hinsichtlich der klinischen Verläufe und der durch die Patientinnen bewerteten Ergebnisse darzustellen. Hierzu wurden Daten von 35 Patientinnen erhoben, die wegen Stressinkontinenz nach der endoskopischen Blasenhalssuspension (BHS) am Krankenhaus Moabit/Berlin versorgt worden waren. Als Vergleichgruppe dienten fünfzehn Patientinnen, die wegen Stressinkontinenz eine Faszienzügelplastik nach Fischer an der Fachklinik St. Joseph II/Berlin erhalten hatten. Methode: Als historische Kohortenstudie angelegt, wurde nach einem Follow-up von mindestens drei Monaten an alle Patientinnen, die am Krankenhaus Moabit im Zeitraum 1989-93 und am St. Josephkrankenhaus im Zeitraum 1987-1992 behandelt worden waren, ein Fragebogen zur aktuellen Symptomatik der Stressinkontinenz und zur präoperativen, perioperativen und aktuellen Lebensqualität verschickt. Klinische Daten zum präoperativen Status und zum perioperativen Verlauf wurden aus den Krankenakten der Patientinnen entnommen. Ergebnisse: In die Studie konnten 75 % aller Frauen, die die Einschlusskriterien erfüllten, einbezogen werden. In der BHS-Gruppe betrug die Heilungsrate/Besserungsrate bezogen auf den Inkontinenzgrad nach einer mittleren Beobachtungszeit von zehn Monaten 43 % bzw. 51 %. In der FZP-Gruppe lag die Erfolgsrate nach durchschnittlich drei Jahren bei 27 % bzw. 53%. In dieser Gruppe befanden sich fünf Rezidivpatientinnen bezogen auf eine vorangegangene Inkontinenzoperation. Vier von ihnen profitierten von dem Eingriff. Es kam in beiden Gruppen zu einer signifikanten Besserung der mittleren Lebensqualität (p<0,001) und deOperationen traten Komplikationen in Form von Wundinfektionen oder Blasenentleerungsstörungen auf. Diskussion: Bei der FZP-Methode als invasivere Technik wird der Vorteil der guten OPErgebnisse bei gynäkologisch voroperierten Patientinnen erkauft durch eine längere OP-Zeit, einen längeren Krankenhausaufenthalt und eine längere Rekonvaleszenszeit. Bei der BHSGruppe fällt die hohe Rezidivrate im Bereich des Follow-ups von 7 bis 36 Monaten auf. Zur weiteren Evaluation von Inkontinenzoperationen sollten Kohortenstudien unter Einsatz von standardisierten Messinstrumenten unternommen werden und ein längere Verlaufsbeobachtung angestrebt werden.s mittleren Vorlagenverbrauchs (p< 0,001). Bei 54 % der BHS- und 40 % der FZP

Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity

Feasibility of at-home self-sampling for HPV testing as an appropriate screening strategy for nonparticipants in Switzerland: preliminary results of the DEPIST study

Nonattendees to cervical cancer screening are at a higher risk of developing cervical cancer. This study assessed women's willingness to perform a home-based self-sampling for human papillomavirus testing (Self-HPV) and explored the feasibility of establishing a home-based Self-HPV screening strategy in Switzerland

Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial.

PURPOSE: The 14 amino acid sequence (aa(450-463)) TKDNNLLGRFELSG (TKD) of heat shock protein 70 (Hsp70) was identified as a tumor-selective recognition structure for natural killer (NK) cells. Incubation of peripheral blood lymphocyte cells with TKD plus low-dose interleukin 2 (IL-2) enhances the cytolytic activity of NK cells against Hsp70 membrane-positive tumors, in vitro and in vivo. These data encouraged us to test tolerability, feasibility, and safety of TKD-activated NK cells in a clinical Phase I trial. EXPERIMENTAL DESIGN: Patients with metastatic colorectal cancer (n = 11) and non-small cell lung cancer (n = 1) who had failed standard therapies were enrolled. After ex vivo stimulation of autologous peripheral blood lymphocytes with Hsp70-peptide TKD (2 microg/ml) plus low-dose IL-2 (100 units/ml), TKD was removed by extensive washing, and activated cells were reinfused i.v. The procedure was repeated for up to six cycles, applying a dose escalation schedule in 4 patients. RESULTS: The percentage of activated NK cells in the reinfused leukapheresis products ranged between 8 and 20% of total lymphocytes, corresponding to total NK cell counts of 0.1 up to 1.5 x 10(9). Apart from restless feeling in 1 patient and itching in 2 patients, no negative side effects were observed. Concomitant with an enhanced CD94 cell surface density, the cytolytic activity of NK cells against Hsp70 membrane-positive colon carcinoma cells was enhanced after TKD/IL-2 stimulation in 10 of 12 patients. Concerning tumor response, 1 patient was in stable disease during therapy by formal staging criteria and another patient showed stable disease in one metastases and progression in another. CONCLUSIONS: Reinfusion of Hsp70-activated autologous NK cells is safe. Immunological results warrant additional studies in patients with lower tumor burden

Improving psychosocial services for vulnerable families with young children: strengthening links between health and social services in Germany

Renner I, Saint VA, Neumann A, et al. Improving psychosocial services for vulnerable families with young children: strengthening links between health and social services in Germany. BMJ. 2018;2018(363): k4786.Ilona Renner and colleagues describe cross-sectoral collaborative efforts in Germany to enhance the skills of parents to care for young childre

Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1–mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression

Materialismo e primado do objeto em Adorno Materialism e priority of the object on Adorno

Este artigo investiga a "Tese" do primado do objeto na obra de Theodor W. Adorno, central ao seu materialismo não dogmático e relativamente pouco estudada. O primado do objeto será apresentado em seus elementos constitutivos, como crítica ao modo essencialmente idealista da dialética que perpassa o conjunto da obra de Adorno, em especial nos textos e discussões que precederam a publicação da Dialektik der Aufklãrung, para se explicitar no período de elaboração da Negative Dialektik. A "Tese" desenvolve momentos apresentados por Lukács, Benjamin e Horkheimer, particularmente quanto ao nexo entre razão e experiência e se fundamenta especialmente no trajeto Kant - Hegel, como crítica ao idealismo, incorporando de modo estruturante as perspectivas de Marx e de Nietzsche. Ao romper a pretensa "simetria" entre sujeito e objeto, a "Tese" do primado do objeto revela como é insustentável a alegação habermasiana do Discurso filosófico da modernidade segundo a qual Adorno e Horkheimer incidiriam num ceticismo total frente à razão e à sua totalização ideológica. Ao contrário: estes autores, ao articularem de um modo original substância material histórica e argumentação teórica, contribuíram de modo fundamental para examinar o problema da reificação mediante sua relação à objetividade - como o não-idêntico - no âmbito da razão.<br>The thesis of the priority of the object, essential to Adorno's non dogmatic materialism, is analyzed in its constitutive elements, as a criticism of idealism which is present mainly at the works Dialectic of enlightenment and Negative dialectic. As a criticism of idealism, particularly on the relationships between reason and experience as first developed from Kant to Hegel, the thesis is based on Lukács, Benjamin, and Horkheimer contributions and is embedded on the perspectives of Marx and Nietzsche. With its disruption of symmetry between subject and object, the thesis of the priority of the object reveals the frailty of Habermas assertion, in his Philosophical discourse of modernity, of Adorno's and Horkheimer's skepticism towards reason. The present author argues that, in opposition to this claim, Adorno and Horkheimer contributed, with their new way of relating historical material and theoretical approach, to the analysis of the problem of reification in its relations to objectivity - as the non-identical - within the realm of reason, and not outside of it

Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia—a phase 3 study

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 - dose-dense) and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 - standard). 387 evaluable patients were randomly assigned to S-HAM (N - 203) and to standard double induction (N - 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks