G-CSF, rt-PA and combination therapy after experimental thromboembolic stroke

BACKGROUND: Granulocyte Colony-Stimulating Factor (G-CSF) has remarkable neuroprotective properties. Due to its proven safety profile, G-CSF is currently used in clinical stroke trials. As neuroprotectants are considered to be more effective in the early phase of cerebral ischemia and during reperfusion, G-CSF should to be tested in combination with thrombolysis. Therefore, combination therapy was investigated in an experimental model of thromboembolic stroke. METHODS: Male Wistar rats (n = 72) were subjected to a model of thromboembolic occlusion (TE) of the middle cerebral artery. Different groups (n = 12 each) treated by recombinant tissue-plasminogen activator (rt-PA) or/and G-CSF: group control (control), group early G-CSF (G-CSF 60 min after TE), group rt-PA (rt-PA 60 min after TE), group com (combination rt-PA/G-CSF), group delayed rt-PA (rt-PA after 180 min), group deco (G-CSF after 60 min, rt-PA after 180 min). Animals were investigated by magnetic resonance imaging (MRI) and silver infarct staining (SIS) 24 hours after TE. RESULTS: Early G-CSF or rt-PA reduced the infarct size compared to all groups (p \u3c 0.05 to p \u3c 0.01) with the exception of group com, (p = n.s.) as measured by T2, DWI, and SIS. Late administration of rt-PA lead to high mortality and larger infarcts compared to all other groups (p \u3c 0.05 to p \u3c 0.01). Pre-treatment by G-CSF (deco) reduced infarct site compared to delayed rt-PA treatment (p \u3c 0.05). G-CSF did not significantly influence PWI when combined with rt-PA. All animals treated by rt-PA showed improved parameters in PWI indicating reperfusion. CONCLUSIONS: G-CSF was neuroprotective when given early after TE. Early combination with rt-PA showed no additional benefit compared to rt-PA or G-CSF alone, but did not lead to side effects. Pretreatment by G-CSF was able to reduce deleterious effects of late rt-PA treatment

Primary mediastinal synovial sarcoma: a case report and review of the literature

Primary mediastinal synovial sarcoma is a rare malignancy with only a few cases reported so far. A 56-year-old woman was admitted to our hospital for an investigation of a nodule in the left middle lung on chest radiography. Computed tomography revealed a mediastinal mass first described as a solitary fibrous tumor. The diagnosis of synovial sarcoma was established by computed tomography-guided percutaneous needle biopsy. Work up showed no metastasis to distant organs or contralateral pleural cavity. The mass was surgically resected; pathological and immunohistochemical analyses confirmed the diagnosis of a monophasic spindle cell synovial sarcoma probably originating from phrenic nerve. The patient received adjuvant chemotherapy and radiation and is free of recurrence after a follow up of 16 months

E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy

Background Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. Methods A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. Results Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2− to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. Conclusion These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.publishedVersio

Determinants of seasonal influenza vaccination in pregnant women in Valencia, Spain

Background: In most countries the coverage of seasonal influenza vaccination in pregnant women is low. We investigated the acceptance, reasons for rejection and professional involvement related to vaccine information in pregnant women in Valencia, Spain. Methods: Observational retrospective study in 200 pregnant women, 100 vaccinated and 100 unvaccinated, were interviewed during the 2014/2015 vaccination campaign. Electronic medical records, immunization registry and telephone interviews were used to determine reasons for vaccination and immunization rejection. Results: 40.5% of pregnant women in the health department were vaccinated. The midwife was identified as source of information for 89% of women. The vaccine was rejected due to low perceptions of risk of influenza infection (23%), lack of information (19%), considering the vaccine as superfluous (16%), close proximity of delivery date (13%) and fear of side effects (12%). Conclusion: Pregnant women in Spain declined to be vaccinated due to under-estimation of the risk of contracting or being harmed by influenza, and lack of information. Interventions aiming to optimize vaccination coverage should include information addressing the safety and effectiveness of the current vaccine together with improved professional training and motivation

Spoluvytvářené fotografie

The intention of this thesis is to investigate the phenomenon of the mutual relationship between the photographer and the photographed person. The main interest here is how and with which intention the photographer/ artist works with the subject in front of the lens. At the beginning of the work I would like to discuss the concept of the authorship and how it has developed over time. It should give an insight into this complex topic and an insight into how important this topic is for the cooperation of people in the field of art. Subsequently, different artists are introduced who work in this field or have gained experience and rendered services in their own projects. The handling is presented and should clarify why they have decided to use such a collaboration. Among those artists are the names: Anthony Luvera, Micky Allan,Wendy Ewald and Broomberg & Chanarin. At the end of the work, the approach of the collaborative work of the artist and the photographed subject will be summarized once again. By introducing the artists in the previous chapter, it is easier to reference to their apporaches. It is important to discuss which effects can be achieved by this approaches. What difficulties may arise as a result. But above all, the reader should be able to grasp why this way of collective photography enables a different point of view

Untersuchungen zum Einfluss des HMG-CoA-Reduktase-Inhibitors Lovastatin auf die Toxizität ionisierender Strahlung sowie des Anthrazyklinderivats Doxorubicin im Mausmodell

Hintergund: HMG-CoA-Reduktase-Inhibitoren (Statine) sind klinisch etablierte Cholesterinsenker. Über die Inhibition der intrinsischen Cholesterinbiosynthese hinaus zeigen sie sogenannte pleiotrope biologische Effekte. Ein Großteil dieser Wirkungen wird auf die Inhibition kleiner Ras homologer GTPasen (Rho GTPasen) zurückgeführt. In vitro schützt das Statinderivat Lovastatin (Lova) primäre humane Endothelzellen vor der Zytotoxizität von ionisierender Strahlung (IR) und dem Krebsmedikament Doxorubicin (Doxo). Zielsetzung: Die Relevanz dieser Befunde für ein in vivo Mausmodell sollte in der vorliegenden Arbeit überprüft werden. Dafür wurden BALB/c-Mäuse mit IR oder Doxo behandelt und der Einfluss einer Kobehandlung mit Lova auf verschiedene Toxizitätsendpunkte untersucht (24 h nach einer einzelnen hohen Dosis IR (i), 14 Tage nach zwei geringen Dosen IR (ii), 48 h nach einer einzelnen hohen Dosis Doxo (iii), sowie 8 Tage nach drei niedrigen Dosen Doxo (iv)). Eine mögliche gleichzeitige Protektion von Tumorzellen durch die Statingabe wurde in einem Xenotransplantationsexperiment überprüft (v), in dem das gleiche Behandlungsschema wie bei iv angewendet wurde. Ergebnisse: Es konnte gezeigt werden, dass eine Statinbehandlung Normalgewebe vor Doxo- und IR-induzierter Toxizität schützt, ohne gleichzeitig protektiv auf transformierte Zellen zu wirken. Dieser Effekt ist wahrscheinlich von einer Inhibition der kleinen GTPasen Rac1 und RhoA abhängig und einer daraus folgenden Modifizierung der DNA-Schadensantwort. i: Die Statinvorbehandlung der Mäuse hatte keinen Einfluss auf die Bildung von initialen IR-induzierten DNA-Doppelstrangbrüchen (DSB) in der Leber. Die Lova-Behandlung wirkte sich jedoch auf IR-induzierte Stressantworten aus, was sich in einer Minderung der Expression von Inflammations- und Fibrosesurrogatmarkern in Leber und Darm widerspiegelte. ii: In der Lunge der Tiere wurde ein Anstieg von molekularen Inflammations- und Fibrosesurrogatmarkern detektiert, der bei Statinkobehandlung ausblieb. Zudem verhinderte die Kobehandlung mit Lova eine IR-induzierte Abnahme der Thrombozytenzahl, ohne sich auf die durch IR verringerte Leukozytenzahl im Blut auszuwirken. iii: Die Verabreichung einer hohen Dosis Doxo induzierte DSB-Formation in der Leber. Die Statinvorbehandlung reduzierte deren Menge um ca. 50 %. Dieser genoprotektive Effekt war unabhängig von der Entstehung reaktiver Sauerstoffspezies sowie einer Änderung des Doxo-Imports oder Exports. Die Expression von proinflammatorischen und profibrotischen Genen fiel besonders in der Leber und im Herzen durch die Lova-Kobehandlung geringer aus, als in der nur mit Doxo behandelten Gruppe. Zudem verringerte Lova die durch Doxo induzierte Hochregulation von für den AP1-Komplex kodierenden Genen sowie von Zellzykluskontrollfaktoren. Die Lova-Vorbehandlung führte darüber hinaus im Herzen zu einem reduzierten mRNA-Spiegel der Topoisomerasen II α und β. iv: Es konnten schwere Herz- und Leberschäden detektiert werden (gemessen an Gldh-, Gpt- sowie cTn-I-Serumkonzentrationen), die bei einer Kobehandlung mit dem Statin nicht auftraten. Die Lova-Kobehandlung verhinderte außerdem eine durch die Doxo-Behandlung verringerte Leukozytenzahl. Molekulare Marker für frühe fibrotische Ereignisse, sowie für Inflammation und Hypertrophie waren in der Leber und im Herzen nach der Doxo-Behandlung erhöht. Das Statin war auch hier in der Lage, diese toxischen Wirkungen des Anthrazyklins zu mindern. Auch die Doxo-induzierte Expression von Surrogatmarkern für Zellantworten auf oxidativen Stress wurde in der Leber abgeschwächt. In der Leber und im Herzen wiesen die mit Doxo behandelten Tiere höhere mRNA Spiegel von an Zellzykluskontrolle beteiligten Faktoren sowie von DNA-Reparatur und Fremdstoffmetabolismus assoziierten Genen auf. Am stärksten wurde die Expression von Topoisomerase II alpha - ein molekularer Marker für Zellproliferation und bedeutsame Zielstruktur von Doxo - in der Leber hochreguliert. Die Statin-Kobehandlung verhinderte all diese Doxo-induzierten Expressionsänderungen. Im Gegensatz zur Leber wurde die Top2a-mRNA Menge im Herzen durch die Doxo-Applikation reduziert. Auch hier bewirkte die Kobehandlung mit dem Statin, dass die Expression nahe dem Kontrollniveau blieb. v: Die Kobehandlung mit Lova führte zu keinem Schutz der Tumorzellen vor Doxo, sondern erhöhte sogar dessen antineoplastisches Potential.rnFazit: Die Erkenntnisse aus vorhergegangenen in vitro Versuchen konnten zum großen Teil auf die in vivo Situation im Mausmodell übertragen werden. Sie stehen im Einklang mit Ergebnissen anderer Gruppen, welche die Inhibition kleiner GTPasen mit einer geringeren, durch zytotoxische Substanzen induzierten, Inflammation und Fibrose korrelieren konnten. Eine Kobehandlung mit Lova während einer Krebstherapie erscheint somit als vielversprechende Möglichkeit Doxo- oder IR-induzierte Nebenwirkungen auf Normalgewebe zu mildern.Background: HMG-CoA reductase inhibitors (statins) are clinically well established cholesterol lowering drugs. They also exhibit so called pleiotropic biological effects, which are considered to be independent of the inhibition of intrinsic cholesterol biosynthesis. The majority of these effects are most likely related to the inhibition of small Ras-homologous GTPases (Rho GTPases). The statin derivative lovastatin (lova) protects human endothelial cells from the cytotoxicity of ionizing radiation (IR) and the anti-cancer drug doxorubicin (doxo) in vitro. Aim: The aim of this work was to test the in vivo relevance of these results using BALB/c mice as in vivo model. To this end, different endpoints of cytotoxicity were analysed in BALB/c mice treated with IR or doxo (24 h after a single high dose of IR (i), 14 days after two low doses of IR (ii), 48 h after a single high dose of doxo (iii) and 8 days after three low doses of doxo (iv)) with or without co-treatment with lova. Possible protective effects of the statin on tumour cells were analysed by performing a xenograft experiment (v) with doses and time points analogous to treatment scheme iv. Results: Lova treatment protected normal tissue from doxo or IR induced toxicity without protecting transformed cells. Most probably, the beneficial statin effect rests on inhibition of the small GTPases Rac1 and RhoA leading to a modification of the DNA damage response. i: Statin treatment of the mice did not alter IR-induced initial formation of DNA double-strand breaks (DSBs) in the liver. However, lova co-treatment altered IR-induced stress responses as reflected by a reduced hepatic and intestinal expression of genes involved in inflammation and fibrosis. ii: IR led to an increase in mRNA expression of molecular surrogate markers for inflammation and fibrosis in the lung which was prevented by statin treatment. Additionally, co-treatment with lova protected from IR-induced reduction of platelet count without altering the IR derived decrease in leukocyte count. iii: Intraperitoneal injection of a single high dose of doxo induced DSB formation in the liver. Lova treatment reduced the level of DSBs by about 50 %. This genoprotective effect was independent from the generation of reactive oxygen species (ROS) or from altered cellular import or export of doxo. As compared to a single doxo treatment, co-treatment with lova lowered the expression of pro-inflammatory and pro-fibrotic genes in liver and heart. Additionally, lova reduced doxo-induced expression of genes coding for the AP1 complex and cell cycle control factors. Furthermore, pre-treatment with lova caused a reduction in the mRNA levels of topoisomerase II alpha and beta in the heart. iv: After multiple treatments with low dose of doxo, severe heart and liver damage was detected (reflected by cTn-I, GLDH and GPT serum concentrations) 8 days after administration of the last dose doxo. Such organ toxicities did not occur in the statin co-treated groups. The co-treatment with lova prevented doxo-induced reduction in leukocyte count. Doxo treatment elevated the mRNA levels of early fibrotic markers as well as of markers for inflammation and hypertrophy in liver and heart. Again, statin co-treatment was able to reduce these toxic effects of the anthracycline. The doxo-induced expression of genes involved in the cellular responses to oxidative stress was alleviated by the co-treatment in the liver, too. Moreover, the doxo-treated animals showed up-regulated expression of genes associated with cell cycle control, DNA repair and metabolism of xenobiotics. Doxo stimulated a high expression of topoisomerase II alpha (Top2a, a molecular marker for cell proliferation and important target of doxo) in the liver. The statin co-treatment largely mitigated all of these doxo-induced changes in gene expression. By contrast, doxo treatment caused a strong down-regulation of Top2a expression in the heart. In mice co-treated with the statin the Top2a expression remained close to the level of untreated controls. v: In the xenograft experiment co-treatment with lova did not lead to protection of subcutaneous injected human tumor cells from doxo-induced cytotoxicity. It even significantly enhanced the anti-neoplastic potential of doxo.rnConclusion: The findings from previous in vitro experiments were shown to be of relevance in vivo. The data are consistent with results from other groups which demonstrated that the inhibition of small Rho GTPases goes along with reduced inflammation or fibrosis following treatment of animals with cytotoxic drugs or ionizing radiation. Implementation of lova into current cancer-therapeutic regimen could be a promising strategy to alleviate doxo- or IR-induced adverse effects on normal tissue

Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?

The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death