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- Bard-Chapeau, Emilie A, et al.
(författare)
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Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:1
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Tidskriftsartikel (refereegranskat)abstract
- The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.
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| 6. |
- Chew, Michelle, et al.
(författare)
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No beneficial effects of levosimendan in acute porcine endotoxaemia.
- 2011
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 55, s. 851-861
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Tidskriftsartikel (refereegranskat)abstract
- Background: Levosimendan has been proposed as an attractive alternative to adrenergic agents for the treatment of sepsis-induced heart failure and haemodynamic derangements. Its use in this setting is, however, still not well investigated. The aim of this study was to test the hypothesis that levosimendan is able to attenuate endotoxin-induced pulmonary hypertension and improve myocardial function in a porcine model. The secondary aims were to investigate its effect on renal and liver function, and the plasma cytokine response. Methods: Endotoxaemia was induced in 18 pigs, randomized to placebo and Levosimendan groups. All pigs were fluid resuscitated and Noradrenalin infusion was given according to a predefined protocol. Systemic haemodynamics and myocardial function were measured using pulmonary artery catheterization and transthoracic echocardiography. Renal and liver function tests and cytokine concentrations were measured in plasma. Results: Levosimendan did not attenuate endotoxin-induced pulmonary hypertension and did not improve myocardial function. There were no differences in renal or liver function. Increases in arterial lactate and decreases in base excess were observed in the Levosimendan group, as well as significant increases in plasma interleukin (IL)-6 and IL-8. Conclusions: Contrary to our hypothesis, levosimendan given in conjunction with a protocolized vasopressor and fluid resuscitation did not improve cardiac, renal or liver function in this model of acute porcine endotoxaemia. Hyperlactataemia, acidosis and increases in plasma pro-inflammatory cytokines were observed, the mechanisms and implications of which remain unclear.
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| 7. |
- Chew, Michelle, et al.
(författare)
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Soluble CD40L (CD154) is increased in patients with shock.
- 2010
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 59, s. 979-982
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent data suggest that soluble CD40L (sCD40L) plays an important role in murine sepsis. The aim of the present study was to determine plasma levels of CD40L in critically ill patients with systemic inflammatory response syndrome (SIRS) and shock, with and without sepsis. DESIGN: A prospective observational one-centre cohort study in a mixed-bed ICU of an university hospital. Fifty-three consecutive patients fulfilling the criteria for SIRS with shock as well as seven age-matched controls were included. ELISA was used to determine sCD40L in the plasma. RESULTS: The level of sCD40L in plasma from healthy controls was 0.18 +/- 0.03 ng/ml. It was found that sCD40L levels were significantly higher in patients with non-septic shock (0.72 +/- 0.18 ng/ml) and septic shock (0.50 +/- 0.1 ng/ml). However, the levels of sCD40L were not different between these two groups of patients, or in those with low and high APACHE scores. CONCLUSION: Our data show that sCD40L is increased in patients with shock from septic and non-septic etiologies. However, further studies are needed to delineate the functional significance of sCD40L in the clinical outcome in shock patients.
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| 8. |
- Dhanani, Jayesh, et al.
(författare)
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Antimicrobial chemotherapy and lung microdialysis: a review
- 2010
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 36:6, s. 491-500
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Forskningsöversikt (refereegranskat)abstract
- Pneumonia is a form of lung infection that may be caused by various micro-organisms. The predominant site of infection in pneumonia is debatable. Advances in the fields of diagnostic and therapeutic medicine have had a less than optimal effect on the outcome of pneumonia and one of the many causes is likely to be inadequate antimicrobial concentrations at the site of infection in lung tissue. Traditional antimicrobial therapy guidelines are based on indirect modelling from blood antimicrobial levels. However, studies both in humans and animals have shown the fallacy of this concept in various tissues. Many different methods have been employed to study lung tissue antimicrobial levels with limited success, and each has limitations that diminish their utility. An emerging technique being used to study the pharmacokinetics of antimicrobial agents in lung tissue is microdialysis. Development of microdialysis catheters, along with improvement in analytical techniques, has improved the accuracy of the data. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied. These studies generally suggest that this technique is a safe and effective way of assessing the pharmacokinetics of antimicrobial agents in lung tissue. Further descriptive studies need to be conducted to study the pharmacokinetics and pharmacodynamics of different antimicrobial classes in lung tissue. Data emanating from these studies could inform decisions for appropriate dosing schedules of antimicrobial agents in pneumonia. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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- Fung, Y.L., et al.
(författare)
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Stored blood transfusion induces transient pulmonary arterial hypertension without impairing coagulation in an ovine model of nontraumatic haemorrhage.
- 2013
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Ingår i: Vox Sanguinis. - : Wiley. - 1423-0410 .- 0042-9007. ; 105:2, s. 150-158
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Transfusion of blood products in particular older products is associated with patient morbidity. Previously, we demonstrated a higher incidence of acute lung injury in lipopolysaccharide-treated sheep transfused with stored blood products. As transfusion following haemorrhage is more common, we aimed to determine whether a 'first hit' of isolated haemorrhage would precipitate similar detrimental effects following transfusion and also disrupt haemostasis. MATERIALS AND METHODS: Anaesthetized sheep had 33% of their total blood volume collected into Leukotrap bags (Pall Medical), which were processed into packed red blood cells and cross-matched for transfusion into other sheep. After 30 mins, the sheep were resuscitated with either: fresh (<5 days old) or stored (35-42 days old) ovine blood followed by 4% albumin to replacement volume, albumin alone or normal saline alone and monitored for 4 h. RESULTS: The first hit of haemorrhage precipitated substantial decreases in mean arterial pressure however haemostasis was preserved. Transfusion of stored ovine blood induced (1) transient pulmonary arterial hypertension but no oedema and (2) reduced fibrinogen levels more than fresh blood, but neither induced coagulopathy. Thus, transfusion of stored blood affected pulmonary function even in the absence of overt organ injury. CONCLUSION: The fact that stored blood transfusions: (1) did not induce acute lung injury in contrast to previous lipopolysaccharide-primed animal models identifies the 'first hit' as an important determinant of the severity of transfusion-mediated injury; (2) impaired pulmonary dynamics verifies the sensitivity and vulnerability of the pulmonary system to injury.
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| 10. |
- Ganerod, M., et al.
(författare)
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Geochronology of the Tardree Rhyolite Complex, Northern Ireland : Implications for zircon fission track studies, the North Atlantic Igneous Province and the age of the Fish Canyon sanidine standard
- 2011
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Ingår i: Chemical Geology. - : Elsevier BV. - 0009-2541 .- 1872-6836. ; 286:3-4, s. 222-228
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Tidskriftsartikel (refereegranskat)abstract
- The British-Irish Palaeogene Igneous Province (BIPIP) is part of the larger North Atlantic Igneous Province and includes the lava fields of Antrim, Mull, and Skye. The Tardree Rhyolite Complex (TRC) in Northern Ireland forms an important stratigraphic unit between the Lower and Upper Basalt Formations of the Antrim Lava Group (ALG). Previous zircon age determinations obtained from the TRC have been used as a standard in zircon fission track studies, but contradict several (40)Ar/(39)Ar sanidine and U-Pb zircon results. We provide new (40)Ar/(39)Ar sanidine and U-Pb CA-TIMS zircon ages which resolve this discrepancy. Two sanidine samples from the Sandy Braes vent and the columnar-jointed dome-forming rhyolites of Tardree Forest yield a weighted mean (40)Ar/(39)Ar age of 61.13 +/- 0.42 Ma (2 sigma, internal error). Ten U-Pb CA-TIMS zircon analyses were undertaken, eight of which employed the CA-TIMS approach on both multi-grain fractions and single grains. Six of the CA-TIMS data yield a disequilibrium-corrected weighted mean (206)Pb-(238)U age of 61.32 +/- 0.09 Ma (2 sigma). The consistency of the (40)Ar/(39)Ar ages with the CA-TIMS U-Pb zircon age, points to a closed system of both K and Ar since eruption. We propose that the crystallization age of the TRC be taken as 61.32 +/- 0.09 Ma and that the currently used age of the zircon fission track standard (58.4 +/- 0.7 Ma) be changed accordingly. This also places the eruption of the TRC in magnetochron C26r, which is consistent with the reversed polarity magnetic remanence observed in the ALG, and supports the conclusion of Ganered et al. (2010) that the Lower Basalt Formation is older than the Vaigat Formation in Western Greenland. No resolvable zircon inheritance has been detected by the TIMS analyses, consistent with the fact that the temporal and geographic extent of rhyolitic magmatism within this sector of the BIPIP was very limited, and hence was unlikely to provide inherited magmatic zircons from slightly older magmas (antecrysts). Potentially older zircon xenocrysts would be derived from the underlying Caledonian basement (>400 Ma) or yet older rocks. These should be easily detectable if the Tardree zircon was to be employed as a U-Pb zircon standard. The paired (40)Ar/(39)Ar and (206)Pb-(238)U results from this study indicate an age of 28.393 +/- 0.194 Ma for the widely used Fish Canyon sanidine standard and gives further support to the recent calibrations of Kuiper et al. (2008) and Renne et al. (2010).
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