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Operative Eingriffe am offenen Herzen wie die häufig durchgeführten Bypass- und Herzklappenersatzoperationen bedürfen fast immer der Unterstützung durch die Herz Lungenmaschine bzw. extrakorporale Zirkulation. Durch den Kontakt des Blutes mit nichtorganischen Fremdoberflächen der EKZ kommt es zur Induktion einer transienten Hyperaktivität neutrophiler Granulozyten. Nachdem Herz und Lunge nach Öffnung der Aortenklemme ihre physiologische Funktion wieder aufnehmen und reperfundiert werden, werden aus diesen ischämischen Organen darüber hinaus pathogene Moleküle wie freie Sauerstoffradikale freigesetzt. Von aktivierten Neutrophilen freigesetzte, immmunkompetente Moleküle (z.B. Zytokine) führen zusammen mit diesem oxidativen Stress zu Organdysfunktionen durch Ödembildung in Körpergeweben wie Myokard, Lunge, Gehirn und Gastrointestinaltrakt und dadurch zu typischen Folgeerscheinungen wie z.B. verlängerter postoperativer Beatmungszeit oder (meist transienten) neuropsychologischen Dysfunktionen im Sinne von kognitiven Defiziten. Andere Pathomechanismen wie Mikroembolien durch z.B. Kleinstteilchen und Gasbildungen aus dem OP Gebiet verstärken diese pathogenen Effekte. Resultat ist eine verlängerte Regenerationsdauer und ein verlängerter Krankenhausaufenthalt der operierten Patienten. Zur Minimierung dieser unerwünschten Wirkungen der EKZ wurden in den letzen 20 Jahren diverse Techniken zur Filtration der unterschiedlichen Kreislaufbestandteile innerhalb der EKZ entwickelt. Von besonderem Interesse ist die seit ca. 8 bis 10 Jahren etablierte Filtration aktivierter neutrophiler Granulozyten, die die Hauptverantwortung für das aseptische Entzündungsgeschehen unter Anwendung der EKZ tragen. Entwicklung und Einsatz dieser leukozytenspezifischen Filtersysteme führt zwar zu einer deutlichen Reduktion der zirkulierenden immunaktiven Zellen und zu einer geringgradigen Verringerung der pathogenen EKZ Folgeerscheinungen, die Effektivität der gegenwärtigen Leukozytenfiltration stellt sich allerdings nur in einzelnen Berichten als positiv dar. Die Daten, die einen deutlichen klinischen Vorteil der Leukozytenfiltration zeigen, sind nicht vorhanden. Die unterstützende Anwendung antiinflammatorischer, systemisch angewandter Pharmaka führte zwar bei den meisten Präparaten zu Erfolg versprechenden Ergebnissen im Tierversuch, konnte aber beim operierten Patienten selbst zu keiner deutlichen Verminderung der unerwünschten EKZ Wirkungen beitragen. Unter der Vorstellung, dass gefilterte, aktivierte Leukozyten zum Großteil zwar nicht in den Patientenkreislauf zurückgepumpt werden, jedoch immer noch immunaktive Stoffe von ihnen synthetisiert und sezerniert werden können, liegt es auf der Hand, dass die aktuell zum klinischen Einsatz kommenden Filtersysteme zum Zwecke der Filtrationsoptimierung und konsekutiver Pathogenitätsminimierung durchaus verbesserungsbedürftig sind. Die in Abschnitt 3 angeführten Ergebnisse belegen, dass antikörperbeschichtete Leukozytenfiltermembranen durchaus in der Lage sind, in einem Kreislaufmodell ihre entsprechenden Antigene herauszufiltern und damit zu inaktivieren. Als klinische Anwendung ist dieses Modell allerdings nur unter einem immensem Technik- sowie Kostenaufwand umsetzbar, so dass sich die Frage nach alternativen Lösungsstrategien stellt. Diese Arbeit leistete die theoretische Grundlage zur Entwicklung eines in naher Zukunft möglicherweise klinisch praktikablen Moduls zur Leukozyteninaktivierung. Da anti CD95 IgM in der Lage sind, Apoptose in CD95 Rezeptor tragenden Zellen zu induzieren und diese damit bzgl. ihrer Stoffwechselaktivität zu limitieren bzw. zu inaktivieren, konnte ein ebenfalls in Abschnitt 3 vorgestelltes Modell zeigen, dass in CD 95 Rezeptor tragenden Zellen über ihren Kontakt mit anti CD95 IgM beschichteten Leukozytenfiltermembranen Apoptose induziert werden kann. Ein detailverbessertes, anti CD95 IgM beschichtetes Leukozytenfiltersystem (Leukozyteninhibitionsmodul, „LIM“) zeigte bereits im Schweineversuch eine deutliche Verbesserung der postoperativen Herzfunktion gegenüber der Tiergruppe, die mit herkömmlichem Leukozytenfiltersystem operiert wurde. Außerdem konnte eine deutlich reduzierte Transmigrationsfähigkeit (als Maß des Aktivierungszustandes) der aus dieser EKZ isolierten Neutrophilen nachgewiesen werden, so dass Grund zur Annahme besteht, dass dieses Modell in Zukunft den herkömmlichen Leukozytenfilter ablösen könnte. Mit dieser Arbeit wurde eine Möglichkeit aufgezeigt, wie die Problematik der EKZ induzierten Immunpathogenese grundlegender bekämpft werden kann.
Background: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.
Methods: Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.
Results: Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.
Conclusions: PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
Objective We assessed the effectiveness and safety of daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in a large real-world cohort, including patients with advanced liver disease.
Design Adults with chronic HCV infection at high risk of decompensation or death within 12 months and with no available treatment options were treated in a European compassionate use programme. The recommended regimen was DCV 60 mg plus SOF 400 mg for 24 weeks; RBV addition or shorter duration was allowed at physicians' discretion. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12).
Results Of the 485 evaluable patients, 359 received DCV+SOF and 126 DCV+SOF+RBV. Most patients were men (66%), white (93%) and treatment-experienced (70%). The most frequent HCV genotypes were 1b (36%), 1a (33%) and 3 (21%), and 80% of patients had cirrhosis (42% Child–Pugh B/C; 46% Model for End-Stage Liver Disease score >10). SVR12 (modified intention-to-treat) was achieved by 91% of patients (419/460); 1 patient had virological breakthrough and 13 patients relapsed. Virological failure was not associated with treatment group (adjusted risk difference DCV+SOF minus DCV+SOF+RBV: 1.06%; 95% CI −2.22% to 4.35%). High SVR12 was observed regardless of HCV genotype or cirrhosis, liver transplant or HIV/HCV coinfection status. Twenty eight patients discontinued treatment due to adverse events (n=18) or death (n=10) and 18 died during follow-up. Deaths and most safety events were associated with advanced liver disease and not considered treatment related.
Conclusions DCV+SOF with or without RBV achieved high SVR12 and was well tolerated in a diverse cohort of patients with severe liver disease.
Trial registration number NCT0209966.
Background: Anemia is the most important complication during major surgery and transfusion of red blood cells is the mainstay to compensate for life threating blood loss. Therefore, accurate measurement of hemoglobin (Hb) concentration should be provided in real-time. Blood Gas Analysis (BGA) provides rapid point-of-care assessment using smaller sampling tubes compared to central laboratory (CL) services. Objective: This study aimed to investigate the accuracy of BGA hemoglobin testing as compared to CL services. Methods: Data of the ongoing LIBERAL-Trial (Liberal transfusion strategy to prevent mortality and anemia-associated ischemic events in elderly non-cardiac surgical patients, LIBERAL) was used to assess the bias for Hb level measured by BGA devices (ABL800 Flex analyzer®, GEM series® and RapidPoint 500®) and CL as the reference method. For that, we analyzed pairs of Hb level measured by CL and BGA within two hours. Furthermore, the impact of various confounding factors including age, gender, BMI, smoker status, transfusion of RBC, intraoperative hemodilution, and co-medication was elucidated. In order to ensure adequate statistical analysis, only data of participating centers providing more than 200 Hb pairs were used. Results: In total, three centers including 963 patients with 1,814 pairs of Hb measurements were analyzed. Mean bias was comparable between ABL800 Flex analyzer® and GEM series®: - 0.38 ± 0.15 g/dl whereas RapidPoint 500® showed a smaller bias (-0.09 g/dl) but greater median absolute deviation (± 0.45 g/dl). In order to avoid interference with different standard deviations caused by the different analytic devices, we focused on two centers using the same BGA technique (309 patients and 1,570 Hb pairs). A Bland-Altman analysis and LOWESS curve showed that bias decreased with smaller Hb values in absolute numbers but increased relatively. The smoker status showed the greatest reduction in bias (0.1 g/dl, p<0.001) whereas BMI (0.07 g/dl, p = 0.0178), RBC transfusion (0.06 g/dl, p<0.001), statins (0.04 g/dl, p<0.05) and beta blocker (0.03 g/dl, p = 0.02) showed a slight effect on bias. Intraoperative substitution of volume and other co-medications did not influence the bias significantly. Conclusion: Many interventions like substitution of fluids, coagulating factors or RBC units rely on the accuracy of laboratory measurement devices. Although BGA Hb testing showed a consistently stable difference to CL, our data confirm that BGA devices are associated with different bias. Therefore, we suggest that hospitals assess their individual bias before implementing BGA as valid and stable supplement to CL. However, based on the finding that bias decreased with smaller Hb values, which in turn are used for transfusion decision, we expect no unnecessary or delayed RBC transfusion, and no major impact on the LIBERAL trial performance.
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.
Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.
Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome.
Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.
Background: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
Methodology/Principal Findings: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.
Conclusions/Significance: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.
Background & Aims: NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care. Methods: The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months. Results: In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%. Conclusions: This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients. Lay summary: FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany
(2012)
Objectives: This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany.
Methods: Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011.
Results: 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41-86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality.
Conclusions: Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.