1,721,240 research outputs found
Quantitative versus morphological assessment of liver fibrosis: semi-quantitative scores are more robust than digital image fibrosis area estimation
No full textBACKGROUND/AIM: Digital image analysis (DIA) allows quantitative assessment of fibrosis on liver biopsy. Accurate determination of a threshold greyscale level representing fibrous tissue is critical. This method has not been fully evaluated in clinical practice.METHODS: Digital images of stained liver biopsy sections were captured by microscopy and converted to greyscale. A novel method of determining the threshold greyscale value at which to measure fibrosis area was developed (peak proportion area change (PPAC)). Reproducibility was tested in comparison with standard interactive thresholding and with semi-quantitative scoring using the Histological activity index (HAI) system by a histopathologist. Fibrosis areas for different sections from the same biopsy core were also compared by each method.RESULTS: Comparison between PPAC and interactive thresholding method demonstrated superior reproducibility of the PPAC method: r > 0.7, P < 0.001 compared with r = 0.19-0.64 (not all reaching significance). On a single section, reproducibility was similar for PPAC and the modified HAI system. When different sections from the same core were compared, the HAI system was more robust.CONCLUSIONS: The PPAC method is superior to standard interactive thresholding. However, variability in DIA scores between sections invalidates the technique for clinical use and semi-quantitative scoring systems remain the gold standard for fibrosis assessment.</p
Parenchymal extinction: coagulation and hepatic fibrogenesis
No full textObservations that hepatic inflammation and cirrhosis are associated with the presence of thrombi within the hepatic microvasculature and fibrin-fibrinogen deposition have led to epidemiologic studies showing that carriage of the factor V Leiden mutation, protein C deficiency, and increased expression of factor VIII are associated with rapid progression to cirrhosis in a chronic hepatitis C virus. Additional data suggest that this process may extend more broadly to progression in many forms of chronic liver disease. This article discusses the evidence for a role for coagulation cascade activity in hepatic fibrogenesis and explores the proposed pathogenic mechanisms including the downstream events of thrombin activation. Interference with either the generation of thrombin or its downstream activity may reduce hepatic fibrosis. Also examined are the implications for future therapeutic intervention.</p
Understanding the host genetics of chronic hepatitis B and C
No full textThe outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Monocyte dysfunction in alcoholic hepatitis
Full text linkSevere alcoholic hepatitis (SAH) is the most florid form of alcohol-related liver disease (ALD). It is caused by hepatic inflammation after a prolonged period of heavy alcohol drinking. Causes of death include liver failure and infection. Inflammatory hepatic injury and systemic immunoparesis are therefore key features in disease pathogenesis.
This thesis seeks to evaluate this immune dysfunction in detail, focussing on a key component of the innate immune system, the circulating monocyte. A variety of techniques such as flow cytometry, Western blotting and polymerase-chain reaction (PCR) were used to characterise the phenotype and function of monocytes from peripheral blood. Dysfunction was then related to patient outcome and treatments administered by the randomised placebo controlled Steroids and Pentoxyfilline for Alcoholic Hepatitis (STOPAH) clinical trial.
Novel findings from this work include the identification of preserved uptake of bacteria by phagocytosis but defective monocyte oxidative burst and bacterial killing of Escherichia coli. Further, I show that the presence of this defect predicts the subsequent development of infection. In addition, this defect is associated with reduced expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme and may be treatable with N-acetylcysteine (NAC). Secondly, I identify an expanded population of an inflammatory intermediate monocyte subset in SAH that bears high expression of chemokine CC chemokine receptor type 5 (CCR-5), and may be amenable to targeted antibody therapy to reduce hepatic inflammation in SAH patients.Open Acces
Analysis of Hepatitis B in novel primary hepatocyte cultures
Full text linkCurrent model systems for the study of HBV infection and replication in vitro and in vivo are mainly based on transgenic ectopic expression of the HBV genome in either human hepatoma cell lines or transgenic mice. Failure to establish a durable cell culture using primary or tumor derived cells lines is thought to be due to the poor levels of hepatocyte differentiation. A novel primary hepatocyte culture system (LiverChip), which preserves primary hepatocyte differentiation and mimics the in-vivo microenvironment of the human liver, was used in this study to address this limitation. LiverChip provides cylindrical wells and a three- dimensional microfluidics system to culture primary hepatocytes and has been shown to reproduce microstructural features such as bile canaliculi between hepatocytes.
This study aimed to create and evaluate a cell culture system for HBV using the LiverChip system.
The objectives were:
• To determine whether infection could be established reproducibly by
exposure of cells to infected human serum
• To demonstrate the full replication cycle of HBV in the cell culture system
• To prove that viral progeny were infectious in naïve hepatocytes
• To establish whether susceptibility to infection is broadly similar across a
range of hepatocyte donors
• To investigate whether infection could be established using serum from
patients carrying either the HBeAg positive or the HBeAg negative variants
of HBV
• To investigate the interferon response to HBV infection in cell culture
Described in this study, is a novel culture system for HBV based on the culture of primary human hepatocyte in a three-dimensional microfluidics system. Each experiment was conducted over 10 to 21 days. Multiple hepatocyte donors were
i
used with infection from HBeAg+/- patient isolates (serum). Infection with HBeAg+ patient serum leads to high levels of HBV DNA being secreted longitudinally. This model system proves the infection is sustained for at least 40 days in culture. HBV infection leads to the accumulation of HBV replication intermediates inside the cell and pregenomic(pg) RNA is detectable, increasing over the course of infection. LiverChip is also able to show the secretion of high level of HBV surface antigen (HBsAg) indicating virus replication. PHH in these cultures are permissive to both HBeAg +/- patient isolates. Accumulation of covalently closed circular DNA (cccDNA), replication intermediates, pregenomic RNA as well as de novo production of significant titers of infectious virus progeny, as determined by HBsAg secretion and reinfection of naïve cells, confirms that the complete HBV life cycle is supported in vitro. In addition to HBeAg-positive isolates, infection is successfully launched in liver microtissues using HBeAg- negative patient isolates, and viral replication is inhibited upon treatment with direct acting antiviral drugs.
This project also studied in parallel to compare the robustness and susceptibility of LiverChip along with other established tissue culture system. The molecular virological characteristics of both model systems with a focus on viral kinetics and infection frequencies are explained. DNA and RNA from cultured PHH were extracted for detailed analysis, to investigate persistence of cccDNA and to evaluate the replication process of HBV. Host response to innate immune activity using NK cell/ Kupffer cell co-cultures and human cytokines production analysis was also explored using samples from LiverChip. These results were analyzed to provide a better understanding of HBV infection and the role of cccDNA in the viral cycle in disease progression of chronically infected patients. With these proven results, further research is now possible towards the cure of HBV.Open Acces
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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