Hot topics in liver transplantation: Organ allocation – extended criteria donor – living donor liver transplantation

Liver transplantation has become the mainstay for the treatment of end-stage liver disease, hepatocellular cancer and some metabolic disorders. Its main drawback, though, is the disparity between the number of donors and the patients needing a liver graft. In this review we will discuss the recent changes regarding organ allocation, extended donor criteria, living donor liver transplantation and potential room for improvement. The gap between the number of donors and patients needing a liver graft forced the transplant community to introduce an objective model such as the modified model for end-stage liver disease (MELD) in order to obtain a transparent and fair organ allocation system. The use of extended criteria donor livers such as organs from older donors or steatotic grafts is one possibility to reduce the gap between patients on the waiting list and available donors. Finally, living donor liver transplantation has become a standard procedure in specialized centers as another possibility to reduce the donor shortage. Recent data clearly indicate that center experience is of major importance in achieving good results. Great progress has been made in recent years. However, further research is needed to improve results in the future

Corynebacterium diphtheriae invasion-associated protein (DIP1281) is involved in cell surface organization, adhesion and internalization in epithelial cells

<p>Abstract</p> <p>Background</p> <p><it>Corynebacterium diphtheriae</it>, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about <it>C. diphtheriae </it>factors crucial for colonization of the host. In this study, we investigated the function of surface-associated protein DIP1281, previously annotated as hypothetical invasion-associated protein.</p> <p>Results</p> <p>Microscopic inspection of DIP1281 mutant strains revealed an increased size of the single cells in combination with an altered less club-like shape and formation of chains of cells rather than the typical V-like division forms or palisades of growing <it>C. diphtheriae </it>cells. Cell viability was not impaired. Immuno-fluorescence microscopy, SDS-PAGE and 2-D PAGE of surface proteins revealed clear differences of wild-type and mutant protein patterns, which were verified by atomic force microscopy. DIP1281 mutant cells were not only altered in shape and surface structure but completely lack the ability to adhere to host cells and consequently invade these.</p> <p>Conclusions</p> <p>Our data indicate that DIP1281 is predominantly involved in the organization of the outer surface protein layer rather than in the separation of the peptidoglycan cell wall of dividing bacteria. The adhesion- and invasion-negative phenotype of corresponding mutant strains is an effect of rearrangements of the outer surface.</p

A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

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

Association of Hepatitis C Virus—Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)—specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-γ (IFN-γ) production after specific stimulation. The highest numbers of IFN-γ—producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P < .001). Our data show that the number of IFN—γ-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infectio

Association of Hepatitis C Virus—Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)—specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-γ (IFN-γ) production after specific stimulation. The highest numbers of IFN-γ—producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P < .001). Our data show that the number of IFN—γ-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infection

Acute hepatitis C: Current status and remaining challenges

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Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection

CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists

Overlooked and undervalued: The neglected role of fauna and a global bias in ecological restoration assessments

Globally increasing rates of mine site discontinuations are resulting in the need for immediate implementation of effective conservation and management strategies. Surveying vegetation structure is a common method of assessing restoration success; however, responses of fauna to mine site restoration remain largely overlooked and understudied despite their importance within ecosystems as ecological engineers, pollinators, and restoration facilitators. Here we review the current state of the use of fauna in assessments of mine site restoration success globally, and address biases or shortcomings that indicate the assessment approach may undershoot closure and restoration success. We identified just 101 peer-reviewed publications or book chapters over a 49-year period that assess responses of fauna to mine site restoration globally. Most studies originate in Australia, with an emphasis on just one company. Assessments favour general species diversity and richness, with a particular focus on invertebrate responses to mine site restoration. Noteworthy issues included biases towards origin of study, study type, and target taxa. Further searches of the grey literature relating to fauna monitoring in mine site restoration, which was far more difficult to access, yielded six monitoring/guidance documents, three conference proceedings, two book chapters without empirical data, and a bulletin. As with peer-reviewed publications, grey literature focussed on invertebrate responses to restoration, or mentioned fauna only at the most basic level. We emphasise the need for global re-evaluation of regulatory standards to address these major limitations in assessing the capacity of the mining industry to comprehensively and representatively restore faunal communities after mining