Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease

Background

Quantification of hepatotocyte death is useful to evaluate the progression of alcoholic liver diseases. Our aims were to quantify and correlate the circulating levels of Cytokeratin 18 (CK18) and its caspases-generated fragment to disease severity in heavy alcoholics.

Methodology/Principal Findings

CK18 and CK18-fragment were evaluated in the serum of 143 heavy alcoholics. Serum levels of markers of hepatocyte death (CK18), apoptosis (CK18 fragment) and necrosis (CK18 -CK18 fragment) increased in patients with severe fibrosis compared to patients with mild fibrosis. These markers strongly correlated with Mallory-Denk bodies, hepatocyte ballooning, fibrosis and with hepatic TNFα and TGFβ assessed in the liver of 24 patients. Elevated levels of serum hepatocyte death and apoptotic markers were independent risk factors in predicting severe fibrosis in a model combining alkaline phosphatase, bilirubin, prothrombin index, hyaluronate, hepatocyte death and apoptotic markers. The level of markers of hepatocyte death and apoptosis had an area under the receiving operator curve that predicted severe fibrosis of 0.84 and 0.76, respectively.

Conclusion/Significance

Death of hepatocytes can be easily evaluated with serum markers and correlated with severe fibrosis in heavy alcohol drinkers. These biomarkers could be useful to rapidly evaluate liver injuries and the efficacy of therapies.     

Seaweed Oligosaccharides Stimulate Plant Growth by Enhancing Carbon and Nitrogen Assimilation, Basal Metabolism, and Cell Division

It is now well established that plant cell wall oligosaccharides can stimulate or inhibit growth and development in plants. In addition, it has been determined that seaweed (marine algae) cell wall polysaccharides and derived oligosaccharides can enhance growth in plants. In particular, oligo-alginates obtained by depolymerization of alginates from brown seaweeds increase growth of different plants by enhancing nitrogen assimilation and basal metabolism. Interestingly, oligo-alginates also stimulate growth of marine and fresh water green microalgae, increasing the content of fatty acids. On the other hand, oligo-carrageenans obtained by depolymerization of carrageenans from red seaweeds increase growth of tobacco plants by enhancing photosynthesis, nitrogen assimilation, basal metabolism, and cell division. In addition, oligo-carrageenans increase protection against viral, fungal, and bacterial infections in tobacco plants, which is determined, at least in part, by the accumulation of several phenylpropanoid compounds (PPCs) with antimicrobial activity. Moreover, oligo-carrageenans stimulate growth of 3-year-old Eucalyptus globulus trees by increasing photosynthesis, nitrogen assimilation, and basal metabolism. Furthermore, oligo-carrageenans induce an increase in cellulose content and in the level of essential oil and some PPCs with antimicrobial activities, suggesting that defense against pathogens may be also enhanced. Thus, seaweed oligosaccharides induce a dual beneficial effect in plants and trees, enhancing growth, which is determined by the increase in carbon and nitrogen assimilation, basal metabolism, and cell division, and defense against pathogens, which is determined by the accumulation of compounds with antimicrobial activities. In this sense, molecular mechanisms that potentially interconnect activation of plant growth and defense responses are discussed.     

Heterochromatin formation in Drosophila requires genome-wide histone deacetylation in cleavage chromatin before mid-blastula transition in early embryogenesis

Chromosoma - Su(var) mutations define epigenetic factors controlling heterochromatin formation and gene silencing in Drosophila. Here, we identify SU(VAR)2-1 as a novel chromatin regulator that...     

MHC Multimer-Guided and Cell Culture-Independent Isolation of Functional T Cell Receptors from Single Cells Facilitates TCR Identification for Immunotherapy

Adoptive therapy using T cells redirected to target tumor- or infection-associated antigens is a promising strategy that has curative potential and broad applicability. In order to accelerate the screening process for suitable antigen-specific T cell receptors (TCRs), we developed a new approach circumventing conventional in vitro expansion-based strategies. Direct isolation of paired full-length TCR sequences from non-expanded antigen-specific T cells was achieved by the establishment of a highly sensitive PCR-based T cell receptor single cell analysis method (TCR-SCAN). Using MHC multimer-labeled and single cell-sorted HCMV-specific T cells we demonstrate a high efficacy (approximately 25%) and target specificity of TCR-SCAN receptor identification. In combination with MHC-multimer based pre-enrichment steps, we were able to isolate TCRs specific for the oncogenes Her2/neu and WT1 even from very small populations (original precursor frequencies of down to 0.00005% of CD3⁺ T cells) without any cell culture step involved. Genetic re-expression of isolated receptors demonstrates their functionality and target specificity. We believe that this new strategy of TCR identification may provide broad access to specific TCRs for therapeutically relevant T cell epitopes.     

Cerebellar Soluble Mutant Ataxin-3 Level Decreases during Disease Progression in Spinocerebellar Ataxia Type 3 Mice

Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Förster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis.     

Working on and with Relationships: Relational Work and Spatial Understandings of Good Care in Community Mental Healthcare in Trieste

Culture, Medicine, and Psychiatry - Deinstitutionalization is often described as an organizational shift of moving care from the psychiatric hospital towards the community. This paper analyses...