EASL Clinical Practice Guideline : Occupational liver diseases

A variety of chemicals have been linked to occupational liver diseases, including several solvents and mixtures thereof, pesticides, and metals. Workplace exposures have been associated with virtually the entire spectrum of acute and chronic liver diseases. However, their prevalence is inadequately quantified and their epidemiology limited. Occupational liver diseases may result from high accidental or from prolonged lower level exposures. Whereas the former is uncommon and easily recognised, the latter are relatively more frequent but often overlooked because they may display normal values of conventional markers, have an insidious onset and be asymptomatic or be obfuscated and confounded by concurrent conditions. In addition, specific tests of toxicity are not available, histopathology may not be revealing and the assessment of internal dose of chemicals is usually not decisive. Given these circumstances, the diagnosis of these liver disorders is challenging, one of exclusion and often requires an interdisciplinary approach. These recommendations offer a classification of the type of liver injuries associated with occupational exposures \u2013 based in part on the criteria for drug-induced liver injury \u2013 a grading of their severity, and the diagnostic and preventive criteria for chemically induced occupational liver disease

Inhibition of HIV-1 gene expression by Sam68ΔC: multiple targets but a common mechanism?

Two recent publications have explored the mechanisms by which a mutant of the host protein Sam68 blocks HIV-1 structural protein synthesis and expands its activity to encompass Nef. Although the two studies propose different mechanisms for the responses observed, it is possible that a common activity is responsible. Understanding how this Sam68 mutant discriminates among the multiple viral mRNAs promises to reveal unique properties of HIV-1 RNA metabolism

Understanding the pharmacokinetics of synthetic cathinones: Evaluation of the blood–brain barrier permeability of 13 related compounds in rats

This is the pre-peer reviewed version of the following article:Understanding the pharmacokinetics of synthetic cathinones: Evaluation of the blood–brain barrier permeability of 13 related compounds in rats, which has been published in final form at https://doi.org/10.1111/adb.12979. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Synthetic cathinones are the second most commonly seized new psychoactive substance family in Europe. These compounds have been related to several intoxication cases, including fatalities. Although the pharmacological effects, metabolism, and pharmacokinetics of cathinones have been studied, there is little information about the permeability of these compounds through the blood–brain barrier (BBB). This is an important parameter to understand the behavior and potency of cathinones. In this work, 13 selected cathinones have been analyzed in telencephalon tissue from Sprague–Dawley rats intraperitoneally dosed at 3 mg/kg. Our results revealed a direct relationship between compound polarity and BBB permeability, with higher permeability for the more polar cathinones. The chemical moieties present in the cathinone had an important impact on the BBB permeability, with lengthening of the α‐alkyl chain or functionalization of the aromatic ring with alkyl moieties resulting in lower concentration in telencephalon tissue. Our data suggest that transport of cathinones is a carrier‐mediated process, similar to cocaine transport across the BBB

Drawing Boundaries

In “On Drawing Lines on a Map” (1995), I suggested that the different ways we have of drawing lines on maps open up a new perspective on ontology, resting on a distinction between two sorts of boundaries: fiat and bona fide. “Fiat” means, roughly: human-demarcation-induced. “Bona fide” means, again roughly: a boundary constituted by some real physical discontinuity. I presented a general typology of boundaries based on this opposition and showed how it generates a corresponding typology of the different sorts of objects which boundaries determine or demarcate. In this paper, I describe how the theory of fiat boundaries has evolved since 1995, how it has been applied in areas such as property law and political geography, and how it is being used in contemporary work in formal and applied ontology, especially within the framework of Basic Formal Ontology

Protective effects of antiâ C5a peptide antibodies in experimental sepsis

We evaluated antibodies to different peptide regions of rat C5a in the sepsis model of cecal ligation and puncture (CLP) for their protective effects in rats. Rabbit polyclonal antibodies were developed to the following peptide regions of rat C5a: aminoâ terminal region (A), residues 1â 16; middle region (M), residues 17â 36; and the carboxylâ terminal region (C), residues 58â 77. With rat neutrophils, the chemotactic activity of rat C5a was significantly inhibited by antibodies with the following rank order: antiâ C > antiâ M â « antiâ A. In vivo, antibodies to the M and C (but not A) regions of C5a were protective in experimental sepsis, as determined by survival over a 10â day period, in a doseâ dependent manner. The relative protective efficacies of antiâ C5a preparations (in descending order of efficacy) were antiâ C â ¥ antiâ M â « antiâ A. In CLP rats, a delay in infusion of antibodies, which were injected at 6 or 12 h after CLP, still resulted in significant improvement in survival rates. These in vivo and in vitro data suggest that there are optimal targets on C5a for blockade during sepsis and that delayed infusion of antiâ C5a antibody until after onset of clinical evidence of sepsis still provides protective effects.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154417/1/fsb2fj000653fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154417/2/fsb2fj000653fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154417/3/fsb2fj000653fje-sup-0002.pd

HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells

To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and molecules capable of presenting HIV antigens to the immune system (MHC-I). To accomplish this, Nef binds to the cytoplasmic tails of both molecules and then, by mechanisms that are not well understood, disrupts the trafficking of each molecule in different ways. Specifically, Nef promotes CD4 internalization after it has been transported to the cell surface, whereas Nef uses the clathrin adaptor, AP-1, to disrupt normal transport of MHC-I from the TGN to the cell surface. Despite these differences in initial intracellular trafficking, we demonstrate that MHC-I and CD4 are ultimately found in the same Rab7+ vesicles and are both targeted for degradation via the activity of the Nef-interacting protein, β-COP. Moreover, we demonstrate that Nef contains two separable β-COP binding sites. One site, an arginine (RXR) motif in the N-terminal α helical domain of Nef, is necessary for maximal MHC-I degradation. The second site, composed of a di-acidic motif located in the C-terminal loop domain of Nef, is needed for efficient CD4 degradation. The requirement for redundant motifs with distinct roles supports a model in which Nef exists in multiple conformational states that allow access to different motifs, depending upon which cellular target is bound by Nef

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

<p>Abstract</p> <p>Objective</p> <p>To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children.</p> <p>Study design</p> <p>Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.</p> <p>Results</p> <p>21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications.</p> <p>Conclusion</p> <p>Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.</p

Porcine Sialoadhesin (CD169/Siglec-1) Is an Endocytic Receptor that Allows Targeted Delivery of Toxins and Antigens to Macrophages

Sialoadhesin is exclusively expressed on specific subpopulations of macrophages. Since sialoadhesin-positive macrophages are involved in inflammatory autoimmune diseases, such as multiple sclerosis, and potentially in the generation of immune responses, targeted delivery of drugs, toxins or antigens via sialoadhesin-specific immunoconjugates may prove a useful therapeutic strategy. Originally, sialoadhesin was characterized as a lymphocyte adhesion molecule, though recently its involvement in internalization of sialic acid carrying pathogens was shown, suggesting that sialoadhesin is an endocytic receptor. In this report, we show that porcine sialoadhesin-specific antibodies and F(ab')2 fragments trigger sialoadhesin internalization, both in primary porcine macrophages and in cells expressing recombinant porcine sialoadhesin. Using chemical inhibitors, double immunofluorescence stainings and dominant-negative constructs, porcine sialoadhesin internalization was shown to be clathrin- and Eps15-dependent and to result in targeting to early endosomes but not lysosomes. Besides characterizing the sialoadhesin endocytosis mechanism, two sialoadhesin-specific immunoconjugates were evaluated. We observed that porcine sialoadhesin-specific immunotoxins efficiently kill sialoadhesin-expressing macrophages. Furthermore, porcine sialoadhesin-specific albumin immunoconjugates were shown to be internalized in macrophages and immunization with these immunoconjugates resulted in a rapid and robust induction of albumin-specific antibodies, this compared to immunization with albumin alone. Together, these data expand sialoadhesin functionality and show that it can function as an endocytic receptor, a feature that cannot only be misused by sialic acid carrying pathogens, but that may also be used for specific targeting of toxins or antigens to sialoadhesin-expressing macrophages