Endothelial Injury in Scleroderma

Scleroderma, which follows rheumatoid arthritis and systemic lupus erythematosus as the third most prevalent rheumatic disorder, is poorly understood. Connective tissue abnormalities have been explored extensively (1); recently, vascular involvement has been emphasized as a unifying pathogenetic concept (2, 3). The vascular features in scleroderma include Raynaud\u27s phenomenon; an early, edematous phase of the disorder; telangiectasia; capillary abnormalities as seen by nailfold and ultrastructural microscopy; and widespread vascular pathology noted in all involved organs. The most striking histological abnormalities occur in small arteries and arterioles and consist of distinctive intimal proliferation of cells arranged concentrically in a matrix of ground substance; the cells are thought to originate from medial smooth muscle and to migrate toward the intima after injury to the endothelium (4). Evidence for endothelial injury includes: (a) the disappearance of endothelium in association with thrombosis or fibrinoid necrosis in ultrastructural studies; (b) the absence of endothelial cells within the thickened intima (4, 3) the duplication of basement membrane, a common observation in scleroderma and known to occur after endothelial perturbation in other settings. The ability to isolate, characterize, and maintain endothelial cells in vitro provides a target-cell population to study endothelial damage in scleroderma. The present report describes the effect of scleroderma serum on endothelial, smooth muscle, and fibroblast cell types. Sera from patients with scleroderma (31/52) and Raynaud\u27s syndrome (11/19) contain cytotoxic activity specific for endothelial cells which is nondialyzable, heat-stable, and elutes with albumin on gel-filtration chromatography

Scaling violation in hadron-nucleus interaction

The scaling violation within the pionization region in the energy range of 0.2 to 2.0 TeV is shown on the basis of the analysis of angular characteristics in the interactions of the cosmic radiation hadrons with the nuclei of various substances (CH2, Al, Cu, Pb)

Endothelial injury in scleroderma.

Scleroderma, which follows rheumatoid arthritis and systemic lupus erythematosus as the third most prevalent rheumatic disorder, is poorly understood. Connective tissue abnormalities have been explored extensively (1); recently, vascular involvement has been emphasized as a unifying pathogenetic concept (2, 3). The vascular features in scleroderma include Raynaud\u27s phenomenon; an early, edematous phase of the disorder; telangiectasia; capillary abnormalities as seen by nailfold and ultrastructural microscopy; and widespread vascular pathology noted in all involved organs. The most striking histological abnormalities occur in small arteries and arterioles and consist of distinctive intimal proliferation of cells arranged concentrically in a matrix of ground substance; the cells are thought to originate from medial smooth muscle and to migrate toward the intima after injury to the endothelium (4). Evidence for endothelial injury includes: (a) the disappearance of endothelium in association with thrombosis or fibrinoid necrosis in ultrastructural studies; (b) the absence of endothelial cells within the thickened intima (4, 3) the duplication of basement membrane, a common observation in scleroderma and known to occur after endothelial perturbation in other settings. The ability to isolate, characterize, and maintain endothelial cells in vitro provides a target-cell population to study endothelial damage in scleroderma. The present report describes the effect of scleroderma serum on endothelial, smooth muscle, and fibroblast cell types. Sera from patients with scleroderma (31/52) and Raynaud\u27s syndrome (11/19) contain cytotoxic activity specific for endothelial cells which is nondialyzable, heat-stable, and elutes with albumin on gel-filtration chromatography

Assembly of the Murine Leukemia Virus Is Directed towards Sites of Cell–Cell Contact

Applying 4D imaging, this study investigates the mechanism by which cell-cell contact enhances retrovirus spreading and demonstrates that viral budding is highly polarized towards sites of cell-cell contact

Guidelines for clinical pharmacological practices in Huntington's disease

OBJECTIVE: Evidence-based medicine is a difficult goal to achieve in rare diseases where randomized controlled trials are lacking. This report provides guidelines that capitalize on both the literature and expertise of the French National Huntington Disease Reference Centre to optimalize pharmacological therapeutic interventions for Huntington\u27s disease (HD). MATERIAL AND METHODS: HD experts conducted a systematic analysis of the literature from 1965 to 2013, using a scoring procedure established by the French National Authority for Health. These experts offered their views when evidence was missing to set up provisional guidelines for care in HD. These guidelines were then scored and amended through two subsequent online questionnaires (using SurveyMonkey scoring), and one face-to-face meeting with an external multidisciplinary working group as a step towards validation. RESULTS: Except for the beneficial effects of tetrabenazine in chorea, none of the published recommendations were grounded on established scientific evidence. Second-generation antipsychotics are nevertheless the first choice for patients with psychiatric manifestations (low level of evidence). All other guidelines are based on low-level evidence and little professional agreement. CONCLUSION: Patients\u27 care has greatly improved over the last few years despite the lack of high-level evidence standards. Guidelines are based on the expertise of trained specialists from the French National Plan for Rare Diseases. This strategy should now be extended internationally to promote future studies and to harmonize worldwide care of HD

Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness.

In the fourth article of a five-part series providing a global perspective on integrating mental health, Sylvia Kaaya and colleagues discuss the importance of integrating mental health interventions into HIV prevention and treatment platforms. Please see later in the article for the Editors' Summary

The Diagnostic Utility of Anti-cyclic Citrullinated Peptide Antibodies, Matrix Metalloproteinase-3, Rheumatoid Factor, Erythrocyte Sedimentation Rate, and C-reactive Protein in Patients with Erosive and Non-erosive Rheumatoid Arthritis

Objective: To compare the diagnostic utility of laboratory variables, including matrix metalloproteinase-3 (MMP-3), anti-cyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in patients with erosive and non-erosive rheumatoid arthritis (RA)

Murine Leukemia Virus Spreading in Mice Impaired in the Biogenesis of Secretory Lysosomes and Ca2+-Regulated Exocytosis

Retroviruses have been observed to bud intracellularly into multivesicular bodies (MVB), in addition to the plasma membrane. Release from MVB is thought to occur by Ca(2+)-regulated fusion with the plasma membrane.To address the role of the MVB pathway in replication of the murine leukemia virus (MLV) we took advantage of mouse models for the Hermansky-Pudlak syndrome (HPS) and Griscelli syndrome. In humans, these disorders are characterized by hypopigmentation and immunological alterations that are caused by defects in the biogenesis and trafficking of MVBs and other lysosome related organelles. Neonatal mice for these disease models lacking functional AP-3, Rab27A and BLOC factors were infected with Moloney MLV and the spread of virus into bone marrow, spleen and thymus was monitored. We found a moderate reduction in MLV infection levels in most mutant mice, which differed by less than two-fold compared to wild-type mice. In vitro, MLV release form bone-marrow derived macrophages was slightly enhanced. Finally, we found no evidence for a Ca(2+)-regulated release pathway in vitro. Furthermore, MLV replication was only moderately affected in mice lacking Synaptotagmin VII, a Ca(2+)-sensor regulating lysosome fusion with the plasma membrane.Given that MLV spreading in mice depends on multiple rounds of replication even moderate reduction of virus release at the cellular level would accumulate and lead to a significant effect over time. Thus our in vivo and in vitro data collectively argue against an essential role for a MVB- and secretory lysosome-mediated pathway in the egress of MLV

CD81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells

Hepatitis C virus (HCV) infects cells by the direct uptake of cell-free virus following virus engagement with specific cell receptors such as CD81. Recent data have shown that HCV is also capable of direct cell-to-cell transmission, although the role of CD81 in this process is disputed. Here, we generated cell culture infectious strain JFH1 HCV (HCVcc) genomes carrying an alanine substitution of E2 residues W529 or D535 that are critical for binding to CD81 and infectivity. Co-cultivation of these cells with naïve cells expressing enhanced green fluorescent protein (EGFP) resulted in a small number of cells co-expressing both EGFP and HCV NS5A, showing that the HCVcc mutants are capable of cell-to-cell spread. In contrast, no cell-to-cell transmission from JFH1ΔE1E2-transfected cells occurred, indicating that the HCV glycoproteins are essential for this process. The frequency of cell-to-cell transmission of JFH1W529A was unaffected by the presence of neutralizing antibodies that inhibit E2–CD81 interactions. By using cell lines that expressed little or no CD81 and that were refractive to infection with cell-free virus, we showed that the occurrence of viral cell-to-cell transmission is not influenced by the levels of CD81 on either donor or recipient cells. Thus, our results show that CD81 plays no role in the cell-to-cell spread of HCVcc and that this mode of transmission is shielded from neutralizing antibodies. These data suggest that therapeutic interventions targeting the entry of cell-free HCV may not be sufficient in controlling an ongoing chronic infection, but need to be complemented by additional strategies aimed at disrupting direct cell-to-cell viral transmission