A Successful Method of Attaining Traction in Above-Knee Amputation Patients With Intertrochanteric Hip Fractures.

Intertrochanteric fractures are a common occurrence in the general population; however, in patients with above-knee amputations, they are relatively rare. In this patient population, positioning on a fracture table presents a particularly difficult problem prior to the fixation of an intertrochanteric fracture. Here, we describe a 57-year-old man with extensive vasculopathy and reduced bone density who presents with an intertrochanteric fracture after a fall from standing.

Thioredoxin-related transmembrane protein 1 negatively regulates coagulation and phosphatidylserine exposure.

Background: Five secreted platelet protein disulfide isomerases (PDIs) and 1 transmembrane PDI regulate platelet function and thrombosis. Thioredoxin-related transmembrane protein 1 (TMX1) was the first member of the PDI family found to negatively regulate platelet aggregation and platelet accumulation . The effect of TMX1 on coagulation is unknown.

Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis.

There have been substantial advances in vascular protein disulfide isomerases (PDIs) in platelet function and thrombosis in recent years. There are 4 known prothrombotic thiol isomerases; PDI, endoplasmic reticulum protein (ERp)57, ERp72, and ERp46, and 1 antithrombotic PDI; transmembrane protein 1. A sixth PDI, ERp5, may exhibit either prothrombotic or antithrombotic properties in platelets.

Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma.

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11).

Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis.

VEGFR2 signaling in endothelial cells (ECs) is regulated by reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) and mitochondria, which plays an important role in postnatal angiogenesis. However, it remains unclear how highly diffusible ROS signal enhances VEGFR2 signaling and reparative angiogenesis. Protein disulfide isomerase A1 (PDIA1) functions as an oxidoreductase depending on the redox environment.

A novel role for endoplasmic reticulum protein 46 (ERp46) in platelet function and arterial thrombosis in mice.

Although several members of protein disulfide isomerase (PDI) family support thrombosis, other PDI family members with the CXYC motif remain uninvestigated. ERp46 has 3 CGHC redox-active sites and a radically different molecular architecture than other PDIs. Expression of ERp46 on the platelet surface increased with thrombin stimulation.

Vascular thiol isomerases in thrombosis: The yin and yang.

There has recently been considerable progress of the field of extracellular protein disulfide isomerases with vascular thiol isomerases in the forefront. Four members of protein disulfide isomerase (PDI) family of enzymes, PDI, ERp57, ERp72, and ERp5, have been shown to be secreted from activated platelets and endothelial cells at the site of vascular injury. Each isomerase individually supports platelet accumulation and coagulation, as indicated by multiple levels of evidence, including inhibitory antibodies, targeted knockout mice, and mutant isomerases.

Mediastinal Lymphoma Presenting in Cardiogenic Shock with Superior Vena Cava Syndrome in a Primigravida at Full Term: Salvage Resection after Prolonged Extracorporeal Life Support.

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare type of non-Hodgkin lymphoma that typically has a good response rate to first line chemotherapy regimens. There have been reports of successful chemotherapy, but with a residual mass from fibrosis. Here, we report the case of a 19-year-old primigravida presenting with cardiogenic shock and superior vena cava (SVC) syndrome at full term who was found to have a PMBCL.

The b' domain of protein disulfide isomerase cooperates with the a and a' domains to functionally interact with platelets.

Essentials Protein disulfide isomerase (PDI) interacts with the αIIbβ3 integrin on platelets We generated PDI domain fragments and full-length PDI containing point mutations PDI interacts with αIIbβ3 through the b' domain, with the a and a' domains contributing This is the first report demonstrating PDI binding to a native protein on intact cells SUMMARY: Background Protein disulfide isomerase (PDI) is an oxidoreductase consisting of four domains arranged in the order a-b-b'-a' with an x-linker between the b' and a' domains. PDI binds to α β integrin on activated platelets, and potentiates activation of this integrin through the C-terminal CGHC active-site motif. How PDI binds to platelet α β is unknown.

The transmembrane protein disulfide isomerase TMX1 negatively regulates platelet responses.

Secreted platelet protein disulfide isomerases, PDI, ERp57, ERp5, and ERp72, have important roles as positive regulators of platelet function and thrombosis. Thioredoxin-related transmembrane protein 1 (TMX1) was the first described transmembrane member of the protein disulfide isomerase family of enzymes. Using a specific antibody, the recombinant extracellular domain of TMX1 (rTMX1) protein, a knockout mouse model, and a thiol-labeling approach, we examined the role of TMX1 in platelet function and thrombosis.

Multiple protein disulfide isomerases support thrombosis.

Purpose Of Review: The present review provides an overview of recent findings on new members of the protein disulfide isomerase (PDI) family required for thrombosis.

Recent Findings: Twenty years ago PDI was shown to mediate platelet aggregation, and 10 years ago PDI was shown to support thrombosis in vivo. Subsequently, other members of this endoplasmic reticulum family of enzymes, ERp57 and ERp5, were demonstrated to support thrombosis.

Protein disulfide isomerase enhances tissue factor-dependent thrombin generation.

Protein disulfide isomerase (PDI) plays an important role in fibrin generation in vivo, but the underlying mechanism remains largely unknown. In this study, using thrombin generation assay (TGA), we investigated whether PDI contributes to tissue factor (TF)-mediated thrombin generation. Human peripheral blood mononuclear cells (PBMCs) were treated with 100 ng/ml lipopolysaccharide (LPS), the expression of TF on cell surface was analyzed by flow cytometry.

Immunohistochemical Analysis of Scarring Trachoma Indicates Infiltration by Natural Killer and Undefined CD45 Negative Cells.

Introduction: The phenotype and function of immune cells infiltrating the conjunctiva in scarring trachoma have yet to be fully characterized. We assessed tissue morphology and immunophenotype of cellular infiltrates found in trachomatous scarring compared to control participants.

Methodology: Clinical assessments and conjunctival biopsy samples were obtained from 34 individuals with trachomatous scarring undergoing trichiasis surgery and 33 control subjects undergoing cataract or retinal detachment surgery.

P2Y12 receptor inhibition and LPS-induced coagulation.

Platelets play a major role in the complex interactions involved in blood coagulation via multiple mechanisms. As reported in this issue, Schoergenhofer et al. tested the hypothesis that platelet inhibition by prasugrel, a potent platelet P2Y12 ADP receptor antagonist, attenuates the effect of lipopolysaccharide (LPS) on the blood coagulation system in healthy human subjects.

The C-terminal CGHC motif of protein disulfide isomerase supports thrombosis.

Protein disulfide isomerase (PDI) has two distinct CGHC redox-active sites; however, the contribution of these sites during different physiologic reactions, including thrombosis, is unknown. Here, we evaluated the role of PDI and redox-active sites of PDI in thrombosis by generating mice with blood cells and vessel wall cells lacking PDI (Mx1-Cre Pdifl/fl mice) and transgenic mice harboring PDI that lacks a functional C-terminal CGHC motif [PDI(ss-oo) mice]. Both mouse models showed decreased fibrin deposition and platelet accumulation in laser-induced cremaster arteriole injury, and PDI(ss-oo) mice had attenuated platelet accumulation in FeCl3-induced mesenteric arterial injury.

The disulfide isomerase ERp57 is required for fibrin deposition in vivo.

Background: ERp57 is required for platelet function; however, whether ERp57 contributes to fibrin generation is unknown.

Methods And Results: Using an inhibitory anti-ERp57 antibody (mAb1), Pf4-Cre/ERp57(fl/fl) mice, Tie2-Cre/ERp57(fl/fl) mice, and mutants of ERp57, we analyzed the function of ERp57 in laser-induced thrombosis. Fibrin deposition was decreased in Pf4-Cre/ERp57(fl/fl) mice, consistent with a role for platelet ERp57 in fibrin generation.

Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin.

The platelet protein disulfide isomerase called ERp57 mediates platelet aggregation, but its role in thrombus formation is unknown. To determine the specific role of platelet-derived ERp57 in hemostasis and thrombosis, we generated a megakaryocyte/platelet-specific knockout. Despite normal platelet counts and platelet glycoprotein expression, mice with ERp57-deficient platelets had prolonged tail-bleeding times and thrombus occlusion times with FeCl3-induced carotid artery injury.

The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis.

A close homologue to protein disulfide isomerase (PDI) called ERp57 forms disulfide bonds in glycoproteins in the endoplasmic reticulum and is expressed on the platelet surface. We generated 2 rabbit Abs to ERp57. One Ab strongly inhibited ERp57 in a functional assay and strongly inhibited platelet aggregation.

Vicinal thiols are required for activation of the αIIbβ3 platelet integrin.

Background:  Closely spaced thiols in proteins that interconvert between the dithiol form and disulfide bonds are called vicinal thiols. These thiols provide a mechanism to regulate protein function. We previously found that thiols in both αIIb and β3 of the αIIbβ3 fibrinogen receptor were required for platelet aggregation.

In vitro target validation and in vivo efficacy of p38 MAP kinase inhibition in established chronic collagen-induced arthritis model: a pre-clinical study.

Objectives: The aim of the present study was to determine the in vivo efficacy of p38 mitogen-activated protein kinase (MAPK) inhibitors, namely GW856553X and GSK678361, in murine models of arthritis.

Methods: The effect of p38 MAPK inhibitors was tested in 2 variants of the collagen-induced arthritis model (CIA) in DBA/1 mice, acute arthritis induced by heterologous collagen and chronic relapsing arthritis induced by homologous collagen. Animals were treated after onset of arthritis.

Myofibroblast distribution in Dupuytren's cords: correlation with digital contracture.

Purpose: Dupuytren's tissue has typically been described as being composed of myofibroblast-rich palmar nodules and relatively acellular tendon-like cords. We aimed to determine myofibroblast distribution (alpha-smooth muscle actin [alpha-SMA] positive cells) within Dupuytren's tissue and to correlate histologically defined alpha-SMA-positive nodules with digital contracture and recurrent disease.

Methods: One hundred and three digital Dupuytren's cords (72 fasciectomy, 31 dermofasciectomy) were stained with anti-alpha-SMA antibody.

Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis.

Objective: Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO.

Methods: Arthritis was induced by immunization with type II collagen.