Design and characterization of novel activated protein C variants for the proteolysis of cytotoxic extracellular histone H3.

Background: Extracellular histone H3 is implicated in several pathologies including inflammation, cell death, and organ failure. Neutralization of histone H3 is a strategy that was shown beneficial in various diseases, such as rheumatoid arthritis, myocardial infarction, and sepsis. It was shown that activated protein C (APC) can cleave histone H3, which reduces histone cytotoxicity.

[Tubulointerstitial nephritis and uveitis syndrome].

Background: Uveitis and acute renal failure can be seen in various immune-mediated systemic diseases. Here we present a case of a young man with a rare inflammatory oculorenal syndrome.

Case Report: A man in his thirties was admitted with a constellation of fatigue, flank pain, weight loss and bilateral acute anterior uveitis.

Tolerability and safety of long-term rituximab treatment in systemic inflammatory and autoimmune diseases.

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs.

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.

[This corrects the article DOI: 10.1186/s13054-016-1208-6.].

Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients.

Objective: Sepsis is a leading cause of death worldwide. Extracellular histones are cytotoxic compounds mediating death in murine sepsis and circulating nucleosome levels predict mortality in human inflammation and sepsis. Whether or not circulating extracellular histone H3 correlates with other plasma parameters and/or ICU scoring systems has not been completely established, nor if levels of circulating extracellular histones can be used as predictive markers for clinical outcome in sepsis.

Effects of exogenous recombinant APC in mouse models of ischemia reperfusion injury and of atherosclerosis.

Activated protein C (APC) is a serine protease that has both anticoagulant and cytoprotective properties. The cytoprotective effects are protease activated receptor 1 (PAR-1) and endothelial protein C receptor (EPCR) dependent and likely underlie protective effects of APC in animal models of sepsis, myocardial infarction and ischemic stroke. S360A-(A)PC, a variant (A)PC that has no catalytic activity, binds EPCR and shifts pro-inflammatory signaling of the thrombin-PAR-1 complex to anti-inflammatory signaling.

Identification of novel small molecule inhibitors of activated protein C.

Introduction: Activated protein C (APC) is the central enzyme of the anticoagulant protein C pathway. Low concentrations of APC circulate in plasma and are believed to contribute to the maintenance of a normal haemostatic balance.

Materials And Methods: We have used a structure-based virtual screening approach to discover small drug-like molecules that inhibit the interaction between APC and its substrate FVa through inhibition of a predominant APC exosite, known to be involved in FVa substrate binding.

Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis.

Extracellular histones are considered to be major mediators of death in sepsis. Although sepsis is a condition that may benefit from low-dose heparin administration, medical doctors need to take into consideration the potential bleeding risk in sepsis patients who are already at increased risk of bleeding due to a consumption coagulopathy. Here, we show that mechanisms that are independent of the anticoagulant properties of heparin may contribute to the observed beneficial effects of heparin in the treatment of sepsis patients.

The structure-function relationship of activated protein C. Lessons from natural and engineered mutations.

Protein C is the central enzyme of the natural anticoagulant pathway and its activated form APC (activated protein C) is able to proteolyse non-active as well as active coagulation factors V and VIII. Proteolysis renders these cofactors inactive, resulting in an attenuation of thrombin formation and overall down-regulation of coagulation. Presences of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity.

Inhibition of thrombin formation by active site mutated (S360A) activated protein C.

Activated protein C (APC) down-regulates thrombin formation through proteolytic inactivation of factor Va (FVa) by cleavage at Arg(506) and Arg(306) and of factor VIIIa (FVIIIa) by cleavage at Arg(336) and Arg(562). To study substrate recognition by APC, active site-mutated APC (APC(S360A)) was used, which lacks proteolytic activity but exhibits anticoagulant activity. Experiments in model systems and in plasma show that APC(S360A), and not its zymogen protein C(S360A), expresses anticoagulant activities by competing with activated coagulation factors X and IX for binding to FVa and FVIIIa, respectively.

Development of sarcoidosis following etanercept treatment: a report of three cases.

After over 10 years of use of tumor necrosis factor-alpha (TNF-α) inhibitors, their side effects and complications are reasonably well documented. Recently, however, granulomatous reactions and cases of complete sarcoidosis have been reported, especially in patients treated with the TNF-α receptor protein, etanercept. This is intriguing because the TNF-α antibody drugs infliximab and adalimumab are reportedly used to treat sarcoidosis.

Intravenous cyclophosphamide in patients with chronic systemic inflammatory diseases: morbidity and mortality.

Background: Few data exist concerning the development of malignancies and haemorrhagic cystitis in patients with systemic autoimmune diseases previously treated with intravenous (iv) cyclophosphamide (CYC). The use of mesna prophylaxis is also controversial.

Methods: The medical records of all patients with chronic systemic inflammatory diseases treated with iv or oral CYC at Stavanger University Hospital from 1985 to 1999 were reviewed.

Anti-CD20 therapy of treatment-resistant Wegener's granulomatosis: favourable but temporary response.

Rituximab is a genetically engineered chimeric monoclonal immunoglobulin (Ig)G1 antibody. It binds the CD20 trans-membrane surface antigen expressed by mature B cells but not by antibody secreting plasma cells, and removes the cells by activating complement, inducing cell-mediated lysis, and by apoptosis. Mainly used for the treatment of non-Hodgkin's lymphomas, rituximab has recently been tried with favourable responses in rheumatoid arthritis, systemic lupus erythematosus, and other chronic immunological diseases.

[Mycophenolate mofetil--a new therapeutic agent for chronic autoimmune diseases].

Background: Mycophenolate mofetil is an immunosuppressive agent frequently used in regimens to prevent allograft rejection. In this review we focus on mycophenolate mofetil as a potential drug for chronic autoimmune diseases.

Materials And Methods: We searched PubMed for relevant literature and present two case histories.

Respiratory arrest in systemic lupus erythematosus due to phrenic nerve neuropathy.

Diaphragmatic weakness in patients with systemic lupus erythematosus (SLE) is a controversial issue and is claimed to have a neuropathic, myopathic or unknown pathogenesis. In this patient a predominantly motor neuropathy with diaphragmatic paralysis due to axonal involvement of the phrenic nerve was discovered and successfully treated with immunosuppressive drugs.

Detection of Ureaplasma urealyticum in urine of patients with systemic lupus erythematosus and healthy individuals by culture and polymerase chain reaction.

A method was developed to detect Ureaplasma urealyticum in urine by the polymerase chain reaction (PCR). A 457-bp fragment of the urease gene of U. urealyticum was amplified by PCR.

Positron emission tomography and magnetic resonance imaging for cerebral involvement in patients with systemic lupus erythematosus.

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI.

Drug-related lupus in a patient with rheumatoid arthritis under sulfasalazine treatment.

The induction of lupus-like syndromes with the appearance of single-stranded DNA antibodies is a well-known complication of drug therapy. In this report we present a patient with an erosive seropositive rheumatoid arthritis developing the clinical and serological features of systemic lupus erythematosus including the occurrence of double-stranded DNA antibodies under sulfasalazine treatment.

Follow-up of patients with double stranded DNA antibodies induced by sulfasalazine during the treatment of inflammatory rheumatic diseases.

Twenty-four patients with chronic inflammatory joint diseases developed double stranded DNA (dsDNA) antibodies during sulfasalazine (SAS) therapy and 20 of these 24 patients could be followed over a mean period of 11 months. Only one of the patients showed clinical symptoms of systemic lupus erythematosus (SLE). DsDNA antibodies were transient in two thirds of the patients discontinuing SAS treatment and in the same proportion of the individuals who did not interrupt this medication.

Positron emission tomography in neuropsychiatric lupus erythematosus.

We performed positron emission tomography (PET) using 18F-labeled 2-F-2-deoxyglucose in 13 patients with systemic lupus erythematosus (SLE). Ten of them had clinical signs of central nervous system involvement (NP-SLE). All patients with neurologic symptoms showed pathologic changes on PET, always in accordance with the clinical state.

[Imaging diagnosis of central nervous system involvement in panarteritis nodosa].

Central nervous system involvement of periarteritis nodosa is a rare complication of this disease. The diagnosis of CNS manifestation in vasculitis has been improved by using imaging techniques (i.e.

[Use of fluorodeoxyglucose PET in the diagnosis of central nervous system lupus erythematosus and a comparison with CT and MRI].

Central nervous system involvement has been found in 30-75% of all cases of systemic lupus erythematosus (SLE). Up to now, clinical diagnosis is difficult and there are no markers for disease activity. We have compared cranial computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) using fluorodesoxyglucose (FDG) in two cases.