Steven A. Krilis

Bio: Steven A. Krilis is an academic researcher from University of New South Wales. The author has contributed to research in topics: Beta 2-Glycoprotein I & Antiphospholipid syndrome. The author has an hindex of 52, co-authored 185 publications receiving 15113 citations. Previous affiliations of Steven A. Krilis include Commonwealth Scientific and Industrial Research Organisation & St George's Hospital.

Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H).

Abstract: Anti-phospholipid (aPL) antibodies that exhibit binding in cardiolipin (CL) ELISA can be purified to greater than 95% purity by sequential phospholipid affinity and ion-exchange chromatography. However, these highly purified aPL antibodies do not bind to the CL antigen when assayed by a modified CL ELISA in which the blocking agent does not contain bovine serum, nor do they bind to phospholipid affinity columns. Binding to the phospholipid antigen will only occur if normal human plasma, human serum, or bovine serum is present, suggesting that the binding of aPL antibodies to CL requires the presence of a plasma/serum cofactor. Using sequential phospholipid affinity, gel-filtration, and ion-exchange chromatography, we have purified this cofactor to homogeneity and shown that the binding of aPL antibodies to CL requires the presence of this cofactor in a dose-dependent manner. N-terminal region sequence analysis of the molecule has identified the cofactor as beta 2-glycoprotein I (beta 2GPI) (apolipoprotein H), a plasma protein known to bind to anionic phospholipids. These findings indicate that the presence of beta 2GPI is an absolute requirement for antibody-phospholipid interaction, suggesting that bound beta 2GPI forms the antigen to which aPL antibodies are directed. Recent evidence indicates that beta 2GPI exerts multiple inhibitory effects on the coagulation pathway and platelet aggregation. Interference with the function of beta 2GPI by aPL antibodies could explain the thrombotic diathesis seen in association with these antibodies.

The Pathogenesis of the Antiphospholipid Syndrome

Abstract: The antiphospholipid syndrome is a prothrombotic disorder associated with autoantibodies. It is associated with obstetrical complications (mainly spontaneous abortion) as well as venous and arterial thrombotic risks. Insights into disease mechanisms have led to new therapies.

Immunology and clinical importance of antiphospholipid antibodies.

Abstract: Having reviewed the literature on the association of aPL antibodies with clinical manifestations, it is clear that this group of autoantibodies are of considerable importance. The presence of aPL antibodies in some but not all individuals confers a risk of a clinical syndrome characterized by recurrent arterial or venous thrombosis, thrombocytopenia, hemolytic anemia, or positive Coombs' test, and in females, recurrent idiopathic fetal loss. In SLE, the risk is approximately 40%, compared with a risk of 15% in the absence of aPL antibodies. However, only one half of persons possessing these antibodies have SLE, and overall the risk is around 30%. In some circumstances, such as in chlorpromazine or infection-associated aPL antibodies, there appears to be no increased risk. At the other end of the spectrum are seen patients whose only clinical manifestations comprise features of this clinical syndrome, and this entity has been designated the primary antiphospholipid syndrome (PAPS). aPL antibodies are also important because they are not uncommon. They have been found frequently in women with idiopathic recurrent fetal loss (30%), in non-autoimmune patients with ischemic heart disease (20%), or venous thrombosis (up to 30%), or stroke (4-47%), and in chronic immune thrombocytopenia (30%). These autoantibodies can be detected using sensitive solid-phase immunoassays employing the CL antigen, or in appropriate coagulation tests to detect LA activity. These assays are simple to perform but require care in selection of the best test and in interpretation of results. Current tests do not distinguish between those persons at risk of the clinical events and those not at risk. Detection of specific isotypes (especially IgG) and antibody level may aid in such a designation. Treatment of aPL antibody-associated syndromes remains a controversial subject. Since thromboses are associated with significant morbidity and potential mortality, there is a good argument for long-term preventive antithrombotic therapy, at least for as long as the antibodies are detectable, in those patients in whom clinical complications have previously occurred. It is not generally recommended that this treatment be offered to individuals in whom aPL antibodies are detected but who have not suffered previous thromboses, since the risk of such events does not appear to be equal within a group of aPL antibody-positive persons. This particularly applies to pregnant women, since live births and uncomplicated pregnancies are observed regularly in the presence of aPL antibodies without specific treatment. A previous history of at least one unexplained, late fetal loss is considered a prerequisite before intervention in subsequent pregnancies.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a Task Force at the 13th International Congress on Antiphospholipid Antibodies

Abstract: The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association

Abstract: The aim of this updated guideline is to provide comprehensive and timely evidence-based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines.

Collaborative overview of randomized trials of antiplatelet therapy .1. prevention of death, myocardial-infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

Abstract: Abstract Objective: To determine the effects of “prolonged” antiplatelet therapy (that is, given for one month or more) on “vascular events” (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. Design: Overviews of 145 randomised trials of “prolonged” antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. Setting: Randomised trials that could have been available by March 1990. Subjects: Trials of antiplatelet therapy versus control included about 70 000 “high risk” patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30 000 “low risk” subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10 000 high risk patients. Results: In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20 000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P< 0.00001)); (b) among about 20 000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P<0.00001)); (c) among about 10 000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P<0.00001)); (d) among about 20 000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P<0.00001)) and 6% v 8% in 16 000 other high risk patients (one year benefit about 20/1000 (2P<0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and non: diabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one sixth in vascular death (each 2P<0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was “medium dose” (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P<0.00001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of “primary prevention” a significant reduction of one third in non: fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year benefit only about four per 1000 patients treated) and was not significant (2P=0.09). Conclusions: Among a much wider range of patients at high risk of occlusive vascular disease than is currently treated routinely, some years of antiplatelet therapy - with aspirin 75-325 mg/day or some other antiplatelet regimen (provided there are no contraindications) - offers worthwhile protection against myocardial infarction, stroke, and death. Significant benefit is evident not only among patients with unstable angina, suspected acute myocardial infarction, or a past history of myocardial infarction, stroke, or transient ischaemic attack, but also among many other categories of high risk patients (such as those having vascular procedures and those with stable angina or peripheral vascular disease). There is as yet, however, no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low risk subjects.

Comparative Protein Structure Modeling Using MODELLER

Abstract: Functional characterization of a protein sequence is a common goal in biology, and is usually facilitated by having an accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.

Allergic Rhinitis and Its Impact on Asthma

Abstract: Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada