David Kandiah

Beta 2-glycoprotein I.

an apparent molecular weight of 50 kD and is highly glycosylated . Schultze et all reported the carbohydrate content of !32GPI as being approximately 18% of the molecular weight. When tested in phosphate buffer at pH 7.4, P2GPI existed as 40% !3-sheet, 30% 0-tum and 30% random coil. They suggested that after removal of at least 90% of the carbohydrate (deglycosylation) from P2GPI, the primary structure of the polypeptide chain is maintained but the secondary structure alters with greater number of !3-turns, accompanied by reduction in random coil structures. P2GPI inhibits contact activation of the intrinsic coagulation pathway8, platelet prothrombinase activity~ and ADPinduced platelet aggregation. P2GPI can bind negatively charged macromolecular structures other than phospholipids, including DNA&dquo;, heparin1Z, platelets 13 and negatively charged phospholipid vesicles 14

Fatigue, muscle strength and vitamin D status in women with systemic lupus erythematosus compared with healthy controls

Recent studies have demonstrated an inverse relationship between vitamin D levels and fatigue in systemic lupus erythematosus (SLE). The aims of this study were to evaluate proximal muscle strength, fatigue and vitamin D levels in women with SLE compared with healthy controls and to investigate relationships between these factors in a cohort of women with SLE. Forty-five women (24 SLE, 21 healthy controls) participated. Primary outcome measures were the fatigue severity scale (FSS), isometric muscle strength of dominant limbs using hand held dynamometry, two functional tests – the 30-second chair stand test and the 1-kg arm lift test, with vitamin D status measured using 25(OH)D. Overall 25(OH)D levels were 68.4 (22.4) nmol/L with no difference between SLE and control groups. There was a statistically and clinically significant difference in fatigue, 1-kg arm lift, 30-second sit to stand, knee extension, hip flexion, hip abduction, shoulder flexion and grip strength in the SLE group compared with the control group (p < 0.05). In the SLE group FSS was moderately correlated with both functional measures (1-kg arm lift r = −0.42, 30-second chair stand r = −0.44, p < 0.05). However, no statistically significant correlation between dynamometry measures and fatigue was evident. There was no association between fatigue and 25(OH)D level (r = −0.12). In summary, women with SLE were weaker and demonstrated reduced physical function and higher fatigue levels than healthy controls. Fatigue was related to physical function but not vitamin D status or maximal isometric strength in vitamin D replete individuals with SLE.

Review : β 2-Glycoprotein I : Target antigen for 'antiphospholipid' antibodies. Immunological and molecular aspects

It has become clear that β2-glycoprotein I (β2GPI) is the most common and best-characterised antigenic target for ‘antiphospholipid’ (aPL) autoantibodies. These antibodies preferentially bind β2GPI that has been immobilised on anionic phospholipid membranes or certain synthetic surfaces. These surfaces appear to act by increasing antigen density to allow binding of intrinsically low-affinity anti-β2GPI autoantibodies. Binding of β2GPI in fluid phase is weak and requires high concentrations of β2GPI. Our understanding of the pathophysiology of the ‘Antiphospholipid’ Syndrome (APS) has increased exponentially with the number of studies into the interactions of aPL antibodies and β2GPI.

BETA 2-GLYCOPROTEIN I : TARGET ANTIGEN FOR AUTOANTIBODIES IN THE 'ANTIPHOSPHOLIPID SYNDROME'

‘Antiphospholipid’ (aPL) antibodies are of important clinical significance because of their association with thrombosis both arterial and venous, recurrent foetal loss, specific neurological sequelae like seizures and chorea, cardiac valvular abnormalities and thrombocytopenia.1 Traditionally these autoantibodies have been assayed using phospholipid (PL) dependent tests and are classified as lupus anticoagulants (LA) and anticardiolipin (aCL) antibodies based on the method of detection.2 The antibodies thus, had been thought to bind PLs but it has now become clear that the true antigens are PL-binding proteins. The major protein consistently found as the target antigen for these autoantibodies is β2-glycoprotein I (β2-GPI).3 Other candidate PL-binding proteins have also been investigated including prothrombin, protein C and protein S4 but thus far appear to play less important roles in the binding of these antibodies.

Test–retest reliability of hand-held dynamometry and functional tests in systemic lupus erythematosus

The aim of this study was to evaluate the test–retest reliability and determine the degree of measurement error of tests of isometric muscle strength and upper and lower limb function in women with systemic lupus erythematosus (SLE). Twelve women with SLE (age 39.8 ± 10 years) were assessed on two occasions separated by a 7–10-day interval. Strength of six muscle groups was measured using a hand-held dynamometer; function was measured by the 30-s sit to stand test and the 30-s 1 kg arm lift. Relative reliability was estimated using the intraclass correlation coefficient (ICC), model 2,1 (ICC2,1). Absolute reliability was estimated using standard error measurement and the minimal detectable difference was calculated. All ICCs were greater than 0.87. Muscle strength would need to increase by between 18% and 39% in women with SLE to be 95% confident of detecting real changes. The functional tests demonstrated a systematic bias between trials. This study demonstrates that hand-held dynamometry in SLE can be performed with excellent reliability. Further work needs to be completed to determine the number of trials necessary for both the 30-s sit to stand and 30-s 1 kg arm lift to decrease the systematic bias.

A possible drug interaction between rifampicin and enalapril

SummaryWhen a 35-year-old man with essential hypertension was treated with antibiotics for brucellosis his blood pressure rose significantly. While all other treatment was kept constant rifampicin was discontinued. On rechallenge rifampicin did not alter serum concentrations of enalapril or the area under the curve (AUC) between 0 and 7 h, but it did reduce the AUC of the active metabolite enalaprilat by 31%. These observations suggest that there may be an interaction between rifampicin and enalapril, causing reduced hypotensive efficacy of enalapril. The mechanism of such an interaction merits further study, but it could be due to enhanced renal clearance of enalaprilat.

Anti-β2-glycoprotein I and anti-prothrombin antibodies in patients with the ‘antiphospholipid’ syndrome: Immunological specificity and clotting profiles

Lupus anticoagulant (LA) antibodies have been shown to be directed to protein-phospholipid complexes. In this study, we report on LA antibodies from patients with the ‘antiphospholipid’ syndrome (APS), that are directed to prothrombin and b2-glycoprotein I, but not to the complexes of these plasma proteins to anionic phospholipids. The anti-prothrombin antibodies studied had different reactivities in two clotting assays: the dilute Russells viper venom time (dRVVT) and the dilute kaolin clotting time (dKCT). Anti-prothrombin and anti-b2-glycoprotein I (anti-b2GPI) antibodies, affinity-purified from one patient with APS were not cross-reactive and had different effects in the dRVVT and dKCT clotting tests. Polyclonal anti-prothrombin antibodies, affinity-purified on a prothrombin column, from two patients with prothrombin reactivity in their plasma, have affinity constants to prothrombin of 104 and 192 nM. The patient with affinity-purified antibodies to prothrombin and b2GPI, had affinity constants to prothrombin and b2GPI, respectively, of 192 nM and 3030 nM, respectively. LA antibodies are a heterogenous population of antibodies that have different immunological specificities and clotting test reactivities in different patients.

Progression of antiphospholipid antibody syndrome to catastrophic antiphospholipid antibody syndrome acutely with cessation of antithrombotic therapy.

Catastrophic antiphospholipid antibody syndrome (CAPS) is a serious condition that is often unrecognised with a high mortality. Cessation of anticoagulation in antiphospholipid antibody syndrome (APS) can have devastating consequences with progression to CAPS. Making a diagnosis of APS can however be challenging because of the evolving diagnostic criteria and difficulty in confirming thromboses. Management of these patients can also be complex, especially in those with coexistent thrombocytopenia. New potential treatments are emerging targeted on the immunomodulation of APS rather than just prevention of thrombosis. This article aims to highlight these diagnostic and management difficulties by reporting and discussing three cases of APS with progression to CAPS following cessation of anticoagulation, one with fatal consequences, with confirmation of CAPS on autopsy, and two with successful treatment and outcomes.

The role of β2-glycoprotein I in the antiphospholipid syndrome

Antiphospholipid antibodies were originally thought to bind negatively-charged (aniomic) phospholipids. Current evidence suggests that the target antigen is considerably more complex and includes β2-glycoprotein I, a phospholipid-binding plasma protein. Our under standing of the pathophysiology of the antiphospholipid syndrome has increased exponen tially with a number of studies into the interactions of antiphospholipid antibodies and β2-glycoprotein I.

Hyperimmunoglobulin E Syndrome (Job Syndrome) Discovered in a Patient Following Corrective Spine Surgery: Case Report and Review of the Literature

Study Design. A case report of the hyperimmunoglobulin E syndrome (Job syndrome) presenting in the context of late postoperative infection after corrective surgery for scoliosis. Objective. To describe the clinical presentation and treatment of a patient with Job syndrome, and its implications for spine surgeons. Summary of Background Data. Job syndrome classically presents with a triad of increased serum immunoglobulin E, multiple abscesses, and pneumonia with pneumatocele formation. In recent years nonimmunologic manifestations have been described, including scoliosis, joint hypermobility, eosinophilia, and atopy. Methods. A 15-year-old female presented with local swelling and fever 2 years after anterior lumbar discectomy and fusion with spinal instrumentation involving T11–L3 levels. Computerized tomography revealed paravertebral, psoas, and pulmonary abscesses. The implants were removed and antibiotic therapy instituted. Further investigation revealed features of the hyperimmunoglobulin E syndrome (Job syndrome). Results. The patients symptoms resolved, as did markers of inflammation. Conclusions. Job syndrome is a primary immunodeficiency often associated with scoliosis. Given the implications for surgical outcome in immunodeficient patients, the diagnosis should be considered and, blood tests instituted in patients with scoliosis with any of the associated history and physical findings of Job syndrome.