Actin-free Gc globulin: a rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis.

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.     

A study of 100 high risk lupus pregnancies.

Certain subgroups of lupus patients and those with circulating antiphospholipid antibodies (aPL) in particular, suffer a high rate of fetal loss. Over the past 4 years, we have prospectively studied 100 pregnancies in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome. In addition to conventional methods of monitoring SLE and fetal development, we have also used Doppler flow assessment of placental perfusion from the 14th wk of pregnancy onward. Patients with the antiphospholipid syndrome and previous history of thrombotic events were treated with daily heparin (10,000 IU) and low-dose aspirin (75 mg). Those without a history of thrombosis were treated with low-dose prednisolone, azathioprine, or hydroxychloroquine. Pregnancy loss was reduced from 81.3% in 101 previous pregnancies to 36.8% in 100 pregnancies managed by us. None of the patients who received hydroxychloroquine throughout the pregnancy presented fetal malformations. Careful management and close monitoring of the lupus pregnancy has substantially improved fetal outcome.     

Fine specificity of autoantibodies to calreticulin: epitope mapping and characterization

Extracellular calreticulin (CRT) as well as anti‐CRT antibodies have been reported in patients with various autoimmune disorders and CRT has been implicated in ‘epitope spreading’ to other autoantigens such as the Ro/SS‐A complex. In addition, antibodies against parasite forms of the endoplasmic reticulum chaperone, CRT, have been found in patients suffering from onchocerciasis and schistosomiasis. In this study, we screened sera for anti‐CRT antibodies from patients with active and inactive systemic lupus ertythematosus (SLE) and primary or secondary Sjögren’s syndrome. Approximately 40% of all SLE patients were positive for anti‐CRT antibodies. The antigenic regions of CRT were determined using full length CRT and fragments of CRT prepared in yeast and Escherichia coli, respectively. Synthetic 15mer peptides corresponding to the major autoantigenic region of CRT (amino acids 1–289), each one overlapping by 12 amino acids, were used to map the B cell epitopes on the CRT protein recognized by autoimmune sera. Major antigenic epitopes were found to be associated with the N‐terminal half of the protein in 69% of the SLE sera from active disease patients, while the C‐domain was not antigenic. Major epitopes were found to be reactive with antibodies in sera from SLE patients with both active and inactive disease, spanning different regions of the N and P‐domains. Sera from both healthy and disease controls and primary Sjögren’s syndrome patients were non‐reactive to these sequences. Limited proteolysis of CRT with two major leucocyte serine proteases, elastase and cathepsin G, demonstrated that an N‐terminal region of CRT is resistant to digestion. Interestingly, some of the epitopes with the highest reactivity belong to the fragments of the protein which bind to C1q and inhibit complement activation. Whether C1q association with CRT is a pathological or protective interaction between these two proteins is currently under investigation.     

Neonatal Liver Disease Associated with Placental Transfer of Anti-mitochondrial Antibodies

Background: Anti-mitochondrial antibody is the diagnostic hallmark of primary biliary cirrhosis. Its role in the aetiology of primary biliary cirrhosis is controversial. Methods: Two cases of neonatal hepatitis seropositive for anti-mitochondrial antibody are described. Anti-mitochondrial antibody Ig isotype and epitopic specificity were investigated by immunofluorescence and enzyme immunoassays. Results: In both infants anti-mitochondrial antibody was of the G class, mainly G1 and G3 subclasses, and reacted with two synthetic peptides reproducing major M2 epitopic regions: inner lipoyl domain pyruvate dehydrogenase complex (PDC)-E2_162-176 and PDC-E3 binding protein (PDC-E3BP)_86-100. One infant also reacted with outer lipoyl domain PDC-E2_35-49, and 2-oxoglutarate dehydrogenase complex (OGDC)-E2_99-113. An identical pattern of reactivity was present in their mothers, indicating the maternal origin of the antibodies. Anti-mitochondrial antibody disappeared in the infants with the disappearance of the liver pathology. Conclusions: The simultaneous disappearance of hepatitis and anti-mitochondrial antibody in the infants suggests a possible causal link between the two.     

Accumulation of coronary artery disease risk factors over three years: data from an international inception cohort

OBJECTIVE: To examine the accumulation of risk factors over 3 years in a multicenter, international inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: The Systemic Lupus International Collaborating Clinics registry for atherosclerosis comprises 27 centers from 11 countries. An inception cohort of 935 patients with SLE was assembled, according to a standardized protocol, from 2000 to 2006 to study risk factors for atherosclerosis. Both classic and other coronary artery disease (CAD) risk factors were collected at entry and through 3 years of followup. Therapy was documented over the 3 years. The Framingham 10-year risk factor profile was calculated for each patient at year 1 and year 3. RESULTS: A total of 278 patients from the inception cohort were followed for 3 years and constituted the population for this study. At enrollment a substantial number of patients already demonstrated several risk factors for CAD, both classic and other. All risk factors increased from enrollment over the 3 years of followup. Treatment of hypertension and hypercholesterolemia also increased over 3 years, but less so for hypercholesterolemia. The Framingham 10-year CAD risk profile was higher in men than in women both at entry and at 3 years, and remained unchanged over the 3 years. Corticosteroid use increased only slightly over 3 years, but use of antimalarials and immunosuppressive agents increased to a greater extent. CONCLUSION: Patients with SLE should be monitored for CAD risk factors from the time of diagnosis and appropriate treatment should be instituted early.     

Pregnancy in granulomatous vasculitis.

OBJECTIVE--To study the fetal and maternal outcome of pregnancy in patients with granulomatous vasculitis. METHODS--Four pregnancies in two patients with Wegener's granulomatosis (WG) and one patient with Churg-Strauss syndrome (CSS) were identified and followed in our specialised clinic for pregnancy and connective tissue diseases. RESULTS--Three pregnancies ended with live babies and one with intrauterine death at 25 weeks of gestation. One WG patient remained in remission throughout pregnancy and the other experienced severe activity at 12 weeks. The CSS patient was in remission during her first pregnancy, but the disease flared severely in the second. CONCLUSIONS--Pregnancy in patients with granulomatous vasculitis requires preconceptual planning, careful clinical management, and vigorous treatment of active disease.     

Testing of a New T‐Wave Subtraction Algorithm as an Aid to Localizing Ectopic Atrial Beats

Background: Identifying the timing and morphology of an ectopic P wave from the surface electrogram can aid in the diagnosis and localization of atrial arrhythmias. Given the relatively short coupling interval of atrial ectopic beats, the P wave is often obscured by the larger amplitude QRS‐T wave complex. A method to uncover such “buried” P waves using a standard 12‐lead surface ECG would be clinically useful and could potentially be a noninvasive guide to catheter ablation of focal atrial tachycardia. Methods: We developed an automated computerized program (BARD DUO LAB SYSTEM?) designed to subtract the QRS‐T wave complex from the surface electrogram and uncover a previously obscured P wave. The purpose of the present study was to validate this program. The surface ECG from 21 patients undergoing atrial pacing during electrophysiologic study (group I) and 10 patients with atrial tachycardia (group II) were analyzed and the derived P‐wave morphology assessed using correlation waveform analysis (CWA) and visual grading by three reviewers. Results: The algorithm successfully uncovered the P wave in each surface ECG. For the 21 patients in group I, average CWA comparing the derived P wave with the previous paced P wave was 83%. Average CWA for group II was 82%. Visual grading of the match between derived P waves and paced P waves revealed a 21/21 match in group I patients and a 12/12 match in 9/10 of group II patients. Conclusions: An ectopic atrial P wave obscured by a coincident QRS‐T wave complex can be accurately uncovered using this new algorithm. Addition of this technique to existing methods may improve the diagnosis of atrial arrhythmias and aid in the localization and ablation of ectopic atrial foci.     

Ethnic and geographical variation in antiphospholipid (Hughes) syndrome

Investigation of the clinical epidemiology of the antiphospholipid syndrome (APS) is in its early stages. During the past 20 years, studies of antiphospholipid antibodies (aPL) and APS have been made in many countries and ethno-geographical groups. aPL appear to occur in all populations studied, with some variations noted in their frequency and in the clinical complications. Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus inter-ethnic differences in disease patterns may be due to environmental or genetic factors, or both.