Agonistic autoantibody-mediated disease

Agonistic antibodies that stimulate G protein-coupled receptors are accepted as causing diseases of the thyroid gland. Agonistic anti-thyrotropin receptor antibodies (TSAb) that mimic the action of thyrotropin (TSH) characterize Graves' disease. Nonetheless, the immunological mechanisms of TSAb production remain obscure. Autoantibodies directed against specific epitopes in the insulin receptor are rarely the cause of either recurrent hypoglycemia or a severe form of insulin resistance (type B insulin resistance). In cancer chemotherapy, antibodies against the death receptors DR4 and DR5 of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) are interesting therapeutic targets, since agonistic antibodies against DR5 and DR2 induce apoptosis in cancer cells. Furthermore, agonistic anti-CD40 antibodies profoundly suppress the immune response to infection with lymphocytic choriomeningitis virus.4 Thus agonistic antibodies directed against cell-surface receptors appear to have an in vivo functional capacity. © 2009 Elsevier Inc. All rights reserved

Normal and abnormal volume homeostasis

This chapter describes changes in volume, renin–angiotensin–aldosterone, and other mineralocorticoids in abnormal pregnancies such as preeclampsia. Pregnancy is a physiologic process where repeated adjustments occur in the steady state marked by changes in both intracellular and extracellular volume. Each new steady state value is then held within relatively narrow limits, that is, these changes are sensed as normal and “defended” in face of variations in fluid and sodium intake. There is a 30–50% increase in extracellular fluid (ECF), plasma, and blood volume (associated with 30–50% increases in cardiac output, glomerular filtration rate (GFR) and renal blood flow. Women who develop preeclampsia seem to fall into two subgroups: those who experience an abnormal shift of ECF from the vascular to the extravascular compartment, and those with a total reduction of ECF volume. This dichotomy may possibly reflect different disturbances in the normal volume homeostatic mechanisms of pregnancy. Women with preeclampsia/eclampsia have significantly reduced plasma volumes. The degree of contraction appears to be an index of severity, and in this respect the greatest decreases have been reported in nulliparas with eclampsia, the convulsive phase of the disease associated with extreme severity

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: Results from the BIOSIGNAL study

Aims: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. Methods and results: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). Conclusion: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease. © 2021 Published on behalf of the European Society of Cardiology. All rights reserved