Arrhythmogenic right ventricular dysplasia: an uncommon cause of ventricular tachycardia in young and old?

Right ventricular dysplasia is a little understood condition and is almost certainly underdiagnosed as an important cause of recurrent ventricular tachycardia and sudden death. This report describes two patients with right ventricular dysplasia. Their clinical presentation reflects the remarkable diversity of the disease while the potentially life-threatening nature of their arrhythmias and their lack of response to medical treatment justified the antiarrhythmic surgical procedure of right ventricular disarticulation.     

Melanin photoprotection in the human retinal pigment epithelium and its correlation with light-induced cell apoptosis

Time-resolved electron paramagnetic resonance (TREPR) spectroscopy was used to study melanin free radicals in human retinal pigment epithelium (RPE) cells and tyrosine-derived synthetic melanin. TREPR signal traces from RPE cells reveal in vivo light-induced melanin free radical photochemistry in more detail than previously known. Electron spin polarization reflecting a non-Boltzmann population within the energy levels of the spin system is observed in RPE cells as the result of the triplet state photoproduction and subsequent disappearance of free radicals in the melanin polymer. In a set of RPE cells cultured from individual sources, differences in optical absorption, continuous wave EPR spectra, and TREPR signals were correlated with apoptosis assays performed by flow cytometry. Continuous wave EPR spectra of RPE cells and TREPR of acidified synthetic melanin suggest that increased melanin aggregation provides an increase in photoprotection in the RPE cells that are relatively less susceptible to blue light-induced apoptosis.     

Safety and efficacy of repeat thrombolytic treatment after acute myocardial infarction.

Thrombolytic treatment for acute myocardial infarction increases the risk of subsequent reocclusion of the infarct related artery. The efficacy and safety of repeat thrombolytic treatment was assessed in 31 patients treated with streptokinase (n = 13) or tissue plasminogen activator (n = 18) a median of five days (1-716) after the first infusion. The indication for readministration was prolonged chest pain with new ST segment elevation. Efficacy was assessed by infarct artery patency at angiography at a median of eight days after readministration in 22 patients and by non-invasive criteria in 23 patients (reperfusion was deemed to be likely if serum creatine kinase was not increased or reached a peak less than 12 hours after infarction). Angiography showed patency of 70% of the infarct arteries after readministration of streptokinase and of 75% after tissue plasminogen activator. The corresponding patency rates assessed noninvasively were 73% and 75%. Reinfarction was prevented in nine (29%) patients. Allergic reactions occurred in four of eight patients who received streptokinase twice (plasmacytosis and acute reversible renal failure developed in one patient). Two patients had major bleeding and two minor bleeding, all after tissue plasminogen activator, and one of them died of cerebral haemorrhage. Repeat thrombolytic treatment results in late patency rates similar to the rates after the initial administration. Allergic reactions were common in those treated twice with streptokinase.     

Phospholipase A2 regulates eicosanoid class switching during inflammasome activation

Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA₄ receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X₇, a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2–derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X₇ results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A₂, and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro- and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.A complex network of danger-sensing receptors and bioactive peptide and lipid signals, including cytokines and eicosanoids, regulates innate immunity. Toll-like receptor (TLR) priming is suggested as a precautionary step in building a significant inflammatory response by driving production of IL-1 family protokines, which remain inactive until a second stimulus drives them to bioactive maturation and secretion (1). The second step of this process has been most strongly linked to extracellular ATP and specifically to one of its purinergic receptors, P2X₇ (2, 3), particularly in macrophages (4).TLR stimulations also increase prostaglandin synthesis by activating cytosolic phospholipase A₂ (cPLA₂) through a Ca²⁺-independent mechanism to release arachidonic acid (AA) from phospholipids, and by increasing expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E₂ synthase-1. P2X₇ stimulation activates cPLA₂ through a Ca²⁺-dependent mechanism that couples AA metabolism with 5-lipoxygenase (5-LOX)-activating protein (FLAP), Ca²⁺-activated 5-LOX, and constitutive COX-1 to form leukotrienes (LTs) and prostaglandins (PGs). Short-term (∼1 h) TLR priming of Ca²⁺ ionophore/P2X₇-activated immune cells enhances LT synthesis (5, 6), but long-term TLR priming (16–18 h) significantly suppresses LT synthesis by different cell-type–specific mechanisms (7, 8).Whereas PGE₂, PGI₂, and LTC₄ promote local edema from postcapillary venules, and LTB₄ amplifies neutrophil recruitment to initiate pathogenic killing, subsequent “class switching” to lipoxin (LX) formation by “reprogrammed” neutrophils inhibits additional neutrophil recruitment during self-resolving inflammatory resolution (9). The direct link between inflammatory commitment and resolution mediated by eicosanoid signaling in macrophages remains unclear from short-term vs. long-term priming, but the complete temporal changes and important interconnections within the entire eicosadome are now demonstrated.     

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia,even in patients with early stage disease

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high‐resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere ‘fusogenic’ range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI] = 11·6–106·4) and this was preserved in early‐stage disease patients (P < 0·0001, HR=19·3, 95% CI = 17·8–802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high‐resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.