Clinical strategies for amyloid A amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an important complication of rheumatoid arthritis (RA) and has remarkable variation in frequency worldwide. It is a serious, potentially life-threatening disorder caused by deposition in organs of AA fibrils, which are derived from the circulatory, acute-phase-reactant, serum amyloid A protein (SAA). The SAA1.3 allele can serve not only as a risk factor for the association of AA amyloidosis but also as a poor prognostic factor in Japanese RA patients. Both the association of AA amyloidosis arising early in RA disease course and symptomatic variety and severity were found in amyloidotic patients carrying the SAA1.3 allele. Etanercept for patients with AA amyloidosis who carry the SAA1.3 allele showed the amelioration of rheumatoid inflammation, including marked reduction of SAA and improvement of renal function. In light of the SAA1.3 allele significance in Japanese RA patients, both a tight control by disease-modifying antirheumatic drugs and an early intervention of biologics for RA inflammation should be applied to suppress acute-phase response, thus preventing the association of AA amyloidosis. It is suggested that SAA plays not only an important role in the development of AA amyloidosis but also interacts with events closely involved in metabolic syndrome as a high- and low-grade inflammatory modulator, respectively.     

MDS与AA患者骨髓CD34+和CD71+CD45-细胞水平的变化

本研究旨在观察MDS和AA患者骨髓血CD34＋和CD71＋CD45-细胞数的变化。2010年1月至2013年10月在河北联合大学附属医院血液科门诊和住院的25例初治MDS和43例AA患者（其中SAA18例,NSAA25例）纳入本研究。对所有患者均进行血常规、骨髓涂片、骨髓活检、染色体核型分析以及骨髓血细胞免疫分型检测（主要是CD34＋、CD71＋CD45-细胞占有核细胞的比例）;比较CD34＋和CD71＋CD45-细胞在MDs组、AA（sAA、NSAA）组中的变化;比较MDS和NSAA组CD71＋CD45-细胞数≥15％或〈15％有核细胞数的患者的外周血白细胞数、血小板数和血红蛋白含量的差异。结果表明,MDS组CD34＋数明显高于AA组、NSAA组和SAA组（P〈0．05）;MDS组CD71＋CD45-细胞数明显高于SAA组（P〈0．05）,MDS组与NSAA组间差异无统计学意义。CD71＋CD45-≥15％的MDS组外周血小板数明显高于NsAA组（P〈0．05）;而CD71＋CD45-〈15％的MDS组白细胞、血小板数和血红蛋白含量与NSAA组比较均无统计学差异（P〉0．05）。结论：MDS组CD34＋细胞数显著高于AA组和sAA组。MDS纽CD71＋CD45-细胞数显著高于sAA组。CD71＋CD45-细胞≥15％的MDS组外周血小板数显著高于NSAA组。     

Vascular endothelial growth factor confers endothelial resistance to apoptosis through poly(ADP‐ribose) polymerase

Summary. Background: Vascular endothelial growth factor (VEGF) inhibits the endothelial apoptosis that is induced by caspases during vascular remodeling; however, the underlying mechanisms have not been completely elucidated. Objectives: We hypothesized that VEGF upregulates poly(ADP‐ribose) polymerase‐1 (PARP) as a caspase mediator, and sought to investigate the link between apoptosis inhibition by VEGF and PARP regulation in the human vasculature. Methods: Human endothelial cells (primary cells, macrovascular/microvascular lines) were incubated with 100 pg mL^?1 to 1 μg mL^?1 VEGF‐A(165) in the absence or presence of PARP small interfering RNA (siRNA). Apoptosis induced by integrin inhibition was measured by flow cytometry, trypan blue exclusion, and nuclear morphology. PARP expression and activity were determined by real‐time RT‐PCR, Western blot, and ribosylation assay. VEGF receptors and signal transduction were analyzed by inhibitor experiments, enzyme assays, western blot, and immunofluorescence microscopy. Immunohistochemistry was applied to a vascular culture model and to 24 atherosclerotic and 10 normal human arteries. Results: VEGF‐A(165) induced resistance to apoptosis caused by caspase activation in endothelial cells in a time‐dependent manner. VEGF, but not fibroblast growth factor‐2 or transforming growth factor‐β, time‐dependently and dose‐dependently induced PARP expression and activity, involving VEGF receptor‐2 colocalized with neuropilin‐1 as well as the signal transduction molecules c‐Jun N‐terminal kinase and Akt. The antiapoptotic effect of VEGF was abrogated by PARP siRNA. The relationship between local VEGF influence and endothelial PARP expression was confirmed in human arteries and the vascular culture model. Conclusions: VEGF exerts its antiapoptotic effect on the endothelium through the regulation of PARP expression. PARP has been attributed an ambiguous role in apoptosis; here, we show that PARP promotes vascular endothelial integrity in VEGF‐associated processes.     

New drugs vs. old concepts: a fresh look at antiarrhythmics

Common arrhythmias, particularly atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are a major public health concern. Classic antiarrhythmic (AA) drugs for AF are of limited effectiveness, and pose the risk of life-threatening VT/VF. For VT/VF, implantable cardiac defibrillators appear to be the unique, yet unsatisfactory, solution. Very few AA drugs have been successful in the last few decades, due to safety concerns or limited benefits in comparison to existing therapy. The Vaughan-Williams classification (one drug for one molecular target) appears too restrictive in light of current knowledge of molecular and cellular mechanisms. New AA drugs such as atrial-specific and/or multichannel blockers, upstream therapy and anti-remodeling drugs, are emerging. We focus on the cellular mechanisms related to abnormal Na⁺ and Ca²⁺ handling in AF, heart failure, and inherited arrhythmias, and on novel strategies aimed at normalizing ionic homeostasis. Drugs that prevent excessive Na⁺ entry (ranolazine) and aberrant diastolic Ca²⁺ release via the ryanodine receptor RyR2 (rycals, dantrolene, and flecainide) exhibit very interesting antiarrhythmic properties. These drugs act by normalizing, rather than blocking, channel activity. Ranolazine preferentially blocks abnormal persistent (vs. normal peak) Na⁺ currents, with minimal effects on normal channel function (cell excitability, and conduction). A similar “normalization” concept also applies to RyR2 stabilizers, which only prevent aberrant opening and diastolic Ca²⁺ leakage in diseased tissues, with no effect on normal function during systole. The different mechanisms of action of AA drugs may increase the therapeutic options available for the safe treatment of arrhythmias in a wide variety of pathophysiological situations.     

Health for wealth: decomposing the role of health on productivity in England using individual and population-level longitudinal data from the UK

BackgroundThe productivity gap between the north and rest of England is around £44 billion per year. There is a substantial health gap, with mean average life expectancy 2 years lower and increased morbidity in the north. This study estimated how much of the productivity difference between the north and rest of England can be explained by poor health.MethodsAn individual analysis used data from Understanding Society: The UK Household Longitudinal Study, an annual household survey of around 40 000 households from 2008–16. A macro-level analysis used longitudinal data from the Office for National Statistics and other sources at the local-authority level from 2004–17. Analysis was restricted to individuals of working age (18–64 years) without missing data. The outcome variable was productivity, measured at the individual level by employment rate and at local-authority level by gross value added per head. The key exposure variable was health, measured at the individual level by self-reported health, presence of a long-standing illness or impairment, and mental health measured by the general health questionnaire. At the population level, health was measured by mortality and the proportion of the working-age population claiming incapacity benefit as a proxy for morbidity. We used decomposition methods to estimate how productivity differences between the north and rest of England could be explained by health.FindingsAt the individual level, 33% of the regional differences in productivity between the north and rest of England could be explained by health. Poorer physical health contributed 24% to the regional differences and higher incidence of poor mental health contributed 9%. At the local-authority level, 30% of the productivity gap between the north and rest of England could be attributed to poorer health in the north, 17% by morbidity, and 12% by premature mortality. Based on these findings, if health were the same in both regions an additional £13·2 billion gross value added would be generated.InterpretationHealth improvement focusing on the north of England can increase UK productivity and promote regional growth. Our findings are robust to different proxies of productivity. However, we cannot establish a causal relationship between health and productivity.FundingNorthern Health Service Alliance.     

Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors

Cardiac fibroblasts (CFs) play a key role in response to injury and remodeling of the heart. Nucleotide (P2) receptors regulate the heart but limited information is available regarding such receptors in CFs. We thus sought to determine if extracellular nucleotides regulate fibrotic responses (e.g., proliferation, migration and expression of profibrotic markers) of CFs in primary culture. UTP increased rat CF migration 3-fold (p < 0.001), proliferation by 30% (p < 0.05) and mRNA expression of profibrotic markers: alpha smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor beta, soluble ST2, interleukin-6 and monocyte chemoattractant protein-1 (MCP-1) by 3.0-, 15-, 2.0-, 7.6-, 11-, and 6.1-fold, respectively (p < 0.05). PAI-1 protein expression induced by UTP was dependent on protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), based on blockade by the PKC inhibitor Ro-31-8220 and the ERK inhibitor U0126, respectively. The rank order for enhanced expression of PAI-1 and α-SMA by nucleotides (UTPγS> > UDPβS> > ATPγS), the expression of P2Y2 receptors as the most abundantly expressed P2Y receptor in rat CFs and a blunted response to UTP in P2Y2^-/- mice all implicate P2Y2 as the predominant P2Y receptor that mediates nucleotide-promoted profibrotic responses. Additional results indicate that P2Y2 receptor-promoted profibrotic responses in CFs are transient, perhaps as a consequence of receptor desensitization. We conclude that P2Y2 receptor activation is profibrotic in CFs; thus inhibition of P2Y2 receptors may provide a novel means to diminish fibrotic remodeling and turnover of extracellular matrix in the heart.     

The effect of tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) on monoamine metabolism and the platelet aggregation response in human platelets

Tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) are structurally related to 5-hydroxytryptamine. Using the human platelet preparation as a model of central serotoninergic neurons the action of various tryptolines on 5-hydroxytryptamine and epinephrine metabolism have been examined. All these compounds are competitive selective inhibitors of monoamine oxidase ‘type A’, 5-hydroxytryptamine being ‘type A’ substrate. 5-hydroxytryptoline and 5-methoxytryptoline are the most active monoamine oxidase inhibitors with IC₅₀ 0.5 μm and 1.5 μm respectively using 5-hydroxytryptamine as substrate. Tetrahydro-β-carbolines are also potent uptake inhibitors of 5-hydroxytryptamine and epinephrine; a significantly greater uptake inhibitory selectivity being shown for 5-hydroxytryptamine than epinephrine. Platelet aggregation response induced by 5-hydroxytryptamine, epinephrine and adenosine 5'-diphosphate are mediated by specific receptors on the platelet. Tetrahydro-β-carbolines by themselves do not induce platelet aggregation but are potent inhibitors of 5-hydroxytryptamine and epinephrineinduced aggregation. However, they are ineffective on aggregation induced by adenosine 5'-diphosphate. The comparison of the inhibition kinetics of tetrahydro-β-carbolines for 5-hydroxytryptamine and epinephrine uptake with that of the platelet aggregation response to these amines have shown that 5-hydroxymethtryptoline, methtryptoline, and tryptolin are poor inhibitors of uptake. However, 5-hydroxymethtryptoline and tryptoline are potent inhibitors of the aggregation response. It is suggested that tryptoline derivatives can distinguish between receptors for uptake and the platelet aggregation response to 5-hydroxytryptamine. In all respects 5-hydroxytryptoline and 5-methoxytryptoline showed greater pharmacological activity than the tryptoline and methtryptoline.Although the in vivo formation of tryptolines has been a matter of controversy, they have profound pharmacological activity. This is reflected in their actions described above. The results confirm what has been observed using rat brain preparations and would suggest that human platelets can be used as a model to study the action of these compounds on central serotoinergic neurons.     

The role of aspirin in cardiovascular prevention: implications of aspirin resistance

Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.