SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model

Neurodegeneration in familial amyotrophic lateral sclerosis (ALS) is associated with enhanced redox stress caused by dominant mutations in superoxide dismutase-1 (SOD1). SOD1 is a cytosolic enzyme that facilitates the conversion of superoxide (O(2)(*-)) to H(2)O(2). Here we demonstrate that SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity. Oxidation of Rac1 by H(2)O(2) uncoupled SOD1 binding in a reversible fashion, producing a self-regulating redox sensor for Nox-derived O(2)(*-) production. This process of redox-sensitive uncoupling of SOD1 from Rac1 was defective in SOD1 ALS mutants, leading to enhanced Rac1/Nox activation in transgenic mouse tissues and cell lines expressing ALS SOD1 mutants. Glial cell toxicity associated with expression of SOD1 mutants in culture was significantly attenuated by treatment with the Nox inhibitor apocynin. Treatment of ALS mice with apocynin also significantly increased their average life span. This redox sensor mechanism may explain the gain-of-function seen with certain SOD1 mutations associated with ALS and defines new therapeutic targets.     

Moyamoya disease associated with hemoglobin Fairfax and beta-thalassemia

Moyamoya disease is a rare cerebrovascular condition characterized by steno-occlusive disease of the major intracranial arteries at the base of the brain, and the appearance of innumerable, tiny, arterial collaterals that resemble a "puff of smoke." Although it has been associated with hematologic diseases such as sickle-cell disease, the association with other hemoglobinopathies is less frequently observed. We describe the association of a unique hemoglobinopathy (hemoglobin Fairfax) with beta-thalassemia and moyamoya disease in a 9-year-old girl with a history of stroke. To our knowledge, this is the first report of this unstable hemoglobin with moyamoya disease, and it emphasizes the potential for cerebral infarction due to the severe anemia of hemolytic disease.     

内镜下切开术治疗难治性食管癌术后吻合口狭窄的疗效

目的 探究食管支架置入术(ESP)和内镜下切开术(EIM)在难治性食管癌术后吻合口狭窄治疗中的应用效果.方法 将70例难治性食管癌术后吻合口狭窄患者按照手术方式不同分为ESP组(n=41)与EIM组(n=29).对比两组患者临床疗效、吞咽困难评分及并发症发生情况.结果 两组患者总有效率比较,差异无统计学意义(P>0.0...     

α-葡萄糖苷酶抑制剂治疗2型糖尿病的系统评价

目的评价α-葡萄糖苷酶抑制剂治疗2型糖尿病患者的效果。方法检索Cochrane图书馆、MEDLINE、EMBASE、CurrentContents、LILACS在研试验数据库,主题为α-葡萄糖苷酶抑制剂的综述的参考文献,并联系纳入试验的专家与实施者。最近检索日期为2003年月12月(CurrentContents)和2003年4月(其他数据库)。纳入α-葡萄糖苷酶抑制剂单一疗法与其它干预比较,治疗2型糖尿病疗程至少12周的随机对照试验,并且试验至少包括以下结局之一:病死率、患病率、生活质量、血糖控制、血脂、胰岛素水平、体重、不良事件。两名评价者独立阅读所有摘要,评价质量并提取数据,分歧通过协商解决或由第三位评价者裁决。由一位统计学家在对提取数据输入数据库时进行检查。我们尽量联系所有作者以核实数据。结果共纳入41个试验、8130例受试者,其中30个针对阿卡波糖,7个针对米格列醇,1个针对优格列波糖,还有3个为不同α-葡萄糖苷酶抑制剂间的比较。绝大多数研究疗程为24周,仅有2个研究超过1年。与安慰剂相比,阿卡波糖血糖控制效果更好:糖化血红蛋白–0.8%[95%CI(–0.9,–0.7)],空腹血糖–1.1mmol/L[95%CI(–1.4,–0.9)],负荷血糖–2.3mmol/L[95%CI(–2.7,–1.9)],阿卡波糖对糖化血红蛋白的作用呈非剂量依赖。我们发现其可降低负荷胰岛素,但对血脂和体重未见临床相关的作用。不良反应主要来自胃肠道且与剂量相关。相对于磺脲,阿卡波糖将空腹和负荷胰岛素水平分别降低至–24.8pmol/L[95%CI(–43.3,–6.3)]和–133.2pmol/L[95%CI(–184.5,–81.8)],但阿卡波糖引起的不良反应更多。结论关于α-葡萄糖苷酶抑制剂是否影响2型糖尿病患者的病死率和患病率仍不清楚。相反,其对血糖控制或胰岛素水平作用明显,对血脂和体重的作用差异无统计学意义。α-葡萄糖苷酶抑制剂更长疗程的效果仍不确定。阿卡波糖剂量超过50mg(TID)时不能进一步影响糖化血红蛋白水平,不良反应反而更多,与磺脲相比,α-葡萄糖苷酶抑制剂降低了空腹和负荷胰岛素水平,但在血糖控制和不良反应方面存在不利影响。     

Drug-eluting stents during ST-segment elevation acute myocardial infarction: a critical analysis

Primary percutaneous coronary intervention is the preferred reperfusion therapy for ST-segment elevation acute myocardial infarction patients within 12 hours of symptom-onset. Routine stent implantation during the procedure significantly reduces the rate of target vessel revascularization, although restenosis still represents a current limitation of the technique. Drug-eluting stents were developed to treat and prevent coronary restenosis. Randomized trials, meta-analysis, and registries proved their efficacy and safety in different clinical situations, including acute myocardial infarction. However, the increased risk of late stent thrombosis associated with drug-eluting stents during primary percutaneous coronary interventions encourages a careful analysis to identify which patients most benefit from them, as well as those where a prolonged dual antiplatelet therapy does not represent a limiting factor.     

A respiratory hemocyanin from an insect

Insects possess an elaborate tracheal system that enables transport of gaseous oxygen from the atmosphere directly to the inner organs. Therefore, the presence of specialized oxygen-transport proteins in the circulatory system of insects has been considered generally unnecessary. Here, we show for the first time, to our knowledge, the presence of an ancestral and functional hemocyanin (Hc) in an insect. In the hemolymph of nymphs and adults of the stonefly Perla marginata, a hexameric Hc was identified, which consists of two distinct subunit types of 659 and 655 amino acids. P. marginata Hc displays cooperative oxygen binding with a moderately high oxygen affinity [(half-saturation pressure, P(50) approximately 8 torr (1 torr = 133 Pa)]. No evidence was found for the presence of Hcs in the more evolutionarily advanced holometabolan insects, suggesting that this type of respiratory protein was lost later in insect evolution. However, our results demonstrate that, in contrast to the accepted paradigm, certain basal insects have retained an ancestral blood-based mechanism of gas exchange.     

Monoclonal antibodies recognizing epitopes on the extracellular face and intracellular N-terminus of the human erythrocyte anion transporter (band 3) and their application to the analysis of South East Asian ovalocytes

This report describes the production and characterization of 13 rodent monoclonal antibodies to the human erythrocyte anion transport protein AE1 (syn. band 3). Eleven antibodies (4 murine and 7 rat) recognize epitopes dependent on the integrity of the third extracellular loop of the protein. Two antibodies (1 murine and 1 rat) recognize epitopes on the N-terminal cytoplasmic domain. Quantitative binding studies using radioiodinated IgG and Fab fragments of antibodies to extracellular epitopes on AE1 ranged from 77,000 to 313,000 (IgG) and from 241,000 to 772,000 (Fab) molecules bound at saturation. The results indicate that the epitopes recognized by different antibodies vary in their accessibility and suggest that there is heterogeneity in the organization of individual AE1 molecules in the red blood cell membrane. Quantitative binding studies on South East Asian ovalocytes using several antibodies to AE1 and an anti-Wrb show a marked reduction in the number of antibody molecules bound at saturation. These results are consistent with the existence of highly cooperative interactions between transmembrane domains of AE1 in normal erythrocytes and the disruption of these interactions in the variant AE1 found in South East Asian ovalocytes.     

Dense red blood cell and oxygen desaturation in sickle‐cell disease

Production of abnormal hemoglobin (HbS) in sickle‐cell disease (SCD) results in its polymerization in deoxygenated conditions and in sickled‐RBC formation. Dense RBCs (DRBCs), defined as density >1.11 and characterized by increased rigidity are absent in normal AA subjects, but present at percentages that vary of a patient to another remaining stable throughout adulthood for each patient. Polymerized HbS has reduced affinity for oxygen, demonstrated by the rightward shift of the oxygen‐dissociation curve, leading to disturbances in oxygen transport. Ninety‐two SCD patients' total RBCs were separated into LightDRBC (LRBC) (d < 1.11 g/mL) and DRBC fractions. Venous blood partial oxygen pressure and RBC‐fraction–deoxygenation and –reoxygenation Hb–oxygen‐equilibrium curves were determined. All patients took a 6‐minute walking test (6MWT); 10 had results before and after >6 months on hydroxyurea. 6MWT time with SpO₂ < 88% (TSpO₂ < 88) assessed the physiological impact of exertion. Elevated mean corpuscular hemoglobin (Hb) concentrations, decreased %HbF, and 2,3‐bisphosphoglycerates in DRBCs modulated Hb–oxygen affinity. Deoxygenation and reoxygenation Hb–oxygen equilibrium curves differed between normal Hb AA and SS RBCs and between LRBCs and DRBCs, with rightward shifts confirming HbS‐polymerization's role in affinity loss. In bivariate analyses, 50% Hb saturation correlated positively with %DRBCs (P < 0.0001, r² = 0.34) and negatively with %HbF (P < 0.0001, r² = 0.25). The higher the %DRBCs, the longer the TSpO₂88 (P = 0.04). Hydroxyurea was associated with significantly shorter TSpO₂ < 88 (P = 0.01). We report that the %DRBCs directly affects SCD patients' SpO₂ during exertion; hydroxyurea improves oxygen affinity and lowers the %DRBCs. Am. J. Hematol. 91:1008–1013, 2016. © 2016 Wiley Periodicals, Inc.