Decreased specific anti-elastase activity in the uninvolved skin of patients with psoriasis

Summary Inhibitory activities against elastase, chymotrypsin and trypsin were studied in the fluid from experimentally developed suction blisters in the uninvolved skin of patients with psoriasis. These activities determined by spectrophotometry of specific synthetic low molecular weight substrates were compared with respective antiproteinase activities in sera of 32 patients with psoriatic lesions, ten patients in remission, and ten healthy volunteers. A marked reduction (29.2%) in the specific elastase inhibitory activity of blister fluid was found in patients with psoriasis when compared with normal subjects (p<0.05), since neither chymotrypsin nor trypsin inhibitory activities were altered. This reduction was despite about a 30% increase in the elastase inhibitory activity in the sera of these patients, which was related presumably to their increased activity of ₁-proteinase inhibitor, the main serum antiserine proteinase inhibitor. A decreased blister fluidserum elastase inhibition ratio was shown in a large majority of patients with psoriasis, even in symptomless patients. The deficiency in specific elastase inhibitory activity of suction blister fluid was predominantly associated with early onset of psoriasis, guttate lesions and inactive lesions, skin involvement less than 20% of body surface, duration of relapse shorter than 2 months, and frequent relapses. These data indicate that the uninvolved skin of patients with psoriasis contains low concentrations of specific elastase tissue inhibitor, which deficiency might result in an excessive in vivo hydrolytic activity of neutrophil elastase released from migrating cells in the psoriatic skin.     

脑室注射左旋硝基精氨酸对短暂性前脑缺血时迟发性神经元坏死的影响

目的 研究一氧化氮合酶抑制剂在短暂笥前脑缺血再灌注损伤中的作用。方法 钳夹沙土鼠的双侧颈总动脉制造脑缺血模型,应用尼氏染色观察迟发性神经元坏死的分布与。结果 短暂性前脑缺血导致海马ＣＡ１区锥体细胞迟发性神经元坏死,一氧化氮合酶抑制剂左旋硝基精氨酸（Ｌ－ＮＮＡ）明显地减少了迟发性神经元坏死。结论Ｌ－ＮＮＡ可能通过抑制ＮＯＳ对脑缺血起保护作用。     

卡托普利对家兔动脉粥样硬化纤溶酶原激活物抑制物-1基因表达的影响

目的　研究卡托普利对家兔动脉粥样硬化纤溶酶原激活物抑制物 - 1(PAI- 1)基因表达的影响。方法　37只家兔随机分为正常对照组、胆固醇喂养组、卡托普利组 ,饲养 12周。取一段靠近升主动脉起始部的动脉做常规病理切片 ,一近端胸主动脉抽提总RNA ,应用逆转录多聚酶链式反应测定PAI- 1mRNA的表达。结果　卡托普利尽管不影响血浆总胆固醇水平 ,但能抑制动脉粥样硬化的形成。而 3组动脉壁PAI - 1mRNA的相对值分别为 0 5 10± 0 0 75、1 32 1± 0 0 5 6、0 6 87± 0 119,相互间有统计学差异 (P <0 0 1)。结论　卡托普利能抑制动脉粥样硬化时PAI- 1基因的过度表达 ,这种作用可能是血管紧张素转化酶抑制剂治疗效益的重要机制之一。     

新型一氧化氮合酶抑制剂对败血性休克大鼠升压作用的研究

观察一种新型一氧化氮合酶抑制剂对败血性休克大鼠血压的影响。结果表明该化合物有明显增加败血休克大鼠血压的作用,且优越必硝基精氨酸,可能开发出新的ＮＯＳ抑制剂。     

LIMK与结直肠癌关系的研究进展

目的 了解LIM激酶(LIMK)与结直肠癌的关系,为结直肠癌的转移、侵袭及靶向治疗提供研究依据.方法 复习近年来国内外关于LIMK的结构功能以及其与结直肠癌关系研究进展的相关文献并加以综述.结果 LIMK及其主要通路ROCK/LIMK/cofilin及PAK/LIMK/cofilin上下游因子均参与了肿瘤细胞周期进展、...     

A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent

Summary. Background: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen. Objectives: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2. Patients/Methods: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg^?1; cohort 2 (n = 6) received 1.0 mg kg^?1; cohort 3 (n = 6) received 3.0 mg kg^?1; and cohort 4 (n = 8) received 2.0 mg kg^?1. In cohorts 1–3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single‐dose (n = 4) or multidose (n = 4) anivamersen. Results: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 μg mL^?1 at 84 h, 5.19 μg mL^?1 at 72 h, 9.32 μg mL^?1 at 90 h, and 32.5 μg mL^?1 at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half‐life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed. Conclusions: In our first‐in‐human study, REG2 was well tolerated and provided dose‐proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics.     

Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma

Summary. Background: Tissue factor pathway inhibitor (TFPI) is the major inhibitor of tissue factor‐initiated coagulation, making it an interesting and novel therapeutic target in hemophilia treatment. The aptamer BAX499 (formerly ARC19499) is designed to improve hemostasis by specifically inhibiting TFPI. Objectives: The aim of the study was to examine the concentration‐dependent augmentation of clotting by BAX499. Methods: Whole blood clot formation was quantified by rotational thromboelastometry and thromboelastography, and thrombin generation in platelet‐poor plasma was assessed with the calibrated automated thrombogram, in samples from patients with congenital hemophilia A (N = 55) and B (N = 11), patients with acquired hemophilia A (N = 1), and healthy controls (N = 37). Results: BAX499 significantly improved clotting of samples from hemophilic patients in a concentration‐dependent manner, resulting in clotting profiles in samples from patients with severe hemophilia that were similar to those of healthy controls. Conclusion: BAX499 improved ex vivo clotting parameters in blood and plasma from patients with hemophilia A and B with different severity of disease, and also in a patient with acquired hemophilia. These results further support the contention that anti TFPI strategies may be an effective treatment for hemophilic patients.     

Lentivirus‐mediated platelet gene therapy of murine hemophilia A with pre‐existing anti‐factor VIII immunity

Summary. Background: The development of inhibitory antibodies, referred to as inhibitors, against exogenous factor VIII in a significant subset of patients with hemophilia A remains a persistent challenge to the efficacy of protein replacement therapy. Our previous studies using the transgenic approach provided proof‐of‐principle that platelet‐specific expression could be successful in treating hemophilia A in the presence of inhibitory antibodies. Objective: To investigate a clinically translatable approach for platelet gene therapy of hemophilia A with pre‐existing inhibitors. Methods: Platelet FVIII expression in preimmunized FVIII^null mice was introduced by transplantation of lentivirus‐transduced bone marrow or enriched hematopoietic stem cells. FVIII expression was determined with a chromogenic assay. The transgene copy number per cell was quantitated with real‐time PCR. Inhibitor titer was measured with the Bethesda assay. Phenotypic correction was assessed by the tail clipping assay and an electrolytically induced venous injury model. Integration sites were analyzed with linear amplification‐mediated PCR. Results: Therapeutic levels of platelet FVIII expression were sustained in the long term without evoking an anti‐FVIII memory response in the transduced preimmunized recipients. The tail clip survival test and the electrolytic injury model confirmed that hemostasis was improved in the treated animals. Sequential bone marrow transplants showed sustained platelet FVIII expression resulting in phenotypic correction in preimmunized secondary and tertiary recipients. Conclusions: Lentivirus‐mediated platelet‐specific gene transfer improves hemostasis in mice with hemophilia A with pre‐existing inhibitors, indicating that this approach may be a promising strategy for gene therapy of hemophilia A even in the high‐risk setting of pre‐existing inhibitory antibodies.     

Inhibition of HIV-1 by modification of a host membrane protease

While it is clear that CD4 Is the receptor for the gp120 envelopeprotein of HIV-1, substantial evidence suggests that other hostcell proteins are required for successful membrane fusion. Studieswere initiated to examine the potential for a protein receptorwhich has an elastase-like character to participate in fusionof HIV-1 with permissive host cells. A synthetic elastase inhibitorwas shown to significantly reduce HIV-1 infectivity when presentduring, but not after, the initial contact between virus andcells. A human T cell elastase-like membrane component was purifiedand shown to be lipid-associated. By competitive Inhibition,the purified protein was shown to bind gp160 within the HIV-1fusion domain. The binding parameters of whole T cell membraneextract, with a hydrophobic pentapeptide representative of thefusion domain, suggested an elastase-like protein is the single,secondary T cell receptor for HIV-1 (K = 1x10³ M^–1). Thepentapeptide interacted with porcine and human (epithelial andpolymorphonuclear leukocyte), but not murine, elastase isoforms,suggesting its participation In the permissiveness of host cellsto infection.