Indications and techniques for the use of heparin in the treatment of thromboembolism

Heparin acts by binding to antithrombin, thereby potentiating its ability to destroy activated clotting factors. There are two distinct, mutually exclusive modes of heparin therapy. These are (a) full-dose intravenous heparin for treatment of established venous thromboembolic disease, and (b) low-dose subcutaneous heparin for prevention of venous thrombosis in patients at risk. Substantial evidence from prospective clinical trials indicates that heparin is the single most effective agent in both the prevention and treatment of venous thromboembolic disease. Although the administration of heparin necessarily increases the risk of bleeding, attention to details of treatment can minimize that risk. In the appropriate clinical setting, heparin is truly a lifesaving drug.

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Résumé L'héparine agit en se liant à l'antithrombine, dont elle potentialise la capacité de détruire les facteurs de coagulation activés. Il y a deux méthodes d'héparinothérapie: (a) héparine intraveineuse à dose forte pour le traitement de la maladie thromboembolique, (b) héparine sous-cutanée à faible dose pour la prévention des thromboses. Il faut employer l'une ou l'autre. Des essais cliniques prospectifs ont prouvé que l'héparine est la drogue la plus efficace dans la prévention et le traitement de la maladie thromboembolique. L'héparine accroît, bien sûr, le risque d'hémorragie; mais ce risque peut-être réduit si l'on fait attention à tous les détails de cette thérapeutique. Lorsque l'indication est bien posée, l'héparine sauve des vies.

     

Exhaled nitric oxide in patients with asthma: association with NOS1 genotype

An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.     

丰富环境刺激对缺氧缺血性脑损伤大鼠脑超微结构改变及神经丝蛋白表达的影响

目的:观察丰富环境刺激对缺氧缺血性脑损伤大鼠脑超微结构及神经丝蛋白(NF)的影响。方法:实验于2005-03/2006-06在新桥医院中心实验室完成。取7日龄健康SD大鼠52只随机分为3组:①丰富环境干预组:20只,采用Rice法建立缺氧缺血性脑损伤模型,予早期抚触(15min/次,2次/d)和丰富环境(2h/次,1次/d)刺激共28d。②缺氧缺血非干预组:20只,同前造模,造模后不干预。③正常对照组:12只,不造模,不干预。饲养至1月龄时各组随机选10只进行Morris水迷宫测试学习记忆功能;行为学测定后处死大鼠取脑,免疫组织化学方法观察海马神经丝蛋白的染色情况,借助自动图像分析系统对其进行定量分析;利用透射电镜观察海马神经元超微结构、神经丝蛋白及突触情况。结果:52只进入结果分析。①隐匿平台逃避潜伏期(学习能力):缺氧缺血非干预组较正常对照组明显延长[(39.98±7.86),(26.12±4.03)s,P<0.001],丰富环境干预组较缺氧缺血非干预组缩短[(29.06±5.11)s,P<0.01],与正常对照组无差异。②跨越平台次数(记忆能力):缺氧缺血非干预组明显少于正常对照组[(2.13±1.33),(4.91±2.01)次,P<0.001],丰富环境干预组多于缺氧缺血非干预组[(4.45±1.59)次,P<0.01],与正常对照组无差异。③缺氧缺血非干预组左侧与右侧脑组织NF-H积分吸光度值之比值明显小于正常对照组和丰富环境干预组(0.398±0.110,0.975±0.011,0.821±0.138,P<0.01),后2组比较无差异。④超微结构显示缺氧缺血非干预组海马神经细胞固缩改变,线粒体肿胀,神经丝数量减少,排列稀疏,突触数量减少;丰富环境干预组海马神经元和突触无明显异常。结论:早期抚触及丰富环境刺激可以促进缺血缺氧的脑损伤恢复,脑组织神经网络重建及脑的可塑性增加是其可能的机制之一。     

The Assessment of Drug-Dependent and Isoimmune Antiplatelet Antibodies by the Use of Platelet Aggregometry

The technique of platelet aggregometry provides a simple, quantitative, and specific method for the detection of drug-dependent and isoimmune antiplatelet antibodies. In the presence of antiquinidine antibody, quinidine causes lysis of normal platelets in platelet-rich plasma. The resulting changes in optical density are readily detected in the aggregometer. The initial rate of lysis is a function of the antibody titer, but is relatively independent of the platelet count. In vitro, quinidine produces platelet swelling and inhibits aggregation of platelets by adenosine diphosphate, epinephrine, and collagen. Isoimmune antibodies cause aggregation of platelets in platelet-rich plasma. In studies of a single family the rate of aggregation is proportional to the number of HL-A antigens present on the normal platelets against which the antibody is directed. The simple technique of platelet aggregometry may be a useful adjunct in the selection of compatible donors for platelet transfusion. Serum derived from patients with idiopathic thromboytopenic purpura did not cause platelet aggregation.     

Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta

The effects of glucose on endothelium-dependent responses and vasoactive prostanoid production were determined by incubating isolated rabbit aortae in control (5.5 or 11 mM) or elevated (44 mM) glucose for 6 h to mimic euglycemic and hyperglycemic conditions. Rings of aortae incubated in elevated glucose, contracted submaximally by phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with the aortae incubated in control glucose. Treatment with indomethacin, a cyclooxygenase inhibitor, or SQ29548, a prostaglandin H2/thromboxane A2 receptor antagonist, restored acetylcholine relaxations of rings in elevated glucose to normal, while these agents had no effect on the relaxation of rings incubated in control glucose. Aortae incubated with mannose (44 mM) as a hyperosmotic control relaxed to acetylcholine normally. The relaxations in response to A23187 and sodium nitroprusside were not different between rings exposed to control and elevated glucose. Radioimmunoassay measurements showed a significant increase in acetylcholine-stimulated release of thromboxane A2 and prostaglandin F2 alpha in aortae with, but not without endothelium incubated with elevated, but not with control glucose. Thus a possible mechanism for endothelium dysfunction in diabetes mellitus is the hyperglycemia-induced increased generation of endothelium-derived vasoconstrictor prostanoids.     

Purification and properties of M protein extracted from group A streptococci with pepsin: covalent structure of the amino terminal region of type 24 M antigen

M protein was extracted from type 24, group A streptococci with pepsin at pH 5.8 and was further purified by ammonium sulfate precipitation, ribonuclease digestion, ion-exchange chromatography, and isoelectric focusing. The purified pepsin extract of M (pep M) protein was shown to be free of nontype-specific immunoreactivity in (a) complement fixation tests with heterologous M antiserum, (b) skin tests in normal adult guinea pigs, and (c) passive hemagglutination tests for the presence of lipoteichoic acid sensitizing or antigenic activity. The pep M24 was highly immunogenic; two of three rabbits developed opsonic antibody titers of 1:256 and the third a titer of 1:32 6 wk after a single injection of 100-pg doses of pep M24 emulsified in complete Freund's adjuvant. The antisera lacked nontype-specific antibodies and produced single precipitin lines in agar gel diffusion tests against crude HC1 extracts of the homologous M protein. Thus, the type-specific antigenic determinant(s) of type 24 M protein appears to be separable from immunotoxic, cross-reactive antigens without loss of immunogenicity in rabbits. The mobility of pep M24 upon electrophoresis in 10 percent sodium dodecyl sulfate pelyacrylamide gel was consistent with an average mol wt of 33,500 daltons. Amino acid analysis demonstrated a predominance of alanine, followed by glutamic acid, lysine, leucine, and aspartic acid. Pep M24 contained an estimated six to seven methionine residues and approximately ten phenylalanine residues per molecule. No other aromatic amino acids were detected. Automatic Edman degradation of pep M24 yielded the sequence of the first 29 amino acids (the amino terminal amino acid being valine) of the amino terminal region of the molecule. The detection of only one new amino acid at each step of Edman degradation confirmed the homogeneity of the purified pep M24.     

Neointimal hyperplasia occurring after carotid endarterectomy in a canine model: effect of endothelial cell seeding vs. perioperative aspirin

Neointimal hyperplasia of the arterial wall may occur after carotid endarterectomy. This proliferative lesion is a pathologic response of the injured arterial wall and may lead to progressive stenosis. We investigated the effect of endothelial cell seeding (ECS) or antiplatelet therapy with aspirin (ASA) on inhibition of this lesion in a canine model. Endarterectomies were performed in 160 carotid arteries; 46 endarterectomies were treated perioperatively with aspirin (325 mg per day), 34 were seeded with a high density (3 X 10(6)) of autogenous endothelial cells, and 80 were untreated control arteries. At selected time intervals, the patent arteries were perfusion-fixed and the cross-sectional area (measured in square millimeters) of neointimal hyperplasia was measured by means of digital planimetry. At 6 weeks, patency of the endarterectomized carotid artery was 88% in the ASA and ECS groups, in contrast to 35% in the control group (p less than 0.01). The cross-sectional area of neointimal hyperplasia was not significantly different in the ASA and the control groups at 6 weeks. However, the ECS group showed a marked reduction in neointimal hyperplasia at 6 weeks (p less than 0.01). This inhibition of neointimal hyperplasia after carotid endarterectomy by ECS may reflect accelerated luminal healing or a direct inhibition of smooth muscle cell proliferation in the injured arterial wall.     

Effects of BG9928, an adenosine A₁ receptor antagonist, in patients with congestive heart failure

Previous studies suggest that adenosine A? receptor antagonists may promote natriuresis without deleterious effects on renal function. This study evaluated renal and hemodynamic effects as well as safety, pharmacokinetics, and tolerability of BG9928, a selective adenosine A?-receptor antagonist, in patients with heart failure. In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation study, 33 patients received a single dose of BG9928 (0.03, 0.3, 1.0, or 3.0 mg/kg) or placebo intravenously. Change from baseline in urinary sodium excretion for the 8-hour postdose interval was greater for all dosing groups versus placebo. The 0.03-mg/kg and 0.3-mg/kg groups had significant reductions in body weight versus placebo (-0.8 kg, -1.1 kg, 0.3 kg, respectively; P < 005). No changes in creatinine clearance or hemodynamic parameters were observed among any of the BG9928 groups versus placebo. However, pulmonary capillary wedge pressure tended to decrease and correlated with weight loss. Across the range of doses studied, pharmacokinetic parameters were linear and predictable. One patient who received the highest dose (3.0 mg/kg) developed seizures, and no further patients received that dose. Single intravenous BG9928 doses of up to 1.0 mg/kg were well tolerated and increased sodium excretion without worsening renal function. Further studies are needed to determine the clinical benefit of adenosine A? receptor antagonism.     

Do “placebo responders” exist?

The placebo effect has been the subject of much controversy. For a scientific investigation of placebo effects to advance it is important to establish whether a placebo response in any particular illness is reliable — i.e., if there is a response to a single placebo administration there will also be a placebo response to the repeated administration of a similar placebo in similar conditions. A positive answer would allow more sophisticated clinical trial designs and more precise basic research experiments on the placebo effect. This article reviews experiments that used multiple administrations of placebo to answer the question “do reliable placebo responders exist?” This paper also examines the evidence for the existence of a consistent placebo responder, i.e. a person who responds to placebo in one situation will respond in another condition or using a different type of placebo ritual. Much of the existing evidence for these two questions was performed before 1967. This early evidence is contradictory, methodologically weak and is sufficiently old to be considered medical history. Since 1969, at least eight experiments exposed asthma patients to multiple administrations of placebo given with deceptive suggestions that the “treatment” was an active medication. While the results of this research are not unequivocal, and may not be equivalent to non-deceptive conditions, this line of inquiry suggests that if a reliable and consistent placebo response exists it could be detected within this population. Finally, this paper proposes one model to rigorously investigate the stability of placebo responses.