Effects of intraperitoneal injection of Rofecoxib in a mouse model of ALS

There is increasing evidence that inflammatory mechanisms are involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Inhibition of a key mediator of inflammation, cyclooxygenase 2 (COX-2), represents a promising therapeutic approach in ALS. Here we tested the in vivo effects of a specific COX-2 inhibitor, Rofecoxib, administered by intraperitoneal injection, in the SOD1(G93A G1H) mouse model of the familial form of ALS (fALS). Rofecoxib administration commenced at postnatal day 60 (P60), since the hallmarks of inflammation in the spinal cord were found to occur beyond this time-point in this mouse model of fALS. We found a significant but small delay in the onset of locomotor impairment in mice treated with Rofecoxib at the dose of 10 mg/kg of weight. However, survival was not effected by treatment. As prostaglandin E2 levels in spinal cord or in plasma were not reduced by Rofecoxib treatment, these results may suggest lack of sufficient bioavailability as the reason for the modest clinical changes observed.     

Antithrombotic effects of aspirin and LMWH in a laser-induced model of arterials and venous thrombosis

Antiplatelet drug aspirin and anticoagulant low molecular weight heparin (LMWH) were compared as arterial and venous antithrombotic preparations in the rat experimental model of the laser induced thrombus formation.

A method to induce microthrombi in small mesenteric vessel (15–25 μm) has been developed to investigate antithrombotic drugs and to study platelet reactions. Mesenteric injuries are induced in the vascular system of Wistar rats with an argon laser. The laser beam induced formation of the vessel wall injury with damage of endothelial cells. Thrombus was formed within seconds after laser injury and grew rapidly. The aggregate can be swept away by the flow and a new thrombus was formed again. This embolization began within the minute following the laser flash. Thrombus formation and embolization were repetitive phenoma. Aspirin (100 mg/kg) and LMWH (1 mg/kg) are approximately the same as to decrease the number of emboli detached from the thrombus and the duration of embolization; both in venules and in arterioles.

This results suggest reflexion about the role of platelets in venous thrombosis induced by laser beam.     

Antithrombotic effect of ticlopidine in a platelet-independent model of venous thrombosis

The antithrombotic activity of ticlopidine demonstrated in a variety of experimental models of thrombosis has been explained by its antiaggregating properties. This study describes the antithrombotic effect of ticlopidine in a platelet independent model of venous thrombosis. In the rat, ligature of the inferior vena cava induces thrombosis. Antiaggregating drugs (acetylsalicylic acid, dipyridamole, sulfinpyrazone) are inactive while anticoagulants (heparin, acenocoumarol) are highly antithrombotic. Ticlopidine reduces thrombus weight significantly and dose-dependently (ED 50 = 150 mg/kg/day X 3 days). Thrombocytopenia induced by injection of anti-platelet anti-serum was found not to modify thrombus formation. Yet, even in these conditions, ticlopidine remains active. Acetylsalicylic acid treatment does not prevent the antithrombotic effect of ticlopidine, indicating that its action is independent of PGI2 synthesis. These results demonstrate that ticlopidine acts as an antithrombotic agent in a venous thrombosis model in which platelets play a minor role.     

颅内静脉血栓形成的临床特点分析

目的探讨颅内静脉血栓形成（CVT）的病因、临床特点、诊断、治疗。方法回顾性分析12例CVT患者的临床资料,并结合文献分析。结果12例CVT患者中8例病因明确,临床表现以头痛伴恶心呕吐、视乳头水肿为主,脑脊液（CSF）检查以压力升高为主要特点,D-二聚体（DD）检查有62.5%的患者高于正常,CT主要表现局限性脑梗死及脑水肿,MRI联合MRV表现静脉窦闭塞者占91.7%,病因及脱水、溶栓、抗凝治疗疗效较好。结论CVT临床表现复杂多样,产褥期、感染、白塞病可继发CVT,MRI和MRV相结合诊断率高,肝素抗凝为首选治疗。     

脑静脉窦血栓形成的临床和影像学分析

目的 通过对24例脑静脉窦血栓形成（CVST）患者的临床和影像学资料分析,揭示CVST的临床特点.方法 回顾性总结24例CVST患者的临床资料,从病因、临床特点和影像学特点三个方面进行分析.影像学特点作为重点讨论部分,包括MRI、MRV和DSA表现.结果 24例CVST患者中16例的病因分别为凝血机制异常（33.3%）、产褥期（12.5%）,高同型半胱氨酸血症（8.3%）、雌激素水平异常（4.2%）、贫血（4.2%）、肿瘤（4.2%）,另8例病因不明;24例患者起病症状包括：头痛、复视、抽搐发作、肢体无力和视力障碍.体征包括：视乳头水肿、偏瘫、脑膜刺激征和意识障碍.影像学特点：MRI 18例有异常改变,其中12例显示静脉窦部分或全部节段性流空消失,代之以短T1长T2信号;MRV 23例相应静脉窦不同程度显影缺失.DSA检查,每例患者均见一处或多处静脉窦狭窄、充盈缺损和显影不良.结论 CVST多数伴有头痛、视乳头水肿、颅压升高,影像学窦腔或浅静脉有异常,临床应想到CVST,确诊需要DSA检查.     

Proteomics of microparticles after deep venous thrombosis

Background

Microparticles (MP) are submicron size membrane vesicles released from activated cells that are associated with thrombosis and inflammation. MP present diverse biological expressions that may be linked to a unique subset of proteins derived from their origin cells.

Methods

To identify these proteins, plasma samples were taken from 9 patients with deep venous thrombosis (DVT) documented by duplex ultrasound, 9 with leg pain but negative for DVT by duplex, and 6 healthy controls without a history of thrombosis, for fold variation. MP were extracted from platelet-poor plasma, digested separately with trypsin and tagged using iTRAQ reagents. The digests were subjected to 2-D LC separation followed by MALDI tandem mass spectrometry. Peak lists were generated and searched against all human sequences. For protein identification, a minimum of two peptides at 95% confidence was required. Later, iTRAQ ratios were generated comparing relative protein levels of DVT patients to baseline. The proteomic analysis was performed twice for each blood sample. Proteins were considered elevated or depressed if the iTRAQ ratio (R) deviated by 20% change from normal and a p-value less than 0.05.

Results

Two proteins (Galectin-3 Binding Protein, [Gal3BP], R = 1.76 and Alpha-2 macroglobulin [A2M] R = 1.57) were differentially expressed on DVT patients. Nine proteins were depleted including fibrinogen beta and gamma chain precursors (R = 0.65).

Conclusions

These proteins influence thrombosis through inflammation, cell shedding, inhibition of fibrinolysis and hemostatic plug formation. Further studies are needed to confirm the mechanistic role of these proteins in the pathogenesis of venous thrombosis in humans.     

外伤性脑静脉窦血栓的临床诊治

目的 探讨外伤性脑静脉窦血栓的诊治方法。方法 对近两年来临床工作中发现的27例外伤性脑静脉窦血栓患者资料进行回顾性分析。所有病例均采用核磁共振成像（MRV）证实，行尿激酶静脉溶栓治疗，首齐20万U，每日增加5万U。最大剂量达100万U。结果 19例再通，7例建立侧支循环，1例死亡。结论 对临床工作中出现的腰穿颅内压大于300mm H20的病例、跨窦骨折的病例、病情平稳后又出现反复（如头痛加剧、呕吐等）而复查头颅CT无异常的病例，应高度怀疑脑静脉窦或深静脉血栓形成。MRV成像是脑静脉安或深静脉血栓诊断的首选方法。     

Administration of a small molecule tissue factor/factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time

INTRODUCTION: Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation. MATERIALS AND METHODS: PHA inhibits the TF/VIIa complex with an IC(50) of 13.5 nM (K(i) 9 nM) and is more than 2000-fold selective for the TF/VIIa complex with respect to IC(50)s for factor Xa and thrombin. In the model, a thrombogenic surface was introduced into the vena cava of a primate, and the amount of thrombus accumulated after 30 min was determined. RESULTS: PHA-798 reduced thrombus formation on the thrombogenic surface in a dose-dependent manner (56+/-1.9% and 85+/-0.3% inhibition with 100 and 200 microg/kg/min PHA-798, respectively) indicating that the model is sensitive to TF/VIIa inhibition. Treatment with 1 mg/kg intravenous (IV) acetyl salicylic acid (ASA) resulted in only a slight (4-12%), non-significant inhibition of thrombus formation. However, the combination of 100 microg/kg/min PHA-798 and 1 mg/kg ASA resulted in an 89% inhibition of thrombus formation. Additionally, while ASA alone increased bleeding time (BT) from 3.3 min at baseline to 4.6 min following treatment, addition of PHA-798 (100 microg/kg/min) to ASA did not significantly increase the BT further (4.7 min). CONCLUSIONS: The results of this study indicate that inhibition of TF/VIIa may be safe and effective for the prevention of the proprogation of venous thrombosis and that the combination of ASA and PHA may provide increased efficacy with little change in safety.     

磁共振血管成像对脑静脉窦血栓形成的诊断和疗效评价

目的 探讨MR脑血管成像在脑静脉窦血栓(CVST)形成的诊断和疗效评价中的作用. 方法 回顾性分析北京大学深圳医院影像中心自2001年8月至2007年1月期间收治的12例CVST患者的影像学资料,所有病例均作常规SE序列和2D-TOF静脉成像(MRV),10例患者做DSA,8例患者做3D-TOF动脉成像(MRA).比较不同成像方法对CVST病变的显示情况. 结果 12例患者共显示34个CVST.SE序列显示9例17个,表现为静脉窦正常流空信号消失,出现异常信号.MRV显示11例32个,表现为正常静脉窦高信号消失或其内充盈缺损.DSA显示10例30个.MRA显示2例(2/8)脑动脉血管减少.MRV显示的病变静脉窦数日明显高于SE序列,病变检出的阳性率为93.3%(相对DSA).MRV示6例经导管内注药溶柃治疗后随访的患者大部分病变静脉窦恢复正常高信号,溶栓前MRA所示脑动脉血管减少的2例患者则显示动脉血管明显增多. 结论 MR脑血管成像在CVST的诊断和疗效评价中能发挥重要作用.     

Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study

The present study was designed to assess to what extent single and combined clotting abnormalities influence spontaneous vascular accidents in pediatric patients, and how the children affected differ in their prothrombotic risk profiles from their biological first-degree family members. In addition, this study was performed to investigate if relatively mild thrombophilic polymorphisms not leading to thrombosis in the parents cause severe clinical expression when coinherited with an established prothrombotic risk factor. The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, the plasminogen activator inhibitor (PAI)-1 promoter polymorphism, lipoprotein (Lp)(a), antithrombin, protein C, and protein S were investigated in 48 childhood patients aged neonate to <18 years (median 0.5 years) with spontaneous venous thromboembolism (SVT) compared with the carrier status of their first-degree family members. In 19 of the 48 patients (39.6%), one prothrombotic risk factor was diagnosed, and in 27 of the 48 subjects (56.3%) at least two prothrombotic defects/alleles. In the majority of cases with SVT, the FV G1691A mutation was involved either with a second mutated allele or combined with elevated Lp(a), the 4G/4G genotype of the PAI -1 promoter polymorphism, and the T677T MTHFR genotype. The rate of combined prothrombotic risk factors was significantly higher in childhood patients compared with their parents. In conclusion, based on the data presented here we suggest that early-onset SVT in childhood patients is mainly caused by combinations of at least two prothrombotic risk factors.     

脑静脉窦血栓形成的早期诊断与治疗

目的探讨脑静脉窦血栓形成的早期临床特点及治疗方法。方法回顾性分析16例脑静脉窦血栓形成患的发病年龄、发病形式、首发症状、临床表现、影像学特征及脑脊液等检查结果与治疗方法。结果发病年龄以20～60岁多见，多数患为急性发病，早期临床表现为头痛、呕吐，伴或不伴局灶性神经功能缺损或癫痫发作。影像学检查表现为静脉窦闭塞及局限性梗死灶。脑脊液压力明显增高，白细胞数及蛋白质含量正常或增高，但感染性或癌性脑静脉窦血栓形成除外。应用脱水、抗凝、局部溶栓及病因治疗等方法后，16例患中6例基本痊愈，7例症状好转，1例无变化，2例死亡。结论脑静脉窦血栓形成的临床表现复杂多样，无特异性，对临床急性发病的头痛、呕吐、伴或不伴局灶性神经功能缺损及乏癫痫发作的年轻患，应高度怀疑脑静脉窦血栓形成，及时行磁共振成像(MRI)及磁共振血管造影(MRA)联合检查，以明确诊断。确诊后应尽早开始治疗。     

Inhibition of arterial thrombosis by polyamines in a canine coronary artery injury model

Polyamines are polycations present in all living organisms and have been shown to play an important role in various physiological functions. Previous studies have shown that various amines including polyamines inhibit platelet activation. Among the amines tested tetra-amine, spermine is the potent inhibitor of platelet aggregation. In spite of vast literature on the anti-aggregatory effect of amines, there are no definitive studies testing their efficacy in an in vivo thrombosis model. In the present study, we investigated if polyamines could inhibit in-vivo thrombosis. A partially occlusive thrombus was generated by application of electric current in canine coronary artery. In control animals, the artery was completely in 76+/-14 min after the current was discontinued. When 40 mg/kg (1.44 mM) spermine was given immediately after stopping the current blood flow remained patent for >240 min. At equimolar concentration, triamine, spermidine and diamine putrescine are also equally effective in preventing thrombus development. The anti thrombic effect of polyamines was not associated with increased bleeding tendency, as judged by the amount of blood adsorbed by a gauge pad placed in a surgical incision extending to the muscle tissue and by a standard template bleeding. These results indicate that apart from inhibiting in-vitro platelet aggregation polyamines can also inhibit in-vivo thrombus formation.     

Cerebral venous thrombosis in Behcet's disease. A report on 24 cases

IntroductionCerebral venous thrombosis (CVT) is the most common manifestation of vasculo-Behçet's disease and may be superficial and/or deep localization. The aim of our study was to evaluate the clinical and radiological features of CVT associated with Behçet's disease in our population and to compare findings with previous studies.Materials and methodsWe report a retrospective study of 24 cases of CVT secondary to Behçet's disease, collected between 1999 and 2019 in the neurology department of the Mohamed V Military Hospital (Rabat), the Avicenne Military Hospital (Marrakech) and the Mohamed VI Hospital (Marrakech). The diagnosis of Behçet's disease was made in all cases according to the 2014 International Study Group Criteria for Behçet diseases. Patients received antithrombotic treatment, combined with corticosteroids, in six cases of superficial CVT and with immunosuppressants in cases of deep CVT.ResultsClinical manifestations were dominated by motor deficit in deep localizations and intracranial hypertension in superficial locations. The diencephalic-mesencephalic syndrome was found in 18 patients, whereas intracranial hypertension (71%) and headache (57%) were the most common presentations of superficial CVT. Unlike previous studies, magnetic resonance angiography and conventional angiography performed in our patients confirmed the predominance of deep venous thrombosis (18 cases), whereas superficial CVT was observed only in six cases.DiscussionIn our series, the benefit of conventional angiography was undeniable, by confirming the diagnosis of basal vein of Rosenthal thrombosis in 75% of our patients. Short-term outcome was favorable, but sequelae of CVT were noted in 20 patients (75%). The outcome of patients was commonly mRS 02, however 70% of patients presenting with deep CVT at the beginning had a poor outcome (mRS 03) and we did not record any case of venous thrombosis relapse.     

Weight gain after acute deep venous thrombosis: a prospective observational study

INTRODUCTION: The onset of acute disorders often results in a significant reduction in physical exercise, thus predisposing to further increase in body weight. Weight gain is strongly associated with an increase in metabolic and cardiovascular risk factors. The aim of this study was to assess weight changes occurring after an episode of acute deep venous thrombosis (DVT). MATERIALS AND METHODS: To compare the prevalence of overweight and obesity at baseline and 6 months after acute DVT, and to compare weight changes between patients with DVT treated in hospital or at home over a similar time frame, we evaluated 72 patients (mean age 59.8+/-15.3 years, 34 men and 38 females) with objectively diagnosed DVT. Body mass index (BMI) was recorded at baseline and at 6 months; waist circumference was recorded at 6 months to assess individual patterns of body fat distribution. RESULTS: At baseline, BMI was 27.6+/-4.6 kg/m(2). Overweight and obesity were observed in 33 (45.8%) and 19 (26.4%) patients, respectively. After 6 months, BMI was 28.7+/-5.0 kg/m(2). The prevalence of overweight and obesity was 44.4% and 32%, respectively; visceral pattern of body fat distribution was found in 64.8% of overweight or obese patients. Mean weight gain was 7.12%; inpatients (n=42) showed a higher weight gain than outpatients (n=30) (8.6% and 4.9%, respectively, p=0.046). CONCLUSIONS: We observed a significant weight gain after acute DVT. This weight gain was more marked in hospitalised patients than in outpatients. Our findings suggest that weight control should be considered in all patients with acute DVT.     

颅内静脉窦血栓形成后硬脑膜动静脉瘘(附5例报告)

目的探讨硬脑膜动静脉瘘(DAVF)与静脉窦血栓形成发生的关系,以及其临床表现和治疗方法。方法回顾性分析2005年9月至2009年8月收治的5例继发于或伴发颅内静脉窦血栓形成的DAVF患者的临床资料。结果 5例患者中,3例表现为颅内出血,2例表现为突眼和结膜红肿。3例经开颅手术及1例经血管内介入栓塞治疗,术后均恢复良好;另1例未行外科处理,神经功能障碍呈进行性加重。结论静脉窦血栓形成可继发DAVF,但部分患者先期难以明确静脉窦血栓形成,而表现为DAVF伴静脉窦血栓性闭塞;颅内静脉窦血栓形成后继发的DAVF易发生颅内出血,应积极行血管内栓塞或开颅手术治疗。     

Acyl-enzymes as thrombolytic agents in a rabbit model of venous thrombosis

A derivative of human lys-plasmin in which the active site has been reversibly acylated (BRL 26920; p-anisoyl human lys-plasmin) has been examined as a fibrinolytic agent in a previously described rabbit model of venous thrombosis and shown to be significantly more active and less fibrinogenolytic than free plasmin. A p-anisoylated derivative of a streptokinase (SK)-activated plasmin preparation was significantly less fibrinogenolytic in vivo than the non-acylated enzyme. Acylation increased the fibrinolytic activity of preparations of SK-plasmin activator complexes. BRL 26921, the active site anisoylated derivative of the primary 2-chain SK-plasminogen complex was the most potent fibrinolytic agent studied. SK-Val442-plasminogen complexes, free or acylated, were biologically inactive in this model and confirm the essential nature of fibrin binding processes for effective thrombolysis in vivo.     

Electrical induction of coronary artery thrombosis in the ambulatory canine: A model for evaluation of anti-thrombotic agents

A simple technique for the reliable induction of coronary artery thrombosis in a conscious dog by delivery of low amperage electric current to the intimal surface of the artery is described. Ibuprofen, an agent known to inhibit platelet function and prostaglandin synthesis is evaluated in this model. Comparison of myocardial infarct size, thrombus weight, arrhythmia development and scanning electron micrographs of drug treated and control animals indicate that Ibuprofen is capable of protecting against the deleterious effects of coronary artery thrombosis produced by this technique. This method holds considerable potential as an in vivo model of coronary artery thrombosis and one in which evaluation of anti-thrombotic agents is possible.     

A sensitive model of venous thrombosis in rats

Several antithrombotics (heparin, acetylsalicylic acid, sulfinpyrazone and dipyridamole) as well as an antiserotonin ketanserin were tested in a new sensitive model of venous thrombosis in rats. Intravenous injection of hypotonic saline was used for thrombus induction combined with the vena cava ligation. Formation of thrombi was evaluated by their weights. With i.v. heparin, oral sulfinpyrazone and acetylsalicylic acid, i.v. dipyridamole and ketanserin an effective inhibition was obtained, whereas with oral dipyridamole and ketanserin the inhibition remained incomplete.     

14例颅内静脉窦血栓形成临床特征分析

目的探讨颅内静脉窦血栓形成患者的临床特征。方法回顾性分析14例CVST患者的临床资料。结果本组患者男性2例,女性12例;年龄15-55岁,平均年龄32±5岁。12例有明确病因,多数以急性、亚急性起病。首发症状以头痛多见,临床表现以颅高压三主征及皮层功能损害的局灶症状体征为主。缓慢起病者确诊时间延长。疾病易误诊为单纯的脑出血、脑梗死等。影像学表现为静脉窦闭塞及以皮质为主的梗死或水肿,可伴出血。治疗以抗凝、脱水为主。4例治愈,5例好转,5例死亡。结论 CVST患者临床差异较大,缺乏特异性,需要综合分析避免漏诊和误诊,及早行MR I+MRV检查,及早抗凝。