The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: A novel pain modulation pathway

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG–brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm–VLO–PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-δ and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of μ-opioid receptors, serotonin 1_A receptors, and dopamine D₂-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.     

氟伐他汀对脂多糖和血管紧张素Ⅱ致大鼠主动脉内皮细胞TF和TFPI表达的影响

目的 研究氟伐他汀(fluvastatin)对脂多糖(LPS)和血管紧张素Ⅱ(AngⅡ)诱导的离体大鼠主动脉内皮细胞(RAEC)表达组织因子(TF)和组织因子途径抑制物(TFPI)的影响.方法 体外培养RAEC,分别给予LPS和AngⅡⅡ刺激,采用ELISA法检测氟伐他汀对RAEC TF和TFPI表达的影响.结果 氟伐他汀0.01、O.1、1和10μmol/L组能剂量依赖性抑制LPS和AngⅡ引起的TF表达增强;氟伐他汀0.01、0.1、1和10μmnol/L.组TFPI表达增强,呈剂量依赖性.结论 氟伐他汀能抑制引起血栓形成的TF表达,增加TFPI表达.     

Evaluation of the procoagulant activity in the plasma of cancer patients using a thrombin generation assay

Introduction

Circulating microparticles are reported to play a role in cancer hypercoagulability. The procoagulant properties of microparticles derive from the amount of tissue factor and/or phosphatidylserine that they can expose. The aim of our study is to assess the procoagulant activity, including microparticles’ activity, in the plasma of newly diagnosed cancer patients with a simple assay, easy to implement in the laboratory.

Material and methods

Newly diagnosed cancer patients (n = 31) before the start of anticoagulant or chemotherapy were compared to matched controls. We used a thrombin generation assay in four conditions: 1: addition of 1pM tissue factor and 4 μM procoagulant phospholipids, 2: without any trigger, 3 and 4: addition of tissue factor or procoagulant phospholipids alone respectively.

Results

When we added only phospholipids, so that thrombin generation is dependent upon endogenous tissue factor, the lag time was significantly shorter in cancer patients. When we added only tissue factor, i.e. made the results dependent upon phospholipids, the endogenous thrombin potential, the peak, and the velocity index were significantly higher and the time-to-peak was significantly shorter. This suggests that the plasma of cancer patients contained a higher activity of endogenous phospholipids and/or tissue factor which may be borne by microparticles.

Conclusion

This new simple methodology can demonstrate a procoagulant activity in the plasma of newly diagnosed cancer patients which can be explained by higher procoagulant phospholipids and tissue factor activity and thus, brings potentially useful information that current coagulation tests cannot provide.     

Correlation between factors involved in the local haemostasis and angiogenesis in full term human placenta

INTRODUCTION: Few studies have been carried out to investigate whether distinct areas of full term placenta express different amounts of markers involved in the placental haemostasis and angiogenesis. A possible relationship between the expression of genes involved in the haemostasis and angiogenesis of human placenta has not been investigated. MATERIALS AND METHODS: Twenty-eight fresh human placentas (35-41 weeks of gestation) from uneventful pregnancies were dissected with two different methods. Quantitative mRNA expression of the tissue factor (TF), TF pathway inhibitor (TFPI), TFPI-2, plasminogen activator inhibitor (PAI-2), annexin V (Anx V), vascular endothelial growth factor (VEGF), and thrombomodulin (TM) genes was evaluated by quantitative real time PCR system. Histology of each sample was graded. RESULTS: Gene expression of all the considered markers was not significantly different in each area, using both the different methods of dissection. A significant correlation (p<0.05) was found between the expression of TF and TFPI-2. TF and TFPI-2 were significantly (p<0.05) associated with VEGF, whereas a stronger association (p<0.01) was found between TFPI and TFPI-2. TFPI and TFPI-2 were strongly associated with PAI-2 expression (p<0.01). CONCLUSIONS: In placentas with central cord insertion, gene expression is not dependent on the method of sampling site. A significant relationship between haemostasis and angiogenesis in at term placentas was shown.     

Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults

Introduction

Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis, respectively. Plasma coagulative and fibrinolytic potentials in normal children and adults, and in representative pathologically altered hemostatic states, were evaluated via simultaneous assessment of thrombin and plasmin generation.

Materials and Methods

An assay of Simultaneous Thrombin and Plasmin generation (STP) was developed to measure thrombin and plasmin in plasma using individual fluorometric substrates. Coagulation is initiated with dilute tissue factor, phospholipid, and calcium in platelet-poor plasma; fibrinolysis is accelerated via tissue plasminogen activator (tPA). Abnormal states of hemostasis were investigated.

Results

STP assay reproducibility and normal adult and pediatric values for measured and calculated parameters have been established. Onset of both thrombin and plasmin generation was significantly delayed in children relative to adults (p < 0.001) and the maximum amplitudes of thrombin and plasmin generation were less in children than adults (p < 0.01). No significant differences were measured among pediatric age groups. The most profound impairments in thrombin generation were observed for extrinsic and common pathway factor deficiencies, with the exception of afibrinogenemia. Plasmin generation was severely impaired in deficiencies of fibrinogen and plasminogen as well as with decreased tPA reagent concentration and addition of aminocaproic acid. Plasmin generation was greatly enhanced by alpha-2-antiplasmin deficiency and excess tPA reagent.

Conclusion

Simultaneous assessment of thrombin and plasmin generation in plasma shows promise for affording an enhanced understanding of overall coagulative and fibrinolytic functions in physiological and pathologically altered states of hemostasis in children and adults.     

Coagulation activation and ultrasound characteristics in patients with carotid artery disease

Introduction

Elevated levels of markers for thrombin activation are associated with plaque echogenicity and degree of stenosis in patients with carotid artery stenosis. The Activated Protein C-Protein C Inhibitor (APC-PCI) complex reflects activation of the Protein C system and is a measure of thrombin generation. The aim of the present study was to examine APC-PCI complex in patients undergoing thrombendartherectomy for carotid artery stenosis, and to relate the findings to clinical characteristics and plaque morphology as determined by ultrasound.

Materials and Methods

Blood was obtained from 125 patients (39 female, median age 71 years) with carotid artery stenosis admitted from September 2005 to May 2007. The APC-PCI complex was measured using a sandwich immunofluorometric method and compared to an age- and sex-matched healthy control-group. Clinical and demographic characteristics, routine laboratory markers and ultrasound characteristics were analysed using univariate and multivariate analysis.

Results

APC-PCI complex concentration was significantly increased in patients with carotid artery stenosis (median 0.21 µg/L; 10th to 90th percentile 0.15-0.36) compared to a healthy control-group (0.19 µg/L; 0.11-0.31; P = .009). There was no significant difference in APC-PCI-values between asymptomatic (n = 48) and symptomatic (n = 77) patients with carotid artery stenosis (0.22 vs. 0.20 µg/L; p = 0.626). Patients with minor stroke (n = 31) had a higher median APC-PCI-concentration (0.27 µg/L; 0.15-0.63) than patients with amaurosis fugax (0.19 µg/L; 0.15-0.36) or transient ischemic attack (0.21 µg/L; 0.12-0.36) (p = 0.016). No association was found between APC-PCI-values and the degrees of carotid artery stenosis or the time from the latest neurological symptoms to blood sampling. Patients with echolucent plaques had significantly lower APC-PCI concentrations (0.20 µg/L; 0.14-0.35 vs. 0.24 µg/L; 0.15-0.60; p = 0.043), according to the Gray-Weale classification.

Conclusions

Patients with carotid artery disease exhibit increased concentrations of APC-PCI compared to a healthy control-group, particularly those patients with echogenic plaques, who have significantly higher APC-PCI levels than patients with echolucent plaques.     

Elevated plasma tissue factor antigen level in patients with disseminated intravascular coagulation

The plasma tissue factor (TF) antigen level was measured in patients with disseminated intravascular coagulation (DIC). The plasma TF antigen was detected In normal volunteers, and it was significantly higher in DIC patients than in non-DiC patients. However, in some patients with DiC, the plasma TF antigen level was within the normal range. The plasma TF antigen level in patients with DIC significantly decreased after therapy, but it was not correlated with organ failure or outcome. The plasma TF antigen level in patients with DIC was not correlated with other hemostatic markers. The plasma TF antigen level tended to be higher in DIC patients with nonlymphoid leukemia than in those with lymphoid tumor. TF might be implicated in the occurrence and progression of DIC. © 1994 Wiley-Liss, Inc.     

肝细胞癌病人血浆TF,uPA及uPAR检测的临床意义

目的 探讨肝细胞癌病人血浆TF,uPA和uPAR水平变化及临床病理意义。方法应用酶联免疫法(ELISA)检测肝细胞癌病人50例及对照组30例的血浆TF,uPA和uPAR水平,并结合临床病理资料探讨其临床意义。结果 肝细胞癌病人血浆TF,uPA及uPAR均较对照组升高,差异有显著性(P<0.05)。肝细胞癌病人血浆TF在低分化组,肿瘤较大组及合并肝硬化组显著升高(P<0.05),而在不同癌灶数目及包膜情况组间无显著差异(P>0.05)。血浆uPA水平只在合并肝硬化组升高(P<0.05),uPAR水平与以上病理指标均无关(P>0.05)。肝细胞癌病人血浆TF,uPA和uPAR水平均与侵袭转移指标有关,在有淋巴转移,肝外脏器转移及门脉癌栓组较无转移及癌栓组升高(P<0.05)。结论 肝细胞癌病人存在凝血,纤溶激活状态。血浆 TF,uPA和uPAR升高与肝细胞癌的发生及侵袭转移有关,其检测有助于早期诊断病情及判断预后。     

Association Between Maximal Activated Clotting Time and Major Bleeding Complications During Transradial and Transfemoral Percutaneous Coronary Intervention

Objectives

This study sought to determine whether higher maximal activated clotting time (ACT) during transradial (TR) percutaneous coronary intervention (PCI) is associated with greater bleeding risk.

Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis

Cancer metastasis and immune suppression are critical issues in cancer therapy. Here, we show that a β-galactoside–binding lectin [galectin-3 (gal3)] that recognizes the Thomsen-Friedenreich disaccharide (TFD, Galβ1,3GalNAc) present on the surface of most cancer cells is involved in promoting angiogenesis, tumor-endothelial cell adhesion, and metastasis of prostate cancer cells, as well as evading immune surveillance through killing of activated T cells. To block gal3-mediated interactions, we purified a glycopeptide from cod (designated TFD₁₀₀) that binds gal3 with picomolar affinity. TFD₁₀₀ blocks gal3-mediated angiogenesis, tumor-endothelial cell interactions, and metastasis of prostate cancer cells in mice at nanomolar levels. Moreover, apoptosis of activated T cells induced by either recombinant gal3 or prostate cancer patient serum-associated gal3 was inhibited at nanomolar concentration of TFD₁₀₀. Because the gal3–TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD₁₀₀ should be a promising antimetastatic agent for the treatment of various cancers, including prostate adenocarcinoma.