Behcet's disease with sinus thrombosis and arteriovenous malformation in brain

Summary A 55-year-old man suffered from Behcet's disease with bilateral sigmoid sinus thrombosis and dural arteriovenous malformation has been studied clinically and pathologically. A possible causal relationship between Behcet's disease and sigmoid sinus thrombosis is discussed.

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Zusammenfassung Bei einem 55jährigen Patienten mit Behcetscher Krankheit fand sich sowohl eine Thrombose des Sinussigmoides wie auch eine arteriovenöse Mißbildung der Dura und des Gehirnes. Es wird über das Ergebnis der klinischen und pathologisch-anatomischen Untersuchung dieses Falles berichtet und die möglichen Beziehungen zwischen den obengenannten Besonderheiten des Falles untereinander kommentiert.

     

Excess soluble urokinase-type plasminogen activator receptor in the plasma of dialysis patients correlates with increased fibrinolytic activity

INTRODUCTION: Elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) and other fibrinolytic parameters related to the urokinase-type plasminogen activator (uPA) system can be implicated in clot lysis in plasma. In this study, we examined whether the excess suPAR was associated with increased plasma fibrinolytic activity, determined as plasmin/antiplasmin (PAP) complexes in dialysis patients. MATERIALS AND METHODS: Twenty-six patients on maintenance haemodialysis (HD) and 18 on maintenance peritoneal dialysis (CAPD) were examined together with 20 healthy controls. Pre-dialysis blood levels of suPAR, uPA and PAP were determined using commercially ELISA kits. RESULTS: suPAR, uPA, PAP levels and suPAR/uPA ratio were increased in both groups of dialyzed patients compared to the controls. Moreover, increased suPAR levels directly correlated with those of uPA and PAP (r=0.443 and r=0.393, both p<0.01, respectively); the fibrinolytic markers were also positively associated with each other (r=0.506, p<0.001). CONCLUSIONS: The plasma suPAR antigen levels are significantly increased in uraemic patients undergoing maintenance dialysis compared with healthy volunteers and are closely associated both with uPA as well as PAP. These positive associations suggest a link between suPAR and the fibrinolytic activity in these patients.     

尿激酶型纤溶酶原激活剂及其受体在胶质瘤中的表达

目的 研究人脑胶质瘤组织中尿激酶型纤溶酶原激活剂（uPA)及其受体（uPAR)的表达,探讨uPA、uPAR的表达与人脑胶质瘤恶性程度的关系。方法 采用半定量逆转录－聚合酶链反应（RT－PCR）方法,对49例人脑胶质瘤手术切除标本、U251等3株胶质瘤细胞,12例内减压术中切除的正常脑组织标本的uPA mRNA和uPAR mRNA表达水平进行检测。结果 随着胶质瘤恶性度的升高,其uPA及uPAR mRNA表达率和表达水平逐渐增高。U251等3株胶质瘤细胞也表达了较高水平的uPA及uPAR mRNA,而正常组织表达率及表达水平极低。结论 人脑胶质瘤中纤溶酶原激活系统活性较高,uPA、uPAR基因的高表达反映了胶质瘤的恶性生物学行为。     

Increased expression of urokinase‐type plasminogen activator receptor in the frontal cortex of patients with intractable frontal lobe epilepsy

Urokinase‐type plasminogen activator receptor (uPAR) is a glycosyl phosphatidylinositol‐anchored protein involved in cell adhesion, proliferation, differentiation, migration, invasion, and tissue repair and remodeling. Our aim was to investigate uPAR expression in the frontal cortex of patients with intractable frontal lobe epilepsy and to explore the possible role of uPAR in intractable epilepsy. Tissue samples were obtained from the frontal cortex of 25 patients who had undergone surgery for intractable epilepsy and 15 histologically normal frontal cortex tissues from patients with orbital frontal lobe severe contusion (the control group). The frontal cortex expression of uPAR was studied by Western blot and immnohistochemistry. Double immunofluorescence was used to determine the expression of uPAR in astrocytes, microglia, and neurons. The normal frontal cortex uPAR protein level was shown to be low. In the brain tissue of patients with intractable epilepsy, the expression of uPAR protein increased dramatically. Based on the results of double immunofluorescence, many uPAR‐positive cells are colocalized with the cell soma of NeuN‐positive neurons, whereas only a few GFAP‐ and CD11b‐positive cells colocalized with uPAR staining. These findings provide new information pertaining to the epileptogenesis of intractable epilepsy and suggest that increased expression of uPAR in human brain may be associated with human intractable epilepsy. © 2010 Wiley‐Liss, Inc.     

白塞病相关颅内静脉窦血栓形成9例分析

目的 研究白塞病相关颅内静脉窦血栓形成（cerebral venous sinus thrombosis,CVST）的临床表现、血 栓好发部位、治疗及预后。 方法 回顾性分析2014年1月-2016年8月于首都医科大学附属北京同仁医院神经内科住院的白塞病 相关CVST患者的临床资料。 结果 共收集白塞病相关CVST患者9例,其中男性2例（22.2%）,女性7例（77.8%）,年龄21～47岁,中 位数是35.9岁;急性起病1例（11.1%）,慢性起病8例（88.9%）;头痛4例（44.4%）、头晕1例（11.1%）、 阵发性黑蒙3例（33.3%）、双眼视力下降5例（55.6%）、视盘水肿9例（100%）、复视3例（33.3%）、耳 鸣1例（11.1%）;乙状窦血栓形成7例（77.8%）、横窦血栓5例（55.6%）、直窦血栓1例（11.1%）、下矢状 窦血栓1例（11.1%）、颈内静脉血栓2例（22.2%）;仅1处静脉窦受累的4例（44.4%）,同时有2处及2处 以上静脉窦受累的5例（55.6%）;所有患者均予醋甲唑胺50 mg 2次/日口服,3例予糖皮质激素冲击 治疗,其中1例合并华法林抗凝治疗、2例进行了腰大池-腹腔分流手术。随访1～32个月,所有患者治疗 后均好转。 结论 白塞病可引起颅内静脉窦血栓形成,可累及单处或多处静脉窦,CVST患者需除外白塞病可能。     

尿激酶型纤溶酶原激活剂及其受体在髓母细胞瘤中的表达研究

目的 研究尿激酶型纤溶酶原激活剂（uPA)及受体（uPAR)在髓母细胞瘤中的表达及临床意义。方法 应用免疫组化LSAB法检测50例髓母细胞瘤中uPA及uPAR的表达，结合临床随访，使用Cox回归统计分析。结果 uPA及uPAR染色定位于肿瘤细胞和血管内皮细胞，Cox回归分析显示uPA及uPAR是影响生存时间的预后因子，它们与预后存在一定的负相关关系。结论 uPA及uPAR可作为预测髓母细胞瘤患预后的客观指标。     

Increased plasminogen activator inhibition levels in malignancy

Plasminogen activator(PA)-tissue and urokinase type-and PA-inhibition in plasma were investigated in 52 consecutive cancer patients with a variety of tumors. At first patients were analyzed as one group. Secondly patients were subdivided into two groups, one with (n = 42) and one without (n = 10) metastasis. Our results show that tissue-type-PA antigen (t-PA-antigen) and PA-inhibition were both significantly increased irrespective of the presence or absence of tumor metastasis (p less than 0.001 compared to age matched healthy controls. In the group without metastasis a significantly decreased level of t-PA activity was found (p less than 0.001) but in the group with metastasis t-PA activity was normal. These data seem to reject the hypothesis that decreased plasma fibrinolytic activity is one of the prerequisites for tumor metastasis.     

Resistant bipolar disorder precipitated by Behcet's syndrome

OBJECTIVE: To report a case of a patient with Behcet's syndrome who developed treatment resistant bipolar disorder (BD) several years after the onset of Behcet's syndrome. METHODS: A 62-year-old woman suffering from Behcet's syndrome since the age of 38, who developed a typical BD 6 years after the first manifestations of the syndrome was described. RESULTS: Once BD occurred, Behcet's syndrome became milder, while BD deteriorated and evolved into a rapid cycling illness. Lithium and carbamazepine were ineffective in controlling the affective symptoms, while sodium valproate combined with low doses of carbamazepine and olanzapine resulted in sufficient stabilization of her mood state. CONCLUSIONS: Behcet's syndrome may have been the organic substrate for BD in this case. The appearance of BD in the setting of an organic-immune disorder, like Behcet's syndrome, suggests that such disorders may be the neurobiologic substrate or contributor for BD, at least in certain cases.     

Urokinase plasminogen activator released by alveolar epithelial cells modulates alveolar epithelial repair in vitro

Intra-alveolar fibrin is formed following lung injury and inflammation and may contribute to the development of pulmonary fibrosis. Fibrin turnover is altered in patients with pulmonary fibrosis, resulting in intra-alveolar fibrin accumulation, mainly due to decreased fibrinolysis. Alveolar type II epithelial cells (AEC) repair the injured alveolar epithelium by migrating over the provisional fibrin matrix. We hypothesized that repairing alveolar epithelial cells modulate the underlying fibrin matrix by release of fibrinolytic activity, and that the degree of fibrinolysis modulates alveolar epithelial repair on fibrin. To test this hypothesis we studied alveolar epithelial wound repair in vitro using a modified epithelial wound repair model with human A549 alveolar epithelial cells cultured on a fibrin matrix. In presence of the inflammatory cytokine interleukin-1beta, wounds increase by 800% in 24 hours mainly due to detachment of the cells, whereas in serum-free medium wound areas decreases by 22.4 +/- 5.2% (p < 0.01). Increased levels of D-dimer, FDP and uPA in the cell supernatant of IL-1beta-stimulated A549 epithelial cells indicate activation of fibrinolysis by activation of the plasmin system. In presence of low concentrations of fibrinolysis inhibitors, including specific blocking anti-uPA antibodies, alveolar epithelial repair in vitro was improved, whereas in presence of high concentrations of fibrinolysis inhibitors, a decrease was observed mainly due to decreased spreading and migration of cells. These findings suggest the existence of a fibrinolytic optimum at which alveolar epithelial repair in vitro is most efficient. In conclusion, uPA released by AEC alters alveolar epithelial repair in vitro by modulating the underlying fibrin matrix.     

Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction

A decrease in the fibrinolytic potential, mainly due to an elevation of plasminogen activator inhibitor (PAI), has been described in patients with stable coronary artery disease and a previous myocardial infarction. We investigated plasma levels of PAI and tissue plasminogen activator (t-PA) and their possible circadian variations in patients with unstable coronary artery disease (CAD). Sixty-three patients were studied for at least 2 consecutive days during their stay at the coronary care unit (CCU). Diurnal plasma fluctuations in PAI and t-PA and onset of further myocardial ischemic episodes were monitored. As controls we used 22 age-matched patients submitted to the clinic because of non cardiac chest pain or valvular disease who revealed no evidence of CAD. PAI levels were significantly elevated in patients with unstable CAD (p less than 0.0001) but were not influenced by the extent of underlying CAD, history of previous myocardial infarction, known risk factors for CAD, or by extent of myocardial damage. The circadian variation of PAI levels with peak values between midnight and 6 A.M. found in controls was still present in patients but at a higher level. Preservation of circadian pattern in PAI plasma levels despite myocardial ischemic attacks indicates that elevation of PAI is rather not caused by a reactive phenomenon. On the other hand, elevated PAI levels and episodes of severe myocardial ischemia exhibiting a median time of onset at 10 A.M. seem to be closely related.     

Urokinase-type plasminogen activator inhibits amyloid-beta neurotoxicity and fibrillogenesis via plasminogen

Amyloid-beta (Abeta) appears central to Alzheimer's disease (AD), aggregates spontaneously, and is neurotoxic to neurons in vitro. Recently, several groups reported a familial AD locus on chromosome 10. Here, we note that urokinase-type plasminogen activator (uPA) is located within this locus. Previously, we reported that uPA and its functional homolog, tissue-type plasminogen activator, are induced by Abeta treatment of neurons in vitro as well as in a mouse model of Abeta accumulation in vivo. Moreover, the target of plasminogen activators, plasmin, degraded nonaggregated and aggregated Abeta and modulated Abeta toxicity and deposition. Here, we have evaluated the effects of uPA and plasminogen on Abeta fibril formation and neurotoxicity. We report that the combination of uPA and plasminogen, but neither alone, inhibits Abeta toxicity, reduces Abeta deposition in vitro, and inhibits Abeta fibrillogenesis. We interpret these observations as suggesting that uPA represents a possible candidate gene for the chromosome 10 familial AD locus.     

Characterization of the plasminogen activator isolated from human embryo kidney cells: Comparison with Urokinase

Comparison is made between the plasminogen activator isolated from urine, Urokinase, and the one isolated from human embryo kidney cells grown in tissue culture. Physical, chemical, and immunological studies based primarily on activity measurements show all properties measured as being identical. It is therefore suggested that the two activators are the same.     

Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism

Deep-vein thrombosis (DVT) resolution is thought to be primarily a urokinase plasminogen activator (uPA) -dependent mechanism, although observations suggest other non-fibrinolytic mechanisms may exist. We explored the role of matrix metalloproteinase (MMP) -2 and -9 in early DVT resolution in uPA-deficient mice. Male B6/SVEV (WT) and genetically matched uPA -/- mice underwent inferior vena cava (IVC) ligation to create stasis venous thrombi, with IVC and thrombus harvest. Thrombus size was similar between WT and uPA -/- mice at day 4, suggesting early non uPA-dependent resolution. Intrathrombus neutrophils and monocytes were reduced 3- and 3.5-fold in uPA -/- mice as compared with WT. By ELISA, tumour necrosis factor α and interleukin 1β were not altered, while interferon (IFN)γ was significantly elevated in uPA -/- mice. A compensatory increase in thrombus tPA was not observed, plasmin activity was reduced and PAI-1 was elevated 2.5-fold in uPA -/- mice. Active MMP2, but not MMP9, was elevated 3-fold in uPA -/- mice as compared with WT as well as MMP-14, an MMP2 activator. Collagen type IV and fibrinogen were reduced in uPA -/- mice thrombi as compared with WT. IFNγ induces MMP2, and blockade of IFNγ was associated with larger venous thrombi and reduced active MMP2, as compared with WT. Consistently, MMP2 -/- mice had larger VT as compared with WT controls, despite normal thrombus plasmin levels. Taken together, early experimental venous thrombus resolution is independent of uPA, and, in part, inflammatory cell influx. MMP2-dependent thrombolysis is an important compensatory mechanism of venous thrombus resolution, possibly by collagen type IV metabolism, and may represent an exploitable therapeutic avenue.     

儿童髓母细胞瘤中尿激酶型纤溶酶原激活剂受体表达

目的 研究尿激酶型纤维溶酶原激活剂受体（uPAR)在儿童髓母细胞瘤中的表达及其与预后的关系。方法 采用免疫组化法检测84例经手术病理证实并获随访的儿童髓母细胞瘤（男46例，女38例，年龄6－12岁）中uPAR表达，按术后生存期3、5、10年，分为A、B和C组，使用Cox回归统计分析。结果 84例儿童髓母细胞瘤中，uPAR阳性表达64例（76％），A、B和C组间uPAR阳性表达分别为95％、67％和40％（P＜0．01）；Cox回归分析显示uPAR是影响生存时间的一个独立的预后因子，它与预后存在高度负相关性。结论 uPAR表达水平同儿童髓母细胞瘤预后密切相关。     

Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states

The association of increased PA-inhibitor (PAI) activity and of PAI-1 and PAI-2 antigen levels with different pathological conditions was studied in a collective of over 300 patients. PAI-1 and PAI-2 levels were measured by specific radioimmunoassays. A good correlation was observed of PAI activity with PAI-1 antigen (r = 0.718; p less than 0.0001) but not with PAI-2 (r = 0.070; n.s.). Both in the controls and in the patients, PAI activity and PAI-1 antigen showed an extremely large range of values. PAI activity ranged from 0.5 to 68 U/ml and PAI-1 antigen from 6 to 600 ng/ml. Increased PAI activity and PAI-1 antigen was observed in patients with malignant tumors, cardiovascular or thromboembolic disease, in the postoperative phase, with hepatic insufficiency, after trauma and after extracorporeal circulation. The large spectrum of disease states with increased PAI activity and PAI-1 antigen reinforces previous suggestions that PAI-1 is an acute phase reactant. After extracorporeal circulation, PAI activity and PAI-1 concentrations strongly increased within one hour, remained elevated for at least one week and returned to preoperation values within 7 days. PAI-2 values ranged from below detection limit (15 ng/ml), observed in half of the plasmas, to 485 ng/ml in a pregnant woman. High values of PAI-2 were only observed in pregnancy.     

Relationships between euglobulin clot lysis time and the plasma levels of tissue plasminogen activator and plasminogen activator inhibitor 1

The relationships between tissue plasminogen activator (tPA), its fast acting inhibitor (PAI-1) and euglobulin clot lysis time (ELT) were investigated with healthy volunteers' plasma. Turbidimetric clot lysis assay by the microtiter plate reader was utilized for ELT with a slight modification. Both tPA and PAI-1 showed the significant correlation with ELT. tPA had a significantly positive, not negative, correlation with ELT (R = 0.387, p less than 0.001). Higher correlation coefficients (R = 0.580, p less than 0.001 and R = 0.599, p less than 0.001) were obtained between ELT and total PAI-1 or free PAI-1 than tPA or tPA-PAI-1 complex (R = 0.427, p less than 0.001). The positive correlation was also obtained between tPA and PAI-1. These data suggest that PAI-1 is a highly important factor for ELT, especially, the amounts of free PAI-1 being the key factor to determine the ELT, which can represent the potential activity of the fibrinolytic system.     

Exploring soluble urokinase plasminogen activator receptor and its relationship with arterial stiffness in a bi-ethnic population: the SAfrEIC-study

Introduction

Elevated soluble urokinase-type plasminogen activator receptor (suPAR) indicates an inflammatory state caused by conditions such as HIV and cancer. Recently suPAR was identified as an indicator of cardiovascular disease (CVD). CVD is highly prevalent in black South Africans, but the potential role of suPAR is unknown. We investigated suPAR as a possible marker of arterial stiffness in Africans and Caucasians.

Methods

This study involved 207 Africans and 314 Caucasians (aged 20-70 yrs). C-reactive protein (CRP) and suPAR were determined in fasting blood samples. We measured blood pressure, pulse wave velocity (PWV) and Windkessel arterial compliance (Cwk).

Results

Africans displayed higher suPAR, CRP, PWV and lower Cwk (p < 0.001) compared to Caucasians. SuPAR was elevated in Africans irrespective of gender and smoking. We found strong relationships between PWV and suPAR (r = 0.27; p < 0.001) and Cwk and suPAR (r = − 0.39; p < 0.001) in the whole group, but found no independent relationship of any arterial stiffness measure and suPAR in Africans after adjustment for confounders. Caucasian men indicated a weak significant independent association between Cwk and suPAR (β = − 0.09; p = 0.028).

Conclusion

Africans had higher levels of suPAR and arterial stiffness than Caucasians (p < 0.001), but there was no independent relationship between arterial stiffness and suPAR in the Africans. It is speculated that due to the inflammatory role of suPAR, it will have stronger relationships with atherosclerosis, which has not yet manifested in this relatively young population group. SuPAR may therefore not be an ideal early marker of cardiovascular dysfunction, but may rather indicate established CVD.