Meningiomas and schwannomas: Molecular subgroup classification found by expression arrays

Microarray gene expression profiling is a high-throughput system used to identify differentially expressed genes and regulation patterns, and to discover new tumor markers. As the molecular pathogenesis of meningiomas and schwannomas, characterized by NF2 gene alterations, remains unclear and suitable molecular targets need to be identified, we used low density cDNA microarrays to establish expression patterns of 96 cancer-related genes on 23 schwannomas, 42 meningiomas and 3 normal cerebral meninges. We also performed a mutational analysis of the NF2 gene (PCR, dHPLC, Sequencing and MLPA), a search for 22q LOH and an analysis of gene silencing by promoter hypermethylation (MS-MLPA). Results showed a high frequency of NF2 gene mutations (40%), increased 22q LOH as aggressiveness increased, frequent losses and gains by MLPA in benign meningiomas, and gene expression silencing by hypermethylation. Array analysis showed decreased expression of 7 genes in meningiomas. Unsupervised analyses identified 2 molecular subgroups for both meningiomas and schwannomas showing 38 and 20 differentially expressed genes, respectively, and 19 genes differentially expressed between the two tumor types. These findings provide a molecular subgroup classification for meningiomas and schwannomas with possible implications for clinical practice.

Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aorta

Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aorta Aims: Thoracic ascending aortic aneurysms (TAA) are characterized by elastic fibre breakdown and cystic medial degeneration within the aortic media, associated with progressive smooth muscle cell (SMC) rarefaction. The transforming growth factor (TGF)-beta/Smad2 signalling pathway is involved in this process. Because the pericellular fibrinolytic system activation is able to degrade adhesive proteins, activate matrix metalloproteinase (MMP), induce SMC disappearance and increase the bioavailability of TGF-beta, the aim was to investigate the plasminergic system in TAA. Methods and results: Ascending aortas [21 controls and 19 TAAs (of three different aetiologies)] were analysed. Immunohistochemistry showed accumulation of t-PA, u-PA and plasmin in TAAs, associated with residual SMCs. Overexpression of t-PA and u-PA was confirmed by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting and zymography on TAA extracts and culture medium conditioned by TAA. Plasminogen was present on the SMC surface and inside cytoplasmic vesicles, but plasminogen mRNA was undetectable in the TAA medial layer. Plasmin-antiplasmin complexes were detected in TAA-conditioned medium and activation of the fibrinolytic system was associated with increased fibronectin turnover. Fibronectin-related material was detected immunohistochamically in dense clumps around SMCs and colocalized with latent TGF-beta binding protein-1. Conclusions: The fibrinolytic pathway could play a critical role in TAA progression, via direct or indirect impact on ECM and consecutive modulation of TGF-beta bioavailability.

Clinical trials with glycoprotein IIB/IIIA antagonists - No benefit without bleeding?

As the glycoprotein GPIIb/IIIa receptor is the final common pathway in platelet aggregation, antagonists of this receptor cause a profound inhibition of aggregation induced by any agonist. The short-term efficacy and safety of GPIIb/IIIa antagonists in patients undergoing coronary angioplasty was demonstrated with murine 7E3 Fab, but this antibody was immunogenic. Abciximab is a chimeric human-mouse monoclonal antibody that is less immunogenic. The first major trial with a GPIIb/IIIa antagonist was the EPIC trial with abciximab, which showed that abciximab reduced the ischemic complications of coronary balloon angioplasty and atherectomy in high-risk patients, but increased the risk of bleeding. Subsequent studies showed that using less concurrent heparin reduced bleeding. Abciximab also reduced the rate of revascularization. Further studies have shown that the benefits of abciximab extended to all patients undergoing angioplasty (EPILOG), including patients with unstable angina (CAPTURE) and acute myocardial infarction (RAPPORT). Clinical trials with eptifibatide and tirofiban have failed to demonstrate benefit, at the doses used, in angioplasty. Abciximab and eptifibatide, but not oral xemilofiban, improve the safety of the coronary stenting procedure. Shortterm intravenous treatment with lamifiban, eptifibatide or tirofiban is beneficial in acute coronary syndromes (unstable angina, non-Q wave myocardial infarction). Orally active GPIIb/IIIa antagonists are being developed for use in acute coronary syndromes and myocardial infarction. However, no benefit has been shown with lefradafiban in acute coronary syndromes and sibrafiban and orbofiban are harmful. Eptifibatide, lamifiban and abciximab improve coronary patency in myocardial infarction, and long-term trials of GPIIb/IIIa antagonists are being conducted in acute myocardial infarction. Abciximab can cause thrombocytopenia, and all the GPIIb/IIIa antagonists increase the incidence of bleeding, but there is no excess of intracranial hemorrhage. (C) 2001 Prous Science. All rights reserved.

Alteplase: descendancy in myocardial infarction, ascendancy in stroke

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in Mi. Alteplase is most effective when given early in Mi and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in Mi can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard Mi treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in Mi. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.

Biochemistry of adipose tissue: an endocrine organ

Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.

Trombo na Aurícula Direita: Apresentação Rara da Deficiência do Inibidor do Ativador do Plaminogénio

A presença de trombos móveis na aurícula direita são fenómenos raros, mas associados a uma elevada mortalidade. Apesar de a ecocardiografia ter permitido avanços no seu diagnóstico, a sua abordagem continua a ser motivo de debate. Neste artigo apresentamos o caso de uma doente do sexo feminino, de 24 anos, com antecedentes de tabagismo, obesidade e sob terapêutica anovulatória que recorre ao serviço de urgência por cansaço fácil e tosse com expetoração hemoptoica. O ecocardiograma transtorácico revelou massa, móvel, multilobulada de grandes dimensões na aurícula direita, condicionando abertura da válvula tricúspide. Perante episódios recorrentes de embolia pulmonar, foi submetida a cirurgia cardíaca com exérese da massa, sendo o resultado anatomopatológico compatível com trombo organizado com calcificação. O estudo genético revelou homozigotia para a variante alélica PAI-1:-675G >A(4G/4G) do inibidor do ativador do plasminogénio e heterozigotia para a variante alélica MTHFR 1298 A/C da 5,10-metilenotetrahidrofolato redutase.

A Utilização do Activador Recombinante do Plasminogénio Tecidular na Trombose Venosa do Recém-Nascido

O activador recombinante do plasminogénio tecidular e, de todos os fibrinolíticos, o que tem maior especificidade para a fibrina e semi-vida mais curta; daí a sua grande eficácia na lise dos trombos e a quase inexistência de complicações hemorrágicas. Os autores descrevem o caso de um recém-nascido com trombose extensa da veia cava inferior e veia renal direita em que a terapêutica com activador recombinante do plasminogénio tecidular, levou a uma diminuição progressiva do trombo e repermeabilização completa de ambos os vasos em 12 horas. Nao houve efeitos adversos relevantes.

Successful Thrombolysis despite Having an Incidental Unruptured Cerebral Aneurysm

Purpose. To report a case of successful thrombolysis performed in a patient with an incidental unruptured intracranial aneurysm and review the literature. Case Report. Patient admitted for ischemic stroke due to left posterior cerebral artery occlusion, with an incidental right middle cerebral artery aneurysm, who underwent treatment with tissue plasminogen activator (rtPA) resulting in clinical improvement without complications. Conclusion. The presence of unruptured intracranial aneurysms is considered as a contraindication to thrombolysis, due to a potentially higher hemorrhagic risk of aneurysm rupture. Patients, otherwise, eligible for thrombolysis are usually excluded from receiving this emergent treatment, despite its potential benefits. A reevaluation of the strict exclusion criteria for thrombolysis in acute stroke patients should be considered.

Intramural Hematoma of the Esophagus After Thrombolysis for Ischemic Stroke

Intramural dissecting hematoma is an unusual esophageal condition with a threatening presentation but excellent prognosis when managed conservatively.We report the case of an 88-year-old woman who developed an intramural hematoma of the esophagus after intravenous thrombolysis for an acute ischemic stroke. Before thrombolysis, nasogastric intubation was attempted unsuccessfully. She was kept on nil by mouth, intravenous hydration, proton pump inhibitor, antiemetics,and an antibiotic initiated 2 days before for periodontal disease. The esophageal hematoma regressed, and she resumed oral diet asymptomatically.To our knowledge, this is the first report of this type of lesion after thrombolysis for an ischemic stroke. A brief discussion and literature review are presented.

Thrombolysis in ischemic stroke without arterial occlusion at presentation.

BACKGROUND AND PURPOSE: None of the randomized trials of intravenous tissue-type plasminogen activator reported vascular imaging acquired before thrombolysis. Efficacy of tissue-type plasminogen activator in stroke without arterial occlusion on vascular imaging remains unknown and speculative. METHODS: We performed a retrospective, multicenter study to collect data of patients who presented to participating centers during a 5-year period with ischemic stroke diagnosed by clinical examination and MRI and with imaging evidence of no vascular occlusion. These patients were divided into 2 groups: those who received thrombolytic therapy and those who did not. Primary outcome measure of the study was excellent clinical outcome defined as modified Rankin Scale of 0 to 1 at 90 days from stroke onset. Secondary outcome measures were good clinical outcome (modified Rankin Scale, 0-2) and perfect outcome (modified Rankin Scale, 0). Safety outcome measures were incidence of symptomatic intracerebral hemorrhage and poor outcome (modified Rankin Scale, 4-6). RESULTS: A total of 256 patients met study criteria, 103 with thrombolysis and 153 without. Logistic regression analysis showed that patients who received thrombolysis had more frequent excellent outcomes with odds ratio of 3.79 (P<0.01). Symptomatic intracerebral hemorrhage was more frequent in thrombolysis group (4.9 versus 0.7%; P=0.04). Thrombolysis led to more frequent excellent outcome in nonlacunar group with odds ratio 4.90 (P<0.01) and more frequent perfect outcome in lacunar group with odds ratio 8.25 (P<0.01). CONCLUSIONS: This study provides crucial data that patients with ischemic stroke who do not have visible arterial occlusion at presentation may benefit from thrombolysis.

Break-dance: an unusual cause of hammer syndrome.

We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice.

We explored the role of urokinase and tissue-type plasminogen activators (uPA and tPA), as well as the uPA receptor (uPAR; CD87) in mouse severe malaria (SM), using genetically deficient (-/-) mice. The mortality resulting from Plasmodium berghei ANKA infection was delayed in uPA(-/-) and uPAR(-/-) mice but was similar to that of the wild type (+/+) in tPA(-/-) mice. Parasitemia levels were similar in uPA(-/-), uPAR(-/-), and +/+ mice. Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPAR(-/-) mice. Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR(-/-) mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA(-/-) and uPAR(-/-) mice. Administration of aprotinin, a plasmin antagonist, also delayed mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR(-/-) mice. In contrast, macrophage sequestration in cerebral venules or alveolar capillaries was evident in both +/+ and uPAR(-/-) mice. Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR(-/-) mice. These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping. These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.

In situ stromal expression of the urokinase/plasmin system correlates with epithelial dysplasia in colorectal adenomas.

An increase of urokinase-type plasminogen activator (uPA) and a decrease of tissue-type PA (tPA) have been associated with the transition from normal to adenomatous colorectal mucosa. Serial sections from 25 adenomas were used to identify PA-related caseinolytic activities by in situ zymography, blocking selectively uPA or tPA. The distribution of uPA, tPA, and type 1 PA inhibitor mRNAs was investigated by nonradioactive in situ hybridization, and the receptor for uPA was detected by immunostaining. Low- and high-grade epithelial cell dysplasia was mapped histologically. Results show that 23 of 25 adenomas expressed uPA-related lytic activity located predominantly in the periphery whereas tPA-related activity was mainly in central areas of adenomas. In 15 of 25 adenomas, uPA mRNA was expressed in stromal cells clustered in foci that coincided with areas of uPA lytic activity. The probability of finding uPA mRNA-reactive cells was significantly higher in areas with high-grade epithelial dysplasia. uPA receptor was mainly stromal and expressed at the periphery. Type 1 PA inhibitor mRNA cellular expression was diffuse in the stroma, in endothelial cells, and in a subpopulation of alpha-smooth muscle cell actin-reactive cells. These results show that a stromal up-regulation of the uPA/plasmin system is associated with foci of severe dysplasia in a subset of colorectal adenomas.

Intérêt des faibles doses de rt-PA dans les syndromes inflammatoires et hémorragiques du segment antérieur: étude clinique et revue de la littérature [Treatment of anterior segment fibrinous reactions and hemorrhage with intracameral low dose rt-PA: clinical study and review of the literature].

PURPOSE: to evaluate the efficacy and the safety of low dose intraocular tissue plasminogen activator (rt-PA) in the treatment of traumatic hyphema and postoperative fibrinous membrane. METHODS: Six microg to 10 microg of rt-PA was injected into the anterior chamber to treat severe fibrinous postoperative membranes and total traumatic hyphemae. RESULTS: Thirteen eyes of 13 patients were treated. Four cases of traumatic hyphema and 9 cases of fibrinous membranes were included. Complete fibrinolysis within 24 hours was observed in 4 cases (30.8%). A partial success was noted in 7 eyes (53.8%). No beneficial effect was observed in two cases of traumatic hyphema associated with intravitreal hemorrhage after penetrating trauma. No side effect attributable to rt-PA occurred. CONCLUSION: Low dose intraocular rt-PA appears to be safe and effective in the treatment of postoperative fibrinous membrane and endocular hemorrhage limited to the anterior chamber.

Early profiles of clinical evolution after intravenous thrombolysis in an unselected stroke population.

BACKGROUND: Intravenous recombinant tissular plasminogen activator (rt-PA) is the only approved pharmacological treatment for acute ischaemic stroke. The authors aimed to analyse potential causes of the variable effect on early course and late outcome. METHODS AND RESULTS: 136 patients (42% women, 58% men) treated with intravenous rt-PA within 3 h of stroke onset in an acute stroke unit over a 3-year period, were included. Early clinical profiles of evolution at 48 h were divided into clinical improvement (CI) (decrease >4 points in the National Institute of Health Stroke Scale (NIHSS)); clinical worsening (CW) (increase >4 points NIHSS); clinical worsening after initial improvement (CWFI) (variations of >4 points in the NIHSS). Patients with clinical stability (no NIHSS modification or <4 points) were excluded. The patients showed in 66.9% CI, 13.2% CW 8.1 % CWFI and 11.8% remained stable. Female sex, no hyperlipaemia and peripheral arterial disease were associated with CW. Male sex and smoking were associated with CI. Absence of arterial occlusion on admission (28.4%) and arterial recanalisation at 24 h were associated with CI. Main causes of clinical deterioration included symptomatic intracranial haemorrhage (sICH), persistent occlusion and cerebral oedema. 23.5% developed ICH, 6.6% of which had sICH. At 3 months, 15.5% had died. Mortality was increased in CW, mainly related to sICH and cerebral oedema. The outcome of CWFI was intermediate between CW and CI. CONCLUSIONS: Early clinical profiles of evolution in thrombolysed patients vary considerably. Even with CI, it is critical to maintain vessel permeability to avoid subsequent CW.