Endotoxin producing bacteria cause disseminated intravascular coagulation (DIC); however, the mechanism of endotoxin action in man is still unclear. Impairment of the fibrinolytic system has been suggested as a contributing mechanism.A single injection of Escherichia coli lipopojysaccharide in rabbits resulted in a marked and prolonged increase of the levels of a fast-acting inhibitor of plasminogen activator (PAinhibitor) in plasma (from 3.9±0.7 to 41±13.2 U/ml after 3 h). Gel filtration studies indicated that inhibition of human tissue-type plasminogen activator (t-PA) by rabbit plasma is accompanied by a change in the elution profile of the activator compatible with the formation of an enzyme-inhibitor complex with an apparent molecular weight of 100,000. Injection of human t-PA (1,500 IU/kg body wt) in endotoxin treated animals resulted in very fast inhibition of t-PA and formation of a similar complex.The half-life of circulating PA-inhibitor activity in rabbits was about 7 min as estimated by donor receiver plasma transfusion experiments.Stimulation of cultured human endothelial cells with endotoxin resulted in enhanced rate of accumulation of PAinhibitor activity in the culture medium (two-to sevenfold increase). In five patients with septicemia, markedly increased levels of PA-inhibitor (14.3±15.5 U/ml) as compared with control subjects (13±0.7 U/ml) were observed in plasma.A very strong correlation (r = 0.98) was found between inhibition of t-PA and of urokinase in all conditions, suggesting that this fast-acting inhibitor reacts with both plasminogen activators.These data suggest that the appearance of this fast-acting PA-inhibitor is very sensitive to endotoxin stimulation. The marked increase in the level of PA-inhibitor in blood may contribute to the pathogenesis of DIC in septicemia.

Atherosclerosis is the common pathophysiological substrate of ischemic vascular diseases and their thrombotic complications. The unbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) has been hypothesized to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Different MMPs have been assigned relevant roles in the pathology of vascular diseases and MMP-10 (stromelysin-2) has been involved in vascular development and atherogenesis. This article examines the pathophysiological role of MMPs, particularly MMP-10, in the onset and progression of vascular diseases and their regulation by pro-inflammatory stimuli. MMP-10 over-expression has been shown to compromise vascular integrity and it has been associated with aortic aneurysms. MMP-10 is induced by C-reactive protein in endothelial cells, and it is over-expressed in atherosclerotic lesions. Additionally, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and the presence of atherosclerotic plaques. We have cloned the promoter region of the MMP-10 gene and studied the effect of inflammatory stimuli on MMP-10 transcriptional regulation, providing evidences further supporting the involvement of MMP-10 in the pathophysiology of atherothrombosis.

Tubular carcinoma of the breast is a variant of invasive ductal carcinoma that is well differentiated and characterized by an orderly tubular formation. Although often perceived to have a better prognosis, there continues to be questions regarding the extent of treatment required. A retrospective review of 44 patients diagnosed with tubular carcinoma of the breast from 1987 to 1999 was performed. All documented data regarding patient and tumor characteristics plus the extent of treatment were analyzed and compared. Lymph node metastases were present in 4 of 32 patients (13%) who had nodes examined. Tumor size correlated with axillary status, with tumors less than 15 mm having no axillary nodal involvement. No other factor influenced nodal status. In breast conservation patients without adjuvant radiation, 5% (1 of 20) had local recurrence versus 0% (0 of 13) of patients who received postoperative radiation. Ductal carcinoma in situ (DCIS) was associated with 52% of tubular cancers. Second breast cancers developed in 16% of cases. There was no difference in presentation or outcome for pure versus mixed tubular carcinoma. Overall mortality was 2%. Overall survival for patients with tubular carcinoma is quite good. Breast conservation treatment results in low rates of local recurrence for tubular carcinoma with or without the use of adjuvant radiation therapy. Pure tubular carcinomas had the same behavior and overall prognosis as mixed tubular carcinomas and should be classified together. Lymph node status did not influence disease-free or overall survival.

A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients.Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients.

Background and purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Conclusion Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial.