Relationships between Body Composition and Plasma Levels of Pancreatic, Gut, and Adipose Tissue Hormones in db/db Mice, a Model of Type 2 Diabetes Mellitus.

We studied the relationships between body composition parameters and plasma levels of pancreatic, gut, and adipose tissue hormones regulating energy balance and glucose metabolism in diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J). The body composition parameters in mice aged 8, 12, and 16 weeks were assessed by magnetic resonance imaging. The concentrations of insulin, glucagon, ghrelin, glucagon-like peptide-1, glucose-dependent immunotropic peptide, leptin, resistin, and plasminogen activator-1 were measured by multiplex analysis at the age of 8 and 16 weeks. In comparison with non-diabetic control (db/+), db/db mice demonstrated high fat mass and reduced lean body mass and water content. In 8- and 16-week-old db/db mice, the levels of leptin (p<0.001), insulin (p<0.01), and glucagon-like peptide-1 (p<0.05) were elevated and the concentration of ghrelin (p<0.05) was reduced. The body weight and fat mass positively correlated with the levels of leptin, insulin, plasminogen activator-1, and glucagon-like peptide-1 and negatively correlated with ghrelin concentration. The results provide further details for characteristics of db/db mice, a widely used model of obesity and type 2 diabetes mellitus.

Prognostic role of tumor-associated proteases in colorectal cancer.

The relationship between the tumor and plasma levels of tumor-associated proteases - components of plasminogen activation system (uPA, tPA, and PAI-1), matrix metalloproteinases (MMP) 2, 7, 9 and their inhibitor (TIMP-1) - and the survival rate of patients with colorectal cancer was analyzed in order to evaluate the clinical significance of these markers. The study was carried out in two groups of patients, observed for 5 and 10 years, in whom the levels of these proteins were previously measured by enzyme immunoassays. High level of PAI-1 in the tumor (≥4.0 ng/mg protein) was found to be a significant, but not independent unfavorable prognostic factor for overall 5- and 10-year survival. The role of this factor was mainly significant in patients with stage III disease. High preoperative plasma levels of MMP-7 and TIMP-1 (threshold values 4.0 and 347 ng/ml, respectively) were independent unfavorable prognostic factors, while in unifactorial analysis, high level of MMP-7 (≥7.8 ng/mg protein) in the tumors of patients with disseminated process was olso an unfavorable prognostic factor.

Interaction of Leptospira interrogans with human proteolytic systems enhances dissemination through endothelial cells and protease levels.

We have recently reported the ability of Leptospira to capture plasminogen (PLG) and generate plasmin (PLA) bound on the microbial surface in the presence of exogenous activators. In this work, we examined the effects of leptospiral PLG binding for active penetration through the endothelial cell barrier and activation. The results indicate that leptospires with PLG association or PLA activation have enhanced migration activity through human umbilical vein endothelial cell (HUVEC) monolayers compared with untreated bacteria. Leptospira cells coated with PLG were capable of stimulating the expression of PLG activators by HUVECs. Moreover, leptospires endowed with PLG or PLA promoted transcriptional upregulation matrix metalloprotease 9 (MMP-9). Serum samples from patients with confirmed leptospirosis showed higher levels of PLG activators and total MMP-9 than serum samples from normal (healthy) subjects. The highest level of PLG activators and total MMP-9 was detected with microscopic agglutination test (MAT)-negative serum samples, suggesting that this proteolytic activity stimulation occurs at the early stage of the disease. Furthermore, a gelatin zymography profile obtained for MMPs with serum samples from patients with leptospirosis appears to be specific to leptospiral infection because serum samples from patients with unrelated infectious diseases produced no similar degradation bands. Altogether, the data suggest that the Leptospira-associated PLG or PLA might represent a mechanism that contributes to bacterial penetration of endothelial cells through an activation cascade of events that enhances the proteolytic capability of the organism. To our knowledge, this is the first proteolytic activity associated with leptospiral pathogenesis described to date.

Assays for prostate cancer : changing the screening paradigm?

Prostate cancer (PCa) screening and detection have changed dramatically since the introduction of serum prostate-specific antigen (PSA) testing. Despite the resulting improvement in early PCa detection and stage migration, in clinical practice the use of PSA testing may cause overdetection and ultimately overtreatment. As a consequence, novel biomarkers are needed to increase the specificity of PCa detection. The aim of this article is to present an overview of novel blood- and urine-based biomarkers that may optimize PCa detection, with improved identification of patients with significant PCa and avoidance of unnecessary prostate biopsies. A systematic and comprehensive PubMed search was performed using the MeSH search terms 'prostate cancer', 'biomarker', 'marker', and 'detection'. Results were restricted to the English language. Several blood- and urine-based biomarkers have the potential to improve prediction of the presence and/or significance of PCa. Ideally, biomarkers should be used in combination within multivariate models, leading to superior accuracy for prediction of any PCa or clinically significant PCa, compared with the use of a single marker.

Biomarkers for abdominal aortic aneurysms from a sex perspective.

BACKGROUND: Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses. OBJECTIVE: The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs. METHODS: In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA. RESULTS: Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs. CONCLUSION: The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.

Effects of rosiglitazone on the cardiovascular profile in postmenopausal women without diabetes mellitus: interplay of thiazolidinediones and hormone therapy.

OBJECTIVE: Thiazolidinediones have antiatherothrombotic effects on persons with diabetes. Hormone therapy among postmenopausal women has both positive and negative cardiovascular effects. However, the effects of rosiglitazone with or without concurrent long-term hormone therapy on the cardiovascular profile of nondiabetic postmenopausal women are unknown. METHODS: Thirty-eight nondiabetic postmenopausal women were enrolled in this double-blind and placebo-controlled study. Eighteen participants received 4 mg rosiglitazone, and 20 participants took placebo daily for 12 weeks. Global endothelial function and plasma biomarkers were measured. RESULTS: Baseline characteristics and parameters were similar between the groups. Rosiglitazone, but not placebo, significantly reduced leukocyte count and plasma levels of matrix metalloproteinase-9 and inhibited the elevation of plasma levels of plasminogen activator inhibitor-1 and tissue plasminogen activator (P < 0.05 for all). Most of the favorable effects provided by rosiglitazone were still present in participants with concurrent hormone therapy. Increased body weight and waist size as well as elevation of the plasma levels of total and low-density lipoprotein cholesterol were noted after rosiglitazone treatment among participants without concurrent hormone therapy. No significant change in the global endothelial function occurred in response to treatment in either group. CONCLUSIONS: Rosiglitazone treatment provided both protective and harmful cardiovascular effects in nondiabetic postmenopausal women. Concurrent hormone therapy resulted in the maintenance of the major beneficial effects while neutralizing the unfavorable effects of rosiglitazone.

Induction of plasminogen activators in pregnant women with Toxoplasma gondii infection.

OBJECTIVE: To determine whether plasminogen activators (PAs) are involved in the pathologic process of toxoplasmosis. MATERIALS AND METHODS: Out of 220 pregnant women the study included 26 with a diagnosis of toxoplasmosis: six based on seropositivity for Toxoplasma gondii IgM and 20 based on seropositivity for T. gondii IgG. We measured serum activities and protein levels of PAs by casein zymography and Western blotting, respectively. RESULTS: Serum PAs were higher in healthy pregnant women than in their healthy nonpregnant counterparts. Furthermore, serum PAs were significantly higher in pregnant women infected with T. gondii than in their healthy counterparts. CONCLUSION: PAs participate in the pathogenesis of toxoplasmosis in pregnant women and may be useful markers of T. gondii infection.

Altered fibrinolytic activities in gastric cancer and uremic patients after intervention.

INTRODUCTION: Although thromboembolism is the most recognized cause of death in cancer and uremic patients following tumorectomy or hemodialysis, respectively, little data exist concerning its etiologies and treatments in post-intervention settings. In this study, we determined the post-intervention fibrinolytic activities to exploit their implications in gastric cancer and uremic patients. MATERIALS AND METHODS: A small-scale case-control study with totally 56 cases aimed to compare the difference of the post-intervention fibrinolytic activities of two hypercoagulable groups of gastric cancer and uremic patients versus healthy controls was conducted. In-house functional assays for plasma plasminogen (Pg) and plasminogen activators (PA) activities were employed. RESULTS: As compared to the control, both variable-stratified patient groups disclosed reduced Pg activities, synonyms at the "hypofibrinolytic" state, suggesting that the alleged post-intervention hypercoagulability of the two patient groups could be rationalized by the hypofibrinolysis mechanism. On the other hand, cancer patients showed elevated PA activity, concomitantly implicating that there was associated fibrinolytic consumption. Moreover, the altered PA activity could be ascribed to tumor metastasis according to literature review. CONCLUSIONS: Our data suggested that the PA/Pg fibrinolytic activities were altered in gastric cancer and uremic patients post-interventionally. Measurement of the post-intervention fibrinolytic activities could be useful in projection of some potential risks.

Effect of thyroxine on plasminogen activator and inhibitor activity in rat.

Thyroid hormones influence mineral metabolism, distribution of water and electrolytes and are therefore of great importance in the maintenance of homeostasis under normal and diseased conditions such as renal failure. The present study was carried out to determine the effect of thyroxine on fibrinolytic parameters such as plasminogen activators (PA) in rat kidney, levels of PA and plasminogen activator inhibitor (PAI), glucose in plasma and serum lipid profile injected with thyroxine (75 microg eltroxine/ 100 g(-1) body weight, ip for 7 days). Treatment increased PA activity significantly in rat kidneys. No changes were seen in PA, PAI and glucose in plasma of rats. There was significant decrease in total cholesterol and LDL-cholesterol levels in serum of treated group resulting in the decrease of HDL/LDL and total cholesterol/cholesterol ratios. However, triglycerides and VLDL showed significant higher activity in the serum of treated group as compared to controls. The results suggest beneficial effects of thyroxine treatment by increasing PA activity in kidney and reducing the cholesterol content in blood. It may be helpful to prevent hypercoagulable state by maintaining the normal homeostatic balance and restoring renal function.

Role of selectins and fibrinolysis in VTE.

Venous thromboembolism (VTE) accounts for an estimated 900,000 cases of deep venous thrombosis (DVT) and pulmonary embolism (PE) yearly, resulting in approximately 300,000 deaths [1]. For the past 150 years, Virchow's triad has encompassed the elements of venous thrombogenesis, including stasis, changes in the vessel wall, and thrombogenic changes in the blood. However, in the early 1970s, through the work of Gwendylen Stewart, a relationship between thrombosis and inflammation was suggested. In this review, we will address the role of selectins and fibrinolysis in the process of venous thrombogenesis.

Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance.

Fibrinolysis serves an important role in the process of coagulation, ensuring that clots that are formed in response to injury resolve after the injured tissue is repaired. Fibrinolysis occurs because the protein plasminogen is converted to the active serine protease plasmin by its activating molecules (primarily tissue plasminogen activator). One of the inhibitors of fibrinolysis is alpha(2)-antiplasmin, which acts as the primary inhibitor of plasmin(ogen). Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Despite the rare nature of this disorder, understanding of the actions of alpha(2)-antiplasmin and the results of its deficiency has provided the opportunity for better understanding of the fibrinolytic system in both how it affects the risk of bleeding and its impact on other bodily systems. Here, we review the history of the discovery of alpha(2)-antiplasmin, our understanding of its genetics and function, and our current knowledge of its congenital deficiency. We also discuss some of the current avenues of investigation into its impact on other diseases and physiological states.

The effect of levonorgestrel-releasing intrauterine system use on menstrual blood loss and the hemostatic, fibrinolytic/inhibitor systems in women with menorrhagia.

BACKGROUND: Menorrhagia is known to be associated with uterine fibroids, adenomyosis, pelvic infections, endometrial polyps and clotting defects. A viable alternative therapy to hysterectomy should alleviate heavy menstrual blood flow and consequently improve the quality-of-life measures in women presenting with menorrhagia. The levonorgestrel-releasing intrauterine system (LNG-IUS) ranks higher than medical treatments in terms of efficacy, comparable improvements in quality of life and psychological well-being. OBJECTIVE: The purpose of the study was to determine the effects of 6 months of LNG-IUS use on menstrual blood loss and the hemostatic, fibrinolytic/inhibitor systems in blood and the endometrium in women with menorrhagia with known pathologic causes. PATIENTS AND METHODS: Samples from 41 women were analyzed. Hemoglobin, hematocrit, thrombelastography, tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), u-PA receptor (u-PAR), plasminogen activator inhibitor-1/2 (PAI-1/2), D-dimer and von Willebrand factor (VWF) were determined, and t-PA, u-PA and PAI-1/2 were also determined in endometrial tissue extracts. RESULTS: Menorrhagia was reduced in 89% of women by 3 months; by 6 months all women had no menorrhagia, and 39% of women had become amenorrhoeic. Hemoglobin and hematocrit levels showed improvement, and reached normal reference levels by 6 months. There were no systemic changes in the fibrinolytic/inhibitor systems and VWF, except for a decreased u-PAR level. However, in the endometrium, significant elevations in PAI-1/2 together with u-PAR levels were seen at 6 months. CONCLUSIONS: The slow levonorgestrel-release intrauterine device use results in high expression of fibrinolytic inhibitors (PAI-1/2) and upregulated u-PAR expression in the endometrium. Systemic hemostasis was not significantly altered. The study demonstrated that LNG-IUS is highly effective in the treatment of menorrhagia with known pathologic causes.

Plasma levels of t-PA and PAI-1 correlate with the formation of experimental post-surgical peritoneal adhesions.

This study has evaluated whether systemic changes of plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) parallel the adhesions development and whether they could be used as predictors of adhesion risk. This has been studied in an animal model of post-surgical peritoneal adhesion by monitoring for 10 days the plasma and tissue levels of t-PA and PAI-1. The results showed that both tissular and plasmatic levels of t-PA were decreased in concomitance with the development of peritoneal adhesions. In contrast, PAI-1 was found increased into the tissue and into the plasma samples of the rats taken at 5 and 10 days time points. Inflammatory mediators such as ICAM-1, VCAM-1, and IL-6 within the peritoneal lavage fluid also correlated with the adhesion formation process. In conclusion, post-surgical peritoneal adhesions provide alterations of local inflammatory components and local and systemic fibrinolytic components, possibly with PAI-1 quenching t-PA. This may have potential for the identification of high-risk patients.

CSF levels of growth factors and plasminogen activators in leptomeningeal metastases.

OBJECTIVE: To investigate the diagnostic value of transforming growth factor beta(1) (TGFbeta(1)), vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) in CSF for leptomeningeal metastasis (LM). METHODS: The authors measured concentrations of biomarkers by ELISA in matched samples of CSF and serum, collected from 132 patients with a solid malignancy with LM (n = 19) and without LM (n = 54) and patients with viral (n = 16) and bacterial (n = 16) meningitis and a variety of nonmalignant, noninfectious neurologic disorders (n = 27). Indexes of the biomarkers (CSF/serum value relative to CSF/serum albumin ratios) were calculated to correct for the serum contribution to the CSF marker concentration. RESULTS: CSF VEGF concentration was significantly higher in LM than in all other groups. VEGF indexes were also higher, although not significant. In contrast, the tPA index was significantly decreased in LM compared with all other groups. The combination of the VEGF and tPA indexes resulted in a sensitivity of 100% for LM and a specificity of 73% for the patient group with a primary tumor but without LM. CONCLUSION: Patients with leptomeningeal metastasis have high vascular endothelial growth factor (VEGF) indexes and low tissue-type plasminogen activator (tPA) indexes. As cytologic examination of CSF lacks 100% sensitivity for the diagnosis of leptomeningeal metastasis (LM), the combination VEGF and tPA index analysis may be of additional value in the diagnostic workup of patients suspected of having LM.

Monitoring of plasmin and plasminogen activator activity in blood of patients under fibrinolytic treatment by reteplase.

There are no reliable data on plasmin or plasminogen activator (PA) activities in blood of patients receiving fibrinolytic treatment. This is due to continuing in vitro action of PA after blood withdrawal. These artefactual changes of PA or plasmin activities have been prevented by arginine stabilization of blood samples of myocardial infarction patients treated with plasminogen activators. Twelve patients with myocardial infarction were treated with reteplase 2 x 10,000,000 units in bolus application; one patient was treated with 100 mg t-PA in continuous infusion. Blood was immediately stabilized with EDTA and arginine. The plasma was analyzed with newly developed assays for plasmin and PA. Maximal plasmin activities in blood were obtained at 40 to 60 minutes reteplase treatment time (0.1-0.6 U/mL = approximately 0.05-0.3 micromol/L plasmin). The 50% clearance rate for plasmatic Pli was greater than 30 minutes. The plasmatic reteplase concentration peaked at approximately 2,000 U/mL after the first bolus infusion and at approximately 1,500-3,500 U/mL after the second bolus infusion. Reteplase was cleared to 50% within less than 30 minutes, also with great inter-individual variation. Arginine stabilization of blood allows reliable determinations of activities of plasmin and PA in blood of patients under fibrinolytic treatment: substantial plasmin activities occur in patients treated by reteplase. Therapeutic thrombolysis might be improved, imitating the physiologic cellular thrombolysis; i.e., polymorphonuclear phagocytes (PMN) that can be activated by singlet oxygen ((1)O(2)). PMN might be superior to PA in selective lysis of pathologic thrombi.

Effects of losartan on urinary secretion of extracellular matrix and their modulators in type 2 diabetes mellitus patients with microalbuminuria.

PURPOSE: Angiotensin II receptor Type 1 antagonists postpone the development of nephropathy in type 2 diabetes mellitus (DM). We hypothesize that Losartan may ameliorate renal function in diabetic patients through the regulation on the generation of transforming growth factor (TGF)-beta and fibrinolytic regulators. METHODS: Twenty-two type 2 DM patients with microalbuminuria were treated with 50-100 mg/day of Losartan for 6 months. Urinary secretion of TGF-, plasminogen activator inhibitor-1 (PAI-1), tissue and urokinase plasminogen activators (tPA and uPA) fibronectin, collagen IV and plasma levels of TGF-beta, PAI-1, tPA and uPA of the patients before and after the treatment were analyzed using enzyme-linked immunoabosorbance assay. RESULTS: Losartan effectively reduced arterial blood pressure and urinary albumin excretion. The levels of TGF-beta in urine, but not in plasma, were reduced after 2, 4 and 6 months of the treatment (-32% to -48%, P < 0.05 or 0.01). Urinary or plasma levels of PAI-1, tPA or uPA, and urinary secretion of fibronectin or collagen IV were not significantly altered by Losartan treatment. Urinary levels of collagen IV positively correlated with uPA, and that of fibronectin negatively correlated with PAI-1 in the patients (P < 0.01). Urinary TGF-beta negatively correlated uPA in urine of the patients (P < 0.01). CONCLUSION: Losartan reduced urinary excretion of TGF-beta and albumin in type 2 DM patients with microalbuminuria. Fibrinolytic regulators and TGF-beta are implicated in the regulation of ECM turnover in kidneys of the patients with diabetic nephropathy.

Coagulation and fibrinolysis in preeclampsia and neonates.

Coagulation and fibrinolysis were determined in 67 Indonesian women admitted to the University Hospitals for delivery in Medan. They were diagnosed to be at term gestation (mean 39.3 +/- 1.1 weeks) with moderate and severe preeclampsia (n=32) and in labor, and 8 had preterm labor (gestation mean 33.5 +/- 2.6 weeks). Twenty-seven normal pregnant women in labor (gestation mean 39.7 +/- 1.0 weeks) served as controls. Cord blood from 23 neonates from normal pregnancy and 31 neonates from preeclampsia was also evaluated. Preeclamptic women in labor showed further enhanced coagulation activation (F(1+2)) with raised urokinase-like plasminogen activator (u-PA) activity and reduced plasminogen activator inhibitor-2 (PAI-2) levels. In preterm preeclampsia, significantly reduced antithrombin III (ATIII) and PAI-2 levels with further elevated tissue-type PA (t-PA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen were seen compared to normal pregnancy. These would suggest a state of enhanced thrombin generation with elevated fibrinolytic/inhibitor proteins in preterm preeclampsia. The reduced PAI-2 levels seen in preeclampsia have been suggested to be associated with reduced placental function. Neonates born to mothers of either normal pregnancy or preeclampsia at term showed similar hemostatic changes with reduced fibrinogen, ATIII, t-PA, u-PA antigen, PAI-1 levels, and coagulation activation compared to their respective maternal plasma levels. No significant differences in hemostatic parameters studied between the neonates of both cohorts were seen, and this would suggest that the neonates were protected from the adverse effects of preeclampsia and their hemostatic system was physiologically balanced.

[Haemostatic and fibrinolytic variables in women with anorexia nervosa]. / Ocena wybranych parametrów ukladu krzepniecia i fibrynolizy u pacjentek z jadlowstretem psychicznym.

AIM: The aim of this study was to evaluate haemostatic variables in women with anorexia nervosa --AN. MATERIAL AND METHODS: 23 obese female patients, and 39 female anorexic patients diagnosed acc. to DSM-IV and ICD-10 criteria were recruited. The studied group was compared to a control group--37 healthy female volunteers. BMI was calculated for AN, obese, and the control group. The following measurements were taken: prothrombin index, prothrombin time, thrombin time, fibrinogen, factor VII, ATIII, D-dimers, INR, APTT, protein C and PAI-1 activity, t-PA activity, PAI-1 antigen, t-PA antigen, glucose level, insulin level, E2 and total fat. RESULTS: In the AN group the INR, prothrombin time, PAI-1 activity, t-PA activity, protein C level were increased, whereas PAI-1 antigen, t-PA antigen, prothrombin index, fasting insulin level and fasting glucose level were decreased. CONCLUSIONS: We conclude that, in the AN group, an impaired fibrinolysis and coagulation are observed and there is a correlation between fibrinolytic and coagulation parameters and carbohydrate metabolism.

Fibrinolytic activity in children with Plasmodium falciparum malaria.

BACKGROUND: Malaria infection is still one of the major causes of morbidity and mortality among the under five year children in tropical Africa. Clinical and laboratory methods of assessing the risk factors for severity in order to adequately manage these children, therefore needs to be identified so that prompt and adequate treatment can be instituted early. Fibrinolytic activity has been postulated as one of the risk factors associated with severity of malaria infection. OBJECTIVE: To measure fibrinolytic activity euglobulin lysis time, (ELT) and fibrinogen levels in 50 Nigerian children with Plasmodium falciparum infection. DESIGN: A cross sectional study. SETTING: University of Benin Teaching Hospital, Benin City, Nigeria between January and December 2002. SUBJECTS: Fifty Nigerian children who were admitted with Plasmodium falciparum malaria infection in the paediatric wards of the hospital were recruited into the study. Thirty-four apparently healthy children who did not have malaria fever but who came for growth monitoring exercise and had some investigations done as part of this exercise were used as control for the study. The fibrinolytic activity in all the 84 children (both that had malaria infection and those who did not have malaria infection) were estimated by measuring the euglobulin lysis time (ELT). The fibrinogen levels in all the children were also estimated. The packed cell volume of the children was determined and some severely anaemic children had blood transfusions. RESULTS: Euglobin lysis time (ELT) was found to be higher in children with Plasmodium falciparum malaria infection (430 +/- 149) than in the controls (158 +/- 21.7, P< 0.01). Fibrinogen levels of 3.40 +/- 0.98 in children with malaria infection were high when compared to 2.21 +/- 0.81 in the controls. The children with malaria infection therefore had a decreased fibrinolytic activity and a proportionately high fibrinogen level. The average packed cell volume of the children with malaria infection was 29.64 +/- 2.13 while in the control it was 36.41 +/- 3.24. The study also showed that 50% of children with malaria had severe anaemia and subsequently had blood transfusions. Twenty percent of those who had transfusions died while being transfused. CONCLUSION: Children who have malaria infection have decreased fibrinolytic activity and proportionately high fibrinogen level which may contribute to the possible thromboembolic process in these children and hence higher risk of mortality from Plasmodium falciparum malaria infection.

Plasminogen activators contribute to age-dependent impairment of NMDA cerebrovasodilation after brain injury.

Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation in an age-dependent manner. This study was designed to investigate the contribution of plasminogen activators to impaired NMDA dilation after FPI in newborn and juvenile pigs equipped with a closed cranial window. In the newborn pig, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with the plasminogen activator inhibitor PAI-1 derived hexapeptide (EEIIMD) (10(-7) M) prevented post injury vasoconstriction (9 +/- 1 and 16 +/- 1, vs. -6 +/- 2 and-11 +/- 3, vs. 5 +/- 1 and 9 +/- 1% for responses to NMDA 10(-8), 10(-6) M prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). In contrast, in the juvenile pig, NMDA dilation was only attenuated following FPI and EEIIMD pretreatment partially prevented such inhibition (9 +/- 1 and 16 +/- 1 vs. 2 +/- 1 and 4 +/- 1 vs. 5 +/- 1 and 7 +/- 1% for responses to NMDA prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). Additionally, EEIIMD blunted age-dependent pial artery vasoconstriction following FPI. EEIIMD blocked dilation to the plasminogen activator agonists uPA and tPA while responses to SNP and papaverine were unchanged. Pretreatment with suPAR, which blocked dilation to uPA, elicited effects on pial artery diameter and NMDA vascular activity post FPI similar to that observed with EEIIMD. These data show that EEIIMD and suPAR partially prevented FPI induced alterations in NMDA dilation and reductions in pial artery diameter. EEIIMD and suPAR are efficacious and selective inhibitors of plasminogen activator induced dilation. These data suggest that plasminogen activators contribute to age-dependent impairment of NMDA induced dilation following FPI.