Biomedical subjects

José Castillo

Publications and source records attributed to José Castillo.

At least 19 recordsLinked to original sources

PubMed2006

Increased body iron stores are associated with poor outcome after thrombolytic treatment in acute stroke.

BACKGROUND AND PURPOSE: Iron overload has been associated with greater oxidative stress and brain injury in experimental cerebral ischemia and reperfusion. This study investigates whether high serum ferritin levels, as an index of increased cellular iron stores, are associated with poor outcome, hemorrhagic transformation, and brain edema after treatment with tissue plasminogen activator in patients with acute ischemic stroke. METHODS: A total of 134 consecutive patients treated with intravenous tissue plasminogen activator were prospectively studied in four centers. Serum ferritin levels were determined at baseline, 24 and 72 hours after treatment. Cranial computed tomography was performed on admission and at 24 to 36 hours after tissue plasminogen activator infusion. Stroke severity and outcome were evaluated by using the National Institute of Health Stroke Scale and the modified Rankin Scale. RESULTS: Computed tomography showed hemorrhagic transformation in 27 patients (hemorrhagic infarction in 15 and parenchymal hematoma in 12; symptomatic in four) and brain swelling with midline shift in 15. Poor outcome (modified Rankin Scale >2) at 90 days was observed in 54.5% of patients. Ferritin levels at baseline were higher in patients with poor outcome at 90 days (median [quartiles], 165 [98,307] versus 17 [12,37] ng/mL; P<0.001) and in those who developed parenchymal hematoma (P=0.006), symptomatic hemorrhagic transformation (P=0.008), and severe brain edema (P<0.001). Serum ferritin levels higher than 79 ng/mL before tissue plasminogen activator treatment were independently associated with poor outcome (OR, 117 [95% CI, 25 to 557]). CONCLUSIONS: Increased body iron stores are associated with poor outcome, symptomatic hemorrhagic transformation, and severe edema in patients treated with tissue plasminogen activator after ischemic stroke. These findings suggest that iron overload may offset the beneficial effect of thrombolytic therapies.

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PubMed2006

High blood pressure and inflammation are associated with poor prognosis in lacunar infarctions.

UNLABELLED: Lacunar infarction has long been considered to be associated with good prognosis, however a significant percentage of these patients remain functionally dependent. In this study we sought to investigate the factors associated with poor outcome in patients with lacunar infarction. SUBJECTS AND METHODS: We have performed a secondary study in 113 patients with lacunar infarctions admitted within the first 24 h of symptom onset (mean age 70 years, 57.5% men). Blood pressure, body temperature, serum glucose levels, neurotransmitters and pro-inflammatory markers were measured at admission and during the first 72 h. Stroke severity was assessed by the Canadian Stroke Scale (CSS). Neuroimaging evaluation was performed at admission and between days 4 and 7. Poor functional outcome was considered as a Barthel index <85 at 3 months. RESULTS: 36 patients (31.9%) had poor outcome. Older age (p = 0.009), history of hypertension (p = 0.005), higher body temperature (p < 0.0001), systolic blood pressure (SBP) (p = 0.010), serum glucose (p = 0.002) and interleukin-6 (IL-6) (p < 0.0001) levels, as well as lower CSS score at admission (p < 0.0001) were all predictive factors of poor outcome in bivariate analyses. SBP at admission (OR 2.07, CI 95% 1.04-3.28, p = 0.015) was the only clinical predictor on multivariate analysis. When the logistic model was further adjusted for biomarkers of inflammation and excitotoxicity, IL-6 levels (OR 1.09, CI 95% 1.01-1.26, p = 0.003), but not SBP, was independently associated with poor outcome. This association persisted even after adjusting for potential predictors recorded during the first 72 h of hospitalization. CONCLUSION: High SBP and IL-6 levels on admission may predict poor outcome in patients with lacunar infarction.

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PubMed2006

Vascular protection in brain ischemia.

Vascular damage occurring after cerebral ischemia may lead to a worse outcome in patients with ischemic stroke, as it facilitates edema formation and hemorrhagic transformation. There are several phases in the development of vascular injury (acute, subacute and chronic) and different mediators act in each one. Therapeutic options to avoid vascular injury must be focused on acting in each phase. However, even though experimental studies have demonstrated the benefit of therapeutic interventions both in the acute and chronic phases of cerebral ischemia, only the chronic phase offers a therapeutic window sufficiently wide enough to provide vascular protection in clinical practice. Several drugs including erythropoietin and HMG-CoA reductase inhibitors (statins), antihypertensive (angiotensin modulators), antibiotics (minocycline) and antihyperglycemic drugs (thiazolidinediones) have been proved to provide vascular protection in patients with ischemic stroke. Anti-inflammatory, antioxidant, and antiapoptotic actions are responsible for the vascular protective effect related to these drugs.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Ischemic preconditioning: a novel target for neuroprotective therapy.

Ischemic preconditioning involves a brief exposure to ischemia in order to develop a tolerance to injurious effects of prolonged ischemia. The molecular mechanisms of neuroprotection that lead to ischemic tolerance are not yet completely understood. However, it seems that two distinct phases are involved. Firstly, a cellular defense function against ischemia may be developed by the mechanisms inherent to neurons such as posttranslational modification of proteins or expression of new proteins via a signal transduction system to the nucleus. Secondly, a stress response and synthesis of stress proteins (heat shock proteins) may be activated. These mechanisms are mediated by chaperones. The objective of ischemic preconditioning research is to identify the underlying endogenous protective cellular receptors and signaling cascades, with the long-term goal of allowing therapeutic augmentation of the endogenous protective mechanisms in cerebral ischemia and possibly development of new neuroprotective strategies for ischemic stroke treatment.

Adenosine Triphosphate↗

PubMed2006

Neurorepair versus neuroprotection in stroke.

Stroke is the second to third leading cause of death and the main cause of severe, long-term disability in adults. However, treatment is almost reduced to fibrinolysis, a therapy useful in a low percentage of patients. Given that the immediate treatment for stroke is often unfeasible in the clinical setting, the need for new therapy strategies is imperative. After stroke, the remaining impairment in functions essential for routine activities, such as movement programming and execution, sensorimotor integration, language and other cognitive functions have a deep and life-long impact on the quality of life. An interesting point is that a slow but consistent recovery can be observed in the clinical practice over a period of weeks and months. Whereas the recovery in the first few days likely results from edema resolution and/or from reperfusion of the ischemic penumbra, a large part of the recovery afterwards is due mainly to brain plasticity, by which some regions of the brain assume the functions previously performed by the damaged areas. Neurogenesis and angiogenesis are other possible mechanisms of recovery after stroke. An understanding of the mechanisms underlying functional recovery may shed light on strategies for neurorepair, an alternative with a wide therapeutic window when compared with neuroprotective strategies.

Animals↗

PubMed2006

Evolving paradigms for neuroprotection: molecular identification of ischemic penumbra.

Ischemic penumbra defines the existence of tissue at risk of infarction and which is, hence, potentially salvageable and the target for current stroke reperfusion and neuroprotective therapies. Penumbral tissue evolves toward irreversibly damaged tissue at different rates in individual stroke patients yielding different therapeutic windows depending on the individual duration of risk of infarction of this tissue. An accurate identification of the penumbra is then necessary in order to individualize the window of opportunity for therapeutic interventions. Imaging techniques, although helpful, may not give the most accurate information as to the existence of penumbra given that the threshold for identification of penumbra varies depending on the technique used. A better identification of the true penumbral tissue might be based on the cascade of molecular events that are responsible for the evolution of the penumbra toward infarcted tissue. Multiple penumbras can be defined in molecular terms taking into account which vessel is occluded, the time of evolution of the ischemia, the degree of the ischemia, and the sensitivity to ischemia of the different cells. Future studies are necessary to clarify whether the enhancement of cytoprotective mechanisms, and/or the block of cytotoxic mechanisms confirming the existence of penumbra at different times of ischemic evolution, are effective neuroprotective strategies.

Animals↗

PubMed2006

A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke.

It remains unclear why some individuals are susceptible to excitotoxicity after stroke. A possible explanation is impaired glutamate uptake. We have found a highly prevalent polymorphism in the promoter of the glutamate transporter EAAT2 gene that abolishes a putative regulatory site for activator protein-2 (AP-2) and creates a new consensus binding site for the repressor transcription factor GC-binding factor 2 (GCF2). The mutant genotype is associated with increased plasma glutamate concentrations and with a higher frequency of early neurological worsening in human stroke. After transfection into astrocytes, the mutant promoter was not activated by AP-2 and was effectively repressed by GCF2, and its activity in the presence of GCF2 was reduced when compared with the AP-2-cotransfected wild-type promoter. We also show that GCF2 is expressed in ischemic rat brain, suggesting that decreased glutamate uptake occurs in individuals carrying the mutation after stroke. These findings may explain individual susceptibility to excitotoxic damage after stroke as well as the failure of glutamate antagonists in those patients without this polymorphism.

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PubMed2006

Citicoline in intracerebral haemorrhage: a double-blind, randomized, placebo-controlled, multi-centre pilot study.

BACKGROUND: In experimental models citicoline has shown beneficial effects in intracerebral haemorrhage. Citicoline is a neuroprotectant drug with some beneficial effects in human ischaemic stroke and with an excellent safety profile. We decided to carry out a pilot study to test its safety and efficacy in human intracerebral haemorrhaging. METHODS: In this double-blind, placebo-controlled pilot study, patients had to be previously independent, aged between 40 and 85 years, and had to be admitted within 6 h after onset of symptoms of an acute primary supratentorial hemispheric cerebral haemorrhage diagnosed by neuroimaging (CT or MRI). Baseline severity was defined as patients with a score larger than 8 points on the Glasgow Coma Scale and larger than 7 on the National Institutes of Health Stroke Scale. Patients received either a placebo or 1 g/12 h citicoline for 2 weeks (orally or intravenously). The primary aim was to evaluate safety with respect to the number of adverse events that occurred. The efficacy endpoint was the percentage of patients with a modified Rankin Score (mRS) at 3 months. RESULTS: 19 patients in each group were included in the study. The incidence of serious adverse events was not different among groups (4 patients in each group). One patient in the placebo group was categorised as independent (mRS<or=2) in comparison with 5 patients in the citicoline group (OR, 5.38; 95% CI, 0.55-52). CONCLUSIONS: Citicoline seems to be a safe drug in human intracerebral haemorrhage with a positive trend regarding efficacy. These data should be confirmed in a larger trial.

Activities of Daily Living↗

PubMed2006

Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 cause potent neuroprotection after experimental stroke through noncompletely overlapping mechanisms.

Stroke triggers an inflammatory cascade which contributes to a delayed cerebral damage, thus implying that antiinflammatory strategies might be useful in the treatment of acute ischaemic stroke. Since two unrelated peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, the thiazolidinedione rosiglitazone (RSG) and the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been shown to possess antiinflammatory properties, we have tested their neuroprotective effects in experimental stroke. Rosiglitazone or 15d-PGJ2 were administered to rats 10 mins or 2 h after permanent middle cerebral artery occlusion (MCAO). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected for protein expression, gene array analyses and gene shift assays. Our results show that both compounds decrease MCAO-induced infarct size and improve neurological scores. At late times, the two compounds converge in the inhibition of MCAO-induced brain expression of inducible NO synthase and the matrix metalloproteinase 9. Interestingly, at early times, complementary DNA microarrays and gene shift assays show that different mechanisms are recruited. Analysis of early nuclear p65 and late cytosolic IkappaBalpha protein levels shows that both compounds inhibit nuclear factor-kappaB signalling, although at different levels. All these results suggest both PPARgamma-dependent and independent pathways, and might be useful to design both therapeutic strategies and prognostic markers for stroke.

Animals↗

PubMed2005

Platelets, inflammation, and atherothrombotic neurovascular disease: the role of endothelial dysfunction.

The vascular endothelium is an indispensable organ in the regulation of tonicity and vascular homeostasis. Endothelial dysfunction is a marker of atherosclerosis and contributes to the atherogenic process and the development of atherothrombotic complications. Endothelial dysfunction is the common meeting point among factors for vascular risk and launches complex cellular and biochemical interactions that are characterized by oxidative stress and an intense inflammatory response. The strategic importance of the concept of endothelial dysfunction arises from the following facts: its diagnosis is simple, it allows the identification of asymptomatic arteriosclerotic subjects with a high risk of developing atherothrombotic complications, it is reversible, and it responds to various therapeutic strategies.

Animals↗

PubMed2005

The prediction of malignant cerebral infarction by molecular brain barrier disruption markers.

BACKGROUND AND PURPOSE: Space-occupying brain edema is a life-threatening complication in patients with large hemispheric stroke. The aim of the study was to determine whether molecular markers of endothelial damage may help to predict secondary brain edema and, secondly, to identify patients who could benefit from aggressive therapies such as decompressive hemicraniectomy or hypothermia. METHODS: We studied 40 consecutive patients with malignant middle cerebral artery (MCA) infarction and 35 controls with massive MCA infarctions <70 years of age and matched by stroke severity on admission. Cranial computed tomography (CT) was performed at entry and repeated between days 4 and 7, or earlier if there was neurological worsening. Malignant MCA (m-MCA) infarction was diagnosed when follow-up CT detected a more than two-thirds space-occupying MCA infarction with midline shift, compression of the basal cisterns, and neurological deterioration. Plasma concentrations of glutamate, glycine, gamma-aminobutyric acid, interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha, matrix metalloproteinase-9 (MMP-9), and cellular-fibronectin (c-Fn) were determined in blood samples obtained at admission. RESULTS: Mean time from stroke onset to blood sampling was 6.3+/-4.8 in m-MCA and 7.7+/-6.0 hours in the control group (P=0.63). Baseline characteristics were comparable in both groups. c-Fn and MMP-9 levels were significantly higher in patients with m-MCA than in controls (all P<0.001). c-Fn >16.6 microg/mL had the highest sensitivity (90%), specificity (100%), and negative and positive predictive values (89% and 100%, respectively) for the prediction of m-MCA infarction. CONCLUSIONS: A plasma c-Fn concentration >16.6 microg/mL at admission is associated with the development of m-MCA infarction with high sensitivity and specificity, suggesting that c-Fn might be useful in therapeutic decision making.

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PubMed2005

Increased plasma levels of 15-deoxyDelta prostaglandin J2 are associated with good outcome in acute atherothrombotic ischemic stroke.

BACKGROUND AND PURPOSE: The 15-deoxyDelta prostaglandin J2 (15-dPGJ2) is an anti-inflammatory prostaglandin that has been proposed to be the endogenous ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma), a nuclear receptor that can exert potent anti-inflammatory actions by repressing inflammatory genes when activated. It has been suggested that 15-dPGJ2 could be beneficial in neurological disorders in which inflammation contributes to cell death such as stroke. METHODS: We investigated the relationship between plasma levels of 15-dPGJ2 and early neurological deterioration (END), infarct volume, and neurologic outcome in 552 patients with an acute stroke admitted within 24 hours after symptoms onset. RESULTS: Median [quartiles] plasma 15-dPGJ2 levels on admission were significantly higher in patients than in controls (60.5 [11.2 to 109.4] versus 5.0 [3.8 to 7.2] pg/mL; P<0.0001). Levels of this prostaglandin were also significantly higher in patients with vascular risk factors (history of hypertension or diabetes) and with atherothrombotic infarcts (113.9 [81.6 to 139.7] pg/mL), than in those with lacunar (58.7 [32.7 to 86.2] pg/mL), cardioembolic (12.1 [6.5 to 39.2] pg/mL), or undetermined origin infarcts (11.4 [5.6 to 24.3] pg/mL) (P<0.0001). In the subgroup of patients with atherothrombotic infarcts, the adjusted odds ratio of END and poor outcome for 1 pg/mL increase in 15-dPGJ2 were 0.95 (95% CI, 0.94 to 0.97) and 0.97 (95% CI, 0.96 to 0.98), respectively. In a generalized linear model, by 1 U increase in 15-dPGJ2, there was a reduction of 0.47 mL (95% CI, 0.32 to 0.63) in the mean estimated infarct volume. CONCLUSIONS: Increased plasma 15-dPGJ2 concentration is associated with good early and late neurological outcome and smaller infarct volume. These findings suggest a neuroprotective effect of 15-dPGJ2 in atherothrombotic ischemic stroke.

Acute Disease↗

PubMed2005

Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport.

BACKGROUND AND PURPOSE: Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine, has shown beneficial effects in a number of CNS injury models including cerebral ischemia. Citicoline is the only neuroprotectant that has proved efficacy in patients with moderate to severe stroke. However, the precise mechanism by which citicoline is neuroprotective is not fully known. The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia. METHODS: Focal brain ischemia was produced in male adult Fischer rats by occluding both the common carotid and middle cerebral arteries. Brain glutamate levels were determined at fixed intervals after occlusion. Animals were then sacrificed, and infarct volume and brain ATP levels were measured. As in vitro model of ischemia, rat cultured cortical neurones or astrocytes, isolated or in co-culture, were exposed to oxygen-glucose deprivation (OGD) either in the absence or in the presence of citicoline (1-100 microM). Viability was studied by measuring LDH release. Glutamate release and uptake, and ATP levels were also determined. RESULTS: Citicoline (0.5, 1 and 2 g/kg i.p. administered 1 h before the occlusion) produced a reduction of the infarct size measured at striatum (18, 27 and 42% inhibition, respectively, n = 8, P < 0.05 vs. ischemia), effect that correlated with the inhibition caused by citicoline on ischemia-induced increase in glutamate concentrations after the onset of the ischemia. Citicoline also inhibited ischemia-induced decrease in cortical and striatal ATP levels. Incubation of cultured rat cortical neurones with citicoline (10 and 100 microM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 microM) caused an increase in glutamate uptake and in EAAT2 glutamate transporter membrane expression in cultured rat astrocytes. CONCLUSIONS: Our present findings show novel mechanisms for the neuroprotective effects of citicoline, which cooperate to decrease brain glutamate release after ischemia.

Adenosine Triphosphate↗

PubMed2005

Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia.

BACKGROUND AND PURPOSE: It has been shown that the reversed operation of glutamate transporters when ATP levels fall accounts for most glutamate release induced by severe cerebral ischemia. Nitric oxide (NO) is formed after ischemia and causes ATP depletion. Our purpose is to test if NO release from inducible NO synthase (iNOS) after stroke may cause a delayed glutamate release due to ATP depletion that might underlie progression of the ischemic infarct. We have studied the effect of the highly selective inhibitor of iNOS activity 1400W on brain ATP levels, extracellular glutamate, and stroke outcome after transient focal cerebral ischemia in rats. METHODS: To induce focal ischemia, the middle cerebral artery (MCA) was occluded by using the intraluminal thread technique (tMCAO). 1400W was administered, after tMCAO, by using an Alzet osmotic pump to yield a drug delivery rate of 2.5 mg/kg/h. Results. Postischemic treatment with 1400W induced a reduction in the neurofunctional impairment and in the total volume of brain infarct. Western blot analysis showed ischemia-induced expression of iNOS. Treatment with 1400W partially prevented delayed ATP reduction and produced inhibition of the subsequent delayed increase in glutamate levels caused by the ischemic insult. CONCLUSIONS: Our data indicate that 1400W improves stroke outcome, an effect concomitant to the inhibition of both ischemia-induced decrease in brain ATP levels and increase in glutamate release. These results provide evidence indicating that the expression of iNOS induced by ischemia may contribute to the progression of the ischemic infarct and have important therapeutic implications for the management of stroke.

Adenosine Triphosphate↗

PubMed2005

TNFR1 upregulation mediates tolerance after brain ischemic preconditioning.

A short ischemic event (ischemic preconditioning (IPC)) can result in subsequent resistance to severe ischemic injury (ischemic tolerance (IT)). The expression and neuroprotective role of tumor necrosis factor (TNF-alpha) have been described in models of IPC and we have showed the participation of its processing enzyme, the TNF-alpha convertase enzyme (TACE) in this process. We have now decided to explore the expression and localization of TNF receptors (TNFR) as well as other signalling mechanisms involved in IT. A period of 10 mins of temporary middle cerebral artery occlusion (tMCAO) was used for focal IPC. To evaluate the ability of IPC to produce IT, permanent MCAO was performed 48 hours after IPC. Ischemic preconditioning produced a reduction in infarct volume, as we showed previously. Ischemic preconditioning caused upregulation of neuronal TNFR1 that was reduced by the selective TACE inhibitor BB1101. Intracerebral administration of TNFR1 antisense oligodeoxynucleotide, which caused a reduction in TNFR1 expression, inhibited the IPC-induced protective effect, showing that TNFR1 upregulation is implicated in IT. Moreover, treatment with BB1101, TNFR1 antisense and lactacystin-a specific proteasome inhibitor-blocked IPC-induced NF-kappaB. Immunohistochemical studies showed the expression of TACE and TNFR1 in neurons. In summary, these data show that IPC produces neuronal upregulation of TACE and TNFR1, and that the pathway TACE/TNF-alpha/TNFR1/NF-kappaB is involved in IT.

ADAM Proteins↗

PubMed2005

Headache in cerebral hemorrhage is associated with inflammatory markers and higher residual cavity.

BACKGROUND AND PURPOSE: The mechanisms responsible for headache in patients with intracerebral hemorrhage (ICH) are not completely understood. The present study was undertaken to analyze the headache-associated factors, the possible related biochemical mechanisms, and the headache potential predictors of outcome in spontaneous ICH. METHODS: We prospectively studied 189 patients from a large cohort of 266 consecutive patients with supratentorial ICH admitted within the first 12 hours of symptoms onset. The presence of headache at stroke onset was evaluated in these patients. The volumes of the initial ICH, peripheral edema at 48 hours, and the residual cavity at 3 months were measured on CT scan. Glutamate, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha levels were measured in blood samples obtained on admission. The Canadian Stroke Scale (CSS) and the modified Rankin Scale were used to evaluate stroke severity and neurological outcome, respectively. RESULTS: Headache at onset of stroke was observed in 65 patients (34.4%). Patients who experienced headache had a significantly higher frequency of history of infection (P= .009) or inflammation (P= .045), as well as higher body temperature (P= .021), leukocyte count (P= .038), ESR (P= .011), and mass effect (P= .017) on admission. Plasma concentrations of IL-6 and TNF-alpha were significantly higher in patients with headache than in those without. Headache was an independent predictor of the residual cavity volume in patients with spontaneous ICH (odds ratio 6.49; 95% CI 2.51 to 16.78; P= .0001). CONCLUSIONS: Headache at ICH onset is associated with clinical and biochemical markers of inflammation and is an independent predictor of higher residual cavity volume after spontaneous ICH.

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PubMed2004

Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: To investigate whether molecular markers of inflammation and endothelial injury are associated with early growth of intracerebral hemorrhage (ICH). METHODS: In a multicenter prospective study, we determined concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) in blood samples obtained on admission from 183 patients with primary hemispheric ICH of <12 hours' duration. Patients had a neurological evaluation and a computed tomography (CT) scan performed at baseline and at 48+/-6 hours. Early growth of the ICH was defined as a volume increase >33% between the 2 CT examinations for ICH with a baseline volume <20 mL and >10% for ICH > or =20 mL. Clinical, radiological, and biochemical predictive factors of ICH enlargement were analyzed by logistic regression analysis. RESULTS: Fifty-four (29.5%) patients showed a relevant early growth of ICH. High leukocyte count and fibrinogen levels, low platelet count, and intraventricular bleeding were associated with early ICH growth in bivariate analyses. Plasma concentrations of IL-6 (median [quartiles]: 19.6 [13.6; 29.9] versus 15.9 [11.5; 19.8] pg/mL), TNF-alpha (13.5 [8.4; 30.5] versus 8.7 [4.7; 13.5] pg/mL), MMP-9 (153.3 [117.7; 204.7] versus 70.6 [47.8; 103.8] ng/mL), and c-Fn (8.8 [6.2; 12.5] versus 2.8 [1.6; 4.2] microg/mL) were significantly higher in patients with early growth of ICH (all P<0.001). C-Fn levels >6 microg/mL (OR, 92; 95%CI, 22 to 381; P<0.0001) and IL-6>24 pg/mL (OR, 16; 95%CI, 2.3 to 119; P=0.005) were independently associated with ICH enlargement in the logistic regression analysis. CONCLUSIONS: Molecular signatures of vascular injury and inflammatory markers in the early acute phase of ICH are associated with subsequent enlargement of the hematoma.

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PubMed2004

Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke.

BACKGROUND AND PURPOSE: Elevated plasma levels of cellular fibronectin (c-Fn) reflect vascular damage, so c-Fn might be a marker of secondary bleeding risk in cerebral ischemia. We investigated whether high plasma levels of c-Fn were associated with hemorrhagic transformation (HT) after treatment with tissue plasminogen activator (tPA) in patients with acute stroke. METHODS: Eighty-seven patients (mean age: 67+/-12) received tPA after the ECASS II criteria (mean time to infusion: 160+/-46 minutes; median NIHSS: 12). HT and hypodensity volume were studied on computed tomography (CT) performed 24 to 36 hours after treatment. HT was classified according to the ECASS II definitions. c-Fn and matrix metalloproteinase 9 (MMP-9) levels were determined by ELISA in blood samples obtained before treatment and in 30 healthy subjects. RESULTS: HT was found in 26 patients (30%); 15 patients had hemorrhagic infarction type 1 (HI-1), 7 had HI-2, and 4 had parenchymal hemorrhage (PH). Median c-Fn concentrations were 1.3, 1.7, 4.2, 5.4, and 7.3 microg/mL in controls, non-HT, HI-1, HI-2, and PH groups, respectively (P<0.001); median MMP-9 values were 54, 87, 154, 176, and 225 ng/mL (P<0.001). Logistic regression analysis showed that only c-Fn plasma levels remained independently associated with HT after adjusting for potential confounders (OR, 2.1; 95% CI, 1.3 to 3.4; P=0.002). Similar results were obtained in the 71 patients treated within 3 hours. CONCLUSIONS: High plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with tPA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment.

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