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Biomedical subjects

Markku Kaste

Publications and source records attributed to Markku Kaste.

At least 19 recordsLinked to original sources
PubMed2006

Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PlA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival.

BACKGROUND AND PURPOSE: Smoking, increased fibrinogen levels, and platelet activation are related to the risk of ischemic stroke. The platelet fibrinogen receptor glycoprotein (Gp) IIb/IIIa Pl(A1/A2) polymorphism affects the binding of platelets to fibrinogen and is suggested to interact with smoking. METHODS: We explored the association of smoking and the Pl(A1/A2) polymorphism with ischemic stroke and survival in the Stroke Aging Memory cohort, comprising 486 consecutive patients (55 to 85 years old) who were analyzed 3 months after an ischemic stroke and followed up for 15 months. Stroke subtype determined by magnetic resonance imaging and GpIIb/IIIa Pl(A1/A2) genotype data were available for 272 patients. RESULTS: In multivariate analysis, smoking was the only factor related to the risk of lacunar infarcts (odds ratio [OR]=1.87, 95% CI=1.05 to 3.31; P=0.033), and it was also a predictor of death (n=24, 8.8%) at 15 months (OR=5.13, 95% CI=1.61 to 16.36; P=0.006), along with age (OR=1.10, 95% CI=1.01 to 1.19; P=0.008). The GpIIb/IIIa Pl(A1/A2) polymorphism alone showed no association with stroke subtype or survival. However, there was a smoking-by-genotype association with the risk of lacunar infarcts (OR=2.10, 95% CI=0.90 to 4.89; P=0.087) and with survival (OR=2.78, 95% CI=0.89 to 8.61; P=0.077). Among younger (55 to 69 years) stroke patients, smokers carrying the Pl(A2) allele were at a higher (OR=5.81, 95% CI=1.26 to 26.80; P=0.024) risk of lacunar infarcts than noncarrier smokers (OR=3.12, 95% CI=1.06 to 9.24; P=0.039). The effect of Pl(A2) and smoking combined on survival was also stronger (OR=8.86, 95% CI=1.68 to 46.55; P=0.010) than the effect of smoking alone (OR=5.06, 95% CI=1.20 to 21.35; P=0.027). CONCLUSIONS: Our results indicate that prothrombotic genetic factors may interact with smoking by modifying the stroke phenotype and affecting midterm survival.

Age Distribution↗
PubMed2006

Microarray analysis reveals overexpression of CD163 and HO-1 in symptomatic carotid plaques.

OBJECTIVE: We studied by microarray analysis whether symptomatic and asymptomatic carotid plaques from the same patient differ in gene expression and whether the same changes are present in an independent sample set. METHODS AND RESULTS: Carotid plaques from four patients with bilateral high-grade stenosis, one being symptomatic and the other asymptomatic, were analyzed on Affymetrix U95Av2 arrays. 33 genes showed >1.5-fold change between symptomatic and asymptomatic plaques in an intraindividual comparison with FDR ranging from 0.28 to 0.40. Three genes involved in iron-heme homeostasis, CD163, HO-1, and transferrin receptor, were further analyzed in 40 independent plaques. HO-1 (fold-change 1.93, 95%CI 1.04 to 3.94, P=0.040) and CD163 (1.58, 1.11 to 2.40, P=0.013) mRNAs were again induced, and also HO-1 protein was overexpressed in symptomatic plaques (4.38, 1.54 to 12.20, P=0.024). The expression of HO-1 and CD163 correlated with tissue iron content but iron itself was not associated with the symptom status. CONCLUSIONS: Symptomatic plaques show overexpression of CD163 and HO-1 both in intraindividual and interindividual comparison. Their expression correlates with iron deposits but asymptomatic and symptomatic plaques from isolated patients do not differ in macroscopic hemorrhages or iron deposits. We suggest that symptomatic plaques show a more pronounced induction of CD163 and HO-1 in response to plaque hemorrhages.

Aged↗
PubMed2006

Endothelial apoptosis does not determine symptom status in carotid artery disease.

BACKGROUND: We examined the hypothesis that endothelial denudation in advanced carotid plaques (CPs) occurs by increased apoptosis of endothelial cells (ECs) using scanning electron microscopy (SEM) as well as markers of cellular proliferation and apoptosis in advanced symptomatic CPs (SCPs) and asymptomatic CPs (ACPs). METHODS: 93 consecutive patients underwent carotid endarterectomy. Five additional specimens were studied by SEM. We performed TUNEL assays, and immunostaining against Fas receptor (FasR), Fas ligand (FasL), activated caspase 3 (ACA3) and Ki-67. RESULTS: SEM revealed morphological changes consistent with EC detachment. Surprisingly, ACA3 positivity was more pronounced on the endothelium of ACPs (4.6 +/- 0.7% of total EC count) than on SCPs (3.3 +/- 0.7%, p = 0.049), and was found to correlate positively with nuclear Ki-67 expression (r(s) = 0.275, p = 0.040). FasL expression was significantly increased on the endothelium of SCPs compared with ACPs (66.4 +/- 4.4 vs. 53.9 +/- 4.5%, p = 0.047). CONCLUSIONS: Absence of increased positivity of apoptotic markers dismisses apoptosis as a dominant mechanism underlying endothelial detachment of SCPs. Rather, increased ACA3 with co-expression of Ki-67 in ACPs might suggest that renewal of endothelium by active cell turnover may contribute to clinically silent evolution of plaques with preserved EC integrity. These observations may assist in designing novel therapies to prevent endothelial decay and symptom generation in advanced carotid artery disease.

Aged↗
PubMed2006

Evidence, education and practice.

Stroke causes greater loss of quality-adjusted life years than any other disease and is also one of the most expensive disorders. The burden of stroke will increase in the future due to change in the age structure of populations. We have a vast body of evidence on how to prevent stroke and how to treat stroke patients. Good examples are treatment of hypertension, antithrombotic agents and carotid surgery in stroke prevention, thrombolysis in ischaemic stroke and stroke unit care for all stroke patients. We only have to translate scientific evidence into daily practice. If some pieces are missing, it is our duty to generate them through research. While taking part in randomized clinical trials (RCTs), the discipline, an essential part of RCTs, will improve the daily care of all stroke patients. Besides RCTs there are many other sources of scientific evidence for stroke management, one of which is the European Stroke Initiative (EUSI). The mission of the EUSI is to improve and optimize stroke management in Europe through education and by offering best practice guidelines. Also national and international societies and organizations play an important role in providing education. The human factor is one obstacle to more successful stroke management because to be more effective we must change our own clinical routine. We can make a difference by applying available evidence to our daily practice.

Acute Disease↗
PubMed2006

Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee.

This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.

Emergency Medical Services↗
PubMed2005

Effect of the Glycine Antagonist Gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy.

BACKGROUND AND PURPOSE: Gavestinel, GV150526, is a selective antagonist at the glycine site of the N-methyl-D-aspartate receptor. The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials]. A planned MRI substudy within these trials investigated the effect of gavestinel on infarct volume. METHODS: Patients enrolled in the GAIN trials at designated MRI substudy sites were eligible if they had a pretreatment acute cortical lesion on diffusion-weighted MRI of at least 1.5 cm diameter or 5 cm(3). Final lesion assessment was performed on T(2)-weighted MRI at month 3. Blinded image analysis was performed centrally. The primary hypothesis was that gavestinel would attenuate lesion growth from baseline relative to placebo. RESULTS: A total of 106 patients were eligible, 75 (34 gavestinel, 41 placebo) of whom had month 3 scans (primary analysis population). No effects of gavestinel on infarct volume were observed in the primary or other analyses. However, significant associations of lesion volume to clinical severity and outcomes were observed. Ischemic lesion volume decrease was predictive of substantial clinical improvement. CONCLUSION: Consistent with the clinical outcomes in the GAIN trials, no effects of gavestinel on ischemic infarction was observed. Concordance of results of the clinical outcome trials with those of this infarct volume substudy as well the associations of infarct volume to clinical outcomes further support the potential role of infarct volume as a marker of outcome in dose finding and proof of principle acute stroke trials.

Cerebral Infarction↗
PubMed2005

Characteristics of blood pressure profiles as predictors of long-term outcome after acute ischemic stroke.

BACKGROUND AND PURPOSE: Most patients have elevated blood pressure (BP) in the early phase after an acute ischemic stroke. Mechanism and effects of this BP elevation are not well understood. The benefits of intervention by lowering the initial BP or waiting for spontaneous return to normal values remain debated. We studied the hypothesis that increased BP level and profile variability will adversely affect long-term outcome after stroke with and without thrombolytic treatment. METHODS: We studied the 615 patients with acute ischemic hemispheric stroke in the first European Cooperative Acute Stroke Study (ECASS). BP was measured at 2-hour intervals during the first 20 hours after randomization, and then every 4 hours, up to 72 hours after admission. Studied features of individual 0- to 72-hour BP profiles were: baseline BP, maximum and minimum BP, mean level, and successive variation in the BP profile. The end point was good functional recovery (modified Rankin Scale [mRS] score of 0 to 1) at 90 days. Logistic regression was used to adjust for known prognostic factors, demographic, initial stroke severity, disease and medication histories, and computed tomography signs. RESULTS: Higher systolic BP or diastolic BP at baseline were associated with favorable outcome assessed on modified mRS at 90 days (adjusted odds ratio [OR], 1.22; 95% CI, 1.01 to 1.49; and OR, 1.22; 95% CI, 1.01 to 1.49 per 10 mm Hg), lower within-patient 0- to 72-hour average systolic BP (SBP), or DBP implied favorable outcome (OR, 0.74; 95% CI, 0.61 to 0.90; and OR, 0.61; 95% CI, 0.41 to 0.90 per 10 mm Hg). Reduced variability of 0- to 72-hour DBP profile was an independent predictor of favorable outcome (OR, 0.58; 95% CI, 0.39 to 0.85 per 5 mm Hg). CONCLUSIONS: Higher baseline SBP or DBP was associated with favorable outcome after stroke. Other characteristics of first 72-hour BP profiles: lower mean level of SBP or DBP and reduced successive variability of DBP profile were independent predictors of favorable outcome at 90 days.

Aged↗
PubMed2005

The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study.

BACKGROUND AND PURPOSE: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke. METHODS: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy. RESULTS: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14- 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication.

Acute Disease↗
PubMed2005

Association of the fibrinolytic system and hemorheology with symptoms in patients with carotid occlusive disease.

BACKGROUND AND OBJECTIVES: The risk of stroke caused by a symptomatic high-grade carotid stenosis (CS) is high. Disturbed balance between the procoagulant and fibrinolytic activity in blood associated with unfavorable hemorheology could render CS symptomatic. We wanted to assess whether hemostatic and fibrinolytic plasma markers as well as basic indicators of hemorheology differentiate asymptomatic and symptomatic patients with a high-grade CS and whether they are associated with the macroscopic appearance of the plaque and the rate of microembolization. METHODS: We recruited 92 consecutive consenting patients referred to the neurological or the surgical department of our university teaching hospital for treatment of their high-grade CS. Blood samples were collected before surgery for determination of prothrombin fragments F1 and 2, thrombin-antithrombin complex, tissue-type plasminogen activator (tPA) activity and antigen, plasminogen activator inhibitor-1 (PAI-1) activity and antigen, D-dimer, homocysteine, fibrinogen, in plasma, and hematocrit in blood, and the patients underwent transcranial Doppler ultrasonology for evaluation of microembolic signals (MES). RESULTS: Patients with symptomatic plaques had higher hematocrit levels (p = 0.04), as well as trends for higher tPA antigen and MES rate (p = 0.07). Hematocrit, tPA antigen, and PAI-1 antigen and activity were positively correlated with the degree of stenosis. Ulceration was more common in symptomatic plaques but did not reflect variables of hemostasis or fibrinolysis. In multivariate analysis, tPA antigen and hematocrit were risk factors for a symptomatic high-grade stenosis. CONCLUSION: Mediators of fibrinolysis and unfavorable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade CS.

Aged↗
PubMed2005

Carotid plaque mast cells associate with atherogenic serum lipids, high grade carotid stenosis and symptomatic carotid artery disease. Results from the helsinki carotid endarterectomy study.

OBJECTIVE: Increased numbers of mast cells (MCs) are present in ruptured coronary plaques, suggesting to play a role in acute coronary syndromes. We evaluated the distribution densities of MCs, macrophages and T cells in carotid plaques and correlated these findings to stroke risk factors as well as history of stroke or TIA. METHODS AND RESULTS: Seventy-eight carotid samples from 75 patients (16 plaques from asymptomatic patients and 62 from patients with recent ischemic symptoms) undergoing carotid endarterectomy with an internal carotid stenosis >70% that were immunostained and quantified for MCs, macrophages and T cells. The MC distribution density showed positive correlation with the degree of carotid stenosis (p = 0.012), serum levels of total cholesterol (p = 0.021), LDL cholesterol (p = 0.013) and triglycerides (p = 0.005), and an inverse correlation with serum HDL cholesterol levels (p = 0.001). The average MC density (p = 0.023), but not the macrophage (p = 0.58) or T cell (p = 0.74) density, was higher in the symptomatic than in the asymptomatic patients. In a comparison of plaques ipsilateral and contralateral to the thromboembolic event, the densities of the three types of inflammatory cells were similar. CONCLUSIONS: Increased MC distribution density is associated with an atherogenic serum lipid profile, high-grade carotid artery stenosis and symptomatic carotid artery disease. These findings suggest a potential involvement of MCs in the pathophysiology of carotid artery stenosis.

Aged↗
PubMed2005

Depression among caregivers of stroke survivors.

BACKGROUND AND PURPOSE: We aimed to assess the prevalence of depressive symptoms among caregivers of stroke survivors and to determine which patient- or stroke-related factors are associated with and can be used to predict caregiver depression during an 18-month follow-up after stroke. METHODS: We examined 98 caregivers of 100 consecutive patients experiencing their first ischemic stroke in Helsinki University Central Hospital. The caregivers were interviewed at the acute phase and at 6 months and 18 months. Depression was assessed with the Beck Depression Inventory. The neurological, functional, cognitive, and emotional status of the patients was assessed 5x during the follow-up with a comprehensive test battery. RESULTS: A total of 30% to 33% of all caregivers were depressed during the follow-up; the rates were higher than those of the patients. At the acute phase, caregiver depression was associated with stroke severity and older age of the patient, and at 18 months the older age of the patient was associated with depression of the spouses. In later follow-up, caregiver depression was best predicted by the caregiver's depression at acute phase. CONCLUSIONS: Identifying those caregivers at highest risk for poor emotional outcome in follow-up requires not only assessment of patient-related factors but also interview of the caregiver during the early poststroke period.

Caregivers↗
PubMed2005

Depression-executive dysfunction syndrome in stroke patients.

OBJECTIVE: It has been suggested that executive dysfunction could be the core defect in patients with geriatric or vascular depression, and that this depression-dysexecutive syndrome (DES) might be related to frontal-subcortical circuit dysfunction. The authors tested this hypothesis in 158 poststroke patients, of whom 21 had both depression and executive dysfunction. METHODS: In this cross-sectional cohort study, a neurological, psychiatric, and neuropsychological examination was carried out 3 months after ischemic stroke, and brain infarcts, white-matter changes, and brain atrophy were recorded by MRI. RESULTS: The 21 patients with DES had significantly more brain infarcts affecting their frontal-subcortical circuit structures than the 137 patients without DES, or the 41 patients with depression but without executive dysfunction. Patients with DES also had more severe depressive symptoms and worse psychosocial functioning, and they coped less well in complex activities of daily living. CONCLUSIONS: DES is a valid concept and may define a subgroup of poststroke patients with frontal-subcortical pathology and with distinct prognosis and treatment options.

Aged↗
PubMed2004

Abnormal intravoxel cerebral blood flow heterogeneity in human ischemic stroke determined by dynamic susceptibility contrast magnetic resonance imaging.

BACKGROUND AND PURPOSE: The determination of cerebral blood flow heterogeneity (FH) by dynamic susceptibility contrast (DSC) magnetic resonance imaging has recently been proposed as a tool to predict final infarct size in acute stroke. In this study, we describe the evolution of FH during the first week as well as its correlation to the patients' clinical status. METHODS: Ten patients with ischemic stroke were studied with DSC MRI and diffusion-weighted imaging in hyperacute (<6 hours) phase, at 24 hours, and 1 week after symptom onset. In addition to intravoxel FH, cerebral blood volume (CBV), cerebral blood flow (CBF), and contrast agent mean transit time (MTT) were determined from DSC MRI. All patients were evaluated neurologically with National Institute of Health Stroke Scale concurrently with the imaging sessions. RESULTS: All patients showed infarct growth, judged by diffusion-weighted imaging, during the week with simultaneous decrease in the sizes of FH, CBV, CBF, and MTT abnormalities. The FH abnormality was shown to be larger than CBV and CBF abnormalities at the hyperacute phase and 24 hours, but smaller than MTT abnormality in all 3 imaging sessions. The sizes of hyperacute FH, CBV, CBF, and MTT abnormalities correlated well with infarct size at 24 hours and at 1 week. Additionally, FH was the only perfusion parameter that correlated with the clinical score. CONCLUSIONS: FH predicts infarct size equally well with the other perfusion parameters but is superior in correlation with the clinical score. FH can easily be incorporated to hyperacute stroke imaging without additional efforts.

Aged↗
PubMed2004

The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase.

BACKGROUND AND PURPOSE: Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. METHODS: DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 microg/kg, 90 microg/kg, and 125 microg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. RESULTS: Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 microg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 microg/kg; P=0.757) and 60.0% (125 microg/kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. CONCLUSIONS: Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 microg/kg.

Acute Disease↗