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Biomedical subjects

Turgut Tatlisumak

Publications and source records attributed to Turgut Tatlisumak.

At least 19 recordsLinked to original sources
PubMed2006

Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and there is no widely approved clinical therapy. Poor outcome after ICH results mostly from a mass effect owing to enlargement of the hematoma and brain swelling, leading to displacement and disruption of brain structures. Cerebral mast cells (MC) are resident inflammatory cells that are located perivascularly and contain potent vasoactive, proteolytic, and fibrinolytic substances. We previously found pharmacological MC stabilization and genetic MC deficiency to be associated with up to 50% reduction of postischemic brain swelling in rats. Here, we studied the role of MC and MC stabilization in ICH using in vivo magnetic resonance imaging and ex vivo digital imaging for calculating brain edema and hematoma volume. In a rat ICH model of autologous blood injection into the basal ganglia, four groups of Wistar rats received either saline or sodium cromoglycate (MC stabilizer, two groups) or compound 48/80 (MC degranulator). Evaluated 24 h later, MC stabilization had resulted in highly significantly better neurologic scores (P<0.001), decrease mortality (P=0.002), less brain swelling (P<0.001), and smaller hematoma volume growth (P<0.001) compared with saline and compound 48/80. Moreover, to support our hypothesis, we induced ICH in MC-deficient rats and their wild-type littermates (WT). MC-deficient rats responded with significantly better neurologic scores (P<0.001), decrease mortality (0% versus 25%), less brain swelling (P<0.05), and smaller hematoma growth (P<0.05) than WT. The role of MC deserves a close evaluation as a potential target in the development of novel forms of ICH therapy.

Animals↗
PubMed2006

The pre-ischaemic neuroprotective effects of the polyamine analogues BU43b and BU36b in permanent and transient focal cerebral ischaemia models in mice.

The present study investigated the neuroprotective potential of two novel polyamine analogues, BU43b and BU36b, when administered 30 min prior to cerebral ischaemia. Neuroprotection in a permanent and a transient focal cerebral ischaemia mouse model (induced by intraluminal middle cerebral artery occlusion (MCAO)) was investigated using a range of histological and behavioural assessments. In the permanent ischaemia model, BU43b reduced oedema and showed a trend towards reduction in %HLV (percentage hemisphere lesion volume) when administered at a dose of 30 mg/kg i.p. Following transient ischaemia, treatment with BU43b decreased the %HLV and reduced oedema when administered at 30 mg/kg. BU43b also improved the locomotor activity (LMA) in MCAO mice at both 20 mg/kg and 30 mg/kg doses. BU36b was less effective than BU43b in both the permanent and the transient models, with its most pronounced effect being a trend towards reduction in oedema in both models. These results demonstrate that BU43b administered 30 min before ischaemia provided a good level of neuroprotection in the two models of cerebral ischaemia used and may have potential as a neuroprotective treatment for stroke.

Animals↗
PubMed2006

Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation.

We previously observed degranulated mast cells (MC) in association with perivascular brain edema formation during focal cerebral ischemia. Brain MC are typically located perivascularly and contain potent fast-acting vasoactive and proteolytic substances. We examined in a rat model of transient middle cerebral artery occlusion (MCAO) whether, in the early phase of ischemia, MC regulate microcirculation, the blood-brain barrier (BBB) permeability, and edema formation. First, animals received MC inhibitor (cromoglycate), MC-degranulating drug (compound 48/80), or saline. Thereafter, we performed transient MCAO in gene-manipulated MC-deficient rats and their wild-type (WT) littermates, calculating brain swelling, visualizing BBB leakage by intravenously administered Evans blue albumin, and determining neutrophil infiltration with light microscopy. Cerebral blood flow, monitored by laser-Doppler flowmetry in separate experiments, was similar among pharmacological treatments. Ischemic swelling resulted in increased hemispheric volume of 13.4%+/-1.0% in controls, 8.1%+/-0.4% (39% reduction) after cromoglycate, and 25.2%+/-2.0% (89% increase) after compound 48/80 (P<0.05). Early ischemic BBB leakage was reduced by 51% after cromoglycate, and 50% enhanced by compound 48/80 (P<0.05). The cromoglycate group showed 37% less postischemic neutrophil infiltration than did controls (P<0.05). Furthermore, MC-deficient rats responded to focal ischemia with 58% less brain swelling (6.7%+/-1.2%) than did their WT littermates (15.8%+/-1.4%, P<0.05). Blood-brain barrier damage was 47% lower in MC-deficient rats than in the WT (P<0.05). Neutrophil infiltration after MCAO was decreased 47% in MC-deficient rats in comparison to WT (P<0.05). Pharmacological MC inhibition thus appears to deserve further investigation regarding reduction of brain swelling and inflammation early after stroke.

Animals↗
PubMed2006

Thrombolytic therapy in acute ischemic stroke - basic concepts.

Thrombolytic therapy with alteplase in acute ischemic stroke is currently established within 3 h from symptom onset in carefully selected patients. Expansion of the time window is being assessed in trials with alteplase and desmoteplase. Also, tenecteplase, reteplase and staphylokinase are being evaluated in stroke patients. A better understanding of the coagulation and fibrinolytic systems may provide insight into drug development, interactions, complications, and may ultimately improve patient triage and treatment regimens. Future adjuvant and additional therapies could prove useful for patients who do not benefit from standard thrombolytic treatment or may augment the overall gain.

Blood Coagulation↗
PubMed2005

The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice.

The pre-ischaemic neuroprotective potential of a novel polyamine/NMDA antagonist N1-dansyl-spermine (1-5 mg kg(-1)) was studied in a transient focal cerebral ischaemia model in mice in comparison to a reference compound, MK-801 (1 or 3 mg kg(-1)). The intraluminal suture transient middle cerebral artery occlusion (MCAO) model was used. N1-dansyl-spermine and MK-801 were administered (i.p.) 30 min prior to ischaemia. A range of histological and behavioural assessments was employed. N1-dansyl-spermine had a comparable effect to MK-801 at reducing the percentage hemisphere lesion volume (%HLV) at the doses tested. Furthermore, N1-dansyl-spermine reduced the ischaemic brain oedema, which MK-801 did not. N1-dansyl-spermine significantly reversed the decrease of locomotor activity (LMA) caused by the MCAO and showed a significant effect at improving the rotarod performance impaired by MCAO. In contrast, MK-801 had no beneficial effect on sensorimotor function and even worsened the LMA. These results clearly demonstrate the pre-ischaemic neuroprotective effect of N1-dansyl-spermine in a transient focal cerebral ischaemia model.

Animals↗
PubMed2004

The pre-ischaemic neuroprotective effect of a novel polyamine antagonist, N1-dansyl-spermine in a permanent focal cerebral ischaemia model in mice.

The polyamine sites on the NMDA receptor complex offer a therapeutic target for focal ischaemia, potentially devoid of most side effects associated with NMDA antagonists. In this study, we investigated the effect of a novel polyamine antagonist, N(1)-dansyl-spermine (0.5-10 mg kg(-1)) in a permanent focal cerebral ischaemia model in mice, and compared its effect to that of MK-801 (0.3-3 mg kg(-1)) following administration 30 min prior to ischaemia. A battery of histological and behavioural tests was employed following permanent middle cerebral artery occlusion to assess any neuroprotective effect. Following middle cerebral artery occlusion, N(1)-dansyl-spermine (1-5 mg kg(-1)) and MK-801 (1 or 3 mg kg(-1)) caused a comparable and significant reduction in the percentage hemisphere lesion volume. Similarly, both drugs significantly reduced oedema and neurological deficit score to a similar extent. Locomotor activity in MCAO mice was not significantly improved by MK-801 or N(1)-dansyl-spermine, although N(1)-dansyl-spermine induced a trend towards significant improvement. Significant improvement in rotarod performance was observed at neuroprotective doses with both drugs. Upon comparison of the profile of effects, N(1)-dansyl-spermine at least matched the effectiveness of MK-801 as a neuroprotective agent in this model. In addition, in sham-operated control mice, N(1)-dansyl-spermine was well tolerated, in contrast to the pronounced adverse effects of MK-801 on locomotor activity and rotarod performance. In conclusion, this study has shown that N(1)-dansyl-spermine is as effective a neuroprotective drug as MK-801 in this model. Moreover, in contrast to MK-801, N(1)-dansyl-spermine could be a promising therapeutic candidate for stroke as it is well tolerated at neuroprotective doses in sham-operated animals.

Analysis of Variance↗
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

Long-term outcome after intravenous thrombolysis of basilar artery occlusion.

CONTEXT: Basilar artery occlusion (BAO) is an infrequent disease with high morbidity and mortality. Intra-arterial thrombolysis is advocated for treatment but is limited to use at specialized centers. OBJECTIVE: To evaluate outcomes for patients with BAO treated with intravenous thrombolytic therapy. DESIGN, SETTING, AND PARTICIPANTS: During 1995 to 2003, 50 consecutive patients with angiographically proven BAO were treated according to an institutional therapy protocol based on intravenous thrombolysis with recombinant tissue plasminogen activator (alteplase). Patients were treated at an urban university teaching hospital receiving all patients with ischemic stroke who were considered for thrombolysis in a catchment area of 1.5 million inhabitants in Helsinki, Finland. INTERVENTION: Intravenous administration of alteplase (0.9 mg/kg) during a 1-hour infusion. MAIN OUTCOME MEASURES: Basilar artery recanalization determined by magnetic resonance angiography and clinical outcomes at 3 months and at 1 year or longer determined by modified Rankin Scale and Barthel Index scores. RESULTS: Recanalization was studied in 43 patients and verified in 26 (52%) of all patients. By 3 months, 20 patients (40%) had died while 11 had good outcomes (modified Rankin Scale score, 0-2); 12 (24%) reached independence in activities of daily living (Barthel Index score, 95-100), and 6 (16%) were severely disabled (Barthel Index score, 0-50). In the long term (median follow-up 2.8 years), 15 patients (30%) reached good outcomes (modified Rankin Scale score, 0-2) while 23 (46%) died. CONCLUSIONS: Intravenous administration of alteplase for patients with BAO appears to be associated with rates of survival, recanalization, and independent functional outcome comparable with those reported with endovascular approaches. These data suggest that a randomized trial is needed to compare these approaches for treatment of BAO.

Adult↗
PubMed2004

Secondary prevention of ischemic stroke.

Stroke strikes often suddenly, causes long-term disability and death, and is a huge economical burden for the society, not to mention the human tragedy for the patient and the family. At least 15% of stroke survivors will have a second stroke during the next five years, quarter of which prove out to be fatal within four weeks. Secondary prevention of ischemic stroke (IS) targets at reducing stroke recurrence by means of 1) detection and modification of risk factors, 2) antithrombotic or anticoagulant treatment, and 3) surgical interventions for selected patient subgroups. In this review we will discuss these issues in detail and also offer our personal suggestions for treatment choices. Detecting and treating the modifiable risk factors is the major challenge of secondary prevention of IS.

Anticoagulants↗
PubMed2004

The role of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke: from laboratory to clinics.

Ischemic stroke is a major cause of mortality and morbidity in industrialized countries and is almost always caused by occlusion of a cerebral artery by a clot. As the reversibly injured brain tissue evolves into irreversible infarction within a short period of time after onset of ischemia, it is extremely important and urgent to reverse the serious consequences of brain ischemia in the hyperacute phase when the ischemic brain tissue is still salvageable. Numerous thrombolytic and potentially neuroprotective agents have been studied in stroke patients with little success as the only approved therapy is thrombolysis with recombinant tissue plasminogen activator (r-tPA) within 3 h of stroke onset in highly selected patients (approximately 5 to 10 % of all acute stroke patients). One major obstacle in the development of effective therapies for ischemic stroke has been the lack of versatile imaging techniques. New magnetic resonance imaging (MRI) modalities, specially diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) have been used in experimental studies with great success for over a decade and now are gradually entering clinical use. DWI and PWI can detect brain ischemia in the early phase in its full extent thus ensuring a definite diagnosis, allowing for follow-up of the ischemic lesion size over time with good spatial and temporal resolution, demonstrating perfusion deficit and reperfusion and the existence and the extent of penumbra while only requiring a few minutes of imaging time. DWI and PWI do not just give us the correct diagnosis of ischemic stroke, but allow us to acquire in vivo lesion size before therapeutic regimen is started and monitor the therapeutic efficacy thereafter, thus overcoming the potential pretreatment bias. We used DWI and PWI to evaluate novel therapeutic approaches for ischemic stroke in numerous experimental studies and lately in humans. With DWI and PWI, we are able to determine the in vivo efficacy (or lack of efficacy) of new therapeutic regiments (both neuroprotective and thrombolytic agents, or combination therapies) in a rapid, safe, and reliable way and in a relatively small number of well-selected, well-defined, and homogeneous patients. This approach may, therefore, significantly accelerate the development of new remedies for stroke patients.

Animals↗
PubMed2003

Cerebral hemodynamics in asymptomatic and symptomatic patients with high-grade carotid stenosis undergoing carotid endarterectomy.

BACKGROUND AND PURPOSE: Asymptomatic patients with carotid stenosis benefit less from carotid endarterectomy (CEA) than symptomatic patients because the risk of embolic events is lower, but it is not known whether the hemodynamic effect of CEA is different between the groups. We evaluated hemodynamics of symptomatic and asymptomatic patient groups before and after CEA. METHODS: Forty-six independent patients with a unilateral high-grade carotid stenosis, 23 asymptomatic and 23 symptomatic, underwent dynamic susceptibility contrast MRI (DSC-MRI) and transcranial Doppler ultrasound (TCD) evaluation before CEA and 3 and 100 days afterward. Quantitative perfusion parameters were calculated separately in selected regions of white and gray matter and watershed regions in each hemisphere, and mean transit time (MTT) maps were assessed visually by 2 independent observers. Vasomotor reactivity was determined with breath-holding index and flow impedance with pulsatility index ipsilaterally. RESULTS: In contrast to the asymptomatic carotid stenosis group, symptomatic carotid stenosis patients had preoperatively increased MTT and lower cerebral blood flow values in the ipsilateral hemisphere, more in white matter and watershed regions than in gray matter. Visually detected perfusion deficits were associated with symptomatic status. The interhemispheric asymmetries were abolished by CEA. The improving trend over time was greater in the symptomatic carotid stenosis group and was best seen in MTT. On TCD, pulsatility index was lower in symptomatic carotid stenosis patients preoperatively, with no postoperative difference, whereas the breath-holding index improved only in the symptomatic carotid stenosis group after CEA. CONCLUSIONS: Patients with asymptomatic and symptomatic carotid stenosis differ significantly by means of DSC-MRI and TCD before and in response to CEA.

Aged↗
PubMed2003

Community-based thrombolytic therapy of acute ischemic stroke in Helsinki.

BACKGROUND AND PURPOSE: Thrombolysis with alteplase is used in acute ischemic stroke within 3 hours after symptom onset in many stroke centers, but experience remains limited in Europe. METHODS: Using eligibility and management criteria similar to those published by the American Heart Association, we treated 75 consecutive patients aged 21 to 83 years (mean age, 63.6 years; median Scandinavian Stroke Scale score, 32/58) with hemispheric infarction with alteplase in 1998-2001. Their neuroradiological findings (ischemic and hemorrhagic changes) and functional outcome at 3 months were evaluated. RESULTS: Sixty-one percent of the patients had recovered functional independence (Barthel Index 95 to 100) at the 3-month follow-up. On the modified Rankin Scale (mRS), 37% (28/75) of patients had no or minimal symptoms (mRS 0 to 1), while 17% (13/75) remained dependent (mRS 4 to 5) and 5% (4/75) died. Cerebral parenchymal hematomas occurred in 8% (6/75) and hemorrhagic transformation in 8% (6/75) of the patients. Low initial diastolic blood pressure and administration of intravenous antihypertensive medication were associated with unfavorable outcome (mRS 3 to 6). CONCLUSIONS: We conclude that our management protocol for thrombolytic therapy is safe. These rates of functional outcome, case fatality, and hemorrhagic cerebral events compare favorably with those of other published series of stroke thrombolysis with similar time windows and management guidelines. Associations between blood pressure and its treatment during thrombolysis with functional outcome deserve further analysis.

Academic Medical Centers↗
PubMed2003

Use of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke.

Diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI, respectively) are novel imaging modalities that can detect brain ischemia early in its full extent, can be performed in minutes, can be repeated easily, and allow for follow-up of the ischemic lesion size over time with good spatial and temporal resolution. We have used DWI and PWI in evaluating novel therapeutic approaches for ischemic stroke in numerous studies in the rat and lately in humans. It is now clear that DWI and PWI offer a good combination for safe and reliable evaluation of novel drugs on the size and tissue characteristics of brain ischemia. After inducing focal brain ischemia in the rat, one can first detect the presence and extent of ischemia by DWI and hypoperfusion by PWI, calculate the volume of ischemic brain tissue, and then follow the development of the ischemic lesion over time for several hours during treatment, thus detecting in vivo effects of the novel drug on brain ischemia. Successful reperfusion (either mechanically or as a result of thrombolytic therapy) can also be detected easily. DWI and PWI when performed before starting treatment can also exclude the pretreatment bias, a potential reason for false-positive studies in which proper imaging studies are not employed. Thus we can determine the in vivo efficacy (or lack of efficacy) of new therapeutic regimens (both neuroprotective and thrombolytic) rapidly, safely, and reliably by using a small sample size only, and adapt the same strategy to clinical trials.

Animals↗
PubMed2002

Leukoaraiosis, ischemic stroke, and normal white matter on diffusion-weighted MRI.

BACKGROUND AND PURPOSE: Leukoaraiosis is a radiological finding of uncertain pathogenesis with bilateral patchy or diffuse areas of hyperintensity of the cerebral white matter (WM) on T2-weighted MRI. Using diffusion-weighted MRI (DWI), we aimed to test (1) whether the average apparent diffusion coefficient (ADC(av)) values of the regions of leukoaraiosis vary according to the degree of the severity of leukoaraiosis and whether the regions of leukoaraiosis could be distinguished (2) from normal WM or (3) from ischemic strokes of various ages. METHODS: We compared 85 patients with leukoaraiosis, 22 healthy subjects with no leukoaraiosis on the conventional MR images, and 10 patients with ischemic strokes serially imaged <6 hours, 24 hours, 1 week, 1 month, and 3 months after stroke onset. All subjects were studied with DWI in 3 orthogonal directions with 2 b values (b=0 and b=1000 s/mm(2)) at 1.5 T. ADC(av) values were determined for the regions of leukoaraiosis, ischemic lesions, and normal WM. RESULTS: The more severe the leukoaraiosis was, the higher the ADC(av) values of the leukoaraiotic regions became. The ADC(av) values (in 10(-3) mm(2)/s) of the regions of leukoaraiosis (0.92 to 1.27) were significantly higher than that of the normal WM (0.69+/-0.04) and that of the ischemic strokes at 6 hours (0.38+/-0.07), 24 hours (0.36+/-0.10), and 1 week (0.51+/-0.09). One-month-old ischemic strokes (1.08+/-0.33) had ADC(av) values similar to those of leukoaraiotic regions, whereas 3-month-old infarcts (1.59+/-0.32) showed significantly higher ADC(av) values than the leukoaraiotic regions. CONCLUSIONS: The regions of leukoaraiosis show characteristic changes in ADC(av) values, and DWI can be used to differentiate acute and chronic ischemic stroke lesions from leukoaraiosis.

Acute Disease↗