Biomedical subjects

Mario Siebler

Publications and source records attributed to Mario Siebler.

At least 19 recordsLinked to original sources

PubMed2006

Aldolase C/zebrin II is released to the extracellular space after stroke and inhibits the network activity of cortical neurons.

Cell death after stroke involves apoptotic, autophagocytic and necrotic mechanisms which may cause the release of cytosolic proteins to the extracellular space. Aldolase C (AldC) is the brain specific isoform of the glycolytic enzyme fructose-1,6-bisphosphate aldolase. According to its characteristic striped expression pattern in the adult cerebellum AldC is also termed zebrin II. Here, we demonstrate release of AldC into the cerebrospinal fluid (CSF) after stroke in vivo. Studies with cell cultures confirmed that AldC is released to the extracellular space after hypoxia. Moreover, addition of purified recombinant AldC to networks of cortical neurons plated on multielectrode arrays reversibly inhibited the spontaneous generation of action potentials at AldC concentrations which can be expected to occur after lesions of the human cerebral cortex. This mechanism could be relevant in the pathogenesis of the electrophysiological changes in the penumbra region after stroke.

Adult↗

PubMed2006

P2Y receptor-mediated excitation in the posterior hypothalamus.

Histaminergic neurons located in the posterior hypothalamus (tuberomamillary nucleus, TMN) project widely through the whole brain controlling arousal and attention. They are tonically active during wakefulness but cease firing during sleep. As a homeostatic theory of sleep involves ATP depletion and adenosine accumulation in the brain, we investigated the role of ATP and its analogues as well as adenosine on neuronal activity in the TMN. We show increased firing of rat TMN neurons by ATP, ADP, UTP and 2meSATP, indicating activation of receptors belonging to the P2Y family. Adenosine affected neither membrane potential nor firing of these cells. Single-cell reverse transcriptase-polymerase chain reaction revealed that P2Y1 and P2Y4 are prevailing receptors in TMN neurons. P2Y1 receptor mRNA was detected with a higher frequency in 2-week-old than in 4-week-old rats; in accordance, 2meSATP was more potent than ATP. Semi-quantitative real-time polymerase chain reaction revealed a developmental downregulation of mRNA levels for P2Y1 and P2Y4 receptors. Immunocytochemistry demonstrated neuronal and glial localization of the P2Y1 receptor protein. Network activity measured with multielectrode arrays in primary cultures made from the posterior hypothalamus was enhanced by UTP and 2meSATP (P2Y4 and P2Y1 agonists, respectively). ATP caused an inhibition of firing, which was reversed in the presence of suramin or gabazine [gamma-aminobutyric acid (GABA)A receptor antagonist], indicating that GABAergic neurons are preferentially activated by ATP in this network. Excitation of the wake-active TMN neurons by nucleotides and the lack of adenosine action may be important factors in sleep-wake regulation.

Action Potentials↗

PubMed2006

The use of embolic signal detection in multicenter trials to evaluate antiplatelet efficacy: signal analysis and quality control mechanisms in the CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial.

BACKGROUND AND PURPOSE: The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts. METHODS: As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (ps+/-values). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator). RESULTS: For the reference tape, the cumulative ps+/-value was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative rho=0.84; P<0.001). CONCLUSIONS: Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important.

Aspirin↗

PubMed2006

Significance of the perfusion-diffusion mismatch in chronic cerebral ischemia.

PURPOSE: To determine whether the perfusion deficit could predict brain infarction in patients with chronic cerebral ischemia who experienced recurring episodes of neurological symptoms and showed a perfusion-diffusion mismatch on magnetic resonance (MR) images. MATERIALS AND METHODS: In 53 consecutive patients (38 males and 15 females, 62+/-13 years old) with ischemia in the middle cerebral artery (MCA) territory, lesion volumetry was performed on parametric maps of the time-to-peak, the cerebral blood volume, and diffusion-weighted (DW) images. The infarct lesions were assessed on follow-up T2-weighted (T2W) MR images after eight days. Cerebrovascular changes were determined by time-of-flight (TOF) MR angiography (MRA). Inferential and correlation statistics were used. RESULTS: Patients with chronic ischemic brain disease (N=39) who presented with a severe perfusion-diffusion mismatch in the presence of a normal cerebral blood volume had no or small brain infarctions as found on follow-up T2W images. MRA revealed widespread abnormalities of the basal cerebral arteries compatible with brain perfusion abnormalities. In contrast, in acute stroke patients (N=14) the deficit of cerebral perfusion predicted the infarct lesion in the T2W images. CONCLUSION: Our results suggest that in chronic cerebral ischemia the normal blood volume was maintained despite the depression of cerebral perfusion and recurring minor insults.

Adult↗

PubMed2006

Motor recovery as assessed with isometric finger movements and perfusion magnetic resonance imaging after acute ischemic stroke.

OBJECTIVE: Recovery from hemiparetic stroke is variable. An important goal for clinicians and clinical researchers is to identify predictors of recovery. The initial phase after acute ischemic stroke is considered to be of major importance for neurological outcome. The authors sought to determine in patients with acute ischemic stroke whether early motor recovery, as measured by repetitive isometric index-thumb oppositions, is correlated with ischemic lesion volume. METHODS: Thirty-six acute hemiparetic stroke patients with residual hand function were investigated. The European Stroke Scale (ESS) score was determined on admission and at discharge. Performance of repetitive index finger-thumb pinch movements was measured daily during the 1st 8 days after stroke onset. Brain ischemia volume was determined digitally in time-to-peak magnetic resonance images of per-fusion. RESULTS: The recovery of patients with (P = 0.002) and without (P < 0.001) thrombolysis as assessed with the ESS was paralleled by an increase in isometric grip force and movement rate (P < 0.05). Recovery was predicted by the area of moderately impaired perfusion indicated by the per-fusion mismatch volume (r = 0.578, P < 0.001). CONCLUSIONS: In acute stroke, recovery of hand function is predicted by the volume of salvageable ischemic tissue, as determined by the perfusion mismatch.

Aged↗

PubMed2005

Initial ischemic event: perfusion-weighted MR imaging and apparent diffusion coefficient for stroke evolution.

PURPOSE: To prospectively determine if the degree of acute perfusion or diffusion abnormalities measured prior to treatment onset help predict the evolution of brain infarction on magnetic resonance (MR) images. MATERIALS AND METHODS: Local ethics committee approval and informed consent were obtained. On parametric maps obtained in 64 patients (mean age, 64 years +/- 13 [standard deviation]; 37 men and 27 women) with acute middle cerebral artery infarction, lesion volumetry was performed to determine time to peak, mean transit time, cerebral blood volume, and apparent diffusion coefficient obtained within 3 hours of symptom onset. The infarct lesions were assessed on T2-weighted MR images obtained at follow-up on day 8. Cerebrovascular changes were determined on MR angiograms. Inferential and correlation statistics were used. RESULTS: A perfusion delay of more than 6 seconds relative to the nonaffected hemisphere on time-to-peak maps helped to predict the lesion volume on T2-weighted images (r = 0.686, P < .001). In contrast, neither the volume nor the degree of the diffusion abnormality helped to predict the infarct volume (r < 0.46). This was because in one subgroup of patients there was an increase and in one subgroup there was a decrease in infarct volume on the T2-weighted images (P < .001). There was a greater prevalence (P < .02) of cerebral artery abnormalities in the patients with larger infarcts. Clinically, the neurologic impairment was more severe (P < .01) and the mean arterial pressure higher (P < .04) in these patients. CONCLUSION: The results suggest that in acute stroke the severity of the initial ischemic event as determined on time-to-peak maps indicates hemodynamic compromise in addition to internal carotid artery or middle cerebral artery occlusion, because of abnormalities in other cerebral arteries.

Adult↗

PubMed2005

Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.

BACKGROUND: Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach. METHODS AND RESULTS: Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic > or =50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean+/-SD: 24.4+/-27.7 versus 8.9+/-11.5 per hour; P=0.0003). CONCLUSIONS: In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.

Aged↗

PubMed2005

Partial rescue of the perfusion deficit area by thrombolysis.

PURPOSE: To investigate the evolution of the perfusion deficit area following systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) in a clinical study on acute cerebral ischemia. MATERIALS AND METHODS: We performed volumetric measurements of the acute ischemic lesions in MR images of perfusion (TTP, MTT, and rCBV) and in diffusion-weighted (DW) images, as well as the manifest stroke lesions in T2-weighted MR images on day 8. We compared the data of 29 patients who were subjected to systemic thrombolysis with those of 18 patients who were not eligible for thrombolysis. RESULTS: In the treated patients there were prominent MTT/DWI and TTP/DWI mismatches (P < 0.0006). The acute TTP volumes were smaller than the acute MTT volumes, but as large as the T2 lesions on day 8. The MTT/T2 lesion volume reduction was significant (P < 0.03) in patients who received the GPIIb/IIIa receptor antagonist tirofiban (N = 13) in addition to the low-dose rtPA. This corresponded to a greater neurological improvement compared to patients who received rtPA alone (P < 0.05). In contrast, in the nontreated patients the initial MTT and TTP lesion volumes were of similar magnitude and predicted the T2 lesions on day 8. In the treated and nontreated patients the TTP lesion signified the viability threshold of acute ischemia, which corresponded to a rCBF of 25 +/- 11 mL/100 g/min. CONCLUSION: The perfusion deficit area comprises the ischemic core that is destined to undergo necrosis, and an ischemic rim that is salvageable by systemic thrombolysis.

Adult↗

PubMed2004

Neuronal network properties of human teratocarcinoma cell line-derived neurons.

Understanding the structural and functional development of neurons in networks has a high impact to estimate the potentials for restorative therapies. Neurons derived from the human NT2 cell line (hNT) formed networks with a clustered neuritic architecture in vitro, whereas primary dissociated embryonic rat cortical neurons (Cx) displayed a more homogenous cell assembly. Spontaneous spikes of both cell types were recorded on microelectrode arrays within 2 weeks after seeding, but hNT showed a mostly uncorrelated firing pattern in contrast to Cx with highly synchronized bursting. hNT neurons were less sensitive to TTX (IC50 = 5.7 +/- 0.1 nM vs. IC50 = 1.1 +/- 0.2 nM), magnesium (IC50 = 1.83 +/- 0.01 mM vs. IC50 = 0.161 +/- 0.023 mM), and APV (IC50 > 100 microM vs. IC50 = 18 microM). We conclude that embryonic cortical neurons and hNT neurons have different network properties. This should be carefully considered before hNT neurons are used in therapeutic approaches, e g., central nervous system (CNS) grafting.

2-Amino-5-phosphonovalerate↗

PubMed2004

Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity.

Severe hyperhomocysteinemia (50-200 microM) often presents itself with acute neuronal dysfunction including seizures and psychosis. Its moderate form (15-50 microM) is associated with cognitive impairment and dementia. We investigated the neuropharmacological effects of homocysteine and its oxidized forms, homocysteinesulfinic acid (HCSA) and homocysteic acid (HCA), on neuronal network function utilizing dissociated cortical neurons from embryonic Wistar rats on microelectrode arrays. All substances inhibited dose-dependently and reversibly spontaneous neuronal network activity within seconds: L-HCSA and L-HCA blocked spontaneous spike rate (SSR) significantly at very low concentrations, with an IC50 of 1.9 and 1.3 microM, respectively; whereas the dose-response curve of D,L-homocysteine revealed an IC50 of 401 microM. These effects were antagonized by 2-amino-5-phosphonovaleric acid (APV) pointing to the NMDA receptor as mediator of this fast and reversible inhibition of network activity. We conclude that a neuronal dysfunction observed in hyperhomocysteinemia is likely due to HCSA and HCA since effective concentrations of homocysteine are not reached in patients.

Action Potentials↗

PubMed2004

Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study.

BACKGROUND AND PURPOSE: We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. METHODS: Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. RESULTS: Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P=0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. CONCLUSIONS: The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

Blood Flow Velocity↗

PubMed2004

Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: In acute ischemic stroke, thrombolytic treatment with recombinant tissue plasminogen activator (rtPA) is limited by a concomitant activation of the coagulatory system, leading to incomplete or delayed reperfusion, microcirculatory disturbances, or even repeated vessel occlusions. Our pilot study sought to assess the therapeutic potential of a new treatment strategy combining rtPA at reduced dosages with a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitory agent in acute middle cerebral artery occlusion. METHODS: Nineteen patients suffering from acute middle cerebral artery occlusion (Thrombolysis in Myocardial Infarction [TIMI] flow grade 0 to 1) underwent combined intravenous thrombolytic treatment using rtPA at reduced dosages and the GPIIb/IIIa antagonist tirofiban. Stroke MRI (diffusion- and perfusion-weighted imaging) and MR angiography were performed at baseline and between days 1 and 2 after treatment. Clinical scores (National Institutes of Health Stroke Scale and modified Rankin Scale) were assessed at baseline and after 1 week. RESULTS: Middle cerebral artery recanalization (TIMI flow grade 2 and 3) occurred in 13 of 19 patients (68%). The ischemic lesion on follow-up MRI was significantly smaller in patients with recanalization compared with those without recanalization (P=0.001). Only patients with recanalization improved neurologically (P<0.001). Because no symptomatic hemorrhage was observed, the power of our study to detect a symptomatic bleeding rate of > or =8% was at least 80%. CONCLUSIONS: Combined thrombolysis with a GPIIb/IIIa antagonist and rtPA at reduced dosages is promising but cannot be recommended for general use before prospective randomized clinical trials are completed.

Acute Disease↗

PubMed2004

Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging.

BACKGROUND AND PURPOSE: Although modern multisequence stroke MRI protocols are an emerging imaging routine for the diagnostic assessment of acute ischemic stroke, their sensitivity for intracerebral hemorrhage (ICH), the most important differential diagnosis, is still a matter of debate. We hypothesized that stroke MRI is accurate in the detection of ICH. To evaluate our hypotheses, we conducted a prospective multicenter trial. METHODS: Stroke MRI protocols of 6 university hospitals were standardized. Images from 62 ICH patients and 62 nonhemorrhagic stroke patients, all imaged within the first 6 hours after symptom onset (mean, 3 hours 18 minutes), were analyzed. For diagnosis of hemorrhage, CT served as the "gold standard." Three readers experienced in stroke imaging and 3 final-year medical students, unaware of clinical details, separately evaluated sets of diffusion-, T2-, and T2*-weighted images. The extent and phenomenology of the hemorrhage on MRI were assessed separately. RESULTS: Mean patient age was 65.5 years; median National Institutes of Health Stroke Scale score was 10. The experienced readers identified ICH with 100% sensitivity (confidence interval, 97.1 to 100) and 100% overall accuracy. Mean ICH size was 17.3 mL (range, 1 to 101.5 mL). The students reached a mean sensitivity of 95.16% (confidence interval, 90.32 to 98.39). CONCLUSIONS: Hyperacute ICH causes a characteristic imaging pattern on stroke MRI and is detectable with excellent accuracy. Even raters with limited film-reading experience reached good accuracy. Stroke MRI alone can rule out ICH and demonstrate the underlying pathology in hyperacute stroke.

Acute Disease↗

PubMed2004

Development of brain infarct volume as assessed by magnetic resonance imaging (MRI): follow-up of diffusion-weighted MRI lesions.

PURPOSE: To investigate the development of ischemic brain lesions, as present in the acute stroke phase, by diffusion-weighted magnetic resonance imaging (DWI), and in the subacute and chronic phases until up to four months after stroke, in fluid-attenuated inversion recovery (FLAIR)- and T2-weighted (T2W) magnetic resonance (MR) images. MATERIALS AND METHODS: Twelve consecutive patients with their first middle cerebral artery (MCA) infarction were included. Lesion volumes were assessed on T2W images recorded with a turbo spin echo (TSE) and on images recorded with the FLAIR sequence on average on day 8 and after about four months. They were compared with acute lesion volumes in perfusion and DWI images taken within 24 hours of stroke onset. RESULTS: On day 8, lesion volumes in images obtained with FLAIR exceeded the acute infarct volumes in DWI. The chronic lesion volumes were almost identical in T2W and FLAIR images but significantly reduced compared with the acute DWI lesions. The lesion volumes assessed on DWI images correlated highly with the lesions in the images obtained with TSE or FLAIR, as did the lesions in the images obtained with FLAIR and TSE. The secondary lesion shrinkage was accompanied by ventricular enlargement and perilesional sulcal widening, as most clearly visible in the images obtained with FLAIR. CONCLUSION: Our results show that the acute DWI lesions are highly predictive for the infarct lesion in the chronic stage after stroke despite a dynamic lesion evolution most evident in MR images obtained with FLAIR.

Acute Disease↗

PubMed2003

Cryopreserved rat cortical cells develop functional neuronal networks on microelectrode arrays.

Neurons growing on microelectrode arrays (MEAs) are promising tools to investigate principal neuronal network mechanisms and network responses to pharmaceutical substances. However, broad application of these tools, e.g. in pharmaceutical substance screening, requires neuronal cells that provide stable activity on MEAs. Cryopreserved cortical neurons (CCx) from embryonic rats were cultured on MEAs and their immunocytochemical and electrophysiological properties were compared with acutely dissociated neurons (Cx). Both cell types formed neuritic networks and expressed the neuron-specific markers microtubule associated protein 2, synaptophysin, neurofilament and gamma-aminobutyric acid (GABA). Spontaneous spike activity (SSA) was recorded after 9 up to 74 days in vitro (DIV) in CCx and from 5 to 30 DIV in Cx, respectively. Cx and CCx exhibited synchronized burst activity with similar spiking characteristics. Tetrodotoxin (TTX) abolished the SSA of both cell types reversibly. In CCx SSA-inhibition occurred with an IC50 of 1.1 nM for TTX, 161 microM for magnesium, 18 microM for D,L-2-amino-5-phosphonovaleric acid (APV) and 1 microM for GABA. CCx cells were easy to handle and developed long living, stable and active neuronal networks on MEAs with similar characteristics as Cx. Thus, these neurochips seem to be suitable for studying neuronal network properties and screening in pharmaceutical research.

Action Potentials↗

PubMed2003

Thrombolysis with recombinant tissue plasminogen activator and tirofiban in stroke: preliminary observations.

BACKGROUND AND PURPOSE: We sought to investigate the feasibility of the combined use of low-dose recombinant tissue plasminogen activator (rtPA) and tirofiban, a glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist, for systemic thrombolysis in acute stroke. METHODS: Consecutive patients who were treated with systemic application of low-dose rtPA and body weight-adjusted tirofiban (rtPA+T group; n=37) were evaluated retrospectively during 1999-2001. Patients in the rtPA+T group were compared with a group of patients treated with a dose of 0.9 mg/kg body weight in a different center (rtPA group; n=119). The 41 patients with infarctions of the middle cerebral artery territory who were not eligible for thrombolytic treatment because of medical contraindications or arrival in the hospital >3 hours after stroke onset served as controls. For matched comparisons, the National Institutes of Health Stroke Scale on admission and the Rankin Scale on discharge 5 days after stroke were used. RESULTS: The patients treated with rtPA+T or rtPA improved (P<0.05) compared with the controls at discharge; patients in the rtPA+T and rtPA groups reached a Rankin Scale score of 0 to 2 in 63% and 55%, respectively, while only 16% of the controls achieved this score. Death rates (8% in rtPA+T group and 5% in rtPA group) were similar among the 2 treatment groups. They included 1 fatal hemorrhage in the rtPA+T group and 4 fatal hemorrhages in the rtPA group. Five percent of the untreated patients developed symptomatic, nonfatal cerebral hemorrhage. CONCLUSIONS: Systemic combined thrombolysis with rtPA+T seems to be a feasible treatment in acute stroke.

Acute Disease↗

PubMed2003

Cerebral microembolism is blocked by tirofiban, a selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist.

BACKGROUND: Microembolic signals (MES) as detected by transcranial Doppler ultrasound define an individual stroke risk in patients with carotid artery disease. To study the composition of MES in vivo, we used the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist tirofiban, a highly selective platelet aggregation inhibitor. METHODS AND RESULTS: Twenty-four patients with recent cerebral or retinal embolism of arterial origin and a MES rate >6 per hour on initial transcranial Doppler ultrasonography recording received the short-acting GPIIb/IIIa antagonist tirofiban. With tirofiban, the MES rate dropped from a median (range) of 38 (9 to 324) to zero in all patients. After cessation of infusion, the inhibitory effect of tirofiban was reversible, with a significant increase of MES (median 13.5; range, 0 to 35; n=16; P=0.001). Six patients received overlapping oral antiplatelet agents and remained MES-negative. CONCLUSIONS: Cerebral microembolism of arterial origin has the property of solid emboli, with platelet-fibrinogen units as predominant constituent parts. GPIIb/IIIa antagonists may have the potential to bridge the ischemic risk in patients with unstable carotid disease.

Adult↗

PubMed2003

Disturbance of cultured rat neuronal network activity depends on concentration and ratio of leucine and alpha-ketoisocaproate: implication for acute encephalopathy of maple syrup urine disease.

Increased concentrations of leucine and its respective ketoacid alpha-ketoisocaproate (KIC) in plasma and cerebrospinal fluid are related to acute and reversible encephalopathy in patients with maple syrup urine disease. We studied electrophysiological properties of primary dissociated rat neurons at increased extracellular concentrations of leucine and KIC (1-10 mM). Spontaneous neuronal network activity was reversibly reduced or blocked by leucine as well as by KIC in a dose-dependent manner. Simultaneous incubation with both substances led to a minor inhibition compared to the effect of each substance alone. Neuronal resting potential, voltage dependent Na(+) (I(Na)) and K(+) (I(K)) currents, the GABA- and glycine-elicited membrane currents, and glutamate-induced intracellular Ca(2+) increase of single neurons, however, were unaffected by both substances. We conclude that acute neuronal network dysfunction in maple syrup urine disease is mainly based on an imbalance of the presynaptic glutamatergic/GABAergic neurotransmitter concentrations or their release.

Animals↗