Biomedical subjects

M Siebler

Publications and source records attributed to M Siebler.

At least 19 recordsLinked to original sources

PubMed2000

Time course of inwardly rectifying K(+) current reduction in glial cells surrounding ischemic brain lesions.

K(+) currents of activated glial cells surrounding ischemic infarcts are investigated using acutely dissociated cells from the periinfarct area after permanent middle cerebral artery occlusion in rats. Inwardly rectifying K(+) currents (K(IR)) were markedly reduced in cells neighboring infarcts with maximal alteration at day 3 after infarct followed by a partial recovery. This reduction of glial K(IR) currents may contribute to the functional disturbances in the periinfarct area.

Animals↗

PubMed2000

[Unstable carotid stenosis--an inflammatory disease?].

Arterioarterial thromboembolism from extracranial internal carotid artery (ICA) stenosis is an important pathogenic mechanism of ischemic stroke. However, even a high-grade ICA stenosis carries a greatly variable annual risk of stroke, as high as 13% following a recent occurrence of transient or minor cerebral ischemia or as low as 1-2% in clinically asymptomatic patients. There is increasing evidence that inflammatory processes play a central role in atherosclerosis and particularly in plaque destabilization converting chronic atherosclerosis into an acute neurological disorder. In thromboendarterectomy specimens from patients with high-grade ICA stenoses, the extent of inflammatory infiltration and the expression of matrixmetalloproteinase-9 correlated to clinical and ultrasonic features of plaque destabilization such as cerebral microembolism. Inflammation might become a new therapeutic target in symptomatic carotid artery disease.

Carotid Artery, Internal↗

PubMed2000

Diffusion- and perfusion-weighted MRI in a patient with a prolonged reversible ischaemic neurological deficit.

We report acute and follow-up diffusion- and perfusion-weighted MRI (DWI, PWI) findings in a patient with a prolonged reversible ischaemic neurological deficit. PWI 12 h after the patient was last seen to be without symptoms revealed a large perfusion deficit in the left posterior MCA territory with a relatively inconspicuous and much smaller abnormality on DWI. Follow-up showed resolution of abnormalities on both DWI and PWI, and conventional MRI was normal, apart from a very slight abnormality, visible only on FLAIR images, at the centre of the initially DWI-positive region. These findings demonstrate the utility of PWI when be used in combination with DWI to investigate the pathophysiology of transient ischemic syndromes.

Aged↗

PubMed2000

Diffusion- and perfusion-weighted MRI: influence of severe carotid artery stenosis on the DWI/PWI mismatch in acute stroke.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) have been used increasingly in recent years to evaluate acute stroke in the emergency setting. In the present study, we compared DWI and PWI findings in acute stroke patients with and without severe extracranial internal carotid artery (ICA) disease. METHODS: Twenty-seven patients with nonlacunar ischemic stroke were selected for this analysis. DWI, PWI, and conventional MRI were performed in all patients within 24 hours of symptom onset and after 1 week. To exclude patients with partial or complete reperfusion, we included only patients with a PWI deficit larger than the DWI lesion. Severe ICA disease (>70% stenosis) was present unilaterally in 9 and bilaterally in 2 patients. Acute DWI lesion volume, the size of the acute PWI/DWI mismatch, and final infarct size (on T2-weighted images) were determined. RESULTS: The PWI/DWI mismatch was significantly larger in patients with severe ICA disease than in patients without extracranial carotid stenosis, both when time-to-peak and mean transit time maps (P<0.01) were used to calculate the mismatch. Quantitative analysis of the time-to-peak delay in the mismatch indicated that a relatively smaller fraction of the total mismatch was critically ischemic in patients with carotid stenosis than in those without. Average lesion volume increased less in the stenosis group (P=0.14), despite the larger PWI/DWI mismatch, and final infarct size was smaller in the stenosis group (P<0.05). In the 2 patients with bilateral ICA disease, variable hemodynamic involvement of the contralateral hemisphere was found in addition to the ipsilateral PWI deficit. CONCLUSIONS: In most acute stroke patients with severe ICA stenosis, a considerably smaller fraction of the total PWI/DWI mismatch is at risk than in patients without carotid disease.

Acute Disease↗

PubMed2000

Evaluation of new online automated embolic signal detection algorithm, including comparison with panel of international experts.

BACKGROUND AND PURPOSE: The clinical application of Doppler detection of circulating cerebral emboli will depend on a reliable automated system of embolic signal detection; such a system is not currently available. Previous studies have shown that frequency filtering increases the ratio of embolic signal to background signal intensity and that the incorporation of such an approach into an offline automated detection system markedly improved performance. In this study, we evaluated an online version of the system. In a single-center study, we compared its performance with that of a human expert on data from 2 clinical situations, carotid stenosis and the period immediately after carotid endarterectomy. Because the human expert is currently the "gold standard" for embolic signal detection, we also compared the performance of the system with an international panel of human experts in a multicenter study. METHODS: In the single-center evaluation, the performance of the software was tested against that of a human expert on 20 hours of data from 21 patients with carotid stenosis and 18 hours of data from 9 patients that was recorded after carotid endarterectomy. For the multicenter evaluation, a separate 2-hour data set, recorded from 5 patients after carotid endarterectomy, was analyzed by 6 different human experts using the same equipment and by the software. Agreement was assessed by determining the probability of agreement. RESULTS: In the 20 hours of carotid stenosis data, there were 140 embolic signals with an intensity of > or =7 dB. With the software set at a confidence threshold of 60%, a sensitivity of 85.7% and a specificity of 88.9% for detection of embolic signals were obtained. At higher confidence thresholds, a specificity >95% could be obtained, but this was at the expense of a lower sensitivity. In the 18 hours of post-carotid endarterectomy data, there were 411 embolic signals of > or =7-dB intensity. When the same confidence threshold was used, a sensitivity of 95.4% and a specificity of 97.5% were obtained. In the multicenter evaluation, a total of 127 events were recorded as embolic signals by at least 1 center. The total number of embolic signals detected by the 6 different centers was 84, 93, 108, 92, 63, and 78. The software set at a confidence threshold of 60% detected 90 events as embolic signals. The mean probability of agreement, including all human experts and the software, was 0.83, and this was higher than that for 2 human experts and lower than that for 4 human experts. The mean values for the 6 human observers were averaged to give P=0.84, which was similar to that of the software. CONCLUSIONS: By using the frequency specificity of the intensity increase occurring with embolic signals, we have developed an automated detection system with a much improved sensitivity. Its performance was equal to that of some human experts and only slightly below the mean performance of a panel of human experts

Algorithms↗

PubMed1999

Automatic embolus detection by a neural network.

BACKGROUND AND PURPOSE: Embolus detection using transcranial Doppler ultrasound is a useful method for the identification of active embolic sources in cerebrovascular diseases. Automated embolus detection systems have been developed to reduce the time of evaluation in long-term recordings and to provide more "objective" criteria. The purpose of this study was to evaluate the critical conditions of automated embolus detection by means of a trained neural network (EMBotec V5.1 One, STAC GmbH, Germany). METHODS: In 11 normal volunteers and in 11 patients with arterial or cardiac embolic sources, we performed simultaneous recordings from both middle or both posterior cerebral arteries. In the normal subjects, we produced 1342 additional artifacts to use the latter as false-positives. Detection of microembolic signals (MES) was done offline from digital audiotapes (1) by an experienced blinded investigator used as a reference and (2) by a trained 3-layer-feed-forward neural network. RESULTS: From the 1342 provoked artifacts the neural network labeled 216 events as microemboli, yielding an artifact rejection of 85%. In microembolus-positive patients the neural network detected 282 events as emboli, among these 122 signals originating from artifacts; 58 "real" events were not detected. This result revealed a sensitivity of 73.4% and a positive predictive value of 56.7. The spectral power of the detected artifact signals was 16.5+/-5 dB above background signal. MES from patients with artificial heart valves had a spectral power of 6.4+/-2.1 dB; however, in patients with other sources of emboli, MES had an averaged energy reflection of 2.7+/-0.9 dB. CONCLUSIONS: The neural network is a promising tool for automated embolus detection, the formal algorithm for signal identification is unknown. However, extreme signal qualities, eg, strong artifacts, lead to misdiagnosis. Similar to other automated embolus detection systems, good signal quality and verification of MES by an experienced investigator is still mandatory.

Adult↗

PubMed1999

Diffusion- and perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) are relatively new MR techniques increasingly used in acute stroke. During the first hours of stroke evolution, the regions with abnormal perfusion are typically larger than the DWI lesions, and this mismatch region has been suggested to be "tissue at risk." The aim of this study was to evaluate the PWI/DWI mismatch region in acute stroke patients and find parameters indicative of both infarct progression and functional impairment. METHODS: Twenty patients with nonlacunar ischemic stroke were imaged with DWI, PWI, and conventional MRI within 24 hours of symptom onset and after 1 week; in addition, the European Stroke Scale (ESS) score was recorded. With PWI, the volumes of regions with "time-to-peak" (TTP) delays of >/=2, 4, 6, 8, and 10 seconds were measured; these volumes were compared with the acute DWI lesion volumes, final infarct size, and ESS score. RESULTS: In 80% of patients the acute DWI lesion was surrounded by regions with abnormal TTP delays (PWI>DWI lesion). A TTP delay of >/=6 s in the mismatch region was found to be associated with lesion enlargement between the initial and follow-up MRI scans. Lesions increased in 9 of 12 patients (75%) in whom the area with TTP delay >/=6 s was larger than the DWI lesion, but they increased in only 1 of 8 (12.5%) of the remaining patients, in whom the area with a TTP delay >/=6 s was smaller than the DWI lesion. The volume of the regions with TTP delays of >/=4 s correlated better with ESS (r=-0.88, P<0.001) than other PWI (or DWI) volumes, which indicated that a TTP delay of approximately 4 s might be the threshold for functional impairment of brain tissue. CONCLUSIONS: Only patients with severe perfusion deficits in the PWI/DWI mismatch (TTP delays of >/=6 s) are at high risk of lesion enlargement. Functionally, more moderate perfusion deficits (TTP delays >/=4 and <6 s) appear to also contribute to the acute clinical deficit.

Acute Disease↗

PubMed1999

[Ultrasound diagnosis in acute stroke].

Doppler- and Duplex-sonography are noninvasive methods which provide helpful insight into brain blood supply by imaging extracranial neck (extracranial Doppler/Duplex) as well the intracranial basal arteries (transcranial Doppler, transcranial color-coded Duplex). Used in combination with ultrasound contrast agents, these methods are now able to supplement and often replace conventional angiography in clinical decision making processes. In acute stroke ultrasound techniques offer bedside options to localize the underlying pathogenic process and to record the actual cerebral blood flow. In addition, the Doppler method allows both detection of cerebral microemboli and their embolic source. Although technical limitation of the Doppler/Duplex method at present impairs imaging of the distal carotid arteries and of the vertebral arteries, extracranial and intracranial Doppler has been proven to be an important clinical tool providing highly useful clinical information with excellent reliability.

Blood Flow Velocity↗

PubMed1998

TNF alpha induces a protein kinase C-dependent reduction in astroglial K+ conductance.

Incubation of cultured cortical astrocytes with tumor necrosis factor alpha (TNF alpha) led to a marked reduction of membrane potential. Here we report that this depolarization depends on activation of protein kinase C (PKC), since it could be blocked by the PKC antagonists staurosporine and H7 and it could be mimicked by direct activation of PKC using the phorbol ester phorbol 12-myristate 13 acetate (PMA). Analyses of whole cell currents revealed a reduction of inwardly rectifying K+ currents whereas K+ outward currents were not affected. We conclude that TNF alpha induces changes of basic electrophysiological properties of astrocytes which are similar to those induced by proliferation or an in vitro model of traumatic injury.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1998

Ammonia-induced depolarization of cultured rat cortical astrocytes.

Exposure of cultured rat cortical astrocytes to increased concentrations of ammonia has been shown to induce morphological and biochemical changes similar to those found in hyperammonemic (e.g., hepatic) encephalopathy in vivo. Alterations of electrophysiological properties are not well investigated. In this study, we examined the effect of ammonia on the astrocyte membrane potential by means of perforated patch recordings. Exposure to millimolar concentrations of NH4Cl induced a slow dose-dependent and reversible depolarization. At steady state, i.e., after several tens of minutes, the cells were significantly depolarized from a resting membrane potential of -96.2 +/- 0.6 mV (n = 83, S.E.M.) to -89.1 +/- 1.6 mV (n = 7, S.E.M.) at 5 mM NH4Cl, -66.3 +/- 3.6 mV (n = 9, S.E.M.) at 10 mM NH4Cl and -50.4 +/- 2.5 mV (n = 12, S.E.M.) at 20 mM NH4Cl, respectively. In order to examine the underlying depolarizing mechanisms we determined changes in the fractional ion conductances for potassium, chloride and sodium induced by 20 mM NH4Cl. No significant changes were found in the fractional sodium or chloride conductances, but the dominating fractional potassium conductance decreased slightly from a calculated 0.86 +/- 0.04 to 0.77 +/- 0.04 (n = 9, S.E.M.). Correspondingly, we found a significant fractional ammonium ion (NH4+) conductance of 0.23 +/- 0.02 (n = 10, S.E.M.) which was blocked by the potassium channel blocker barium and, hence, most likely mediated by barium-sensitive potassium channels. Our data suggest that the sustained depolarization induced by NH4Cl depended on changes in intracellular ion concentrations rather than changes in ion conductances. Driven by the high membrane potential NH4+ accumulated intracellularly via a barium-sensitive potassium conductance. The concomitant decrease in the intracellular potassium concentration was primarily responsible for the observed slow depolarization.

Ammonia↗

PubMed1998

Analysis of rhG-CSF-effects on platelets by in vitro bleeding test and transcranial Doppler ultrasound examination.

Experimental evidence suggests a stimulatory effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on both platelets and coagulation. RhG-CSF is increasingly used to stimulate healthy volunteer donors for blood stem cell mobilization. We therefore assessed 25 healthy donors receiving rhG-CSF for changes in in vitro bleeding test (IVBT), coagulation parameters and cerebral microembolism by transcranial Doppler (TCD) ultrasound. A significant shortening of IVBT was found on day 4 of rhG-CSF administration together with increased levels of fibrinogen and factor VIII and reduced activities of protein C and protein S. Although these changes are quite small it is possible that they may lead to a hypercoagulable state especially in donors with other risk factors for thromboembolism. However, TCD examination failed to detect any signs of microembolism. We therefore conclude that rhG-CSF leads to significant changes in coagulation parameters, but has no effect on TCD detectable microembolism as a stroke risk factor. However donors receiving rhG-CSF should be examined carefully to detect pre-existing changes in the coagulation system and we would like to suggest a routine thrombophilia screen.

Adolescent↗

PubMed1998

Modifiable stroke risk factors in volunteers willing to participate in a prevention program.

The current trends in stroke incidence require continued efforts to improve primary prevention. Compared to large-scale public health approaches, more limited programs targeting volunteers may offer some advantages. We invited all 12,824 members of a health insurance company program who lived within 50 km form one of two study sites to participate in a vascular screening program and aimed at reducing modifiable risk factors. 1,837 persons registered and participated (14.3%, mean age 53 +/- 12 years, 50% men). Using the Framingham stroke risk profile for persons aged 55 years or above (n = 961, 52.3%), 97 stroke events can be predicted for this age group within 10 years. The majority of these 97 events will occur in those with men resting blood pressure values +/- 140mm Hg (systolic) or +/- 90 mm Hg (diastolic; 420 persons, mean age 64 +/- 7 years, 60 expected events), or with a particularly high age- and sex-adjusted risk (288 persons, mean age 68 +/- 7 years, 60 expected events). Our pilot study provides an estimate of the prevalence of modifiable vascular risk factor among volunteer participants of a prevention program. Possible benefits of this approach will be investigated in a second step using a randomized intervention.

Aged↗

PubMed1998

Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection.

Transcranial Doppler ultrasound is capable of detecting microembolic material, both gaseous and solid, within the intracranial cerebral arteries. To avoid discrediting this promising and exciting new technique, experts in this field met in January 1997 in Frankfurt, Germany, to discuss the limitations and problems of embolus detection and to determine guidelines for its proper use in clinical practice, as well as in scientific investigations. In particular, the authors suggest that studies report the following parameters: (1) ultrasound device, (2) transducer type and size, (3) insonated artery, (4) insonation depth, (5) algorithms for signal intensity measurement, (6) scale settings, (7) detection threshold, (8) axial extension of sample volume, (9) fast Fourier transform (FFT) size (number of points used), (10) FFT length (time), (11) FFT overlap, (12) transmitted ultrasound frequency, (13) high-pass filter settings, and (14) recording time. There was agreement that no current system of automatic embolus detection has the required sensitivity and specificity for clinical use.

Humans↗

PubMed1998

Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization.

BACKGROUND AND PURPOSE: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS: Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS: The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS: Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Adult↗

PubMed1998

Detection of cerebral microemboli in APS--introducing a novel investigation method and implications of analogies with carotid artery disease.

Patients with antiphospholipid syndrome (APS) are prone to thromboembolism. So far, the only predictive parameters for further complications are their number in patient's history and perhaps the titre of aPL. Derived from clinical investigation of stroke and obvious analogies between cerebrovascular ischemia (CVI) in patients with carotid artery disease (CAD) and patients with APS, a novel non-invasive method is introduced using transcranial Doppler (TCD) long-term monitoring to detect high energy ultrasonic signals (so called 'microemboli') in the cerebral vasculature. In patients with CAD, these microemboli proved to correlate with past and impending symptoms of CVI permitting therapeutic stratification by their detectability. In SLE and APS. this technique enabled identification of very similar signals in cerebral bloodstream of APS patients. Microemboli were highly associated with the history of CVI and the titre of aPL. Detection of microemboli offers new possibilities in risk estimation, therapeutic stratification and in studying pathophysiology of APS.

Acoustics↗

PubMed1997

Immunologically induced electrophysiological dysfunction: implications for inflammatory diseases of the CNS and PNS.

During inflammation of the central or peripheral nervous system, a high number of immunologically active molecules, including bacterial or viral products as well as host-derived cytokines, are released. Patients suffering from inflammatory CNS or PNS diseases often develop transient symptoms with a rapid recovery, which obviously cannot be accounted for by immunologically induced tissue damage. These observations led to the hypothesis that immunologically active molecules can affect directly the electrophysiological functions of neurons and glial cells. Evidence for this hypothesis came from in vitro studies showing that cytokines, such as interleukins or tumor necrosis factors, arachidonic acid and its metabolites, interfere with electrophysiological properties of neurons or glial cells. These molecules affect ion currents, intracellular Ca2+ homeostasis, membrane potentials, and suppress or enhance the induction and maintenance of long-term potentiation. Similarly, virus proteins from human immunodeficiency virus type I were found to alter intracellular Ca2+ concentrations of neurons and astrocytes by modulating either transmitter receptors and channels or membrane transporters. Cerebrospinal fluid from MS patients contains factors which increase Na+ current inactivation and thereby reduce neuronal excitability. Immunoglobulins in sera of patients suffering from multifocal motor neuropathy and from acquired neuromyotonia interfere with nerve fibers, inducing alterations of conduction. Increased knowledge of these mechanisms will help to explain the pathogenesis of neurological symptoms and may provide a rationale for new therapeutic strategies.

Bacterial Infections↗

PubMed1997

Intercenter agreement in reading Doppler embolic signals. A multicenter international study.

BACKGROUND AND PURPOSE: Different frequencies of asymptomatic Doppler embolic signals have been reported in studies. There has been concern that different criteria for identification may account for some of this variation. A previous reproducibility study between two centers found good agreement, but no studies among large numbers of centers have been performed. We performed an international reproducibility study among nine centers, each of which had published recent studies of embolic signal detection in peer-reviewed journals. METHODS: Each center performed blinded analysis of a taped audio Doppler signal composed of transcranial Doppler middle cerebral artery recordings from 6 patients with symptomatic carotid artery stenosis. The exact time of any embolic signal was recorded. Six centers also measured the intensity increase of any embolic signals detected. Interobserver agreement was determined by a method based on the proportion of specific agreement. RESULTS: Seven centers reported between 39 and 55 signals, but one center reported 142 embolic signals. The probability of agreement between observers was .678, which rose to .791 when the data from the highest reporting center were excluded. Introducing a decibel threshold resulted in a significant increase in the probability of agreement; a decibel threshold of > 7 dB resulted in a probability of agreement of .902. Intensity measurements made by different centers were usually highly correlated, but this was not always the case, and 3 of the 15 correlations were not significant. The absolute values of the intensities measured varied between centers by as much as 40%. CONCLUSIONS: Although most centers report similar numbers of embolic signals, some use less specific criteria and report more events. The use of a decibel threshold improves reproducibility. However, intensity thresholds developed by one center cannot be directly transferred without validation to another center; differing methods of measurement are being used, and this results in different intensity values for the same embolic signals, even when the same equipment is used.

Carotid Stenosis↗

PubMed1997

Cerebral microemboli in patients with antiphospholipid syndrome.

CNS involvement is one of the hallmarks underlying poor prognosis in SLE and for therapeutic strategies it is difficult to assess which patients are at risk. As detectability of cerebral microembolic signals (MES) using long-term transcranial Doppler ultrasonography (TCD) proved to be predictive of past and future thromboembolic events in patients with carotid artery stenosis, we investigated whether MES might be similarly useful in patients with antiphospholipid syndrome (APS). Our study population consisted of 46 SLE patients and five with primary APS (pAPS). Twelve of the 46 patients with SLE, 10 of them with secondary APS (sAPS), and four of five patients with pAPS had a history of cerebrovascular ischaemia (CVI). MES in the middle cerebral artery were detected in 14 of 16 patients with and in one of 35 without CVI (P < 0.001). Antiphospholipid antibodies (aPL) were positive in 12 of 15 patients with and 18 of 36 without MES, and the rate of MES correlated to the titre of aPL. MES from APS patients resembled in their energy distribution those from patients with symptomatic carotid disease and were significantly different from those associated with artificial heart valves. In conclusion, cerebral MES are detectable in APS patients and correlate with a history of CVI. Whether this innovative method may provide individual risk assessment in APS patients has to be addressed in prospective studies.

Adolescent↗