Biomedical subjects
Publications and source records attributed to E B Ringelstein.
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We report an investigation on the influence of high frequency electromagnetic fields (EMF) on the permeability of an in vitro model of the blood-brain barrier (BBB). Our model was a co-culture consisting of rat astrocytes and porcine brain capillary endothelial cells (BCEC). Samples were characterized morphologically by scanning electron microscopy and immunocytochemistry. The BBB phenotype of the BCEC was shown by the presence of zona occludens protein (ZO-1) as a marker for tight junctions and the close contact of the cells together with the absence of intercellular clefts. Permeability measurements using (14)C-sucrose indicated a physiological tightness which correlated with the morphological findings and verified the usefulness of our in vitro model. Samples were exposed to EMF conforming to the GSM1800-standard used in mobile telephones (1.8 GHz). The permeability of the samples was monitored over four days and compared with results of samples that were cultured identically but not exposed to EMF. Exposure to EMF increased permeability for (14)C-sucrose significantly compared to unexposed samples. The underlying pathophysiological mechanism remains to be investigated.
BACKGROUND AND OBJECTIVE: Advances in understanding the pathophysiology and treatment of stroke have led to changed requirements, including the prehospital phase, for the care of patients with acute stroke. Rapid transport to a regional stroke centre is nowadays considered to be the standard for optimal quality of care. A retrospective cross-sectional analysis was undertaken in 1996 in the region of the town of Münster to test the quality of medical care provided by physicians on emergency call. PATIENTS AND METHODS: 250 of 3001 protocols (8.3%) filled in by emergency call physicians were selected in which the initial diagnosis of transitory ischaemic attack, stroke or cerebral haemorrhage had been made. Quality of patient care was assessed according to the following criteria; (1) complete medical treatment (blood sugar, blood pressure, cardiac rhythm and arterial oxygen saturation, including relevant treatment of any abnormality) (2) action time (arrival of emergency doctor within 12 min and arrival at hospital within 50 min); (3) type of the admission hospital (stroke centre defined as a hospital experienced in the treatment of stroke, with neurological and medical departments, as well as 24-hour cover for computed cranial tomography). A summated indicator of "optimal care" was used to determine whether the three stated criteria were met. RESULTS: Mean age of the stroke patients was 72.3 years. While the above mentioned quality criteria for the action time were met in 93.5% of patients, only 56.0% were admitted to a stroke centre, and this was significantly more often the final destination for patients under the age of 65 years than for older ones (p = 0.049). The quality indicator "complete medical treatment" was met for 27.2% of the transported patients. Measured according to present-day criteria, only 18.6% of patients received such optimal treatment. CONCLUSION: This analysis indicates that modern prehospital treatment of stroke patients does not reach adequate standards. In particular, it is not comprehensive. While the "action time" is usually adequate, there are deficiencies regarding the quality of medical care and the choice of the admission hospital. Further education for emergency physicians with respect to the management of stroke syndrome should be an integral part of any regional quality programme. The number of hospitals with adequate competence in the acute management of stroke cases is still insufficient.
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Hemispheric asymmetry is known for higher brain functions like language and attention. We tested whether such an asymmetry also exists in the representation of elementary sensory functions. Magnetic source imaging was used to compare the cortical somatosensory hand representation in seven right- and five left-handed individuals. In all right-handers the representation of the dominant hand was larger than the contralateral one in the corresponding hemispheres. In contrast, only two out of five left-handers revealed a larger representation of the dominant left hand compared to the right one. In agreement with previous findings on the lateralization of language and attention, there is a strong correlation between handedness and the extent of the cortical hand representation in right-, but not in left-handers. We conclude that a profound functional hemispheric asymmetry also exists in primary sensory cortices.
We investigated the activation of the brain during anticipation of tactile stimuli by continuous cerebral blood flow velocity (CBFV) monitoring with bilateral transcranial Doppler sonography. A forced choice paradigm was performed where a first group of subjects (n=16) was expecting suprathreshold and a second group (n=19) was anticipating threshold tactile stimuli to the index finger after a cueing tone. During the anticipation of suprathreshold stimuli the CBFV always exhibited a significantly stronger increase in the right hemisphere than in the left, even when stimuli were anticipated at the right index finger. Conversely when stimuli at perception threshold were expected, the respective contralateral hemisphere showed a significantly stronger perfusion increase. These data show that preparatory activation of the brain during stimulus anticipation is dependant on the expected stimulus intensity.
Oncostatin M (OSM) is a cytokine of the IL-6 family that modulates the growth of various cell types, at least in vitro. We have recently described that OSM inhibits growth and changes cell morphology of human glioma cell lines. Although leukemia inhibitory factor (LIF) receptor components are also expressed by these cells, the response to LIF was significantly weaker compared to OSM. We have therefore analyzed the signal transduction pathways induced by these cytokines. While OSM induces a number of strong tyrosine phosphorylations, including Janus tyrosine kinases (Jak) and the signal transducer and activator of transcription (Stat) proteins, LIF induces only minor tyrosine phosphorylation of Tyk2 and Stat3. Specific activation of the tyrosine phosphatase SHP-2 as well as the mitogen-activated kinase 2 (MAPK2) was found in glioma cells upon OSM treatment. MAPK2 turns out to be a crucial mediator of the OSM effect in glioma cells since inhibition of MAPK activity by the Mek1 inhibitor PD98059 blocks the OSM-induced inhibition of DNA synthesis by about 70%.
3-[(123)I]Iodo-l-alpha-methyltyrosine ((123)I-IMT) is used for the diagnosis and monitoring of brain tumours by means of single-photon emission tomography (SPET). To date, little has been known about the system for the transport of (123)I-IMT into brain tumour cells. It is assumed that (123)I-IMT is transported by a specific carrier for large, neutral amino acids (L-system). In this study, rat C6 glioma cells were used to characterize the uptake system of (123)I-IMT and to investigate its precise kinetics. The time course of (123)I-IMT uptake into the cells was examined for a range of 1-60 min. (123)I-IMT uptake rates with varying concentrations of (123)I-IMT (2. 5-50 microM) in the medium were quantified to assess the kinetic parameters of (123)I-IMT transport. Furthermore, competition of (123)I-IMT with other amino acids was investigated to identify the distinct transport systems involved in (123)I-IMT uptake. (123)I-IMT uptake into C6 glioma cells was linear for approximately 10 min and reached a steady-state level within 30 min. The analysis of the rate of uptake of (123)I-IMT at different concentrations was concordant with the predominance of a single uptake system. The apparent Michaelis constant (K(m)) of (123)I-IMT was 26.2+/-1.9 microM, and the maximum transport velocity (V(max)) was 35.4+/-1.7 nmol/mg protein per 10 min. 77%+/-10% of (123)I-IMT transport was sodium independent and 23%+/-3% was sodium dependent. Competitive inhibition of (123)I-IMT uptake by 2-aminobicyclo[2.2. 1]heptane-2-carboxylic acid, alpha-(methylamino)isobutyric acid and naturally occurring amino acids revealed a major (123)I-IMT transport via the sodium-independent system L (72%) and a minor uptake via the sodium-dependent system B(0,+) (17%). Our results show that (123)I-IMT transport into C6 glioma cells is principally mediated by the L-system and to a minor extent by the B(0,+)-system. The kinetic parameters of (123)I-IMT uptake are in the range of those of naturally occurring amino acids.
The mammalian brain is capable of a substantial functional reorganization, manifesting on a cortical somatotopical and on a behavioral level. Possible mechanisms are reviewed based on the work by others and ourselves on somatosensory reorganization in humans. The somatosensory system is characterized by divergent projections from the periphery to the cerebral cortex. Changes in synaptic weights allow for reorganization of sensory processing: On one side, limb amputation will result in a representational "invasion" of the differentiated cortex from neighboring regions with concomitant perceptual changes. On the other side, sensorimotor training can increase the representational cortical zone of a limb. Plastic changes can be temporary or persistent. Modulating factors like pain and certain drugs seem to induce a permissive state in the cortex resulting in enhanced reorganization. Thus, specific physical training combined with pharmacoceutical modulation holds promise to improve functional recovery after brain lesions.
OBJECTIVE: Embolus detection by transcranial Doppler ultrasound is very time consuming and semi-automated detection is mandatory. The device studied, a TC4040, Nicolet-EME, uses the four-gate technique and allows for audiovisual off-line verification of the recorded events. METHODS: Twenty controls, 10 patients with mechanical prosthetic heart valves and 12 patients with occlusive carotid artery disease were investigated by transcranial colour-coded duplex sonography and, subsequently, underwent a 1-h unilateral embolus detection from the middle cerebral artery using four-gate TCD. We investigated the Doppler spectrum background, microembolic signals (MES) and artefacts produced. A detection threshold of 5 dB or more was defined taking into account natural fluctuations of the Doppler spectrum. RESULTS: Sensitivity of the software was 91.9% and observer-software agreement on MES was 7.8% in the valve patients, and 77.7% and 7.5% in the carotid artery disease patients, respectively. Weaker MES were more likely not to be detected in all four channels. The artefact signal rejection rate was 62%. MES produced either positive or zero time delays in adjacent channels. Artefact signals produced either no delay, or a positive or a negative time delay. Duration of MES ranged from 1-88 ms. CONCLUSIONS: Besides refined recognition of MES using the time delay, four gates give faint MES no less than four opportunities to overcome the detection threshold. With this device's satisfying sensitivity, regions of interest in a 1-h recording can audiovisually be evaluated off-line in a few minutes by an investigator.
Ciliary neurotrophic factor (CNTF) promotes the survival of various neuronal cell populations. It is produced by astrocytes and influences the development and differentiation of glial cells. CNTF and related neuropoietic cytokines affect growth and differentiation of various neoplasms. Moreover, they induce the reactive transformation of astrocytes (gliosis) and influence growth and differentiation of neuroectodermal tumor cell lines in vitro. However, their role in gliomas is largely unknown. We studied the expression of CNTF and its receptor subunits in human astrocytomas and glioblastomas. In more than 95% of the tumors, CNTF transcripts were found by RNAase protection assay; in more than 80% of the cases, tumor cells were CNTF immunoreactive. CNTF receptor alpha (CNTFR alpha), the specific component of the tripartite CNTF receptor system, was detectable by Northern blot analysis in 80% of the cases. In situ hybridization revealed CNTFR alpha mRNA in the cytoplasm of neoplastic cells. Transcripts of the remaining two components of the CNTF receptor system, gp130 and LIFR beta, were found by Northern blotting in 83% and 70% of the tumors, respectively. Simultaneous expression of CNTF and all its receptor components was detected in approximately half of the tumors. These results indicate that CNTF and its receptor components are expressed by human glioma cells. The simultaneous expression of ligands and receptor subunits suggests that CNTF might act on human glioma cells via an auto- or paracrine mechanism.
Atrial fibrillation (AF) is a well-recognized independent risk factor of ischemic stroke. The aim of this study was to investigate the amount of microembolic signals (MES) in 15 patients with 'lone' AF representing the subgroup of AF patients with the lowest lifelong risk of stroke. All patients had been put on effective anticoagulation due to a scheduled electric cardioversion. Additional cardiac and arterial sources of embolism were excluded by echocardiography and extracranial color-coded duplex sonography of the carotid arteries. Unilateral one-hour transcranial Doppler monitorings revealed complete absence of MES in this series. This observation fits the concept that the amount of microembolisation is related to the risk of manifest thromboembolism. Further studies on this patient group treated with less intensive antihemostatic therapy should be undertaken to define more clearly the disease-specific microembolic activity.
Recent studies suggest that high plasma levels of tissue-type plasminogen activator (tPA) and its inhibitor (plasminogen activator inhibitor-1, PAI-1) are markers of an increased risk of atherothrombotic ischemic events such as stroke and myocardial infarction. In this prospective study, we measured tPA antigen, PAI-1 antigen and activity, as well as tPA/PAI-1 complex in patients with acute stroke. Stroke subtypes were classified according to the TOAST criteria. From 132 consecutively screened patients, 89 (100%) were enrolled in this study, including 42 patients (47%) with large artery atherosclerosis (LAA), 32 (36%) with small vessel occlusion (SVO), and 15 (17%) with cardioembolism (CE). Nineteen age-matched neurologic patients without manifestations of cerebrovascular disease served as control subjects (CS). Patients with acute stroke had significantly higher plasma levels of tPA antigen (p < 0.001), PAI-1 antigen (p < 0.05) and PAI activity (p < 0.05) than patients in the control group. t-PA antigen, PAI activity and tPA/PAI-1 complex levels were similar regardless of stroke etiology. Only PAI-1 antigen was lower in patients with cardioembolic stroke than in stroke patients with LAA (p < 0.05). Plasma tPA antigen, PAI-1 antigen, and PAI activity are significantly increased in patients with acute ischemic stroke. Except for PAI-1 antigen, this increase appears not to be related to the underlying stroke etiology.
The perception of music has been investigated by several neurophysiological and neuroimaging methods. Results from these studies suggest a right hemisphere dominance for non-musicians and a possible left hemisphere dominance for musicians. However, inconsistent results have been obtained, and not all variables have been controlled by the different methods. We performed a study with functional transcranial Doppler sonography (fTCD) of the middle cerebral artery to evaluate changes in cerebral blood flow velocity (CBFV) during different periods of music perception. Twenty-four healthy right-handed subjects were enrolled and examined during rest and during listening to periods of music with predominant language, rhythm and harmony content. The gender, musical experience and mode of listening of the subjects were chosen as independent factors; the type of music was included as the variable in repeated measurements. We observed a significant increase of CBFV in the right hemisphere in non-musicians during harmony perception but not during rhythm perception; this effect was more pronounced in females. Language perception was lateralized to the left hemisphere in all subject groups. Musicians showed increased CBFV values in the left hemisphere which were independent of the type of stimulus, and background listeners showed increased CBFV values during harmony perception in the right hemisphere which were independent of their musical experience. The time taken to reach the peak of CBFV was significantly longer in non-musicians when compared with musicians during rhythm and harmony perception. Pulse rates were significantly decreased in non-musicians during harmony perception, probably due to a specific relaxation effect in this subgroup. The resistance index did not show any significant differences, suggesting only regional changes of small resistance vessels but not of large arteries. Our fTCD study confirms previous findings of right hemisphere lateralization for harmony perception in non-musicians. In addition, we showed that this effect is more pronounced in female subjects and in background listeners and that the lateralization is delayed in non-musicians compared with musicians for the perception of rhythm and harmony stimuli. Our data suggest that musicians and non-musicians have different strategies to lateralize musical stimuli, with a delayed but marked right hemisphere lateralization during harmony perception in non-musicians and an attentive mode of listening contributing to a left hemisphere lateralization in musicians.
Echocontrast agents (ECA) are known to improve transcranial color-coded duplex (TCCD) imaging, but its diagnostic benefit in the routine clinical setting has not clearly been defined. The authors investigated the diagnostic benefit of ECA application in 54 patients with insufficient transtemporal bone window, consecutively referred to their ultrasound laboratory. According to the precontrast imaging quality, patients were assigned to three categories: A, no intracranial structures or vessel segments visible on B-mode imaging and TCCD (n = 5); and intracranial structures visible on B-mode imaging and vessel segments less than 5 mm in length (B, n = 21), or larger than 5 mm in length (C, n = 28) visible on TCCD. The effect of the echocontrast enhancement was assessed with respect to signal enhancement, imaging quality, and diagnostic confidence. In 49 out of 54 patients (91%), a significant improvement of the imaging quality was noted, enabling 43 (80%) neurovascular diagnoses of sufficient diagnostic confidence. The diagnostic ECA effect was strongly dependent on the precontrast imaging quality: upon echoenhancement, a satisfactory image quality was obtained in none of the patients of category A, as opposed to 16 (76%) and 27 (96%) patients of categories B and C, respectively. In summary, in 80% of our consecutive patient series with insufficient transtemporal bone window, application of ECA allowed for a conclusive TCCD study. Properties of the transtemporal precontrast scans are strongly predictive of the diagnostic benefit and should be taken into the decisive consideration.
Familial burning feet syndrome inherited as an autosomal dominant trait has been described in only one family. Due to an associated sensory neuropathy the autosomal dominant burning feet syndrome was suggested to represent a variant form of hereditary sensory and autonomic neuropathy type I (HSAN I). Clinical, histopathological, and molecular genetic studies were performed in a large German kindred with autosomal dominant burning feet syndrome. The autosomal dominant burning feet syndrome was associated with a neuropathy predominantly affecting small unmyelinated nerve fibres. Linkage to the HSAN I locus on chromosome 9q22 and to the Charcot-Marie-Tooth disease type 2B (CMT 2B) locus on chromosome 3q13-q22 was excluded. The autosomal dominant burning feet syndrome is neither allelic to HSAN I nor to CMT 2B and thus represents a distinct genetic entity.
Besides the established factors "presence of symptoms" and "degree of stenosis", plaque echolucency is considered to be associated with increased risk of stroke in patients with carotid artery disease. An evaluation was carried out as to whether the prevalence and number of microembolic signals (MES) detected by transcranial Doppler ultrasound were higher in patients with echolucent carotid plaques. One hundred and five patients with carotid artery stenosis from 20%-99% or occlusion underwent clinical investigations, duplex ultrasound of the carotid arteries, and a 1 hour recording from the middle cerebral artery downstream to the carotid artery pathology using the four gate technique. The presence of MES was more frequent and the number greater in symptomatic patients (21 out of 64 patients (33%); mean number of MES in all 64 patients 3.1) than in asymptomatic patients (four out of 41 patients (10%); mean number of MES in all 41 patients 0.3) (p=0.007, and p=0.006, respectively). Echogenicity of the lesions did not affect either number or presence of MES. Positivity for MES and the number of MES increased with increasing degree of stenosis (both p=0.002). Four out of 12 patients with carotid artery occlusion showed MES. No MES could be detected in carotid artery stenosis below 80%. There was a decline in positivity of MES and of the number of MES with the time after the ischaemic event. After 80 days or more after the index event, only one patient showed MES. In conclusion, increasing degree of stenosis and presence of symptoms similarly affect macroembolic and microembolic risk. Thus MES may be a surrogate parameter for risk of stroke. The presence of MES in a few asymptomatic patients suggests that clinically silent circulating microemboli may give additional information on the pending embolic potential of carotid artery stenoses. Echolucency of the plaque was not related to an increased number of MES.