Matthias Kraemer

Neuronal Hyperexcitability and Reduction of GABAA-Receptor Expression in the Surround of Cerebral Photothrombosis:

Changes of neuronal excitability and γ-aminobutyric acid (GABAA)-receptor expression were studied in the surround of photothrombotic infarcts, which were produced in the sensorimotor cortex of the rat by using the rose bengal technique. In a first series of experiments, multiunit recordings were performed on anesthetized animals 2–3 mm lateral from the lesion. Mean discharge frequency was considerably higher in recordings from lesioned animals (>100 Hz in the first postlesional week) compared with control animals (mean, 15 Hz). These alterations were already present after 1 day but were most pronounced 3 to 7 days after lesion induction. Thereafter the hyperexcitability declined again, although it remained visible up to 4 months. In a second series of experiments, the GABAA-receptor expression was studied autoradiographically. This revealed a reduction of GABAA receptors in widespread brain areas ipsilateral to the lesion. The reduction was most pronounced in the first days after lesion induction and declined with longer intervals. It is concluded that cortical infarction due to photothrombosis leads to a long-lasting and widespread reduction of GABAA-receptor expression in the surround of the lesion, which is associated with an increased neuronal excitability. Such alterations may be responsible for epileptic seizures that can be observed in some patients after stroke and may contribute to neurologic deficits after stroke.

Lymphocytic Infiltration and Expression of Intercellular Adhesion Molecule-1 in Photochemically Induced Ischemia of the Rat Cortex:

The contribution of the immune system to the pathogenesis of ischemic lesions is still uncertain. We have analyzed leukocyte infiltration in photochemically induced focal ischemia of the rat parietal cortex by immunocytochemistry. Between 1 and 2 days after photothrombosis, CD5 + T cells adhered to subpial and cortical vessels and infiltrated the ischemic lesion prior to macrophages. By day 3 numerous T cells and some macrophages, whose number increased further between day 3 and day 7, had infiltrated the border zone around the lesion sparing the center. In addition, CD5–/CD8+ lymphocytes that probably represent natural killer cells were found. Intercellular adhesion molecule-1 (ICAM-1) was expressed on endothelial cells on days 1 and 2 and in the border zone on infiltrating leukocytes from day 3 to day 7. Starting on day 7, macrophages infiltrated the core of the lesion to remove debris. When the entire lesion was covered by macrophages at day 14, the number of T cells had decreased and ICAM-1 immunoreactivity was no longer found in or around the infarct. In conclusion, our study shows that ischemic lesions can lead to a local immune reaction in the CNS. Thus, blocking of lymphocyte-derived cytokines or cell adhesionmolecules may provide a new approach to confining the sequelae of stroke.

Electrophysiological changes in the surrounding brain tissue of photochemically induced cortical infarcts in the rat

Small infarctions in the parietal cortex of Wistar rats were produced photochemically using the Rose Bengal technique. The infarctions evoked reproducible cortical lesions of about 2 mm diameter. In the surrounding brain tissue changes in electrophysiological responses occurred. Whereas in control animals a paired-pulse inhibition could be evoked all over the neocortex, in infarcted animals the paired-pulse inhibition was significantly reduced or even absent within an area extending up to 5 mm lateral from the lesion center. The changes in paired-pulse inhibition were already present on the first day and persisted at least up to 60 days after infarction. These functional changes may contribute to neurological deficits occurring after cerebral infarcts.

Astroglial responses in photochemically induced focal ischemia of the rat cortex.

This study investigated astroglial responses after focal cerebral ischemia in the rat cortex induced by photothrombosis. Astrocyte activation was studied at various time points by immunocytochemistry for glial fibrillary acidic protein (GFAP) and vimentin (VIM). We found a dual astrocytic response to focal ischemia: In the border zone of the infarct, GFAP-positive astrocytes were present within 2 days and persisted for 10 weeks. These astrocytes additionally expressed VIM. Remote from the ischemic lesion, cortical astrocytes of the entire ipsilateral hemisphere transiently expressed GFAP, but not VIM, beginning on day 3 after photothrombosis. This response had disappeared on day 14. By recording DC potentials, five to seven spreading depressions (SD) could be detected on the cortical surface during the first 2 h after photothrombosis. Treatment with MK801, a non-competitive NMDA-receptor antagonist, completely abolished SD and remote ipsilateral astrocytic activation, while the reaction in the border zone of the infarct remained unchanged. Functionally, persistent astrocytosis around the infarct might be induced by leukocyte-derived cytokines, while NMDA-receptor-mediated SD might cause remote responses.

Expression of the Na+‐d‐Glucose Cotransporter SGLT1 in Neurons

Abstract: In brains of the rabbit, pig, and human, expression of the high‐affinity Na+‐d‐glucose cotransporter SGLT1 and of the protein RS1, which alters the activity of SGLT1, was demonstrated. In situ hybridization showed that SGLT1 and RS1 are transcribed in pyramidal cells of brain cortex and hippocampus and in Purkinje cells of cerebellum. In neurons of pig brain SGLT1 protein was demonstrated by western blotting with synaptosomal membranes and by immunohistochemistry, which showed SGLT1 in pyramidal and Purkinje cells. To test whether SGLT1 in neurons may be activated during increased d‐glucose consumption, an epileptic seizure was induced in rat brain, and the uptake of specific nonmetabolized substrates of SGLT1 {[14C]methyl‐α‐d‐glucopyranoside ([14C]AMG)} and of Na+‐independent transporters {2‐deoxy‐d‐[14C]glucose([14C]2‐DG)} was analyzed by autoradiography. During the seizure the uptake of AMG and 2‐DG was increased in the focus. Within two hours after the seizure 2‐DG uptake in the focus returned to normal. In contrast, the AMG uptake in the focus area was still increased 1 day later. The data show that the high‐affinity Na+‐d‐glucose cotransporter SGLT1 is expressed in neurons and can be up‐regulated.

Delayed Shrinkage of the Brain After Ischemic Stroke: Preliminary Observations With Voxel-Guided Morphometry

Background and Purpose. The most important effect of cerebral ischemia is brain infarction. In this magnetic resonance imaging (MRI) study, the authors aimed at assessing postischemic brain atrophy.Methods. Ten patients suffering from their first acute cerebral ischemia in the territory of the middle cerebral artery were studied retrospectively. Three‐dimensional MRI volume scans were recorded in the acute and chronic stage after infarction and analyzed voxel by voxel intraindividually with the newly developed voxel‐guided morphometry.Results. Shrinkage of brain tissue was detected in all patients, not only in the perilesional cortical structures but also in contralateral homolog cortex areas and subcortically in the striatum and thalamus. This secondary shrinkage was not related to the size of the infarcts or to the clinical outcome of patients.Conclusions. Our study suggests that delayed brain atrophy after acute ischemic stroke involved areas anatomically connected with the ischemic brain lesion but nevertheless was accompanied by a simultaneous improvement of the neurological deficit.

Perforating appendicitis: is it a separate disease?

Objective: To find out whether perforated and unperforated appendicitis are separate diseases and can be distinguished clinically.Design: Prospective multicentre study.Setting: 11 departments of surgery in Germany and Austria.Subjects: 519 patients over 6 years old who had histologically confirmed acute appendicitis between October 1994 and March 1996.Main outcome measures: Differences in history, clinical findings, lab results, clinical course and outcome.Results: 92 of the 519 patients (18%) had perforated appendicitis. The following variables were shown by univariate analysis to be significantly more common in the group with perforated appendicitis: rigiditiy, reduced abdominal wall movement, abdominal distension, reduced bowel sounds (all p < 0.001), pale skin (p < 0.005), generalised abdominal tenderness, severe abdominal tenderness (both p < 0.01), WCC ≥ 109/L (p < 0.05). By multivariate analysis the following variables were significantly more common in the group with perforated appendicitis: age ov...

Voxel-guided morphometry ("VGM") and application to stroke

Monitoring of cerebral diseases associated with a change of morphology (e.g., stroke) requires unprecedented accuracy for quantification of its morphological progression for each voxel. The purpose of this paper is to provide a technique [voxel-guided morphometry (VGM)] to quantify macroscopic anatomical differences. VGM consists of four steps: 1) coarse linear alignment by the extended principle axes theory (ePAT) generalized to affine movements; 2) a cross-correlation-based technique using a matrix-norm for fine linear alignment; 3) the applied high-dimensional multiresolution full multigrid method determines the nonlinear deformations, thereby achieving a complete exploitation of information and effective processing. The method measures a gray-value-guided movement of each voxel from source to target. The resulting high-dimensional deformation field is further processed by 4) determination of volume alterations for each voxel. Furthermore, the effect of linear registration errors on final morphometric measurements is discussed and the conditions for a bijective correspondence of voxels assuming small alterations are derived. To illustrate the technique the changing morphology of different subjects suffering from cerebral infarction is presented by using commonly available T/sub 1/-weighted magnetic resonance volumes. VGM visualizes that ischemic as well as remote regions are affected by stroke.

Metabolic and electrophysiological alterations in an animal model of neocortical neuronal migration disorder.

Cortical migration disorders are a major cause for intractable epilepsy syndromes. High resolution MRI and PET are increasingly capable to identify cortical dysgenesis. In this study we used the rat freeze lesion model to investigate cortical morphological and functional changes in adult rats after induction of a cortical freeze lesion at postnatal day (p) 0. Autoradiographic measurements of basic cortical [14C]deoxyglucose metabolism showed a significant reduction up to 1 mm lateral to the lesion but no remote changes. Electrophysiological in vitro recordings revealed a significant reduction in the amplitude of stimulus-evoked field potential responses recorded lateral to the lesion as compared to medial recording sites. Our data provide further evidence that spatially restricted developmental alterations of cortical morphology cause functional changes in surrounding and histologically normal areas that need to be considered for a better understanding of the resulting pathophysiology.

Hochdimensionale Transformationen zur Bestimmung morphologischer Veränderungen bei Hirninfarkt

Quantifizierung morphologischer Veranderungen, die durch Hirninfarkte verursacht werden, erfordern neue Bildverarbeitungs-Techniken, um die z.T. auch sehr weit vom initialen Infarkt lokalisierten sekundaren Volumenanderungen detektieren zu konnen. Es wird ein System von linearen und nicht-linearen Anpassungs-Verfahren vorgestellt, mit dem eine nicht-invasive, kontinuierliche in-vivo Bestimmung von Raumunterschieden ermoglicht wird. Das Verfahren verwendet — ohne Interpolation — die Grauwert-Information samtlicher Volumenelemente, womit die grostmogliche Ausnutzung an Information zur Bestimmung hochdimensionaler Transformationen erreicht wird. Die Ergebnisse zeigen vom initial kleinen Infarktfokus ausgehende, weit ausgedehnte, betroffene Gebiete.