Biomedical subjects

Clemens Sommer

Publications and source records attributed to Clemens Sommer.

At least 19 recordsLinked to original sources

PubMed2006

Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03.

PURPOSE: To evaluate toxicity and efficacy of the combination of lomustine, temozolomide (TMZ) and involved-field radiotherapy in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Thirty-one adult patients (median Karnofsky performance score 90; median age, 51 years) accrued in two centers received involved-field radiotherapy (60 Gy in 2-Gy fractions) and chemotherapy with lomustine 100 mg/m2 (day 1) and TMZ 100 mg/m2/d (days 2 to 6) with individual dose adjustments according to hematologic toxicity. RESULTS: A median of five courses (range, one to six courses) were delivered. WHO grade 4 hematotoxicity was observed in five patients (16%) and one of these patients died as a result of septicemia. Nonhematologic toxicity included one patient with WHO grade 4 drug-induced hepatitis (leading to discontinuation of lomustine and TMZ) and one patient with WHO grade 2 lung fibrosis (leading to discontinuation of lomustine). The progression-free survival (PFS) rate at 6 months was 61.3%. The median PFS was 9 months (95% CI, 5.3 to 11.7 months), the median overall survival time (MST) was 22.6 months (95% CI, 12.5 to not assessable), the 2-year survival rate was 44.7%. O6-methylguanine-DNA methyltransferase (MGMT) gene-promoter methylation in the tumor tissue was associated with longer PFS (P = .014, log-rank test) and MST (P = .037). CONCLUSION: The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.

Administration, Oral↗

PubMed2006

Short-term ischemia usually used for ischemic preconditioning causes loss of dendritic integrity after long-term survival in the gerbil hippocampus.

Ischemic preconditioning has been established as a powerful experimental neuroprotective strategy, both after global and focal cerebral ischemia. Little is known, however, about the structural and functional long-term outcome. Therefore, our present study was designed to check for potential subtle alterations in the hippocampus after long-term survival. Gerbils were subjected either to short-term ischemia of 2.5 min duration usually used for ischemic preconditioning (n=8) or to sham operation (n=6) and allowed to survive for 6 weeks. Hippocampi with neuronal densities comparable to those of sham-operated control animals were analyzed for dendritic marker proteins MAP2, MAP1B and synaptopodin, respectively. Although MAP2 immunoreactivity was widely unchanged in all hippocampal subfields, both MAP1B and synaptopodin protein expression was decreased to about 80% to 90% of sham controls. A significant reduction, however, was only seen for synaptopodin immunoreactivity in stratum oriens and pyramidale of hippocampal CA1 subfield. In conclusion, our data indicate a dissociation of neuronal survival and dendritic integrity 6 weeks after short-term ischemia usually used for ischemic preconditioning. Analysis of postischemic synaptopodin protein expression is the most sensitive method to detect subtle dendritic changes compared to the classical dendritic marker molecules MAP2 and MAP1B.

Animals↗

PubMed2006

Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra.

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by approximately 40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [(3)H]CP 55,940, [(3)H]MK-801, and [(3)H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [(3)H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [(3)H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.

Animals↗

PubMed2006

Long-term gene expression changes in the cortex following cortical ischemia revealed by transcriptional profiling.

Cerebral ischemia evokes changes in gene expression time-dependently after the ischemic event. Most studies on transcriptional changes following ischemia have centered on relatively early postischemic time points, and detected multiple genes relevant to neuronal cell death. However, functional outcome after ischemia depends critically on adaptations of the postischemic brain. Plasticity may derive from network-inherent changes, or from the formation of new nerve cells in the CNS. We have screened for gene expression changes up to 3 weeks following a limited photothrombotic cortical insult in the rat sensorimotor cortex by using the sensitive restriction-mediated differential display (RMDD) technique. A high number of genes were detected as induced at early or intermediate time points in the ipsi- and contralateral cortex (6 and 48 h). Unexpectedly, at the late time point examined (3 weeks), we still detected 40 genes that were changed in their expression. We further characterized the expression of two genes linked to neurogenesis (nestin and stathmin), and two genes likely involved in reconfiguring neuronal networks (semaphorin VIa and synaptotagmin IV). Conclusively, our data highlight the degree of long-term transcriptional changes in the cortex after ischemia, and provide insight into functional pathways of relevance for compensatory recovery mechanisms in neural networks.

Animals↗

PubMed2006

A new model of thromboembolic stroke in the posterior circulation of the rat.

The prognosis of vertebrobasilar occlusion is grave and therapeutic options are limited. The aim of the present study was to develop a new model of embolic hindbrain ischemia in the rat that closely resembles the clinical situation and that can be used to study pathophysiology and treatment options. After thoracotomy in 20 male Wistar rats, 15 animals received an injection of in vitro prepared autologous blood clots into the left vertebral artery. Five animals without clot injection served as controls. Neurological deficits were assessed in all animals 2 h after embolism. After 2 h, five animals were sacrificed to measure cerebral blood flow (CBF) by iodo-antipyridine autoradiography, and to calculate early cerebellar swelling by comparison of both hemispheres in brain slices. In these animals, autoradiography revealed ipsilesional brain swelling and significantly reduced blood flow values relative to the contralateral (unaffected) structures. Immunohistology showed the typical pattern of focal cerebral ischemia in the brain stem and/or cerebellum in 7 of 10 animals allowed to recover to 24 h. Hence, successful thromboembolism was achieved in 12 of 15 animals (80%). With this novel model, the pathophysiology and potential treatments of posterior circulation stroke can be investigated.

Animals↗

PubMed2006

Immunohistochemical analysis of KCNQ3 potassium channels in mouse brain.

KCNQ-type potassium channels generate the so-called M-current regulating excitability in many neurons. Mutations in KCNQ2/KCNQ3 channels can cause benign familial neonatal convulsions (BFNC). We describe the immunohistochemical staining of adult and developing mouse brain using an antibody directed against the N-terminus of KCNQ3 channels (KCNQ3N). A widespread KCNQ3N immunoreactivity predominantly of neuropil but also of somata was detected in different regions of the adult mouse brain, in particular in the hippocampus, cortex, thalamus and cerebellum. This staining pattern appeared gradually and became more intense during development. In the pyramidal cell layer of the hippocampus, the immunoreactivity changed from a more somatic to a neuropil staining during development. These changes during maturation might be related to the age-dependent phenotype of BFNC.

Animals↗

PubMed2006

Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain.

The syndrome of benign familial neonatal convulsions (BFNC) is characterized by seizures starting within the first days of life and disappearing within weeks to months. BFNC is caused by loss-of-function mutations in the potassium channels KCNQ2 and KCNQ3 which can well explain the resulting neuronal hyperexcitability. However, it is not understood why seizures predominantly occur in the neonatal period. A potential explanation might be a change in the expression pattern of these channels during development. We therefore performed an immunohistochemical analysis of mouse brain slices at different stages of postnatal development using an antibody recognizing the C-terminus of the KCNQ2 channel. A widespread immunohistochemical staining was observed, particularly in the hippocampus, caudoputamen, globus pallidus, cortex, thalamus, hypothalamus and midbrain. In the adult mouse brain, a predominantly axonal staining pattern was found, most observed in the caudoputamen, the alveus and the mossy fiber pathway of the hippocampus. The hippocampal staining pattern of adult mice was not observed before P8 and gradually developed between P11 and P21. Differences in the distribution of KCNQ2 channels within neurons between the neonatal period and adult stages might contribute to the increased seizure susceptibility in BFNC in humans.

Animals↗

PubMed2005

Short-term ischemia usually used for ischemic preconditioning down-regulates central cannabinoid receptors in the gerbil hippocampus.

Transient forebrain ischemia of 5-min duration causes delayed neuronal death (DND) of vulnerable CA1 neurons in the gerbil hippocampus, which can be prevented by "preconditioning" with a short ischemic stimulus of 2.5-min duration. While a key role of excitatory glutamate receptors for both phenomena has been widely accepted, little is known about the postischemic regulation of central cannabinoid (CB1) receptors. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of protein expression and/or ligand binding of these receptors compared to ischemia severe enough to induce DND. Gerbils were subjected to either a 5-min ischemic period resulting in DND of CA1 neurons, or a 2.5-min period of ischemia usually used for preconditioning. Postischemic hippocampal CB1 receptor protein expression was investigated immunohistochemically, while postischemic ligand binding of [3H]CP 55940 to CB1 receptors was analyzed by quantitative receptor autoradiography in both experimental groups after 24, 48, and 96 h (n=4-5 per time point), respectively, and compared to sham-treated gerbils (n=10). Short-term ischemia of 2.5-min duration caused a transient reduction of hippocampal CB1 receptor protein expression, while receptor binding density was permanently decreased. In contrast, 5-min ischemia did not alter protein expression or ligand binding up to 48 h. Based on these data, postischemic down-regulation of hippocampal CB1 receptors, specifically seen after short-term ischemia usually used for preconditioning, may participate in the mechanisms of endogenous postischemic neuroprotection.

Animals↗

PubMed2005

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis.

G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.

Animals↗

PubMed2004

A mouse model of cerebral oligemia: relation to brain histopathology, cerebral blood flow, and energy state.

An animal model involving stepwise occlusion of the common carotid arteries (sCCAO) in DBA/2 mice is presented in which the right and left carotid arteries were permanently ligated within a time interval of four weeks. Thereafter, cerebral functional and structural parameters were determined at acute (15 min) and subchronic (1 day; 3, 7, and 14 days) time points after sCCAO. Quantitative changes in regional cerebral blood flow (rCBF) as determined by the [14C]iodoantipyrine method, energy state (ATP, phosphocreatine, ADP, AMP, adenosine) as shown by HPLC, brain histopathology, and neuronal densities were measured in both hemispheres. Acute sCCAO was accompanied by a drastic reduction in cerebral energy-rich phosphate concentrations, ATP and phosphocreatine, and in rCBF of more than 50%. In contrast, cortical adenosine increased around five-fold. Subchronic sCCAO, however, was associated with normalization in brain energy metabolites and near-complete restoration of rCBF, except in the caudate nucleus (-40%). No marked signs of necrotic or apoptotic cell destruction were detected. Thus, during the subchronic period, compensatory mechanisms are induced to counteract the drastic changes seen after acute vessel occlusion. In conclusion, this sCCAO mouse model may be useful for long-lasting investigations of stepwise deterioration contributing to chronic cerebrovascular disorders.

Adenosine↗

PubMed2004

Juxtaposition of an epidural intraforaminal cavernous hemangioma and an intradural schwannoma.

STUDY DESIGN: A case of juxtaposition of a purely extradural cavernous hemangioma and an intradural schwannoma in the thoracic spine is reported. OBJECTIVES: The objectives of this study were to present a rare and before-surgery unexpected combination of spinal tumors, which may complicate surgical removal; and to discuss the radiologic features and the possible pathogenesis of this combination of tumors and its implications on surgical therapy. SUMMARY OF BACKGROUND DATA: Juxtaposition of different spinal tumors is exceedingly rare in patients without neurofibromatosis. To the authors' knowledge, no combination of a purely epidural spinal cavernous hemangioma with an intradural schwannoma has been previously reported. MATERIAL AND METHODS: A 47-year-old woman presented with progressive paraparesis. Magnetic resonance imaging revealed a partly cystic intradural mass at the T6-T7 level and a solid extradural intraforaminal component that demonstrated slightly different signal characteristics. An intra-/extradural schwannoma was assumed. RESULTS: Surgical exposure displayed a highly vascularized lobulated mass within the left neuroforamen at T6-T7. There was no continuity with the larger intradural, cystic, and mildly vascularized lesion. Histologic examination diagnosed an extradural cavernous hemangioma and an intradural schwannoma. CONCLUSIONS: The segmental juxtaposition of lesions should be considered in the differential diagnosis of spinal pathology.

Epidural Neoplasms↗

PubMed2004

Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI.

BACKGROUND: Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution. METHODS: Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O(2)/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment. RESULTS: HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia. CONCLUSIONS: As monitored by MRI HBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

Animals↗

PubMed2004

Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke.

Moderate hypothermia and application of brain-derived neurotrophic factor (BDNF) have separately been identified as neuroprotective strategies in experimental cerebral ischemia. To assess their separate and combined effects on striatal glutamate release in the hyperacute phase of stroke, we inserted microdialysis probes into the striatum of rats 2 h before permanent middle cerebral artery occlusion (MCAO). The animals (N = 28) were randomly assigned to one of four treatment strategies commencing 30 min after MCAO: (1) hypothermia at 33 degrees C (n = 7); (2) intravenous BDNF infusion [300 microg/(kg/h) for 2 h, n = 7]; (3) combination of hypothermia and BDNF (n = 7); (4) control group (saline, n = 7). Infarct size at 5 h after MCAO was assessed with the silver-staining method. Total infarct volume was significantly reduced in the hypothermia (202.7 +/- 3.5 mm(3), P = 0.0002) and BDNF group (206.5 +/- 6.9 mm(3), P = 0.0006) as compared to control group (254.4 +/- 9.3 mm(3)). In the combination group, infarct size was further reduced with overall significance in post hoc tests (157.3 +/- 6.2 mm(3), P < 0.0001). Postischemic glutamate concentrations in the control group constantly remained significantly higher than in all other treatment groups. At 255 and 270 min after MCAO, striatal glutamate in the combination group decreased significantly more than in animals treated with hypothermia or BDNF alone.Combining hypothermia and BDNF therapy in the acute stage of ischemia has a synergistic effect in attenuating striatal glutamate release and reducing early infarct size.

Animals↗

PubMed2004

May 2004: newborn with intracranial mass.

May 2004: We present the case of a male newborn (38th week of gestation) with a 3-week history of a sonographically detected parietal mass of 5-cm diameter. The entire mass was removed at surgery. Surprisingly, microscopy revealed an intracerebral hemorrhage and nests of glycophorin-A immunoreactive blasts and nucleated erythrocytes in the surrounding parenchyma. The final diagnosis was chronic intracerebral hemorrhage of unknown etiology with reactive changes of the surrounding brain tissue and perifocal extramedullary erythropoiesis. This case is unique because, to date, intracranial extramedullary erythropoiesis has only been described in chronic subdural hemorrhage.

Central Nervous System Diseases↗

PubMed2003

Differentiating primary central nervous system lymphoma from glioma in humans using localised proton magnetic resonance spectroscopy.

In order to characterise primary central nervous system lymphomas (PCNSL) and to evaluate if 1H spectroscopy improves the preoperative differential diagnosis of PCNSL and glioma, seven immunocompetent patients with PCNSL and 21 patients with glioma were examined using single voxel, short echo time magnetic resonance spectroscopy (MRS; 1.5 T, STEAM 1500/20). All PCNSL demonstrated massively elevated lipid resonances and markedly elevated choline. Similarly increased lipid resonances were only found in seven necrotic glioblastomas, PCNSL differing from all solid astrocytomas by massively elevated lipid resonances. Additionally, PCNSL had higher Cho/Cr ratios than all grades of astrocytoma. In conclusion, we found that massively elevated lipid resonances are a hallmark of PCNSL in immunocompetent patients. Together with a markedly elevated Cho/Cr ratio, MRS provides metabolic information which may improve the preoperative differentiation of PCNSL and glioma.

Central Nervous System Neoplasms↗

PubMed2003

Exogenous brain-derived neurotrophic factor prevents postischemic downregulation of [3H]muscimol binding to GABA(A) receptors in the cortical penumbra.

We have previously shown that exogenous application of brain-derived neurotrophic factor (BDNF) reduces infarct volume in the cortical ischemic penumbra after experimental focal ischemia [Stroke 31 (2000) 2212-2217]. Since BDNF is known to modulate the expression and function of various neurotransmitter receptors, we addressed the question whether BDNF may act via modification of postischemic ligand binding to excitatory NMDA and AMPA and/or inhibitory GABA(A) receptors, respectively. Transient focal cerebral ischemia was induced in male Wistar rats for 2 h using the suture occlusion technique. A period of 30 min after occlusion of the middle cerebral artery, BDNF (300 microg/kg per hour in vehicle; n=5) or vehicle alone (n=5) was continuously infused intravenously for 3 h. Using quantitative receptor autoradiography, postischemic ligand binding of [(3)H]MK-801, [(3)H]AMPA and [(3)H]muscimol was analyzed in the ischemic core, the ischemic cortical penumbra and corresponding regions of the contralateral hemisphere. Transient focal ischemia caused a significant reduction of [(3)H]muscimol binding to GABA(A) receptors within the ischemic cortical penumbra of placebo-treated rats. This was largely prevented by exogenous application of BDNF. [(3)H]MK-801 and [(3)H]AMPA binding values were also reduced in the cortical penumbra and the corresponding area of the contralateral hemisphere. Our data suggest that the neuroprotective effect of BDNF against ischemic damage in the cortical penumbra may be mediated in part by maintained activity of the inhibitory GABAergic system which likely counteracts glutamate induced excitotoxicity.

Animals↗

PubMed2003

Distinguishing of primary cerebral lymphoma from high-grade glioma with perfusion-weighted magnetic resonance imaging.

To assess the usefulness of perfusion-weighted echo-planar magnetic resonance imaging in the differential diagnosis of primary supratentorial lymphoma (PCNSL) and glioblastoma (GBM), 12 patients with a PCNSL and 12 with a GBM were examined using a 1.5 T magnetic resonance (MR) imager. With dynamic-susceptibility contrast MR imaging the intensity-time curves of each tumor were analyzed, and we determined the relative regional cerebral blood volume ratios (rrCBV [tumor/contralateral white matter (WM)]) to find out whether these parameters could be used to separate PCNSL from GBM. The maximum rrCBV ratio in the PCNSL was significantly lower than that of the GBM (P<0.0001). Comparing the intensity-time curves for the two tumor groups, the PCNSL showed a characteristic type of curve with a significant increase in signal intensity above the baseline due to massive leakage of contrast media into the interstitial space. PCNSL tend to have low maximum CBV ratios and typical intensity-time curves. These two parameters may be useful in distinguishing PCNSL from GBM.

Brain Neoplasms↗

PubMed2003

Severe forward flexion of the trunk in Parkinson's disease: focal myopathy of the paraspinal muscles mimicking camptocormia.

Pronounced forward flexion of the trunk, often termed camptocormia, is a typical symptom of patients with Parkinson's disease. In 4 parkinsonian patients with camptocormia, paraspinal muscles were studied by electromyography (EMG) and axial computerized tomography (CT) or magnetic resonance imaging (MRI) scans and muscle biopsy. EMG of the lumbar and thoracic paravertebral muscles showed abundant fibrillations, positive sharp waves, and bizarre high-frequency discharges. Spinal CT and MRI scans revealed variable degrees of atrophy and fatty replacement of the thoracolumbar paraspinal muscles on both sides. No other signs of neuromuscular disease were found. Biopsy of the paraspinal muscles revealed end-stage myopathy with autophagic vacuoles, chronic inflammatory myopathy, unspecific myopathic changes, or mitochondrial myopathy. In parkinsonian patients with pronounced forward flexion of the trunk, myopathy confined to the erector spinae muscles must be considered.

Aged↗