Showing papers by "Ulrich Bogdahn published in 2006"

Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients

Abstract: Although chronic back pain is one of the most frequent reasons for permanent impairment in people under 65, the neurobiological mechanisms of chronification remain vague. Evidence suggests that cortical reorganisation, so-called functional plasticity, may play a role in chronic back pain patients. In the search for the structural counterpart of such functional changes in the CNS, we examined 18 patients suffering from chronic back pain with voxel-based morphometry and compared them to 18 sex and age matched healthy controls. We found a significant decrease of gray matter in the brainstem and the somatosensory cortex. Correlation analysis of pain unpleasantness and the intensity of pain on the day of scanning revealed a strong negative correlation (i.e. a decrease in gray matter with increasing unpleasantness/increasing intensity of pain) in these areas. Additionally, we found a significant increase in gray matter bilaterally in the basal ganglia and the left thalamus. These data support the hypothesis that ongoing nociception is associated with cortical and subcortical reorganisation on a structural level, which may play an important role in the process of the chronification of pain.

Effects of the implementation of a telemedical stroke network: the Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria, Germany

Abstract: Summary Background Telemedical networks are a new approach to improve stroke care in community settings. We aimed to assess the effects of a stroke network with telemedical support in Germany on quality of care, according to acute processes and long-term outcome. Methods Five community hospitals without pre-existing specialised stroke care were included in a network with telemedical support by two academic hospitals. In a non-randomised, open intervention study, five community hospitals without specialised stroke care served as the control group, matched individually to the network hospitals by predefined characteristics. Stroke patients admitted consecutively to one of the participating hospitals between July 7, 2003, and March 31, 2005, were included in the study. Patients in network and control hospitals were assessed in the same manner and were followed up for vital status, living situation, and disability at 3 months. Poor outcome was defined by death, institutional care, or disability (Barthel index 3). Predefined indicators for quality of acute stroke care were achieved. Findings A total of 5696 patients with a sudden, non-convulsive loss of neurological function who were diagnosed with having suspected stroke were admitted to the ten hospitals participating in the study. After exclusion, 3122 were included in the final analysis, of whom 1971 (63%) were treated in the network hospitals. All indicators related to quality of acute stroke care were more commonly met in the network than in the control hospitals. After 3 months, 44% of patients treated in network hospitals versus 54% treated in control hospitals had a poor outcome (p Interpretation Telemedical networks with academic stroke centres offer new and innovative approaches to improve acute stroke care at community level for stroke patients living in non-urban areas.

Transforming growth factor-beta1 is a negative modulator of adult neurogenesis.

Abstract: Transforming growth factor (TGF)-beta1 has multiple functions in the adult central nervous system (CNS). It modulates inflammatory responses in the CNS and controls proliferation of microglia and astrocytes. In the diseased brain, TGF-beta1 expression is upregulated and, depending on the cellular context, its activity can be beneficial or detrimental regarding regeneration. We focus on the role of TGF-beta1 in adult neural stem cell biology and neurogenesis. In adult neural stem and progenitor cell cultures and after intracerebroventricular infusion, TGF-beta1 induced a long-lasting inhibition of neural stem and progenitor cell proliferation and a reduction in neurogenesis. In vitro, although TGF-beta1 specifically arrested neural stem and progenitor cells in the G0/1 phase of the cell cycle, it did not affect the self-renewal capacity and the differentiation fate of these cells. Also, in vivo, TGF-beta1 did not influence the differentiation fate of newly generated cells as shown by bromo-deoxyuridine incorporation experiments. Based on these data, we suggest that TGF-beta1 is an important signaling molecule involved in the control of neural stem and progenitor cell proliferation in the CNS. This might have potential implications for neurogenesis in a variety of TGF-beta1-associated CNS diseases and pathologic conditions.

Mesenchymal Stem Cells Instruct Oligodendrogenic Fate Decision on Adult Neural Stem Cells

Abstract: Adult stem cells reside in different tissues and organs of the adult organism. Among these cells are MSCs that are located in the adult bone marrow and NSCs that exist in the adult central nervous system (CNS). In transplantation experiments, MSCs demonstrated neuroprotective and neuroregenerative effects that were associated with functional improvements. The underlying mechanisms are largely unidentified. Here, we reveal that the interactions between adult MSCs and NSCs, mediated by soluble factors, induce oligodendrogenic fate decision in NSCs at the expense of astrogenesis. This was demonstrated (a) by an increase in the percentage of cells expressing the oligodendrocyte markers GalC and myelin basic protein, (b) by a reduction in the percentage of glial fibrillary acidic protein (GFAP)-expressing cells, and (c) by the expression pattern of cell fate determinants specific for oligodendrogenic differentiation. Thus, it involved enhanced expression of the oligodendrogenic transcription factors Olig1, Olig2, and Nkx2.2 and diminished expression of Id2, an inhibitor of oligodendrogenic differentiation. Results of (a) 5-bromo-2'-deoxyuridine pulse-labeling of cells, (b) cell fate analysis, and (c) cell death/survival analysis suggested an inductive mechanism and excluded a selection process. A candidate factor screen excluded a number of growth factors, cytokines, and neurotrophins that have previously been shown to influence neurogenesis and neural differentiation from the oligodendrogenic activity derived from the MSCs. This work might have major implications for the development of future transplantation strategies for the treatment of degenerative diseases in the CNS.

Targeted transgene expression in neuronal precursors: watching young neurons in the old brain

Abstract: Progress in the field of neurogenesis is limited by the lack of animal models allowing direct detection and analysis of living cells participating in neurogenesis. We engineered a transgenic mouse model that expresses the fluorescent reporter proteins enhanced green fluorescent protein or Discoma sp. reef coral red fluorescent protein under the control of the doublecortin (DCX) promoter, a gene specifically and transiently active in neuronal precursors and young neurons. The expression of the reporter proteins correlated with expression of the endogenous DCX protein, and with developmental and adult neurogenesis. Neurogenesis was unaffected by the presence of the fluorescent proteins. The transgenic mice allowed direct identification of the very few newly generated neurons present in the aged brain. We performed electrophysiological analysis and established that newly generated hippocampal granule cells in aged and young mice shared identical physiological properties. Hence, although the rate of neurogenesis tapers with ageing, a population of highly excitable young neurons indistinguishable to those found in younger animals is continuously generated. Therefore, maintenance of the fundamental properties of neuronal precursors even at advanced age suggests that stimulation of neurogenesis may constitute a valid strategy to counteract age-related neuronal loss and cognitive declines.

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.

Abstract: Background: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome. Methods: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome. Results: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities). Conclusions: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

Autologous adult rodent neural progenitor cell transplantation represents a feasible strategy to promote structural repair in the chronically injured spinal cord

Abstract: Adult neural progenitor cells (NPCs) represent an attractive source for cell-based regenerative strategies in CNS disease. In animal models of spinal cord injury, syngenic adult NPCs, which were isolated from pooled post-mortem CNS tissue and co-transplanted together with fibroblasts, have been shown to promote substantial structural repair. The autologous transplantation of adult NPCs represents a major advantage compared with other sources of neural stem/progenitor cells. However, the feasibility of autologous NPC generation from a single biopsy in a relevant preclinical CNS disease model has yet to be demonstrated. To investigate this matter, adult Wistar rats underwent a cervical spinal cord lesion, which was followed by a minimal subventricular zone aspiration biopsy 2 days later. NPCs were isolated and propagated separately for each animal for the following 8 weeks. Thereafter, they were co-transplanted with simultaneously harvested skin fibroblasts in an autologous fashion into the cervical spinal ...

In Vivo High-Resolution MR Imaging of Neuropathologic Changes in the Injured Rat Spinal Cord

Abstract: BACKGROUND AND PURPOSE: MR imaging is the most comprehensive noninvasive means to assess structural changes in injured central nervous system (CNS) tissue in humans over time. The few published in vivo MR imaging studies of spinal cord injury in rodent models by using field strengths ≤7T suffer from low spatial resolution, flow, and motion artifacts. The aim of this study was to assess the capacity of a 17.6T imaging system to detect pathologic changes occurring in a rat spinal cord contusion injury model ex vivo and in vivo. METHODS: Seven adult female Fischer 344 rats received contusion injuries at thoracic level T10, which caused severe and reproducible lesions of the injured spinal cord parenchyma. Two to 58 days postinjury, high-resolution MR imaging was performed ex vivo (2) or in vivo in anesthetized rats (5 spinal cord injured + one intact control animal) by using 2D multisection spin- and gradient-echo imaging sequences, respectively, combined with electrocardiogram triggering and respiratory gating. RESULTS: The acquired images provided excellent resolution and gray/white matter differentiation without significant artifacts. Signal intensity changes, which were detected with ex vivo and in vivo MR imaging following spinal cord injury, could be correlated with histologically defined structural changes such as edema, fibroglial scar, and hemorrhage. CONCLUSIONS: These results demonstrate that MR imaging at 17.6T allows high-resolution structural analysis of spinal cord pathology after injury.

Calcified neurocysticercosis lesions trigger symptomatic inflammation during antiparasitic therapy.

Abstract: We report a patient with neurocysticercosis who developed numerous cerebral edematous lesions while undergoing cysticidal therapy. These lesions outnumbered viable cystic lesions seen before therapy. Most new lesions were subsequently found to be associated with former calcifications not seen on initial MR imaging. Calcified neurocysticercosis lesions can trigger inflammatory reactions during therapy, and the number and location of calcified neurocysticercosis lesions may influence treatment decisions.

Tenascin-C protein is induced by transforming growth factor-beta1 but does not correlate with time to tumor progression in high-grade gliomas

Abstract: Background Tenascin-C is an extracellular matrix protein known to correlate with prognosis in patients with glioblastoma, probably by stimulation of invasion and neoangiogenesis. Transforming Growth Factor-s1 (TGF-s1) plays an important role in the biology of high-grade gliomas, partly by regulating invasion of these tumors into parenchyma. This study was designed to evaluate if TGF-s1 induces the expression and deposition of Tenascin-C in the extracellular matrix of high-grade gliomas which may be pivotal for the invasion of these tumors into healthy parenchyma.

Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells.

Abstract: The epidermal growth factor receptor (EGFR, ErbB1) is frequently dysregulated in a variety of solid human tumors, including malignant glioma. EGFR expression has been associated with disease progression, resistance to standard therapies and poor survival. The application of small interfering RNAs (siRNAs) has become an effective and highly specific tool to modulate gene expression, and a wide range of oncogenes have been silenced successfully. Here we show the siRNA-mediated down-regulation of EGFR in two established glioma cell lines with different EGFR expression levels (U373 MG, LN18). The expression of EGFR mRNA and protein was down-regulated by 70-90%. However, siRNA treatment had no inhibitory effect on cell proliferation, migration and activation status of EGFR-coupled signaling cascades. In accordance with these results, gene expression analysis with microarrays revealed only small, albeit specific changes in expression patterns. In conclusion, these data indicate that the specific down-regulation of EGFR might not be sufficient for a single agent therapeutic approach in malignant glioma.

Relation between Laterality and Immune Response after Acute Cerebral Ischemia

Abstract: Objective: During the last 2 decades, right/left hemisphere dominance was supposed to affect the immune system differently. Experimental and clinical observations indicate that the

Failure of Schwann cells as supporting cells for adult neural progenitor cell grafts in the acutely injured spinal cord.

Abstract: Adult neural progenitor cells (NPC) co-grafted with fibroblasts replace cystic lesion defects and promote cell-contact-mediated axonal regeneration in the acutely injured spinal cord. Fibroblasts are required as a platform to maintain NPC within the lesion; however, they are suspected to create an inhospitable milieu for regenerating central nervous system (CNS) axons. Therefore, we thought to replace fibroblasts by primary Schwann cells, which might serve as a superior scaffold to maintain NPC within the lesion and might further enhance axon regrowth and remyelination following spinal cord injury. Adult rats underwent a cervical dorsal column transection immediately followed by transplantation of either NPC/Schwann cell or NPC/Schwann cell/fibroblast co-grafts. Animals receiving Schwann cell or fibroblast grafts alone, or Schwann cell/fibroblast co-grafts served as controls. At 3 weeks after injury/transplantation, histological analysis revealed that only fibroblast-containing grafts were able to replace the cystic lesion defect. In both co-cultures and co-grafts, Schwann cells and NPC were segregated. Almost all NPC migrated out of the graft into the adjacent host spinal cord. As a consequence, only peripheral-type myelin, but no CNS-type myelin, was detected within co-grafts containing NPC/Schwann cells. Corticospinal axon regeneration into Schwann-cell-containing co-grafts was reduced. Taken together, Schwann cells within NPC grafts contribute to remyelination. However, Schwann cells fail as a supporting platform to maintain NPC within the graft and impair CNS axon regeneration; this makes them an unfavorable candidate to support/augment NPC grafts following spinal cord injury.

Seasonal patterns of birth in patients with glioblastoma.

Abstract: Seasonal distribution of birth rates was only recently described in patients with high-grade gliomas. We analyzed 501 cases from the database of a Regional Cancer Center in Bavaria to assess annual periodicity in the birth dates of glioma patients. Prior to analysis, the number of births per month was normalized [number of births x 100,000/total number of births in Germany] to obtain birth rates per month. The approximation of the time series data by a one-year cosine model found that the glioblastoma birth rate exhibits a statistically significant annual variation, with the peak rate in January. Vitamin intake, infections, and other as-yet-unknown factors and exposures during pre- and perinatal early life may contribute to the seasonality of birth rate in patients with brain tumors.

Results of G004, a phase IIb actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma

Abstract: 1566 Background: In 3 phase I/II dose-escalation studies the TGF-β2 specific compound AP 12009 proved to be well tolerated and revealed an excellent safety profile. Furthermore, antitumor activity ...

A lightning strike to the head causing a visual cortex defect with simple and complex visual hallucinations.

Abstract: The case of a 23-year-old mountaineer who was hit by a lightning strike to the occiput causing a large central visual field defect and bilateral tympanic membrane ruptures is described. Owing to extreme agitation, the patient was set to a drug-induced coma for 3 days. After extubation, she experienced simple and complex visual hallucinations for several days, but otherwise recovered largely. Neuropsychological tests revealed deficits in fast visual detection tasks and non-verbal learning, and indicated a right temporal lobe dysfunction, consistent with a right temporal focus on electroencephalography. Four months after the accident, she developed a psychological reaction consisting of nightmares with reappearance of the complex visual hallucinations and a depressive syndrome. Using the European Cooperation for Lightning Detection network, a meteorological system for lightning surveillance, the exact geographical location and nature of the lightning flash were retrospectively retraced.

Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-b2 targeted compound AP 12009

Abstract: 1553 Background: In high-grade glioma (HGG), TGF-β2 expression strongly correlates with tumor grade and is highly predictive of disease outcome. The compound AP 12009 inhibits TGF-β2 expression. Pr...

Combined regimen of temozolomide and liposomal pegylated doxorubicin in glioblastoma--Toxicity and efficacy

Abstract: 11501 Background: Temozolomide (Temodar, TMZ) recently showed promising efficacy in an EORTC trial on first-line therapy of glioblastoma (Stupp R, 2005). Pegylated liposomal doxorubicin (Caelyx, PE...

ORIGINAL RESEARCH In Vivo High-Resolution MR Imaging of Neuropathologic Changes in the Injured Rat Spinal Cord

Abstract: MR imaging is the most comprehensive noninvasive means to assessstructural changes in injured central nervous system (CNS) tissue in humans over time. The fewpublished in vivo MR imaging studies of spinal cord injury in rodent models by using field strengths 7T suffer from low spatial resolution, flow, and motion artifacts. The aim of this study was to assessthe capacity of a 17.6T imaging system to detect pathologic changes occurring in a rat spinal cordcontusion injury model ex vivo and in vivo.