Showing papers by "Ulrich Bogdahn published in 2014"

TeleStroke Units Serving as a Model of Care in Rural Areas 10-Year Experience of the TeleMedical Project for Integrative Stroke Care

Abstract: Background and Purpose—Stroke Unit care improves stroke prognosis and is recommended for all patients with stroke. In rural areas, population-wide implementation of Stroke Units is challenging. Therefore, the TeleMedical Project for integrative Stroke Care (TEMPiS) was established in 2003 as a TeleStroke Unit network to overcome this barrier in Southeast Bavaria/Germany. Evaluation of its implementation between 2003 and 2005 had revealed improved process quality and clinical outcomes compared with matched hospitals without TeleStroke Units. Data on sustainability of these effects are lacking. Methods—Effects on the stroke care of the local population were analyzed by using data from official hospital reports. Prospective registries from 2003 to 2012 describe processes and outcomes of consecutive patients with stroke and transient ischemic attack treated in TEMPiS hospitals. Quality indicators assess diagnostics, treatment, and outcome. Rates and timeliness of intravenous thrombolysis as well as data on te...

TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons.

Abstract: Members of the transforming growth factor (TGF)-β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-β1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-β1 signalling in adult NPCs. The results demonstrate that TGF-β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-β1 in ageing and neurodegenerative diseases, TGF-β1 signalling presents a molecular target for future interventions in such conditions.

Ocular color-coded sonography - a promising tool for neurologists and intensive care physicians.

Abstract: Ocular color-coded duplex sonography (OCCS), when performed within the safety limits of diagnostic ultrasonography, is an easy noninvasive technique with high potential for diagnosis and therapy in diseases with raised intracranial pressure and vascular diseases affecting the eye. Despite the capabilities of modern ultrasound systems and its scientific validation, OCCS has not gained widespread use in neurological practice. In this review, the authors describe the technique and main parameter settings of OCCS systems to reduce potential risks as thermal or cavitational effects for sensitive orbital structures. Applications of OCCS are the determination of intracranial pressure in emergency medicine, and follow-up evaluations of idiopathic intracranial hypertension and ventricular shunting by measuring the optic nerve sheath diameter. A diameter of 5.7 – 6.0 mm corresponds well with symptomatically increased intracranial pressure (> 20 cmH2O). OCCS also helps to discriminate between different etiologies of central retinal artery occlusion – by visualization of a “spot sign” and Doppler flow analysis of the central retinal artery – and aids the differential diagnosis of papilledema. At the end perspectives are illustrated that combine established ultrasound methods such as transcranial color-coded sonography with OCCS.

Prehospital stroke diagnostics based on neurological examination and transcranial ultrasound.

Abstract: Transcranial color-coded sonography (TCCS) has proved to be a fast and reliable tool for the detection of middle cerebral artery (MCA) occlusions in a hospital setting. In this feasibility study on prehospital sonography, our aim was to investigate the accuracy of TCCS for neurovascular emergency diagnostics when performed in a prehospital setting using mobile ultrasound equipment as part of a neurological examination. Following a ‘911 stroke code’ call, stroke neurologists experienced in TCCS rendezvoused with the paramedic team. In patients with suspected stroke, TCCS examination including ultrasound contrast agents was performed. Results were compared with neurovascular imaging (CTA, MRA) and the final discharge diagnosis from standard patient-centered stroke care. We enrolled ‘232 stroke code’ patients with follow-up data available in 102 patients with complete TCCS examination. A diagnosis of ischemic stroke was made in 73 cases; 29 patients were identified as ‘stroke mimics’. MCA occlusion was diagnosed in ten patients, while internal carotid artery (ICA) occlusion/high-grade stenosis leading to reversal of anterior cerebral artery flow was diagnosed in four patients. The initial working diagnosis ‘any stroke’ showed a sensitivity of 94% and a specificity of 48%. ‘Major MCA or ICA stroke’ diagnosed by mobile ultrasound showed an overall sensitivity of 78% and specificity of 98%. The study demonstrates the feasibility and high diagnostic accuracy of emergency transcranial ultrasound assessment combined with neurological examinations for major ischemic stroke. Future combination with telemedical support, point-of-care analysis of blood serum markers, and probability algorithms of prehospital stroke diagnosis including ultrasound may help to speed up stroke treatment.

Versican isoform V1 regulates proliferation and migration in high-grade gliomas.

Abstract: Versican is a large chondroitin sulphate proteoglycan produced by several tumor cell types, including high-grade gliomas. Increased expression of distinct versican isoforms in the extracellular matrix plays a role in tumor cell growth, adhesion and migration. We have recently shown that transforming growth factor (TGF-beta)2, an important modulator of glioma invasion, interacts with versican isoforms V0/V1 during malignant progression of glioma in vitro. However, the distinct subtype of versican that modulates these effects could not be specified. Here, we show that transient down-regulation of V1 by siRNA leads to a significant reduction of proliferation and migration in glioblastoma cell lines and glioblastoma progenitor cells, whereas tumor cell attachment stays unaffected. We conclude that V1 plays a predominant role in modulating central pathophysiological mechanisms as proliferation and migration in glioblastoma. Considering that TGF-beta is a master regulator of glioma pathophysiology, and that V0/1 is induced by TGF-beta2, therapeutic regulation of V1 may induce meaningful effects on glioma cell migration not only in vitro, but also in vivo.

Thoracic Rat Spinal Cord Contusion Injury Induces Remote Spinal Gliogenesis but Not Neurogenesis or Gliogenesis in the Brain

Abstract: After spinal cord injury, transected axons fail to regenerate, yet significant, spontaneous functional improvement can be observed over time. Distinct central nervous system regions retain the capacity to generate new neurons and glia from an endogenous pool of progenitor cells and to compensate neural cell loss following certain lesions. The aim of the present study was to investigate whether endogenous cell replacement (neurogenesis or gliogenesis) in the brain (subventricular zone, SVZ; corpus callosum, CC; hippocampus, HC; and motor cortex, MC) or cervical spinal cord might represent a structural correlate for spontaneous locomotor recovery after a thoracic spinal cord injury. Adult Fischer 344 rats received severe contusion injuries (200 kDyn) of the mid-thoracic spinal cord using an Infinite Horizon Impactor. Uninjured rats served as controls. From 4 to 14 days post-injury, both groups received injections of bromodeoxyuridine (BrdU) to label dividing cells. Over the course of six weeks post-injury, spontaneous recovery of locomotor function occurred. Survival of newly generated cells was unaltered in the SVZ, HC, CC, and the MC. Neurogenesis, as determined by identification and quantification of doublecortin immunoreactive neuroblasts or BrdU/neuronal nuclear antigen double positive newly generated neurons, was not present in non-neurogenic regions (MC, CC, and cervical spinal cord) and unaltered in neurogenic regions (dentate gyrus and SVZ) of the brain. The lack of neuronal replacement in the brain and spinal cord after spinal cord injury precludes any relevance for spontaneous recovery of locomotor function. Gliogenesis was increased in the cervical spinal cord remote from the injury site, however, is unlikely to contribute to functional improvement.

Response-Predictive Gene Expression Profiling of Glioma Progenitor Cells In Vitro

Abstract: Background High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist. Methods In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a) to enrich specimens for brain tumor initiating cells and (b) to confront cells with a therapeutic agent before expression profiling. Results As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro. Conclusion For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.

P17.39turn old into new: metformin as antineoplastic agent in glioblastoma.

Abstract: Metformin is one of the most widely prescribed oral antidiabetic drugs. In addition to its known hypoglycemic effects there is current evidence, that metformin may also reduce the risk and mortality of cancer in diabetic patients. The antineoplastic role of metformin has been extensively studied in breast-, prostate-, pancreatic-, lung- and colon cancer, however, the effect of metformin on glioblastomas, one of the most devastating forms of human tumors, has not been thoroughly investigated. We examined the effects of metformin on a variety of brain tumor initiating cells (BTIC) from fresh tumor resections of primary glioblastomas using proliferation assays (cell count, BRDU-assay) and migration assays (scratch and spheroid migration assay), and investigated differentiation of cells by means of immunocytochemistry. Tumor cell metabolism was investigated by measuring extracellular lactate levels, mitochondrial respiration by high resolution respirometry and determination of cellular oxygen consumption under cell culture conditions using the PreSens-assay. Important signalling molecules, such as AMPK, Akt and mTOR were investigated by means of Western Blot analysis. Functional assays were compared in BTIC and differentiated tumor cells from the same patients. In BTIC, we observed a markedly impaired proliferation and migration of cells after treatment with metformin and inhibition of complex I of the respiratory chain. In addition, we observed increased extracellular lactate levels and activation of the AMPK/mTOR signalling cascade. Metformin-treated BTIC showed reduced expression of stem cell markers. Differentiated tumor cells were distinctly less responsive to treatment with metformin. We hypothesize that differential sensitivity of brain tumor initiating cells and differentiated tumor cells to metformin is due to different use of and dependence on oxidative energy production and impaired glycolytic and glutaminolytic rescue pathways in BTIC. Further investigation of metformin as a possible antineoplastic agent in glioblastoma is warranted, especially in the light of a multitude of promising ongoing clinical studies on metformin and other tumor types.

Clinical reasoning: a 49-year-old man with fever and proximal weakness of his arms.

Abstract: A 49-year-old man with no significant medical history was seen by a neurologic consultant in eastern Bavaria, Germany, after he developed weakness of both arms. A few days earlier he had been referred to the internal medicine department with flu-like symptoms lasting for 2 weeks, which improved only transiently with trimethoprim/sulfamethoxazole for suspected urinary tract infection. The neurologic examination revealed an alert and oriented patient who was febrile (39.8°C, 103.6°F) but without meningeal signs or headache. He had normal cranial nerves and weakness of the shoulder girdle and both proximal arms. He had no sensory deficits, was hyporeflexic, and had flexor plantar responses. Gait was unsteady. Bladder function was reportedly normal. The patient was a passionate mushroom hunter and had no sick contacts. The authors thank the patient, Dr. G. Schuierer for providing the MRI, and Dr. L. Walter for comments on the manuscript.