Granulocyte colony-stimulating factor and acute myocardial infarction.
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Brain↗
Biomedical subjects
Armin Schneider
Publications and source records attributed to Armin Schneider.
An extended window of opportunity for G-CSF treatment in cerebral ischemia.
BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is known as a powerful regulator of white blood cell proliferation and differentiation in mammals. We, and others, have shown that G-CSF is effective in treating cerebral ischemia in rodents, both relating to infarct size as well as functional recovery. G-CSF and its receptor are expressed by neurons, and G-CSF regulates apoptosis and neurogenesis, providing a rational basis for its beneficial short- and long-term actions in ischemia. In addition, G-CSF may contribute to re-endothelialisation and arteriogenesis in the vasculature of the ischemic penumbra. In addition to these trophic effects, G-CSF is a potent neuroprotective factor reliably reducing infarct size in different stroke models. RESULTS: Here, we have further delayed treatment and studied effects of G-CSF on infarct volume in the middle cerebral artery occlusion (MCAO) model and functional outcome in the cortical photothrombotic model. In the MCAO model, we applied a single dose of 60 microg/kg bodyweight G-CSF in rats 4 h after onset of ischemia. Infarct volume was determined 24 h after onset of ischemia. In the rat photothrombotic model, we applied 10 microg/kg bodyweight G-CSF daily for a period of 10 days starting either 24 or 72 h after induction of ischemia. G-CSF both decreased acute infarct volume in the MCAO model, and improved recovery in the photothrombotic model at delayed timepoints. CONCLUSION: These data further strengthen G-CSF's profile as a unique candidate stroke drug, and provide an experimental basis for application of G-CSF in the post-stroke recovery phase.
Animals↗
Comparison between breast volume measurement using 3D surface imaging and classical techniques.
Quantification of the complex breast region can be helpful in breast surgery, which is shaped by subjective influences. However, there is no generally recognized method for breast volume calculation. Three-dimensional (3D) body surface imaging represents a new alternative for breast volume computation. The aim of this work was to compare breast volume calculation with 3D scanning and three classic methods, focusing on relative advantages, disadvantages, and reproducibility. Repeated breast volume calculations of both breasts in six patients (n=12) were performed using a 3D laser scanner, nuclear magnetic resonance imaging (MRI), thermoplastic castings, and anthropomorphic measurements. Mean volumes (cc) and mean measurement deviations were calculated, and regression analyses were performed. MRI showed the highest measurement precision, with a mean deviation (expressed as a percentage of mean breast volume) of 1.56+/-0.52% compared with 2.27+/-0.99% for the 3D scanner, 7.97+/-3.53% for thermoplastic castings, and 6.26+/-1.56% for the anthropomorphic measurements. Breast volume calculations using MRI showed the best agreement with 3D scanning measurement (r=0.990), followed by anthropomorphic measurement (r=0.947), and thermoplastic castings (r=0.727). Compared with three classical methods of breast volume calculation, 3D scanning provides acceptable accuracy for breast volume measurements, better spatial interpretation of the anatomical area to be operated on (due to lack of chest deformation), non-invasiveness, and good patient tolerance. After this preliminary study and further development, we believe that 3D body surface scanning could provide better preoperative planning and postoperative control in everyday clinical practice.
Adult↗
Developing granulocyte-colony stimulating factor for the treatment of stroke: current status of clinical trials.
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Brain Ischemia↗
Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease.
We have recently shown that the hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) is neuroprotective in rodent stroke models, and that this action appears to be mediated via a neuronal G-CSF receptor. Here, we report that the G-CSF receptor is expressed in rodent dopaminergic substantia nigra neurons, suggesting that G-CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of Parkinson's disease. Thus, we investigated protective effects of G-CSF in 1-methyl-4-phenylpyridinium (MPP+)-challenged PC12 cells and primary neuronal midbrain cultures, as well as in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Substantial protection was found against MPP+-induced dopaminergic cell death in vitro. Moreover, subcutaneous application of G-CSF at a dose of 40 microg/Kg body weight daily over 13 days rescued dopaminergic substantia nigra neurons from MPTP-induced death in aged mice, as shown by quantification of tyrosine hydroxylase-positive substantia nigra cells. Using HPLC, a corresponding reduction in striatal dopamine depletion after MPTP application was observed in G-CSF-treated mice. Thus our data suggest that G-CSF is a novel therapeutic opportunity for the treatment of Parkinson's disease, because it is well-tolerated and already approved for the treatment of neutropenic conditions in humans.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
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↗
Toward a multimodal neuroprotective treatment of stroke.
BACKGROUND AND PURPOSE: Stroke remains a common medical problem with importance attributable to the demographic changes in industrialized societies. SUMMARY OF REVIEW: After years of setbacks, acute stroke therapy has finally emerged, including thrombolysis with tissue plasminogen activator (t-PA). However, t-PA treatment is limited by a narrow time window and side effects, so that only 3% of all stroke patients receive thrombolysis. Unimodal targeting of key events in stroke pathophysiology was not effective in providing long-term benefits, leading to negative results in previous clinical neuroprotective stroke trials. A successful future stroke therapy should approach multiple pathophysiological mechanisms besides revascularization at once, including reduction of t-PA-related side effects, prevention of cell death, stimulation of neuroregeneration, and plasticity. CONCLUSIONS: Strategies targeting these processes include multiple combination therapies as well as treatment with multimodal drugs that interact with these mechanisms. Here, we review such combination approaches, and outline how this concept could be developed into future stroke treatment.
Animals↗
New aspects of breast volume measurement using 3-dimensional surface imaging.
Precise and objective calculation of breast volume is helpful to evaluate the aesthetic result of breast surgery, but traditional methods are unsatisfactory. Three-dimensional (3D) scanning of the body surface allows reproducible and objective assessment of the complex breast region but requires further investigation before clinical application. The main goal of this study was to investigate the precision and accuracy of breast volume measurement using 3D body scanning. Five independent observers standardized the 3D scanning method using 2 dummy models (n = 200) and examined its applicability with 6 test subjects and 10 clinical patients (n = 2220). Breast volume measurements obtained with the 3D-scanner technology were compared with reference measurements obtained from test subjects through nuclear magnetic resonance imaging. The mean deviation of the breast volume measurements of 1 test subject by all observers, expressed as percentage of volume, was 2.86 +/- 0.98, significantly higher than the deviation for the dummy models, 1.65 +/- 0.42 (P < 0.001). With respect to all clinical patients, the mean measurement precision obtained preoperatively was less precise than that obtained postoperatively (3.31 +/- 1.02 versus 1.66 +/- 0.49, respectively). Interobserver differences in measurement precision were not statistically significant. The mean breast volumes obtained by nuclear magnetic resonance imaging (441.42 +/- 137.05 mL) and 3D scanning (452.51 +/- 141.88 mL) significantly correlated (r = 0.995, P < 0.001). Breast volume measurement with 3D surface imaging represents a sufficiently precise and accurate method to guarantee objective and exact recording.
Breast↗
Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.
Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1(G93A)-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.
Adult↗
A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system.
G-CSF (Granulocyte-colony stimulating factor) is a hematopoietic growth factor that has been known for 20 years, and has been named for its role in the proliferation and differentiation of cells of the myeloic lineage. We have uncovered a novel spectrum of activities of G-CSF in the central nervous system. G-CSF and its receptor are expressed by neurons in many brain regions, and are upregulated upon experimental stroke. In neurons, G-CSF acts anti-apoptotically by activating several protective pathways. In vivo, G-CSF decreases infarct volumes in acute stroke models in rodents. Moreover, G-CSF stimulates neuronal differentiation of adult neural stem cells in the brain, and improves long-term recovery in more chronic stroke models. Thus, G-CSF is a novel neurotrophic factor, and a highly attractive candidate for the treatment of neurodegenerative conditions. Here we discuss this new property of G-CSF in contrast to its known functions in the hematopoietic system, summarize data from other groups on G-CSF's actions in cerebral ischemia, compare G-CSF to Erythropoietin (EPO) in the CNS, and highlight clinical implications.
Animals↗
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↗
Impaired expression of acyl-CoA synthetase 5 in sporadic colorectal adenocarcinomas.
Several pathways of fatty acid metabolism have been shown to be associated with the pathogenesis of colorectal cancer. Fatty acid acyl-CoA thioesters are formed from free fatty acids and coenzyme A by the activity of acyl-CoA synthetases (ACSs). Whilst an increase in ACS4 expression has been associated with colorectal carcinogenesis, little is known about possible pathogenetic functions of other ACS isoforms, such as ACS5, in tumourigenesis. In the present study, gene expression, protein synthesis, and enzymatic activity of ACS5 in sporadic colorectal adenocarcinomas, adenomas, and established cell lines were analysed using RT-PCR, western blot analysis, immunofluorescence, and an enzymatic assay. Enhanced expression of ACS5 mRNA and protein as well as enzymatic activity was found in adenomas and in 11 (73%; group 1) of 15 colorectal adenocarcinomas investigated, while a decrease of ACS5 was seen in four tumours (27%; group 2). However, basal ACS5 enzymatic activity was increased as a percentage of the total activity of ACSs in both groups, arguing for an absolute (group 1) or relative (group 2) increase in ACS5 enzymatic activity in all adenocarcinomas investigated. These findings are reflected by in vitro analysis of three established colorectal adenocarcinoma cell lines, in which activity of ACS5 occurred. The results suggest the involvement of ACS5 in the early genesis of colorectal cancer, most likely by modification of the transport and pool formation of long-chain acyl-CoA thioesters, as recently demonstrated for other isoforms of the ACS family.
Adenocarcinoma↗
Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia.
The transcription factor NF-kappaB is a key regulator of inflammation and cell survival. NF-kappaB is activated by cerebral ischemia in neurons and glia, but its function is controversial. To inhibit NF-kappaB selectively in neurons and glial cells, we have generated transgenic mice that express the IkappaBalpha superrepressor (IkappaBalpha mutated at serine-32 and serine-36, IkappaBalpha-SR) under transcriptional control of the neuron-specific enolase (NSE) and the glial fibrillary acidic protein (GFAP) promoter, respectively. In primary cortical neurons of NSE-IkappaBalpha-SR mice, NF-kappaB activity was partially inhibited. To assess NF-kappaB activity in vivo after permanent middle cerebral artery occlusion (MCAO), we measured the expression of NF-kappaB target genes by real-time polymerase chain reaction (PCR). The induction of c-myc and transforming growth factor-beta2 by cerebral ischemia was inhibited by neuronal expression of IkappaBalpha-SR, whereas induction of GFAP by MCAO was reduced by astrocytic expression of IkappaBalpha-SR. Neuronal, but not astrocytic, expression of the NF-kappaB inhibitor reduced both infarct size and cell death 48 hours after permanent MCAO. In summary, the data show that NF-kappaB is activated in neurons and astrocytes during cerebral ischemia and that NF-kappaB activation in neurons contributes to the ischemic damage.
Amino Acid Substitution↗
Electromagnetic catheter navigation during bronchoscopy: validation of a novel method by conventional fluoroscopy.
BACKGROUND: Electromagnetic navigation in bronchoscopy is a novel method for assisting in the localization of peripheral lung lesions. STUDY OBJECTIVE: To assess the usability, accuracy, and safety of electromagnetic navigation during flexible bronchoscopy in a clinical setting. DESIGN: Prospective evaluation. PATIENTS: Consecutive patients referred to the bronchoscopy unit for the diagnosis of peripheral infiltrates or solitary pulmonary nodules (SPNs). METHODS: Navigation was performed using an electromagnetic tracking system with a position sensor encapsulated in the tip of a flexible catheter that was pushed through the working channel of the bronchoscope. Real-time, multiplanar reconstruction of a previously acquired CT data set provided three-dimensional views for localization of the catheter. To match the position of the sensor with the CT scan, four anatomic landmarks were used for registration. The sensor position generated in the navigation system was controlled by fluoroscopy, and the corresponding error distances were measured. This was performed with all SPNs and at two different peripheral locations of the right upper lobe (RUL). RESULTS: Sixteen patients (10 men and 6 women; mean age, 63.7 years) were studied. Navigation prolonged bronchoscopy by 3.9 +/- 1.3 min (mean +/- SD). The navigation system identified all lesions. The position sensor achieved a direct hit in three of five SPNs. Fluoroscopy failed to recognize three SPNs (60%) and three infiltrates (38%). The mean error distances between sensor tip position and fluoroscopically verified RUL reference position were 10.4 mm (lateral position) and 12.5 mm (apical position) respectively. The mean error distances between the sensor tip and two endobronchial registration points at the end of the procedure were 4.2 mm and 5.1 mm, respectively. CONCLUSION: Electromagnetic navigation is useful, accurate, and safe in the localization of peripheral lung lesions and may help to improve the yield of diagnostic bronchoscopic procedures.
Adult↗
Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor (TNF) family of cytokines. It has proangiogenic and proinflammatory properties in vivo and induces cell death in tumor cell lines. TWEAK effects are mediated by the membrane receptor Fn14. In a systematic search for genes regulated in a murine stroke model with the tag-sequencing technique massively parallel signature sequencing, we have identified TWEAK as an induced gene. After 24 hr of focal cerebral ischemia in vivo or oxygen glucose deprivation in primary cortical neurons, both TWEAK and its receptor Fn14 were significantly upregulated. TWEAK induced cell death in primary neurons. Transfection of a nuclear factor (NF)-kappaB-luciferase fusion gene demonstrated that TWEAK stimulated transcriptional activity of NF-kappaB through Fn14 and the IkappaB kinase. Inhibition of NF-kappaB reduced TWEAK-stimulated neuronal cell death, suggesting that NF-kappaB mediates TWEAK-induced neurodegeneration at least in part. Intraperitoneal injection of a neutralizing anti-TWEAK antibody significantly reduced the infarct size after 48 hr of permanent cerebral ischemia. In summary, our data show that TWEAK induces neuronal cell death and is involved in neurodegeneration in vivo.
Animals↗
Identification of regulated genes during transient cortical ischemia in mice by restriction-mediated differential display (RMDD).
Cerebral ischemia induces transcriptional changes in a number of pathophysiologically important genes. Here we have systematically studied gene expression changes in the cortex after 150 min of focal cortical ischemia and 2 and 6 h reperfusion in the mouse by a fragment display technique (restriction-mediated differential display, RMDD). We identified 57 transcriptionally altered genes, of which 46 were known genes, and 11 unknown sequences. Of note, 14% of the regulated genes detected at 2 h reperfusion time were co-regulated in the contralateral cortex. Four genes were verified to be upregulated by quantitative PCR. These were Metallothionein-II (mt2), Receptor (calcitonin)-activity modifying protein 2 (ramp2), Mitochondrial phosphoprotein 65 (MIPP65), and the transcription elongation factor B2/elongin B (tceb). We could identify several genes that are known to be induced by cerebral ischemia, such as the metallothioneins and c-fos. Many of the genes identified provide hints to potential new mechanisms in ischemic pathophysiology. We discuss the identity of the regulated genes in view of their possible usefulness for pharmacological intervention in cerebral ischemia.
Animals↗
Verge: a novel vascular early response gene.
Vascular endothelium forms a continuous, semipermeable barrier that regulates the transvascular movement of hormones, macromolecules, and other solutes. Here, we describe a novel immediate early gene that is expressed selectively in vascular endothelial cells, verge (vascular early response gene). Verge protein includes an N-terminal region of approximately 70 amino acids with modest homology (approximately 30% identity) to Apolipoprotein L but is otherwise unique. Verge mRNA and protein are induced selectively in the endothelium of adult vasculature by electrical or chemical seizures. Verge expression appears to be responsive to local tissue conditions, because it is induced in the hemisphere ipsilateral to transient focal cerebral ischemia. In contrast to the transient expression in adult, Verge mRNA and protein are constitutively expressed at high levels in the endothelium of developing tissues (particularly heart) in association with angiogenesis. Verge mRNA is induced in cultured endothelial cells by defined growth factors and hypoxia. Verge protein is dramatically increased by cysteine proteinase inhibitors, suggesting rapid turnover, and is localized to focal regions near the periphery of the cells. Endothelial cell lines that stably express Verge form monolayers that show enhanced permeability in response to activation of protein kinase C by phorbol esters. This response is accompanied by reorganization of the actin cytoskeleton and the formation of paracellular gaps. These studies suggest that Verge functions as a dynamic regulator of endothelial cell signaling and vascular function.
Amino Acid Sequence↗
TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice.
Early-onset torsion dystonias are caused by a mutation in TorsinA, a protein widely expressed in the nervous system. Here we report the cloning of the murine TorsinA cDNA and a mRNA in situ hybridization analysis of the expression patterns of TorsinA over developmental periods relevant to the etiology of early-onset dystonias. Several studies have demonstrated a functional involvement of the nigrostriatal dopaminergic system in pathological mechanisms underlying dystonia. In this study, we show that the expression of TorsinA is significantly increased in the brain within hours of treatment with the dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, suggesting that the TorsinA gene is regulated by cellular stress. These results provide insights into the pathophysiology of early-onset dystonia and strengthen links between the dopaminergic system and dystonia.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗