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K Fassbender

Publications and source records attributed to K Fassbender.

At least 19 recordsLinked to original sources
PubMed2006

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

In idiopathic Parkinson's disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

Adult↗
PubMed2006

[Stroke].

Today stroke represents a major medical and political problem in Western industrial nations. High demands need to be placed on the initial diagnostic work-up and therapeutic treatment to ensure that the patients benefit from the recent advancements achieved in diagnostic and therapeutic fields. According to the motto "time is brain" the clinical examination and imaging have to be performed within 60 min ("door to needle time") so that potential patients can be quickly treated with systemic or intra-arterial lysis. However, it should be taken into consideration that the selection of diagnostic imaging facilities depends on several factors such as infrastructure, the time remaining in the diagnostic window, and the severity of the clinical symptoms.

Critical Care↗
PubMed2003

The LPS receptor (CD14) links innate immunity with Alzheimer's disease.

To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe-detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimer's disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimer's disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimer's disease.

Alzheimer Disease↗
PubMed2002

Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide.

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.

Aged↗
PubMed2001

Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo.

Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Abeta42 levels and the varepsilon4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Abeta42 and Abeta40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Abeta42 and Abeta40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Abeta42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.

Alzheimer Disease↗
PubMed2001

Alzheimer's disease: molecular concepts and therapeutic targets.

The beta amyloid peptide is the major component of the neuritic plaques, the characteristic lesions in Alzheimer's disease. Mutations in three genes (APP, PS-1, and PS-2) cause familial Alzheimer's disease by alteration of the rate of generation of amyloid peptide or the length of this peptide. However, in the 90% non-familial cases, other factors play a major pathogenetic role. These include the apolipoprotein E genotype, the "plaque-associated" proteins promoting the formation of toxic fibrillar aggregates or the chronic inflammatory responses. The aim of this review is to explain the steps in the complex cascade leading to Alzheimer's disease and, based on this, to report the current efforts to intervene in these different pathophysiological events in order to prevent progression of Alzheimer's disease. Whereas acetylcholine substitution is currently used in clinical practice, future therapeutical strategies to combat Alzheimer's disease may include anti-inflammatory treatments, vaccination against beta amyloid peptide, or treatment with cholesterol-lowering drugs.

Alzheimer Disease↗
PubMed2001

Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells.

Staphylococcus aureus plays an important role in sepsis, pneumonia and wound infections. Here, we demonstrate that infection with several S. aureus strains results in apoptosis of human endothelial cells. S. aureus induced an activation of cellular caspases, the acid sphingomyelinase, a release of cytochrome c and a stimulation of Jun NH2-terminal kinase (JNK). The significance of these findings is indicated by a prevention of S. aureus triggered apoptosis of human cells deficient for ASM or upon genetic or pharmacological inhibition of JNK or caspases, respectively.

Apoptosis↗
PubMed2001

Descriptive patient data as an explanation for the variation in average daily costs in intensive care.

Intensive care patients require therapy that can vary considerably in type, duration and cost, so making it extremely difficult to predict patient resource use. Few studies measure actual costs; usually average daily costs are calculated and these do not reflect the variation in resource use between individual patients. The aim of this study was to analyse a data set of 193 critically ill adult patients to look for associations between routinely collected descriptive data and patient-specific costs. Regression analysis was used to explore any relationships between average daily patient-specific costs and the following variables: duration of intensive care unit stay, Acute Physiology and Chronic Health Evaluation II scores in the first 24 h, gender, age, mechanical ventilation at any point during the stay, postoperative status, emergency admission and mortality. Overall, this analysis explained 33.6% of the variation in average daily costs. The additional costs of an extra day of care, mechanical ventilation, an extra point on the Acute Physiology and Chronic Health Evaluation II score, and survival were obtained.

APACHE↗
PubMed2001

Hypertonic-hyperoncotic solutions decrease cardiac troponin I concentrations in peripheral blood in a porcine ischemia-reperfusion model.

In this study we addressed the question of whether the measurement of cardiac Troponin I (cTnI) is able to reflect beneficial effects of hypertonic-hyperoncotic solutions after transient cardiac arrest. Ten pigs were anaesthetized and cardiac arrest was induced by electric fibrillation. After 5 minutes of global ischemia, cardiac arrest was reversed by electric defibrillation. Upon return of spontaneous circulation 5 animals received hypertonic-hyperoncotic solutions (10% Hydroxyethylstarch 200/0.5 and 7.2% NaCl). The other animals received equivalent volumes of physiological saline. We observed that cTnI serum levels of animals treated with hypertonic-hyperoncotic solutions were significantly lower than those treated with saline. We conclude that hypertonic-hyperoncotic solutions may have cardioprotective effects.

Animals↗
PubMed2001

Invasion of human epithelial cells by Pseudomonas aeruginosa involves src-like tyrosine kinases p60Src and p59Fyn.

Pseudomonas aeruginosa plays a major role in respiratory tract infections or sepsis in patients with cystic fibrosis or upon suppression of the immune system. Several P. aeruginosa strains have been shown to be internalized by human epithelial cells; however, the molecular mechanisms of the invasion process are poorly characterized. Here, we show that the internalization of P. aeruginosa into human epithelial cells results in and requires activation of the Src-like tyrosine kinases p59Fyn and p60Src and the consequent tyrosine phosphorylation of several eukaryotic proteins. The significance of Src-like tyrosine kinase activation is shown by an almost complete blockade of P. aeruginosa internalization, but not adhesion, upon inhibition of Src-like tyrosine kinases. Likewise, inhibition of P. aeruginosa binding to CFTR, which has been shown to block P. aeruginosa internalization, prevents Src and Fyn activation, supporting a pivotal role of Src-like tyrosine kinases for invasion by P. aeruginosa.

Cells, Cultured↗
PubMed2001

Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries.

Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF)-alpha) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH.

Adult↗
PubMed2001

Aggregation-Dependent interaction of the Alzheimer's beta-amyloid and microglia.

Chronic glial activation possibly plays a role in chronic neurodegeneration in Alzheimer's disease (AD). It has been shown that amyloid peptide is capable of activating microglial cells in vitro. The aim of this study was to further characterize the structural preconditions for amyloid peptide in order to activate glial cells and to investigate whether this peptide is also able to induce glial activation in the living brain. We observed that amyloid peptide induced strong cellular activation in primary microglial cell culture as detected by the release of stable metabolites of nitric oxide (NO), when the peptide was fibrillar. For this activation, co-stimulation with interferon-gamma was a precondition. Using microdialysis of the living brain in a rat we observed pronounced NO generation when fibrillar amyloid peptide was stereotaxically injected. Non-fibrillar amyloid peptide did not induce such a glial reaction. No administration of interferon-gamma or any other co-stimulatory factor was necessary in vivo. Thus, we show that fibrillar, but not non-fibrillar amyloid peptide induced glial activation also in vivo. In the case of the living brain, the presence of deposits of fibrillar amyloid peptide could maintain a chronic microglial activation, ultimately leading to the progressive neurodegeneration associated with Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Protein S-100B: a serum marker for ischemic and infectious injury of cerebral tissue.

The S-100B protein is released by injured astrocytes. After passage through a disintegrated blood-brain barrier (BBB) the molecule can be detected in the peripheral circulation. We investigated the association between the extent of brain injury and S-100B concentration in serum in cerebral injury caused by cerebral ischemia and cerebral fungal infection. Study I: The S-100B serum concentration was serially determined in 24 patients with ischemic stroke at 4, 8, 10, 24, 72 hours after the onset of symptoms. We observed that patients with brain lesions larger than 5 cm3 exhibited significantly increased serum levels of S-100B at 10, 24 and 72 hours compared to those with lesion volumes below 5 cm3. Furthermore, an association between S-100B serum concentration and neurological outcome was observed. Study II: In a mouse model of systemic fungal infection with Candida albicans we observed that serum levels of S-100B increased at day 1 after intravenous infection. At this time we could histologically demonstrate brain tissue injury by invading hyphae which had crossed the BBB. Furthermore, reactive astrogliosis was demonstrated by immunohistochemistry. On day 7 we found a significant decrease of S-100B serum level compared to day 1 and 4. This was associated with a demarcation of the fungi with leukocytes in brain tissue at this late phase of infection. No further invasion through the BBB was seen on day 7. In conclusion, serum levels of S-100B reflect the time course of tissue injury in cerebral ischemia and cerebral infection to a similar extent. Thus, S-100B may be a useful marker to assess cerebral tissue injury.

Adult↗
PubMed2001

Source of endothelin-1 in subarachnoid hemorrhage.

Endothelin-1 is the most potent vasoconstrictor known to date. This peptide is believed to play a pathophysiological role in the development of vasospasm, the most important complication of subarachnoid hemorrhage (SAH). In the present study we investigated the release of endothelin-1 in SAH and analyzed the cellular source of this peptide. At a protein and mRNA level we were able to show that endothelin-1 is produced by mononuclear leukocytes. Complementary in vitro studies revealed that aging and subsequent hemolysis of blood is sufficient to induce production of endothelin-1 by mononuclear leukocytes. Thus, cerebrospinal fluid-derived mononuclear leukocytes are a source of endothelin-1 in patients suffering from SAH. This finding may have important therapeutic implications as anti-leukocyte strategies could prevent cerebrovascular complications in SAH patients.

Adult↗
PubMed2001

Homocysteine in cerebrovascular disease: an independent risk factor for subcortical vascular encephalopathy.

Hyperhomocysteinemia is a risk factor for obstructive large-vessel disease. Here, we studied plasma concentrations of homocysteine and vitamins in patients suffering from subcortical vascular encephalopathy (SVE), a cerebral small-vessel disease leading to dementia. These results were compared to the homocysteine and vitamin plasma concentrations from patients with cerebral large vessel disease and healthy control subjects. Plasma concentrations of homocysteine, vascular risk factors and vitamin status (B6, B12, folate) were determined in 82 patients with subcortical vascular encephalopathy, in 144 patients with cerebral large-vessel disease and in 102 control subjects. Patients with SVE, but not those with cerebral large-vessel disease, exhibited pathologically increased homocysteine concentrations in comparison with control subjects without cerebrovascular disease. Patients with SVE also showed lower vitamin B6 values in comparison to subjects without cerebrovascular disease. Logistic regression analysis showed that homocysteine is associated with the highest risk for SVE (odds ratio 5.7; CI 2.5-12.9) in comparison to other vascular risk factors such as hypertension, age and smoking. These observations indicate that hyperhomocysteinemia is a strong independent risk factor for SVE.

Aged↗
PubMed2000

Temporal profile of release of interleukin-1beta in neurotrauma.

Timing and extent of trauma-induced release of interleukin-1beta (IL-1beta) in extracellular fluid of the CNS were analyzed. In brain tissue perfusates obtained by in vivo microdialysis a marked release of IL-1beta was unexpectedly detected within less than 60 min. At such an early stage of neurotrauma, mRNA expression of IL-1beta was detected whereas immunoreactivity for the IL-1beta protein was negative. Concentrations of extracellularly secreted IL-1beta protein gradually increased, peaked at day 2 and decreased thereafter. Drugs acting on mononuclear phagocytes significantly modulated IL-1beta secretion. This so far unrecognized acuity of IL-1beta release demonstrated here, may represent a precondition for the orchestrating role of this mediator in the cascade of inflammatory host response.

Animals↗
PubMed2000

Subacute NO generation induced by Alzheimer's beta-amyloid in the living brain: reversal by inhibition of the inducible NO synthase.

Glial activation contiguous to deposits of amyloid peptide (Abeta) is a characteristic feature in Alzheimer's disease. We performed complementary in vitro and in vivo experiments to study the extent, kinetics, and mechanisms of microglial generation of nitric oxide (NO) induced by challenge with Abeta. We showed that Abeta fibrils dose-dependently induced a marked release of stable metabolites of NO in vivo that was strikingly similar regarding extent and temporal profile to the one in the parallel designed microglial cell culture experiments. However, costimulation with interferon gamma, which was a prerequisite for Abeta-induced NO generation in vitro, was not required in vivo, demonstrating that factors are present in the living brain that activate glial cells synergistically with Abeta. Therefore, in Alzheimer's disease, deposits of Abeta fibrils alone may be sufficient to induce a chronic release of neurotoxic microglial products, explaining the progressive neurodegeneration associated with this disease. Our observation that systemic administration of selective iNOS inhibitors abolishes Abeta-induced NO generation in vivo may have implications for therapy of Alzheimer's disease.

Amyloid beta-Peptides↗