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Biomedical subjects

K Fassbender

Publications and source records attributed to K Fassbender.

At least 19 recordsLinked to original sources
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↗
PubMed2000

Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes.

BACKGROUND AND PURPOSE: The most potent vasoconstrictor known, endothelin-1, is currently considered to mediate cerebral vasospasm in subarachnoid hemorrhage (SAH), which can cause delayed cerebral ischemia. In our study, we performed clinical and in vitro experiments to investigate the origin and the mechanisms of the secretion of endothelin-1 in SAH. METHODS: Endothelin-1 and markers of inflammatory host response (interleukin [IL]-1ss, IL-6, and tumor necrosis factor-alpha) were comparatively quantified in the cerebrospinal fluid (CSF) of SAH patients and control subjects, and concentrations were related to clinical characteristics. Furthermore, mononuclear leukocytes isolated from the CSF of SAH patients and control subjects were analyzed regarding their mRNA expression of endothelin-1 and inflammatory cytokines. Finally, complementary in vitro experiments were performed to investigate whether coincubation of blood and CSF can trigger leukocytic mRNA expression and release of these factors. RESULTS: Activated mononuclear leukocytes in the CSF of SAH patients synthesize and release endothelin-1 in parallel with known acute-phase reactants (IL-1ss, IL-6, and tumor necrosis factor-alpha). Complementary in vitro experiments not only further confirmed this leukocytic origin of endothelin-1 but also showed that aging and subsequent hemolysis of blood is sufficient to induce such endothelin-1 production. CONCLUSIONS: The demonstration that endothelin-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and delayed cerebral ischemia after SAH.

Acute-Phase Proteins↗
PubMed2000

Subacute but not acute generation of nitric oxide in focal cerebral ischemia.

BACKGROUND AND PURPOSE: Excessive release of nitric oxide (NO) has been implicated in the pathophysiology of neurodegeneration in ischemic stroke. We compared intracerebral release of indicators of NO generation at the acute and subacute stages of transient focal cerebral ischemia. METHODS: In vivo microdialysis in the rat striatum was performed at the acute (first hours) and subacute (after 24 or 48 hours) stages of cerebral ischemia or sham operation to monitor intracerebral release of the stable NO metabolites nitrite and nitrate. RESULTS: Whereas only a nonsignificant trend toward increased release of these NO metabolites was evidenced in acute cerebral ischemia, a significant NO generation was observed subacutely, 48 hours after induction of cerebral ischemia. Aminoguanidine, a selective inhibitor of inducible NO synthase, suppressed this delayed release of nitrite and nitrate. CONCLUSIONS: Whereas these observations do not support a major NO generation in acute cerebral ischemia, they indicate an inducible NO synthase-dependent NO generation predominantly at the subacute phase of ischemic neurodegeneration. Therefore, NO generation may play a pathophysiological role in delayed ischemic neurodegeneration.

Animals↗
PubMed2000

The Frontal Lobe Score: part II: evaluation of its clinical validity.

OBJECTIVE: To evaluate the ability of the Frontal Lobe Score (FLS) to differentiate patients with frontal lobe lesions from those with nonfrontal lesions and normal controls. DESIGN: In a prospective, blind setup, the sensitivity and specificity of the Frontal Lobe Score was compared with the Wisconsin Card Sorting Test (WCST) and the Stroop Test. PATIENTS: A sample of 108 subjects (26 patients with cerebral lesions confined to the frontal lobes, 28 patients with cerebral lesions without involvement of the frontal lobes, 31 patients with mixed frontal/nonfrontal lesions, 23 controls without cerebral lesions) was examined. MEASURES: Frontal Lobe Score, Wisconsin Card Sorting Test, Stroop Test. RESULTS: The Frontal Lobe Score detected pure frontal lesions with a sensitivity of 92.3%. It discriminated patients with frontal lesions from normal controls with a specificity of 100%; differentiation from patients with nonfrontal lesions was obtained with a specificity of 75.0%. For the WCST, sensitivity for detection of pure frontal lesions was 65.4%, while specificity was 60.9% compared with normal controls and 53.6% compared with nonfrontal lesions. The Stroop Test showed a sensitivity of 30.8%, a specificity compared with normal controls of 95.7% and compared with nonfrontal lesions of 92.9%. CONCLUSION: The Frontal Lobe Score has clinical usefulness for screening of effects of frontal lobe damage superior to that of the WCST and the Stroop Test.

Adult↗
PubMed1999

Inverse association between endogenous glucocorticoid secretion and L-selectin (CD62L) expression in trauma patients.

Exogenously administered glucocorticoids downregulate inflammatory host response, i.e. by inhibition of adhesion molecule expression on leukocyte surfaces. Here, possible associations between the trauma-induced endogenous secretion of cortisol and the expression of neutrophil adhesion molecules (L-selectin/CD62L, CD 11b, CD54) were studied in humans. Standardized elective hip arthroplasty was investigated as an exemplary condition of acute inflammation. In 20 patients, blood for quantification of cortisol and adrenocorticotropic hormone was obtained at minutes 10, 20, 30, 60, hours 1, 2, 4 and 10 and days 1,3 and 7. Expression of L-selectin/CD62L, CD11b and CD54 on neutrophil surfaces was determined preoperatively, and postoperatively at hours 1, 2, 3, 4, and 10 and at days 1 and 3. Secretion of both, adrenocorticotropic hormone and cortisol was significantly increased between 1-10 hours after onset of tissue injury. Compared to baseline values, CD11b expression was increased at hour 1 and normalized after day 1, whereas L-selectin/CD62L expression, mirroring this pattern was decreased until day 1. Patients with high endogenous glucocorticoid secretion exhibited significantly decreased expression selectively of L-selectin/CD62L. However, we also observed that glucocorticoids do not directly induce L-selectin shedding from neutrophil surfaces in vitro, arguing for more indirect glucocorticoid action on adhesion molecule expression. Together, this study showed that increased endogenous cortisol secretion is associated with lower expression of L-selectin on neutrophil surfaces in humans that is consistent with a downmodulating role of this neuroendocrine stress response in inflammatory leukocyte recruitment.

Adrenocorticotropic Hormone↗