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Hans-Walter Pfister

Publications and source records attributed to Hans-Walter Pfister.

At least 19 recordsLinked to original sources
PubMed2006

Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases.

Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis.

Animals↗
PubMed2006

TGFbeta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis.

In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1beta (IL-1beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFbeta) is a potent deactivator of PMN and macrophages since TGFbeta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFbeta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFbeta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFbeta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFbeta receptor II. L-selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFbeta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.

Animals↗
PubMed2006

Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients.

The diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2-3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies.

Adult↗
PubMed2006

Adhesion of Borrelia garinii to neuronal cells is mediated by the interaction of OspA with proteoglycans.

To study pathogenic mechanisms of Lyme meningoradiculitis, dorsal root ganglia (DRG) cells and two neuronal cell lines (B50, SH-SY5Y) were incubated with Borrelia garinii, the Borrelia species most frequently isolated from CSF of Lyme neuroborreliosis patients in Europe. We demonstrated that (I) OspA-positive B. garinii adhere to neuronal cells, (II) Borrelia adhesion can be blocked by a monoclonal antibody against OspA, (III) preincubation with proteoglycans interferes with the adhesion process and (IV) rOspA directly binds to the proteoglycans. This indicates that both OspA and the cell bound proteoglycans are involved in the attachment of B. garinii to neuronal cells.

Animals↗
PubMed2006

The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.

In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Protein expression pattern in experimental pneumococcal meningitis.

In this study, we investigated cytokine expression during experimental pneumococcal meningitis. Mice were intracisternally infected with Streptococcus pneumoniae and treated with ceftriaxone starting at 24 h after infection. At different time points before and after antibiotic therapy, the cytokine expression pattern was determined in mouse brains using protein arrays. Underlining the power of this method, the meningitis-relevant cytokines interleukin-1beta (IL-1beta), IL-6, KC, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1/CCL2) were markedly elevated in infected animals. Newly identified proteins during the acute stage of the disease (until 30 h after infection) included lymphotactin (XCL-1), MIP-1gamma (CCL9) and MCP-5 (CCL12), cytokine responsive gene- 2 (CRG-2/CXCL10) and CXCL16, and insulin-like growth factor binding protein 3 (IGFBP3). During later stages, an induction of T-cell activation-3 (TCA-3/CCL1), platelet factor-4 (PF-4/CXCL4) and stromal derived factor-1alpha (SDF-1alpha/CXCL13), and IL-4 was observed. The validity of this method was supported by an additional ELISA analysis of the expression profile of CXCL16 and IGFBP3, which was identical to that observed by protein array. In conclusion, the use of protein array technology led to an extension of the current picture of protein expression in pneumococcal meningitis. Most important, new factors that might play a role in pneumococcal meningitis were identified.

Animals↗
PubMed2005

CXCL11 is involved in leucocyte recruitment to the central nervous system in neuroborreliosis.

We investigated the role of the CXCR3 chemokine CXCL11 (I-TAC) for leukocyte recruitment to the CSF in neuroborreliosis (NB). CXCL11 levels in the CSF of 17 patients with acute NB were elevated compared with 20 non-inflammatory controls (100.1 vs. 54.1 pg/ml, p = 0.002). Using a modified Boyden chamber chemotaxis-assay, the CSF of patients with acute NB was more chemotactic than the control CSF-samples (p = 0.001). A strong correlation (p < 0.001) between CXCL11 levels, chemotactic activity and CSF-white cell count was detected. Though the chemotactic activity of CSF from NB patients was only partially reduced by a human recombinant CXCL11 antibody, these findings suggest that, among other chemotactic factors, CXCL11 may play a role in the chemotaxis of mononuclear cells in NB.

Adult↗
PubMed2005

Urokinase-type plasminogen activator receptor regulates leukocyte recruitment during experimental pneumococcal meningitis.

Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) have been suggested to play an important role in inflammatory diseases. Increased levels of tPA, uPA, uPA receptor (uPAR), and their inhibitor, plasminogen activator inhibitor (PAI)-1, have been found in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Here, we show that expression of tPA, uPA, uPAR, PAI-1, and PAI-2 is up-regulated during experimental pneumococcal meningitis. In uPAR-deficient mice, CSF pleocytosis was significantly attenuated 24 h after infection, compared with that in infected wild-type (wt) mice. Lack of uPAR did not influence blood-brain barrier permeability, intracranial pressure, expression of chemokines (keratinocyte-derived cytokine and macrophage inflammatory protein-2), bacterial killing, or clinical outcome. No differences in pathophysiological alterations were observed in tPA-deficient mice, compared with those in infected wt mice. These results indicate that uPAR participates in the recruitment of leukocytes to the CSF space during pneumoccal meningitis.

Animals↗
PubMed2005

Patterns of protein expression in infectious meningitis: a cerebrospinal fluid protein array analysis.

Seventy-nine cytokines, chemokines, and growth factors were measured by protein array analysis in the cerebrospinal fluid of patients with meningitis and controls. Several factors were found to be regulated, which have not been studied in the CNS before, e.g., macrophage inflammatory protein-1delta (CCL15) and neutrophil-activating peptide-2 (CXCL7). In pneumococcal meningitis, other new observations were an increase of macrophage migration inhibitory factor, monocyte chemoattractant protein-2 (CCL8), pulmonary and activation-regulated chemokine (CCL18), and macrophage inflammatory protein-3alpha (CCL20), and a sustained upregulation of several growth factors. In viral meningitis, new findings were an elevation of CCL8, thrombopoietin, and vascular endothelial growth factor.

Chemokines↗
PubMed2005

Development of adjunctive therapies for bacterial meningitis and lessons from knockout mice.

Bacterial meningitis is a medical emergency and is optimally managed in an intensive care environment. Despite the use of antibiotics, the prognosis of this disease is poor because of central nervous system complications such as brain edema formation, cerebrovascular alterations, intracranial hemorrhage, and hydrocephalus. Effective adjunctive therapies are still missing. Experimental studies with animal models have provided new insights into the pathophysiology during the acute phase of bacterial meningitis. In recent years, knockout mice have become a powerful tool to investigate the role of particular genes and have also been applied in bacterial meningitis research. The use of these mice offered new insights into the role of different cytokines, proteases, and oxidants involved in the inflammatory cascade. Translating this knowledge into new therapies will provide new treatment strategies for this serious disease in the future.

Animals↗
PubMed2004

Protective role of NF-kappaB1 (p50) in experimental pneumococcal meningitis.

Nuclear factor-kappaB (NF-kappaB) is a critical regulator of many genes involved in the pathogenesis of bacterial meningitis. Recently, activation of NF-kappaB was shown to be a key event in the inflammatory host response and the development of intracranial complications during experimental pneumococcal meningitis. Since the p50 subunit of NF-kappaB lacks a transactivation domain and can therefore act as a transcriptional repressor, we investigated whether NF-kappaB1 (p50) exerts anti-inflammatory effects in pneumococcal meningitis. p50-deficient mice had higher cerebellar pneumococcal titers (10.06+/-0.47 vs. 8.51+/-1.06 log colony-forming units [cfu]/cerebellum), cerebrospinal fluid (CSF) leukocyte counts (11,475+/-2340 vs. 8444+/-1405 cells/microl) and brain concentrations of interleukin-1beta (125.9+/-50.3 vs. 58.5+/-52.2 pg/mg protein) than their wild-type littermates. With ceftriaxone therapy, none of the wild-type mice but 43% of the p50-deficient animals died. In conclusion, lack of NF-kappaB1 (p50) was associated with impaired bacterial clearing, enhanced inflammatory host response and increased mortality during pneumococcal meningitis.

Animals↗
PubMed2004

MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS.

Myeloid differentiation factor 88 (MyD88) is an essential intracellular signal transducer in Toll-like receptor (TLR) and interleukin (IL)-1 receptor family member-mediated cell activation. In order to characterize the role of MyD88 in pneumococcal meningitis we used gene-targeted mice lacking functional MyD88 expression. At 24 h after intracisternal infection, MyD88- deficient mice displayed a markedly diminished inflammatory host response in the CNS, as evidenced by reduced CSF pleocytosis and expression of cytokines, chemokines and complement factors. The reduced CNS inflammation was paralleled by a marked reduction in the prognostic relevant CNS complications, such as brain oedema formation. Nevertheless, MyD88 deficiency was associated with a worsening of disease which seemed to be attributable to severe bacteraemia. This notion was supported by the unexpected observation that infected MyD88-deficient mice displayed enhanced mRNA expression of inflammatory mediators [such as the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the CXC chemokine macrophage inflammatory protein (MIP-2)] in the lung and consequently increased cell influx in the bronchoalveolar lavage fluid, compared with infected wild-type mice. Thus, the present study demonstrated for the first time an important role of MyD88 in immune activation to bacterial pathogens within the CNS. The role played by MyD88 in mounting an immune response to Streptococcus pneumoniae, however, seems to be dependent on the anatomical compartment involved.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Inflammatory response during bacterial meningitis is unchanged in Fas- and Fas ligand-deficient mice.

Fas (CD95) and Fas ligand (FasL, CD95L) have been implicated to be involved in the acute inflammatory response by attracting neutrophils and regulating their survival. Increased levels of soluble Fas and FasL are found in cerebrospinal fluid (CSF) samples of patients with bacterial meningitis but not in controls. Functional FasL (gld)- or Fas (lpr)-deficient mice were used to assess their role in the pathophysiology of pneumococcal meningitis. Induction of meningitis in wild-type (WT) mice caused an increase in CSF white blood cell (WBC) count, intracranial pressure (ICP), and vessel permeability, paralleled by a worse clinical status at 24 h. The inflammatory response was accompanied by elevated levels of IL-1beta, MMP-2, and MMP-9 in the brain. Neither gld- nor lpr-mice showed significant differences in the above-mentioned pneumococci-induced pathophysiological alterations. These results indicate that Fas and FasL are not essential in the regulation of the acute inflammatory response during pneumococcal meningitis.

Animals↗
PubMed2004

Successful cardic surgery 24 hours after craniotomy in a patient with infective endocarditis and embolic cerebellar infarction: case report.

Follow up management in a patient already treated with decompressive craniotomy for a space-occupying endocarditic stroke is difficult. While immediate valve replacement eliminates the focus and therefore the high risk of re-embolization, a neurosurgical intervention is considered a contraindication to early cardiosurgery. Herein, the first report is presented of a critically ill patient with bacterial endocarditis and a space-occupying cerebellar infarction with imminent herniation, who successfully underwent mitral valve replacement only 24 h after decompressive craniotomy. To prevent rebleeding, maximal hemostasis was ensured during the neurosurgical intervention. For cardiosurgery, the patient was cooled to 21 degrees C, mildly hyperventilated, and maintained at an adequate perfusion pressure during cardiopulmonary bypass. A bioprosthesis was used to reduce the time of anticoagulation. The patient did not develop new infarcts after either intervention, and there was only a very small hemorrhagic transformation without a relevant mass effect. At five months after surgery the patient had minimal neurological abnormalities and was able to conduct his daily life without help.

Brain Infarction↗
PubMed2003

Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis.

Heterologous expression of Toll-like receptor (TLR)2 and CD14 in Chinese hamster ovary fibroblasts was reported to confer responsiveness to pneumococcal peptidoglycan. The present study characterized the role of TLR2 in the host immune response and clinical course of pneumococcal meningitis. Pneumococcal infection of mice caused a significant increase in brain TLR2 mRNA expression at both 4 and 24 h postchallenge. Mice with a targeted disruption of the TLR2 gene (TLR2-/-) showed a moderate increase in disease severity, as evidenced by an aggravation of meningitis-induced intracranial complications, a more pronounced reduction in body weight and temperature, and a deterioration of motor impairment. These symptoms were associated with significantly higher cerebellar and blood bacterial titers. Brain expression of the complement inhibitor complement receptor-related protein y was significantly higher in infected TLR2-/- than in wild-type mice, while the expression of the meningitis-relevant inflammatory mediators IL-1beta, TNF-alpha, IL-6, macrophage-inflammatory protein (MIP)-2, inducible NO synthase, and C3 was similar in both genotypes. We first ectopically expressed single candidate receptors in HEK293 cells and then applied peritoneal macrophages from mice lacking TLR2 and/or functional TLR4 for further analysis. Overexpression of TLR2 and TLR4/MD-2 conferred activation of NF-kappaB in response to pneumococcal exposure. However, pneumococci-induced TNF-alpha release from peritoneal macrophages of wild-type and TLR2/functional TLR4/double-deficient mice did not differ. Thus, while TLR2 plays a significant role in vivo, yet undefined pattern recognition receptors contribute to the recognition of and initiation of the host immune defense toward Streptococcus pneumoniae infection.

Animals↗
PubMed2003

Meningitis-associated hearing loss: protection by adjunctive antioxidant therapy.

Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.

Acetylcysteine↗
PubMed2003

CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system.

The new CX(3)C-chemokine fractalkine (CX(3)CL1) was measured by Western blot in the cerebrospinal fluid (CSF) and serum of patients with inflammatory diseases of the peripheral and central nervous system (Bell's palsy, BP; Guillain-Barré Syndrome, GBS; multiple sclerosis, MS; viral meningitis, VM; bacterial meningitis, BM) and patients with noninflammatory neurological diseases (controls). In controls, fractalkine was detectable at low concentrations in the CSF and, at much higher levels, in serum. In all inflammatory neurological diseases under study, CSF fractalkine levels were significantly (p<0.01) increased vs. controls (BM>>GBS>VM>MS>BP>controls). In serum, fractalkine levels were significantly increased only in MS patients. The fractalkine CSF/serum ratios (a measure of the chemotactic gradient) were significantly elevated in BM, VM and GBS; furthermore, they tended to be increased in BP and to be decreased in MS. The elevated fractalkine CSF/serum ratios in diseases without CSF pleocytosis (GBS, BP) and a lack of correlation between fractalkine levels and CSF leukocyte counts suggested that soluble fractalkine is not a major chemokine in the CSF. There was no evidence of significant intrathecal production of fractalkine as the mean fractalkine indices (fractalkine CSF/serum ratio:albumin CSF/serum ratio) were <1 in all inflammatory diseases and not significantly elevated vs. controls.

Adult↗