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Biomedical subjects

R Nau

Publications and source records attributed to R Nau.

At least 19 recordsLinked to original sources
PubMed2006

Sleep disorders are long-term sequelae of both bacterial and viral meningitis.

BACKGROUND: Many bacterial meningitis patients experience neurological or neuropsychological sequelae, predominantly deficits in short-term memory, learning, and attention. Neuropsychological symptoms after viral meningitis are observed less frequently. Sleep disturbance has been reported after both viral and bacterial meningitis. OBJECTIVES: To examine systematically the frequency and extent of sleep disturbance in meningitis patients. METHODS: Eighty six viral or bacterial meningitis (onset of acute disease at least 1 year previously) patients were examined using two standardised questionnaires (Schlaffragebogen B and the Pittsburgh Sleep Quality Index, PSQI) in conjunction with a standardised neurological examination, and compared to a control group of 42 healthy age-matched volunteers. RESULTS: Patients after both viral and bacterial meningitis described their sleep as reduced in quality and less restful than that of healthy control subjects; both patient groups had a pathological mean PSQI total score. Impaired sleep scores after meningitis were not correlated to either the Glasgow Coma Scale or the Glasgow Outcome Scale. Moreover, no relationship between residual neurological dysfunction or depressivity and sleep quality was observed. CONCLUSIONS: Impaired sleep is a long-term consequence of meningitis. Additional, so far undetermined, factors other than the severity of concomitant neurological deficits are responsible for the development of this sequela.

Acute Disease↗
PubMed2005

Neuropsychological sequelae of bacterial and viral meningitis.

Survivors of meningitis often complain about neurological and neuropsychological consequences. In this study, the extent of these sequelae was quantified and correlated to MRI findings. Neurological, neuropsychological and neuroradiological examinations were performed with adult patients younger than 70 years, 1-12 years after recovery from bacterial meningitis (BM; n = 59), or from viral meningitis (VM; n = 59). Patients with other potential causes for neuropsychological deficits (e.g. alcoholism) were carefully excluded. Patients were compared to 30 healthy subjects adjusted for age, gender and length of school education. With the exception of attention functions, both patient groups showed more frequently pathological results than the control group for all domains examined. Applying an overall cognitive sum score, patients after BM did not differ significantly in their performance from patients after VM. Separate analyses of various cognitive domains, however, revealed a higher rate of persistent disturbances in short-term and working memory after BM than after VM. Moreover, patients after BM exhibited greater impairment of executive functions. Associative learning of verbal material was also reduced. These deficits could not be ascribed to impaired alertness functions or decreased motivation in BM patients. Applying a logistic regression model, the neuropsychological outcome was related to the neurological outcome. Patients with a Glasgow Outcome Scale (GOS) of <5 had more frequently impaired test results for non-verbal learning and memory. GOS was also correlated with performance in executive functions. Brain volume was lower and ventricular volume was higher in the bacterial than in the VM group, and cerebral volume and the amount of white matter lesions of patients after BM were negatively correlated with short-term and working memory. In conclusion, patients after both BM and VM with favourable outcome showed affected learning and memory functions. More patients after BM than after VM displayed pathological short-term and working memory. BM resulted in poorer performance in executive functions, language, short-term memory and verbal learning/memory tests. As a result of neurological and neuropsychological sequelae, BM with a GOS > or = 4 led to decreased activities of daily living but only a minority of patients were disabled in a way that social functions were affected. The extent of neuropsychological sequelae of BM might have been overestimated in earlier studies which often had not been controlled for comorbidity factors such as alcoholism.

Activities of Daily Living↗
PubMed2003

Regional differences in glutamine synthetase inhibition by L-methionine sulfoximine: a microdialysis study in the rabbit brain.

Elevated levels of glutamate, an endogenous excitatory amino acid, contribute to the development of neuronal injury in various cerebral diseases. Using a microdialysis approach, the response of extracellular levels of amino acids and metabolic parameters to glutamine synthetase inhibition by l-methionine sulfoximine was monitored simultaneously in the hippocampal formation and in the frontal cortex of the rabbit brain. In the hippocampal formation the decrease of glutamine levels during l-methionine sulfoximine treatment was more pronounced than in the frontal cortex, and was accompanied by a delayed decline of extracellular glutamate concentrations. Furthermore, l-methionine sulfoximine diminished the increase of lactate and pyruvate concentrations in the hippocampal formation, but not in the frontal cortex. Neither l-methionine sulfoximine treatment nor microdialysis probe insertion caused neuronal apoptosis, as measured by in situ tailing. An impaired function of hippocampal astrocyte glutamate uptake mechanisms or a higher functional capacity of the cortical glutamine synthetase may be possible explanations for the differences demonstrated. The present data are in accordance with regional differences in glutamine synthetase activation during bacterial meningitis and may explain, in part, the higher susceptibility of certain areas of the hippocampal formation (i.e., the dentate gyrus) to neuronal injury.

Animals↗
PubMed2003

[Polyneuropathy as a sole syndrome in malignant thymoma].

Up to 40% of patients with malignant thymoma suffer from paraneoplastic symptoms (90% myasthenia, 10% other symptoms). A 55-year-old patient developed ascending symmetrical sensorimotor tetraparesis. A malignant thymoma without metastases was diagnosed 6 months later. Despite thymectomy followed by radiation and high-dose corticosteroid therapy, the polyneuropathy progressed. Six months after onset, the patient was bound to a wheelchair. Immunosuppressive therapy with cyclophosphamide was initiated, leading to marked remission. After ten cycles, the patient was able to walk independently with walking aids. After the sixth and tenth cycle, respectively, attempts to discontinue immunosuppression led to relapse. In several diagnostic workups, however, there was no tumour relapse. After 13 cycles, cyclophosphamide was replaced by immunoglobulins (0.4 g/kg per day i.v. for 5 days/month) due to progressive renal failure. The patient died just before the second course of this treatment. In conclusion, in the differential diagnosis of rapidly progressive polyneuropathy, a malignant thymoma should be considered, even in the absence of myasthenia. Immunosuppression with cyclophosphamide resulted in amelioration of symptoms in this patient.

Activities of Daily Living↗
PubMed2003

Deep cerebral venous sinus thrombosis often presents with neuropsychologic symptoms.

The outcome of cerebral venous sinus thrombosis (CVST) depends on rapid diagnosis and initiation of effective anticoagulation. We report seven cases of a subgroup with deep cerebral venous sinus thrombosis (DCVST) treated in our institution since 1990. Six of our seven patients presented with early neuropsychological deficits (mental obtundation, bradyphrenia or apathia). This clinical presentation, in combination with headache, and focal neurological deficits, aids the early diagnosis of DCVST. Thalamic hyperintensities on T2-weighted MRI images, previously considered infarctions, were fully reversible during treatment with heparin. This indicates that early in the course of the disease they correspond to vasogenic oedema.

Adolescent↗
PubMed2001

The cell wall-associated serine protease PrtA: a highly conserved virulence factor of Streptococcus pneumoniae.

The surface-associated subtilisin-like serine protease PrtA was identified by screening a genomic expression library from Streptococcus pneumoniae using a convalescent-phase serum. In Western blot analysis two forms of PrtA were detected in whole cell lysate and a truncated form only in culture supernatant suggesting that PrtA is produced as a precursor protein, translocated to the cell surface, truncated, and released into the surroundings. A 5' fragment of the gene was found highly conserved among 78 pneumococcal isolates of clinical relevance. Immunogenicity of PrtA, limited genetic variation, and the involvement in pneumococcal virulence demonstrated in in vivo experiments might identify PrtA as a promising candidate for a protein based vaccine.

Amino Acid Sequence↗
PubMed2001

Organotypic hippocampal cultures. A model of brain tissue damage in Streptococcus pneumoniae meningitis.

Hippocampal slices of newborn rats were exposed to either heat-inactivated Streptococcus pneumoniae R6 (hiR6) equivalent to 10(6) and 10(8) CFU/ml, lipoteichoic acid (LTA) (0.3 microg/ml and 30 microg/ml), peptidoglycans (PG) (0.3, 30, 50 and 100 microg/ml), pneumococcal DNA (pDNA) (0.3 and 30 microg/ml) or medium only (control). Cell injury was examined by Nissl staining, Annexin V and NeuN immunohistochemistry, and quantified by propidium iodide (PI) uptake and by determining neuron-specific enolase (NSE) concentration in the culture medium. Necrotic and apoptotic cell damage occurred in all treatment groups. Overall damage (Nissl and PI staining) was most prominent after hiR6 (10(8) CFU/ml), followed by LTA (30 microg/ml), pDNA (30 microg/ml), and not detectable after PG (30 microg/ml) exposure. PG (100 microg/ml) induced severe damage. Apoptotic cells were most frequent after exposure to LTA and hiR6. Damage in the neuronal cell layers (NeuN, NSE) was most severe after treatment with hiR6 (10(8) CFU/ml), followed by PG (100 microg/ml), pDNA (30 microg/ml), and LTA (30 microg/ml).

Animals↗
PubMed2001

Reduced release of DNA from streptococcus pneumoniae after treatment with rifampin in comparison to spontaneous growth and ceftriaxone treatment.

In order to study the release of DNA from Streptococcus pneumoniae in vitro during spontaneous growth and treatment with ceftriaxone or rifampin, a semiquantitative polymerase chain reaction was used. During spontaneous growth, high concentrations of bacterial DNA were released. Exposure to 10 microg/ml of ceftriaxone decreased the DNA release, in median, by 19 times (P=0.03 vs. spontaneous growth). Treatment with 10 microg/ml of rifampin led to a reduction of DNA release, in median, by a factor of 49 (P=0.03 vs. ceftriaxone; six experiments performed on different days).

Base Sequence↗
PubMed2001

A mouse model of Streptococcus pneumoniae meningitis mimicking several features of human disease.

The course of bacterial titers, meningeal inflammation, behavioral abnormalities, and neuronal damage was studied in a mouse model of Streptococcus pneumoniae meningitis. At 24 h after injection of 10(4) colony-forming units (CFU) S. pneumoniae into the right forebrain, infected mice became severely lethargic. Bacterial titers in cerebrospinal fluid and cerebellum rose to 10(9) CFU/ml, with strong granulocyte invasion into the meninges and neuronal necroses in the neocortex, striatum and hippocampal formation. Meningeal inflammation and neuronal damage in intercellular cell adhesion molecule-1- and macrophage colony-stimulating factor-deficient mice was similar to that in wild-type littermates. Untreated, the infection was fatal. Wild-type mice treated earlier than 24 h after infection with ceftriaxone (2 mg every 12 h for 3 days) survived without apparent behavioral abnormalities. Delay of treatment beyond 30 h led to the death of more than 50% of the infected mice. This mouse model is suitable for therapeutic studies and for the investigation of inflammation in knockout mice. The neuronal damage resembles morphological abnormalities observed in humans.

Animals↗
PubMed2001

D- and L-lactate in rabbit and human bacterial meningitis.

Increased total CSF lactate is an important indicator differentiating bacterial from aseptic meningitis. Bacteria can produce D- and L-lactate; mammalian cells produce only L-lactate. We measured D- and L-lactate production of Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis and Escherichia coli in vitro, of S. pneumoniae and E. coli in rabbit experimental meningitis and of various common pathogens in CSF from patients with bacterial meningitis. Despite marked in vitro production of D-lactate by S. aureus (maximum: 4.59 mmol/l; i.e. 34.9% of total lactate), N. meningitidis (4.62 mmol/l; i.e. 98.1%) and E. coli (3.14 mmol/l; i.e. 97.2%), minimal amounts were measured in human S. aureus (0.38 mmol/l; i.e. 1.3% of total lactate) or N. meningitidis (0.28 mmol/l; i.e. 3.9%) and experimental E. coli meningitis (0.75 mmol/l; i.e. 4.4%). In only 9 of 54 human CSF samples did D-lactate exceed 0.15 mmol/l. S. pneumoniae did not produce significant amounts of D-lactate in vitro (maximum: 0.55 mmol/l; i.e. 2.7% of total lactate), in experimental meningitis (0.18 mmol/l; i.e. 3%) or in human cases of meningitis (0.28 mmol/l; i.e. 1.9%). In conclusion, increased total CSF lactate in meningitis consists mainly of L-lactate and originates predominantly from host cells. CSF D-lactate is of limited diagnostic value.

Animals↗
PubMed2001

Transcriptional regulation of caspases in experimental pneumococcal meningitis.

Apoptosis and necrosis in brain account for neurological sequelae in survivors of bacterial meningitis. In meningitis, several mechanisms may trigger death pathways leading to activation of transcription factors regulating caspases mRNA synthesis. Therefore, we used a multiprobe RNA protection assay (RPA) to examine the expression of 9 caspase-mRNA in the course of experimental Streptococcus pneumoniae meningitis in mouse brain. Caspase-6, -7 and -11 mRNA were elevated 6 hours after infection. 12 hours after infection caspases-1, -2, -8 and -12 mRNA rose. Caspase-14 mRNA was elevated 18 h and caspase-3 mRNA 24 h after infection. In situ hybridization detected caspases-3, -8, -11 and -12 mRNA in neurons of the hippocampal formation and neocortex. Development of sepsis was paralleled by increased transcription of caspases mRNA in the spleen. In TNFalpha-deficient mice all caspases examined were less upregulated, in TNF-receptor 1/2 knockout mice caspases-1, -2, -7, -11 and -14 mRNA were increased compared to infected control animals. In caspase-1 deficient mice, caspases-11, and -12 mRNA levels did not rise in meningitis indicating the necessity of caspase-1 activating these caspases. Hippocampal formations of newborn mice incubated with heat-inactivated S. pneumoniae R6 showed upregulation of caspase-1, -3, -11 and -12 mRNA. These observations suggest a tightly regulated caspases network at the transcriptional level in addition to the known cascade at the protein level.

Animals↗
PubMed2001

Expression of death-related proteins in dentate granule cells in human bacterial meningitis.

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase-3 and the active enzyme, bcl-2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0-15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase-3), 0.9/mm2 (activated caspase-3), 1.8/mm2 (bcl-2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase-3 had an apoptotic morphology, whereas only 10% of all procaspase-3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase-3, bcl-2 and bax suggests an involvement of these proteins in neuronal death.

Adolescent↗
PubMed2001

Activity of LY333328 in experimental meningitis caused by a Streptococcus pneumoniae strain susceptible to penicillin.

In a rabbit model of Streptococcus pneumoniae meningitis single doses of 10 and 2.5 mg of the glycopeptide LY333328 per kg of body weight reduced bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone at 10 mg/kg/h (changes in log CFU, -0.29 +/- 0.21 and -0.26 +/- 0.22 versus -0.34 +/- 0.15/ml/h). A dose of 1 mg/kg was bacteriostatic (change in log CFU, 0.01 +/- 0.11/ml/h). In two animals receiving LY333328 at a dose of 40 mg/kg the bacterial titers were reduced by 0.54 and 0.51 log CFU/ml/h. The penetration of CSF by LY333328 was 1 to 5%. The concentrations of lipoteichoic and teichoic acids in CSF and neuronal damage were similar in ceftriaxone- and LY333328-treated animals.

Animals↗
PubMed2001

Effect of deficiency of tumor necrosis factor alpha or both of its receptors on Streptococcus pneumoniae central nervous system infection and peritonitis.

Tumor necrosis factor alpha (TNF-alpha) and TNF-beta are key mediators in bacterial inflammation. We therefore examined the role of TNF-alpha and its two receptors in murine pneumococcal central nervous system infection. TNF-alpha knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-alpha-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-alpha deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-alpha or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 10(2) CFU of S. pneumoniae produced fatal peritonitis in TNF-alpha-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-alpha-deficient mice. The lack of TNF-alpha or its receptors renders mice more susceptible to S. pneumoniae infections.

Adult↗
PubMed2000

Spatial memory and learning deficits after experimental pneumococcal meningitis in mice.

Survivors of bacterial meningitis frequently suffer from long-term sequelae, particularly from learning and memory deficits. For this reason, spatial memory and learning was studied in a mouse model of ceftriaxone-treated Streptococcus pneumoniae meningitis. Persistent deficits of spatial learning despite normal motor function were observed in mice infected with 10(4) colony-forming units (CFU) in 25 microl of saline into the right forebrain in comparison to mice treated with an equal amount of saline. Survivors of meningitis performed significantly worse in memorizing a hidden platform in a Morris water maze. After 2 weeks, the difference between post-meningitis and control mice diminished. Yet, when the platform was moved after 180 days, learning of the new location was still strongly impaired in mice surviving meningitis.

Animals↗
PubMed2000

Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis.

Bacterial compounds induce the production of reactive oxygen species (ROS) in meningitis. Rifampin releases smaller quantities of proinflammatory compounds from Streptococcus pneumoniae than do beta-lactam antibiotics. Therefore, rabbits infected intracisternally with S. pneumoniae were treated intravenously either with rifampin 5 mg/kg/h or ceftriaxone 10 mg/kg/h (n=9 each). Before initiation of antibiotic treatment, a strong positive correlation between ROS production of cerebrospinal fluid (CSF) phagocyte populations and bacterial CSF titers was observed (granulocytes: rs=.90, P<.0001; monocytes: rs=.81, P<.0001). CSF leukocytes from rifampin-treated rabbits produced less ROS (monocytes at 2 h after initiation of treatment: P=.045; at 5 h: P=.014; granulocytes at 5 h: P=.036) than did leukocytes from animals receiving ceftriaxone. The CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower in rifampin- than in ceftriaxone-treated animals (P=.002 and.005). The use of rifampin to reduce the release of ROS and to decrease secondary brain injury appears promising.

Animals↗