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Biomedical subjects

J R Weber

Publications and source records attributed to J R Weber.

At least 19 recordsLinked to original sources
PubMed2004

[Neurological complications of infective endocarditis].

Infective endocarditis involves the brain in 20-40% of cases. The neurologic syndrome often is the presenting feature. The most frequent neurologic complication is cerebral ischemia. In these patients and those with intracranial hemorrhage, a heart murmur as well as systemic signs of inflammation point to endocarditis. The encephalopathy in endocarditis is mostly due to cerebral infarction. In bacterial meningitis and brain abscess an uncommon isolate arouses suspicion. The most important therapy is antibiotic treatment. Valve replacement improves outcome; in the acute phase of endocarditis, however, it is only necessary in a third of the patients. Neurologic complications interfere with the timing of the valve replacement. If it is urgently required, its risk is reasonable within 3 days after cerebral ischemia; if possible 2-4 weeks should be waited. Cases of successful valve replacement within 4 weeks after intracranial hemorrhage have been reported, but it is recommended to postpone it for 4-6 weeks. There are no data available for the other neurologic complications. Even today patients with endocarditis challenge the diagnostic and therapeutic capacity of various disciplines.

Brain Diseases↗
PubMed2004

Isolated bacterial meningitis as the key syndrome of infective endocarditis.

BACKGROUND: Bacterial meningitis is an unusual first manifestation but a major complication of infective endocarditis. PATIENTS AND METHODS: We present three well documented cases of isolated bacterial meningitis in endocarditis. Against this background we review the literature. RESULTS: All patients presented with bacterial meningitis. Staphylococcus aureus was isolated in blood cultures of all patients, but was found only in the cerebrospinal fluid (CSF) of one patient. The underlying endocarditis was confirmed histologically in all three cases. Two patients recovered completely and one died. CONCLUSION: An extensive search for endocarditis is recommended in every case of an unusual isolate in bacterial meningitis whether it is isolated from blood or CSF.

Aged↗
PubMed2001

Apoptosis-inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus.

Streptococcus pneumoniae is the major cause of bacterial meningitis and it damages the hippocampus by inducing neuronal apoptosis. The blocking of caspases provides only partial protection in experimental meningitis, which suggests that there is an additional apoptotic pathway. A trigger of this pathway is the bacterium itself, as exposure of microglia or neurons to live pneumococci induces rapid apoptosis. In this study, apoptosis was not associated with the activation of caspases-1-10 and was not inhibited by z-VAD-fmk, a broad-spectrum caspase inhibitor. Rather, apoptosis was attributed to damage to mitochondria, which was followed by the release of apoptosis-inducing factor (AIF) from the mitochondria, large-scale DNA fragmentation, and hypodiploidy. Furthermore, intracytoplasmatic microinjection of AIF-specific antiserum markedly impaired pneumococcus-induced apoptosis. These findings indicate that AIF may play a central role in brain cell apoptosis and bacterial pathogenesis.

Animals↗
PubMed2001

The trigeminovascular system in bacterial meningitis.

Headache as a cardinal symptom of acute meningitis reflects activation of trigeminal afferents from the meninges. With their perivascular endings, these fibers form the so-called trigeminovascular system (TVS), which releases proinflammatory neuropeptides upon nociceptive stimulation. In the present article, we review a role of the TVS in enhancing the early inflammatory response of bacterial meningitis. Furthermore, we discuss inhibition of neuropeptide release from the TVS using 5HT(1B/D) agonists as a potential new anti-inflammatory treatment strategy for early bacterial meningitis.

Afferent Pathways↗
PubMed2001

Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration.

The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen-glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 beta-estradiol in the dose range of 0.5-1.0 microm significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-alpha and the modulation of Bcl proteins by 17 beta-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.

Animals↗
PubMed2001

The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls.

Central nervous system (CNS) infections caused by Streptococcus pneumoniae still have a disastrous outcome. Underlying immunological and CNS cellular events are largely enigmatic. We used pneumococcal cells walls (PCW) to investigate microglial responses as these cells are prominent sensors and effectors during neuropathological changes. PCW stimulation of mouse microglia in vitro evoked the release of the cyto- and chemokines, TNF-alpha, IL-6, IL-12, KC, MCP-1, MIP-1alpha, MIP-2 and RANTES as well as soluble TNF receptor II, a potential TNF-alpha antagonist. The release induction followed extremely steep dose-response relations, and short exposure periods (15 min) were already sufficient to trigger substantial responses. PCW signaling controlling the release depended on both p38 and p42/p44 (ERK2/ERK1) MAP kinase activities. The kinase inhibitor, tyrphostin AG126 prevented the PCW-inducible phosphorylation of p42/p44(MAPK), potently blocked cytokine release and drastically reduced the bioavailable TNF-alpha, since it only marginally affected the release of soluble TNF receptors. Moreover, in an in vivo model of pneumococcal meningitis, AG126 significantly attenuated the PCW-induced leukocyte influx to the cerebrospinal fluid. The findings imply that pneumococcal CNS infection can cause a rapid and massive microglial activation and that ERK/MAPK pathway(s) are potential targets for pharmacological interventions.

Animals↗
PubMed2001

Chronic inflammatory demyelinating polyradiculoneuropathy with histologically proven optic neuritis.

Although patient series of clinical, electrophysiological, or magnetic resonance imaging evidence for involvement of the central nervous system in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been published, the histological proof has never been reported. We present the case of a 46-year-old male patient who developed CIDP in his early 20s and who died of relapsing severe pneumonia. In late stages of the disease the patient presented visual loss and bilateral atrophy of the optic nerve. Neuropathological examination revealed severe peripheral neuropathy consistent with CIDP and central involvement with bilateral optic neuritis. This is the first case reporting CIDP and histologically proven optic neuritis.

Axons↗
PubMed2001

Low sensitivity of serum procalcitonin in bacterial meningitis in adults.

Several studies have suggested high predictive values of serum procalcitonin (PCT) for the discrimination of bacterial and viral meningitis in children and adults. Here, we report PCT serum concentrations in 12 adults suffering from bacterial meningitis. PCT on admission was normal ( < or = 500 pg/ml) in 3 and between 500 and 1,000 pg/ml in 2 patients without evidence of concurrent bacterial infections. Conversely, in 5 patients with PCT concentrations between 2,268 and 38,246 pg/ml other infections were present. PCT concentrations were higher with typical meningitis agents (pneumococci and meningococci 12,679 +/- 13,092 pg/ml vs. other bacteria 4048 +/- 9187 pg/ml, p = 0.041) whilst in nosocomial bacterial meningitis after neurosurgery (n = 3) serum PCT remained normal. We believe that PCT is of limited diagnostic value in adults suffering from bacterial meningitis, especially in cases due to unusual agents or of nosocomial origin. Elevated PCT in bacterial meningitis may indicate the presence of bacterial inflammation outside the central nervous system.

Adolescent↗
PubMed2001

Hemicraniectomy in elderly patients with space occupying media infarction: improved survival but poor functional outcome.

OBJECTIVE: To assess the survival rate and functional outcome in elderly patients with space occupying supratentorial infarction who underwent hemicraniectomy compared with those who received medical treatment alone. METHODS: All patients older than 55 years with space occupying middle cerebral artery (MCA) infarction treated in our clinic between January 1998 and July 1999 were included in this retrospective analysis. Patients were eligible for decompressive surgery if they were younger than 75 and had no severe comorbidity. Hemicraniectomy was performed regardless of the affected hemisphere. All patients were followed up for assessment of functional outcome; data were assessed according to the Barthel index and modified Rankin scale and cover a period of 3 to 9 months after infarction. RESULTS: Twelve out of 24 patients underwent hemicraniectomy. Eight patients who were operated on survived; only one patient died of transtentorial herniation, three other deaths were due to medical complications. None of the survivors had a Barthel score above 60 or a Rankin score below 4. Nine out of 12 medically treated patients died of transtentorial herniation, one patient died of medical complications. The two surviving patients had a Barthel score below 60 and a Rankin score of 4. CONCLUSIONS: Craniectomy in elderly patients with space occupying MCA infarction improves survival rates compared with medical treatment alone. However, functional outcome and level of independence are poor. Craniectomy in elderly patients should not be performed unless a prospective randomised trial proves beneficial.

Aged↗
PubMed2001

Clinical, radiological, immunological and pathological findings in inflammatory CNS demyelination--possible markers for an antibody-mediated process.

The present report describes immunopathological, radiologcal and serological characteristics of antibody-mediated demyelination in a multiple sclerosis (MS) case with the main findings: (1) immunoglobulin and complement deposits in areas of active demyelination accompanied by massive macrophage activation; (2) ring-enhancing lesions in T1-weighted MRI after gadolinium application; (3) high titers of serum anti-myelin antibodies; and (4) signs of macrophage activation in the serum. Plasmapheresis may be a successful treatment for the type of inflammatory demyelination shown in the present case.

Autoantibodies↗
PubMed2000

Role of nitric oxide in the ethylcholine aziridinium model of delayed apoptotic neurodegeneration in vivo and in vitro.

The involvement of nitric oxide in neurodegenerative processes still remains incompletely characterized. Although nitric oxide has been reported to be an important mediator in neuronal degeneration in different models of cell death involving NMDA-receptor activation, increasing evidence for protective mechanisms has been obtained. In this study the role of nitric oxide was investigated in a model of NMDA-independent, delayed apoptotic cell death, induced by the neurotoxin ethylcholine aziridinium ethylcholine aziridinium both in vivo and in vitro. For the in vivo evaluation rats received bilateral intracerebroventricular injections of ethylcholine aziridinium (2nmol/ventricle) or vehicle. In the hippocampus a transient decrease in nitric oxide synthase activity occurred, reaching its lowest levels three days after ethylcholine aziridinium treatment (51.7+/-9.8% of controls). The decrease coincided with the maximal reduction in choline acetyltransferase activity as marker for the extent of cholinergic lesion. The effect of pharmacological inhibition of nitric oxide synthase was tested by application of various nitric oxide synthase inhibitors with different selectivity for the nitric oxide synthase-isoforms. Unspecific nitric oxide synthase inhibition resulted in a significant potentiation of the loss of choline acetyltransferase activity in the hippocampus measured seven days after ethylcholine aziridinium application, whereas the specific inhibition of neuronal or inducible nitric oxide synthase was ineffective. These pharmacological data are suggestive for a neuroprotective role of nitric oxide generated by endothelial nitric oxide synthase. In vitro experiments were performed using serum-free primary neuronal cell cultures from hippocampus, cortex and septum of E15-17 Wistar rat embryos. Ethylcholine aziridinium-application in a range of 5-80microM resulted in delayed apoptotic neurodegeneration with a maximum after three days as confirmed by morphological criteria, life-death assays and DNA laddering. Nitric oxide synthase activity in harvested cells decreased in a dose- and time-dependent manner. Nitric oxide production as determined by measurement of the accumulated metabolite nitrite in the medium was equally low in controls and in ethylcholine aziridinium treated cells (range 0.77-1.86microM nitrite). An expression of inducible nitric oxide synthase messenger RNA could not be detected by semiquantitative RT-PCR 13h after ethylcholine aziridinium application. The present data indicate that in a model of delayed apoptotic neurodegeneration as induced by ethylcholine aziridinium neuronal cell death in vitro and in vivo is independent of the cytotoxic potential of nitric oxide. This is confirmed by a decrease in nitric oxide synthase activity, absence of nitric oxide production and absence of inducible nitric oxide synthase expression. In contrast, evidence for a neuroprotective role of nitric oxide was obtained in vivo as indicated by the exaggeration of the cholinergic lesion after unspecific nitric oxide synthase inhibition by N-nitro-L-arginine methylester.

Animals↗
PubMed2000

Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures.

To assess the neuroprotective potential of melatonin in apoptotic neuronal cell death, we investigated the efficacy of melatonin in serum-free primary neuronal cultures of rat cortex by using three different models of caspase-dependent apoptotic, excitotoxin-independent neurodegeneration and compared it to that in necrotic neuronal damage. Neuronal apoptosis was induced by either staurosporine or the neurotoxin ethylcholine aziridinium (AF64A) with a delayed occurrence of apoptotic cell death (within 72 h). The apoptotic component of oxygen-glucose deprivation (OGD) unmasked by glutamate antagonists served as a third model. As a model for necrotic cell death, OGD was applied. Neuronal injury was quantified by LDH release and loss of metabolic activity. Although melatonin (0.5 mM) partly protected cortical neurons from OGD-induced necrosis, as measured by a significant reduction in LDH release, it was not effective in all three models of apoptotic cell death. In contrast, exaggeration of neuronal damage by melatonin was observed in native cultures as well as after induction of apoptosis. The present data suggest that the neuroprotectiveness of melatonin strongly depends on the model of neuronal cell death applied. As demonstrated in three different models of neuronal apoptosis, the progression of the apoptotic type of neuronal cell death cannot be withhold or is even exaggerated by melatonin, in contrast to its beneficial effect in the necrotic type of cell death.

Animals↗
PubMed2000

Induced hypothermia in experimental pneumococcal meningitis.

Pneumococcal meningitis resulting from Streptococcus pneumoniae has a death rate of 28% in adults. In severe head injury and stroke, inflammatory changes and intracranial hypertension are improved by induced hypothermia, which also is neuroprotective. We hypothesized that moderate hypothermia ameliorates inflammatory changes in experimental pneumococcal meningitis. Wistar rats were cooled systemically, and meningitis was induced by pneumococcal cell wall components. The increase of regional cerebral blood flow in the meningitis animals was blocked by hypothermia at 6 hours. The reduction of intracranial pressure correlated with temperature. The influx of leukocytes into the cerebrospinal fluid and levels of tumor necrosis factor alpha in the cerebrospinal fluid were decreased. Cooling the animals 2 hours after meningitis induction to 30.5 degrees C was also protective. We conclude that hypothermia is a new adjuvant approach to reduce meningitis-induced changes, in particular intracranial pressure, in the early phase of the disease.

Animals↗
PubMed1999

Cerebral endothelial cells release TNF-alpha after stimulation with cell walls of Streptococcus pneumoniae and regulate inducible nitric oxide synthase and ICAM-1 expression via autocrine loops.

TNF-alpha, inducible NO synthase (iNOS), and ICAM-1 are considered to be key proteins in the inflammatory response of most tissues. We tested the hypothesis that cell walls of Streptococcus pneumoniae (PCW), the most common cause of adult bacterial meningitis, induce TNF-alpha, iNOS, and ICAM-1 expression in rat primary brain microvascular endothelial cell cultures. We detected TNF-alpha mRNA by RT-PCR already 1 h after stimulation with PCW, while TNF-alpha protein peaked at 4 h (9.4 +/- 3.6 vs 0.1 +/- 0.1 pg/microgram protein). PCW induced iNOS mRNA 2 h after stimulation, followed by an increase of the NO degradation product nitrite (18.1 +/- 4 vs 5.8 +/- 1.8 at 12 h; 18.1 +/- 4 vs 5.8 +/- 1.8 pmol/microgram protein at 72 h). The addition of TNF-alpha Ab significantly reduced nitrite production to 62.2 +/- 14.4% compared with PCW-stimulated brain microvascular endothelial cells (100%). PCW induced the expression of ICAM-1 (measured by FACS), which was completely blocked by TNF-alpha Ab (142 +/- 18.6 vs 97.5 +/- 12.4%; 100% unstimulated brain microvascular endothelial cells). Cerebral endothelial cells express TNF-alpha mRNA as well as iNOS mRNA and release the bioactive proteins in response to PCW. PCW-induced NO production is mediated in part by an autocrine pathway involving TNF-alpha, whereas ICAM-1 expression is completely mediated by this autocrine loop. By these mechanisms, cerebral endothelial cells may regulate critical steps in inflammatory blood-brain-barrier disruption of bacterial meningitis.

Animals↗