Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus.
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Upregulation of certain growth factors in the central nervous system can alter brain fluid dynamics. Hydrocephalus was produced in adult Sprague-Dawley rats by infusing recombinant basic fibroblast growth factor (FGF-2) at 1 microg/day into a lateral ventricle for 2, 3, 5, or 10-12 days. Lateral and third ventricular enlargement progressively increased from 2 to 10 days. Ventriculomegaly was also induced by a 75% reduced dose of FGF-2. At 10-12 days, there was a 29% attenuation in cerebrospinal fluid (CSF) formation rate, from 2. 5 to 1.8 microliter/min (P < 0.01). Choroid plexus, the main site of CSF secretion, had an augmented number of dark epithelial cells, which have previously been associated with decreased choroidal fluid formation. The twofold elevated resistance to CSF absorption, i.e., 0.8 to 1.7 mmHg. min(-1). microliter(-1), was attributable, at least in part, to enhanced fibrosis and collagen deposits in the arachnoid villi, a major site for CSF absorption. Normal CSF pressure (2-3 mmHg) was consistent with a patent cerebral aqueduct and reduced CSF formation rate. The FGF-2-induced ventriculomegaly is interpreted as an ex vacuuo hydrocephalus brought about by an altered neuropil and interstitium of the brain. (+info)
HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system.
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Recombinant HIV-1 Nef protein, but not Tat, gp120, and gp160, provoked leukocyte recruitment into the CNS in a rat model. The strong reduction of bioactivity by heat treatment of Nef, and the blocking effect of the mAb 2H12, which recognizes the carboxy-terminal amino acid (aa) residues 171-190 (but not of mAb 3E6, an anti-Nef Ab of the same isotype, which maps the aa sequence 168-175, as well as a mixture of mAbs to CD4) provided evidence for the specificity of the observed Nef effects. Using a modified Boyden chamber technique, Nef exhibited chemotactic activity on mononuclear cells in vitro. Coadministration of the anti-Nef mAb 2H12, as well as treatment of Nef by heat inhibited Nef-induced chemotaxis. Besides soluble Nef, chemotaxis was also induced by a Nef-expressing human astrocytoma cell line, but not by control cells. These data suggest a direct chemotactic activity of soluble Nef. The detection of elevated levels of IL-6, TNF-alpha, and IFN-gamma in rat cerebrospinal fluid 6 h after intracisternal Nef injection hint at the additional involvement of indirect mechanisms in Nef-induced leukocyte migration into rat CNS. These data propose a mechanism by which HIV-1 Nef protein may be essential for AIDS neuropathogenesis, as a mediator of the recruitment of leukocytes that may serve as vehicles of the virus and perpetrators for disease through their production of neurotoxins. (+info)
Anti-human immunodeficiency virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2'-deoxy-3'-oxa-4'-thiocytidine.
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The racemic nucleoside analogue 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5'-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The K(i) values for dOTC-TP obtained against human DNA polymerases alpha, beta, and gamma were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 microM, rising to only 2.53 and 2.5 microM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [(3)H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 microM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 microM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid. (+info)
Differential expression of matrix metalloproteinases in bacterial meningitis.
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Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system. (+info)
TRH microdialysis into the RTN of the conscious rat increases breathing, metabolism, and temperature.
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Thyrotropin-releasing hormone (TRH) injected into the retrotrapezoid nucleus (RTN) of anesthetized rats produces a large, prolonged stimulation of ventilatory output (C. L. Cream, A. Li, and E. E. Nattie. J. Appl. Physiol. 83: 792-799, 1997). Here we inject or dialyze TRH into the RTN of conscious rats. In 6 of 17 injections (200 nl, 3.1 +/- 1.7 mM), ventilation (VE) increased 31% by 10 min, with recovery by 60 min. With dialysis, each animal of one group (n = 5) received, in random order, 10 mM TRH, 10 mM TRHOH (a metabolite of TRH), and artificial cerebrospinal fluid (aCSF); each animal of a second group (n = 5) received aCSF and 1 mM TRH. TRHOH and aCSF had no sustained effects. TRH (1 mM) increased VE (32%, P < 0.02, by 10 min, with recovery by 60 min), O(2) consumption (VO(2); 19%, P < 0. 03), and body (rectal) temperature (T(re); 0.5 degrees C, P < 0.09). TRH (10 mM) increased VE (78%, P < 0.01, by 10 min, with no recovery at 60 min), VO(2) (48%, P < 0.01), and T(re) (1.0 degrees C, P < 0. 01). TRH also induced arousal. The tissue volume affected in dialysis, estimated by spread of dialyzed fluorescein (332.3 mol wt, mol wt of TRH = 362.4), was 1,580 +/- 256 nl for 10 mM (n = 5) and 590 +/- 128 nl for 1 mM (n = 5). We conclude that 1) the RTN is involved in the integration of VE, VO(2), T(re), and arousal and 2) TRH may establish the responsiveness of RTN neurons. (+info)
Successful treatment of ceftazidime-resistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review.
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Increasing prevalence of multidrug-resistant gram-negative organisms has led to a rise in clinically significant infections with these organisms and an increasing therapeutic dilemma. We present a case of a neurosurgical patient who developed ventriculoperitoneal shunt-associated ventriculitis due to ceftazidime-resistant Klebsiella pneumoniae susceptible to cefepime, imipenem, meropenem, and polymyxin B only. Successful management was accomplished by removal of the shunt and therapy with systemic meropenem and intraventricular polymyxin B. Rapid cerebrospinal fluid (CSF) sterilization occurred, with CSF bactericidal titers of 1:32 to 1:128. Polymyxin B should be considered as adjunctive therapy for life-threatening multidrug-resistant gram-negative infections. Prior literature on use of intrathecal polymyxin B in therapy for meningitis supports its potential efficacy. (+info)
Clinical significance of Candida species isolated from cerebrospinal fluid following neurosurgery.
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Twenty-one patients for whom adequate clinical data were available were identified in a retrospective review of cases of Candida species isolated from cerebrospinal fluid (CSF) following neurosurgery; 86% had indwelling cerebrospinal devices (shunts). Candida species were isolated from multiple CSF samples from 10 patients; CSF samples from seven of 10 were initially drawn through indwelling devices and those from nine of 10 were obtained by subsequent lumbar punctures. All of these patients were treated with antifungals, although therapy was delayed in 50% of cases until the second positive culture was reported. In 11 cases, Candida was the only isolate recovered from CSF samples drawn through indwelling devices; cultures of subsequent CSF samples obtained by lumbar puncture were negative in 10 of 11 cases. Only two patients for whom a single culture was positive for Candida species were treated with antifungals (both of whom were symptomatic), and none of the untreated patients died of infection. The clinical significance of a single positive CSF sample drawn through an indwelling device is difficult to assess, and a definitive diagnosis may require repeated cultures of CSF samples obtained by lumbar puncture. (+info)
Role of peroxynitrite as a mediator of pathophysiological alterations in experimental pneumococcal meningitis.
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This study investigated the role of peroxynitrite in an adult rat model of pneumococcal meningitis. Immunohistochemically, nitrotyrosine residues, as a marker for peroxynitrite formation, were detected perivascularly and in proximity to inflammatory cells in the subarachnoid space. Nitrotyrosine immunoreactivity was colocalized with blood-brain barrier breaching, which was visualized by fluorescence microscopy after intravenous application of Evans blue. Treatment of infected rats with uric acid (300 mg/kg intraperitoneally), a scavenger of peroxynitrite, significantly attenuated intracranial pressure, cerebrospinal fluid white blood cell count, and blood-brain barrier leakage, as indicated by Evans blue concentration in the cerebrospinal fluid (21.6+/-9.3 mm Hg, 5776+/-1790 cells/microL, 9.7+/-6.4 microgram/mL in infected, untreated rats vs. 7.2+/-1.6 mm Hg, 2004+/-904 cells/microL, 1.1+/-1.0 microgram/mL infected, uric acid-treated rats, mean+/-SD, P<.05). These data suggest that peroxynitrite plays a central role in mediating pathophysiological alterations during bacterial meningitis. (+info)