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Ovadia H.,Agnes Ginges Center for Human Neurogenetics | Ovadia H.,Hadassah University Hospital | Siegal T.,Hebrew University of Jerusalem | Weidenfeld J.,Agnes Ginges Center for Human Neurogenetics
NeuroImmunoModulation | Year: 2013

Background: Central nervous system (CNS) irradiation has detrimental effects which become evident within hours to few days and after a long latency of months and years. However, the delayed effect of irradiation on neuroimmune diseases has not been thoroughly examined. Objectives: We evaluated the delayed effects of irradiation on the course of experimental autoimmune encephalomyelitis (EAE), which is used as a model for neuroimmune inflammation and multiple sclerosis. Methods: Adult male rats were exposed to a dose of 15 Gy given to the thoracolumbar spinal cord. Six months later, EAE was induced by inoculation of rat spinal cord homogenate in complete Freund's adjuvant (CFA). The disease was evaluated by clinical, histopathological and immunological parameters. Results: Irradiated rats developed clinical signs of EAE earlier than the control group and their disease was much more severe. Unlike the control group, all rats in the EAE-irradiated group died within 5 days after the onset of clinical signs. Sections taken from irradiated rats showed diffuse and large hemorrhagic infiltrates of lymphocytes and granulocytes. In contrast, control rats displayed fewer infiltrates, which were less prominent and not hemorrhagic. Conclusions: CNS irradiation has a delayed effect that caused a marked aggravation of the clinical and pathological signs of EAE. The severity of the disease may be a consequence of the effect of irradiation on the CNS vascular bed and impaired blood-brain barrier. © 2012 S. Karger AG, Basel.

Weidenfeld J.,Agnes Ginges Center for Human Neurogenetics | Siegal T.,Hebrew University of Jerusalem | Ovadia H.,Agnes Ginges Center for Human Neurogenetics | Ovadia H.,Hadassah University Hospital
NeuroImmunoModulation | Year: 2013

Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI. © 2012 S. Karger AG, Basel.

Ben-Hur T.,Agnes Ginges Center for Human Neurogenetics | Ben-Hur T.,Hadassah University Hospital | Fainstein N.,Agnes Ginges Center for Human Neurogenetics | Nishri Y.,Agnes Ginges Center for Human Neurogenetics
Current Neurology and Neuroscience Reports | Year: 2013

The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment. © Springer Science+Business Media New York 2013.

Paldor I.,Agnes Ginges Center for Human Neurogenetics | Eliashar R.,Hebrew University of Jerusalem | Hirshoren N.,Hebrew University of Jerusalem
Laryngoscope | Year: 2015

Objectives/Hypothesis: The objectives of this study were to examine the presence of β-2 transferrin (β2TRNSF) in cerebrospinal fluid (CSF) contaminated in vitro by various bacteria and explore the mechanism (passive or active) responsible for β2TRNSF elimination. Early diagnosis of CSF leakage may change treatment decisions and minimize the risk of meningitis and encephalitis. β2TRNSF is a protein present exclusively in CSF. Its detection is highly useful in cases of CSF leakage, although it has never been examined in the presence of central nervous system infection. Study Design: Prospective patient analysis. Methods: Sterile CSF drawn from patients was contaminated in vitro with several microorganisms chosen for their ability to cause neurosurgical-related infections: Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. β2TRNSF was examined at two time points: following immediate inoculation (t0) and following an overnight incubation (t18) over various bacterial concentrations. Samples of CSF inoculated with S pneumoniae were also examined in the presence of ciprofloxacin. For β2TRNSF analysis we used immunoblotting electrophoresis and enzyme-linked immunosorbent assay (ELISA). Results: CSF samples collected from nine patients were analyzed. β2TRNSF was not detected following S pneumoniae inoculation at both time points when immunoblotting electrophoresis was used. Quantitative analysis using ELISA demonstrated significant β2TRNSF concentration decrease. The addition of ciprofloxacin led to the same results. Conclusions: CSF leak detection using β2TRNSF may be deceiving in the presence of a S pneumoniae cerebral nervous system infection. A passive process is suggested, as β2TRNSF disappeared either immediately or following incubation with inactive bacteria. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Weidenfeld J.,Agnes Ginges Center for Human Neurogenetics | Leker R.R.,Agnes Ginges Center for Human Neurogenetics | Leker R.R.,Hebrew University of Jerusalem | Gai N.,Agnes Ginges Center for Human Neurogenetics | And 5 more authors.
Brain Research | Year: 2011

We characterized the effect of acute ischemic stroke on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and evaluated the role of glucocorticoids (GC) in the clinical outcome following ischemic stroke. Male spontaneous hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and developed a cortical infarct. At 4 h post-PMCAO or sham operation, serum levels of ACTH and corticosterone (CS) were elevated 5 and 4 fold respectively as compared to controls and then returned to basal levels at 24 h post surgery. In these experimental groups we found also a significant depletion of median eminence (ME)-CRH 41. In adrenalectomized (Adx) rats that underwent PMCAO the degree of motor disability and infarct volume was similar to that of intact rats. Administration of dexamethasone (Dex) to Adx-PMCAO rats significantly improved the motor disability and decreased the infarct volume. However, in sham-Adx with PMCAO, Dex had no effect on these two parameters. In rats with PMCAO or sham-PMCAO, brain production of PGE 2 was significantly increased. This effect was further enhanced in Adx-PMCAO rats and significantly inhibited by Dex. In conclusion, activation of the HPA axis following PMCAO is due to stress induced by surgery. This activation is mediated by hypothalamic CRH 41. Absence of endogenous GC or administration of Dex in naïve rats does not alter motor and pathological parameters in the acute stage following PMCAO. In contrast, administration of Dex significantly improved the outcome following cerebral ischemia in Adx rats which may be due to increased glucocorticoid receptors. Brain production of PGE 2 does not play an important role in the pathophysiology of the acute phase of cerebral ischemia. © 2011 Elsevier B.V.

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