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ABSTRACT: Experimental autoimmune neuritis (EAN) serves as an animal model for human Gullain-Barre syndrome (GBS), an autoimmune disease causing demyelination and inflammation of peripheral nerves. Macrophages, which play a major role in this autoimmune inflammatory process, can be selectively targeted by high doses of bisphophonates. The goal of this study was to examine the effect of the bisphosphonate, clodronate, on the severity of the EAN model. EAN was induced in female adult rats by immunization with bovine peripheral myelin. A number of treatment protocols with clodronate were used based on the common dosage regimen of 20 mg/kg in humans starting with the appearance of clinical signs on day 10 post-immunization. The clinical parameters measured included a clinical score, a motor performance test performed on a Rotarod and body weight. The expression of the matrix metaloprotease (MMP-9) in the sciatic nerves was measured as a marker of inflammatory macrophages. Treatment with clodronate, 20 mg/kg daily and 40 mg/kg every 2 days, significantly reduced the disease severity (a 75 % decrease in severity, p < 0.01 by ANOVA) as measured by the clinical score compared to controls. Performance on the Rotarod test and body weight confirmed the clinical score findings. MMP-9 expression levels were significantly lower in the sciatic nerves of clodronate-treated rats. The present findings support the efficiency of clodronate in inflammatory diseases of the peripheral nervous system. The mechanism of action includes inhibition of inflammatory macrophages. The results suggest the use of bisphosphonates be considered in humans with GBS.
Immunologic Research 04/2013; · 3.03 Impact Factor
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ABSTRACT: Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on long term potentiation (LTP) in mice hippocampal slices. Surprisingly, different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. High thrombin concentrations induced an NMDA dependent, slow onset LTP, whereas low concentrations of thrombin promoted a VGCCs, mGluR-5 dependent LTP through activated Protein C (aPC). Remarkably, aPC facilitated LTP by activating PAR1 through an Endothelial Protein C Receptor (EPCR)-mediated mechanism which involves intracellular calcium stores. These findings reveal a novel mechanism by which PAR1 may regulate the threshold for synaptic plasticity in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions.
Experimental Neurology 02/2013; · 4.70 Impact Factor
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ABSTRACT: Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barré syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.
Current Medicinal Chemistry 01/2013; · 4.86 Impact Factor
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ABSTRACT: Excessive influx of immunoglobulin (IgG) into the brain has been reported to induce central nervous system (CNS) dysfunction. Depressed patients may exhibit immune activation manifested by elevated inflammatory markers and pro-inflammatory cytokines. The brain and especially the limbic system contain high concentrations of high affinity Fc receptors. We reviewed the literature on this phenomena and present data on the behavioral effects of pooled normal IgG on the brain. Many disease states are associated with depression and we examined whether this may be linked to high IgG influx. Female Balb/C mice were injected intra-cerbroventricularly with human immunoglobulin whole molecule, or human IgG F(ab')(2) or Fc fragments. Control mice were injected with saline. The four groups were subjected to behavioral (staircase, forced swimming test, and elevated plus maze) and cognitive tests (passive avoidance test). IgG-injected mice exhibited depression-like behavior as reflected by significantly higher immobility time in the forced swimming test (p < 0.05) and hyperactive behavior as reflected by higher number of stairs climbed in the staircase test compared to controls (p < 0.01). Fc-fragments-injected mice showed hyperactive behavior as reflected by both higher number of stairs climbed and rearing events in the staircase test compared to controls. The results indicate that high levels of normal IgG in the cerebrospinal fluid can cause hyperactivity and depression-like behavior. The mechanism involved in these CNS manifestations include possibly Fc receptor binding.
Clinical Reviews in Allergy & Immunology 01/2013; · 3.68 Impact Factor
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Eran Cohen,
Dana Avrahami,
Kati Frid,
Tamar Canello,
Ephrat Levy Lahad,
Sharon Zeligson,
Shira Perlberg, Joab Chapman,
Oren S Cohen,
Esther Kahana,
Iris Lavon,
Ruth Gabizon
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ABSTRACT: Since preventive treatments for prion disease require early identification of subjects at risk, we searched for surrogate peripheral markers characterizing the asymptomatic phases of such conditions. To this effect, we subjected blood mRNA from E200K PrP CJD patients and corresponding family members to global arrays and found that the expression of Snord3A, a non-coding RNA transcript, was elevated several times in CJD patients as compared to controls, while asymptomatic carriers presented intermediate Snord3A levels. In the brains of TgMHu2ME199K mice, a mouse model mimicking for E200K CJD, Snord 3A levels were elevated in an age and disease severity dependent manner, as was the case for brains of these mice in which disease was exacerbated by copper administration. Snord3A expression was also elevated in scrapie infected mice, but not in PrP(0/0) mice, indicating that while the expression levels of this transcript may reflect diverse prion etiologies, they are not related to the loss of PrP(C)'s function. Elevation of Snord3A was consistent with the activation of ATF6, representing one of the arms of the unfolded protein response system. Indeed, SnoRNAs were associated with reduced resistance to oxidative stress, and with ER stress in general, factors playing a significant role in this and other neurodegenerative conditions. We hypothesize that in addition to its function as a disease marker, Snord3A may play an important role in the mechanism of prion disease manifestation and progression.
PLoS ONE 01/2013; 8(1):e54433. · 4.09 Impact Factor
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ABSTRACT: Thrombin is a serine protease playing an essential role in the blood coagulation cascade. Recent work, however, has identified a novel role for thrombin-mediated signaling pathways in the central nervous system. Binding of thrombin to protease-activated receptors (PARs) in the brain appears to have multiple actions affecting both health and disease. Specifically, thrombin has been shown to lead to the onset of seizures via PAR-1 activation. In this perspective article, we review the putative mechanisms by which thrombin causes seizures and epilepsy. We propose a potential role of PAR-1 antagonists and novel thrombin inhibitors as new, possible antiepileptic drugs.
Frontiers in Cellular Neuroscience 01/2013; 7:19. · 4.17 Impact Factor
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Shaye Kivity,
Aviva Katzav,
Maria Teresa Arango,
Moran Landau-Rabi,
Yaron Zafrir,
Nancy Agmon-Levin,
Miri Blank,
Juan-Manuel Anaya,
Edna Mozes, Joab Chapman,
Yehuda Shoenfeld
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ABSTRACT: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naïve mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intra-cerebra-ventricularly (ICV) with the 16/6-Id antibody.
C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes.
16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control.
Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus.See related Commentary article: http://www.biomedcentral.com/1741-7015/11/91.
BMC Medicine 01/2013; 11:90. · 6.03 Impact Factor
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ABSTRACT: We investigated interactions between genetically and autoimmune-mediated coagulopathies by inducing experimental antiphospholipid syndrome (eAPS) in mice carrying the factor V Leiden (FVL) mutation.
eAPS was induced in heterozygous and homozygous FVL transgenic mice (C57BL/6 background) by immunization with β2-glycoprotein I (β2-GPI). Autoantibody levels were measured at 1 and 5 months post-immunization. Mice were tested at 4 months post-immunization for behavior and cognitive function in the staircase, elevated plus-maze, and swim T-maze tests. Brains were removed and analyzed by immunohistochemistry for inflammatory markers and neurodegenerative processes.
A single immunization with β2-GPI induced significantly higher and longer-lasting immune responses, and this was dependent on the number of FVL alleles. At 1 and 5 months post-immunization, levels of antibodies rose from 1.17 ± 0.07 to 1.62 ± 0.17 (optical density units; ODU) in homozygous FVL mice, compared with stable levels of 0.59 ± 0.17 and 0.48 ± 0.16 ODU in heterozygous FVL mice and a drop from 1.62 ± 0.21 to 0.61 ± 0.13 ODU in wild-type mice. Behavioral and cognitive clinical features of eAPS were also correlated with FVL allele load, as assessed by the elevated plus-maze (altered anxiety), staircase (hyperactivity and higher exploration), and swim T-maze (impaired learning) tests. Histological studies identified significant neurodegenerative changes in both grey and white matter in the eAPS-FVL brains. In spite of the potential interaction of two prothrombotic disease states, there were no ischemic lesions seen in this group.
The results indicate that genetically mediated coagulopathies increase the risk of developing coagulation-targeted autoimmune responses, and suggest the importance of antibody-mediated neurodegenerative processes in the brain in APS.
BMC Medicine 01/2013; 11:92. · 6.03 Impact Factor
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ABSTRACT: Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of Thrombin and a PAR-1 agonist on neuronal excitability and synaptic currents was assessed by whole cell-patch recordings of pyramidal neurons in rat hippocampal slices. In addition, PAR-1 distribution in different hippocampal regions was assessed using immunohistochemistry. We found that thrombin caused an increase in spontaneous action potential discharges of CA3 but not of CA1 pyramidal neurons. When excitatory synaptic activity was blocked, thrombin caused a marked reduction in spontaneous IPSCs in CA3 neurons, and a marked increase in the frequency of IPSCs in CA1 neurons. These effects are likely to be local, as they were reproduced in TTX-treated slices. In parallel, thrombin increased both the frequency and the amplitude of mEPSCs only in CA3 neurons. These effects were blocked by a selective PAR-1 antagonist. The higher expression of PAR-1 in stratum lucidum of CA3 is correlated with the effects of thrombin in this region. These results suggest that thrombin triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons, providing a novel insight to the pathophysiology of seizures following cerebrovascular events and present new avenues for therapeutic intervention.
Neurobiology of Disease 10/2012; · 5.40 Impact Factor
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ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts. In experimental APS (eAPS), a mouse model of APS, behavioral abnormalities develop in the absence of vessel occlusion or infarcts. Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits, we checked for lymphocytic infiltration, activation of glia and macrophages, as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior. Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3, CD4, CD8 and forkhead box P3 (Foxp3), respectively. GFAP, Iba1 and CD68-immunohistochemistry was performed, to check for activation of astrocytes, microglia and macrophages. Ligand binding densities of NMDA, AMPA, GABA(A) and 5-HT(1A) receptors were analyzed by in vitro receptor autoradiography. No significant inflammatory reaction occurred in eAPS mice. There was neither activation of astrocytes or microglia nor accumulation of macrophages. Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged. However, ligand binding densities of the modulatory serotonergic 5-HT(1A) receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed.
Immunobiology 06/2012; · 3.20 Impact Factor
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Michal Benkler,
Nancy Agmon-Levin,
Sharon Hassin-Baer,
Oren S. Cohen,
Oscar-Danilo Ortega-Hernandez,
Amalia Levy,
Samuel-Datum Moscavitch,
Martine Szyper-Kravitz,
Maya Damianovich,
Miri Blank, Joab Chapman,
Yehuda Shoenfeld
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ABSTRACT: Recent revelations of immune alterations in Parkinson’s disease have led to the convergence that an autoimmune mechanism may
play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson’s disease patients
and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with
central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine,
anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics,
clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson’s disease patients
(antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson’s disease, particularly dyskinesia and depression, were found to be associated
with the presence of these autoantibodies.
KeywordsParkinson’s disease–Autoimmune–Autoantibodies–Dyskinesia–Depression
Clinical Reviews in Allergy & Immunology 04/2012; 42(2):164-171. · 3.68 Impact Factor
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ABSTRACT: While myoclonus and ataxia are considered common in patients with familial Creutzfeld-Jakob disease (fCJD), other movement disorders are less prevalent. Objectives: To systemically evaluate the frequency of extrapyramidal signs and movement disorders in patients with fCJD.
A detailed neurological examination, with special emphasis on movement disorders and extrapyramidal signs, was conducted in 43 consecutive symptomatic CJD patients (26 males and 17 females; mean age 58.7 +/- 8.9 yrs, range 43-77 years) carrying the E200K mutation in the PRNPgene.
Limb or gait ataxia was noted in 38 patients (88%) (37 patients, 86%, had ataxia at presentation). Myoclonus was evident in 25/43 patients (58%) (21 patients, 49%, at presentation). In 95% of the patients (41/43) (37/43, 86% at presentation) at least one extrapyramidal sign throughout the disease course was noted, the most prevalent being rigidity (28/43, 65% of the patients; and 22/43, 51% at presentation), followed by the glabellar sign (24/43, 56% of the patients; and 22/43, 51% at presentation), bradykinesia (19/43, 44%; and 15/43, 35% at presentation), dystonia (15/43, 35%; 12/43, 28% at presentation) and tremor (13/43, 30%; 12/43, 28% at presentation).
In this unique population of fCJD patients, myoclonus was less prevalent than previously reported while other extrapyramidal signs were common and occurred at a relatively early stage of the disease. The high prevalence of movement disorders can be added to other phenomena characteristic of this familial disorder among Libyan lews. Whether this is attributable to the E200K mutation itself or to some other mechanism has still to be elucidated.
The Israel Medical Association journal: IMAJ 03/2012; 14(3):162-5. · 1.02 Impact Factor
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ABSTRACT: Antiphospholipid syndrome (APS) is characterized by thromboses and neuropsychiatric manifestations possibly linked to brain inflammation. In order to examine the levels of proinflammatory and anti-inflammatory cytokines in experimental APS (eAPS) mice brains, we measured the levels of TNF-α, IFN-γ, and IL-10 in brain homogenates (cytosolic fractions) and in brain slices (secreted level) at 6, 15, and 24 weeks after immunization. We induced eAPS by immunization of Balb/c mice with β(2)-glycoprotein I (β(2)GPI), the major autoantigen in the disease and controls with adjuvant alone. We found increased levels of secreted TNF-α in eAPS mice for the entire experiment period. Cytosolic and secreted IL-10 and IFN-γ levels in eAPS mice were lower at 6 and 15 weeks and higher at 24 weeks after immunization. The results suggest that brain disease in APS is associated with significant and complex changes in proinflammatory and anti-inflammatory cytokines.
Autoimmune diseases. 01/2012; 2012:404815.
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ABSTRACT: We studied the localization, activation and function of protease-activated receptor 1 (PAR-1) at the CNS synapse utilizing rat brain synaptosomes and slices. Confocal immunofluoresence and transmission electron microscopy in brain slices with pre-embedding diaminobenzidine (DAB) immunostaining found PAR-1 predominantly localized to the peri-synaptic astrocytic endfeet. Structural confocal immunofluorescence microscopy studies of isolated synaptosomes revealed spherical structures stained with anti-PAR-1 antibody which co-stained mainly for glial-filament acidic protein compared with the neuronal markers synaptophysin and PSD-95. Immunoblot studies of synaptosomes demonstrated an appropriate major band corresponding to PAR-1 and activation of the receptor by a specific agonist peptide (SFLLRN) significantly modulated phosphorylated extracellular signal-regulated kinase. A significant membrane potential depolarization was produced by thrombin (1 U/mL) and the PAR-1 agonist (100 μM) and depolarization by high K(+) elevated extracellular thrombin-like activity in the synaptosomes preparation. The results indicate PAR-1 localized to the peri-synaptic astrocytic endfeet is most likely activated by synaptic proteases and induces cellular signaling and modulation of synaptic electrophysiology. A protease mediated neuron-glia pathway may be important in both physiological and pathological regulation of the synapse.
Journal of Neurochemistry 08/2011; 119(3):460-73. · 4.06 Impact Factor
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ABSTRACT: The aim of the study was to examine the relationship between EEG abnormalities and the pattern of MRI changes in familial Creutzfeldt-Jakob Disease (fCJD) patients with E200K mutation. As part of a controlled, prospective study, 13 E200K fCJD patients underwent comprehensive evaluations, with EEG and an extensive MRI protocol that included one of the most prion-disease sensitive sequences, diffusion-weighted imaging (DWI). The relationship between EEG abnormalities and the pattern of DWI hyperintensities was examined. EEG demonstrated the classical CJD finding of PSWC (periodic sharp wave complexes) in five patients (38%) while in eight patients (62%) the EEG showed only slow activity. Six patients showed the typical cortical changes on MRI, and in five of them (83%) concordance between the MRI and the EEG was found. Five patients had isolated basal ganglia involvement per MRI, and in two of them (40%) concordance between the MRI and the EEG laterality was found. In the remaining two patients MRI did not show any changes suggesting CJD and EEG showed focal slow activity. The EEG of our E200K fCJD patients appears similar to that of the largest prion disease patient group, sporadic CJD (sCJD). EEG abnormalities in E200K fCJD appear to correlate mainly with cortical pathology, as revealed by DWI, rather than basal ganglia pathology. The observation that PSWC abnormalities reflect cortical rather than basal ganglia pathology is significant with respect to theories of the origins of EEG abnormalities in prion disease.
Journal of Neurology 08/2011; 259(3):491-6. · 3.47 Impact Factor
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Zeev Meiner,
Esther Kahana,
Fanny Baitcher,
Amos D Korczyn, Joab Chapman,
Oren S Cohen,
Ron Milo,
Judith Aharon-Perez,
Oded Abramsky,
Ruth Gabizon,
Hanna Rosenmann
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ABSTRACT: One of the largest clusters of genetic Creutzfeldt-Jakob disease (gCJD) is found among Jews of Libyan origin in Israel and is linked to the E200K mutation in PRNP (gCJDE200K). The aim of this study was to compare the levels of cerebrospinal fluid (CSF) biomarkers, Tau and 14-3-3 proteins, between gCJDE200K patients, sporadic CJD (sCJD) patients and non-CJD controls in Israel between the years 1996-2006. The levels of Tau and 14-3-3 proteins in CSF were measured by ELISA and immunoblotting, respectively. CSF Tau levels were similar in gCJDE200K and sCJD, both were significantly higher than in controls [1,107 ± 470 pg/ml [33/46 (72%)] of the cases >1,000 pg/ml, 1,280 ± 580 pg/ml [25/30 (83.3%)], and 354 ± 338 pg/ml [17/243 (6.9%)], respectively, p < 0.001]. 14-3-3 was detected in CSF of 41/53 (77%) of each gCJDE200K and sCJD patients tested, but only in 70/417 (16.8%) of controls (p < 0.001). An inverse correlation was found between disease duration and Tau levels in both gCJDE200K and sCJD (r = -0.464 and r = -0.284). No difference was found in Tau or 14-3-3 between the various codon 129 genotypes. We conclude that CSF biomarkers, Tau and 14-3-3, may be used in the diagnosis in both patients' populations, presenting a similar sensitivity yet Tau assay having higher specificity.
Journal of Neurology 02/2011; 258(2):255-62. · 3.47 Impact Factor
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ABSTRACT: Pruritus, a common feature of animal prion diseases such as scrapie, is rarely reported in humans with Creutzfeldt-Jakob disease (CJD), and its anatomical background is not well defined. The present study was undertaken to carry out a methodical prospective search for the prevalence of pruritus in CJD patients and investigate its anatomical substrate by MRI. The study group included consecutive familial and sporadic CJD patients carrying the E200K PRNP mutation followed up in a longitudinal prospective study between the years 2005 and 2008. Pruritus was prospectively screened for and diffusion-weighted imaging (DWI) was used to correlate brain diffusion abnormalities with pruritus in CJD patients. Pruritus was present in 6/31 (19.35%) patients with familial disease (fCJD) and in none of the patients with sporadic disease (sCJD). Pruritus was a presenting symptom in one patient and evolved during the course of the disease in the other five patients. The pruritus was generalized in three patients, regional in two and localized in one patient. It was transient in one patient and continued throughout the disease in five patients. DWI showed that pruritus was significantly associated with reduced diffusion in the several areas known to be affected by CJD, but most significantly in the midbrain periaqueductal grey matter. Pruritus is relatively common in patients with familial CJD carrying the E200K mutation. Our findings point to a central origin that involves damage to the inhibitory gating mechanism for itch in the periaqueductal grey matter.
Journal of Neurology 01/2011; 258(1):89-95. · 3.47 Impact Factor
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Michal Benkler,
Nancy Agmon-Levin,
Sharon Hassin-Baer,
Oren S Cohen,
Oscar-Danilo Ortega-Hernandez,
Amalia Levy,
Samuel-Datum Moscavitch,
Martine Szyper-Kravitz,
Maya Damianovich,
Miri Blank, Joab Chapman,
Yehuda Shoenfeld
[show abstract]
[hide abstract]
ABSTRACT: Recent revelations of immune alterations in Parkinson's disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson's disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson's disease patients (antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson's disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.
Clinical Reviews in Allergy & Immunology 01/2011; 42(2):164-71. · 3.68 Impact Factor
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Yoram Nevo,
Shlomit Aga-Mizrachi,
Edva Elmakayes,
Nurit Yanay,
Keren Ettinger,
Moran Elbaz,
Zivia Brunschwig,
Oshrat Dadush,
Galit Elad-Sfadia,
Roni Haklai,
Yoel Kloog, Joab Chapman,
Shimon Reif
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ABSTRACT: The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy(2J)/dy(2J) mouse model of merosin deficient congenital muscular dystrophy. The dy(2J)/dy(2J) mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy(2J)/dy(2J) mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy(2J)/dy(2J) mouse model of congenital muscular dystrophy.
PLoS ONE 01/2011; 6(3):e18049. · 4.09 Impact Factor
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ABSTRACT: Glatiramer acetate (GA) significantly ameliorates multiple sclerosis and was initially discovered through its effects on the animal model experimental autoimmune encephalomyelitis (EAE). Guillain-Barré syndrome (GBS) is a relatively common demyelinating disease of peripheral nerves for which there is a parallel animal model, experimental autoimmune neuritis (EAN). We review the treatments found useful in EAN with special emphasis on the need for quick onset of action and the relevance of treatments used for EAE and multiple sclerosis. We evaluated the effect of GA administered by a novel intraperitoneal route in EAN. GA significantly ameliorated the severity of disease in rats (F = 6.3, p = 0.01 by analysis of variance (ANOVA)) and course of disease (F = 4.9, p = 0.02 by repeated-measures ANOVA with a day x treatment interaction term). Neurophysiology data supported the trend for the beneficial effect of GA. Myelin-induced immune cell proliferation was significantly modulated by GA (p < 0.025). This report describes a novel route of administration of GA and a rapid beneficial effect of GA in EAN. GA may be useful in human diseases, such as GBS, where the intravenous route may offer a rapid onset of drug action.
Clinical Reviews in Allergy & Immunology 01/2011; 42(2):181-8. · 3.68 Impact Factor
