The Chaim Sheba Medical Center

Tel Aviv, Israel

The Chaim Sheba Medical Center

Tel Aviv, Israel
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Maggio N.,The Chaim Sheba Medical Center | Maggio N.,Weizmann Institute of Science | Cavaliere C.,The Second University of Naples | Papa M.,The Second University of Naples | And 5 more authors.
Neurobiology of Disease | Year: 2013

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. © 2012 Elsevier Inc.


Maggio N.,Weizmann Institute of Science | Maggio N.,The Chaim Sheba Medical Center | Segal M.,Weizmann Institute of Science
Experimental Neurology | Year: 2012

The role of stress hormones in the initiation of epileptic seizures has been studied extensively in the past decade, with conflicting observations, from suppression to exacerbation of spontaneous seizures. We have now studied the effects of an acute stress on reactivity of juvenile rats to kainic acid (KA), which produces epileptic seizures. With a short (30. s) stress-KA delay, stress exacerbated epilepsy via activation of mineralocorticosterone receptors (MR). With a long (60. min) stress-KA delay, seizures were suppressed through activation of a glucocorticosterone receptor (GR). In a parallel study with CA1 pyramidal neurons in acute hippocampal slices, activation of MRs reduced the frequency of mIPSCs, whereas activation of GRs produced a slow onset, 2.5 fold increase in amplitudes of mIPSCs. GR effects were not mediated by protein synthesis, but did require activation of some protein kinases. These experiments suggest that stress can either facilitate or suppress seizures, in a time and receptor dependent manner. © 2011 Elsevier Inc.


Maggio N.,Weizmann Institute of Science | Maggio N.,The Chaim Sheba Medical Center | Segal M.,Weizmann Institute of Science
Hippocampus | Year: 2012

The ventral hippocampus (VH) was recently shown to express lower magnitude LTP compared to the dorsal hippocampus (DH). Exposure to acute stress reversed this difference, and VH slices from stressed rats expressed larger LTP than that produced in the DH, which was reduced by stress. In an attempt to uncover the mechanisms responsible for this differential action, we found that activation of mineralocorticosteroid receptors (MR) by aldosterone mimics the effects of stress in the VH, to facilitate LTP. We also found that aldosterone reduces GABAergic inhibition in both the DH and VH. We now examined if the reduction in inhibition caused by MRs can underlie the altered LTP in the VH. Rat hippocampal slices were recorded before and after exposure to the GABA antagonist bicuculline and to aldosterone. As expected, blockade of GABA with bicuculline enhanced LTP in both DH and VH. However, its effect did not occlude that of aldosterone in the VH, indicating that the latter drug does not operate by blockade of inhibition. Furthermore, the NMDA receptor antagonist APV blocked LTP induced in the presence of bicuculline, but did not block LTP facilitation by aldosterone, indicating that the effect of aldosterone is not mediated by the conventional NMDA-dependent LTP generating mechanism. Furthermore, rapid effects of aldosterone on LTP were blocked by the L-type calcium channel antagonist nifedipine, indicating that aldosterone facilitates calcium influx via nifedipine-sensitive channels, to enhance LTP in the VH. The locus of effect of aldosterone may be the presynaptic terminal, as it caused a marked facilitation of paired pulse potentiation in the VH but not in the DH. These experiments confirm and extend previous suggestions for the effects of MRs on neuronal plasticity in the hippocampus. © 2010 Wiley Periodicals, Inc.


Maggio N.,The Chaim Sheba Medical Center | Maggio N.,The gol Neuroscience Center | Shavit Stein E.,The gol Neuroscience Center | Segal M.,Weizmann Institute of Science
Hippocampus | Year: 2015

A transient ischemic episode causes a reduction in evoked EPSPs in hippocampal slices, followed by an NMDA dependent LTP. We explored the relations between ischemic LTP (iLTP) and the more conventional tetanic LTP (tLTP) in CA1 region of slices along the dorsal/ventral axis of the hippocampus. Dorsal hippocampal (DH) slices produced a much larger iLTP than their ventral hippocampal (VH) counterparts. In both regions, iLTP and tLTP shared the same NMDA mediated potentiation, such that one LTP saturated the ability of the other treatment to generate LTP. The smaller LTP in VH was correlated with a lower NMDA-mediated EPSP, and a parallel lower density of NMDA receptors. Calcium permeable AMPA receptors did not contribute to the DH/VH disparity. We conclude that a differential distribution of NMDA receptor subunits along the septotemporal axis of the hippocampus controls the diverse ability to evoke iLTP and tLTP in the two regions and may underlie their characteristic behavioral outputs as well as their differential sensitivity to ischemia. © 2015 Wiley Periodicals, Inc.


Maggio N.,The Chaim Sheba Medical Center | Vlachos A.,Goethe University Frankfurt
Neuroscience | Year: 2014

Work from the past 40years has unraveled a wealth of information on the cellular and molecular mechanisms underlying synaptic plasticity and their relevance in physiological brain function. At the same time, it has been recognized that a broad range of neurological diseases may be accompanied by severe alterations in synaptic plasticity, i.e., 'maladaptive synaptic plasticity', which could initiate and sustain the remodeling of neuronal networks under pathological conditions. Nonetheless, our current knowledge on the specific contribution and interaction of distinct forms of synaptic plasticity (including metaplasticity and homeostatic plasticity) in the context of pathological brain states remains limited. This review focuses on recent experimental evidence, which highlights the fundamental role of endoplasmic reticulum-mediated Ca2+ signals in modulating the duration, direction, extent and type of synaptic plasticity. We discuss the possibility that intracellular Ca2+ stores may regulate synaptic plasticity and hence behavioral and cognitive functions at the interface between physiology and pathology. © 2014 IBRO.


Segal M.,Weizmann Institute of Science | Richter-Levin G.,Haifa University | Maggio N.,Weizmann Institute of Science | Maggio N.,The Chaim Sheba Medical Center
Hippocampus | Year: 2010

Recent observations have caused a drastic shift in the conception of the hippocampus as a homogeneous structure that subserves cognitive functions, either spatial maps or short term episodic memory, to a structure that is associated with both cognitive and emotional functions. In fact, the assignment of cognitive functions to the hippocampus is restricted to its dorsal sector. In contrast, the ventral hippocampus (VH) appears to be associated with control of behavioral inhibition, stress and emotional memory, but not with strictly cognitive functions. Curiously, the VH but not the dorsal hippocampus (DH) is associated with the development of affective disorders. In line with these collective observations, we and others have found that the ability to evoke a sustained long term potentiation (LTP), a cellular correlate of learning and memory, is much lower in the VH compared to the DH. Strikingly, acute stress as well as direct exposure to corticosterone affect DH and VH in an opposite manner; causing facilitation of LTP in the VH and its suppression in the DH. This double dissociative action results from activation of different steroid receptor species in the DH and VH. Since the DH and VH differ in efferent connectivity, and since the strength of LTP can be considered as an indicator of strength of synaptic connectivity, these results suggest that stress regulates the routes by which the hippocampus is functionally linked to the rest of the brain such that under stress, the ventral route to the amygdala is enabled while the dorsal route to the neocortex is suppressed. This selective routing may underlie the complex outcome of stress on hippocampal and amygdala physiology and behavior. © 2009 Wiley-Liss, Inc.


Bangalore S.,New York University | Kumar S.,University of Nebraska Medical Center | Kjeldsen S.E.,University of Oslo | Makani H.,Columbia University | And 6 more authors.
The Lancet Oncology | Year: 2011

Background: The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials. Methods: We undertook traditional direct comparison meta-analyses, multiple comparisons (network) meta-analyses, and trial sequential analyses. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from 1950, to August, 2010, for randomised clinical trials of antihypertensive therapy (ARBs, angiotensin-converting-enzyme inhibitors [ACEi], β blockers, calcium-channel blockers [CCBs], or diuretics) with follow-up of at least 1 year. Our primary outcomes were cancer and cancer-related deaths. Findings: We identified 70 randomised controlled trials (148 comparator groups) with 324 168 participants. In the network meta-analysis (fixed-effect model), we recorded no difference in the risk of cancer with ARBs (proportion with cancer 2·04%; odds ratio 1·01, 95% CI 0·93-1·09), ACEi (2·03%; 1·00, 0·92-1·09), β blockers (1·97%; 0·97, 0·88-1·07), CCBs (2·11%; 1·05, 0·96-1·13), diuretics (2·02%; 1·00, 0·90-1·11), or other controls (1·95%, 0·97, 0·74-1·24) versus placebo (2·02%). There was an increased risk with the combination of ACEi plus ARBs (2·30%, 1·14, 1·02-1·28); however, this risk was not apparent in the random-effects model (odds ratio 1·15, 95% CI 0·92-1·38). No differences were detected in cancer-related mortality for ARBs (death rate 1·33%; odds ratio 1·00, 95% CI 0·87-1·15), ACEi (1·25%; 0·95, 0·81-1·10), β blockers (1·23%; 0·93, 0·80-1·08), CCBs (1·27%; 0·96, 0·82-1·11), diuretics (1·30%; 0·98, 0·84-1·13), other controls (1·43%; 1·08, 0·78-1·46), and ACEi plus ARBs (1·45%; 1·10, 0·90-1·32). In direct comparison meta-analyses, similar results were recorded for all antihypertensive classes, except for an increased risk of cancer with ACEi and ARB combination (OR 1·14, 95% CI 1·04-1·24; p=0·004) and with CCBs (1·06, 1·01-1·12; p=0·02). However, we noted no significant differences in cancer-related mortality. On the basis of trial sequential analysis, our results suggest no evidence of even a 5-10% relative risk (RR) increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and ARB combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk. Interpretation: Our analysis refutes a 5·0-10·0% relative increase in the risk of cancer or cancer-related death with the use of ARBs, ACEi, β blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out. Funding: None. © 2011 Elsevier Ltd.


Silverberg D.,The Chaim Sheba Medical Center
Vascular and endovascular surgery | Year: 2010

We report a single-center experience with the endovascular management of mycotic aortic aneurysms. Four cases of mycotic aortic aneurysms are described; all treated with endovascular stent graft with variable configurations. All patients underwent successful placement of stent grafts for their aneurysms. No 30-day perioperative mortality was observed. One patient died during the follow-up period from a cause unrelated to the aneurysm. Repair of mycotic aneurysms can be accomplished with endovascular repair. This may be a valid alternative to open repair particularly in patients who are not candidates for conventional open repair.


Hajdu S.D.,The Chaim Sheba Medical Center | Agmon-Levin N.,The Chaim Sheba Medical Center | Shoenfeld Y.,The Chaim Sheba Medical Center | Shoenfeld Y.,Tel Aviv University
European Journal of Clinical Investigation | Year: 2011

Eur J Clin Invest 2011; 41 (2): 203-211Background Since the 1960s, silicone implants have been successfully used for breast augmentation and reconstruction. However, safety issues regarding the use of silicone have led to a moratorium by the US Food and Drug Administration between 1992 and 2006.Design To date, although the moratorium has been removed and women overwhelmingly prefer silicone over saline implants, local and systemic adverse effects still remain a concern.Results Silicone-elicited inflammatory fibro-proliferative response and capsular contracture is irrefutable. Studies on silicone breast implants have not supported a relationship to carcinogenesis, whereas that to autoimmunity mainly to nondefined autoimmune phenomena seems very plausible. These silicone-related autoimmune adverse events termed 'siliconosis' are probably limited to a small minority of implanted patients.Conclusions Risk factors, such as characteristic environmental exposure and/or genetic predisposition, still require further elucidation. Similarly to antibacterial agents, texturized implants and Zafirlukast that were found to be beneficial in inhibiting fibro-proliferative response and capsular contracture, elucidating autoimmune-related risk factors might subsequently enable physicians to accurately predict long-term health status of silicone implant recipients. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.


Grossman E.,The Chaim Sheba Medical Center | Grossman E.,Tel Aviv University | Laudon M.,Neurim Pharmaceuticals Ltd | Zisapel N.,Neurim Pharmaceuticals Ltd | Zisapel N.,Tel Aviv University
Vascular Health and Risk Management | Year: 2011

Background: Patients with nocturnal hypertension are at higher risk for cardiovascular complications such as myocardial infarction and cerebrovascular insult. Published studies inconsistently reported decreases in nocturnal blood pressure with melatonin. Methods: A meta-analysis of the efficacy and safety of exogenous melatonin in ameliorating nocturnal blood pressure was performed using a random effects model of all studies fitting the inclusion criteria, with subgroup analysis of fast-release versus controlled-release preparations. Results: Seven trials (three of controlled-release and four of fast-release melatonin) with 221 participants were included. Meta-analysis of all seven studies did not reveal significant effects of melatonin versus placebo on nocturnal blood pressure. However, subgroup analysis revealed that controlled-release melatonin significantly reduced nocturnal blood pressure whereas fastrelease melatonin had no effect. Systolic blood pressure decreased significantly with controlledrelease melatonin (-6.1 mmHg; 95% confidence interval [CI] -10.7 to -1.5; P = 0.009) but not fast-release melatonin (-0.3 mmHg; 95% CI -5.9 to 5.30; P = 0.92). Diastolic blood pressure also decreased significantly with controlled-release melatonin (-3.5 mmHg; 95% CI -6.1 to -0.9; P = 0.009) but not fast-release melatonin (-0.2 mmHg; 95% CI -3.8 to 3.3; P = 0.89). No safety concerns were raised. Conclusion: Add-on controlled-release melatonin to antihypertensive therapy is effective and safe in ameliorating nocturnal hypertension, whereas fast-release melatonin is ineffective. It is necessary that larger trials of longer duration be conducted in order to determine the long-term beneficial effects of controlled-release melatonin in patients with nocturnal hypertension. © 2011 Grossman et al, publisher and licensee Dove Medical Press Ltd.

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