West Jerusalem, Israel
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Elishmereni M.,Hebrew University of Jerusalem | Alenius H.T.,Finnish Institute of Occupational Health | Bradding P.,University of Leicester | Mizrahi S.,Hebrew University of Jerusalem | And 6 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Background: Mast cells (MCs) and eosinophils (Eos) are the key effector cells of the allergic reaction. Although classically associated with different stages of the response, the cells co-exist in the inflamed tissue in the late and chronic phases in high numbers and are likely to cross-talk. While some mediators of MCs are known to affect Eos biology and vice versa, paracrine and physical interplay between the two cells has not been described yet. We aimed to investigate whether intercellular MC-Eos communication could take place in the allergic response and exert functional bidirectional changes on the cells. Methods: Tissue sections from various allergic disorders were specifically stained for both cells. Human cord blood-derived MCs and peripheral blood Eos, co-cultured under different conditions, were studied by advanced microscopy and flow cytometry. Results: Several co-localized MC-Eos pairs were detected in human nasal polyps and asthmatic bronchi, as well in mouse atopic dermatitis. In vitro, MCs and Eos formed stable conjugates at high rates, with clear membrane contact. In the presence of MCs, Eos were significantly more viable under several co-culture conditions and at both IgE-activated and steroid-inhibited settings. MC regulation of Eos survival required communication through soluble mediators but was even more dependent on physical cell-cell contact. Conclusions: Our findings provide the first evidence for a complex network of paracrine and membrane interactions between MCs and Eos. The prosurvival phenotype induced by this MC-Eos interplay may be critical for sustaining chronic allergic inflammation. © 2010 John Wiley & Sons A/S.


Durrani O.,University of Birmingham | Banahan K.,Trinity College Dublin | Sheedy F.J.,Trinity College Dublin | McBride L.,King's College London | And 10 more authors.
Rheumatology | Year: 2011

Objectives: The initiating cause of Behç et's disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD. Methods: TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain-containing adaptor protein) in patients with BD from different geographical regions. Results: TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients. Conclusion: TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.


Cohen J.E.,Hadassah University | Cohen J.E.,Hebrew University of Jerusalem | Moscovici S.,Hadassah University | Halpert M.,Hebrew University of Jerusalem | Itshayek E.,Hadassah University
Journal of Clinical Neuroscience | Year: 2012

The poor natural history of central retinal artery occlusion (CRAO) is usually not modified with conventional, conservative management techniques. Guidelines for selective intraarterial ophthalmic thrombolysis are still lacking. While many centers continue to perform this procedure with promising results, others are reluctant due to conflicting findings in recent studies. We present our experience in a 36-year-old male with CRAO. Based on the patient's clinical presentation, we planned to perform selective intraarterial ophthalmic thrombolysis via the ophthalmic artery. When angiography demonstrated that the retina was not supplied by the ophthalmic artery, but by a meningo-ophthalmic artery branching from the internal maxillary artery, we instead administered thrombolytic agents via the meningo-ophthalmic artery. The patient's vision recovered completely, with visual acuity and visual field examination at 30 day follow up comparable to his pre-treatment status. This case emphasizes the need for external carotid artery examination in cases of nonvisualization of the ophthalmic artery. In addition, it illustrates the successful use of the meningo-ophthalmic artery to perform selective intraarterial thrombolysis for CRAO. © 2011 Elsevier Ltd. All rights reserved.


Guerrero-Preston R.,Johns Hopkins University | Guerrero-Preston R.,University of Puerto Rico at San Juan | Goldman L.R.,Johns Hopkins University | Brebi-Mieville P.,Johns Hopkins University | And 13 more authors.
Epigenetics | Year: 2010

Environmental exposures in utero may alter the epigenome, thus impacting chromosomal stability and gene expression. We hypothesized that in utero exposures to maternal smoking and perfluoroalkyl compounds (PFCs) are associated with global DNA hypomethylation in umbilical cord serum. Our objective was to determine if global DNA methylation could be used as a biomarker of in utero exposures to maternal smoking and PFCs. Using an ELISA-based method, global DNA methylation was quantified in umbilical cord serum from 30 newborns with high (>10 ng/ml, mean 123.8 ng/ml), low (range 1-10 ng/ml, mean 1.6 ng/ml) and very low (<1 ng/ml, mean 0.06 ng/ml) cord serum cotinine levels. Y chromosome analysis was performed to rule out maternal DNA cross-contamination. Cord serum global DNA methylation showed an inverse dose response to serum cotinine levels (p < 0.001). Global DNA methylation levels in cord blood were the lowest among newborns with smoking mothers (mean = 15.04%; 95% CI, 8.4, 21.7) when compared to babies of mothers who were second-hand smokers (21.1%; 95% CI, 16.6, 25.5) and non-smokers (mean = 29.2%; 95% CI, 20.1, 38.1). Global DNA methylation was inversely correlated with serum PFOA (r = -0.35, p = 0.06) but not PFOS levels. Serum Y chromosome analyses did not detect maternal DNA cross-contamination. This study supports the use of global DNA methylation status as a biomarker of in utero exposure to cigarette smoke and PFCs. © 2010 Landes Bioscience.


Rubinger D.,Hadassah University | Backenroth R.,Hadassah University | Sapoznikov D.,Hadassah University
Seminars in Dialysis | Year: 2013

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality. © 2013 Wiley Periodicals, Inc.


Flori E.,San Gallicano Dermatologic Institute IRCCS | Mastrofrancesco A.,San Gallicano Dermatologic Institute IRCCS | Kovacs D.,San Gallicano Dermatologic Institute IRCCS | Ramot Y.,Hadassah University | And 7 more authors.
Pigment Cell and Melanoma Research | Year: 2011

Given the importance of the tanning response in protecting human skin from the harmful effects of UV radiation, one important research priority is to identify novel molecules that are capable of promoting pigmentation and/or antioxidant defence. Parrodienes share some structural features with carotenoids and retinoids, stimulate cell antioxidant defence and counteract senescence-like phenotype in fibroblasts. We selected the parrodiene-derivative 2,4,6-octatrienoic acid (Octa) to study its impact on key parameters of melanogenesis and antioxidant defence in organ-cultured human skin and in normal human melanocytes. Octa promoted melanogenesis by up-regulating tyrosinase and microphthalmia-associated transcription factor expression. This correlated with an increase of melanin content in both human epidermis in situ and cultured human epidermal melanocytes. Moreover, Octa increased the biological antioxidant potential content and the expression and activity of catalase. Activation of peroxisome proliferator-activated receptor (PPAR)-γ was necessary to evoke these effects. These data strongly encourage the systematic study of Octa as a novel candidate promoter of human skin photoprotection. © 2011 John Wiley & Sons A/S.


Cohen J.E.,Hadassah University | Gomori J.M.,Hadassah University | Leker R.R.,Hadassah University | Ben-Hur T.,Hadassah University | And 2 more authors.
Neurological Research | Year: 2010

Background and Purpose: Internal carotid artery dissections (ICADs) with occlusion present with a high morbidity and mortality. No specific medical treatment has proven to be effective in this setting. In selected cases of ICAD with occlusion, stent-assisted angioplasty has been shown to be effective in restoring the perfusion. Spontaneous ICAD causing occlusion successfully recanalized with multiple telescoped stents extending intracranially has only been reported exceptionally. Methods: We report cases of symptomatic acute carotid occlusion after spontaneous dissection extending from the cervical to the petrocavernous ICA segments. Imaging studies revealed the presence of an extensive penumbra area in every case. Patients were treated by means of multiple stents deployed in a telescoped fashion with the aid of a delayed double-contrast road map. Results: Post-procedural angiography demonstrated restitution of the carotid lumen with no signs of residual dissection or intracranial emboli. The patients improved rapidly, showing no residual neurological deficit after a week. At follow-up, patients are clinically asymptomatic and the vessel is patent with no radiological signs of myointimal hyperplasia. Conclusions: The successful angiographic and clinical results observed in our cases of extraintracranial stenting of a long carotid dissection causing occlusion contribute to the literature of carotid dissection treated with multiple stents. © 2010 W. S. Maney & Son Ltd.


Elishmereni M.,Hebrew University of Jerusalem | Bachelet I.,Hebrew University of Jerusalem | Ben-Efraim A.H.N.,Hebrew University of Jerusalem | Mankuta D.,Hadassah University | Levi-Schaffer F.,Hebrew University of Jerusalem
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2013

Background Mast cells (MCs) and eosinophils (Eos), the key effector cells in allergy, are abundantly co-localized particularly in the late and chronic stages of allergic inflammation. Recent evidence has outlined a specialized 'allergic effector unit' in which MCs and Eos communicate via both soluble mediators and physical contact. However, the functional impact of this bi-directional crosstalk on the cells' effector activities has not yet been revealed. We aimed to investigate whether MC/eosinophil interactions can influence the immediate and late activation phenotypes of these cells. Methods Human and murine MCs and Eos were co-cultured under various conditions for 1-2 h or 1-3 days, and in selected experiments cell-cell contact was blocked. Cell migration and mediator release were examined, and flow cytometry was applied to stain intracellular signaling molecules and surface receptors. Results Eosinophils enhanced basal MCs mediator release and co-stimulated IgE-activated MCs through physical contact involving CD48-2B4 interactions. Reciprocally, resting and IgE-stimulated MCs led to eosinophil migration and activation through a paracrine-dependent mechanism. Increased phosphorylation of activation-associated signaling molecules, and enhanced release of tumor necrosis factor α, was observed in long-term co-cultures. Eosinophils also showed enhanced expression of intercellular adhesion molecule 1, which depended on direct contact with MCs. Conclusions Our findings reveal a new role for MC/eosinophil interplay in augmenting short- and long-term activation in both cells, in a combined physical/paracrine manner. This enhanced functional activity may thus critically contribute to the perpetuation of the inflammatory response in allergic conditions. © 2012 John Wiley & Sons A/S.


Bayya A.,Hadassah University | Rubinger D.,Hadassah University | Linton D.M.,Hadassah University | Sviri S.,Hadassah University
International Urology and Nephrology | Year: 2011

Background Hypotension during hemodialysis is frequent in patients with cardiovascular disease who have a limited physiological compensatory response. Recent advances in technology allow non-invasive monitoring of cardiac output and derived hemodynamic parameters. This prospective study evaluated episodes of intradialytic hypotension using clinical data and continuous non-invasive hemodynamic monitoring by impedance cardiography. Methods Forty-eight chronic hemodialysis patients, with prevalence for intradialytic hypotensive episodes, underwent evaluation with non-invasive impedance cardiography (Physioflow®) before, during and after a regular dialysis session. Results During continuous non-invasive cardiac monitoring, a fall of systolic arterial blood pressure of 20% or more at least once during hemodialysis was detected in 18 patients (37.5%)-thereafter identified as the "Unstable" group. In 30 patients- thereafter called the "Stable" group, the blood pressure did not change significantly. During hypotension, a decrease in cardiac output was found in 11 of the 18 unstable patients, and a significant fall in peripheral resistance in the remaining 7. Enddiastolic filling ratio was significantly lower in the unstable group. The most significant predictors associated with intradialytic hypotension were the presence of ischemic heart disease (P = 0.05), and medication with beta blockers (P = 0.037) and calcium channel blockers (P = 0.018). Conclusions Hemodynamic changes in dialysis patients with hypotensive episodes included decreased cardiac output or decreased peripheral resistance. A lower end-diastolic filling ratio may be regarded as a marker for reduced preload in these patients. Noninvasive impedance cardiography may be used to evaluate risk factors for hypotension in dialysis patients. © Springer Science+Business Media, B.V. 2010.


Hurley K.,Sloan Kettering Cancer Center | Rubin L.R.,New School for Social Research | Werner-Lin A.,New York University | Sagi M.,Hadassah University | And 6 more authors.
Cancer | Year: 2012

BACKGROUND: Studies have shown that BRCA1/2 mutation carriers are interested in learning about reproductive options such as preimplantation genetic diagnosis (PGD) to prevent passing their risk onto their children. However, attitudes vary widely, and the procedure raises complex ethical and psychosocial issues. This complexity, plus the highly technical nature of PGD, makes it difficult to integrate PGD information into genetic counseling sessions that already cover probabilistic, emotionally charged risk information. METHODS: A total of 33 carriers of the BRCA1/2 mutation who were of reproductive age and had previously undergone genetic counseling viewed a tutorial regarding PGD and were interviewed concerning their attitudes toward PGD and preferences about how to include PGD information in genetic counseling. RESULTS: The majority of participants preferred to be briefly informed of the availability of PGD information, and to receive written materials regarding PGD, but with the option of deferring detailed discussion if they already believed themselves to be overloaded or perceived that PGD was not immediately relevant to their risk management and/or childbearing plans. For some individuals, the stress of testing temporarily interfered with information processing, producing states of cognitive avoidance ("in a fog," or "tuning out"). Some preferred to discuss PGD with a physician with whom they had an ongoing relationship (eg, obstetrician/gynecologist, primary care provider, or oncologist). CONCLUSIONS: Providers offering cancer genetic testing may consider indicating the availability of PGD information to their patients, while attending to the patients' level of interest and ability to absorb information. Research is needed to link patient responses to information overload with psychosocial outcomes (eg, distress, and quality of decision-making). Continuing medical education is needed to support providers in facilitating informed decisions regarding PGD. © 2012 American Cancer Society.

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