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Netanya, Israel

Solmesky L.,Tel Aviv University | Lefler S.,Tel Aviv University | Jacob-Hirsch J.,Cancer Research Center | Bulvik S.,Laniado Hospital | And 2 more authors.
PLoS ONE | Year: 2010

Human mesenchymal stem cells (hMSC) are easily isolated from the bone marrow by adherence to plastic surfaces. These cells show self-renewal capacity and multipotency. A unique feature of hMSC is their capacity to survive without serum. Under this condition hMSC neither proliferate nor differentiate but maintain their biological properties unaffected. Therefore, this should be a perfect platform to study the biological effects of defined molecules on these human stem cells. We show that hMSC treated for five days with retinoic acid (RA) in the absence of serum undergo several transcriptional changes causing an inhibition of ERK related pathways. We found that RA induces the loss of hMSC properties such as differentiation potential to either osteoblasts or adipocytes. We also found that RA inhibits cell cycle progression in the presence of proliferating signals such as epidermal growth factor (EGF) combined with basic fibroblast growth factor (bFGF). In the same manner, RA showed to cause a reduction in cell adhesion and cell migration. In contrast to these results, the addition of EGF+bFGF to serum free cultures was enough to upregulate ERK activity and induce hMSC proliferation and cell migration. Furthermore, the addition of these factors to differentiation specific media instead of serum was enough to induce either osteogenesis or adipogenesis. Altogether, our results show that hMSC's ability to survive without serum enables the identification of signaling factors and pathways that are involved in their stem cell biological characteristics without possible serum interferences. © 2010 Solmesky et al.

Shimoni Z.,Infectious Disease Unit and Internal Medicine B | Rodrig J.,Laniado Hospital | Kamma N.,Infectious Control Nurse | Froom P.,Tel Aviv University
BMJ Open | Year: 2012

Objectives: To determine if more restrictive indications for urinary catheterisation reinforced by daily chart review will lower catheterisation rates. Design: An historical comparative observational study. Setting: An internal medicine department in a regional hospital in Israel. Participants: The authors compared 882 patients hospitalised after a change in policy to an historical cohort of 690 hospitalised patients. Exclusions included patients less than age 30 and those with bladder outlet obstruction. Intervention: Emergency and internal medicine department physicians received instruction on a more restricted urinary catheterisation policy. During daily chart rounds, admissions were discussed with an emphasis on the appropriateness of all new urinary catheter insertions. Main outcome measures: The primary outcome measure was catheterisation rate by admission diagnosis. Secondary outcome measures were the need for post-admission in hospital catheterisations and the rate of indwelling catheters 14 or more days after discharge. Results: There was a reduction in catheterisation rate in patients with congestive heart failure from 30/106 (29.3%) to 3/107 (2.8%) (p<0.001), in patients with an admission diagnosis of fever unable to provide a urine sample for culture from 35/132 (26.5%) to 12/153 (7.8%) (p<0.001) and in patients admitted for palliative care from 51.7% (15/29) to 12.0% (3/25) (p=0.002). The overall rate of catheterisation decreased from 17.5% (121/690) to 6.6% (58/882) (p<0.001). There was only one indicated catheterisation after admission due to the change in policy, and the proportion of patients discharged with catheters decreased. Conclusion: The use of more restrictive indications for urinary catheterisation along with daily chart rounds can reduce the rate of urinary catheterisation in an internal medicine department without adverse consequences.

Markowitz S.Y.,Laniado Hospital | Baron E.P.,Cleveland Clinic | Hentz J.G.,Mayo Medical School | Kalidas K.,University of South Florida | And 4 more authors.
Headache | Year: 2014

Objective To identify factors associated with triptan discontinuation among migraine patients. Background It is unclear why many migraine patients who are prescribed triptans discontinue this treatment. This study investigated correlates of triptan discontinuation with a focus on potentially modifiable factors to improve compliance. Methods This multicenter cross-sectional survey (n = 276) was performed at US tertiary care headache clinics. Headache fellows who were members of the American Headache Society Headache Fellows Research Consortium recruited episodic and chronic migraine patients who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years). Univariate analyses were first completed to compare current triptan users to past users for: migraine characteristics, other migraine treatments, triptan education, triptan efficacy, triptan side effects, type of prescribing provider, Migraine Disability Assessment (MIDAS) scores and Beck Depression Inventory (BDI) scores. Then, a multivariable logistic regression model was selected from all possible combinations of predictor variables to determine the factors that best correlated with triptan discontinuation. Results Compared with those still using triptans (n = 207), those who had discontinued use (n = 69) had higher rates of medication overuse (30 vs 18%, P =.04) and were more likely to have ever used opioids for migraine treatment (57 vs 38%, P =.006) as well as higher MIDAS (mean 63 vs 37, P =.001) and BDI scores (mean 10.4 vs 7.4, P =.009). Compared with discontinued users, current triptan users were more likely to have had their triptan prescribed by a specialist (neurologist, headache specialist, or pain specialist) (74 vs 54%, P =.002) and were more likely to report headache resolution (53 vs 14%, P <.001) or a reduction in pain intensity (71 vs 28%, P <.001) most of the time from their triptan. On a 1-5 scale (1 = disagree, 5 = agree), triptan users felt they had more: control over their migraine attacks (2.9 vs 2.1), confidence in their prescribing provider (4.5 vs 4.0), and were more educated about triptan use (4.2 vs 3.7) compared with triptan discontinuers (P <.001 for all comparisons). Although both current and prior users reported similar rates of side effects (48 vs 43%, P =.44), of those who discontinued use, the main reasons were for lack of effect (44%) and side effects (29%). Our multivariable modeling revealed that the strongest correlate of triptan discontinuation was lack of efficacy (odds ratio = 17, 95% confidence interval [8.8, 33.0]). Other factors associated with discontinuation included MIDAS > 24 (2.6, [1.5, 4.6]), BDI >4 (2.5, [1.4, 4.5]), and a history of ever using opioids for migraine therapy (2.2, [1.3, 3.8]). Having a triptan prescribed by a specialist and using at least 1 other abortive medication with the triptan were associated with a decreased likelihood of triptan discontinuation (0.41, [0.2-0.7] and 0.44 [0.3, 0.8], respectively). Conclusions As expected, discontinuation was most correlated with lack of efficacy, but other important factors associated with those who had discontinued use included greater migraine-related disability, depression, and the use of opioids for migraine attacks. Compared with patients who had discontinued triptans, current triptan users felt more: educated about their triptan, control over their migraine attacks, and confidence in their prescribing provider. Current triptan users had their triptan prescribed by a specialist and used other abortive medications with their triptan more often compared with patients who had discontinued triptans. Given the cross-sectional nature of this study, we cannot determine if these factors contributed to triptan discontinuation or reflect the impact of such discontinuation. Interventions that address modifiable risk factors for triptan discontinuation may decrease the likelihood of triptan discontinuation and thus improve overall migraine control. Because lack of efficacy was most strongly associated with triptan discontinuation, future research should determine why triptans are effective for some patients but not others. © 2013 American Headache Society.

Yaakov K.B.,Tel Aviv University | Gershoni-Emek N.,Tel Aviv University | Bulvik S.,Laniado Hospital | Kassis I.,Hadassah Medical Organization | And 2 more authors.
Human Molecular Genetics | Year: 2013

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons. Although most cases of ALS are sporadic (sALS) and of unknown etiology, there are also inherited familial ALS (fALS) cases that share a phenotype similar to sALS pathological and clinical phenotype. In this study, we have identified two new potential genetic ALS biomarkers in human bone marrow mesenchymal stem cells (hMSC) obtained from sALS patients, namely the TDP-43 (TAR DNA-binding protein 43) and SLPI (secretory leukocyte protease inhibitor). Together with the previously discovered ones-CyFIP2 and RbBP9, we investigated whether these four potential ALS biomarkers may be differentially expressed in tissues obtained from mutant SOD1G93A transgenic mice, a model that is relevant for at least 20% of the fALS cases. Quantitative real-time PCR analysis of brain, spinal cord and muscle tissues of the mSOD1G93A and controls at various time points during the progression of the neurological disease showed differential expression of the four identified biomarkers in correlation with (i) the tissue type, (ii) the stage of the disease and (iii) the gender of the animals, creating thus a novel spatiotemporal molecular signature of ALS. The biomarkers detected in the fALS animal model were homologous to those that were identified in hMSC of our sALS cases. These results support the possibility of a molecular link between sALS and fALS and may indicate common pathogenetic mechanisms involved in both types of ALS. Moreover, these results may pave the path for using the mSOD1G93A mouse model and these biomarkers as molecular beacons to evaluate the effects of novel drugs/treatments in ALS. © The Author 2013.

Nachmany H.,Tel Aviv University | Wald S.,Tel Aviv University | Abekasis M.,Tel Aviv University | Bulvik S.,Laniado Hospital | Weil M.,Tel Aviv University
Disease Markers | Year: 2012

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder caused by degeneration of motor neurons. The cause for most cases of ALS is multi-factorial,this enhances the need to characterize and isolate specific biomarkers found in biological samples from ALS patients. To this end we use human mesenchymal stem cells (hMSC) derived from the bone marrow of six ALS patients (ALS hMSC) and identified two genes, Cytoplasmic FMR Interacting Protein 2 (CyFIP2) and Retinoblastoma (Rb) Binding Protein 9 (RbBP9) with a significant decrease in post transcriptional A to I RNA editing compared to hMSC of healthy individuals. At the transcriptional level we show abnormal expression of these two genes in ALS hMSC by quantitative real time-PCR (qRT-PCR) and Western blot suggesting a problem in the regulation of these genes in ALS. To strengthen this view we tested by qRT-PCR the expression of these genes in peripheral blood leukocytes (PBL) isolated from blood samples of 17 ALS patients and found that CyFIP2 and RbBP9 levels of expression were significantly different compared to the levels of expression of these two genes in 19 normal PBL samples. Altogether we found two novel ALS potential biomarkers in non-neural tissues from ALS patients that may have direct diagnostic and therapeutic implications to the disease. © 2012 - IOS Press and the authors. All rights reserved.

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