Gur C.,Institute for Medical Research Israel Canada IMRIC |
Doron S.,Hadassah University Medical Center |
Kfir-Erenfeld S.,Institute for Medical Research Israel Canada IMRIC |
Horwitz E.,Institute for Medical Research Israel Canada IMRIC |
And 3 more authors.
Gut | Year: 2012
Background: Liver fibrosis, which involves activation of hepatic stellate cells (HSC), is a major health problem and is the end outcome of all chronic liver diseases. The liver is populated with lymphocytes, among which are natural killer (NK) cells, whose activity is controlled by inhibitory and activating receptors. NKp46, one of the major NK activating receptors expressed by NK cells, is also a specific NK marker that discriminates NK cells from all other lymphocyte subsets. It recognises viral haemagglutinins and unknown cellular ligands. Methods: The anti-fibrotic activity of the NKp46 receptor was assessed in vivo and in vitro using NKp46-deficient mice (NCR1 gfp/ gfp), the carbon tetrachloride model and in vitro NK killing assays. Primary murine and human HSC were stained for the expression of the NKp46 ligand using fusion proteins composed of the extracellular portions of the murine and human NKp46 receptors fused to human IgG1. Results: It was shown that murine HSC express a ligand for the murine orthologue of the NKp46 receptor, NCR1. NCR1 inhibited liver fibrosis in vivo; in vitro, murine HSC were killed in an NCR1-dependent manner. In humans it was shown that human HSC also express a ligand for the human NKp46 receptor and that the killing of human HSC is NKp46 dependent. Conclusions: In addition to NKG2D, NKp46/NCR1 play an important role in inhibition of liver fibrosis. This suggests that fibrosis can be better controlled through the manipulation of NKp46 activity.
Landesberg G.,Hadassah University Medical Center |
Jaffe A.S.,Mayo Medical School |
Gilon D.,Hebrew University of Jerusalem |
Levin P.D.,Hadassah University Medical Center |
And 6 more authors.
Critical Care Medicine | Year: 2014
Objective: Serum troponin concentrations predict mortality in almost every clinical setting they have been examined, including sepsis. However, the causes for troponin elevations in sepsis are poorly understood. We hypothesized that detailed investigation of myocardial dysfunction by echocardiography can provide insight into the possible causes of troponin elevation and its association with mortality in sepsis. Design: Prospective, analytic cohort study. Setting: Tertiary academic institute. Patients: A cohort of ICU patients with severe sepsis or septic shock. Interventions: Advanced echocardiography using global strain, strain-rate imaging and 3D left and right ventricular volume analyses in addition to the standard echocardiography, and concomitant high-sensitivity troponin-T measurement in patients with severe sepsis or septic shock. Measurements and Main Results: Two hundred twenty-five echocardiograms and concomitant high-sensitivity troponin-T measurements were performed in a cohort of 106 patients within the first days of severe sepsis or septic shock (2.1 ± 1.4 measurements/patient). Combining echocardiographic and clinical variables, left ventricular diastolic dysfunction defined as increased mitral E-to-strain-rate e′-wave ratio, right ventricular dilatation (increased right ventricular end-systolic volume index), high Acute Physiology and Chronic Health Evaluation-II score, and low glomerular filtration rate best correlated with elevated log-transformed concomitant high-sensitivity troponin-T concentrations (mixed linear model: t = 3.8, 3.3, 2.8, and-2.1 and p = 0.001, 0.0002, 0.006, and 0.007, respectively). Left ventricular systolic dysfunction determined by reduced strain-rate s′-wave or low ejection fraction did not significantly correlate with log(concomitant high-sensitivity troponin-T). Forty-one patients (39%) died in-hospital. Right ventricular end-systolic volume index and left ventricular strain-rate e′-wave predicted in-hospital mortality, independent of Acute Physiology and Chronic Health Evaluation-II score (logistic regression: Wald = 8.4, 6.6, and 9.8 and p = 0.004, 0.010, and 0.001, respectively). Concomitant high-sensitivity troponin-T predicted mortality in univariate analysis (Wald = 8.4; p = 0.004), but not when combined with right ventricular end-systolic volume index and strain-rate e′-wave in the multivariate analysis (Wald = 2.3, 4.6, and 6.2 and p = 0.13, 0.032, and 0.012, respectively). Conclusions: Left ventricular diastolic dysfunction and right ventricular dilatation are the echocardiographic variables correlating best with concomitant high-sensitivity troponin-T concentrations. Left ventricular diastolic and right ventricular systolic dysfunction seem to explain the association of troponin with mortality in severe sepsis and septic shock. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Kisos H.,Hebrew University of Jerusalem |
Pukass K.,University of Oldenburg |
Ben-Hur T.,Hadassah University Medical Center |
Richter-Landsberg C.,University of Oldenburg |
Sharon R.,Hebrew University of Jerusalem
PLoS ONE | Year: 2012
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a synucleinopathy, and α-Synuclein (α-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal α-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted α-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of α-Syn soluble oligomers or intracellular α-Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, we show that primary oligodendrocytes from rat brain and oligodendroglial cell lines take-up neuronal-secreted or exogenously added α-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance α-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on α-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T α-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA. © 2012 Kisos et al.
Wexler I.D.,Hadassah University Medical Center |
Corn B.W.,Tel Aviv University
Current Opinion in Supportive and Palliative Care | Year: 2012
Purpose of review: Patients with cancer face both physical and psychological challenges. In the past, oncologists often limited themselves to the medical aspects of cancer care and delegated psychosocial interventions to professionals from other disciplines. In this review, we explore the methods by which oncologists can expand their role in treating cancer patients. Recent findings: Recent studies have shown that individuals with cancer are not always satisfied with the care that they are receiving and believe that their existential needs are not being met. A model is suggested for improving the interaction between oncologists and their patients that involves focusing on the existential needs of an individual with cancer. Specific interventions and their appropriateness are discussed. Summary: Oncologists should consider expanding their role and involving themselves in the more holistic aspects of cancer care. As a result of the bonds that they develop with patients, these professionals often find themselves in a position of being able to help and counsel cancer patients who are coping with feelings of isolation, loneliness, and fear. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Greenberg D.,Ben - Gurion University of the Negev |
Givon-Lavi N.,Ben - Gurion University of the Negev |
Newman N.,Ben - Gurion University of the Negev |
Bar-Ziv J.,Hadassah University Medical Center |
Dagan R.,Ben - Gurion University of the Negev
Pediatric Infectious Disease Journal | Year: 2011
BACKGROUND: We aimed at estimating pneumococcal serotype-specific disease potential in pediatric community-acquired alveolar pneumonia (CAAP), by comparing nasopharyngeal pneumococcal carriage during disease to carriage in healthy children. METHODS: Pneumococcal nasopharyngeal cultures were obtained from children <5 years old admitted to the emergency room or hospitalized with radiologically diagnosed CAAP and from healthy controls. Disease potential was estimated by calculating serotype-specific odds ratios (OR) of a given serotype to be carried during disease compared with healthy children (after adjustment for age, ethnicity, previous antibiotic therapy, and season). RESULTS: A total of 603 and 1504 isolates were obtained from CAAP and healthy children, respectively. A significant OR >1.0 of a specific serotype being carried during disease (suggesting a higher disease potential) was observed with serotypes (by decreasing rank) 1, 5, 22F, 7F, 14, 9V, and 19A. A significant OR <1.0 of being carried during disease (suggesting a lower disease potential) was observed with serotypes 6A, 6B, 23A, and 35B. Carriage of PCV7 serotypes (grouped) during CAAP was highest in age group 6 to 17 months. PCV10 and PCV13 provided significantly higher coverage for both 6 to 17 and 18 to 35 month age groups. CONCLUSIONS: It is suggested that serotypes 1, 5, 7F, 9V, 14, 19A, and 22F have a higher disease potential for childhood pneumonia than do serotypes 6A, 6B, 23A, and 35B. © 2011 Lippincott Williams & Wilkins, Inc.
Ben-Shushan E.,Hadassah University Medical Center |
Feldman E.,Hadassah University Medical Center |
Reubinoff B.E.,Hadassah University Medical Center |
Reubinoff B.E.,University of Michigan
Stem Cells | Year: 2015
In the pMN domain of the spinal cord, Notch signaling regulates the balance between motor neuron differentiation and maintenance of the progenitor state for later oligodendrocyte differentiation. Here, we sought to study the role of Notch signaling in regulation of the switch from the pMN progenitor state to differentiated motor neurons in a human model system. Human embryonic stem cells (hESCs) were directed to differentiate to pMN-like progenitor cells by the inductive action of retinoic acid and a Shh agonist, purmorphamine. We found that the expression of the Notch signaling effector Hes5 was induced in hESC-derived pMN-like progenitors and remained highly expressed when they were cultured under conditions favoring motor neuron differentiation. Inhibition of Notch signaling by a γ-secretase inhibitor in the differentiating pMN-like progenitor cells decreased Hes5 expression and enhanced the differentiation toward motor neurons. Conversely, over-expression of Hes5 in pMN-like progenitor cells during the differentiation interfered with retinoic acid- and purmorphamine-induced motor neuron differentiation and inhibited the emergence of motor neurons. Inhibition of Notch signaling had a permissive rather than an inductive effect on motor neuron differentiation. Our results indicate that Notch signaling has a regulatory role in the switch from the pMN progenitor to the differentiated motor neuron state. Inhibition of Notch signaling can be harnessed to enhance the differentiation of hESCs toward motor neurons. © 2014 AlphaMed Press.
Sapoznikov D.,Hadassah University Medical Center |
Backenroth R.,Hadassah University Medical Center |
Rubinger D.,Hadassah University Medical Center
Journal of Hypertension | Year: 2010
Objectives: The role of the baroreflex function in the pathogenesis of hemodialysis-associated hypotension is controversial. Complex demodulation technique (CDM), providing continuous assessment of the amplitude of cardiovascular oscillation over time, is particularly suitable to assess dynamic changes in autonomic nervous system and baroreceptor sensitivity (BRS) during dialysis. In the present study, CDM was used to determine the effects of dialysis treatment on BRS and to characterize BRS changes during acute intradialytic hypotension. Methods: Continuous beat-to-beat blood pressure and interbeat intervals (IBIs) were monitored in 93 chronic patients without (n = 70) and with (n = 26) hypotension during 96 dialysis sessions. The amplitudes of SBP and DBP, IBIs, and BRS change in the low-frequency (around center frequency of 0.09 Hz) and high-frequency (around center frequency of 0.30 Hz) ranges were followed during the whole dialysis session. Results: Hemodialysis treatment was associated with increased low-frequency BRS, especially in sessions without hypotension. Hypotensive episodes were associated with significant increases in both low-frequency BRS and high-frequency BRS, mainly in patients with severe hypotension. The magnitude of the increase in baroreflex indices was proportional to the decrease in blood pressure. Low-frequency IBI/high-frequency IBI ratio, a marker of sympatho-vagal balance, did not significantly change during hypotension. Conclusion: Our study shows that the baroreflex mechanism is preserved and adequately activated during intradialytic hypotension. Other factors, such as ischemic heart disease, left ventricular dysfunction, and inadequate arteriolar tone, rather than failure of baroreflex function, are more likely to be responsible for dialysis-induced hypotension. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Rubinger D.,Hadassah University Medical Center |
Backenroth R.,Hadassah University Medical Center |
Sapoznikov D.,Hadassah University Medical Center
PLoS ONE | Year: 2012
Background: The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. Methodology/Principal Findings: Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. Conclusion/Significance: Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension. © 2012 Rubinger et al.
Yachimovich-Cohen N.,Hadassah University Medical Center |
Even-Ram S.,Hadassah University Medical Center |
Shufaro Y.,Hadassah University Medical Center |
Rachmilewitz J.,Hadassah University Medical Center |
Reubinoff B.,Hadassah University Medical Center
Journal of Immunology | Year: 2010
Human embryonic stem cells (hESCs) can proliferate extensively in culture and give rise to progeny of the three germ layers. Several reports suggested that mouse and hESCs may attenuate immune responses. In this study, we focused on the mechanism by which hESCs inhibit T cell responses. Using coculture experiments, we demonstrate that hESCs inhibit cytokine secretion and T cell proliferation in response to potent T cell activators. Furthermore, we show that hESCs downmodulate the TCR-associated CD3-ζ chain. These effects are maintained when hESCs are replaced by their conditioned media and can be restored by the addition of L-arginine to hESC-conditioned media or by treatment of hESCs with a specific arginase inhibitor. Moreover, we show arginase-I expression and activity in hESCs. We further demonstrate that mouse ESCs (mESCs) similarly inhibit T cell activation via arginase I, suggesting an evolutionary conserved mechanism of T cell suppression by ESCs. In addition, we demonstrate that arginase I expression is not limited to ESCs in culture, but can also be detected in the inner cell mass and the trophectoderm of preimplantation mouse embryos and hESC-derived trophectoderm cells. Finally, T cells infiltrating ESC-derived teratomas have significantly lower levels of CD3-ζ chain. Collectively, the data indicate a role for ESC-arginase I activity in the attenuation of T cell activation. Copyright © 2010 by The American Association of Immunologists, Inc.
Freund H.R.,Hadassah University Medical Center
Israel Medical Association Journal | Year: 2011
General Surgery is losing its appeal and is facing a critical shortage of surgeons. It therefore has to change and adapt to this new reality and we surgeons are responsible for meeting this challenge. If we want students and residents to embrace surgery we need to show them the rewards and satisfaction that we derive from the profession. A 5 year curriculum is needed to train the "abdominal surgery" or "general surgery specialist," who will maintain and teach comprehensive care of the surgical patient and practice a more limited scope of surgical procedures. In addition, we should train a limited number of disease-oriented specialists by means of 1-2 year fellowships.