Hadassah Medical School

West Jerusalem, Israel

Hadassah Medical School

West Jerusalem, Israel
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Avraham Y.,Hadassah Medical School | Davidi N.,Hadassah Medical School | Davidi N.,Hebrew University of Jerusalem | Lassri V.,Hebrew University of Jerusalem | And 8 more authors.
Current Neurovascular Research | Year: 2011

Leptin is a potent AMP kinase (AMPK) inhibitor that is central to cell survival. Hence, we explored the effects of leptin on neurogenesis and angiogenesis after stroke. Neural stem cells (NSC) were grown as neurospheres in culture and treated with vehicle or leptin and neurosphere size and terminal differentiation were then determined. We then explored the effects of leptin on endogenous repair mechanisms in vivo. Sabra mice underwent photothrombotic stroke, were given vehicle or leptin and newborn cells were labeled with Bromo-deoxy-Uridine. Functional outcome was studied with the neurological severity score for 90 days post stroke and the brains were then evaluated with immunohistochemistry. In a subset of animals the brains were also evaluated for changes in the expression of leptin receptor and AMPK. In vitro, leptin led to a 2-fold increase in neurosphere size but did not change the differentiation of newborn cells. Following stroke, exogenous leptin led to a 4-fold increase in the number of NSC in the cortex abutting the lesion. There was a 1.5-fold increase in the number of newborn neurons and glia in leptin treated animals. Leptin also significantly increased the number of blood vessels in the peri-lesioned cortex. Leptin treated mice had increased expression of leptin receptor and increased phosphorylated AMPK concentration. Animals treated with leptin also had significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations. This may explain at least in part the better functional outcome observed in leptin treated animals after stroke. © 2011 Bentham Science Publishers.


Oppenheim A.,Hadassah Medical School | Kuksin D.,University of Massachusetts Amherst | Norkin L.,University of Massachusetts Amherst | Stan R.V.,Heart and Vascular Research Center
Biochemical and Biophysical Research Communications | Year: 2011

Plasmalemmal vesicle associated protein (Plvap/PV1) is a structural protein required for the formation of the stomatal diaphragms of caveolae. Caveolae are plasma membrane invaginations that were implicated in SV40 virus entry in primate cells. Here we show that de novo Plvap/PV1 expression in CV-1 green monkey epithelial cells significantly reduces the ability of SV40 virus to establish productive infection, when cells are incubated with low concentrations of the virus. However, in presence of high viral titers PV1 has no effect on SV40 virus infectivity. Mechanistically, PV1 expression does not reduce the cell surface expression of known SV40 receptors such as GM1 ganglioside and MHC class I proteins. Furthermore, PV1 does not reduce the binding of virus-like particles made by SV40 VP1 protein to the CV-1 cell surface and does not impact their internalization when cells are incubated with either high or low VLP concentrations. These results suggest that PV1 protein is able to block SV40 infectivity at low but not at high viral concentration either by interfering with the infective internalization pathway at the cell surface or at a post internalization step. © 2011 Elsevier Inc.


Araten D.J.,New York University | Araten D.J.,NYU Langone Medical Center | Iori A.P.,University of Rome La Sapienza | Brown K.,Sloan Kettering Cancer Center | And 9 more authors.
Journal of Hematology and Oncology | Year: 2014

Background: PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. The combination of thrombosis, splenomegaly, and thrombocytopenia (TST) is challenging because anticoagulants are indicated but thrombocytopenia may increase the bleeding risk. Splenectomy could alleviate thrombocytopenia and reduce portal pressure, but it can cause post-operative thromboses and opportunistic infections. We therefore sought to determine whether selective splenic artery embolization (SSAE) is a safe and effective alternative to splenectomy for TST in patients with PNH. Methods. Four patients with PNH and TST received successive rounds of SSAE. By targeting distal vessels for occlusion, we aimed to infarct approximately 1/3 of the spleen with each procedure. Results: Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT. Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. One patient, who had had only a partial response to eculizumab, responded to SSAE not only with an improved platelet count, but also with an increase in hemoglobin level and decreased transfusion requirement. Conclusions: These data indicate that SSAE can decrease spleen size and reverse hypersplenism, without exposing the patient to the complications of splenectomy. In addition, SSAE probably reduces the uptake of opsonised red cells in patients who have had a limited response to eculizumab, resulting in an improved quality of life for selected patients. © 2014 Araten et al.; licensee BioMed Central Ltd.


Quinn A.M.,Royal Infirmary | Blackhall F.,Christie Hospital | Wilson G.,Royal Infirmary | Danson S.,Weston Park Hospital | And 4 more authors.
Histopathology | Year: 2012

Aims: To evaluate the clinicopathological features of small cell carcinoma arising outside the lung. Methods and results: Thirty-seven cases with a pathology diagnosis of extrapulmonary small cell carcinoma (EPSCC) were selected. The clinical notes were reviewed and tumour blocks were selected for a fresh haematoxylin and eosin (H&E) section and immunohistochemical stains. The most common tumour locations were cervix and bladder. Twenty-five cases (68%) were finally diagnosed as EPSCC, nine of which were found with coexisting non small cell carcinoma. Two cases (5%) were diagnosed as large cell neuroendocrine carcinoma (LCNEC) of the cervix. The remainder was classified as 10 poorly differentiated carcinomas (PDCs) (27%). Positive staining for thyroid transcription factor 1 (TTF-1) was noted in nine cases of EPSCC and in none of the cases of PDC (P=0.034). Synaptophysin immunoreactivity was found in 20 cases of EPSCC and two cases of PDC with neuroendocrine differentiation (P=0.002), as well as two cases of LCNEC. 34βE12 was positive in eight cases of SCC and two cases of PDC. Conclusions: Based on this series, EPSCC may be overdiagnosed. Immunohistochemistry for TTF-1, used in combination with synaptophysin, may help to discriminate EPSCC from PDC. © 2012 Blackwell Publishing Ltd.


Borges B.C.,University of Sao Paulo | Rorato R.,University of Sao Paulo | Avraham Y.,Hadassah Medical School | da Silva L.E.C.M.,University of Sao Paulo | And 5 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMPactivated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p- STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance. © 2011 the American Physiological Society.


Goldberg R.,Weizmann Institute of Science | Schroeder A.,Massachusetts Institute of Technology | Silbert G.,Weizmann Institute of Science | Turjeman K.,Hadassah Medical School | And 2 more authors.
Advanced Materials | Year: 2011

Liposomes of hydrogenated soy phosphatidylcholine (PC) lipids spontaneously self-assemble in close-packed layers on solid surfaces to form boundary lubricants that reduce the coefficient μ of sliding friction between them down to μ ≈ 10 -4 - 2 × 10 -5, at pressures up to ca. 12 MPa. This strikingly low value is attributed to hydration-lubrication by the PC headgroups exposed at the surfaces of the gel-phase vesicles. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Hadassah Medical School and Max Planck Institute
Type: Journal Article | Journal: Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology | Year: 2015

Patients with diabetes mellitus are excessively vulnerable to myocardial ischemia and often suffer from autonomic cardiac dysfunction. They are also known to have specific capillary pathology and abnormalities of substances essential for the neoangiogenic cascade. These background data led us to the hypothesis that the severity of ischemic heart disease in diabetes is attributable (at least in part) to microcirculatory and autonomic inadequacy caused by microangiopathy and failure of postischemic adaptive neoangiogenesis. To test this hypothesis we compared myocardial capillaries, autonomic nerve endings of 19 diabetics, 30 normoglycemics with ischemic heart disease, and 9 valve replacements serving as nonischemic controls. Right atrial appendages obtained during coronary bypass surgery were utilized for light, fluorescent, and electron microscopic morphometry. Although in this series there were no significant differences in the clinical and laboratory hemodynamic values between the ischemic normoglycemic and diabetic patients, the latter showed marked capillary and nerve terminal pathology, and their capillary density as well as capillary to myofiber ratios were significantly lower. In addition, the mean capillary area, volume fraction, and intercapillary distance were higher in diabetics. The mean area of the nerve varicosities was also smaller, and this was correlated with capillary density. We concluded that the findings support the hypothesis that cardiac vulnerability in diabetes is connected with inadequate adaptive neoangiogenesis and that this seems to be associated with atrophic changes in the nerve terminals.

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