Rappaport Faculty of Medicine

About: Rappaport Faculty of Medicine is a based out in . It is known for research contribution in the topics: Population & Heparanase. The organization has 3205 authors who have published 3915 publications receiving 114533 citations.

The haematopoietic effects of growth hormone and insulin-like growth factor-I.

Abstract: The process of haemopoiesis, occurring primarily within the bone marrow, involves the proliferation and differentiation of pluripotent haemopoietic stem cells into committed, or pathway-restricted progenitors /1/. The latter further proliferate and undergo a process of maturation into circulating blood cells of myeloid and erythroid lineages /2/. Haemopoietic cell growth and differentiation is primarily regulated by the local production of various cytokines within the bone marrow micro-environment /3/, as well as by the circulating hormone, erythropoietin (EPO). The formation as well as functional activation of mature blood cells, are also modulated by a variety of hormones and growth peptides, including growth hormone (GH) and insulin-like growth factor-I (IGF-I) /4,5/. Early evidence for the role of GH in modulating haemopoiesis was provided in classical studies in rodents, which showed that removal of the pituitary gland affects blood cell formation and function /6/ and that impairment of the latter can be restored by GH administration /7/. GH exerts its effects on target cells by binding to its own receptor, which belongs to the class I cytokine receptor superfamily /8/. In humans, GH can also bind to and activate the prolactin receptor /9/. Based on the somatomedin hypothesis of Salmon and Daughaday /10/, it is now generally accepted that, in addition to the above, GH exerts many of its effects via autocrine or paracrine IGF-I, as well as via endocrine IGF-I produced in the liver. IGF-I, a small single-chain polypeptide, is one of two highly homologous peptides (IGF-I and IGF-II), that stimulate the proliferation and differentiation of a wide variety of cell types, including bone marrow cells /5,11/. Both IGF-I and IGF-II play an important role in prenatal growth and IGF-I is also essential for postnatal growth and development /12/. Two types of IGF receptors have been described. The type I IGF receptor, a tyrosine kinase receptor highly homologous to the insulin receptor, binds IGF-I and IGF-II with a high affinity. The type II/mannose 6-phosphate receptor which lacks intrinsic kinase activity, binds IGF-II with a high affinity and IGF-I with a low affinity /13,14/. Haemopoietic progenitors and mature blood cells have been shown to produce GH and IGF-I and to express receptors for these peptides. GH and IGF-I may act independently on these cells or, as more commonly observed, in a synergistic manner with primary haemopoietic cytokines. GH and IGF-I receptors are also present on freshly explanted leukemic cells and leukemic cell lines. Thus, their possible contribution to the development of leukemia should also be considered. This review summarizes our current understanding of the role of GH and IGF-I in normal and malignant haemopoiesis.

Risk factors for progression of functional tricuspid regurgitation.

Abstract: The aim of this study was to determine the risk factors for tricuspid regurgitation (TR) progression in a contemporary population of patients referred for echocardiography. In a case-control study, we compared 100 consecutive patients with TR progression on serial echocardiograms (trivial or mild TR on the first echocardiogram and moderate or severe functional TR on a follow-up echocardiogram) with 100 patients matched for age and gender, having mild TR at baseline and no TR progression. Mean age was 72 ± 10 years, 55% were males, and time to TR progression was 5.3 ± 2.9 years. Less than 10% had rheumatic heart disease. Left ventricular ejection fraction was preserved (≥50%) in 85% of the TR progression group and in 74% of the control group (p = 0.06). Pulmonary artery systolic pressure increased from 41 ± 16 to 56 ± 18 mm Hg in the TR progression group and decreased from 44 ± 13 to 41 ± 11 mm Hg in the control group (p

Orthostatic Hypercoagulability: A Novel Physiological Mechanism to Activate the Coagulation System

Abstract: Orthostatic stress causes significant plasma shift and raises transmural pressure in lower extremities, resulting in an increase in endothelial activation and plasma proteins concentrations, possibly including coagulation factors. This may lead to activation of the coagulation system during standing. To test this hypothesis, we recruited 18 healthy volunteers (9 females and 9 males; mean age: 25±1.2 years; body mass index: 21.7±0.5 kg/m 2 ). Hemodynamics, plasma shift (extrapolated from sequential hematocrit concentration), plasma proteins, and coagulation tests, including procoagulants; fibrinogen, factor V, and factor VIII activity; prothrombin fragments 1 and 2; and endothelial activation–related factors (tissue factor and von Willebrand factor), as well as protein C global pathway, were determined at rest supine and at 15 minutes, 30 minutes, and 60 minutes of still standing. Thirty minutes of standing caused a decrease in plasma volume by 12.0±0.5% and an increase in plasma protein by 13.0±0.7%. Fibrinogen, factor V, and factor VIII activity rose by 12.0±1.2%, 13.0±1.0%, and 40.0±6.0% ( P P P

Translocation of Active Heparanase to Cell Surface Regulates Degradation of Extracellular Matrix Heparan Sulfate upon Transmigration of Mature Monocyte-Derived Dendritic Cells

Abstract: After Ag capture and exposure to danger stimuli, maturing dendritic cells (DCs) migrate to regional lymph nodes, where antigenic peptides are presented to T lymphocytes. To migrate from peripheral tissue such as the epidermis to regional lymph nodes, Ag-bearing epidermal Langerhans cells must move through an extracellular matrix (ECM) of various compositions. The nature of their capacity to transmigrate via ECM is not well understood, although MIP-3beta and CCR7 play critical roles. We were interested in verifying whether heparanase, a heparan sulfate-degrading endo-beta-d-glucuronidase that participates in ECM degradation and remodeling, is expressed and functional in monocyte-derived DCs. Using immunohistochemistry, confocal microscopy, RT-PCR, Western blot analysis, assays for heparanase activity, and Matrigel transmigration, we show that heparanase is expressed in both nuclei and cytoplasm of immature DCs, and that gene expression and synthesis take place mainly in monocytes and early immature DCs. We also found that both nuclear and cytoplasm fractions show heparanase activity, and upon LPS-induced maturation, heparanase translocates to the cell surface and degrades ECM heparan sulfate. Matrigel transmigration assays showed a MIP-3beta-comparable role for heparanase. Because heparan sulfate glycosaminoglycans play a key role in the self-assembly, insolubility, and barrier properties of the ECM, the results of this study suggest that heparanase is a key enzyme in DC transmigration through the ECM.