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Biomedical subjects

E Levi

Publications and source records attributed to E Levi.

At least 19 recordsLinked to original sources
PubMed1992

Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells.

Heparin is required for the binding of basic fibroblast growth factor (bFGF) to high-affinity receptors on cells deficient in cell surface heparan sulfate proteoglycan. So that this heparin requirement could be evaluated in the absence of other cell surface molecules, we designed a simple assay based on a genetically engineered soluble form of murine FGF receptor 1 (mFR1) tagged with placental alkaline phosphatase. Using this assay, we showed that FGF-receptor binding has an absolute requirement for heparin. By using a cytokine-dependent lymphoid cell line engineered to express mFR1, we also showed that FGF-induced mitogenic activity is heparin dependent. Furthermore, we tested a series of small heparin oligosaccharides of defined lengths for their abilities to support bFGF-receptor binding and biologic activity. We found that a heparin oligosaccharide with as few as eight sugar residues is sufficient to support these activities. We also demonstrated that heparin facilitates FGF dimerization, a property that may be important for receptor activation.

3T3 Cells↗
PubMed1992

Effect of erythrocyte deformability on renal hemodynamics and plasma renin activity.

Increased blood viscosity has been previously noted in a subgroup of patients with essential hypertension with concomitant high plasma renin activity (PRA). It has been suggested that the cause of hyperviscosity in hypertensives is the presence of circulating red blood cells (RBCs) that were rendered less deformable by significant alterations in their cationic milieu, namely an increase in intracellular concentration of calcium and sodium. The relation between RBC deformability and PRA however is not clear. Our study was conducted to examine this issue. RBC deformability was reduced experimentally, and its effects on renal blood flow, renal artery resistance, glomerular filtration rate and PRA were investigated in experimental (n = 8) and control (n = 4) groups of dogs. Blood was collected from the animals before the experiments and incubated with 0.025% glutaraldehyde. These hardened RBCs were administered to the animals through exchange transfusions. Following the exchange transfusion with the hardened RBCs, there were no changes in renal blood flow, renal artery resistance, and the creatinine clearance. The only change observed was an increase in PRA. In the control group, all parameters that were determined remained unchanged. The data are consistent with the notion that the presence of circulating hardened RBCs may by itself increase PRA, and this effect can be important in some types of hypertension and some other disorders in which impaired deformability of RBCs have been reported.

Animals↗
PubMed1992

Verapamil reverses glucose intolerance in preexisting chronic renal failure: studies on mechanisms.

Glucose-induced insulin secretion is impaired in chronic renal failure (CRF), and this abnormality is due to the elevation of cytosolic calcium [Ca2+]i and other derangements in pancreatic islet metabolism. Verapamil given to rats from day 1 of CRF prevented the rise in [Ca2+]i of islets and the impairment in insulin secretion. However, it is not known whether verapamil can reverse the abnormalities of islet function and metabolism in animals with preexisting renal failure. Such a documentation has important clinical implications for the treatment of carbohydrate intolerance in patients with CRF. The present study examined this question. After 6 weeks of CRF, rats were randomized into two subgroups and maintained for additional 6 weeks. One subgroup received intraperitoneal injections of verapamil (0.1 micrograms/kg body weight twice daily) and the other received vehicle only. At the time of randomization, there were no significant differences between the two subgroups in their body weight, plasma levels of calcium, phosphorus and creatinine, serum parathyroid hormone and creatinine clearance. Similarly, at the time of sacrifice (12 weeks), there were no significant differences in these parameters except for a modestly lower plasma level of creatinine and modestly higher creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1992

Evolution of metabolic and functional derangements of pancreatic islets in phosphate depletion.

Phosphate depletion (PD) causes a rise in basal level of cytosolic calcium ([Ca2+]i) of pancreatic islets, a decrease in their basal and stimulated ATP content, a reduction in the maximum velocity (Vmax) of Ca2+ adenosine triphosphatase (ATPase) and Na(+)-K+ ATPase, impaired glucose-induced calcium signal and decreased glucose-induced insulin secretion. The sequence of events that lead to these derangements during the evolution of PD are not defined. The present study examined this issue by measuring the metabolic and functional profile of pancreatic islets weekly during the evolution of PD over a period of 6 weeks, and whether phosphate repletion reverses these abnormalities. The results show that initial abnormalities are a rise in Vmax of Ca2+ ATPase and modest rise in basal [Ca2+]i. This was followed by a fall in basal and stimulated ATP content. With the fall in ATP content, the Vmax of Ca2+ ATPase and Na(+)-K+ ATPase decreases and the rise in [Ca2+]i becomes more pronounced. A decrease in glucose-induced insulin secretion becomes evident with the fall in ATP, the decrease in glucose-induced calcium signal, and/or delta[Ca2+]i/basal[Ca2+]i. All functional and metabolic derangements of the pancreatic islets returned to normal after phosphate repletion. Taken together, our data are consistent with the notion that PD is associated with an initial increase in calcium influx into the islets. This is followed by modest but significant rise in [Ca2+]i which, in turn, would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter compromises the activity of Ca2+ ATPase and Na(+)-K+ ATPase which are involved, directly or indirectly, in calcium extrusion out of the islets. The increased influx of calcium combined with decreased calcium extrusion is followed by a further rise in basal levels of [Ca2+]i. This sequence of events continues until a steady state is reached and is characterized by reduced basal and stimulated ATP content, reduced Vmax of Ca2+ ATPase and Na(+)-K+ ATPase and elevated basal level of [Ca2+]i. Phosphate repletion reverses all these abnormalities.

Adenosine Triphosphate↗
PubMed1992

Chronology of cellular events leading to derangements in function of pancreatic islets in chronic renal failure.

In chronic renal failure (CRF), a multitude of metabolic derangements occur in the pancreatic islets, resulting in impaired glucose-induced insulin secretion. These abnormalities include a rise in the basal level of cytosolic calcium ([Ca2+]i) in the islet, a decrease in their basal and stimulated ATP and ATP/ADP ratio, a reduction in the Vmax of Ca2+ATPase and Na(+)-K+ATPase, and an impaired glucose-induced calcium signal. The sequence of events that lead to these derangements and to the impairment in insulin secretion during the evolution of CRF are not defined. The study presented here examined this issue by measuring the metabolic profile of pancreatic islets weekly during the evolution of CRF over a period of 6 wk. The results show that serum levels of parathyroid hormone (PTH) begin to rise during the first week of CRF. The Vmax of Ca2+ATPase and Na(+)-K+ATPase increased during weeks 1 to 3 of CRF but fell to low levels thereafter. At week 3 of CRF, the basal level of [Ca2+]i began to rise, whereas basal and the stimulated ATP content and ATP/ADP ratio started to fall. Glucose-induced calcium signal, delta[Ca2+]i/basal [Ca2+]i, and insulin secretion became abnormally low between weeks 3 and 6 of CRF. The data allow the following formulation: as serum levels of PTH begins to rise, calcium entry into islets is augmented; this in turn will stimulate the activity of Ca2+ATPase and the Na(+)-Ca2+ exchanger, and hence, calcium extrusion out of the islets is increased. As a result, [Ca2+] remains normal during the first 2 wk of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Acute effect of parathyroid hormone on Ca2+ ATPase of pancreatic islets.

The Vmax of Ca2+ ATPase of pancreatic islets is reduced in states of chronic excess of PTH. This has been attributed to the reduced ATP content of pancreatic islet and to impaired response of the enzyme to calmodulin. It is also possible that excess PTH directly inhibits the activity of islet Ca2+ ATPase. The present study examined this issue. Small doses of 1-84 PTH (0.0625 and 0.125 x 10(-7) M) stimulated while larger doses (0.25, 0.5, 1.0, 2.0 and 4.0 x 10(-7) M) inhibited the activity of Ca2+ ATPase of intact islets. PTH has no effect on Ca2+ ATPase when the hormone was added to preparation of membrane homogenate of islets. Verapamil abolished both the stimulatory as well the inhibitory effects of PTH on Ca2+ ATPase of intact islets. The data indicate that PTH does not have a direct effect on the Vmax of islet Ca2+ ATPase of islet. Its effect on the enzyme activity of intact islet is most likely mediated through the hormone-induced calcium influx.

Animals↗
PubMed1991

Intracellular signaling by 14-hydroxy-4,14-retro-retinol.

In mammals, retinol is the precursor for retinoids, which affect various aspects of morphogenesis and development. However, B lymphocytes, although retinol-dependent, do not use retinoic acid as mediator. Retinol is metabolized by B lymphocytes and other cell lines to optically active 14-hydroxy-4,14-retro-retinol; it is this compound that mediates the growth control. Thus another second messenger molecule, in addition to retinoic acid and retinal, is derived from retinol.

Animals↗
PubMed1991

Extracellular matrix-resident basic fibroblast growth factor: implication for the control of angiogenesis.

Despite the ubiquitous presence of basic fibroblast growth factor (bFGF) in normal tissues, endothelial cell proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Immunohistochemical staining revealed the localization of bFGF in basement membranes of diverse tissues, suggesting that the extracellular matrix (ECM) may serve as a reservoir for bFGF. Moreover, functional studies indicated that bFGF is an ECM component required for supporting endothelial cell proliferation and neuronal differentiation. We have found that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by heparanase expressed by normal and malignant cells (i.e. platelets, neutrophils, lymphoma cells). It is proposed that restriction of bFGF bioavailability by binding to ECM and local regulation of its release provide a novel mechanism for neovascularization in normal and pathological situations. The subendothelial ECM contains also tissue type- and urokinase type-plasminogen activators which participate in cell invasion and tissue remodeling. These results and studies on the properties of other ECM-immobilized enzymes (i.e. thrombin, plasmin, lipoprotein lipase) and growth factors (GM-CSF, IL-3, osteogenin), suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized and persistent mode of action, as compared to the same molecules in a fluid phase.

Animals↗
PubMed1991

Malignant fibrous histiocytoma of the vagina and vulva successfully treated by combined chemotherapy and radiotherapy.

Combined vaginal and vulvar malignant fibrous histiocytoma has not been reported previously. Radical vulvectomy with node dissection is the currently recommended therapy for a vulvar lesion of this type. We present a case with complete tumor regression after combined chemotherapy and radiotherapy. The surgical approach in our patient was inappropriate due to advanced disease. Follow-up examinations for 6 years after initiation of therapy showed no evidence of local recurrence or distant metastasis. Chemotherapy followed by radiotherapy should be considered as an alternative to surgery in patients with advanced vaginal and vulvar involvement and in patients in whom complex medical problems preclude extensive surgical procedures.

Aged↗
PubMed1991

Inhibition of angiotensin converting enzyme by ramipril in serum and tissue of man.

Studies in animal models have indicated that ramipril is a potent inhibitor of angiotensin converting enzyme (ACE) in serum and tissue. In our study, the normal range of ACE activity and the inhibitory effect of short-term oral administration of ramipril on ACE activity in human serum and tissue samples of renal cortex, heart and blood vessels were determined. ACE activity in the renal cortex (125.2 +/- 11.5 nmol/mg per min) was greater than 600 times that of the heart (0.20 +/- 0.01 nmol/mg per min), greater than 500 times that of the veins (0.23 +/- 0.09 nmol/mg per min) and greater than 150 times that of the arteries (0.80 +/- 0.23 nmol/mg per min). ACE activity in the renal cortex and arteries 2 h after last dosing was almost completely inhibited by ramipril whereas ACE activity in the veins and heart was inhibited to a lesser extent. Our results demonstrate in man, for the first time, an inhibition of tissue ACE following short-term oral treatment with an ACE inhibitor.

Administration, Oral↗
PubMed1991

Effects of atracurium and pancuronium on the oculocardiac reflex in children.

The authors compare the effect of two muscle relaxants, atracurium and pancuronium, on the bradycardia resulting from the oculocardiac reflex during eye surgery for strabismus in children. Two groups, each composed of 15 children, received either pancuronium or atracurium during strabismus operations. Heart rate and rhythm were observed at several points during the operations, and the changes that occurred in the two groups were compared. We found that the incidence and severity of the bradycardia, the incidence of dysrhythmias, and the need for atropine administration were significantly greater in the atracurium group than in the pancuronium group.

Atracurium↗
PubMed1991

Selective inhibition of duodenal and jejunal villous cell alkaline phosphatase by the duodenal ulcerogen cysteamine.

We have found that cysteamine-HCl, a potent duodenal ulcerogen, after a single subcutaneous injection (30 mg/100 g body weight), inhibited villous cell duodenal and jejunal alkaline phosphatase (APase) under in vivo and under in vitro conditions. The duodenal and jejunal crypt-cell APase was not susceptible to cysteamine inhibition. Ileal APase from both the villous and the crypt cells was unaffected by cysteamine. Tissue-nonspecific APase from the kidney and liver was not affected by cysteamine either. The differences in tissue and cellular accumulation of cysteamine, the submolecular differences in APase molecules, and its anatomical localization in mucosal cells along the small intestine could explain the different degrees of susceptibility to cysteamine inhibition. The extent of duodenal APase inhibition by cysteamine was highly pH-dependent and varied from 5% to 85% within a pH range of 7.5-10.5. A shift in pH optimum from 9.6 to 9.3 was found in the presence of cysteamine. The inhibition of duodenal villous cell APase was greatly dependent on cysteamine concentration (Ki = 2.65 mM). At a fixed concentration of cysteamine it was not influenced by substrate concentration. Cysteamine did not change the Km value for duodenal APase but did decrease its Vmax to 46% and 15% of the controls when added in the assay or injected subcutaneously, respectively, indicating that the inhibition was of the linear, 'noncompetitive' type. Somehow cysteamine increased the requirement in the activation energy for substrate hydrolysis as well. The data indicate that macromolecular transformations could take place in the mucosal cells of duodenum after cysteamine administration.

Alkaline Phosphatase↗
PubMed1990

Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors.

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor for an unidentified ligand and is allelic with the murine white-spotting locus (W). W mutations affect melanogenesis, gametogenesis and hematopoiesis during development and in adult life. Cellular targets of W mutations in hematopoiesis include distinct cell populations in the erythroid and mast cell lineages as well as stem cells. In the absence of interleukin-3 (IL-3) mast cells derived from normal mice but not from W mutant mice can be maintained by co-culture with 3T3 fibroblasts. Based on the defective proliferative response of W mast cells in the 3T3 fibroblast co-culture system it had been proposed that fibroblasts produce the c-kit ligand. We have used a mast cell proliferation assay to purify a 30 kd protein, designated KL, from conditioned medium of Balb/3T3 fibroblasts to apparent homogeneity. KL stimulates the proliferation of normal bone marrow derived mast cells but not mast cells from W mice, although both normal and mutant mast cells respond similarly to IL-3. Connective tissue-type mast cells derived from the peritoneal cavity of normal mice were found to express a high level of c-kit protein on their surface and to proliferate in response to KL. The effect of KL on erythroid progenitor cells was investigated as well. In combination with erythropoietin, KL was found to stimulate early erythroid progenitors (BFU-E) from fetal liver and spleen cells but not from bone marrow cells of adult mice and from fetal liver cells of W/W mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1990

In vitro effects of thyroxine on the mechanical properties of erythrocytes.

In vitro effects of thyroxine on erythrocyte deformability and mechanical fragility were observed. Deformability of erythrocytes was improved in a dose dependent manner by thyroxine. Mechanical hemolysis was found to be lower if thyroxine was included in erythrocyte suspensions at concentrations close to the physiological levels (10(-9)M). These changes might be related to the alterations of intracellular calcium concentration, as in the erythrocyte suspensions containing 10(-9)M thyroxine, intracellular calcium concentration was found to be 30 times lower than the control suspensions which did not contain thyroxine. Thyroxine also reduced the mechanical hemolysis ratio in calcium loaded cells. These observations suggest that thyroxine might play some role in the regulation of the mechanical properties of erythrocytes which might be mediated via the effects on calcium metabolism.

Adult↗
PubMed1990

A novel autoregulatory cytokine is required for the regulation of autoaggressive responses.

Limiting dilution studies indicate that cells with the potential to lyse autologous target cells exist in the peripheral blood of all normal individuals. In contrast to allocytotoxic cells, autocytolytic cells are down-regulated by a second less frequent cell population. When recombinant interleukin 2 is substituted for crude lymphocyte conditioned medium in these limiting dilution experiments, autocytotoxicity develops normally. Under these conditions, however, the autocytotoxic response is not down-regulated. Mixing crude lymphocyte-conditioned medium together with recombinant interleukin 2 restores the regulation of autocytotoxicity normally seen at high responder cell dose. These findings indicate that a second soluble factor present in the conditioned medium is necessary either for the activation, growth, or differentiation of the regulatory cell population or alternatively, to render the cytotoxic population responsive to the activity of regulatory cells. Gel filtration studies indicate that the molecular weight of this factor is between 60 and 80 kd. This factor appears to be distinct from known immunologically active cytokines. It is conceivable that deficiencies of this cytokine may be relevant to the pathogenesis of autoimmune diseases or graft-versus-host reactions.

Biological Factors↗
PubMed1990

Effect of duodenal ulcerogens mepirizole and propionitrile on small intestinal and liver alkaline phosphatase activity in rats.

Duodenal ulcer could be induced in rats by a single subcutaneous injection of the anti-inflammatory agent mepirizole (M) or by the alkyl chemical propionitrile (P). Contrary to M, P provokes HCl hypersecretion as well. We used these animal models of duodenal ulcer to study the preulcerogenic molecular changes in the mucosal cells and their causal relationship to HCl hypersecretion. It was found that M and P induced the dose- and time-dependent decrease of duodenal alkaline phosphatase (DAP) activity. The decrease was detected at 4 h, with a nadir at 12 h after the injection of both drugs. The decrease of alkaline phosphatase activity was organ-specific after P administration and it was even regional-specific along the small intestine after M administration. At the level of mucosal cells of duodenum the effect of the ulcerogens was enzyme-selective. Both ulcerogens decreased protein and alkaline phosphatase activities; however, they had no effect on lysosomal acid phosphatase. Contrary to cysteamine (C), the effect of M and P on DAP depletion could not be reproduced under in vitro conditions. An interference of P and a slight additive effect of C on DAP depletion after simultaneous subcutaneous administration with M to the rats was found. The results indicate that the DAP depletion after in vivo administration of the three duodenal ulcerogens could be provoked by at least two different mechanisms. The decrease of DAP activity seems to be a general property of the duodenal ulcerogens independent of their effects on gastric acid secretion or on the suppression of alkaline secretion in the duodenum. As a late molecular event most probably elicited by the early morphological changes, the decrease of DAP activity could rather be related to ulcer healing than to its pathogenesis.

Alkaline Phosphatase↗