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Y Zilberman

Publications and source records attributed to Y Zilberman.

At least 19 recordsLinked to original sources
PubMed2002

Second-generation microstimulator.

The first-generation injectable microstimulator was glass encased with an external tantalum capacitor electrode. This second-generation device uses a hermetically sealed ceramic case with platinum electrodes. Zener diodes protect the electronics from defibrillation shocks and from electrostatic discharge. The capacitor is sealed inside the case so that it cannot be inadvertently damaged by surgical instruments. This microstimulator, referred to as BION, is the main component of a 255-channel wireless stimulating system. BION devices have been implanted in rats for periods of up to 5 months. Results show benign tissue reactions resulting in identical encapsulation around BION and controls. Stimulation threshold levels did not change significantly over time and ranged between 0.81 to 1.35 mA for all the animals at a 60 micros pulse width. All of the tests performed to date indicate that the BION is safe and effective for long-term human implant. We have elected to develop BION applications by seeking collaboration with the research community through our BION Technology Partnership.

Animals↗
PubMed2001

Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice.

In the mouse, ovariectomy (OVX) leads to significant reductions in cancellous bone volume while estrogen (17beta-estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent increase in bone formation would require the proliferation and differentiation of osteoblast precursors, we hypothesized that E2 regulates mesenchymal stem cells (MSCs) activity in mouse bone marrow. We therefore investigated proliferation, differentiation, apoptosis, and estrogen receptor (ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-operated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significant increase in ERalpha mRNA and protein expression as well as alkaline phosphatase (ALP) activity and proliferation rate. In contrast, E2 treatment resulted in a decrease in ERbeta mRNA and protein expression as well as apoptosis in both OVX and sham mice. E2 up-regulated the mRNA expression of osteogenic genes for ALP, collagen I, TGF-beta1, BMP-2, and cbfa1 in MSCs. In a comparison of the relative mRNA expression and protein levels for two ER isoforms, ERalpha was the predominant form expressed in MSCs obtained from both OVX and sham-operated mice. Cumulatively, these results indicate that estrogen in vitro directly augments the proliferation and differentiation, ERalpha expression, osteogenic gene expression and, inhibits apoptosis and ERbeta expression in MSCs obtained from OVX and sham-operated mice. Co-expression of ERalpha, but not ERbeta, and osteogenic differentiation markers might indicate that ERalpha function as an activator and ERbeta function as a repressor in the osteogenic differentiation in MSCs. These results suggest that mouse MSCs are anabolic targets of estrogen action, via ERalpha activation. J. Cell. Biochem. Suppl. 36: 144-155, 2001.

Alkaline Phosphatase↗
PubMed2001

Exogenously regulated stem cell-mediated gene therapy for bone regeneration.

Regulated expression of transgene production and function is of great importance for gene therapy. Such regulation can potentially be used to monitor and control complex biological processes. We report here a regulated stem cell-based system for controlling bone regeneration, utilizing genetically engineered mesenchymal stem cells (MSCs) harboring a tetracycline-regulated expression vector encoding the osteogenic growth factor human BMP-2. We show that doxycycline (a tetracycline analogue) is able to control hBMP-2 expression and thus control MSC osteogenic differentiation both in vitro and in vivo. Following in vivo transplantation of genetically engineered MSCs, doxycycline administration controlled both bone formation and bone regeneration. Moreover, our findings showed increased angiogenesis accompanied by bone formation whenever genetically engineered MSCs were induced to express hBMP-2 in vivo. Thus, our results demonstrate that regulated gene expression in mesenchymal stem cells can be used as a means to control bone healing.

Animals↗
PubMed2001

Imaging transgene expression in live animals.

Monitoring the expression of therapeutic genes in targeted tissues in disease models is important to assessing the effectiveness of systems of gene therapy delivery. We applied a new light-detection cooled charged-coupled device (CCCD) camera for continuous in vivo assessment of commonly used gene therapy delivery systems (such as ex vivo manipulated cells, viral vectors, and naked DNA), without the need to kill animals. We examined a variety of criteria related to real-time monitoring of luciferase (luc) gene expression in tissues including bone, muscle, salivary glands, dermis, liver, peritoneum, testis, teeth, prostate, and bladder in living mice and rats. These criteria included determination of the efficiency of infection/transfection of various viral and nonviral delivery systems, promoter specificity, and visualization of luciferase activity, and of the ability of luciferin to reach various organs. The exposure time for detection of luc activity by the CCCD camera is relatively short (approximately 2 minutes) compared with the intensified CCD camera photon-counting method (approximately 15 minutes). Here we transduce a variety of vectors (such as viruses, transfected cells, and naked DNA) by various delivery methods, including electroporation, systemic injection of viruses, and tail-vein, high-velocity-high-volume administration of DNA plasmids. The location, intensity, and duration of luc expression in different organs were determined. The distribution of luciferin is most probably not a barrier for the detection of in vivo luciferase activity. We showed that the CCCD photon detection system is a simple, reproducible, and applicable method that enables the continuous monitoring of a gene delivery system in living animals.

Adenoviridae↗
PubMed2001

Speech processing strategy preferences among 55 European CLARION cochlear implant users.

This multicentre study investigates the preference and performance of a group of 55 adult CLARION cochlear implant users with the choice of simultaneous analogue stimulation (SAS) and continuous interleaved sampler (CIS) strategies during the first 3 months of implant use. Subjects were programmed with both strategies and instructed to use each of the two strategies in daily life to ascertain preference. Subjects were tested in both strategies with open-set sentence materials, auditory alone, at 2, 6 and 12 weeks after the initial programming session. Questionnaires were completed with preference ratings being recorded for the two strategies: 25% of subjects preferred SAS and 75% CIS. Subjects performed better in their strategy of choice. Preferences were set very early on in the process and did not change. Factors influencing preference are discussed. Offering the choice of fundamentally different strategies improves both individual and group performance.

Acoustic Stimulation↗
PubMed2000

Eosinophils maintain their capacity to signal and release eosinophil cationic protein upon repetitive stimulation with the same agonist.

Eosinophils contain in their granules eosinophil cationic protein (ECP) and other basic proteins that have been implicated in immunity to parasites and pathophysiology of chronic allergic responses. In a model of eosinophil degranulation, we show that eosinophils release ECP upon short-term GM-CSF priming and stimulation with either platelet-activating factor (PAF) or the anaphylatoxin C5a, but not eotaxin. Restimulation with the same agonist (PAF or C5a) was unsuccessful as assessed by monitoring intracellular calcium concentration and ECP release. In contrast, upon an intermediate washing step, eosinophils rapidly transduced PAF and C5a signals followed by significant ECP releases. Ligand-binding studies demonstrated that only a proportion of PAF receptors is internalized upon cell stimulation and that washing of the cells removes the agonist from the cell surface. Upon repetitive stimulation, eosinophils with less than 50% of the original ECP content were obtained. Such eosinophils did not increase cellular ECP levels even in the presence of the eosinophil survival factor GM-CSF in overnight cultures. In vivo studies revealed that eosinophils always express detectable amounts of ECP under chronic inflammatory conditions. In conclusion, we have shown that eosinophils maintain their capacity to degranulate upon repetitive stimulation with the same agonist as long as the receptor is not occupied from a previous stimulation. The cellular content of ECP appears to be a no limiting factor in the case of repetitive stimulation, implying that mature eosinophils may not require a significant ECP resynthesis.

Blood Proteins↗
PubMed2000

p53 and thymic 'death by neglect': thymic epithelial cell-induced apoptosis of CD4+8+ thymocytes is p53-independent.

The involvement of the tumor suppressor protein, p53, in thymic epithelial cell-induced apoptosis of CD4+8+ (double positive) thymocytes, was studied in an in vitro model consisting of a thymic epithelial cell line (TEC) and thymocytes. p53 expression was not augmented in double positive (DP) thymocytes upon co-culturing with TEC, although extensive apoptosis was observed. In the same cells, p53 expression was upregulated in response to low ionizing irradiation, which was accompanied with massive apoptosis. Moreover, TEC induced apoptosis in two DP thymomas, derived from p53(-/-) mice, and in a double positive thymoma clone expressing mutant p53. The extent and kinetics of TEC-induced apoptosis was not affected by the status of p53 in the thymocytes tested. We conclude that thymic epithelial cell-induced apoptosis of immature DP thymocytes is p53-independent and apparently, involves a different apoptotic pathway than that triggered by DNA damage.

Animals↗
PubMed1999

Recombinant TGF-beta1 stimulates bone marrow osteoprogenitor cell activity and bone matrix synthesis in osteopenic, old male mice.

We have previously hypothesized that the osteopenic changes seen in the skeletons of old male BALB/c mice are due to reductions in the availability and/or synthesis of bone TGF-beta which results in fewer, less osteogenic marrow osteoprogenitor cells (CFU-f; OPCs) and lower levels of bone formation. Among other things, this hypothesis would predict that introducing exogenous TGF-beta into old mice (growth factor replacement) should stimulate marrow CFU-f and increase bone formation. In the present study, we have tested this prediction and, indirectly the hypothesis, by injecting human recombinant TGF-beta1, i.p., into both young adult (4 month) and old mice (24 month). The effects of the growth factor on the skeleton were then assessed by measurements of trabecular bone volume, bone formation, fracture healing, and the number, proliferative, apoptotic, and alkaline phosphatase activity of marrow CFU-f/OPCs. Our data show that the introduction of 0.5 or 5.0 ug/day of TGF-beta1 into old mice for 20 days 1) increases trabecular bone volume, bone formation and the mineral apposition rate, 2) augments fracture healing, 3) increases the number and size of CFU-f colonies, and 4) increases proliferation and diminishes apoptosis of CFU-f in primary bone marrow cultures. Importantly, these stimulatory effects of injected growth factor are apparently age-specific, i.e., they are either not seen in young animals or, if seen, are found at much lower levels. While these observations do not exclude other possible mechanisms for the osteopenia of old mice, they provide further support for the hypothesis that, with age, diminished TGF-beta synthesis or availability results in a reduction in the marrow osteoprogenitor pool and bone formation. The findings also demonstrate that the latter changes can be reversed, at least transiently, by introducing exogenous TGF-beta1.

Age Factors↗
PubMed1999

Apoptosis of thymic lymphoma clones by thymic epithelial cells: a putative model for 'death by neglect'.

We have previously described an in vitro system in which thymic epithelial cells induce apoptosis in CD4+ 8+ thymocytes or thymic lymphoma cells, in the absence of an exogenous antigen. A thymic epithelial cell line (TEC) recapitulated the response, by inducing apoptosis in CD4+ 8+ thymocytes of the thymic lymphoma clone, PD1.6. The present study pursues the involvement of the T-cell receptor (TcR) in the response of PD1.6 to TEC. TcR cross-linking did not cause apoptosis of PD1.6, although it induced tyrosine phosphorylation of p95vav. In contrast, TEC did not induce phosphorylation of p95vav but induced apoptosis of PD1.6 cells. These results suggest that TcR-evoked signals are not involved in TEC-induced apoptosis of PD1.6. Intracellular calcium chelation, using BAPTA-loaded PD1.6 cells, diminished TEC-induced apoptosis. Protein kinase C depletion in PD1.6 cells augmented their apoptotic response to TEC. Thus, the response of PD1.6 to TEC is calcium-dependent and inhibited by PKC. Likewise, the apoptotic response of PD1.6 to A23187 was abrogated by PKC activation. PD1.6 cells may represent an immature double positive thymocyte population, which does not undergo negative selection. The interaction of PD1.6 with TEC may thus serve as a model for the TcR-independent 'Death by Neglect', which takes place in the thymus during thymocyte development.

Animals↗
PubMed1999

Simultaneous Analog Stimulation (SAS)--Continuous Interleaved Sampler (CIS) pilot comparison study in Europe.

The recent availability of the enhanced bipolar electrode array in the CLARION Multi-Strategy Cochlear Implant has permitted clinicians to fit patients successfully with the Simultaneous Analog Stimulation (SAS) strategy by means of bipolar coupling. Out of 22 consecutively implanted subjects, 20 subjects could be fitted with both Continuous Interleaved Sampler (CIS) and SAS strategies. Their performance was evaluated up to 3 months postoperatively. Speech perception results, as well as the patient's preference for either CIS or SAS, were examined. It was found that half of the subjects selected SAS as their preferred strategy and that the use of a preferred strategy resulted in higher overall patient performance. Further analyses showed that those subjects preferring SAS had higher electrode impedance values and lower threshold and most comfortable loudness levels than subjects preferring CIS. We presume that these psychophysical findings are, in part, related to the position of the intracochlear electrode array. Specifically, SAS users may have a more modiolus-hugging electrode array position.

Cochlear Implantation↗
PubMed1998

Bone loss (osteopenia) in old male mice results from diminished activity and availability of TGF-beta.

One of the universal characteristics of the long bones and spines of middle-age and older mammals is a loss in bone mass (osteopenia). In humans, if this bone loss is severe enough, it results in osteoporosis, a skeletal disorder characterized by a markedly increased incidence of fractures with sequelae that may include pain, loss of mobility, and in the event of hip fracture, even death within a relatively few months of injury. An important contributing factor to the development of osteoporosis appears to be a diminution in the number and activity of osteoblasts responsible for synthesizing new bone matrix. The findings in the present and other similar studies suggest that this reduction in osteoblast number and activity is due to an age-related diminution in the size and osteogenic potential of the bone marrow osteoblast progenitor cell (OPC or CFU-f) compartment. We previously postulated that these regressive changes in the OPC/CFU-f compartment occurred in old animals because of a reduction in the amount and/or activity of TGF-beta1, an autocrine growth factor important in the promotion of OPC/CFU-f proliferation and differentiation. In support of this hypothesis, we now report that (1) the osteogenic capacity of the bone marrow of 24-month-old BALB/c mice, as assessed in vivo, is markedly reduced relative to that of 3-4-month-old animals, (2) that the matrix of the long bones of old mice contains significantly less TGF-beta than that of young mice, (3) that OPC's/CFU-f's isolated from old mice produce less TGF-beta in vitro than those recovered from young mice, and (4) that OPC's/CFU-f's from old mice express significantly more TGF-beta receptor (Types I, II, and III) than those of young animals and that such cells are more responsive in vitro to exogenous recombinant TGF-beta1. We also find that colony number and proliferative activity of OPC's/CFU-f's of young mice and old mice, respectively, are significantly reduced when incubated in the presence of neutralizing TGF-beta1 antibody. Collectively, these data are consistent with the hypothesis that in old male mice the reduction in the synthesis and, perhaps, availability from the bone matrix of TGF-beta1 contributes to a diminution in the size and development potential of the bone marrow osteoprogenitor pool.

Aging↗
PubMed1998

Mast cells enhance eosinophil survival in vitro: role of TNF-alpha and granulocyte-macrophage colony-stimulating factor.

Mast cell-eosinophil interactions in allergy have not yet been completely defined. To determine whether mast cells influence eosinophil survival, human peripheral blood eosinophils were incubated with rat peritoneal mast cell sonicate. After 3 days, viable eosinophils in medium were 21.3% compared with 44% with mast cell sonicate. Like sonicate, supernatants of compound 48/80-activated mast cells enhanced eosinophil survival, demonstrating that the factor(s) involved is stored preformed and rapidly released. Increased eosinophil survival was due to an inhibition of apoptosis (morphologic analysis; annexin V/PI). Neutralizing Abs to granulocyte-macrophage CSF (GM-CSF), but not to IL-3 or IL-5, decreased by 61.7% the enhancing effect on eosinophil viability. Eosinophils are the source of GM-CSF since its release in the culture medium was inhibited by their incubation with the mast cell sonicate together with dexamethasone. In addition, eosinophils incubated with the sonicate expressed mRNA for GM-CSF. To partially characterize the mast cell-derived factor(s) increasing eosinophil survival, the sonicate was heated (56 degrees C/30 min or 100 degrees C/10 min) or preincubated with antihistamines or with anti-TNF-alpha-neutralizing Abs. Most of the activity was heat labile. TNF-alpha was found to be predominantly (70%) responsible, while histamine had no role. Mast cell sonicate also caused eosinophils to release eosinophil peroxidase and to display morphologic signs of activation. In conclusion, we have demonstrated that mast cells enhance eosinophil survival in part through their activation to produce and release the autocrine survival cytokine GM-CSF.

Adolescent↗
PubMed1997

Orthodontic-prosthetic treatment to replace maxillary incisors exfoliated because of improper use of orthodontic elastics: a case report.

This article describes the iatrogenic exfoliation of maxillary central incisors following the improper use of orthodontic elastic bands. The unsecured rubber band had migrated apically and caused an almost "bloodless extraction" of both maxillary central incisors. A combined orthodontic-prosthetic solution was used to replace the lost incisors.

Adolescent↗
PubMed1996

T cell receptor-independent apoptosis of thymocyte clones induced by a thymic epithelial cell line is mediated by steroids.

We have studied the mechanisms involved in TcR-independent apoptosis of radiation leukemia virus (RadLV)-transformed thymocyte clones induced by a thymic epithelial cell line (TEC). TEC induced apoptosis of an immature CD4+8+3+ (PD1.6) but not of a CD4-8-3- (B10) thymocyte clone. TEC-derived conditioned medium did not mimic the signal induced by TEC in PD1.6 cells. However, the TEC-resistant clone B10 apoptosed in response to TEC, provided that PD1.6 cells were also present in the culture. This effect on bystander cells suggests that a secreted factor was involved. The involvement of glucocorticoid hormones as potential mediators was addressed. PD1.6 cells apoptosed in response to dexamethasone or a cell-permeating analog of cAMP, while BIO cells were relatively resistant to dexamethasone. TcR cross-linking inhibited both TEC- and dexamethasone- but not cAMP-induced apoptosis. Aminoglutethimide and Ru38486 inhibited TEC-induced apoptosis of PD1.6 cells, whereas Ru28318 had a negligible effect. The results suggest that steroid hormones are involved in TcR-independent apoptosis of immature double-positive thymocyte clones induced by TEC.

Aminoglutethimide↗
PubMed1994

High oligomycin concentrations augment 6-keto-PGF1 alpha production in ventricular cardiomyocytes.

Incubation of cultured ventricular cardiomyocytes with high oligomycin concentrations (100 micrograms/ml), either alone or combined with 2-deoxyglucose (20 mM), led to the rapid depletion of cellular ATP. Inositol (poly)phosphate production decreased, and 6-keto PGF1 alpha production was increased. In cells depleted of ATP, either by low oligomycin concentrations or by sodium azide, 6-keto PGF1 alpha was not appreciably increased. There was a 25% rise in the release of fatty acids from the sn-2 position in glycerophospholipids. We suggest that oligomycin at high concentrations causes the release of free arachidonic acid from phospholipids either by non-PIP2-specific PLC and DG lipase or by phospholipase D, phosphatidic acid phosphatase and DG lipase. The effect is unrelated to decreased cellular ATP content.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Mitogenic activation of phosphoinositide turnover and DNA synthesis in murine CD4+8+ thymocytes.

Eighty percent of the lymphoid cells in the murine thymus are premature CD4+8+ (double positive) thymocytes. The vast majority of the double-positive cells do not maturate and die in the thymus. Although these cells are subjected to thymic selection processes, their activation competence has been an enigma. We have separated out CD4+8+ cells and studied their early and late responses to several mitogens. Concanavalin A, anti-CD3 (145-2C11) or anti-Thy1 (G7) monoclonal antibodies enhanced phosphoinositide turnover in double-positive thymocytes. However, DNA synthesis in the mitogen-stimulated cells was only accomplished if IL-2 or IL-4 was added. Alternatively, DNA synthesis could be induced by the calcium ionophore A23187 and phorbol myristate acetate (PMA). The latter mode of activation did not require the addition of exogenous lymphokines. CD4+8+ thymocytes did not secrete IL-2 or IL-4 following activation by either mitogens or A23187 and PMA. These findings demonstrate that CD4+8+ thymocytes resemble mature T cells in their ability to respond with DNA synthesis when activated by T-cell mitogens and IL-4 as well as IL-2. The results also delineate the difference between receptor mediated mitogenesis and pharmacological stimulation.

Animals↗
PubMed1993

Resorbed lateral incisors adjacent to impacted canines have normal crown size.

The importance of detecting maxillary canine impaction is that it may compromise dental health, particularly since a small but significant proportion of impacted canines is associated with the resorption of the roots of neighboring teeth. It has been shown that the existence of small and peg-shaped lateral incisors is highly correlated with maxillary canine palatal impaction. To date, however, it has not been established whether the root resorption that occurs has a similar correlation or a predilection for one or other types of lateral incisor crown structure. Accordingly, a group of patients with buccally or palatally impacted canines, in which root resorption of the lateral incisor could be diagnosed roentgenographically, was examined and compared with a group of cases with palatally impacted canines, none of which showed root resorption, which served as controls. The mesiodistal crown dimension of the lateral incisor in the experimental group was found to be normal in all patients except three (13%), which was significantly different from the distribution of lateral incisor size in the control group (p < 0.001). In the majority of the cases, aggressive root resorption of the lateral incisor root had occurred. We would speculate that in these cases, the normal-sized and early developing lateral incisor root obstructs the deviated eruption path of the canine and consequently stands a considerably greater chance of being damaged by resorption.

Adolescent↗