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Biomedical subjects

R Levy

Publications and source records attributed to R Levy.

At least 127 records · Page 7Linked to original sources
PubMed2000

Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor.

Preeclampsia and fetal growth restriction are associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes diminished trophoblast differentiation and enhanced apoptosis. We tested the hypothesis that hypoxia induces apoptosis in cultured trophoblasts, and that epidermal growth factor (EGF), an enhancer of trophoblast differentiation, diminishes hypoxia-induced apoptosis. Trophoblasts isolated from placentas of term-uncomplicated human pregnancies were cultured up to 72 h in standard (PO(2) = 120 mm Hg) or hypoxic (PO(2) <15 mm Hg) conditions. Exposure to hypoxia for 24 h markedly enhanced trophoblast apoptosis as determined by DNA laddering, internucleosomal in situ DNA fragmentation, and histomorphology, as well as by the reversibility of the apoptotic process with a caspase inhibitor. Apoptosis was accompanied by increased expression of p53 and Bax and decreased expression of Bcl-2. Addition of EGF to cultured trophoblasts or exposure of more differentiated trophoblasts to hypoxia significantly lowered the level of apoptosis. We conclude that hypoxia enhances apoptosis in cultured trophoblasts by a mechanism that involves an increase in p53 and Bax expression. EGF and enhancement of cell differentiation protect against hypoxic-induced apoptosis.

Apoptosis↗
PubMed2000

Microstimulation-induced inhibition of neuronal firing in human globus pallidus.

Neurosurgical treatment of Parkinson's disease (PD) frequently employs chronic high-frequency deep brain stimulation (DBS) within the internal segment of globus pallidus (GPi) and can very effectively reduce L-dopa-induced dyskinesias and bradykinesia, but the mechanisms are unknown. The present study examined the effects of microstimulation in GPi on the activity of neurons close to the stimulation site. Recordings were made from GPi using two fixed or independently controlled microelectrodes, with the electrode tips usually approximately 250 or >600 micrometer apart in PD patients undergoing stereotactic exploration to localize the optimal site for placement of a lesion or DBS electrode. The spontaneous activity of nearly all of the cells (22/23) recorded in GPi in three patients was inhibited by microstimulation at currents typically <10 microA (0.15-ms pulses at 5 Hz). The inhibition had a duration of 10-25 ms at threshold. These findings suggest that microstimulation within GPi preferentially excites the axon terminals of striatal and/or external pallidal neurons causing release of GABA and inhibition of GPi neurons.

Action Potentials↗
PubMed2000

Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment.

PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin's lymphoma who relapsed after a response to rituximab therapy. PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m(2) of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses. RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients' prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P: >.1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders. CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.

Adult↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma modulates differentiation of human trophoblast in a ligand-specific manner.

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the differentiation of several tissues and cell types. PPARgamma was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPARgamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPARgamma expression and found that PPARgamma is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPARgamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPARgamma activity, but has no effect on PPARgamma expression. We demonstrated that the PPARgamma ligand 15-deoxy-delta12,14-prostaglandin J2 (15deltaPGJ2) and the thiazolidinedione troglitazone stimulate PPARgamma activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15deltaPGJ2 diminishes trophoblast differentiation. Furthermore, 15deltaPGJ2, but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPARgamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPARgamma results in opposing effects on trophoblast differentiation. Our results suggest that PPARgamma plays an important role in placental differentiation during human pregnancy.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

The history of the development of vaccines for the treatment of lymphoma.

Exploitation of the immune system is an attractive strategy for developing selective lymphoma therapies. In the past several decades, increased knowledge of tumor immunology has granted investigators the tools to formulate a variety of lymphoma-specific vaccines. Vaccines targeting the tumor-specific immunoglobulin (idiotype) of B-cell lymphomas were the first to be developed, owing to successful active vaccination studies in animal models and clinical studies of passive anti-idiotype monoclonal antibodies. In initial clinical trials, patient-specific idiotype vaccines have been found to induce anti-idiotype immune responses that correlate with improved disease-free and overall survival and the reduction of the level of detectable residual disease. More recent strategies for improving the potency and practicality of idiotype vaccines are utilization of dendritic cells, recombinant idiotype proteins, and DNA vaccination. Custom-made vaccines utilizing whole autologous tumor cells are also being developed. Given the exciting results of these early lymphoma vaccine studies and the accelerated pace of immunologic research, it is hoped that vaccines will someday expand the armamentarium of effective lymphoma therapies.

Allergy and Immunology↗
PubMed2000

Local and systemic immune response in community-dwelling elderly after intranasal or intramuscular immunization with inactivated influenza vaccine.

Intramuscular (IM) influenza vaccines are about 50% effective in preventing clinical illness among the elderly and their effectiveness in eliciting mucosal response may be even lower. The aim of the present study was to evaluate the immunological effect of a novel inactivated intranasal (IN) trivalent whole influenza virus vaccine among community-dwelling elderly. Sixty-one subjects were vaccinated with two doses of an IN vaccine and a control group of 31 subjects was vaccinated with a commercial IM vaccine. Viral strains in the 1997/8 vaccine used were A/Nanchang/933/95(H3N2), A/Johannesburg/82/96(H1N1) and B/Harbin/7/94. Serum IgG and nasal IgA were determined by HI and ELISA, respectively. Only a few minor local adverse events were reported after vaccination. Seroconversion for the three antigens tested was higher after IM vaccination, although not statistically significant. Local antibody response to the three antigens tested was detected in 50-53% and 19-26% of IN and IM immunized subjects, respectively. The IN vaccine tested was significantly more effective than the IM vaccine in inducing mucosal IgA response. This may prevent influenza at its early stages and thus contribute to the reduction of complications in the elderly.

Administration, Intranasal↗
PubMed2000

Neuronal recordings in Parkinson's disease patients with dyskinesias induced by apomorphine.

Dopaminergic agents reverse parkinsonism but commonly induce dyskinesia in patients with Parkinson's disease (PD) on long-term levodopa therapy. The aim of this study was to determine the neurophysiologic correlates of the amelioration of parkinsonism and the involuntary movements produced by the dopamine agonist apomorphine. Seventeen PD patients were given apomorphine (2-6 mg) before surgery. Neural activity was recorded for individual neurons and for populations of neurons before and after apomorphine. Both internal (GPi) and external (GPe) segments of the globus pallidus were sampled in patients undergoing pallidal surgery. The subthalamic nucleus (STN) was sampled in STN surgery patients. Results suggest that dopaminergic agents act by decreasing GPi and STN activity, and increasing GPe activity, and that drug-induced dyskinesias results from a large reduction in GPi firing.

Action Potentials↗
PubMed2000

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a.

Rituximab and IFN have each demonstrated single-agent activity in patients with low-grade non-Hodgkin's lymphoma (NHL). A single-arm, multicenter, Phase II trial was conducted to assess the safety and efficacy of combination therapy with rituximab and IFN-alpha-2a in 38 patients with relapsed or refractory, low-grade or follicular, B-cell NHL. IFN-alpha-2a [2.5 or 5 million units (MIU)] was administered s.c., three times weekly for 12 weeks. Starting on the fifth week of treatment, rituximab was administered by i.v. infusion (375 mg/m2) weekly for 4 doses. All 38 patients received four complete infusions of rituximab and were evaluable for efficacy, although 11 patients (29%) did not-receive all 36 injections of IFN. The mean number of IFN-alpha-2a injections was 31 doses; the mean total units received were 141 MIU (maximum, 180 MIU). The study treatment was reasonably well tolerated with no unexpected toxicities stemming from the combination therapy. No grade 4 events were reported. Frequent adverse events during the treatment period included asthenia (35 of 38 patients), chills (31 of 38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and myalgia (22 of 38). The overall response rate was 45% (17 of 38 patients); 11% had a complete response, and 34% had a partial response. The Kaplan-Meier estimates for the median response duration and the median time to progression in responders are 22.3 and 25.2 months, respectively. Further follow-up is needed to determine whether this treatment combination leads to a significantly longer time to progression than single-agent treatment with rituximab.

Adult↗
PubMed2000

[Uptake of drug-containing nanoparticles in dog catotid and femoral arteries].

OBJECTIVE: To study the uptake of drug-containing nanoparticles in artery for local therapy of restenosis. METHODS: Polylactic polyglycolic acid copolymer (PLGA) nanoparticles containing an antiproliferative agent 2-amino-chromone were formulated with an oil-in-water sonication emulsion/solvent evaporation technique. Arterial uptake of nanoparticles was assessed both in vitro and in vivo models of dog and rat carotid and femoral arteries. Epoxide, cyanoacrylate, fibrinogen, fibronectin, didodecyldimethylammonium bromide (DMAB), L-alpha-phosphatidylethanolaine, and lipofectin were selected to modify the surface of nanoparticles to enhance arterial uptake of nanoparticles. RESULTS: The nanoparticle size ranged from 100 nm to 200 nm, the drug loading in nanoparticles was about 15%, the nanoparticle morphology was observed by scanning electron microscopy and showed spherical shape with smooth surface. Arterial uptake of nanoparticles was enhanced greatly by surface modified nanoparticle with positively charged active agent DMAB. Once nanoparticles located in artery, a high drug level could be maintained at local site for 2 days in vivo model. CONCLUSION: The primary results of animal experiments suggested that nanoparticle could be used as drug carrier of local drug delivery for treating cardiovascular diseases.

Animals↗
PubMed1999

Essential requirement of cytosolic phospholipase A(2) for activation of the H(+) channel in phagocyte-like cells.

The NADPH oxidase-producing superoxide is the major mechanism by which phagocytes kill invading pathogens. We previously established a model of cytosolic phospholipase A(2) (cPLA(2))-deficient differentiated PLB-985 cells (PLB-D cells) and demonstrated that cPLA(2)-generated arachidonic acid (AA) is essential for NADPH oxidase activation (Dana, R., Leto, T., Malech, H., and Levy, R. (1998) J. Biol. Chem. 273, 441-445). In the present study, we used this model to determine the physiological role of cPLA(2) in the regulation of both the H(+) channel and the Na(+)/H(+) antiporter and to study whether NADPH oxidase activation is regulated by either of these transporters. PLB-D cells and two controls: parent PLB-985 cells and PLB-985 cells transfected with the vector only (PLB cells) were differentiated using 1.25% Me(2)SO or 5 x 10(-8) M 1, 25-dihydroxyvitamin D(3). Activation of differentiated PLB cells resulted in a Zn(2+)-sensitive alkalization, indicating H(+) channel activity. In contrast, differentiated PLB-D cells failed to activate the H(+) channel, but the addition of exogenous AA fully restored this activity, indicating the role of cPLA(2) in H(+) channel activation. The presence of the H(+) channel inhibitor Zn(2+) caused significant inhibition of NADPH oxidase activity, suggesting a role of the H(+) channel in regulating oxidase activity. Na(+)/H(+) antiporter activity was stimulated in differentiated PLB-D cells, indicating that cPLA(2) does not participate in the regulation of this antiporter. These results establish an essential and specific physiological requirement of cPLA(2)-generated AA for activation of the H(+) channel and suggest the participation of this channel in the regulation of NADPH oxidase activity.

Amiloride↗
PubMed1999

Association of storage and processing functions in the dorsolateral prefrontal cortex of the nonhuman primate.

The prominent role of the prefrontal cortex (PFC) in working memory (WM) is widely acknowledged both in nonhuman primates and in humans. However, less agreement exists on the issue of functional segregation within different subregions of the PFC with regard to the domains of spatial and nonspatial processing or involvement in simpler versus more complex aspects of WM, e.g., maintenance versus processing function. To address these issues, six monkeys were trained to perform four WM tasks that differed with respect to domain (spatial vs nonspatial) and level of WM demand (recall of one vs three items). The delayed response format was used to assess simple one-item memory, whereas self-ordering tasks were used to require the monkey to maintain and organize three items of information within WM. After training, the monkeys received bilateral PFC lesions in one of two different areas, Walker's areas 9 and 8B (dorsomedial convexity; n = 3) or areas 46 and 8A (dorsolateral cortex, n = 3) and then tested postoperatively on all tasks. Monkeys with lesions of the dorsomedial convexity were not impaired either on spatial or nonspatial WM tasks, whether the task required simple storage or sequential processing. By contrast, lesions of the dorsolateral cortex produced a significant and persistent impairment in both simple and complex spatial WM but no impairment in the two nonspatial WM tasks. These results support a functional segregation within the dorsolateral prefrontal cortex for WM: the dorsolateral prefrontal cortex (area 46/8A) is selectively involved in spatial WM, whereas the dorsomedial convexity (area 9/8B) is not critically engaged in either spatial or nonspatial working memory. Furthermore, the specific involvement of area 46/8A in spatial sequencing as well as in single-item storage WM tasks supports, in the nonhuman primate, an areal dissociation based on domain rather than on processing demand.

Animals↗
PubMed1999

Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein. A possible role for protein kinase C.

Macrophage-mediated oxidation of low density lipoprotein (LDL) is considered to be of major importance in early atherogenesis; therefore, intervention means to inhibit this process are being extensively studied. In the present study, we questioned the ability of the isoflavan glabridin (from licorice) to accumulate in macrophages and to affect cell-mediated oxidation of LDL. We first performed in vitro studies, using mouse peritoneal macrophages (MPMs) and the J-774 A.1 macrophage-like cell line. Both cells accumulated up to 1.5 micrograms of glabridin/mg of cell protein after 2 h of incubation, and this process was time- and glabridin dose-dependent. In parallel, in glabridin-enriched cells, macrophage-mediated oxidation of LDL was inhibited by up to 80% in comparison with control cells. Glabridin inhibited superoxide release from MPMs in response to phorbol 12-myristate 13-acetate, or to LDL when added together with copper ions, by up to 60%. Translocation of P-47, a cytosolic component of NADPH oxidase to the plasma membrane was substantially inhibited. In glabridin-enriched macrophages, protein kinase C activity reduced by approximately 70%. All of the above effects of glabridin required the presence of the two hydroxyl groups on the flavonoid's B phenol ring. In order to assess the physiological significance of these results, we next performed in vivo studies, using the atherosclerotic apolipoprotein E-deficient (E0) mice. MPMs harvested from glabridin-treated E0 mice (20 micrograms/mouse/day for a period of 6 weeks) demonstrated reduced capability to oxidize LDL by 80% in comparison with placebo-treated mice. This latter phenomenon was associated with a reduction in the lesion oxysterols and a 50% reduction in the aortic lesion size. We thus conclude that glabridin accumulation in macrophages is associated with reduced cell-mediated oxidation of LDL and decreased activation of the NADPH oxidase system. These phenomena could be responsible for the attenuation of atherosclerosis in E0 mice, induced by glabridin.

Animals↗
PubMed1999

DNA vaccination against the idiotype of a murine B cell lymphoma: mechanism of tumor protection.

Several studies have shown that immunization with DNA, which encodes the idiotypic determinants of a B cell lymphoma, generates tumor-specific immunity. Although induction of antiidiotypic Abs has correlated with tumor protection, the effector mechanisms that contribute to tumor protection have not been clearly identified. This study evaluated the tumor protective effects of humoral and cellular immune mechanisms recruited by idiotype-directed DNA vaccines in the 38C13 murine B cell lymphoma model. Antiidiotypic Abs induced by DNA vaccination supported in vitro complement-mediated cytotoxicity of tumor cells, and simultaneous transfer of tumor cells and hyperimmune sera protected naive animals against tumor growth. However, in vitro stimulation of immune splenocytes with tumor cells failed to induce idiotype-specific cytotoxicity, and following vaccination, depletion of CD4 or CD8 T cell subsets did not compromise protection. Furthermore, protection of naive recipients against tumor challenge could not be demonstrated either by a Winn assay approach or by adoptive transfer of spleen and lymph node cells. Thus, in this experimental model, current evidence suggests that the tumor-protective effects of DNA vaccination can be largely attributed to idiotype-specific humoral immunity.

Adoptive Transfer↗
PubMed1999

Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study.

The idiotype (Id) determinant on the multiple myeloma (MM) protein can be regarded as a tumor-specific marker. Immunotherapy directed at the MM Id may stem the progression of this disease. We report here on the first 12 MM patients treated at our institution with high-dose therapy and peripheral blood stem cell transplantation (PBSCT) followed by Id immunizations. MM patients received PBSCT to eradicate the majority of the disease. PBSCT produced a complete response in 2 patients, a partial response in 9 patients and stable disease in 1 patient. Three to 7 months after high-dose therapy, patients received a series of monthly immunizations that consisted of two intravenous infusions of Id-pulsed autologous dendritic cells (DC) followed by five subcutaneous boosts of Id/keyhole limpet hemocyanin (KLH) administered with adjuvant. Between 1 and 11 x 10(6) DC were obtained by leukapheresis in all patients even after PBSCT. The administration of Id-pulsed DC and Id/KLH vaccines were well tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed an Id-specific, cellular proliferative immune response and one of three patients studied developed a transient but Id-specific cytotoxic T-cell (CTL) response. Eleven of the 12 patients generated strong KLH-specific cellular proliferative immune responses showing the patients' immunocompetence at the time of vaccination. The two patients who developed a cellular Id-specific immune response remain in complete remission. Of the 12 treated patients, 9 are currently alive after autologous transplantation with a minimum follow-up of 16 months, 2 patients died because of recurrent MM and 1 patient succumbed to acute leukemia. These studies show that patients make strong anti-KLH responses despite recent high-dose therapy and that DC-based Id vaccination is feasible after PBSCT and can induce Id-specific T-cell responses. Further vaccine development is necessary to increase the proportion of patients that make Id-specific immune responses. The clinical benefits of Id vaccination in MM remain to be determined.

Adjuvants, Immunologic↗