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Biomedical subjects

R Levy

Publications and source records attributed to R Levy.

At least 73 records · Page 4Linked to original sources
PubMed2001

Genetic regulation of preimplantation embryo survival.

Mammalian embryonic death is the most common outcome of fertilization. This review focuses on the recent advances concerning genetic regulation of preimplantation embryo survival. The predominant role of the Ped(preimplantation embryo development) gene, which regulates fast or slow cleavage of preimplantation mouse embryos, and its implication on embryo survival are discussed. Recent morphological and biochemical observations suggested that programmed cell death was an essential mechanism in preimplantation embryo fragmentation and survival, thus leading to original investigations on apoptosis and apoptosis-related genes. Other genes, transcripts, or proteins seem to be involved in embryo development and control of survival. In particular, the role of heat shock proteins (HSP), telomerase activity (human telomerase catalytic subunit hTCS), and the developmental significance of regulatory protein polarization (leptin, STAT 3) in preimplantation embryos are discussed.

Actins↗
PubMed2001

Bisphosphonate derivatized polyurethanes resist calcification.

Calcification of polyurethane cardiovascular implants is an important disease process that has the potential to compromise the long-term function of devices such as polymer heart valves and ventricular assist systems. In this study we report the successful formulation and characterization of bisphosphonate-derivatized polyurethanes, hypothesized to resist implant calcification based on the pharmacologic activity of the immobilized bisphosphonate. Fully polymerized polyurethanes (a polyurea-polyurethane and a polycarbonate polyurethane) were modified (post-polymerization) with bromoalkylation of the hard segments followed by attachment of a bisphosphonate group at the bromine site. These bisphosphonate-polyurethanes resisted calcification in rat 60 day subdermal implants compared to nonmodified control polyurethane implants, that calcify. Bisphosphonates-modified polyurethanes were also studied in circulatory implants using a pulmonary valve cusp replacement model in sheep. Polyurethane cusps modified with bisphosphonate did not calcify in 90 day implants. compared to control polyurethane cusps implants, that demonstrated nodular surface oriented calcific deposits. It is concluded that bisphosphonate modified polyurethanes resist calcification both in subdermal implants and in the circulation. This novel biomaterial approach offers great promise for long-term blood stream implantation with calcification resistance.

Animals↗
PubMed2001

Preliminary results of interferon-alpha therapy on woodchuck hepatitis virus-induced hepatocarcinogenesis: possible benefit in female transgenic mice.

BACKGROUND: C-myc activation is a potent oncogenic event in hepatocarcinogenesis. The aim of this study was to test the preventive effect of interferon-alpha (IFN-alpha) on the development of dysplasia and subsequent hepatocellular carcinoma (HCC) in transgenic (Tg) mice overexpressing c-myc in the liver. METHODS: The WHV/c-myc Tg mice recapitulating woodchuck hepatitis virus-induced hepatocarcinogenesis were treated with IFN-alpha, starting early in life until sacrifice at pre-neoplastic or neoplastic stages. Transgene expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR), hepatocyte proliferation was assessed by bromodeoxyuridine incorporation and RT-PCR for proliferating cell nuclear antigen, and apoptosis was assessed by in situ nick-end-labeling of DNA. RESULTS: C-myc expression and hepatocyte proliferation were significantly reduced in treated female mice, without modification of apoptosis, correlating with a lower severity of dysplasia in 9/12 treated animals at pre-neoplastic stages. At the neoplastic stage, 2/3 treated females neither exhibited carcinoma nor dysplasia, while all 6/6 untreated mice and 3/3 treated males developed carcinomas. CONCLUSIONS: Inhibition of c-myc and hepatocyte proliferation by long-term administration of IFN-alpha was associated with a decrease, or a delay, of oncogenesis in the mouse Tg HCC model. Whether c-myc and hepatocyte proliferation down-regulation could be relevant parameters of IFN-alpha efficiency for hepatocarcinogenesis prevention in cirrhotic patients should be established.

Animals↗
PubMed2001

T cell activation following infection of primary follicle center lymphoma B cells with adenovirus encoding CD154.

Purified, high-titer adenovirus encoding murine CD154 (Ad-CD154) or human CD154 (Ad-hCD154) was used to infect lymph node cells isolated from patients with follicle center lymphoma. Infection of lymphoma B cells with Ad-CD154 at a multiplicity of infection (MOI) ratio of 100 or higher resulted in high-level transgene expression. Additionally, upon infection of lymphoma B cells, only Ad-CD154 resulted in surface expression of CD154, despite similar, high-level expression of either human or mouse CD154 by HeLa cells infected with Ad-hCD154 or Ad-CD154, respectively. Moreover, infection of lymphoma B cells with Ad-CD154, but not Ad-hCD154 or adenovirus encoding Eschericheria coli beta-galactosidase (Ad-LacZ), induced the neoplastic B cells to express higher levels of immune co-stimulatory molecules that are required for proficient presentation of antigen to T cells. Consistent with this, we found that Ad-CD154 infected lymphoma B cells could stimulate T cells to proliferate or produce interferon-gamma in allogeneic or autologous mixed lymphocyte interactions. We conclude that lymphoma B cells can be infected with Ad-CD154 and that this significantly enhances their recognition by allogeneic or autologous T cells. As such, Ad-CD154-transduced lymphoma B cells may have potential for the active immune therapy of patients with follicle center lymphoma.

Adenoviridae↗
PubMed2001

Idiotype vaccination following ABMT can stimulate specific anti-idiotype immune responses in patients with B-cell lymphoma.

Vaccination with the idiotype (Id) protein derived from B-cell malignancies can produce Id-specific immune responses that correlate with improved remission duration and survival rates in patients with follicular non-Hodgkin's lymphoma (NHL). A state of minimal or no residual disease correlates strongly with the laboratory detection of a cellular or humoral immune response. High-dose cytotoxic therapy (HDCT) with autologous stem cell support (autologous bone marrow transplantation [ABMT]) can provide profound cytoreduction of B-cell NHL, but the potential immune suppression associated with myeloablative therapy may compromise a patient's ability to mount a specific immune response. To determine whether patients with NHL could mount detectable immuneresponses following ABMT, Id vaccines were administered at 2 to 12 months following myeloablative therapy to a series of patients with relapsed or resistant B-cell NHL. Two different vaccination strategies produced robust immune responses against KLH in all patients, supporting the capacity of the reconstituted immune system following HDCT to react against a strong antigen. Combining the results from both vaccination strategies, 10 of 12 patients mounted Id-specific humoral or cellular responses. Vaccinations were consistently well tolerated. Of the 12 patients, 7 have experienced prolonged remissions with a follow-up from HDCT ranging from 3 to more than 11 years. Our experience serves to document the ability of the recovering immune system to react against both self and xenotypic antigens and supports the feasibility and safety of antigen-specific vaccination following myeloablative therapy in patients with B-cell NHL.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

Perinatal management of fetal cardiac anomalies in a specialized obstetric-pediatrics center.

Perinatal teams dealing with fetal heart disease frequently wonder which pregnancies might be terminated, and when delivery should take place in a specialized surrounding. We present a retrospective study of 229 fetuses, in which prenatal ultrasound showed a cardiac anomaly not compatible with a standard maternity ward delivery. One hundred nineteen pregnancies were terminated (group I) while 110 pregnancies led to the birth of a live baby (group II). Pathology in group I was discovered earlier than in group II (24 vs. 29.3 weeks' gestation; p <0.01), and associated malformations or chromosomal anomalies were much more frequent in group I (80/119 vs. 9/110; p <0.001). Among live born babies, three infants with transposition of the great arteries underwent Rashkind atrioseptostomy in the delivery room. With a minimum follow-up of 12 months, 69 children (63%) have undergone surgery. Among 92 survivors (1 child is lost to follow-up), 78 (71%) are asymptomatic and 14 symptomatic. Early prenatal diagnosis of fetal heart anomalies significantly facilitates prenatal work-up and perinatal care. We present the types of pathology having led to termination and define the situations in which children are at risk of perinatal hemodynamic compromise.

Abortion, Eugenic↗
PubMed2001

Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms.

Inactivation of neurones in the subthalamic nucleus (STN) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkey model of Parkinson's disease has been shown to relieve parkinsonian motor symptoms. In patients with Parkinson's disease, neurones in the STN display hyperactive firing rates and rhythmic discharge activity such as tremor-related oscillations (3-8 Hz) and synchronous high-frequency oscillations (15-30 Hz). In this study, microinjections of lidocaine (n = 4) and muscimol, a GABA(A) receptor agonist (n = 2), were performed in the STN of six patients with Parkinson's disease to determine whether the focal suppression of STN neuronal activity can lead to an improvement in tremor, bradykinesia and rigidity. We also report the first use of microelectrode recording of the effects of microinjections on neuronal activity in the human brain (n = 2). Microinjections of 10-23 microl of lidocaine produced striking improvements in bradykinesia, limb tremor and rigidity in three out of three patients. These improvements were correlated with good therapeutic effects of subsequent STN deep brain stimulation performed in the same microelectrode trajectories as these injections. The most dramatic observation following lidocaine injections was the appearance of dyskinetic limb movements. In one patient, simultaneous microelectrode recording during an injection of 3.5 microl of lidocaine demonstrated a suppression of neuronal activity at distances of < 0.9 mm from the injection site, but no suppression was observed at > or = 1.2 mm from the injection site. Microinjections of 5-10 microl of muscimol in a region with tremor-related activity resulted in suppression of limb tremor in two out of two patients. Interestingly, in one of these patients, 4 Hz oscillatory activity was diminished in a neurone recorded 1.3 mm from the injection site, but there was no reduction in the mean firing rate or 20 Hz oscillatory activity. These results demonstrate that inactivation of neuronal activity in the STN of patients with Parkinson's disease improves motor symptoms. These findings also suggest that a focal block of the STN might alter the oscillatory activity of neurones located beyond the inhibited region.

Aged↗
PubMed2001

The role of dorsolateral prefrontal cortex in the preparation of forthcoming actions: an fMRI study.

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory (WM). Yet its precise contribution (the storage, manipulation and/or utilization of information for the forthcoming response) remains to be determined. To test the hypothesis that the DLPFC is more involved in the preparation of actions than in the maintenance of information in short-term memory (STM), we undertook a functional magnetic resonance imaging investigation in normal subjects performing two delayed response tasks (matching and reproduction tasks) in a visuospatial task sequence (presentation, delay, response). In the two tasks, the presentation and delay phases were similar, but the expected response was different: in the matching task, subjects had to indicate whether a visuospatial sequence matched the sequence presented before the delay period; in the reproduction task, subjects had to reproduce the sequence and, therefore, to mentally organize their response during the delay. Using a fMRI paradigm focusing on the delay period, we observed a significant DLPFC activation when subjects were required to mentally prepare a sequential action based on the information stored in STM. When subjects had only to maintain a visuospatial stimulus in STM, no DLPFC activation was found. These results suggest that a parietal-premotor network is sufficient to store visuospatial information in STM whereas the DLPFC is involved when it is necessary to mentally prepare a forthcoming sequential action based on the information stored in STM.

Adult↗
PubMed2001

T cell antigen receptor vaccines for active therapy of T cell malignancies.

T cell lymphoproliferative disorders continue to be serious management problems, and so alternative therapeutic modalities are continuously being explored. One such strategy involves immunotherapy using the T cell receptor (TCR) as a target. Specifically we are attempting to develop a T cell receptor idiotype (TCR-Id) vaccine because the TCR-Id can serve as a tumor-specific antigen. In this article we will briefly review the rationale for TCR-Id vaccines, the preclinical models as developed in our laboratory, and a discussion of our current plans for a vaccine trial in mycosis fungoides.

Adenoviridae↗
PubMed2001

Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease.

This study examines the effect of apomorphine (APO), a nonselective D(1)- and D(2)-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5-8 mg) were sufficient to produce an ON state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before (n = 309), during (n = 146, 10-60 min), and after the effect of APO had waned (n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson "surprise" analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons (P < 0.01), but there was no change in the overall firing rate of neurons in the STN (P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower than OFF-period baseline values (P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs (P < 0.05). During the OFF state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.

Action Potentials↗
PubMed2001

Immunotherapy of Non-Hodgkin's lymphomas.

Recent years have witnessed the development of a variety of promising immunotherapies for treating patients with non-Hodgkin's lymphomas. Foremost among these advances is the exciting success of monoclonal antibodies directed against lymphocyte surface antigens. Rituximab is a chimeric (human-mouse) anti-CD20 antibody that induces responses in approximately half of the patients with relapsed indolent lymphomas and a third of patients with relapsed aggressive lymphomas when used as a single agent. Response rates appear even higher (up to 70%) for newly diagnosed patients treated with Rituximab monotherapy. Other promising antibodies for treatment of B cell malignancies include epratuzumab (anti-CD22), CAMPATH-1H (anti-CD52w), and Hu1D10 (anti-class II HLA). Even more exciting than antibody monotherapy is the prospect of combination antibody therapy (e.g. rituximab + epratuzumab) or combination chemotherapy and antibody therapy. In this regard, a recent phase III randomized trial from the GELA group in France demonstrated statistically significantly superior complete and overall response rates and superior event-free and overall survivals for elderly patients with newly diagnosed diffuse aggressive B cell lymphomas treated with CHOP + rituximab compared with CHOP alone. Confirmatory cooperative group trials combining chemotherapy with antibody therapies are currently underway. Another approach to augment the efficacy of antibodies is to deploy them in radiolabeled form. Iodine-131, Yttrium-90, and Copper-67 labeled monoclonal antibodies targeting CD-20, CD-22, HLA class II, and other cell surface antigens have been tested and demonstrate higher overall response rates (50-80%) and complete response rates (20-40%) than unlabeled antibodies. Pilot studies combining radiolabeled antibodies with either standard dose chemotherapy or myeloablative chemoradiotherapy with stem cell transplantation also appear very promising. Lymphoma vaccines have also produced very encouraging results in single institution studies at Stanford and the National Cancer Institute, with responding patients demonstrating superior event-free and overall survival than historical controls. Phase III randomized trials of idiotype vaccines are currently underway and novel new vaccine approaches are also being tested.

Antibodies, Monoclonal↗
PubMed2001

Thromboxane A(2) limits differentiation and enhances apoptosis of cultured human trophoblasts.

Prostanoids influence differentiation in diverse cell types. Altered expression of cyclooxygenase and prostaglandins has been implicated in the pathophysiology of placental dysfunction, which results in preeclampsia and fetal growth restriction. We hypothesized that prostanoids modulate differentiation and apoptosis in cultured human trophoblasts. Villous cytotrophoblasts were isolated from term human placentas and cultured in serum-free medium. The level of human chorionic gonadotropin was used as a marker of biochemical differentiation of primary trophoblasts, and syncytia formation was used as a marker of morphologic differentiation. Of the prostanoids tested, we found exposure to thromboxane A(2) hindered both biochemical and morphologic differentiation of cultured trophoblasts. As expected, human chorionic gonadotropin levels in the media were elevated in a concentration-dependent manner in the presence of the thromboxane synthase inhibitor, sodium furegrelate, or the thromboxane A(2) receptor blocker SQ 29,548. Furthermore, thromboxane A(2) enhanced trophoblast apoptosis, determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, cell morphology, and a concentration-dependent increase in p53 expression. We conclude that thromboxane A(2) hinders differentiation and enhances apoptosis in cultured trophoblasts from term human placenta. We speculate that thromboxane may contribute to placental dysfunction by restricting differentiation and enhancing apoptosis in human trophoblasts.

Apoptosis↗
PubMed2001

[Rare association of hypoparathyroidism and mediastinal-pulmonary sarcoidosis].

We report the case of a 52-year-old woman who presented hypoparathyroidism and sarcoidosis. The hypoparathyroidism developed 8 years after the diagnosis of sarcoidosis. No element in favor of an autoimmune disease of the parathyroid could be evidenced. Pathology and immunology blood tests were equally noncontributive. Another pathophysiological mechanism, possibly sarcoidic granulomatous infiltration of the parathyroid glands, was suspected. The patient also presented apparently coincidental vitiligo.

Biopsy↗
PubMed2001

Detection of CD4 T-cell responses to a tumor vaccine by cytokine flow cytometry.

Cytokine flow cytometry (CFC) is a simple and powerful method for measuring antigen-specific T-cell responses by detection of intracellular cytokine staining. We applied this method to the detection of CD4 T-cell responses to tumor vaccines. Patients with multiple myeloma were immunized against their autologous tumor immunoglobulin idiotype, using antigen-pulsed dendritic cell vaccination. Blood samples were drawn before and after vaccination, and CFC and proliferation assays were performed. For CFC, whole blood was incubated overnight with antigen in the presence of costimulatory antibodies to CD28 and CD49d. The blood was then treated with EDTA, erythrocytes were lysed, and leukocytes were fixed, permeabilized, and stained for intracellular cytokines [tumor necrosis factor-alpha (TNF-alpha) or IFN-gamma], CD4, and CD69. Cells were analyzed by flow cytometry and cytokine-producing CD69+ cells enumerated as a percentage of CD4 cells. Of nine patients analyzed, three demonstrated detectable CFC responses to tumor immunoglobulin and/or keyhole limpet hemocyanin (KLH) after vaccination. One of these patients responded only to KLH, whereas the other two responded to both tumor immunoglobulin and KLH. Most responses were detected with both TNF-alpha and IFN-gamma, but one patient's KLH response was detected only with TNF-alpha. There was a positive, but not strong, correlation of cytokine responses with proliferative responses to KLH. Although further follow-up and correlation with clinical outcome is needed, CFC may represent a simple yet detailed assessment of T-cell frequencies and subsets responding to cancer vaccines.

Adult↗
PubMed2001

[Idiopathic orbital myositis].

Orbital myositis is a rare disorder considered as a subgroup of inflammatory orbital pseudotumors. The pathophysiology is still unknown. Patients typically present with orbital pain exacerbated by eye movement and diplopia. Response to steroids is dramatic. We report a case of idiopathic myositis of the right inferior muscle, which recovered after steroid therapy.

Adult↗