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M Schapira

Publications and source records attributed to M Schapira.

At least 19 recordsLinked to original sources
PubMed2005

[Oral anticoagulants in cardiac patients undergoing elective surgical procedures: what attitude to adopt?].

Clinicians are often required to decide how to manage patients receiving long-term anticoagulant therapy, and who need a surgical procedure. The decisions are based on the perceived risk of continuing or stopping the treatment. Generally, warfarin must be stopped before all interventions at high risk of bleeding, but can be maintained unchanged before oral and skin surgery. For patients with a high risk of thromboembolism, heparin should be administered preoperatively, when the INR is <2. The estimation of this risk depends largely on the undelying heart disease. In the postoperative phase, the restarting of anticoagulant therapy must be weighed against both thromboembolic and hemorragic risks.

Administration, Oral↗
PubMed2004

Gait velocity in senior people. An easy test for detecting mobility impairment in community elderly.

BACKGROUND: Functional assessment is an important part of the evaluation of elderly patients. Mobility problems detected by functional tests predict the development of more severe disability and injurious events such as falls and hip fractures. Several tests to evaluate mobility have been described, but most of them are difficult to perform by a primary care physicians or take much time in the ambulatory setting. PURPOSE: To evaluate different mobility test to detect mobility impairment in community senior people. Select an easier test to perform on the ambulatory ward by a GP with the hypothesis that gait velocity could be an easier test to detect early mobility impairment. METHODS: A cohort of 100 elderly subjects of 75 year and older were selected from our database and contacted by phone. The subjects were appointed and assessed by three geriatricians from January to May 2000. The measures including MMSE, Yesavage Test, ADL (Barhtel) and IADL (Lawton), the Get Up and Go test, the POMA, one leg balance test and the Gait Velocity (GV). A gait velocity of 0.8 m/s or lower was defined as a pathological gait velocity (PGV). RESULTS: 95 subjects, mean age 79.63 (+/- 4) ranged form 75 to 95. Women in 71.3%. The ADLs were normal on 85% of the patients and the MMSE was normal on 78%. There was a significant association between pathological gait velocity (<0.8m/sec) and impairment on Get up and Go (OR 2.20; 95% CI 1.44-3.34), incapacity to perform the one leg balance test (OR 2.20; 95%CI: 1.43 - 4.71) and abnormal POMA test (OR 4.60; 95 %CI 1.5-14.7). Only 15% of the subjects with normal gait velocity reported recurrent falls in the previous 6 months while 35% of subjects with pathological gait velocity did. (OR 0.32 CI95% 010-099 p < 0.044). CONCLUSION: The pathological gait velocity (<0.8m/sec) correlates with a pathologic performance of Get Up and Go test and POMA and with the incapacity to perform the One Leg Balance test. Also correlate with previous repeated falls in the last 6 (p <0.04). The gait velocity could be a test easy to perform, no time consuming, and an operative tool to apply in the ambulatory care to detect elderly patients with mobility impairment.

Accidental Falls↗
PubMed2001

Human peripheral blood leukocyte engraftment into SCID mice: critical role of CD4(+) T cells.

We examined the influence of donor T lymphocytes on human peripheral blood leukocytes (PBL) engraftment into severe combined immune deficient (SCID) mice. Mice were injected with unfractionated or subset-depleted human PBL, and treated at various times with OKT3, a cytotoxic monoclonal antibody against human CD3(+) T lymphocytes. PBL engraftment, high levels of human Ig, and high incidence of lymphoproliferative disease (lpd) were found in mice transplanted with unfractionated PBL and CD8- or CD14-depleted PBL, and in mice treated with OKT3 at distance from PBL transfer. Animals xenografted with CD3- or CD4-depleted PBL, or treated at transplantation time with OKT3, had very low levels of human Ig and did not develop lpd. PBL engraftment was minimal or absent in these animals, as determined by immunohistochemistry, dot-blot, and RT-PCR analyses. These results demonstrate that the presence of donor CD4(+) T lymphocytes at transplantation time is necessary for observing human PBL engraftment into SCID mice, an essential condition for human Ig production and lpd development.

Animals↗
PubMed2001

In silico discovery of novel retinoic acid receptor agonist structures.

BACKGROUND: Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. RESULTS: We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro. CONCLUSIONS: Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

Algorithms↗
PubMed2001

Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination.

Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-alpha. Inhibition studies showed that multiple adhesion receptors--including L-selectin, E-selectin, VCAM-1, and CD11/CD18--were involved in blast cell adhesion to TNF-alpha-activated endothelium. Leukemic cells were then cocultured at 37 degrees C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-alpha and IL-1 beta, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells. (Blood. 2001;97:2121-2129)

Antigens, CD↗
PubMed2001

Haemolytic onset of Wilson disease in a patient with homozygous truncation of ATP7B at Arg1319.

We describe a 19-year-old woman with haemolytic anaemia and thrombocytopenia as the initial manifestation of Wilson disease (WD). There are two reasons for reporting such an improbable case. First, it emphasizes the importance of recognizing atypical clinical presentations of potentially lethal recessive traits for which therapy is available. Second, it shows that, even in a monogenic disorder like WD, the phenotype cannot be extrapolated from the mutated genotype in a simple fashion; this patient had a relatively late-onset form of WD despite homozygosity for a genetic lesion leading to an apparent complete loss of function of the WD copper transporter.

Adenosine Triphosphatases↗
PubMed2000

Inhibition of selectin-mediated cell adhesion and prevention of acute inflammation by nonanticoagulant sulfated saccharides. Studies with carboxyl-reduced and sulfated heparin and with trestatin a sulfate.

Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Some heparin preparations can interact with L- and P-selectin; however, the determinants required for inhibiting selectin-mediated cell adhesion have not yet been characterized. We now report that carboxyl-reduced and sulfated heparin (prepared by chemical modifications of porcine intestinal mucosal heparin leading to the replacement of carboxylates by O-sulfate groups) and trestatin A sulfate (obtained by sulfation of trestatin A, a non-uronic pseudo-nonasaccharide extracted from Streptomyces dimorphogenes) exhibit strong anti-P-selectin and anti-L-selectin activity while lacking antithrombin-mediated anticoagulant activity. In vitro experiments revealed that both compounds inhibited P-selectin- and L-selectin-mediated cell adhesion under laminar flow conditions. Moreover, carboxyl-reduced and sulfated heparin and trestatin A sulfate were also active in vivo, as assessed by experiments showing 1) that microinfusion of trestatin A sulfate reduced by 96% leukocyte rolling along rat mesenteric postcapillary venules and 2) that both compounds inhibited (by 58-81%) neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice. These results indicate that nonanticoagulant sulfated saccharides targeted at P-selectin and L-selectin may have therapeutic potential in inflammatory disorders.

Antibodies↗
PubMed2000

C1 inhibitor cross-linking by tissue transglutaminase.

C1 inhibitor, a plasma proteinase inhibitor of the serpin superfamily involved in the regulation of complement classical pathway and intrinsic blood coagulation, has been shown to bind to several components of the extracellular matrix. These reactions may be responsible for C1 inhibitor localization in the perivascular space. In the study reported here, we have examined whether C1 inhibitor could function as a substrate for plasma (factor XIIIa) or tissue transglutaminase. We made the following observations: 1) SDS-polyacrylamide gel electrophoresis and autoradiography showed that C1 inhibitor exposed to tissue transglutaminase (but not to factor XIIIa) incorporated the radioactive amine donor substrate [(3)H]putrescine in a calcium-dependent manner; 2) the maximum stoichiometry for the uptake of [(3)H]putrescine by C1 inhibitor was 1:1; 3) proteolytic cleavage and peptide sequencing of reduced and carboxymethylated [(3)H]putrescine-C1 inhibitor identified Gln(453) (P'9) as the single amine acceptor residue; 4) studies with (125)I-labeled C1 inhibitor showed that tissue transglutaminase was also able to cross-link C1 inhibitor to immobilized fibrin; and 5) C1 inhibitor cross-linked by tissue transglutaminase to immobilized fibrin had inhibitory activity against its target enzymes. Thus, tissue transglutaminase-mediated cross-linking of C1 inhibitor to fibrin or other extracellular matrix components may serve as a mechanism for covalent serpin binding and influence local regulation of the proteolytic pathways inhibited by C1 inhibitor.

Catalysis↗
PubMed2000

Rational discovery of novel nuclear hormone receptor antagonists.

Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor-alpha by using information derived from antagonist-bound estrogen receptor-alpha and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

Algorithms↗
PubMed2000

Epstein-Barr virus-dependent lymphoproliferative disease: critical role of IL-6.

Epstein-Barr virus (EBV)-induced lymphoproliferative disease (lpd) is a B cell neoplasm that affects patients who are immunosuppressed in the context of organ transplantation or HIV infection. A model for the aggressive form of this entity was generated by xenotransplantation of SCID mice with human peripheral blood leukocytes from individuals with prior contact with EBV. This model, where large B cell lymphoma occurs, was used to test the hypothesis that IL-6 has a major role in EBV-induced B cell tumorigenesis. IL-6 is known to differentiate B cells into immunoglobulin-secreting plasma cells and induce EBV replication, and xenochimeric animals have detectable serum levels of human IL-6. Human IL-6 inhibition with a neutralizing monoclonal antibody decreased tumor incidence from 62 % to 27 %. In addition, anti-IL-6 treatment significantly improved xenotransplanted animal survival, with median survival at > 245 days when compared to that of controls at 132 days. In conclusion, IL-6 plays a critical role in the pathogenesis of EBV-induced human lpd, and IL-6 inhibition may represent a new and promising preventive or therapeutic approach against this malignancy.

Animals↗
PubMed2000

Human adult tonsil xenotransplantation into SCID mice for studying human immune responses and B cell lymphomagenesis.

OBJECTIVE: To generate a human-mouse xenochimeric model where human cells remain clustered in the animal to optimize their interactions and recovery. MATERIALS AND METHODS: Severe combined immune deficient mice (SCID) were xenografted subcutaneously with human adult tonsil pieces (hu-ton-SCID mice). Such animals were: (a) compared with those receiving tonsil cells in suspension, and (b) immunized with de novo and recall antigens. RESULTS: Human tonsil pieces survived a long period of time in SCID mice, while polyclonal human T- and B-lymphocytes persisted in close vicinity within the implantation area; however, little or no graft-versus-host disease was detectable. Not surprisingly, local development of lymphoproliferative disease was often observed in animals receiving lymphoid implants from donors previously infected by the Epstein-Barr virus. One month after surgery, higher serum levels of human IgG were found in SCID mice transplanted with tonsil pieces (2x10(7) cells/animal) than in animals injected with 5x10(7) tonsil cells in suspension (1.9 vs. 0.3 mg/mL, p < 0.002). Importantly, the production of human IgG in hu-ton-SCID mice remained polyclonal for at least 6 months and was linked to the presence of cells within the implants. Immunization of hu-ton-SCID mice with hepatitis B core, a de novo antigen, did not produce a significant IgG immune response; however immunization with tetanus toxoid (TT), a thymus-dependent recall antigen, yielded high (> 700-fold increase in anti-TT IgG levels) and long-lasting (> 6 months) secondary immune responses. CONCLUSION: The hu-ton-SCID mouse xenochimeric model described in this report may improve our understanding of human lymphoid cell interactions, secondary immune responses, and lymphomagenesis.

Adult↗
PubMed2000

Regulated translation initiation controls stress-induced gene expression in mammalian cells.

Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2alpha kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2alpha phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.

Activating Transcription Factor 4↗
PubMed2000

Acute myeloid leukemia in the elderly: results of an individualized approach in two centres.

We retrospectively assessed seventy-four consecutive patients with AML over 65 years of age (median 71; range 65-88) treated with an individualized approach in two specialized cancer centers. Patients were managed according to their performance status (PS) and associated diseases in both institutions. The proportion of patients with poor PS (3-4) was higher in center 1 (37%) than in center 2 (10%) and in center 1 palliative treatment was given more frequently (16/32 patients) than in center 2 (7/42 patients). Fifty-one patients received intensive combination chemotherapy including an anthracycline and ara-C or VP16 (2 patients) and 36 patients received a second intensive course as reinduction or as consolidation treatment after complete remission. Patients not eligible for myelosuppressive chemotherapy were treated with palliative measures (23 patients). With intensive chemotherapy, complete remission (CR) was achieved in 29 of 51 patients (57%), after first (20 patients) or second course (9 patients) and the rate of deaths during induction was 14% (7 patients). The CR rate was lower for patients with performance status >or= 2 (48%) as compared to patients with performance status or= 2) was associated with reduced survival (hazard ratio: 3.29, 95% confidence interval: 1.75-6.17). Overall 2-years and 5-years survival were 20% and 11% for the patients treated intensively. From this study it appears that an individualized approach of treatment with intensive chemotherapy for selected patients offers a substantial CR rate and an improvement in survival. This analysis also suggests that differences in outcome between single institutions can be explained mainly by referral and selection biases

Actuarial Analysis↗
PubMed1999

Hypoxic hepatitis caused by acute exacerbation of chronic respiratory failure: a case-controlled, hemodynamic study of 17 consecutive cases.

Out of a prospective series of 142 consecutive episodes of hypoxic (ischemic) hepatitis (HH), we identified 17 episodes associated with an acute exacerbation of chronic respiratory failure (CRF) without left cardiac failure. In the aim to evaluate the role of arterial hypoxemia in the pathogenesis of HH associated with respiratory failure, these 17 episodes of HH (study group) were hemodynamically compared with a control group of 17 episodes of HH associated with congestive heart failure (CHF) (control group 1) and a group of 16 episodes of acute respiratory failure (ARF) not complicated by HH (control group 2). Arterial hypoxemia was significantly more severe in the study group (arterial blood tension in O2 [PaO2], 34 mm Hg) than in control group 1 (PaO2, 70 mm Hg; P <.0001) and control group 2 (PaO2, 45.5 mm Hg; P =.002). The role of arterial hypoxemia, however, appeared weakened by comparable degrees of systemic hypotension and liver passive congestion in episodes of HH associated with CRF and episodes of HH associated with CHF. Finally, the causative role of arterial hypoxemia emerged from hemodynamic measurements of cardiac index (CI), systemic vascular resistances (SVR), and oxygen transport: systemic hypotension in HH associated with CHF (control group 1) was the result of a fall in CI (median, 2. 33 L/min. m2; range, 1.21-3.14 L/min. m2) associated with high SVR (median, 2,492 dyn. s/cm5. m2; range, 1,382-4,053 dyn. s/cm5. m2), whereas in HH associated with respiratory failure (study group), systemic hypotension was the result of a fall in SVR (median, 1,053 dyn. s/cm5. m2; range, 646-3,148 dyn. s/cm5. m2), resulting in high CI (median, 4.23 L/min. m2; range, 1.9-5.32 L/min. m2) (P =.0087 and. 0038 for cardiac index and SVR, respectively). Moreover, measurements of oxygen transport in patients with HH associated with respiratory failure showed low values of O2 delivery (DO2) (median, 376 mL/min. m2; range, 253-427 mL/min. m2) as a result of extreme arterial hypoxemia despite high CI. In conclusion, these hemodynamic results and additional measurements of hepatic blood flow (HBF) by the method of galactose clearance at a low concentration suggest that in the setting of HH associated with respiratory failure, the liver is not "ischemic," despite hypotension, but rather "hypoxic" as a result of the combination of severe arterial hypoxemia and elevated central venous pressure (CVP).

Aged↗
PubMed1999

An open-label trial of sertraline for the treatment of major depression in primary care.

Major depression is one of the most common medical disorders seen in primary care practice. Management frequently fails to meet recommended standards of treatment. For example, only a minority of patients are treated with antidepressants. The goals of this study were to establish the safety and effectiveness in the real world of a protocol-based pharmacological intervention administered by primary care physicians trained by psychiatrists. This was a naturalistic, open, 8-week, noncomparative, multicenter study of sertraline, 50-100 mg, in the treatment of 469 patients with mild-to-moderate major depression seen in primary care office settings. Effectiveness was assessed using the Hamilton Depression Rating Scale. The mean value of the HDRS declined steadily from 25.4 at baseline to 8.5 at day 56 (p < 0.0001). Fifty-two percent of patients achieved a full remission (HDRS <10 on day 56) and 70% had a positive response (50% reduction in HDRS scores). Only 26% had side effects, most of them mild. Major depression can be successfully diagnosed and treated by primary care physicians when adequately trained and supported by psychiatrists.

Adolescent↗
PubMed1999

NRIF3 is a novel coactivator mediating functional specificity of nuclear hormone receptors.

Many nuclear receptors are capable of recognizing similar DNA elements. The molecular event(s) underlying the functional specificities of these receptors (in regulating the expression of their native target genes) is a very important issue that remains poorly understood. Here we report the cloning and analysis of a novel nuclear receptor coactivator (designated NRIF3) that exhibits a distinct receptor specificity. Fluorescence microscopy shows that NRIF3 localizes to the cell nucleus. The yeast two-hybrid and/or in vitro binding assays indicated that NRIF3 specifically interacts with the thyroid hormone receptor (TR) and retinoid X receptor (RXR) in a ligand-dependent fashion but does not bind to the retinoic acid receptor, vitamin D receptor, progesterone receptor, glucocorticoid receptor, or estrogen receptor. Functional experiments showed that NRIF3 significantly potentiates TR- and RXR-mediated transactivation in vivo but has little effect on other examined nuclear receptors. Domain and mutagenesis analyses indicated that a novel C-terminal domain in NRIF3 plays an essential role in its specific interaction with liganded TR and RXR while the N-terminal LXXLL motif plays a minor role in allowing optimum interaction. Computer modeling and subsequent experimental analysis suggested that the C-terminal domain of NRIF3 directly mediates interaction with liganded receptors through an LXXIL (a variant of the canonical LXXLL) module while the other part of the NRIF3 protein may still play a role in conferring its receptor specificity. Identification of a coactivator with such a unique receptor specificity may provide new insight into the molecular mechanism(s) of receptor-mediated transcriptional activation as well as the functional specificities of nuclear receptors.

Amino Acid Motifs↗