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Biomedical subjects

M David

Publications and source records attributed to M David.

At least 181 records · Page 10Linked to original sources
PubMed1996

[Advances in surgery for carotid stenosis. 900 operations (1983-1994)].

OBJECTIVES: To evaluate morbidity and mortality in carotid endarterectomy in a personal series. METHODS: Nine hundred endartectomies were performed from 1983 to 1994. All patients had > 70% carotid narrowing. Five hundred five patients underwent without preoperative angiography. RESULTS: Outcome was analyzed for 3 periods showing decreasing mortality from 4.56% in 1983-86 to 0.67% in 1990-1994. CONCLUSION: The reduction in morbidity and mortality resulted from the combined effects of pre-, per-, and post-operative care including noninvasive preoperative diagnosis of internal carotid artery stenosis using ultrasound duplex and surgery without previous angiography, delayed surgery in case of recent prolonged hemispheric deficit or of ischemic defect detected on computed tomography (CT) or magnetic resonance imaging (MRI), cerebral evaluation with CT-scan or MRI the day before operation, surgery under locoregional anesthesia, monitoring of arm arterial blood pressure during the first 24 hours following surgery.

Aged↗
PubMed1996

Use of electrospray ionization liquid chromatography-mass spectrometry to study the role of CYP2D6 in the in vitro metabolism of 5-hydroxytryptamine receptor antagonists.

An electrospray ionization liquid chromatographic-mass spectrometric (ESI-LC-MS) method has been developed to study the involvement of the cytochrome P450 isoenzyme CYP2D6 in the in vitro metabolism of the indole containing 5-hydroxytryptamine (5-HT(3)++) receptor antagonists tropisetron, ondansetron and dolasetron in human liver microsomes. Compounds were eluted using linear gradients of acetonitrile-20 mM ammonium acetate, solvent A, (10:90, v/v) (pH 6.0) and solvent B, (60:40, v/v) (pH 6.0) and a Nucleosil C(4) column. Microsomal incubations were analysed using selected ion monitoring of the molecular ion of parent drug and the molecular ion of hydroxylated metabolites. The involvement of CYP2D6 in drug metabolism was assessed by inhibition studies using quinidine (5 mu M), a specific inhibitor of human CYP2D6, as well as by incubating compounds with microsomes prepared from cells transfected with cDNA encoding human CYP2D6. Results showed that the oxidation of all three compounds involved CYP2D6, but only that of tropisetron was inhibited by over 90% in the presence of quinidine. The present method can be applied to pre-clinical compounds, at an early stage of drug discovery, to assess the involvement of CYP2D6 in their metabolism and to screen for those compounds where CYP2D6 is the only isoenzyme implicated in the formation of major metabolites.

Chromatography, Liquid↗
PubMed1996

Allograft and xenograft rejection in C3H/SCID mice. A new model for the study of non-T cell graft rejection mechanisms.

Comparative cell transfer experiments have revealed that, despite their equal immune deficiency, C3H/SCID mice were markedly inferior compared with C.B-17/SCID mice in their ability to accept allogeneic and xenogeneic grafts. Allogeneic C.B-17/SCID bone marrow cells were engrafted poorly compared with syngeneic C3H/SCID when transplanted into C3H/SCID recipients, whereas cells of both strains were equally well engrafted into C.B-17/SCID mice. C.B-17/SCID mice were much more permissive for outgrowth of human Burkitt lymphoma (Raji), as well as for Epstein-Barr virus lymphoma development after transplantation of human peripheral blood lymphocytes. Human skin grafts were accepted by the C.B-17/SCID mice but were promptly rejected by the C3H/SCID mice. The resistance to human RaJi cells could be adoptively transferred by infusion of C3H/SCID splenocytes into C.B-17/SCID mice. Because the C.B-17/SCID and C3H/SCID mice equally lack both T and B lymphocytes, the latter may provide a relevant model for studies of non-T mechanisms of allograft or xenograft rejection.

Animals↗
PubMed1996

Activation of protein kinase A inhibits interferon induction of the Jak/Stat pathway in U266 cells.

Activation of early response genes by interferons (IFNs) requires tyrosine phosphorylation of the Stat transcription factors and is mediated by the Jak family of tyrosine kinases. Recent evidence suggests that ERK2 serine/threonine kinase modulates the IFN-stimulated Jak/Stat pathway. In this report we show that in the myeloma cell line U266 protein kinase A specifically interacts with the cytoplasmic domain of the IFNalpha/beta receptor. Treatment of cells with the adenylate cyclase activator forskolin inhibits IFNbeta-, IFNgamma-, and hydrogen peroxide/vanadate-induced formation of complexes that bind to enhancers known to stimulate the expression of IFN-regulated genes. Immunoprecipitations followed by anti-phosphotyrosine immunoblots indicate that tyrosine phosphorylation of the alpha chain of the IFNalpha/beta receptor, Jak1, Tyk2, as well as Stat1 and Stat2 is reduced as a consequence of incubation of cells with forskolin. In contrast, dideoxyforskolin, which fails to activate adenylate cyclase, has no effect on IFN induction of the Jak/Stat pathway. These results indicate a novel regulatory mechanism by which protein kinase A can modulate the Jak/Stat signaling cascade.

Adenylyl Cyclases↗
PubMed1996

Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation.

A variety of cytokines and growth factors act through an induction of gene expression mediated by a family of latent transcription factors called STAT (signal transducers and activators of transcription) proteins. Ligand-induced tyrosine phosphorylation of the STATs promotes their homodimer and heterodimer formation and subsequent nuclear translocation. We demonstrate here that STAT protein heterocomplexes exist prior to cytokine treatment. When unstimulated HeLa cells are ruptured in hypotonic buffer without salt or detergent, immunoadsorption of either STAT1 or STAT2 from the resulting cytosol yields coimmunoadsorption of the other STAT protein. Similarly, STAT1-STAT3 heterocomplexes are coimmunoadsorbed from hypotonic cytosol. STAT1 and STAT2 or STAT1 and STAT3 translated in reticulocyte lysate spontaneously form heterocomplexes when the translation lysates are mixed at 0 degrees C. Our data suggest that interferon-alpha /beta-induced tyrosine phosphorylation increases the stability of a preexisting, latent, STAT1-STAT2 signaling complex. Newly translated STAT1 binds in equilibrium fashion to STAT2 and STAT3, but we show that STAT2 and STAT3 exist in separate heterocomplexes with STAT1, consistent with a model in which STAT1 contains a common binding site for other STAT proteins.

3T3 Cells↗
PubMed1996

Maternal serum markers levels in consecutive pregnancies: a possible genetic predisposition to abnormal levels.

The study comprised 2,361 women, each with two consecutive normal uncomplicated pregnancies screened at 15-20 weeks gestation for maternal serum alpha-fetoprotein levels (AFP). In 1,816 of these women, maternal serum human chorionic gonadotropin (hCG) levels were tested as well. The proportion of women who had a second high AFP level (> or = 2.0 MOM) in their subsequent pregnancy was 6.5-fold higher as compared with the proportion of women who had normal levels of AFP in their first tested pregnancy. The relative chance of having a second positive result of a low level of AFP (AFP < or = 0.5 MOM) in subsequent pregnancies was 3.8-fold higher. The relative chances of having a second positive result of high or low levels of hCG were 3.9- and 2.2-fold higher, respectively. It is concluded that there is a predisposition for abnormal levels of serum markers that is influenced by genetic and/or environmental factors. Therefore it is suggested that the individual's risk of having a Down syndrome baby, or other adverse pregnancy outcome that is derived from the serum markers' levels, should be adjusted taking into account unexplained high or low levels in previous pregnancies. A screening policy is suggested which is designed to yield a lower false-positive rate without affecting the detection rate of abnormal pregnancies. More data are needed before an accurate adjustment based on previous results can be made.

Chorionic Gonadotropin↗
PubMed1996

Human-->mouse radiation chimera do not develop Epstein-Barr virus lymphoma.

It has been shown that engraftment of human peripheral blood lymphocytes (PBL) from Epstein-Barr virus (EBV) seropositive donors in C.B-17/SCID mice is associated with a high incidence of human B cell tumors. More recently, we described a new approach enabling engraftment of human PBL in normal strains of mice or rats receiving lethal split-dose radiation and radioprotected with SCID bone marrow. We now demonstrate that, in contrast to SCID recipients of human PBL, Balb/c and C3H/HeJ recipients of 50-100 x 10(6) human PBL did not develop any EBV lymphoma during a 7-month follow-up period, but were successfully engrafted with human B and T cells. On the other hand, lymphoma developed in 90% of the C.B-17/SCID mice infused with 70 x 10(6) human PBL from the same donor. Likewise, 36% of beige/nude/xid (BNX) mice, exposed to 12 Gy TBI, radioprotected with SCID bone marrow and then transplanted with human PBL developed lymphoma. Similar results were obtained when different strains were infused with PBL of the same donor. Immunohistochemical analysis indicated that the tumor cells were of human B cell origin and expressed the EBV-encoded latent membrane protein-1 and nuclear antigen 2. While further studies are required to understand the mechanisms which suppressed outgrowth of EBV lymphoma in human --> mouse radiation chimera, compared to human --> C.B-17/SCID or human --> BNX chimera, this marked resistance offers new possibilities for transplantation of hematopoietic tissues or cells from EBV-positive donors.

Animals↗
PubMed1996

Anticoagulation without catheter removal in children with catheter-related central vein thrombosis.

Catheter-related central venous thrombosis is a serious and common problem among children. The traditional management has been anticoagulation and early catheter removal. Unfortunately, many patients require a new catheter, which is associated with complications that include possible further thrombosis. Although others have used thrombolytic agents in attempts to avoid catheter removal, the authors of the present study believe that the associated complications occur too frequently and are too serious. They have had success with standard anticoagulation in a limited number of patients. Between February 1991 and April 1994, 17 patients (6 weeks to 19 years of age) were treated for catheter-related deep venous thrombosis. Eight patients underwent early catheter removal accompanied by anticoagulation; two of them had intrinsic catheter problems that necessitated removal, and one had hemophilia. Nine others received anticoagulation without catheter removal. Of these, one required catheter removal after 10 days heparin administration failed to diminish the thrombosis. Another patient responded well to anticoagulation but required catheter removal several weeks later because of catheter-site infection. The other seven patients responded well to anticoagulation, and their catheters were retained. For patients with a functional catheter essential to their care, anticoagulation may safely prevent catheter removal.

Adolescent↗
PubMed1996

Treatment of Candida nail infection with terbinafine.

BACKGROUND: Terbinafine is a highly potent drug against dermatophytes. Data regarding its effectiveness against Candida species are few and variable. OBJECTIVE: Our purpose was to evaluate the efficacy and safety of oral terbinafine in patients with Candida nail infection. METHODS: In an open-label uncontrolled study, 20 patients completed 16 weeks of treatment with terbinafine, 250 mg/day, and an additional 8 weeks with placebo. Efficacy was assessed clinically and mycologically at weeks 0 (baseline), 4, 8, 16, 24, 36, and 48. Routine laboratory studies were performed at baseline and weeks 4, 8, and 16. RESULTS: At the end of the trial 60% of target nails were cured clinically and mycologically; in 10% there was mycologic cure with residual clinical signs, in 25% a moderate improvement (> 50%), and failure in only 5% (one patient). Most nails were infected by Candida parapsilosis. Two of 28 patients showed mild reversible elevation of liver enzymes 1 month after initiation of terbinafine treatment. CONCLUSION: The administration of terbinafine for 16 weeks is effective in the treatment of Candida nail infection. Liver enzyme values should be determined during the first month of treatment.

Administration, Oral↗
PubMed1996

In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor.

Following engraftment of human involved psoriatic skin to nude mice there is a partial normalization of pathology associated with a loss of inflammatory leucocytes. However, the epidermis remains hyperproliferative, which may reflect a primary defect. The roles of TNF-alpha, IL-1 and IL-6 in epidermal hyperproliferation of grafted psoriatic lesions were investigated. Before and after treatment, grafts were analysed to determine epidermal thickness and labelling index (LI). HLA-DR, intercellular adhesion molecule-1 (ICAM-1), and TNF receptor (TNF-R; p75 and p55) expression were determined by immunoperoxidase staining. Psoriatic epidermis was found consistently to be negative for p55 TNF-R and p75 TNF-R before grafting. Following engraftment, TNF-R-positive cells (i.e. p55 by keratinocytes; p75 by epidermal dendritic cells) were identified throughout the epidermis. Higher numbers of p75 TNF-R epidermal dendritic cells were found in grafts following a course of TNF-alpha, IL-6 or IL-1 treatment. The p55 form of the TNF-R expressed by keratinocytes was significantly elevated after treatment with TNF-alpha or IL-6. HLA-DR and ICAM-1 were also expressed in these grafts. TNF-alpha, anti-IL-1, and anti-IL-6 treatment induced a marked decrease in the epidermal thickness and LI of psoriatic graft tissue, correcting the hyperproliferation associated with psoriatic epidermis. Supraphysiological levels of TNF-alpha may saturate and consequently down-regulate their own receptors, leading to a paradoxical inhibitory effect.

Animals↗
PubMed1996

Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase.

Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-alpha/beta)-induced gene expression. The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3gamma protein) does not bind to the interferon-stimulated response element (ISRE). In this report, we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma. Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha. IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN. Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity.

Base Sequence↗
PubMed1996

Effects of cyclosporin and cremophor on working rat heart and incidence of myocardial lipid peroxidation.

Cyclosporin A (CsA) is widely used as the immunosuppressant of choice for preventing graft rejection. However, its clinical use is hampered by certain side effects, especially its nephrotoxicity and other cardiovascular side effects. CsA for intravenous infusion contains cremophor (Cre) and this vehicle has significant adverse effects on endothelial function and vascular muscle. The present study was aimed at investigating the direct effects of CsA and Cre on isolated and perfused rat hearts in the dosage that closely approximates the peak level achieved for the prevention of graft rejection in the rat. Transplantation is a clinical setting in which the myocardium may be exposed to transient ischemia. In this study, we have shown that the vehicle of CsA, namely Cre, has significant adverse effects on cardiac function. We observed a reduction in coronary flow and aortic output. Addition of CsA appeared to induce a further reduction of aortic flow. We have also shown that a significant increase of thiobarbituric acid reactive substances, considered as an index of lipid peroxidation, occurred in the reperfused heart in the presence of Cre+CsA. Our experimental study shows that Cre turned out to be toxic to myocardium by itself. In the heart, potential Cre-CsA interactions possibly potentiating CsA toxicity could not be excluded. The increase of lipid peroxidation in the heart perfused with CsA suggests that reactive oxygen species may be involved in the detrimental effects of this substance on the heart.

3,4-Methylenedioxyamphetamine↗
PubMed1996

[Emergency angioplasty for total thrombosis of the left main coronary artery. Apropos of a case].

Complete thrombosis of the left main coronary artery is a rare angiographic finding and usually gives rise to cardiogenic shock during unstable angina or myocardial infarction. The prognosis of this condition is very dependent on the collateral coronary circulation and the myocardial protection seems to depend on the rapidity of revascularisation. Two therapeutic approaches may be envisaged; emergency coronary bypass grafting or percutaneous angioplasty, the natural history being particularly disastrous. The authors report the case of a 42-year-old patient with complete occlusion of the left main stem responsible for unstable angina and acute pulmonary oedema. The outcome with angioplasty in the acute phase associated with surgical revascularisation four days later, was good.

Angina, Unstable↗
PubMed1996

[Leg embolisms: treatment via percutaneous thrombo-aspiration].

PURPOSE: Benefits of the local thrombolytic therapy in the treatment of acute peripheral arterial ischemia have been proved (13), but the place of thrombo-aspiration in this percutaneous treatment is not well defined. This study evaluates the results of thromboaspiration with or without local thrombolysis for the treatment of arterial embolism associated with a lower limb arteriopathy. METHODS: From May 1991 to May 1992, ten arterial embolisms (below the common femoral artery) associated with a lower limb arteriopathy have been treated by thromboaspiration with or without local thrombolysis. RESULTS: Nine immediate successes have been obtained. One failure has been operated on with success. On the third day, an occlusion of the popliteal artery occured and a femoroperoneal bypass was performed. But the occlusion of the bypass obligated to an amputation above the knee. This patient died one month later (hospital mortality 10%). During the follow-up (2 months), other procedures were patent. CONCLUSIONS: Thromboaspiration with or without thrombolysis is efficient for the treatment of arterial embolism associated with a lower limb arteriopathy.

Aged↗
PubMed1996

Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists.

Dolasetron mesilate [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-c arboxylate monomethane-sulfonate], is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The compound is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite reduced dolasetron (red-dolasetron), which us further metabolized by cytochrome P450 (CYP450). Studies were conducted, using human liver microsomes, to characterize the CYP450 enzymes responsible for the in vitro metabolism of red-dolasetron. Red-dolasetron underwent oxidation of the indole aromatic ring at positions 5, 6, and 7, and also N-oxidation. Enzyme-selective inhibition and correlation studies showed that hydroxylation of red-dolasetron was CYP2D6-dependent, and N-oxidation was conducted by CYP3A4. The rate of formation of 6-hydroxy red-dolasetron was significantly correlated with that of 5-hydroxy red-dolasetron, which further suggested that these metabolites were formed by the same CYP450 enzyme(s). Inhibition studies also demonstrated that 6-hydroxylation was, to a lesser extent, CYP3A4-dependent. This was confirmed by correlation experiments, wherein formation of this metabolite was significantly correlated with that of N-oxide formation, in quinidine-inhibited microsomes. Results were compared with those obtained with two other indole-containing 5-HT3 receptor antagonists: tropisetron and ondansetron. Tropisetron hydroxylation was CYP2D6-dependent, whereas that of ondansetron was both CYP2D6- and CYP2E1-dependent. Results were further confirmed, when compounds were incubated with microsomes containing recombinant human liver CYP2D6, CYP3A4, and CYP2E1. Red-dolasetron was a competitive inhibitor of CYP2D6, with an IC50 value of 70 microM, which is 2 orders of magnitude above maximum plasma concentrations found in humans. The implications of these in vitro results to the in vivo metabolism of these compounds in humans and their potential pharmacokinetic consequences is discussed.

Cytochrome P-450 CYP2D6↗