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Biomedical subjects

M Levi

Publications and source records attributed to M Levi.

At least 109 records · Page 6Linked to original sources
PubMed2000

Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison.

BACKGROUND: Vitamin K antagonist treatment is effective for prevention and treatment of thromboembolic events but frequent laboratory control and dose-adjustment are essential. Small portable devices have enabled patient self-monitoring of anticoagulation and self-adjustment of the dose. We compared this self-management of oral anticoagulant therapy with conventional management by a specialist anticoagulation clinic in a randomised cross-over study. METHODS: 50 patients on long-term oral anticoagulant treatment were included in a randomised controlled crossover study. Patients were self-managed or were managed by the anticoagulation clinic for a period of 3 months. After this period the alternative strategy was followed for each patient. Prothrombin time (expressed as international normalised ratio [INR]) were measured at intervals of 1-2 weeks in both periods without knowledge of type of management. The primary endpoint was the number of measurements within the therapeutic range (therapeutic target value +/-50.5 INR units). FINDINGS: There was no significant difference in the overall quality of control of anticoagulation between the two study periods. Patients were for 55% and for 49% of the treatment period within a range of +/-0.5 from the therapeutic target INR during self-management and anticoagulation clinic management, respectively (p=0.06). The proportion of patients who spent most time in the therapeutic target range was larger during self-management than during anticoagulation clinic-guided management. The odds ratio for a better control of anticoagulation (defined as the period of time in the therapeutic target range) during self-management compared with anticoagulation clinic-guided management was 4.6 (95% CI 2.1-10.2). A patient-satisfaction assessment showed superiority of self-management over conventional care. INTERPRETATION: Self-management of INR in the population in this study is feasible and appears to result in control of anticoagulation that is at least equivalent to management by a specialist anticoagulation clinic. It is also better appreciated by patients. Larger studies are required to assess the effect of this novel management strategy on the incidence of thromboembolic or bleeding complications.

Administration, Oral↗
PubMed2000

[Physical diagnosis--percussion and palpation of liver].

Percussion and palpation of the liver can produce useful information regarding size, consistency and the surface of the lower liver edge. However, the accuracy of the physical examination of the liver is limited, especially concerning the predictive value of the absence at physical examination of hepatomegaly (> or = 15 cm liver width in the right midclavicular line) for the absence of a truly enlarged liver. Also, the inter-observer variability may be considerable. These limitations of the test may be partly due to a number of pitfalls and misconceptions concerning physical examination of the liver.

Hepatomegaly↗
PubMed2000

Characterization of a novel human immunodeficiency virus type 1 neutralizable epitope within the immunodominant region of gp41.

Previously, we generated human monoclonal antibodies using peripheral blood mononuclear cells from an asymptomatic human immunodeficiency virus type 1 (HIV-1)-seropositive donor. One of these monoclonal antibodies (designated clone 3, CL3) recognized 10 amino acids (GCSGKLICTT) within the immunodominant region (cluster I) of the transmembrane envelope glycoprotein gp41 and neutralized infection of target cells with different laboratory isolates. Because the epitope recognized by CL3 has two cysteine residues that could potentially produce a disulfide loop in gp41, we analyzed binding of our monoclonal antibody to the cyclic and linear motif of the peptide sequence IWGCSGKLICTTAVP (residues 600-614). The CL3 antibody did not bind to the synthetic cyclic peptide but did recognize the linear form. Two polyclonal rabbit sera against both the linear and cyclic peptides were then generated. Both antisera bound to viral glycoproteins gp41 and gp160, but neither sera neutralized HIV-1 laboratory isolates. Using a set of alanine-substituted IWGCSGKLICTTAV peptides, we analyzed binding of polyclonal antisera and CL3. The profile of binding of polyclonal antisera to these peptides was different from that of CL3 to the same peptides. This suggests that CL3 recognized a unique neutralizable core epitope, which was not immunogenic in either the cyclic or the linear IWGCSGKLICTTAVP peptides used as immunogens in the rabbits.

Amino Acid Sequence↗
PubMed2000

Mapping of B-cell epitopes in rabbits immunised with various gag antigens for the production of HIV-1 gag capture ELISA reagents.

An HIV-1 p24 capture enzyme linked immunosorbent assay (ELISA) was developed and used in a study of B-cell epitopes in rabbits immunised with different gag p24 antigens. Rabbits were immunised with virion HIV-1/Lai, baculovirus recombinant p24, Escherichia coli recombinant p24-15 and a mixture of synthetic peptides representing sequences of HIV-1 gag p24 protein, respectively. Five out of nine rabbits developed antibodies that could be used for an antigen capture ELISA. No significant differences in IgG titers to the whole gag protein were seen when comparing rabbits immunised with four different antigens. Three major common linear epitope regions were mapped in the rabbits immunised with virion HIV-1/Lai and baculovirus recombinant p24. The rabbit immunised with HIV-1 gag peptides had the broadest linear epitope reactive responses whereas animals immunised with E. coli recombinant antigen had the most restricted linear epitope response. The capture ELISA method thus developed using the different rabbit anti-p24 IgG preparations was shown to capture isolates from HIV-1 subtypes or clades A to G. Only rabbits immunised with virion HIV-1/Lai and baculovirus recombinant p24 developed IgG that was capable of efficiently capturing HIV-1 p24 in ELISA, indicating the importance of preparing antibodies able to recognise native or discontinuous and linear antigen configurations.

Animals↗
PubMed2000

[Blind spots of the diagnostic hemostasis screen].

The most powerful instrument to establish the presence or absence of a coagulation disorder is the history of the patient. In addition, screening laboratory tests (consisting of the platelet count, bleeding time and global clotting assays, such as the prothrombin time and the activated partial thromboplastin time) may be helpful to support the diagnosis. In two patients, a 21-year-old man and a 10-year-old girl, with a marked history of enhanced bleeding normal screening laboratory tests were found. The male patient had a congenital alpha 2-antiplasmin deficiency and the girl had a homozygous deficiency of factor XIII. Some defects in the coagulation system (such as defects in fibrin network formation and fibrinolysis, but also mild Von Willebrand disease) are indeed not detected by screening laboratory tests. In patients with a strong suspicion of a coagulation disorder such defects should be specifically tested for.

Adult↗
PubMed2000

[Disseminated intravascular coagulation].

Disseminated intravascular coagulation is characterised by systemic activation of blood coagulation, resulting in formation of intravascular thrombi and impaired organ perfusion. Simultaneously, the ongoing consumption of platelets and coagulation factors may lead to bleeding. Disseminated intravascular coagulation is seen in septicaemic infections, trauma, malignancies, obstetrical complications, vascular diseases, toxic and immunological reactions. In summary, the systemic deposition of fibrin is caused by enhanced thrombin generation, simultaneous depression of physiological anticoagulant mechanisms and diminished fibrin degradation due to inhibition of fibrinolysis. The increased insight into the pathogenesis of disseminated intravascular coagulation provides a solid basis for development of improved management strategies for patients with this complication. Therapy may include anticoagulants, platelet and plasma transfusion, concentrates of coagulation inhibitors and antifibrinolytic agents.

Anticoagulants↗
PubMed2000

Limitation of nitric oxide production: cells from lymph node and spleen exhibit distinct difference in nitric oxide production.

Many types of cells in the immune system have been found to produce nitric oxide (NO), which performs multiplex functions. However, in myelin basic protein peptide 68-86 (MBP 68-86)-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats, we found that elevated NO production was generated from spleen cells (SC), not from lymph node cells (LNC). LNC expressed lower NO synthase 2 (NOS2) and produced lower levels of NO than SC upon MBP 68-86 stimulation. Expression of B7-1(CD80) and B7-2(CD86) molecules was much lower on LNC than on SC. Blocking of B7-1 or B7-2 ligation resulted in reduced NO production by SC. Unlike SC, LNC were resistant to interferon-gamma- or lipopolysaccharide-induced NO production. NO derived from SC suppressed cell proliferation and induced apoptosis in vitro. Addition of N(omega)-nitrol-L-arginine methylester (L-NAME) into cell cultures promoted cell expansion and reduced apoptosis. These results indicate that NO production originates from SC, but not from LNC. Low expression of co-stimulatory molecules and NOS2 of LNC limits NO induction. The high levels of NO derived from SC are involved in the self-limiting mechanisms of autoimmune responses by inhibiting cell expansion and promoting cell apoptosis.

Amino Acid Sequence↗
PubMed2000

Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia.

Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)

Adult↗
PubMed2000

Rolipram suppresses experimental autoimmune neuritis and prevents relapses in Lewis rats.

Rolipram, a phosphodiesterase type 4 inhibitor, can markedly down-regulate antigen-driven T cell proliferation and suppress TNF-alpha production in vitro and in vivo. Here we report the effects of Rolipram on experimental autoimmune neuritis (EAN), which can be induced by immunization with myelin components of the peripheral nervous system (PNS) combined with Freund's complete adjuvant (FCA), and which represents a CD4+ T cell-mediated animal model for human Guillain-Barré syndrome. EAN induced in Lewis rats by inoculation with the PNS P2 protein peptide 57-81 and FCA was strongly suppressed by Rolipram administered twice daily intraperitoneally from day 9 post immunization (p.i.), i.e. after onset of clinical EAN. Suppression of EAN was associated with down-regulated myelin antigen-induced T cell responses as well as down-regulated IFN-gamma and TNF-alpha production. A relapse of clinical EAN occurred upon treatment of a short duration (7 days), while prolongation of treatment resulted in the prevention of clinical EAN relapse. There was no relationship between clinical EAN relapse and high levels of TNF-alpha. The immunomodulatory effects of Rolipram call for further research into the potential role of drugs acting on the immune system in the treatment of autoimmune diseases.

Animals↗
PubMed2000

A retro-inverso miniantibody with anti-HIV activity.

An HIV-1-specific miniantibody, a peptide representing the third heavy chain complementarity-determining region (CDR) of an HIV-specific mouse antibody, was characterized and modified with unnatural D-isomeric amino acids. The CDR peptide and its parent antibody bound to a similar epitope, located in the V3 region of HIV-1 gp120. A shortened CDR sequence was modified with D-amino acids to create an all-D-amino acid retro-inverso (RI) peptide with a reversed sequence order. The RI CDR was less susceptible to proteolytic degradation than its L-counterpart and had a higher affinity for HIV-1 peptides. The miniantibody and its parent antibody showed neutralization of both primary and laboratory strains of HIV-1. In accordance with the binding studies, the RI CDR showed a stronger HIV-inhibiting capacity than its L-counterpart. We conclude that the anti-HIV retro-inverso CDR identified in this study has the potential to become a future anti-HIV drug. It has a virus-neutralizing capacity in vitro and appears to be stable. Future research should focus on characterizing its antiviral activity in vivo.

Amino Acid Sequence↗
PubMed2000

The complexicity of cytokine treatment in ongoing EAE induced with MBP peptide 68-86 in Lewis rats.

IL-10 and TGF-beta1 are important immunoregulatory cytokines associated with clinical remissions in multiple sclerosis and amelioration of experimental allergic encephalomyelitis (EAE). IL-10 and TGF-beta1 have previously been shown to prevent the development of EAE. Here, we study effects of IL-10 and TGF-beta1 in ongoing EAE. When IL-10 or TGF-beta1 was administered by the nasal route from day 0 to day 7 postimmunization (pi), both IL-10 and TGF-beta1 prevented the development of acute EAE in Lewis rats. When IL-10 or TGF-beta1 was administered by the nasal route from day 5 to day 12 pi, both IL-10 and TGF-beta1 failed to influence clinical EAE. The inhibition of clinical EAE severity in IL-10-prevented rats was associated with reduced proliferation, IFN-gamma mRNA expression, and IFN-gamma secretion, while proliferation as well as IFN-gamma mRNA expression and secretion were augmented in TGF-beta1-prevented rats. TGF-beta1-prevented rats exhibited high levels of NO production by DC, which may mediate apoptosis of CD4+ T cells and of the DC themselves. For prevention, both IL-10 and TGF-beta1 inhibited infiltration of CD4+ T cells within the CNS, but neither IL-10 nor TGF-beta1 induced immune deviation from Th1 to Th2. Expression of IL-4 mRNA was not altered in IL-10- and TGF-beta1-prevented rats. These results demonstrate that IL-10 and TGF-beta administration by the nasal route can prevent the development of acute EAE, but by different mechanisms. The findings in rats with ongoing EAE have implications for the clinical application of cytokine treatment in autoimmune diseases.

Animals↗
PubMed2000

Combined nasal administration of encephalitogenic myelin basic protein peptide 68-86 and IL-10 suppressed incipient experimental allergic encephalomyelitis in Lewis rats.

Mucosal administration of low doses of myelin basic protein (MBP) peptide 68-86 (MBP 68-86) or anti-inflammatory cytokine IL-10 effectively prevented experimental allergic encephalomyelitis (EAE), but failed to suppress the disease if given after 7 days postimmunization (p.i.), i.e., after T cell priming had occurred. We anticipated that combined administration of autoantigen and IL-10 can treat incipient EAE. Lewis rats with EAE actively induced with MBP 68-86 and complete Freund's adjuvant received 120 microg MBP 68-86 + 200 ng IL-10 per rat per day from day 7 p.i. and for 5 consecutive days. These rats showed later onset, lower clinical scores, less body weight loss, and shorter duration of EAE than rats receiving MBP 68-86 or IL-10 only or PBS. EAE amelioration was associated with decreased infiltration of ED1(+) macrophages and CD4(+) T cells within the central nervous system and with decreased proliferative responses of lymph node cells, indicating that combined administration of MBP 68-86 and IL-10 induced immune hyporesponsiveness. IFN-gamma secretion as well as IFN-gamma, TNF-alpha, IL-4, and IL-10 mRNA expression by lymph node MNC was down-regulated in the treated rats. Immune hyporesponsiveness, rather than immune deviation or regulatory mechanisms, seems to be responsible for the protection of EAE after autoantigen + IL-10 administration by the nasal route.

Administration, Intranasal↗
PubMed2000

Mouse models of focal arterial and venous thrombosis.

Mouse models of arterial and venous thrombosis have gained increasing interest over the last 15 years, due to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. In order to provide an overview of suitable models for the study of arterial and venous thrombosis in mice, we have systematically searched MEDLINE electronic databases for publications reporting on murine thrombo-embolic models from 1966-1999. We found that the variety of murine thromboembolic models through 1995 was rather limited, as most methods used intravenous injections of strong coagulation triggers such as thrombin, thromboplastin and collagen, causing lethal thromboembolism. Between 1996 and the end of 1999, a number of more sophisticated murine models of local acute or chronic thrombosis have been established. They seem to be more suitable for mimicking the natural scenario of thrombosis and, therefore, are preferable models for pathophysiological or drug evaluation studies. In this paper various models are described and their advantages and limitations discussed.

Animals↗
PubMed2000

Advanced glycation end products: a Nephrologist's perspective.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic toxins and may have a role in the pathogenesis of vascular and renal complications associated with diabetes and aging. AGEs are formed when a carbonyl of a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotropic responses. AGEs accelerate atherosclerosis through cross-linking of proteins, modification of matrix components, platelet aggregation, defective vascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vitro studies indicate that AGEs have a vital role in the pathogenesis of diabetic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimer's disease, skin changes, and cataracts, may also be mediated by progressive glycation of long-lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl stress of uremia. AGE-modified beta(2)-microglobulin is the principal pathogenic component of dialysis-related amyloidosis in patients undergoing dialysis. Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated that restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucleophilic compound, not only decreases the formation of AGEs but also inhibits their action. A number of studies have shown that treatment with AGN improves neuropathy and delays the onset of retinopathy and nephropathy. N-Phenacylthiazolium bromide is a prototype AGE cross-link breaker that reacts with and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and aging may be prevented with these novel agents.

Aging↗
PubMed2000

Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid.

PURPOSE: The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproic acid toward human microsomal epoxide hydrolase (mEH). METHODS: mEH inhibition was evaluated in human liver microsomes with 25 microM (S)-(+)-styrene oxide as the substrate. Inhibitory potency expressed as the median inhibitory concentration (IC50) was calculated from the formation rate of the enzymatic product, (S)-(+)-1-phenyl-1,2-ethanediol. RESULTS: Inhibitory potency was directly correlated with lipophilicity and became significant for amides with a minimum of eight carbon atoms. Branched eight-carbon amides were more potent inhibitors than their straight chain isomer, octanamide. N-substituted valproylamide analogues had reduced or abolished inhibition potency with the exception of valproyl hydroxamic acid being a potent inhibitor. Inhibition potency was not stereoselective in two cases of chiral valpromide isomers. Valproyl glycinamide, a new antiepileptic drug currently undergoing phase II clinical trials and its major metabolite valproyl glycine were weak mEH inhibitors. Acid isomers of valproic acid were not potent mEH inhibitors. CONCLUSIONS: The structural requirements for valproylamide analogues for potent in vitro mEH inhibition are: an unsubstituted amide moiety; two saturated alkyl side chains; a minimum of eight carbons in the molecule.

Amides↗
PubMed2000

Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men.

The role of melatonin in the regulation of reproduction in humans is still controversial. In the present study the effects of melatonin were examined, 6 mg given orally every day at 1700 h for 1 month in a double-blind, placebo controlled fashion, on the nocturnal secretory profiles of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and inhibin beta in six healthy adult men. Serum concentrations of LH, FSH, testosterone and inhibin beta were determined before and after treatment every 15 min from 1900 to 0700 h over 3 nights in a controlled dark-light environment with simultaneous polysomnographic sleep recordings. The following sleep parameters were determined: total recording time, sleep latency, actual sleep time, sleep efficiency, rapid eye movement (REM) sleep latency and percentages of sleep stages 2, 3/4 and REM. There were no statistically significant differences in all sleep parameters between baseline and placebo or between baseline and melatonin except for longer REM latency and lower percentage REM at baseline than under melatonin treatment. These are explained as reflecting first-night effect at baseline. The mean nocturnal LH, FSH, testosterone and inhibin beta integrated nocturnal secretion values did not change during the treatment period. Likewise, their pulsatile characteristics during melatonin treatment were not different from baseline values. Taken together, these data suggest that long-term melatonin administration does not alter the secretory patterns of reproductive hormones in normal men.

Adult↗