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Biomedical subjects

D Varon

Publications and source records attributed to D Varon.

At least 37 records · Page 2Linked to original sources
PubMed1999

Are the antiarrhythmic-defibrillating effects of D-sotalol due to or despite the prolongation of the action potential duration?

These results support our hypothesis that class III compounds, with a positive inotropic effect, increase intercellular coupling and synchronization, mainly by preventing intracellular Ca overload. They act as defibrillating compound, similar to cAMP and adrenaline, most probably due to their so called sympathomimetic effect. In our opinion, their cardioprotective effects, resembling cardioversion, are not related to their ability to prolong APD and ERP. Moreover, we suggest that any compound that possesses these sympathomimetic effects, but without inducing the arrhythmogenic prolongation of APD, may exhibit a potent, safety and more efficient antiarrhythmic - defibrillating ability.

Action Potentials↗
PubMed1999

Unique antiplatelet effects of a novel S-nitrosoderivative of a recombinant fragment of von Willebrand factor, AR545C: in vitro and ex vivo inhibition of platelet function.

The recombinant fragment of von Willebrand factor (vWF) spanning Ala444 to Asp730 and containing an Arg545Cys mutation (denoted AR545C) has antithrombotic properties that are principally a consequence of its ability to inhibit platelet adhesion to subendothelial matrix. Endothelial-derived nitric oxide (NO) can also inhibit platelet function, both as a consequence of inhibiting adhesion as well as activation and aggregation. Nitric oxide can react with thiol functional groups in the presence of oxygen to form S-nitrosothiols, which are naturally occurring NO derivatives that prolong the biological actions of NO. Because AR545C has a single free cysteine (Cys545), we attempted to synthesize the S-nitroso-derivative of AR545C and to characterize its antiplatelet effects. We successfully synthesized S-nitroso-AR545C and found that it contained 0.96 mol S-NO per mole peptide. S-nitroso-AR545C was approximately 5-fold more potent at inhibiting platelet agglutination than was the unmodified peptide (IC(50) = 0.02 +/- 0. 006 micromol/L v 0.1 +/- 0.03 micromol/L, P =.001). In addition and by contrast, S-nitroso-AR545C was a powerful inhibitor of adenosine diphosphate-induced platelet aggregation (IC(50) = 0.018 +/- 0.002 micromol/L), while AR545C had no effect on aggregation. These effects were confirmed in studies of adhesion to and aggregation on extracellular matrix under conditions of shear stress in a cone-plate viscometer, where 1.5 micromol/L S-nitroso-AR545C inhibited platelet adhesion by 83% and essentially completely inhibited aggregate formation, while the same concentration of AR545C inhibited platelet adhesion by 74% and had significantly lesser effect on aggregate formation on matrix (P </=.004 for each parameter by ANOVA). In an ex vivo rabbit model, we also found that S-nitroso-AR545C had a more marked and more durable inhibitory effect on botrocetin-induced platelet aggregation than did AR545C, and these differences were also reflected in the extent and duration of effect on the prolongation of the bleeding time in these animals. These data show that S-nitroso-AR545C has significant and unique antiplatelet effects, inhibiting both adhesion and aggregation, by blocking platelet GPIb receptor through the AR545C moiety and elevating platelet cyclic 3',5'-guanosine monophosphate through the -SNO moiety. These observations suggest that this NO-modified fragment of vWF may have potential therapeutic benefits as a unique antithrombotic agent.

Adult↗
PubMed1999

Expanding portal haematomata as a complication of knee arthroscopies in persons with haemophilia.

Recurrent haemarthroses stimulate the hypertrophy of synovial tissues that if left in situ will eventually cause joint destruction. Synovectomies have been the cornerstone of joint preservation and a number of different methods exist. We report two patients who suffered complications after an arthroscopic procedure. No previous complications of this nature have been reported in the literature.

Adult↗
PubMed1999

The role of orthoses in the management of elbow joints in persons with haemophilia.

The elbow joint is extremely prone to haemarthroses, and when these occur the elbow requires support and rest. Supporting the limb with a simple collar-and-cuff sling, a triangular bandage either with or without a shoulder immobilization device will provide an analgesic effect without adding an unnecessary heavy orthosis. As the swelling subsides and the pain lessens a dynamic orthosis aids in the support and compression. When considering functional branching of the elbow joints there are a number of basic principles to be followed. One requires to consider problems of orthosis suspension, two dimensional motion and stabilization in the functional range of motion. This article provides the rationale for the special needs of persons with haemophilia who suffer from involvement of their elbow joints.

Contracture↗
PubMed1999

The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus.

We have recently reported that dietary fish oil supplementation (n-3) polyunsaturated fatty acid (PUFA) led to a reduction in blood pressure (BP) and serum triglycerides (TG), in addition to the normalization of the hypercoagulable state in subjects with obesity, hypertension and dyslipidemia without diabetes mellitus (OHD-DM). The aim of the present study was to explore the mechanism of this amelioration by comparing the previous results to those obtained from 19 subjects who, in addition to the conditions described above, also suffer from diabetes mellitus (OHD+DM) and proteinuria. In both the non-diabetic and diabetic groups, a similar reduction was observed in BP (from 158.7/80.8 to 146/72.9 mmHg, and from 157.6/83.2 to 141.9/75.6 mmHg, respectively, P<0.001) and TG levels (from 159.2 to 108.0 mg/dl and from 208.7 to 153.1 mg/dl, respectively, P<0.001). However, a favorable reduction in hemostasis parameters (platelet aggregation on extracellular matrix and (alpha2-antiplasmin) was only seen among the nondiabetic patients (from 12.1+/-4.9 to 4.2+/-3.2%, P<0.001). This difference may stem from a less efficient exchange between n-3 and n-6 PUFA in serum phospholipid of the OHD+DM patients. Overall, this 13-day fasting/refeeding method developed by us has proven to cause the rapid exchange of arachidonic acid for eicosapentaenoic acid. It appears to be an effective regimen for the reduction of cardiovascular risk factors (BP, TG and hemostatic variables) in OHD-DM patients and to a lesser extent in OHD+DM patients.

Aged↗
PubMed1999

Characteristics of septic arthritis in human immunodeficiency virus-infected haemophiliacs versus other risk groups.

The cases are presented of four haemophiliacs infected with human immunodeficiency virus (HIV) and with septic arthritis among the 340 patients followed at our centre. The data of these cases and 39 additional HIV-infected haemophiliacs with septic arthritis, identified in a literature search, are reviewed. The spectrum of bacterial pathogens is limited and somewhat different from that in other risk groups. The localization is exclusively to joints affected by haemophilic arthropathy. The laboratory picture is characterized by the absence of peripheral leucocytosis, varying CD4-helper cell counts, a high erythrocyte sedimentation rate and fever. The clinical picture mimics that of haemarthrosis, often causing a delay in diagnosis. Treatment with systemic antibiotics is often sufficient, obviating the need for arthrotomy and open drainage. Prognosis related to the joint function is relatively good, but poor when related to the medium- to long-term survival of the patient.

Adult↗
PubMed1999

Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment.

The inherited thrombophilias--deficiencies of protein C, protein S, and antithrombin III--and the prothrombotic polymorphisms factor V G1691A and factor II G20210A predispose patients toward venous thromboembolism (VTE). The aim of this study was to determine the prevalence of single and combined prothrombotic factors in patients with idiopathic VTE and to estimate the associated risks. The study group consisted of 162 patients referred for work-up of thrombophilia after documented VTE. The controls were 336 consecutively admitted patients. In all subjects factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were analyzed by specific polymerase chain reactions and restriction enzymes. Activities of antithrombin III and protein C, free protein S antigen, and lupus anticoagulant were determined in a subset of 109 patients who were not receiving oral anticoagulants. The prevalences of heterozygotes and homozygotes for factor V G1691A and factor II G20210A among patients and controls were 40.1% versus 3.9% and 18.5% versus 5.4%, respectively (P=0.0001). The prevalence of homozygotes for MTHFR C677T in patients was 22.8% and in controls, 14.3% (P=0.025). Heterozygous and homozygous factor V G1691A, factor II G20210A, and homozygous MTHFR C677T were found to be independent risk factors for VTE, with odds ratios of 16.3, 3.6, and 2.1, respectively. Two or more polymorphisms were detected in 27 of 162 patients (16.7%) and in 3 of 336 controls (0.9%). Logistic regression analysis disclosed odds ratios of 58.6 (confidence interval [CI], 22.1 to 155.2) for joint occurrence of factor V and factor II polymorphisms, of 35.0 (CI, 14.5 to 84.7) for factor V and MTHFR polymorphisms, and of 7.7 (CI, 3.0 to 19.6) for factor II and MTHFR polymorphisms. Among 109 patients in whom a complete thrombophilic work-up was performed, 74% had at least 1 underlying defect. These data indicate that in most patients referred for evaluation of thrombophilia due to idiopathic VTE, 1 or more underlying genetic predispositions were discernible. The presence of >1 of the prothrombotic polymorphisms was associated with a substantial risk of VTE.

Adult↗
PubMed1999

Increased neonatal platelet deposition on subendothelium under flow conditions: the role of plasma von Willebrand factor.

In vitro platelet function of umbilical cord blood and neonatal peripheral vein blood from full-term newborns was compared with that of adults. Citrated whole blood was subjected to shear stress (1300 s(-1)) on subendothelial extracellular matrix (ECM)-coated wells in a cone and plate(let) analyzer. Adhered platelets on the ECM were quantitated by image analyzer. Both umbilical cord and neonatal peripheral blood platelets demonstrated more extensive adhesion than adult platelets, and similar aggregate formation on ECM. The ability of neonatal platelets to form aggregates on ECM was confirmed by scanning electron microscopy. Similar activation of neonatal and adult platelets after subjection to shear stress, in the suspension phase, was established by flow cytometry, which showed an increase in fibrinogen binding and a decrease in glycoprotein Ib expression on platelet membrane. The difference in adhesion rates between neonatal and adult platelets was preserved even when the hematocrit level of the neonatal blood was adjusted to that of adults. Reconstitution of neonatal or adult platelet-rich plasma with autologous or heterologous red packed cells yielded no change in adhesion and aggregation. When von Willebrand factor-covered plates were used to prevent deposition of plasma von Willebrand factor on the surface, no difference in platelet adhesion was seen between neonatal and adult blood. In conventional aggregometry assay, the response to ristocetin of washed platelets of either neonatal or adult source was higher on addition of plasma from neonates than from adults. Our data suggest that the extensive neonatal platelet deposition on ECM is mediated by plasma von Willebrand factor, which is known to be more multimerized and, therefore, more active in neonates than in adults. This mechanism may provide balanced primary hemostasis in neonates despite the platelet hyporeactivity to agonists without application of shear stress.

Adult↗
PubMed1999

Safety and efficacy of continuous infusion of a combined factor VIII-von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease.

We studied the safety and efficacy of treatment with continuous infusion of a von Willebrand factor (vWF) concentrate Haemate-P in patients with von Willebrand disease (vWD). Three patients with mild and 5 patients with severe forms of vWD, were treated with continuous infusion of Haemate-P by minipump. The indications for treatment were: to prevent bleeding during 9 surgical procedures or 1 vaginal delivery in 6 patients and to treat 2 bleeding episodes in 2 patients. The patients were monitored daily for factor VIII (FVIII:C) and ristocetin cofactor (vWF: RCo) levels and the infusion rate was adjusted to maintain the desired therapeutic level of vWF:RCo. The treatment was effective in preventing surgical bleeding and controlling bleeding episodes. All factor VIII:C and most of the vWF:RCo levels measured during the study period were above the target therapeutic levels. A significant decrease in clearance of FVIII:C and vWF:RCo was observed over the treatment period. Haemate-P consumption averaged 24.3+/-7.9 vWF:RCo U/kg/day which is approximately half the expected dose had intermittent bolus injections been used. We suggest that continuous Haemate-P infusion is superior to intermittent bolus injections for the treatment of vWD patients by virtue of its efficiency, simplicity and considerable savings.

Adolescent↗
PubMed1999

Attenuation of Ca paradox injury in guinea pig heart by K+ channel blocker, d-sotalol.

D-sotalol was shown to prevent Ca overload and intermyocyte uncoupling. The aim of this study was to investigate the effect of d-sotalol in Ca paradox conditions. Guinea pig hearts were perfused at 37 degrees C and constant pressure with oxygenated Tyrode solution. Ca paradox was induced by 10 min Ca free perfusion followed by 10 min Ca repletion. 10(-6) M d-sotalol was administered either during Ca depletion or during Ca repletion period. Electrical activity and ventricular contraction were simultaneously recorded and subcellular alterations were analysed. The contraction terminated in 5 min of Ca free perfusion and electrical activity disappeared within 5 min of Ca repletion. Nonuniform injury of myocardial tissue was observed. The majority of cardiomyocytes were irreversibly injured and profound dissociation of intercellular junctions was detected. Administration of d-sotalol during Ca free period preserved electrical activity and restored ventricular contraction accompanied by apparent protection of the ultrastructure, including intercellular connections. Uniform patterns of sarcomeres reflected synchronous contraction and protection of junctional couplings. In conclusion, d-sotalol attenuates Ca paradox injury. It seems that the protective effect of d-sotalol is most likely related to inhibition of potassium efflux antagonizing Na loading during Ca depletion period, as well as to attenuation of excess of [Ca2+]i via acceleration of sarcoplasmic Ca exchange during Ca repletion.

Animals↗
PubMed1999

Hypokalemia-induced ultrastructural, histochemical and connexin-43 alterations resulting in atrial and ventricular fibrillations.

Perfusion of the isolated guinea pig heart with hypokalemic solution provide simple model for examination of the molecular mechanisms involved in the incidence of atrial and/or ventricular fibrillations. The results point out that dispersion of the metabolic and subcellular alterations and heterogenously impaired intercellular coupling might account for electrical disturbances and desynchronization of the myocardium thus facilitate occurrence of fibrillation.

Animals↗
PubMed1999

The role of sarcoplasmic reticulum in the protective effect of class III drugs against Ca2+ overload.

UNLABELLED: Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III antiarrhythmic drugs with positive inotropic effect) facilitate spontaneous ventricular defibrillation. Following our previous results, we summarized that spontaneous ventricular defibrillation requires high level of intercellular coupling and synchronization, both of which depends on intracellular free Ca2+ concentration. We hypothesized that any antiarrhythmic compound that facilitates spontaneous defibrillation, including d-sotalol and tedisamil, should prevent intracellular free Ca2+ overload most likely by elevating cAMP level and enhancing cAMP-related Ca2+ uptake of the sarcoplasmic reticulum (SR). The aim of the present study was to examine the role of the SR uptake function in their effect against Ca2+ overload. METHODS: The effect of d-sotalol, tedisamil and dbcAMP on increased intracellular Ca2+ level were examined in cultured rat cardiomyocytes during blockade of SR Ca2+ uptake by administration of thapsigargin (TG), a selective inhibitor of Ca2+-ATPase. RESULTS: Administration of 3 x 10(-6) mol/l TG, prior to d-sotalol, tedisamil and dbcAMP, significantly increased intracellular free Ca2+ concentration and prevented the effect of d-sotalol, tedisamil or dbcAMP to decrease intracellular Ca2+ level to its beseline, while 10(-6) mol/l TG prevented it only partially. Administration of either d-sotalol or tedisamil (at concentration of 10(-5) mol/l) before the administration of 10(-6) mol/l TG prevent the TG induced elevation of [Ca2+]i. CONCLUSION: These results support our hypothesis that d-sotalol and tedisamil prevent Ca2+ overload by the cAMP dependent SR Ca2+ uptake.

Animals↗
PubMed1998

Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients.

Increased platelet aggregation has been suggested to play a role in the accelerated atherosclerosis of diabetics. However the physiological relevance of the aggregation tests has been questioned. The purpose of this study was to determine platelet activation in diabetic patients, using a novel device--the cone and plate(let) analyzer--to measure shear-induced platelet adhesion and aggregation on extracellular matrix (ECM). Whole blood platelet adhesion and aggregation in patients with noninsulin-dependent diabetes mellitus (n=82) and in nondiabetic controls (n=71) were compared. Clinical and laboratory characteristics of the diabetic patients were analyzed for possible correlation with parameters of platelet activity. Patients with diabetes had a significantly increased platelet activation compared to nondiabetic subjects, demonstrated by an increased adhesion to the ECM (surface coverage, 23% [95% confidence interval, 22-25%] vs. 19% [95% confidence interval, 18-20%], respectively) and an increased average size of the ECM-bound aggregates (54 microm2 [95% confidence interval, 51-57 microm2] vs. 47 microm2 [95% confidence interval, 43-51 microm2], respectively). Platelet adhesion in the diabetic group was found to correlate with triglyceride levels (r=0.36) and hematocrit values (r=0.31) and inversely with high-density lipoprotein cholesterol levels (r=0.30). There were no correlation, however, between parameters of platelet reactivity and duration of diabetes, vascular complications and low-density lipoprotein levels. Our data demonstrate an increased platelet adhesion and aggregation in diabetic patients and suggest a modulatory role of diabetic dyslipidemia.

Adult↗
PubMed1998

Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets.

Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kD member of the Ig gene superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and selective T-cell subsets. It is also a major component of the endothelial cell intercellular junction. Previous studies have shown that cross-linking PECAM-1 on the surface of leukocytes results in the activation of adhesion molecules of both the beta 1 and beta 2 integrin family. In addition, the process of leukocyte transendothelial migration appears to be mediated, at least in part, by homophilic adhesive interactions that take place between leukocyte and endothelial cell junctional PECAM-1 molecules. However, little is known about the functional role of this membrane glycoprotein in human platelets. In the present study, we examined the effects of PECAM-1 engagement on integrin-mediated platelet-extracellular matrix or platelet-platelet interactions. Bivalent, but not monovalent, anti-PECAM-1 monoclonal antibodies (MoAbs) specific for membrane-proximal Ig-homology domain 6 significantly augmented platelet deposition (increased surface coverage) and aggregation (increased average size) onto extracellular matrix, under both oscillatory or defined low shear flow conditions (200 s-1) in a modified cone and plate viscometer. Moreover, bivalent anti-domain 6 MoAbs were capable of serving as costimulatory agonists to markedly enhance both adenosine diphosphate (ADP)- and platelet activating factor (PAF)-induced platelet aggregation resonses. These antibodies appeared to act via outside-in signal transduction through PECAM-1, as evidenced by the fact that their binding (1) led to conformational changes in the alpha IIb beta 3 integrin complex, (2) induced surface expression of P-selectin, and (3) resulted in the tyrosine phosphorylation of PECAM-1. Together, these data support a role for PECAM-1 in cellular activation and suggest that PECAM-1 may serve as a costimulatory agonist receptor capable of modulating integrin function in human platelets during adhesion and aggregation.

Blood Platelets↗
PubMed1998

Cone and plate(let) analyzer: monitoring glycoprotein IIb/IIIa antagonists and von Willebrand disease replacement therapy by testing platelet deposition under flow conditions.

Exposure of citrated whole blood samples to polystyrene plates under flow conditions with the cone and plate(let) analyzer (CPA) results in surface immobilization of plasma von Willebrand factor (vWF) followed by platelet deposition. Staining the plates allows measurement of the percentage of surface covered (SC) by the adhered particles and their average size (AS). Both SC and AS parameters depend on platelet count and hematocrit level and reach maximal values after 2 minutes; only AS is shear rate dependent. Under optimal assay conditions (2 minutes at 1800 sec(-1)) normal blood samples yielded an SC of 14.9% +/- 2.5% and an AS of 39.4 +/- 5.2 microm2. Severe von Willebrand disease (eight patients) yielded low SC (5.2% +/- 2.1%), which was restored to normal by testing with vWF precoated surfaces. Glanzmann's thrombasthenia (six patients) samples demonstrated no adhesion of platelet at all. Blocking of the glycoprotein (GP) IIb/IIIa receptor by the chimeric antibody abciximab, and of the GPIb by a recombinant vWF fragment, have yielded a dose-response inhibition demonstrating the crucial role of these receptors in platelet deposition on polystyrene plates in this system. Evaluation of a patient with severe von Willebrand disease receiving replacement vWF factor VIII therapy revealed a comparable response as tested by both the CPA and the Ricof methods. In vitro testing of the GPIIb/IIIa blocking by a nonpeptidic analogue tirofiban and abciximab revealed a good correlation between the CPA test and the routine aggregometry. Eleven patients treated by abciximab after coronary angioplasty were studied by the CPA during the first 24 hours, demonstrating a marked decrease in SC and AS, with some diversity in the responses. We conclude that the CPA test is suitable for evaluation of primary hemostasis and for monitoring of anti-platelet drugs.

Blood Circulation↗
PubMed1998

Effect of estradiol on rat ileum.

1. Sex hormones may influence gastrointestinal motility and thus may be responsible for symptoms that are common during pregnancy or hormone replacement therapy. The purpose of this study was to evaluate the effect of estradiol on the gut. 2. Segments of rat ileum (n=9) were suspended in an organ bath and exposed to increasing concentrations of carbachol, in the presence or absence of 17beta-estradiol. 17beta-estradiol markedly reduced the force developed by the ileum in response to carbachol. 3. These results suggest that estradiol reduces gastrointestinal motility.

Animals↗
PubMed1998

Thrombin promotes platelet-mediated melanoma cell adhesion to endothelial cells under flow conditions: role of platelet glycoproteins P-selectin and GPIIb-IIIA.

We investigated the role of platelets in human melanoma cell (line 397) interaction with vascular endothelial cells (ECs) under flow conditions. The ability of the tumour cells to adhere to the EC monolayer was significantly reduced by application of flow at a shear rate of 250 s(-1). A 2.2-fold increase in tumour cell adhesion to ECs under flow was observed upon addition of thrombin receptor agonist peptide (TRAP)-activated platelets but not resting platelets. A similar increase (2.5-fold) in tumour cell adhesion to ECs under flow was observed when the tumour cells were incubated with resting platelets on thrombin-treated ECs. However, thrombin treatment of the ECs alone had no effect on tumour cell adhesion in the absence of platelets. The enhancement of tumour cell adhesion to ECs by TRAP-activated platelets was virtually abolished by blockade of the platelet glycoproteins P-selectin and GPIIb-IIIa by monoclonal antibodies. Blockade of P-selectin also inhibited the direct adhesion of TRAP-activated platelets to ECs, but did not affect the interaction of the tumour cells with platelets immobilized on subendothelial extracellular matrix (ECM). Blockade of GPIIb-IIIa inhibited both platelet-EC and platelet-tumor cell interactions. Our results indicate that tumour cell adhesion to the endothelium under flow is enhanced by platelets under conditions that allow platelet adhesion to ECs. Inhibition studies suggest that activated platelet adhesion to ECs is mediated by P-selectin and GPIIb-IIIA, and tumour cell adhesion to EC-bound platelets--mainly by GPIIb-IIIa.

Animals↗