Facilitation of levodopa-induced dyskinesias by dietary carbohydrates.
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Biomedical subjects
Publications and source records attributed to E Salzman.
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Patients who receive desmopressin acetate (dDAVP) after cardiopulmonary bypass bleed less during operation and in the first 24 hours after operation than do patients who receive a placebo. To study the mechanism of improved hemostasis in bypass patients, we examined the relationship between von Willebrand factor (vWF) and blood loss in 70 cardiopulmonary bypass patients, one-half of whom received desmopressin intraoperatively. vWF concentration and multimeric composition were analyzed before and after bypass, after drug treatment, and 24 hours after operation. Before operation, patients with valvular disease had lower percentages of vWF high-mol-wt multimers (HMWMs) than did healthy subjects or patients with coronary artery disease, but subsequent blood loss, vWF activity, and bleeding times were not related to this finding. Irrespective of drug treatment, patients who had low preoperative vWF and who had a net loss of the protein during bypass bled more after bypass than did similar patients who had a net increase of vWF during bypass. HMWMs rose to above normal levels after bypass regardless of desmopressin infusion. Differences in the concentration of vWF between desmopressin and placebo patients after receipt of the drug, although small, were better correlated with reduced blood loss than were differences in HMWM distribution. We conclude that the beneficial effect of desmopressin on hemostasis following cardiopulmonary bypass cannot be attributed to a drug-induced change in HMWM distribution but may be related to an increase in overall vWF concentration.
The amount and rate of blood expelled with different modes of intermittent external pneumatic compression applied to the lower leg were studied on a regional basis in a series of experiments on healthy human volunteers. Radionuclide imaging of the labelled blood pool, with acquisition of counts synchronised to the pressurisation cycle, provided data on regional blood volumes in the leg in relation to time. To determine the changes in blood volume of the lower leg resulting from external pneumatic compression labelled red blood cell counts were determined during 10 different types of compression cycle. Since venous stasis is considered to be a major cause of venous thrombosis the red blood cell counts were used to calculate regional values of the fraction of blood ejected as well as comparative indices proportional to regional flow rate, regional velocity, and regional wall shear stress. All these indices should be maximised for optimal prophylaxis against deep vein thrombosis. The four compartment cuff in each compression mode applied a mean pressure of 45 mm Hg, but different combinations of values were used for intercompartmental pressure gradation (delta p) and for intercompartmental time sequencing to the onset of compression (delta t). Uniform compression (delta p = 0; delta t = 0) was substantially inferior to cycles with gradation and sequencing. The optimal values of delta p were in the range 5-10 mm Hg and of delta t in the range 0-0.5 seconds.
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Continuous intravenous infusion of prostacyclin (prostaglandin I2, PGI2) in rabbits induced refractoriness to PGI2-induced inhibition of platelet function. Although inhibited during earlier stages, platelet response to adenosine diphosphate and thrombin became normal within 24 hours of PGI2 infusion. Cross-mixing experiments with platelets and plasma from infused and control animals suggested that the altered response to PGI2 was caused by a defect intrinsic in the platelets. PGI2-stimulated cyclic adenosine monophosphate (cAMP) production was reduced in platelets from infused rabbits as compared with those from controls. Platelets refractory to PGI2 were refractory to PGE1 and PGD2, as well. Because PGE1 but not PGD2 shares the same platelet receptor as PGI2, the phenomenon could not be ascribed to receptor-specific downregulation, which was also shown by refractoriness of platelets from infused rabbits to the nonprostanoid inhibitor of platelet function adenosine. Either increased concentrations of ineffective inhibitors or their combination with phosphodiesterase inhibitors overcame refractoriness of resistant platelets, which also responded to inhibition by dibutyryl cAMP, indicating residual activity of adenylate cyclase. That at least the catalytic subunit of the enzyme was still working in refractory platelets was shown by inhibition of aggregation induced by forskolin, a non-receptor-mediated activator of adenylate cyclase. Impairment of the adenylate cyclase regulatory subunit, possibly accompanied by multireceptor downregulation, may explain the paradoxical refractoriness of platelets to prolonged infusion of PGI2. Such an effect may limit the benefit of PGI2 in treatment of thromboembolic disease.
Thirty-four dogs underwent total cardiopulmonary bypass for 1 or 2 hours with a bubble oxygenator and cardiotomy suction. The dogs were divided into three groups: control dogs which received heparin alone, dogs which received prostacyclin (PGI2) and heparin, and dogs which received prostacyclin alone. PGI2 was given as a bolus (6 to 60 microgram) and then as a constant infusion (0.2 to 0.8 microgram/kg/min) in the venous outflow line. The pump flows were equal in the three groups. PGI2 as a bolus led to transient hypotension, and 60 microgram reduced cardiac output temporarily. During cardiopulmonary bypass, dogs treated with prostacyclin and heparin had low mean arterial perfusion pressures which responded to fluid infusion or phenylephrine. After 1 hour of cardiopulmonary bypass and reversal with protamine, dogs treated with prostacyclin and heparin had shorter bleeding times (p < 0.02) and better platelet function than control animals. After 2 hours, they had normal platelet number, but only half showed preservation of platelet function. When heparin was omitted, PGI2 preserved platelet number, but consumption coagulopathy developed, with prolonged prothrombin, partial thromboplastin, and bleeding times and decreased fibrinogen levels. PGI 2 preserves platelet number and function but may cause hypotension, and it cannot replace heparin in cardiopulmonary bypass.
A defect in both the first and second phase of platelet aggregation was found in four subjects with Bartter's syndrome, although template bleeding times were normal. The platelet abnormality was exacerbated by restriction of dietary sodium and lessened by the administration of inhibitors of prostaglandin synthesis. The aggregation defect was not found in other hypokalemic patients or in sodium-restricted normal control subjects. Platelet rich plasma from the subjects with Bartter's syndrome had an abnormally high content of cyclic adenosine 5'-monophosphate (AMP), which may have been responsible for the disordered platelet function. Plasma of these subjects induced both the high content of cyclic AMP and the aggregation defect in normal platelets, whereas suspension of the subjects' platelets in normal plasma improved their aggregation. These findings describe a unique defect of platelet aggregation in Bartter's syndrome, which may be associated with the altered prostaglandin metabolism found in this condition.
Platelet interaction with surfaces to which heparin had been covalently bonded was investigated with a chromatographic technique employing agarose gel beads heparinized via a cyanogen bromide reaction. Heparinization significantly increased platelet retention by the gel. Platelet retention was unchanged after pretreatment of the heparinized gel with albumin but increased after pretreatment with fibrinogen. Pretreatment with plasma or purified AT III decreased platelet retention. Reduction in platelet retention was correlated with the amount of AT III removed from plasma. Plasma with decreased levels of AT III was less effective in surface passivation. Pretreatment of heparinized gel with PF4 or protamine sulfate did not decrease platelet retention, but subsequent exposure to plasma did. The results suggest that a surface with covalently bonded heparin is reactive toward platelets but can be passivated by formation of a heparin/AT III complex.
We studied eight patients with intermittent bleeding episodes usually following trauma and associated with the ingestion of medicine known to interfere with platelet function. All patients had a normal or minimally prolonged baseline bleeding time. All had a normal platelet count, glass bead retention test, and platelet serotonin content and a variable pattern of abnormalities in prothrombin consumption and platelet factor 3 availability. However, all showed abnormal platelet aggregation reactions using epinephrine, adenosine diphosphate, and collagen. Following the administration of 975 mg aspirin, our patients' bleeding times became prolonged to a greater extent than the bleeding times of normal controls (range 13 to greater than 20 min). Review of the literature showed approximately 5% of "normal" controls had findings similar to those we report. We believe we are describing a group of individuals with an intermediate form of platelet dysfunction. Although their bleeding diathesis is not as severe as that of patients with platelet dysfunction syndromes previoulsy described, they do bleed significantly when subjected to trauma following the ingestion of drugs such as aspirin. We propose that this defect is common and should be screened for. The aspirin tolerance test is a simple test for detecting these patients.
Surgical ligation of the vena cava in the treatment of pulmonary embolism is already being superseded by devices introduced via a peripheral vein. A new metal alloy (nitinol) with unique memory characteristics forms the basis of an experimental device which promises even greater safety, simplicity and speed of introduction. It is inserted as a straight thin wire via the small bore catheter used for angiographic diagnosis. Upon reaching the lumen of the inferior vena cava and sensing body temperature, it reverts to its preset complex filter shape and locks into place permanently. It will trap further thromboemboli from the pelvis or lower limbs.
Three patients with severe hypertension and rapidly progressive oliguric renal failure who required dialysis were found by aortography to have bilateral renal artery occlusion or stenosis. Each had peripheral arteriosclerosis or an abdominal bruit. Following renal artery reconstructive surgery, all three patients recovered nearly normal renal function in 3 to 12 weeks, though mild hypertension persisted in two patients. The common findings of a normal-sized kidney with collateral blood flow and nearly normal histological features were predictive of recovery of renal function. Prolonged postoperative oliguria in two patients may have been due to increased preglomerular vascular resistance mediated by the renin-angiotensin system.
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To advance hemocompatibility evaluation techniques, a new in vivo method has been developed for the dynamic testing of candidate biomaterials in suitably-sized experimental animals. One of the salient features this method is that the material to be evaluated constitutes the blood contact surface of a slender body of revolution which is coaxially suspended in a large canine vessel by electromagnetic forces only. The insertion site of the specimen is distal and downstream to the test region, reducing the influence of thrombotic tissue substances. These experimental conditions also insure that the only chronically exposed foreign surface is that of the test material, whose interactions with blood components are not affected by contact with the vessel intima. As demonstrated in simulated Circulation Model experiments, macroscopic thromboembolic phenomena induced by the test material can be continuously monitored. Preliminary in vivo trials have verified the validity of the underlying principles; the feasibility of the required surgical techniques, and the adequate performance of the suspension system.
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