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Biomedical subjects

M J Silver

Publications and source records attributed to M J Silver.

At least 19 recordsLinked to original sources
PubMed1998

Influence of a randomized clinical trial on practice by participating investigators: lessons from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). CAVEAT I and II Investigators.

OBJECTIVES: We sought to determine whether the results of the first Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) influenced subsequent practice patterns among the investigators. BACKGROUND: CAVEAT-I demonstrated that directional coronary atherectomy (DCA) resulted in higher rates of early complications at a higher cost and with no clinical benefit. We sought to determine whether these results influenced subsequent use of procedures among CAVEAT-I investigators. METHODS: We compared the results of a week-long registry of all coronary interventions performed at 35 CAVEAT-I sites in 1994 with those of a similar registry obtained in 1992 before the trial, the results of which were published in 1993. For control purposes, the use of procedures was studied at 24 additional sites to provide insight into practice at hospitals not participating in the trial. A total of 1,465 interventions were analyzed. RESULTS: Ninety-four percent of CAVEAT-I sites responded. Utilization rates differed between CAVEAT-I and CAVEAT-I follow-up (p < 0.001). Balloon angioplasty decreased from 83.8% to 68.5%, DCA increased slightly from 10.7% to 14.1%, and the use of other devices increased from 5.4% to 17.5%. Stand-alone balloon use was more prevalent at nonparticipating control sites than at sites that took part in CAVEAT-I (p < 0.001). CONCLUSIONS: Paradoxically, despite the negative findings of CAVEAT-I, there was a noteworthy trend toward an increase in the use of DCA and other devices at CAVEAT-I sites. Our findings suggest that among investigators in the trial, there may have been a lack of influence of trial data on clinical practice patterns 1 year after publication of the results. Ethics of protocol: Both CAVEAT I and II were approved by the Institutional Review Board at each study site.

Adult↗
PubMed1995

Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model.

BACKGROUND: An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. METHODS AND RESULTS: A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. CONCLUSIONS: Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.

Animals↗
PubMed1993

Evaluation of a new blood-conserving arterial line system for patients in intensive care units.

OBJECTIVE: To evaluate blood samples obtained from a new blood-conserving arterial line system for the presence of hemodilution or heparin contamination. DESIGN: Prospective, clinical trial. SETTING: A coronary intensive care unit in a tertiary-care teaching hospital. PATIENTS: Cardiovascular patients in whom invasive arterial blood pressure monitoring was indicated. INTERVENTIONS: Paired blood samples were obtained from a conventional arterial line system and a new blood-conserving arterial line system for the measurement of hematocrit and partial thromboplastin time, and compared to evaluate for the presence of either hemodilution or heparin contamination. MEASUREMENTS AND MAIN RESULTS: A Bland-Altman bias analysis of the variability between the two blood draw methods was performed. The analysis indicated that a) a randomly determined partial thromboplastin time obtained from the blood-conserving arterial line would lie between 3.32 and -5.11 of the partial thromboplastin time taken from the conventional arterial line value with 95% confidence; and b) a randomly determined hematocrit obtained from the blood-conserving arterial line would lie between 1.97 and -1.85 of the hematocrit taken from the conventional arterial line value with 95% confidence. CONCLUSIONS: We concluded that a) blood samples obtained with the blood-conserving arterial line demonstrate no evidence of hemodilution or heparin contamination; b) the blood-conserving arterial line provides blood samples without the need for an initial volume of blood to be discarded; c) the blood-conserving arterial line provides a means for blood conservation in the intensive care setting.

Blood Pressure Monitors↗
PubMed1993

Reduction of blood loss from diagnostic sampling in critically ill patients using a blood-conserving arterial line system.

STUDY OBJECTIVE: To demonstrate the utility of a new blood-conserving arterial line system in reducing blood loss associated with blood drawing in the critical care setting. DESIGN: Prospective, randomized, crossover comparison between two arterial line systems. SETTING: Medical intensive care unit (ICU); tertiary care teaching institution. PATIENTS: Thirty-one patients who required invasive arterial blood pressure monitoring throughout their ICU course. INTERVENTIONS: For ICU days 1 to 2, patients were randomized to receive either a conventional arterial line system or a new blood-conserving arterial line system. On ICU days 3 to 7, patients with a conventional arterial line were crossed over to the blood-conserving arterial line, and vice versa. Laboratory blood volumes, mixed discard volumes, and blood discard volumes were then recorded to document how much blood loss is associated with each aspect of the blood sampling process. RESULTS: The mean total volume of blood sent to the laboratory for testing was 257.4 ml. As a result of "clearing the line" over the 7-day period, patients with the conventional arterial line system lost a mean volume of 340.2 ml of blood mixed with heparinized saline solution more than patients with the blood-conserving arterial line. In terms of the blood component of the blood-heparinized saline solution mixture, use of the conventional arterial line was associated with an average of 156.8 ml more blood discarded than with the blood-conserving arterial line. CONCLUSION: The new blood-conserving arterial line system provides a simple and effective method for reducing blood loss related to diagnostic sampling in the critical care setting.

Blood Specimen Collection↗
PubMed1991

Eicosapentaenoic acid ethyl ester as an antithrombotic agent: comparison to an extract of fish oil.

Evidence suggesting that dietary omega-3 polyunsaturated fatty acids decrease the risk of thrombosis comes mainly from studies involving supplementation with large amounts (15-20 g/day) of fish oil extract. We investigated the inhibition of platelet function by a moderate amount (4 g/d) of ethyl eicosapentaenoate (E-EPA) compared to a concentrated fish oil extract (6 g/d) when given as a supplement to an ordinary diet. We also determined the effects of these supplements on platelet EPA incorporation, thromboxane synthesis, calcium mobilization and fibrinogen binding. After 4 weeks, both omega-3 supplements increased the amount of EPA in platelet phospholipids. The fish oil extract, which contained docosahexaenoic acid (DHA), had increased the amount of DHA also. The total increase in omega-3 fatty acids was similar for both supplements. E-EPA decreased serum cholesterol by 13% and triacylglycerols, 35%; increased the bleeding time by 57% and the threshold dose of collagen needed to induce platelet aggregation by 46%. Thromboxane synthesis in response to collagen was decreased 65% by E-EPA. Thus, the dietary supplement of pure E-EPA was more effective in limiting platelet reactivity than a concentrated fish oil extract providing an equivalent amount of omega-3 fatty acids. As an antithrombotic agent, E-EPA should allow for reasonable daily doses in long-term treatment of cardiovascular disease.

Adenosine Triphosphate↗
PubMed1988

Model system to study interaction of platelets with damaged arterial wall. II. Inhibition of smooth muscle cell proliferation by dipyridamole and AH-P719.

A new in vivo model for the initial events in atherogenesis was employed to investigate drugs which may inhibit intimal muscle cell proliferation following repeated limited endothelial cell injury. An artery forceps was placed over the central artery of the ear of an anesthetized rabbit for 30 min. The forceps were removed, blood flow resumed in the vessel, and platelets contacted the damaged vessel wall. When a vessel was injured two or more times the smooth muscle cells of the media migrated into the intima and proliferated there between 1 and 3 weeks after the last injury despite restoration of an apparently intact endothelium. The intima of control undamaged vessels sometimes contained a few individual smooth muscle cells while vessels injured two, four, or six times showed correspondingly increasing numbers of layers of intimal smooth muscle cells covering increasing amounts of the intima. Arteries from thrombocytopenic rabbits showed, at most, a single layer of smooth muscle cells covering a small area. In rabbits pretreated with dipyridamole (1.5 mg/kg) for 3 days before each injury, proliferation was also limited to a small area. Neither aspirin (8 mg/kg) nor ticlopidine (40 mg/kg, 5X over 3 days), which inhibit platelet aggregation ex vivo, nor the continuous presence of heparin (800 U/kg, bid), reported to inhibit smooth muscle cell growth in vitro and in vivo, prevented smooth muscle cell proliferation in response to two injuries. However, a potent inhibitor of platelet cyclic-adenosine monophosphate (cAMP) phosphodiesterase, AH-P719 (1.5 or 2.1 mg/kg), was able to inhibit intimal smooth muscle cell proliferation in doses that inhibited platelet aggregation ex vivo.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Prostacyclin synthesis by endothelial cells from human umbilical veins: effect of cumulative population doublings.

There is a wide range of reported values for prostacyclin (PGI2) synthesis by cultured endothelial cells from human umbilical veins (HUVE). Part of this variation may be due to differences in isolation and culture conditions, but part may be due to previously unstudied variation in the number of population doublings (PDs) which the cells have undergone in vitro. Attention is now shifting to arachidonic acid (AA) metabolism by cells from adult human vessels and these cells may require increased PDs to obtain confluent cultures for testing. Therefore, we have examined the effect of number of cell population doublings as well as number of subcultivations on PGI2 synthesis using HUVE as a model system. Primary and first subcultivation cultures inoculated at high density, so that PDs at confluence were less than 4, synthesized 10 times as much PGI2 as the same isolates inoculated at low density with PDs greater than 4. Isolates inoculated and subcultivated so that the PDs at confluence after the fourth subcultivation were less than 6, showed 50% less PGI2 synthesis between the primary and first subcultivation and between the first and second subcultivations. Isolates with less than 4 PDs after the fourth subcultivation were carried further to determine the effect of extensive subcultivation. Four of six isolates showed a sudden increase in PGI2 synthesis which occurred between subcultivations 5 and 12 (PDs 4-6). These results demonstrate that AA metabolism is markedly affected by growth in culture and serial subcultivation.

Calcimycin↗
PubMed1988

The carbon dioxide rate of rise in awake apneic humans.

Currently available estimates of the PaCO2 rate of rise in resting humans with resting lung volume were gathered during general anesthesia. The PaCO2 rate of rise during apnea in awake subjects was determined to acquire a value that may be more applicable to awake, ventilator-dependent, critically ill patients. Clinically, apnea occurs at functional residual capacity. With FiO2 = 1.0, 20 volunteers held their breaths at functional residual capacity for 0, 10, and 20 seconds, and then for as long as possible. They exhaled through an infrared CO2 analyzer after each interval to determine end-tidal pCO2. An estimate of the logarithmic PaCO2 rise during breath holding at functional residual capacity was 7 mmHg during the first 10 seconds (43 mmHg/minute), 2 mmHg during the next 10 seconds (13 mmHg/minute), and 6 mmHg/minute thereafter. In conclusion, PaCO2 increases more rapidly in awake apneic humans than earlier thought. The values reported herein probably are better for estimating duration of apnea in conscious, critically ill patients than are values obtained during general anesthesia.

Adult↗
PubMed1987

Alloxan-induced hyperglycemia in rabbits and the response of platelets to aggregating agents in vitro and to exposed subendothelium in vivo.

Many patients with diabetes mellitus show increased platelet aggregation and prostaglandin synthesis in response to physiological agents such as ADP and collagen when their platelets are tested in platelet-rich plasma or washed platelet suspensions. However, the relationship between increased platelet aggregation in vitro and increased thrombosis in vivo is difficult to establish with certainty. We have developed an in vivo model system in rabbits which tests the response of platelets in circulating native blood to an arterial vessel wall with limited damage such as might occur in arteries of patients with diabetes mellitus. We have used this model system to investigate whether 5 to 9 weeks of alloxan-induced hyperglycemia increases platelet adhesion and aggregation on a damaged vessel wall in vivo as well as platelet aggregation in vitro. Our results show that rabbit platelet function is not affected by extreme hyperglycemia and suggest that alloxan-induced diabetes in the rabbit may not be a good model for human diabetes mellitus.

Adenosine Diphosphate↗
PubMed1987

Metabolism of 1-alkyl-2-acyl-GPC in human platelets in response to stimulation by thrombin.

Washed human platelets were incubated with radioactive 1-[3H]alkyl-2-hydroxyglycero-3-phosphocholine (lyso-PAF) at 37 degrees C. [3H]lyso-PAF was converted by platelets into [3H]alkylacyl-GPC which was incorporated. Incorporation of radioactivity was time dependent and reached a maximum of 57 percent in one h. This formation and incorporation of [3H]alkylacyl-GPC was inhibited (50%) by extracellular calcium (1.3 mM). Labeled platelets were treated for 5 min with either thrombin (2.5 U/ml) or saline solution. While there was no change in the saline control, thrombin induced a reduction in the content of [3H]alkylacyl-GPC, accompanied by an increase in [3H]lyso-PAF presumably by stimulation of phospholipase A2. There was no apparent increase in radioactivity comigrating with PAF. This was probably due to the overwhelming dilution of the radioactive alkylacyl-GPC by the endogenous nonradioactive compound (ratio-1/3200). These studies suggest that human platelets can take up lyso-PAF and acylate it to alkylacyl-GPC which is susceptible to phospholipase A2 activity.

Acylation↗
PubMed1986

Acetyltransferase activity in human platelet microsomes and washed platelets.

It has been demonstrated that human platelets form platelet-activating factor (PAF) when stimulated by thrombin, collagen and ionophore A-23187, but the mechanism of its formation has not been elucidated. In this study we demonstrated increased acetyltransferase activity (i.e., transfer of the acetyl moiety of [3H]acetyl-CoA to lyso-PAF (1-alkyl-sn-glycero-3-phosphocholine) to form PAF) occurring in human platelet microsomes made from platelets stimulated by thrombin or ionophore A-23187. This stimulation resulted in a 2-4-fold increase in acetyltransferase activity over unstimulated platelets. Acetyltransferase activity was also demonstrated by incubating [3H]acetate with whole platelets and stimulating with thrombin or ionophore A-23187. Radioactive PAF was detected when the platelets were stimulated. None was formed without stimulation. These findings indicate that acetyltransferase may play a role in the biosynthesis of PAF by human platelets.

Acetates↗
PubMed1986

Formation of diacyl- and alkylacylphosphatidylcholine by the membranes of human platelets.

We have investigated the distribution and fatty acid preference of two acyl-CoA transferase activities in a human platelet mixed membrane fraction and in well-characterised surface and intracellular membrane subfractions prepared from it by high-voltage free-flow electrophoresis. One transferase inserts long-chain unsaturated fatty acids into 1-acyllysophosphatidylcholine (1-acyl-LPC) and the other into lyso-platelet-activating factor (LPAF). Both transferase activities were approx. 4-fold enriched in the intracellular membranes with respect to their specific activities in the mixed membranes. The surface membrane activities were correspondingly depleted. Using 1-acyl-LPC as the acceptor, all the intracellular membrane preparations showed transferase preference for the CoA ester of 8,11,14-eicosatrienoic acid. In contrast when LPAF was the acceptor the CoA esters of linoleic and arachidonic acid were the preferred donors.

Acyltransferases↗
PubMed1986

Platelet fibrinogen binding in diabetes mellitus. Differences between binding to platelets from nonretinopathic and retinopathic diabetic patients.

While it is known that platelets from diabetic patients bind more fibrinogen than do platelets from normal subjects, there has been no study comparing this phenomenon in platelets from nonretinopathic and retinopathic patients. We have made such a comparison and have found the following. In agreement with previous reports, platelets from nonretinopathic diabetic patients bind abnormally high amounts of fibrinogen. No differences in the amount of fibrinogen bound to platelets (stimulated by collagen or thrombin) were found when data from nonretinopathic and retinopathic patients were compared. However, while aspirin (an inhibitor of thromboxane synthesis) reduced the abnormally high fibrinogen binding of platelets from nonretinopathic patients to normal control levels, it did not normalize the high fibrinogen binding of platelets from retinopathic diabetic patients. The combination of aspirin plus apyrase (an ADP scavenger) almost suppressed fibrinogen binding and aggregation of platelets from normal or nonretinopathic diabetic subjects, whereas it had a somewhat lesser effect on binding and aggregation of platelets from retinopathic subjects. By using a monoclonal antibody (B59.2) to the platelet receptor for fibrinogen, we determined that this receptor was the same in platelets from normal as well as nonretinopathic diabetic subjects and that this antibody could suppress the binding of fibrinogen and the aggregation of platelets from both types of patients just as it did in platelets from normal subjects. Thus, our data indicate that, while platelets from both retinopathic and nonretinopathic patients are hyperaggregable and show abnormally high binding of fibrinogen, they differ in that these abnormalities can be normalized in platelets from nonretinopathic patients by suppressing prostaglandin/thromboxane formation and scavenging ADP, but not in those from retinopathic patients.

Adolescent↗
PubMed1986

Trial of repeated low-dose aspirin in diabetic angiopathy.

We compared the ability of aspirin to suppress platelet aggregation and thromboxane synthesis in ten normal subjects and ten patients with diabetic angiopathy and high rate of entry of new platelets into the circulation. When single doses of 100 to 1,000 mg aspirin were ingested daily for 1 month, there were time gaps between doses in which platelets from diabetics and normals aggregated and formed thromboxane ex vivo in response to the combination of arachidonic acid plus collagen. Similar gaps were also found for diabetics, but not for normals, following four daily doses (every six hours) of 25 or 100 mg. Our data show that dose schedules of aspirin which may suffice in normals are not effective in patients with diabetic angiopathy, presumably because these patients have a high rate of entry of new platelets into the circulation. We suggest that continual suppression of platelet thromboxane synthesis and aggregation by low-dose, "slow-release" preparations of aspirin would be an ideal long-term approach for the prevention of thrombosis in patients with a high rate of entry of new platelets into the circulation.

Adenosine Triphosphate↗
PubMed1985

Phospholipid biosynthesis in human platelets. The acylation of lyso-platelet-activating factor.

Acyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acyltransferase of human platelets is membrane-bound, has a pH optimum of 7.5, is insensitive to 1 mM-Mg2+, is inhibited by 1 mM-Ca2+, and is stimulated slightly by 1 mM-EDTA. Maximal formation of 1-alkyl-2-acyl-sn-glycero-3-phosphocholine is observed at 150 microM-1-alkyl-sn-glycero-3-phosphocholine and 20 microM unsaturated fatty acyl-CoA. The transfer of unsaturated fatty acyl groups to 1-alkyl-sn-glycero-3-phosphocholine is 3-14 times slower than to 1-acyl-sn-glycero-3-phosphocholine. The CoA esters of linoleate and arachidonate, two unsaturated fatty acyl groups commonly found in platelet phospholipids, are the preferred fatty acyl group donors.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1985

Increased binding of fibrinogen to platelets in diabetes: the role of prostaglandins and thromboxane.

Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than platelets from normal subjects. We compared fibrinogen binding to platelets from diabetic subjects with binding to platelets from normal subjects and determined whether aspirin (which inhibits the formation of prostaglandins and thromboxane) would inhibit the binding of fibrinogen to platelets from diabetic subjects and whether this correlated with its effects on platelet aggregation. We found the following: Aspirin suppressed thromboxane formation and rendered the platelets less sensitive to the induction of aggregation by adenosine diphosphate (ADP) or collagen. The amount of U-46619 [( 15s]-hydroxy-11-alpha, 9-alpha [epoxy-methano]-prosta[5Z,13E]-dienoic acid, a stable analog of prostaglandin endoperoxide/thromboxane A2) necessary to induce aggregation, was similar in normal and diabetic subjects and was unchanged after ingestion of aspirin. Binding of 125I-fibrinogen following stimulation of platelets by ADP or collagen was greater in diabetic (because more binding sites were exposed) than in normal subjects. However, following stimulation by U-46619, binding was similar in diabetic and normal subjects. Aspirin caused a reduction in the exposure of binding sites on both platelets from diabetic and normal subjects, so that (in this respect) platelets from diabetic subjects became more like those from normal subjects. Effects of the monoclonal antibody B59.2, which is specific for the platelet glycoprotein IIb-IIIa complex (the presumed receptor for fibrinogen on the platelet surface) were also studied. The amount of this antibody that bound to platelets was the same for normal and diabetic subjects both before and after aspirin and with or without stimulation by ADP or collagen. In addition, B59.2 inhibited aggregation and fibrinogen binding in both platelets from diabetic and normal subjects. The combined data suggest that the glycoprotein IIb-IIIa complex of platelets from diabetic subjects is similar to that of platelets from normal subjects and that the increased fibrinogen binding and aggregation of platelets from diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin endoperoxide or thromboxane A2, or both.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗