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Biomedical subjects

H D White

Publications and source records attributed to H D White.

At least 127 records · Page 7Linked to original sources
PubMed1998

Hirudin (desirudin) and Hirulog (bivalirudin) in acute ischaemic syndromes and the rationale for the Hirulog/Early Reperfusion Occlusion (HERO-2) Study.

Unlike unfractionated heparin, direct thrombin inhibitors such as hirudin and Hirulog inhibit clot-bound as well as fluid-phase thrombin, escape neutralisation by platelet secretion products, do not require monitoring, and are unassociated with immune thrombocytopenia. They have been shown to have modest advantages over heparin when given after thrombolytic therapy, reducing reinfarction by 14%. In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO 2b) trial, patients treated with streptokinase and adjunctive hirudin had a reduction in death or myocardial infarction of 40% at 30 days (8.6% with hirudin versus 14.4% with heparin, p = 0.004). In the Hirulog Early Reperfusion/Occlusion (HERO 1) trial, 48% of patients who received Hirulog as adjunctive therapy with streptokinase had Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow in the infarct-related artery, compared with 35% of patients who received heparin with streptokinase (p < 0.05). The HERO 2 study, involving 17,000 patients, will test the hypothesis that Hirulog and aspirin given before streptokinase will reduce mortality compared with aspirin plus heparin. Early administration of direct thrombin inhibitors may potentially improve the outcome of patients treated with thrombolytic therapy.

Aged↗
PubMed1998

Low molecular weight heparins in acute ischaemic syndromes.

Thrombus formation and ongoing generation play a major role in the pathogenesis of unstable angina and myocardial infarction (MI). Unfractionated heparin is widely used as an adjunctive therapy in the management of acute ischaemic syndromes, but it has a number of limitations including inter-patient variability, need for monitoring, and the fact that its use may be associated with thrombocytopenia. Low molecular weight heparins have pharmacological and pharmacokinetic properties that may result in better clinical outcomes and safety. They are easy to administer and do not require monitoring. Low molecular weight heparins have been shown to reduce mortality and the incidence of MI and recurrent ischaemia compared with placebo in patients with unstable angina and non-Q-wave MI, and have a more predictable anticoagulant effect than standard unfractionated heparin. They also can be used long term in the outpatient setting, in the form of self-administered subcutaneous injections. The clinical relevance of these new developments is still being defined in ongoing clinical trials and cost-effectiveness analyses.

Angina, Unstable↗
PubMed1998

New antiplatelet agents.

Aspirin is an established therapy for the management of acute myocardial infarction (AMI) and unstable angina. Secondary prevention with chronic aspirin therapy is also indicated for patients with stable angina. Aspirin inhibits cyclo-oxygenase-I, a key enzyme in the biosynthetic pathway leading to the production of thromboxane A2. It therefore inhibits only one of the many activation pathways leading to platelet aggregation. Other antiplatelet agents that have also been evaluated in clinical trials include ticlopidine and clopidogrel, which inhibit adenosine diphosphate-mediated platelet aggregation, but these agents are known to be effective against only one of the 90 known agonists that stimulate platelet aggregation. The final common pathway for platelet aggregation involves the glycoprotein IIb/IIIa receptor combining with fibrinogen. Several inhibitors of the glycoprotein IIb/IIIa receptor have been developed and have an important role as adjunctive therapy in angioplasty. Recent trials have been performed in patients with unstable angina, and trials of adjunctive therapy are currently underway in patients receiving thrombolysis for AMI, and for secondary prevention. These drugs have various different features, including specificity for blockade of the glycoprotein IIb/IIIa receptor, half life, duration of the haemostatic effect and potential for antigenicity. Recently concluded and ongoing trials of both intravenous and oral agents are expected to provide further support for the introduction of these agents into clinical management of patients with acute coronary syndromes.

Abciximab↗
PubMed1998

The corrected TIMI frame count. The new gold standard?

Over the last decade Thrombolysis in Myocardial Infarction (TIMI) flow grades have been the gold standard for the assessment of efficacy of infarct-artery reperfusion. However, with the introduction of core angiographic laboratories, the reproducibility of TIMI flow grades has been questioned. The corrected TIMI frame count (CTFC) has been developed as a more reproducible method of quantifying infarct artery blood flow after myocardial infarction (MI). We have utilised the CTFC in two studies to examine infarct-artery blood flow. In the Hirulog in Early Reperfusion and Occlusion (HERO 1) study, the CTFC was measured at 90-120 minutes after administration of aspirin, streptokinase and either Hirulog or heparin. Only 27% of patients had a normal CTFC (< or = 27) in the infarct-related artery. Patients with a prolonged CTFC (> 27) had more abnormal left ventricular function (LVF) as measured by the mean chord score in the 'area at risk' (-2.51 vs -2.06, p = 0.02), on left ventriculography. In a second study, infarct-artery flow was examined four weeks and one year after MI. At four weeks, only 43% of patients with patient infarct-related arteries had a 'normal' CTFC of < or = 27. A prolonged CTFC at four weeks was a univariate predictor of increased reocclusion at one year (p = 0.001). CTFCs are frequently abnormal in patent infarct-related arteries, and predict reocclusion. Whether frame counting is a better predictor of late clinical outcomes than the TIMI flow grade needs to be prospectively examined in large clinical trials.

Blood Flow Velocity↗
PubMed1998

Thrombolysis-related intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis. METHODS: CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing. RESULTS: Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to 13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002). CONCLUSIONS: Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.

Cerebral Hemorrhage↗
PubMed1998

Ongoing clinical trials of anti-platelet agents in the management of acute ischaemic coronary syndromes.

Acute ischaemic coronary syndromes, the clinical sequelae of thrombosis over a fissured atherosclerotic plaque within the coronary circulation, are the leading cause of death and hospitalisation in Western countries. Platelets are fundamental for the initiation and continuation of thrombosis, and currently available anti-platelet agents such as aspirin significantly improve the clinical outcome of patients with these syndromes. Therapeutic success with available therapy is however not universal, and adverse clinical event rates remain high. Several new classes of agents with a variety of anti-platelet actions are currently under development. Those which inhibit the final common pathway of platelet aggregation, the glycoprotein (GP) IIb/IIIa receptor, appear to show the most promise. Much clinical trial evidence already exists supporting the use of GP IIb/IIIa receptor antagonists in the management of acute ischaemic coronary syndromes. Several clinical studies are underway to further refine this knowledge base, and to assess their efficacy in a variety of novel applications.

Journal Article↗
PubMed1998

The mucosal immune system in the human female reproductive tract: potential insights into the heterosexual transmission of HIV.

Using isolated cell suspensions and in situ techniques, we have partially characterized the organization, functional capacity, and sex hormone regulation of the mucosal immune system in the human female reproductive tract. Isolated cells suspensions have been used to demonstrate that the uterus contains antigen-presenting cells that are functionally able to present antigen to autologous tetanus toxoid-specific T cells. Immunophenotypic analyses of the female reproductive tract by three-color immunofluorescent staining has been used to show that lymphoid aggregates, which are absent in postmenopausal women, develop in the uterine endometrium during the menstrual cycle in premenopausal women. Lymphoid aggregates are composed of a B lymphocyte core surrounded by numerous CD8+CD4- T lymphocytes and an outer halo of macrophages. Macrophages, CD4+ and CD8+ T cells, and CD56+ NK cells are distributed throughout the uterine endometrium. In contrast, the Fallopian tube, cervix, and vagina, which lack lymphoid aggregates, contain CD8+ and CD4+ T cells as well as macrophages. The female reproductive tract has also been analyzed for the presence of antigen-independent CD3+ T lymphocyte cytolytic function by an anti-CD3 MAb-mediated redirected lysis assay. High levels of CD3+ T lymphocyte cytolytic activity were demonstrated in cervix and vagina and independent of stage of the menstrual cycle. In the uterus, cytolytic activity changed with endocrine state. In postmenopausal women the uterine endometrium had CD3+ T lymphocytes with high cytolytic activity, whereas premenopausal women had CD3+ T lymphocytes with moderate cytolytic potential during the proliferative phase to low/no cytolytic activity during the secretory phase of the menstrual cycle. In studies to determine whether the upper reproductive tract could be infected with HIV-1, we found on the basis of nef expression and p24 release that epithelial cells from the Fallopian tube, and from the uterus and cervix, are infectable. These studies demonstrate that the human female reproductive tract is an inductive site for immune responses and the cell-mediated immunity is present throughout the female reproductive tract. These studies further indicate that the Fallopian tube and uterus are potential entry sites for HIV-1 infection and that uterine immune cell architecture as well as cytolytic activity are under hormonal control.

Antigen Presentation↗
PubMed1998

The roles for coronary surgery and angioplasty in the management of patients with stable angina: evidence and decision making.

Evidence from the randomized studies of coronary surgery suggests that patients who benefit from surgery in terms of improved survival are those with left main stem stenosis, triple vessel coronary artery disease, impaired left ventricular function or higher angina class. Patients currently undergoing surgery are in general older, with more severe angina, more comorbidity and more extensive coronary disease as compared with the population randomized in the earlier studies. Angioplasty has been shown to improve symptoms and to reduce the need for surgery in certain patients. Recent changes in procedural techniques and adjunctive therapies have reduced the number of acute complications and the rate of restenosis. However, recent evidence suggests that some patients with mild angina (< class 2) or good exercise tolerance may not benefit as much from angioplasty as other patients with more severe angina.

Angina Pectoris↗
PubMed1997

Flexibility within myosin heads revealed by negative stain and single-particle analysis.

Electron microscopy of negatively stained myosin has previously revealed three discrete regions within the heads of the molecule. However, despite a probable resolution of approximately 2 nm, it is difficult to discern directly consistent details within these regions. This is due to variability in both head conformation and in staining. In this study, we applied single-particle image processing and classified heads into homogeneous groups. The improved signal-to-noise ratio after averaging these groups reveals substantially improved detail. The image averages were compared to a model simulating negative staining of the atomic structure of subfragment-1 (S1). This shows that the three head regions correspond to the motor domain and the essential and regulatory light chains. The image averages were very similar to particular views of the S1 model. They also revealed considerable flexibility between the motor and regulatory domains, despite the molecules having been prepared in the absence of nucleotide. This flexibility probably results from rotation of the regulatory domain about the motor domain, where the relative movement of the regulatory light chain is up to 12 nm, and is most clearly illustrated in animated sequences (available at http://www.leeds.ac.uk/chb/muscle/myosinhead.htm l). The sharply curved conformation of the atomic model of S1 is seen only rarely in our data, with straighter heads being more typical.

Animals↗
PubMed1997

Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators.

BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.

Analysis of Variance↗
PubMed1997

Kinetics of nucleoside triphosphate cleavage and phosphate release steps by associated rabbit skeletal actomyosin, measured using a novel fluorescent probe for phosphate.

We have measured the kinetics of inorganic phosphate (Pi) release during a single turnover of actomyosin nucleoside triphosphate (NTP) hydrolysis using a double-mixing stopped-flow spectrofluorometer, at very low ionic strength to increase the affinity of myosin-ATP and myosin-ADP-Pi to actin. Myosin subfragment 1 and a series of nucleoside triphosphates were mixed and incubated for approximately 1-10 s to allow NTP to bind to myosin and generate a steady state mixture of myosin-NTP and myosin-NDP-Pi. The steady state intermediates were then mixed with actin. The kinetics of Pi release were measured using a fluorescent probe for Pi, based on a phosphate binding protein [Brune et al. (1994) Biochemistry 33, 8262-8271]. These data are correlated with quenched-flow data, where the extent of the rapid burst of hydrolysis during the first turnover of ATP hydrolysis was followed by chemical quenching of the reaction mix at various times after rapidly mixing ATP and myosin subfragment 1. From the double-mixing actomyosin measurements, the kinetics of Pi release are biphasic. The fast phase corresponds to Pi release from the associated actomyosin-ADP-Pi complex. The slow phase measures the rate of the cleavage step on associated actomyosin. At saturating actin, there is a correlation between the amplitude of the fast phase and the size of the Pi burst observed by quenched flow in the absence of actin: the size of this phase corresponds to the amount of myosin-ADP-Pi formed during the first mix. For ATP at 20 degrees C the rate of the Pi release step is 75 (+/-5) s-1, 25-fold larger than the cleavage step, which is the rate-limiting step of actomyosin ATP hydrolysis at saturating actin. The rate constant of Pi release varies only slightly with nucleoside structure. The rate constant of the slow phase of the Pi release (measuring cleavage) is highly dependent upon the structure of the NTP substrate.

Actomyosin↗
PubMed1997

Unmet therapeutic needs in the management of acute ischemia.

Unstable angina and myocardial infarction (MI) continue to present a major challenge in clinical management. These acute ischemic coronary syndromes (AICS) are a spectrum of clinical presentations of the same pathophysiologic mechanism: thrombus formation superimposed on atherosclerotic plaque disruption or erosion. Current approaches to the management of AICS, which include both interventional and pharmacologic therapy, have been introduced to clinical practice during the past 20 years, and most of them have demonstrated efficacy in clinical studies. A common inadequacy of current therapies, however, is the lack of significant inhibition of platelet aggregation--the crucial event in the formation of coronary thrombi and the pathogenesis of AICS. The final common pathway to platelet aggregation is the activation of the platelet glycoprotein (GP) IIb-IIIa receptor, which allows the cross-linking of adjacent platelets by the adhesive plasma proteins fibrinogen and von Willebrand's factor. The emergence of the GP IIb-IIIa receptor as a potential treatment target has led to the development of several inhibitors of its function. The inhibitors most advanced in clinical development are the chimeric monoclonal antibody abciximab (ReoPro) and the cyclic peptide eptifibatide (INTEGRILIN). In phase III clinical trials, both abciximab and eptifibatide have been shown to reduce the incidence of cardiac events in patients at risk for abrupt vessel closure after coronary angioplasty. Inhibition of the GP IIb-IIIa receptor is the most promising novel approach to the treatment of unstable angina and MI, and it may soon be an indispensable component of the management of patients with AICS.

Angina, Unstable↗
PubMed1997

End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators.

BACKGROUND: Left ventricular remodeling is an important sequela of myocardial infarction (MI). Although remodeling occurs soon after MI, the effect of early left ventricular dilatation on outcome is not established and may be useful for early risk stratification. We assessed whether end-systolic volume index (ESVI) at 90 to 180 minutes into thrombolytic therapy for MI is associated with adverse outcomes. METHODS AND RESULTS: In the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I study, 41021 patients with evolving MI received one of four thrombolytic regimens. At 90 or 180 minutes into reperfusion therapy, 1300 patients underwent left ventriculography. ESVI was measured and correlated with adverse outcomes: 30-day and 1-year mortality and in-hospital congestive heart failure, shock, and reinfarction. Clinical variables were also tested in a stepwise logistic regression analysis to determine predictors of left ventricular dilatation. ESVI was directly related to all adverse outcomes with univariate analysis. ESVI of > or = 40 mL/m2 was independently associated with mortality (adjusted odds ratio [95% confidence interval]: 30-day, 3.4 [2.0 to 5.9]; 1-year, 4:1 [2.6 to 6.2], both P < .001). Male sex, prior angina or MI, weight of < 70 kg, heart rate of > or = 80 bpm, systolic blood pressure of < 110 mm.Hg, and anterior infarction were independent predictors of an ESVI of > or = 40 mL/m2. CONCLUSIONS: Left ventricular ESVI early into reperfusion therapy for MI strongly predicts adverse outcomes, including early and late mortality. The study establishes the role of very early left ventricular dilatation on outcome in MI and may be useful in identifying high-risk patients who might benefit from aggressive treatment, including the early use of ACE inhibitors.

Aged↗
PubMed1997

CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause.

The human female reproductive tract (RT) has been analyzed by others with respect to NK cell cytolytic activity, but not CD3+ T cell (CTL) cytolytic activity. Here, we describe the cytolytic capacity of mucosal CD3+ T cells both longitudinally within the RT (Fallopian tube, uterine endometrium, endocervix, ectocervix, and vaginal mucosa) and temporally throughout the menstrual cycle, using a redirected lysis assay system. Cytolysis by CD3+ CD8+ T cells is found throughout the RT and appears to be hormonally regulated, since in the uterine endometrium, the capacity for CD3+ T cell cytolytic activity is present during the proliferative phase of the menstrual cycle and absent during the subsequent secretory (postovulatory) phase. In contrast, in postmenopausal women the entire RT, including the uterus, retains the capacity for strong CD3+ T cell cytolytic activity. These findings suggest that the high levels of estradiol and progesterone present during days 14 to 28 of the menstrual cycle down-regulate CTL activity in the uterus. As a consequence, the absence of this activity may allow implantation of a semiallogeneic embryo that would otherwise be rejected. Further, these studies indicate that CTL activity is regulated differentially in different regions of the RT, persisting in the cervix and vagina throughout the menstrual cycle.

Adult↗