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Biomedical subjects

B J Meyer

Publications and source records attributed to B J Meyer.

At least 19 recordsLinked to original sources
PubMed1995

[Unstable angina pectoris: coagulation disorder and its therapy].

The initiating event in unstable angina is plaque rupture. It triggers platelet activation and aggregation, leading to the formation of an intracoronary thrombus, which can be detected on autopsy, angiography, and by fiber-optic coronary angioscopy. Biochemical markers of platelet and thrombin activity are usually increased and support the pathophysiologic role of coronary thrombosis in unstable angina. Aspirin and heparin have been shown to be effective, whereas thrombolytic therapy has no beneficial clinical effect. Newer specific antithrombotic drugs (hirudin, hirulog) and GPIIb/IIIa platelet receptor inhibitors are being tested in clinical trials and seem to provide a new dimension for the treatment of acute coronary syndromes.

Angina, Unstable↗
PubMed1995

xol-1 acts as an early switch in the C. elegans male/hermaphrodite decision.

xol-1 is the earliest-acting gene in the known hierarchy that controls C. elegans sex determination and dosage compensation. We show that the primary sex-determining signal (the X/A ratio) directs the choice of sexual fate by regulating xol-1 transcript levels: high xol-1 expression during gastrulation triggers male development, whereas low expression at that time permits hermaphrodite development. Inappropriately high xol-1 expression causes hermaphrodites to activate the male program of development and die from a disruption in dosage compensation. These results demonstrate that xol-1 functions as an early developmental switch to set the choice of sexual fate and suggest that assessment of the X/A ratio occurs only early in embryogenesis to determine sex. Moreover, sdc-2, a gene that must be repressed by xol-1 to ensure male development, may be a direct target of negative regulation by xol-1.

Alternative Splicing↗
PubMed1995

Discourse comprehension and problem solving: decisions about the treatment of breast cancer by women across the life span.

The 1st study examined the decision making and prose comprehension of 94 women interacting with an authentic, unfolding health scenario about breast cancer. The 2nd study involved questionnaire data focusing on the decisions made by 75 women who had been diagnosed with breast cancer. Two major findings emerged from this laboratory and survey research. First, older women sought less information when making treatment decisions about breast cancer. However, the outcome of those decisions were equivalent to those of younger women. Second, older women made these decisions faster than younger women. In addition, treatment decisions were related to prose processing, the type of information underlined as important while reading as well as the type of information remembered about various treatment options.

Adolescent↗
PubMed1995

Atherectomy (directional, rotational, extractional) and its role in percutaneous revascularization.

After an initial wave of enthusiasm, atherectomy devices face a number of difficult issues today. The first two randomized studies comparing balloon angioplasty with directional atherectomy, the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) and the Canadian Coronary Atherectomy Trial (CCAT), showed no clinical benefit for atherectomy. Data from these trials, as well as other studies, suggest that the mechanism of lumen enlargement with atherectomy may be less beneficial than expected. A number of investigations are currently evaluating the benefit of even more aggressive debulking with directional coronary atherectomy, but in view of the increased incidence of acute complications, it is unlikely that this technique will increase its share in routine coronary angioplasty in the near future. Clinical evaluation of rotational and extractional atherectomy has not reached a conclusive phase yet, but results from registries and single-center observations show that these devices require adjunctive balloon angioplasty in a large proportion of cases, on the one hand, and that they do not solve the issue of restenosis, on the other. The difficulty in delineating the rationale for use of these devices highlights the urgent need for controlled and carefully designed device trials.

Angioplasty, Balloon, Coronary↗
PubMed1995

DPY-30, a nuclear protein essential early in embryogenesis for Caenorhabditis elegans dosage compensation.

DPY-30 is an essential component of the C. elegans dosage compensation machinery that reduces X chromosome transcript levels in hermaphrodites (XX). DPY-30 is required for the sex-specific association of DPY-27 (a chromosome condensation protein homolog) with the hermaphrodite X chromosomes. Loss of dpy-30 activity results in XX-specific lethality. We demonstrate that dpy-30 encodes a novel nuclear protein of 123 amino acids that is present in both hermaphrodites and males (XO) throughout development. DPY-30 itself is not associated with the X chromosomes, nor is its pattern of expression perturbed by mutations in the gene hierarchy that controls dosage compensation. Therefore, DPY-30 is a ubiquitous factor that is likely to promote the hermaphrodite-specific association of DPY-27 with X by affecting the activity of a sex-specific dosage compensation gene. In XO animals, DPY-30 is required for developmental processes other than dosage compensation: coordinated movement, normal body size, correct tail morphology and mating behavior. We demonstrate that rescue of both the XX-specific lethality and the XO-specific morphological defects caused by dpy-30 mutations can be achieved by inducing dpy-30 transcripts either in the mother or in the embryo through the end of gastrulation. dpy-30 appears to be cotranscribed in an operon with a novel RNA-binding protein.

Animals↗
PubMed1994

DPY-27:a chromosome condensation protein homolog that regulates C. elegans dosage compensation through association with the X chromosome.

dpy-27 is an essential dosage compensation gene that acts to reduce expression of both hermaphrodite X chromosomes. The DPY-27 protein becomes specifically localized to the X chromosomes of wild-type XX embryos, but remains diffusely distributed throughout the nuclei of male (XO) embryos. In xol-1 mutant XO embryos that activate the XX mode of dosage compensation and die from inappropriately low X chromosome transcript levels, DPY-27 becomes localized to X. Therefore, sex specificity of the dosage compensation process is regulated at the step of DPY-27 X chromosome localization. DPY-27 exhibits striking similarity to proteins required for assembly and structural maintenance of Xenopus chromosomes in vitro and for segregation of yeast chromosomes in vivo. These findings suggest a link between global regulation of gene expression and higher order chromosome structure. We propose that DPY-27 implements dosage compensation by condensing the chromatin structure of X in a manner that causes general reduction of X chromosome expression.

Amino Acid Sequence↗
PubMed1994

The dpy-30 gene encodes an essential component of the Caenorhabditis elegans dosage compensation machinery.

The need to regulate X chromosome expression in Caenorhabditis elegans arises as a consequence of the primary sex-determining signal, the X/A ratio (the ratio of X chromosomes to sets of autosomes), which directs 1X@A animals to develop as males and 2X/2A animals to develop as hermaphrodites. C. elegans possesses a dosage compensation mechanism that equalizes X chromosome expression between the two sexes despite their disparity in X chromosome dosage. Previous genetic analysis led to the identification of four autosomal genes, dpy-21, dpy-26, dpy-27 and dpy-28, whose products are essential in XX animals for proper dosage compensation, but not for sex determination. We report the identification and characterization of dpy-30, an essential component of the dosage compensation machinery. Putative null mutations in dpy-30 disrupt dosage compensation and cause a severe maternal-effect, XX-specific lethality. Rare survivors of the dpy-30 lethality are dumpy and express their X-linked genes at higher than wild-type levels. These dpy-30 mutant phenotypes superficially resemble those caused by mutations in dpy-26, dpy-27 and dpy-28; however, detailed phenotypic analysis reveals important differences that distinguish dpy-30 from these genes. In contrast to the XX-specific lethality caused by mutations in the other dpy genes, the XX-specific lethality caused by dpy-30 mutations is completely penetrant and temperature sensitive. In addition, unlike the other genes, dpy-30 is required for the normal development of XO animals. Although dpy-30 mutations do not significantly affect the viability of XO animals, they do cause them to be developmentally delayed and to possess numerous morphological and behavioral abnormalities. Finally, dpy-30 mutations can dramatically influence the choice of sexual fate in animals with an ambiguous sexual identity, despite having no apparent effect on the sexual phenotype of otherwise wild-type animals. Paradoxically, depending on the genetic background, dpy-30 mutations cause either masculinization or feminization, thus revealing the complex regulatory relationship between the sex determination and dosage compensation processes. The novel phenotypes caused by dpy-30 mutations suggest that in addition to acting in the dosage compensation process, dpy-30 may play a more general role in the development of both XX and XO animals.

Animals↗
PubMed1994

Identification of X chromosome regions in Caenorhabditis elegans that contain sex-determination signal elements.

The primary sex-determination signal of Caenorhabditis elegans is the ratio of X chromosomes to sets of autosomes (X/A ratio). This signal coordinately controls both sex determination and X chromosome dosage compensation. To delineate regions of X that contain counted signal elements, we examined the effect on the X/A ratio of changing the dose of specific regions of X, using duplications in XO animals and deficiencies in XX animals. Based on the mutant phenotypes of genes that are controlled by the signal, we expected that increases (in males) or decreases (in hermaphrodites) in the dose of X chromosome elements could cause sex-specific lethality. We isolated duplications and deficiencies of specific X chromosome regions, using strategies that would permit their recovery regardless of whether they affect the signal. We identified a dose-sensitive region at the left end of X that contains X chromosome signal elements. XX hermaphrodites with only one dose of this region have sex determination and dosage compensation defects, and XO males with two doses are more severely affected and die. The hermaphrodite defects are suppressed by a downstream mutation that forces all animals into the XX mode of sex determination and dosage compensation. The male lethality is suppressed by mutations that force all animals into the XO mode of both processes. We were able to subdivide this region into three smaller regions, each of which contains at least one signal element. We propose that the X chromosome component of the sex-determination signal is the dose of a relatively small number of genes.

Animals↗
PubMed1994

Sequence heterogeneity in the termini of lymphocytic choriomeningitis virus genomic and antigenomic RNAs.

Sequence analysis of lymphocytic choriomeningitis virus L and S RNAs has revealed evidence of heterogeneity within the termini of the genomic and antigenomic RNAs. The RNAs are missing from 0 to 38 bases, show characteristic patterns of deleted nucleotides at both 5' and 3' termini, and often have a nontemplated base at the terminus. The same deletions, at either the 5' or the 3' terminus of the genomic L and S RNAs, are frequently found in the complementary strand of antigenomic RNA, suggesting that RNAs with deleted termini may be recognized as functional templates for replication. RNAs extracted from virions, or viral nucleocapsids isolated from acutely infected cells, are similar in the nature and extent of terminal heterogeneity that have been observed. This finding brings into question the function of the conserved sequences located at the termini of arenavirus genomic RNAs. Our data suggest that, while replication and packaging of the genomic and antigenomic RNA molecules can occur with terminally deleted molecules, mature transcripts may be derived only from full-length templates containing the conserved terminal sequence.

Animals↗
PubMed1994

A new approach for local intravascular drug delivery. Iontophoretic balloon.

BACKGROUND: Catheter-based systems are being developed to deliver drugs directly into the vessel wall. Pressure-mediated trauma and lack of homogeneous delivery are key limitations of these approaches. METHODS AND RESULTS: We studied a new catheter-based delivery system that uses electrical current to force the drug into the vessel wall. The in vivo feasibility of this approach has been assessed by delivering 125I-hirudin into porcine carotid arteries. Vascular levels of hirudin after active iontophoresis (4 mA/cm2, 5 minutes) were 80-fold greater than those achieved by passive diffusion (without electricity). Tissue hirudin levels declined over time; by 1 hour after delivery, 80% of the drug had left the vessel wall, and by 3 hours later, the levels of hirudin within the wall were similar to those achieved by passive diffusion. Autoradiography revealed distribution of the drug throughout the entire circumference of the arterial wall within the intima, media, and adventitia. Iontophoresis-mediated vessel wall trauma was minimal (less than 10% endothelial denudation and medial smooth muscle cell damage). Balloon injury after local delivery changed neither kinetics nor distribution of the drug into the arterial wall. CONCLUSIONS: (1) High local concentrations of hirudin in the arterial wall may be achieved with the iontophoretic balloon catheter. (2) The drug is distributed throughout the entire vessel wall without significant damage. (3) The retention of hirudin in the arterial wall is time dependent. (4) This technique might be useful to deliver therapeutic agents before or after percutaneous vascular interventions.

Angioplasty, Balloon↗
PubMed1994

Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy.

BACKGROUND: Residual mural thrombus on severely damaged arterial wall is very thrombogenic. We tested the hypothesis that direct thrombin inhibition will block thrombus growth on fresh thrombus better than indirect thrombin inhibition, cyclooxygenase inhibition, or both. METHODS AND RESULTS: A fresh mural thrombus was formed by directly perfusing fresh porcine blood for 5 minutes over severely damaged arterial wall at a high shear rate in a well-characterized ex vivo perfusion system. The average platelet (P) and fibrinogen (F) deposition (D) achieved in 5 minutes were 382 +/- 32 x 10(6) platelets/cm2 and 296 +/- 36 x 10(12) fibrinogen molecules/cm2, respectively. Thrombus growth on the fresh mural thrombus was quantitated by directly perfusing blood from pigs with 111In-labeled platelets and 125I-labeled fibrinogen for an additional 5 minutes over the preformed mural thrombus. Treatment included recombinant hirudin (1 mg/kg per hour IV) as a probe for thrombin, aspirin (5 mg/kg IV) as a platelet inhibitor of cyclooxygenase, heparin (moderate, 100 IU/kg per hour IV; high-dose, 250 IU/kg per hour IV) as an indirect thrombin inhibitor, and heparin (100 IU/kg per hour) plus aspirin (5 mg/kg IV). Thrombus growth as measured by labeled PD (x 10(6)/cm2) and FD (x 10(12) molecules/cm2) was mildly but not significantly reduced by aspirin (1034 +/- 92 and 436 +/- 78, respectively) compared with baseline (1113 +/- 67 and 545 +/- 52, respectively). Inhibition of thrombus growth with heparin was dose dependent. A regression analysis showed an inverse correlation of PD and FD with mean plasma heparin concentrations (r = -.81, P = .0001 and r = -.49, P = .0007, respectively). Recombinant hirudin led to a profound inhibition of thrombus growth (PD, 30 +/- 12; FD, 109 +/- 21), which was significant compared with all groups, even the highest dosage of heparin (250 IU/kg per hour). CONCLUSIONS: Specific thrombin inhibition markedly inhibits platelet and fibrinogen deposition onto fresh mural thrombus at a high shear rate. Aspirin alone or in combination with heparin has little effect on evolving thrombosis. Heparin dose dependently reduces thrombus growth, but even the highest dosage is less effective than hirudin. Thrombin appears to be the primary activator of platelets by fresh thrombus.

Animals↗
PubMed1994

Local delivery of r-hirudin by a double-balloon perfusion catheter prevents mural thrombosis and minimizes platelet deposition after angioplasty.

BACKGROUND: The major morbidity of percutaneous transluminal coronary angioplasty is acute thrombosis and restenosis of the dilated lesion. Platelet-thrombus deposition occurs within minutes after injury, is primarily mediated by thrombin, causes acute occlusion, and contributes to late restenosis. Experimentally, specific thrombin inhibitors have prevented mural thrombosis. However, local therapy may be more effective than systemic treatment. We tested the hypothesis that high local concentrations of an antithrombin drug at the site of arterial injury following balloon angioplasty inhibit platelet thrombus formation equally or better than conventional systemic treatment and at lower systemic anticoagulant levels. METHODS AND RESULTS: Balloon angioplasty of the carotid arteries of 29 pigs was performed using systemic intravenous treatment with heparin (100 U/kg, groups I and II), suboptimal r-hirudin (0.3 mg/kg, group III), and higher-dose r-hirudin (0.7 mg/kg, group IV), which is the lowest dose that completely inhibited arterial thrombosis in the pig. Immediately after balloon angioplasty of the first carotid, additional local therapy with placebo (group I) or r-hirudin (groups II, III, and IV; 0.3 mg/kg in 1 mL) was administered with distal perfusion through a new percutaneous double-balloon catheter. After 1 hour of local drug delivery, angioplasty of the contralateral carotid was performed. Reflow for 1 hour was permitted to both carotids to compare the short-term effect of local plus systemic treatment with systemic treatment on quantitative 111In-labeled platelet deposition and macroscopic mural thrombus formation on deeply injured carotid segments. Local drug delivery of placebo compared with systemic heparin treatment resulted in no change of platelet deposition (x 10(6)/cm2, mean +/- SEM) in controls (group I, 91.0 +/- 23.5 versus 80.8 +/- 19.4), but local delivery of r-hirudin resulted in a significant reduction in group II (15 +/- 2.5 versus 71.3 +/- 14.5; P < .02) and group III (11.4 +/- 2.5 versus 80.5 +/- 11.4; P < .01) and was borderline in group IV (7.4 +/- 1.8 versus 14.1 +/- 7.4; P = .05), respectively. The incidence of macroscopic mural thrombus formation with local and systemic treatment was 86% and 75% in group I, 16% and 70% in group II, 14% and 71% in group III, and 0% and 16% in group IV, respectively. CONCLUSIONS: Local therapy with the specific thrombin inhibitor r-hirudin significantly reduces short-term quantitative platelet deposition and macroscopic mural thrombus formation following balloon angioplasty compared with systemic treatment of conventional doses of heparin and hirudin and requires a significantly smaller amount of the recombinant drug.

Angioplasty, Balloon, Coronary↗
PubMed1993

Conjunctive antithrombotic therapy for thrombolysis in myocardial infarction.

Disruption of an atherosclerotic plaque in coronary arteries with a minor stenosis is the usual stimulus for acute coronary thrombosis and myocardial infarction. In this article the pathogenesis of arterial thrombosis and contributions of local arterial wall substrates, the rheology of blood flow, systemic factors, and the critical role of thrombin in the formation of thrombus are discussed. More potent antithrombotic therapy may accelerate exogenous thrombolysis, allows endogenous thrombolysis, and should reduce recurrent infarction and ischemia and death, as well as need for coronary revascularization. Maximal antithrombotic therapy for acute myocardial infarction includes an intravenous bolus of heparin at 100 U/kg followed by an intravenous infusion--at 1,200 U/hr for patients weighing 60-80 kg, 1,300 U/hr for those weighing > 80 kg, and 1,000 U/hr for those weighing < 60 kg (or 17 U/kg/hr)--to maintain the activated partial thromboplastin time at 2-3 times control (60-90 sec) for at least 5-7 days. To convert intravenous to subcutaneous administration, use 14,000-17,000 U every 12 hours and initially overlap the intravenous infusion by 2 hours. The loading dose of aspirin on admission to the hospital is 160 mg followed by 80 mg/day. High-risk patients should be considered for conversion of heparin to warfarin therapy for at least 3 months at an international normalized ratio of 2.5-4.0 for the prevention of recurrent ischemia, reinfarction, death, thromboembolism, reactivation of thrombosis, and reduced necessity for revascularization.

Animals↗
PubMed1993

Hemodynamic effects and concentration-effect relationship of a graded infusion of piroximone in patients with severe heart failure.

Piroximone is a new phosphodiesterase III inhibitor that combines inotropic and vasodilator properties. To elucidate the optimal dose regimen and the dose-concentration-effect relationships, we studied eight patients with congestive heart failure of New York Heart Association class IV during a continuous multistage infusion over a 24-h period followed by a 4-h washout. After a bolus of 0.5 mg/kg, infusions at a rate of 2.5, 5.0, and 10.0 micrograms/kg/min for 8 h each were given to determine the maintenance dose of piroximone required to achieve an increase in cardiac index > or = 30%. Serial assessment of hemodynamics, plasma piroximone levels, and ventricular ectopic beats was performed. Following the loading dose and at higher infusion rates (5 and 10 micrograms/kg/min) Piroximone produced significant hemodynamic changes compared to baseline, i.e., a maximum increase in cardiac index from 2.2 +/- 0.4 to 3.6 +/- 0.8 L/min/m2 (67 +/- 21%), decreases in right atrial pressure from 14 +/- 3 to 9 +/- 3 mm Hg (40 +/- 16%), pulmonary capillary wedge pressure from 29 +/- 5 to 23 +/- 7 mm Hg (28 +/- 18%), pulmonary vascular resistance from 249 +/- 93 to 151 +/- 59 (45 +/- 19%), and systemic vascular resistance from 1,330 +/- 442 to 752 +/- 272 dyn s/cm5 (44 +/- 19%). Piroximone increased the heart rate by 10% at the highest dose and produced a decrease in mean arterial pressure by 13%. There was a slight increase in ventricular ectopy in two patients (2.2 and 3 VPBs/min) and no change in the remaining six.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Concurrent sequence analysis of 5' and 3' RNA termini by intramolecular circularization reveals 5' nontemplated bases and 3' terminal heterogeneity for lymphocytic choriomeningitis virus mRNAs.

We have used a technique of RNA circularization coupled with polymerase chain reaction amplification for simultaneous analysis of the 5' and 3' termini of subgenomic mRNAs derived from the S RNA of lymphocytic choriomeningitis virus during an acute infection of BHK cells. These mRNAs possess 1 to 7 nontemplated nucleotides of apparently random sequence at their 5' ends. The predominant mRNA species have 4 or 5 nontemplated nucleotides. The 5' termini of the mRNAs also have properties consistent with the presence of a 5' cap structure. The 3' termini of the mRNAs lack poly(A) tails, and we have shown that transcription termination occurs at heterogeneous positions within the intergenic region of the S RNA. The identification of several distinct termini in the vicinity of a putative stem-loop structure in the RNA templates suggests that transcription termination may be mediated by a structural signal rather than a precise sequence signal.

Animals↗
PubMed1992

[Epidemiology and pathophysiology of heart failure].

The role of coronary artery disease in the epidemiology of congestive heart failure is important. In the pathophysiologic process of congestive heart failure, a number of adaptive mechanisms (hypertrophy, dilatation, neurohumoral stimulation) compensate for the decreased cardiac output by the failing heart. A new understanding of the pathophysiology of heart failure has lead to the identification of important cellular alterations. In the final stage of overcompensation these adaptive mechanisms are deleterious. Associated ventricular arrhythmias indicate a high incidence of sudden cardiac death. Recent considerations of clinical relevance are taken into account in tailoring treatment for patients with congestive heart failure.

Autonomic Nervous System↗
PubMed1992

[Anti-angina effect of amiodarone in therapy-resistant angina pectoris].

In a double-blind randomized trial 63 patients on the waiting list for coronary artery bypass grafting, with stable angina NYHA III and a positive stress test on triple (nitrates, beta- and calcium entry blockers) combination therapy, were studied for an additional antianginal effect of amiodarone over a period of 2 months. In the treatment group an increase in exercise duration and a decrease of the double product and of ST-depression were noted. Thus, amiodarone is an effective antianginal agent in patients with limiting angina pectoris on conventional triple therapy.

Adrenergic beta-Antagonists↗