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Biomedical subjects

P Bedard

Publications and source records attributed to P Bedard.

At least 19 recordsLinked to original sources
PubMed2003

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Adenosine A2 Receptor Antagonists↗
PubMed2003

Quality of life and understanding of disease status among cancer patients of different ethnic origin.

Patients managed in European or North American cancer centres have a variety of ethnic backgrounds and primary languages. To gain insight into the impact of ethnic origin, we have investigated understanding of disease status and quality of life (QoL) for 202 patients. Patients completed questionnaires in their first language (52 English, 50 Chinese, 50 Italian, 50 Spanish or Portuguese), including the Functional Assessment of Cancer Therapy - General (FACT-G) QoL instrument, questions about disease status, expectations of cure and the language and/or type of interpretation used at initial consultation. Physicians also evaluated their status of disease and expectation of cure, and performance status was estimated by a trained health professional. The initial consultation was usually provided in English (except for 32% of Chinese-speaking patients); interpretation was provided by a family member for 34% of patients with limited English proficiency (LEP) and by a bilingual member of staff for 21%. Patients underestimated their extent of disease and overestimated their probability of cure (P=0.001 and <0.0001, respectively). Estimates of probability of cure by the English speakers were closer to those of their physicians than the other groups (P=0.02). English-speaking patients reported better and Italian-speaking patients poorer overall QoL (P<0.001 for Italian vs other groups). Performance status was correlated with QoL and most closely related with the extent of disease. Understanding of cultural differences is important for optimal management of patients with cancer.

Activities of Daily Living↗
PubMed2001

Resection of right atrial tumor thrombi without circulatory arrest.

Resectable retroperitoneal tumors with right atrial tumor thrombus extension have been excised previously using cardiopulmonary bypass and deep hypothermic circulatory arrest. We have used a technique involving clamping of the descending aorta with avoidance of deep hypothermic circulatory arrest in 6 patients. The approach provided a virtually bloodless field and allowed complete resection to be performed with low morbidity.

Aged↗
PubMed1999

Aortic dissection: a rare complication of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder, a group that includes Ehlers-Danlos syndrome, Marfan's syndrome and pseudoxanthoma elasticum. OI is a heterogeneous disease of collagen I biosynthesis characterized by variable clinical phenotypes, including skeletal and cardiovascular manifestations. A 65-year-old man with OI who had extensive prior successful cardiac valve surgeries is described. He survived for 18 years after his initial valve surgery, but died of multiorgan failure and sepsis after repair of a spontaneous type A aortic dissection. This is the fourth reported case of aortic dissection secondary to OI and illustrates the extensive cardiovascular pathology associated with OI. Aggressive management of arterial dissection risk factors, such as systemic arterial hypertension, is advocated for patients with OI.

Aged↗
PubMed1998

Compression of anomalous circumflex coronary artery by a prosthetic valve ring.

Anomalous origin of the circumflex coronary artery from the right aortic sinus, with a retroaortic course, is usually without consequence. We report a patient who underwent aortic valve replacement for bicuspid aortic valve. The prosthesis sewing ring distorted the circumflex, producing myocardial infarcts and sudden death during exercise.

Adult↗
PubMed1997

Resonance Raman spectroscopy of soybean peroxidase.

Resonance Raman spectra (600-1700 cm-1) for the heme enzyme soybean peroxidase (Rz = 2.5) were obtained using Soret band excitation at 406.7 nm. The vibrational frequencies and depolarization data indicate a strong similarity between the active sites of soybean and horseradish peroxidase. This similarity suggests that the active site in the resting form of soybean peroxidase contains a ferric iron, is a high-spin 5-coordinate heme binding His as a fifth axial ligand.

Binding Sites↗
PubMed1995

The D-1 dopamine receptor: past, present and future an idiosyncratic review.

1. Key events in the experimental investigation of the D-1 dopamine receptor are reviewed. 2. The efficacy of D-1 receptor agonists in the treatment of experimental parkinsonism in MPTP-treated primates is demonstrated. The diminished dyskinetic liability of D-1 agonists is discussed. 3. The significance of the dopa-induced dyskinesias is discussed from the perspective of deterministic chaos. The unpredictibility and irreproducibility of dyskinetic movements is highlighted and compared with features of the logistic equation. 4. The authors propose that the dopa-induced dyskinesias should be considered to be a manifestation of a chaotic process within the basal ganglia. The loss of the dopaminergic innervation and the subsequent repeated exposure to dopamine (derived from the exogenous dopa administered to the subjects) alters the response properties of the basal ganglia circuitry so that stimulation of dopamine receptors now elicits the dyskinetic movements.

Animals↗
PubMed1994

Cicatricial changes in a Ionescu-Shiley bioprosthesis.

The mitral Ionescu-Shiley standard-profile prosthesis of a 53-year-old woman who had it placed 12 years previously is described. The observed cicatricial retraction of one of the bioprosthesis' cusps is unusual, and it contributed to the bioprosthetic dysfunction which necessitated this valve's replacement.

Aortic Valve↗
PubMed1991

Inhibitory and stimulatory effects of fluoride on the calcium pump of cardiac sarcoplasmic reticulum.

While studying the effects of membrane phosphorylation on active Ca2+ transport in cardiac sarcoplasmic reticulum (SR) we used NaF (a conventional phosphatase inhibitor) in the Ca2+ transport assay medium to suppress protein dephosphorylation by endogenous phosphatases. Unexpectedly, depending on the experimental conditions employed, NaF was found to cause a strong inhibitory or stimulatory effect on ATP-dependent, oxalate-facilitated Ca2+ uptake (Ca2+ pump) activity of SR. Investigation of this phenomenon using canine cardiac SR revealed the following. Exposure of SR to NaF in the absence of Ca2+ or ATP in the Ca2+ transport assay medium (prior to initiating Ca2+ transport by the addition of Ca2+ or ATP) promoted a striking concentration-dependent inhibitory effect of NaF (50% and 90% inhibition with approx. 4 and 10 mM NaF, respectively) on Ca2+ uptake by SR; the magnitude of inhibition did not differ appreciably with varying oxalate concentrations. In contrast, exposure of SR to NaF in the presence of both Ca2+ and ATP resulted in a concentration-dependent stimulatory effect of NaF (half-maximal stimulation at approx. 2.5 mM NaF with 2.5 mM oxalate in assay) on Ca2+ uptake; the magnitude of stimulation decreased with increasing oxalate concentration (greater than 2-fold at 1 mM oxalate, 10% at 5 mM oxalate). The inhibitory effect prevailed when SR was exposed to NaF in the presence of Ca2+ alone (without ATP) or ATP alone (without Ca2+). Both the inhibitory and stimulatory effects of NaF were specific to fluoride ion, as NaCl (1-10 mM) showed no effect on Ca2+ uptake by SR under identical assay conditions. A persistently less active state of the Ca2+ pump (evidenced by decreased Ca2+ transport rates) resulted upon pretreatment of SR with NaF in the absence of Ca2+ or ATP; presence of Ca2+ and ATP during pretreatment prevented this transition. The inhibitory action of NaF on the Ca2+ pump was accompanied by a two-fold increase in K0.5 for Ca2+ and decrements in Hill coefficient (nH) and Ca(2+)-stimulated ATP hydrolysis, as well as steady-state level of Ca(2+)-induced phosphoenzyme. The stimulatory effect of NaF, on the other hand, was associated with an increase in the ratio of Ca2+ transported/ATP hydrolysed with only minor changes, if any, in the above parameters. These findings imply that the divergent effects of fluoride are dependent on specific conformational states of the Ca(2+)-ATPase which evolve during the catalytic and ion transport cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1991

Comparison of accuracy of transesophageal versus transthoracic echocardiography for the detection of mitral valve prolapse with ruptured chordae tendineae (flail mitral leaflet).

The accuracy of transesophageal echocardiography was compared with that of transthoracic echocardiography in the detection of ruptured chordae tendineae (flail mitral leaflet) in 27 patients with mitral valve prolapse (MVP) who underwent valve repair or replacement for mitral regurgitation. Confirmation of the presence of ruptured chordae resulting in a flail leaflet was available at surgery in all cases. The echocardiographic studies were read blindly by 2 independent observers with any differences resolved by a third. Mean (+/- standard deviation) age was 63 +/- 13 years. Men (n = 20) outnumbered women (n = 7) (p less than 0.02), and tended to be younger (p = 0.06). Flail leaflets were identified in 20 of 27 patients. In 1 patient, both leaflets were involved and in the remaining 19 patients posterior leaflets (15 patients) were more frequently affected than anterior leaflets (4 patients). Transesophageal echocardiography correctly identified all 20 patients with flail leaflets, but 1 false positive study occurred among the 7 patients without a flail leaflet. In contrast, transthoracic echocardiography identified only 12 of 20 patients with flail leaflets, with no false positive studies. Transesophageal echocardiography was more accurate, correctly classifying 26 of 27 (96%) cases versus 19 of 27 (70%) by the transthoracic approach (p less than 0.01). This study suggests a higher incidence of chordal rupture to the posterior leaflet in patients with MVP and demonstrates improved accuracy of transesophageal over transthoracic echocardiography in the detection of flail leaflets.

Aged↗
PubMed1990

Severe mitral insufficiency post-balloon valvuloplasty: the late changes found in a disrupted mitral valve.

The case of a 45-yr-old woman who had balloon valvuloplasty for rheumatic mitral stenosis is presented. An anterior mitral leaflet tear occurred as a complication of the procedure. Both partial healing of the anterior mitral leaflet and gradual dilatation of the left atrium occurred which allowed the damaged valve to remain in situ for several months. Some of the late changes which occur after such a complicated valvuloplasty are illustrated here, as this patient eventually required surgery and valve excision for definitive repair.

Catheterization↗
PubMed1990

[Anatomo-physiologic substratum of akinesia in primates].

Severe akinesia can be observed in macaques following MPTP injections destroying dopaminergic nigrostriatal neurons. Akinesia also results from inhalation of toxic substances inducing bilateral lesions of the two pallidal nuclei and of the pars reticulata of the substantia nigra, and not of the pars compacta. Most of the recent studies of the anatomo-physiological substratum of akinesia used MPTP injections. Deoxyglucose studies have shown a clear increase in the neuronal activity of the medial nucleus of the pallidum and of its thalamic projection territory. Electrophysiological studies have shown a major modification of the spontaneous activity of medial pallidal neurons which is influenced in an excessive and non selective manner by sensorimotor inputs. Analysis of the relative three dimensional geometry of nervous arborizations have shown that the striato-pallido-nigral system is extremely convergent. Akinesia consecutive to nigrostriate lesions could be linked to an excessive and anarchic activation of this system. The contradiction which exists between akinesia with an abnormal activity of the medial pallidum and akinesia with bilateral pallidal lesions could only be apparent if akinesia was linked to the ineffective emission or to the interruption of messages to the thalamus.

Animals↗
PubMed1989

Regulation of the ATP-dependent calcium uptake activity of heart sarcolemmal vesicles by endogenous cytosolic proteins.

In a previous study we described the inhibitory action of a cytosolic protein fraction from heart muscle on ATP-dependent Ca2+ uptake by sarcoplasmic reticulum; further, this inhibition was shown to be blocked by an inhibitor antagonist, also derived from the cytosol (Narayanan et al. Biochim Biophys Acta 735: 53-66, 1983). The present study examined the effects of the endogenous cytosolic Ca2+ transport inhibitor and its antagonist on ATP-dependent Ca2+ uptake by sarcolemmal vesicles isolated from rat and canine heart. The cytosolic inhibitor caused strong inhibition (up to 97%) of Ca2+ uptake by sarcolemma (SL); this inhibition could be reversed by the cytosolic inhibitor antagonist. Studies on the characteristics of inhibition revealed the following: a) Inhibition was dependent on the concentration of the inhibitor (50% inhibition with approximately 80 micrograms inhibitor protein). b) The inhibitor reduced the velocity of Ca2+ uptake without appreciably influencing the apparent affinity of the transport system for Ca2+ but caused greater than 2-fold decrease in its apparent affinity for ATP. c) The rates of unidirectional passive Ca2+ release from actively Ca2+ loaded SL vesicles were not altered by low concentrations of the inhibitor (less than 100 micrograms/ml) which were effective in producing marked inhibition of Ca2+ uptake; at higher concentrations (greater than 100 micrograms/ml), the inhibitor caused increase in the rates of passive Ca2+ release. These findings demonstrate that the activity of the ATP-driven Ca2+ pump of cardiac SL can be regulated in vitro by endogenous cytosolic proteins.

Animals↗
PubMed1989

Effects of endogenous calcium transport inhibitor from heart muscle on the active calcium uptake and passive calcium release properties of sarcoplasmic reticulum.

In the present study, the effects of the cytosolic Ca2+ transport inhibitor on ATP-dependent Ca2+ uptake by, and unidirectional passive Ca2+ release from, sarcoplasmic reticulum enriched membrane vesicles were examined in parallel experiments to determine whether inhibitor-mediated enhancement in Ca2+ efflux contributes to inhibition of net Ca2+ uptake. When assays were performed at pH 6.8 in the presence of oxalate, low concentrations (less than 100 micrograms/mL) of the inhibitor caused substantial inhibition of Ca2+ uptake by SR (28-50%). At this pH, low concentrations of the inhibitor did not cause enhancement of passive Ca2+ release from actively Ca2+-loaded sarcoplasmic reticulum. Under these conditions, high concentrations (greater than 100 micrograms/mL) of the inhibitor caused stimulation of passive Ca2+ release but to a much lesser extent when compared with the extent of inhibition of active Ca2+ uptake (i.e., twofold greater inhibition of Ca2+ uptake than stimulation of Ca2+ release). When Ca2+ uptake and release assays were carried out at pH 7.4, the Ca2+ release promoting action of the inhibitor became more pronounced, such that the magnitude of enhancement in Ca2+ release at varying concentrations of the inhibitor (20-200 micrograms/mL) was not markedly different from the magnitude of inhibition of Ca2+ uptake. In the absence of oxalate in the assay medium, inhibition of Ca2+ uptake was observed at alkaline but not acidic pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗