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Biomedical subjects

G Cohen

Publications and source records attributed to G Cohen.

At least 109 records · Page 6Linked to original sources
PubMed1998

Permanent cardiac pacing after a cardiac operation: predicting the use of permanent pacemakers.

BACKGROUND: The need for permanent cardiac pacing after cardiac operations is infrequent but associated with increased morbidity and resource utilization. We identified patient risk factors for pacemaker insertion to enable development of a predictive model. METHODS: Data were collected prospectively for 10,421 consecutive patients who had cardiac operations between January 1990 and December 1995. Two hundred fifty-five patients (2.4%) were identified as having received a permanent pacemaker during the same hospitalization. Logistic regression analysis was performed to determine the independent, multivariate predictors of permanent pacing. The predictive accuracy and precision of the logistic regression model was evaluated in the 1996 database of 2,236 consecutive patients by the calculation of Brier scores. RESULTS: Eight independent predictors of permanent pacemaker requirement were identified. The factor-adjusted odds ratios (OR) with 95% confidence interval (CI) associated with each predictor are as follows: (1) valve replacement surgery (aortic: OR 5.8, CI 3.9-8.7; mitral: OR 4.9, CI 3.1-7.8; tricuspid: OR 8.0, CI 5.5-11.9; double: OR 8.9, CI 5.5-14.6; and triple: OR 7.5, CI 2.9-19.3); (2) repeat operation: OR 2.4, CI 1.8-3.3; (3) age 75 years or older: OR 3.0, CI 2.0-4.4; (4) ablative arrhythmia operation: OR 4.2, CI 1.9-9.5; (5) mitral valve annular reconstruction: OR 2.4, CI 1.4-4.2; (6) use of cold blood cardioplegia: OR 2.0, CI 1.2-3.6; (7) preoperative renal failure: OR 1.6, CI 1.0-2.6; and (8) active endocarditis: OR 1.7, CI 0.9-3.0. A model for postoperative permanent pacemaker requirement using the eight predictors was formulated and tested (Brier score = 0.017+/-0.003; Z = 0.18). CONCLUSIONS: The proposed predictive model correlated highly with actual pacemaker use, which suggests that the requirement for pacing results from either operative trauma or increased ischemic burden. Preoperative identification of patients at increased risk of conduction disturbances may allow for earlier detection and improved treatment. Patients requiring postoperative pacing had increased morbidity and length of stay.

Age Factors↗
PubMed1998

Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyocytes from simulated ischemia.

UNLABELLED: Impaired myocardial metabolism after cardioplegic arrest results in persistent anaerobic lactate production. Insulin may protect the heart from ischemia and reperfusion by enhancing myocardial metabolic recovery. However, the stimulation of glycolysis during ischemia may be detrimental because of an accumulation of metabolic end-products. We examined the effect of insulin on quiescent human ventricular cardiomyocytes subjected to simulated cardioplegic ischemia and reperfusion. METHODS: Primary cardiomyocyte cultures were established from patients undergoing corrective repair of tetralogy of Fallot. Cells were exposed to varying concentrations of glucose and insulin during 30 minutes of stabilization in 10 mL of phosphate-buffered saline solution. Ischemia was simulated by exposing the cells to a low volume (1.5 mL) of deoxygenated phosphate-buffered saline solution for 90 minutes followed by 30 minutes of simulated reperfusion in 10 mL of normoxic phosphate-buffered saline solution. Cell viability was assessed by trypan blue exclusion. The activity of mitochondrial pyruvate dehydrogenase was measured in 3 states: stabilization, ischemia, and reperfusion. In addition intracellular lactate, adenine nucleotides, extracellular lactate, pyruvate, and acid release were measured. RESULTS: Higher ambient glucose concentrations resulted in greater cellular injury although insulin-treated cells displayed less injury after ischemia and reperfusion. Insulin increased the pyruvate dehydrogenase activity by 31% in cardiomyocytes and reduced extracellular lactate production by 40%. Intracellular adenosine triphosphate was improved by 75% in cells exposed to high glucose concentrations in the presence of insulin. CONCLUSIONS: Insulin protected human ventricular cardiomyocytes from ischemia and reperfusion. This protection may be due to a stimulation of pyruvate dehydrogenase activity which resulted in improved aerobic metabolism.

Adenine Nucleotides↗
PubMed1998

Optimal flow rates for integrated cardioplegia.

BACKGROUND: Antegrade cardioplegic delivery may be impaired by coronary occlusions, whereas retrograde delivery of cardioplegic solution may be inhomogeneous, leading to an accumulation of lactate and hydrogen ions, the products of anaerobic metabolism. Integrated cardioplegia using continuous retrograde cardioplegia and antegrade infusions into completed vein grafts washes out metabolites accumulated in regions inadequately perfused by retrograde cardioplegia alone. To determine the flow rates required to achieve the greatest washout, we compared a high flow rate (200 ml/min) to a low flow rate (100 ml/min). METHODS: Twenty patients scheduled for isolated coronary bypass surgery were prospectively randomized to compare two flow rates for integrated cardioplegic protection using tepid (29 degrees C) blood cardioplegia. Arterial and coronary sinus blood samples were collected to evaluate myocardial metabolism. After antegrade arrest, cardioplegic solution was delivered by coronary sinus perfusion and simultaneous infusions into each completed vein graft at either high or low flow. RESULTS: Increasing from low to high flow increased the washout of lactate and hydrogen ions during the aortic crossclamp period. Two hours after crossclamp removal, ventricular function was better in the high flow groups. CONCLUSIONS: Tepid retrograde cardioplegia resulted in an accumulation of toxic metabolites. The addition of antegrade vein graft infusions at a flow rate of 100 ml/min resulted in a washout of these metabolites. A flow rate of 200 ml/min further improved this washout and resulted in improved ventricular function. An integrated approach to myocardial protection using a flow rate of 200 ml/min may improve the results of coronary bypass surgery.

Blood↗
PubMed1998

Physician assessments of patient compliance with medical treatment.

In a study of how physicians evaluate patient compliance, practitioner judgments were compared to the self-reports of 138 adult patients receiving treatment for pulmonary diseases at an outpatient clinic. The research found no significant relationship between physician evaluations of compliance and accounts given by the same patients. The conclusions of physicians regarding patient compliance proved to be influenced by their views on the seriousness of the condition and the effectiveness of treatments, but patient reports were different. Physicians clearly have difficulties in appraising the compliance behavior of their patients.

Adolescent↗
PubMed1998

Renal circulatory effects of adenosine in patients with chronic heart failure.

OBJECTIVES: We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF). BACKGROUND: Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A1 receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied. METHODS: Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10(-5) mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated. RESULTS: Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 +/- 1,469 to 31,494 +/- 3,911 dynes x s x cm(-5), p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 +/- 36 to 146 +/- 22 ml/m2, p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 +/- 0.040 to 0.375 +/- 0.033 cm2, p = 0.3). CONCLUSIONS: Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.

Adenosine↗
PubMed1998

A simple colorimetric method for the simultaneous determination of N-acetylcysteine and cysteine.

The widespread use of N-acetylcysteine as an antioxidant and a precursor for tissue cysteine creates a need for a simple method that measures both and distinguishes them from one another. We describe a procedure based on the use of the enzyme acylase, which hydrolyzes N-acetylcysteine to cysteine. Cysteine is subsequently measured with a specific colorimetric procedure. Unhydrolyzed N-acetylcysteine gives only a weak colorimetric response (11.5% that for cysteine); after hydrolysis, however, the two are equivalent. Hence, N-acetylcysteine can be distinguished by the enhanced response after hydrolysis.

Acetylcysteine↗
PubMed1998

Isolation of modified ubiquitin as a neutrophil chemotaxis inhibitor from uremic patients.

Uremic toxins are factors that accumulate in the serum and peritoneal cavity of uremic patients. They are responsible for a variety of functional disturbances and also contribute to the increased risk of infection by interfering with essential functions of the unspecific immune response. From the peritoneal effluent of peritoneal dialysis (PD) patients, a peptide was isolated by applying three different chromatographic methods. This peptide inhibits the chemotactic movement of polymorphonuclear leukocytes (PMNL) in an in vitro assay in a concentration-dependent, nonreversible manner, and therefore belongs to the group of uremic toxins. Amino acid sequencing showed that the isolated peptide has the same amino terminal sequence as ubiquitin. The peptide also reacted with anti-ubiquitin antibodies in a Western blot experiment, but had a more acidic isoelectric point than ubiquitin. By using affinity chromatography, anti-ubiquitin antibody binding fractions were isolated from all PD and hemodialysis (HD) patients investigated. These fractions contained the same acidic band and also significantly inhibited PMNL chemotaxis. Ubiquitin per se had no effect on PMNL chemotaxis. Therefore, it is concluded that from PD and HD patients a modified form of ubiquitin was isolated, and this modification was responsible for its inhibitory effect.

Antibodies↗
PubMed1998

Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion.

Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.

Amphetamines↗
PubMed1998

[The phenomenon of globalization in the pharmaceutical industry].

The globalization of international trading has increased so much over the last ten years that it would seem, from an economical point of view, irreversible. The Pharmaceutical Industry is very much part of this movement and, with the cost of innovation and the necessity to achieve critical mass, the health industry is continuously reorganising on a worldwide scale. A study of the Pharmaceutical Industry over the past 20 years has shown an ever increasing globalization particularly for the most innovative drugs. This global reorganisation of the pharmaceutical environment is far from being finalized, to the contrary it will continue for several years to come. The point is not to agree or disagree but succeed, not only in terms of economic progress but also in terms of resolving social and public health care issues. Medication must be available to all, not only in our own country, but worldwide. Is there a response to this increasing globalization of the economy other than an increasing solidarity locally, regionally and worldwide?

Commerce↗
PubMed1997

Coronary artery bypass grafting in patients with non-dialysis-dependent renal insufficiency.

BACKGROUND: Preoperative renal failure increases the morbidity and mortality of coronary artery bypass graft (CABG) surgery. The results of CABG in patients with non-dialysis-dependent, mild renal insufficiency are unknown. METHODS: From a population of 2978 consecutive patients undergoing isolated CABG from 1990 to 1996, 38 patients with preoperative renal insufficiency (Renal group; serum creatinine >150 micromol/L) were identified and matched on six prognostic variables to a cohort of 152 control patients (Control group). Two patients with preoperative dialysis-dependent renal failure were excluded from analysis. RESULTS: Compared to the overall population, the Renal group were more likely to be over age 70, diabetic, hypertensive, and suffer from peripheral vascular disease and left ventricular dysfunction. Compared to the Control group, the Renal group were more likely to require perioperative blood transfusions (P<.001) and had a greater requirement for postoperative dialysis (P<.01). The Renal group had longer ventilation times, intensive care unit stay, and postoperative hospital stay. Mild renal insufficiency was found to be an independent predictor of postoperative low output syndrome (odds ratio=3.6). CONCLUSIONS: Mild renal insufficiency, even in the absence of dialysis, increases the risk of blood transfusion, low output syndrome and prolonged the length of intensive care unit and postoperative stay for patients undergoing CABG.

Aged↗
PubMed1997

Early experience with stentless versus stented valves.

BACKGROUND: The Toronto stentless porcine valve (SPV) was designed to improve hemodynamics after aortic valve replacement by maximizing available flow area in comparison to stented valves (STD). METHODS: To assess possible hemodynamic differences between STD and SPV, 59 patients undergoing isolated aortic valve replacement (+/-coronary artery bypass graft) were prospectively evaluated by preoperative and 3- to 6-month postoperative echocardiography. Among these, 23 patients received a STD, whereas 36 received the Toronto SPV. RESULTS: The mean size (mm) of SPV implanted was larger (SPV, 26.6+/-2.1; STD, 24.0+/-2.9; P=0.0002). Patients receiving STD valves were older and had a higher prevalence of coronary artery disease and congestive heart failure. There were no preoperative differences in left ventricular mass index (g/mo2), peak or mean pressure gradients (mmHg), effective orifice area (cm2), extent of fractional shortening (%), or velocity of circumferential shortening (cf/sec). ANOVA demonstrated a significant reduction in left ventricular mass index at 3 to 6 months (P=.0001) but no differences in left ventricular mass index regression between groups (STD, -28.8+/-37.5; SPV, -31.2+/-32.4; P=.36). Effective orafice area was increased postoperatively (P=.0001), particularly among SPV cases (STD, 1.5+/-0.4; SPV, 1.9+/-0.7; P=.01). Postoperative left ventricular mass index and mean pressure gradient were reduced (P=.0001) but did not differ between groups. Fractional shortening and velocity of circumferential shortening were greater in the SPV patients at 3 to 6 months after aortic valve replacement (P=.0004 and .0001, respectively), and an interactive effect was seen between time and prosthetic group (P=.0028 and .032, respectively). CONCLUSIONS: In a consecutive series of patients, we identified no hemodynamic differences between STD and SPV, although ventricular function improved after SPV. Because of the nonrandomized nature of the study, selection bias may have accounted for some of the observed results. A prospective, randomized trial is necessary to determine the hemodynamic advantages, if any, of the SPV valve.

Aged↗
PubMed1997

A comparison of the ventilatory response of sleeping newborn lambs to step and progressive hypoxaemia.

1. Slight variations in the rate at which hypoxaemia develops may significantly alter the ventilatory response (VR) elicited. Here we have developed a technique to compare the VRs elicited from sleeping newborn lambs by specific (step versus progressive), short-duration (< or = 5 min) episodes of hypoxaemia. The results may help us understand the limitations of using tests which deliver poorly defined stimuli to evaluate the postnatal development of the oxygen chemoreflex. 2. The VRs of five lambs elicited by a 5 min step or progressive reduction in the arterial oxygen saturation (Sa,O2) during quiet sleep were compared. Minute ventilation (V1, face mask) and Sa,O2 (pulse oximeter) were measured continuously. Alternate step (Sa,O2 reduced to 80-85% within 60 s and maintained for a further 4 min) and progressive tests (progressive reduction in Sa,O2 to 80% over 5 min) were administered daily between postnatal days 2-14. 3. There was a significant difference between the mean VR to step versus progressive hypoxaemia. The VR to a step challenge was biphasic (delta Vi = +32 +/- 5% at 1 min and -1 +/- 4% at 5 min; mean +/- S.E.M.). Progressive hypoxaemia elicited a more subdued but sustained hyperpnoea (delta Vi = +11 +/- 2% at 1 min and +11 +/- 4% at 5 min). The difference between these two response profiles was statistically significant (P < 0.001). 4. Mean responses of lambs aged < or = 5 days (4 +/- 0.2 days) and > or = 9 days (10 +/- 0.3 days) were also compared. There was an upward shift in the position of step and progressive response curves of older lambs, reflecting primarily the increased vigour of the initial hyperpnoea elicited by step (delta Vi at 1 min = +20 +/- 4% at 4 days vs. +40 +/- 11% at 10 days) as well as progressive (delta Vi at 1 min = +6 +/- 2% at 4 days vs. +17 +/- 5% at 10 days) hypoxaemia. 5. Qualitatively different VRs may be elicited from the newborn, depending upon the specific hypoxaemic profile administered. Therefore, to evaluate the significance of VRs elicited in response to classical, steady-state hypoxia at different postnatal ages properly, the stimulus must be accurately described.

Aging↗
PubMed1997

Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow.

Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.

Animals↗
PubMed1997

The glutamine ligand in the ferrous iron active site of isopenicillin N synthase of Streptomyces jumonjinensis is not essential for catalysis.

Isopenicillin N synthase (IPNS) is a non-heme ferrous iron dependent dioxygenase that catalyses the ring closure of delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N. We previously used site-directed mutagenesis to identify in the IPNS of Streptomyces jumonjinensis two histidines and one aspartic acid that are essential for activity. The recent crystal structure of the IPNS of Aspergillus nidulans establishes that these amino acids are iron ligands and reveals that the fourth ligand is the penultimate glutamine. The two histidines and one aspartic acid are conserved in several classes of non-heme ferrous iron dioxygenases, whereas the glutamine is present only in IPNSs. In this paper we show that the penultimate glutamine in S. jumonjinensis IPNS Gln-328 is not essential for catalysis. In contrast, Gln-230 which is highly conserved among the above dioxygenases and is proximal to the active site is crucial for activity.

Binding Sites↗
PubMed1997

Covalent attachment of DNA oligonucleotides to glass.

A method for synthesizing DNA directly on glass is presented. The process is based on pretreatment of glass with boiling hydrochloric acid, thus exposing the hydroxyl groups of the glass. Phosphite-triester chemistry was used to directly attach the first nucleotide to a glass plate via a covalent bond between the hydroxyl group of the glass and the phosphate group of the protected deoxyribonucleotide. Standard molecular biology procedures, such as ligation and restriction digest, were efficiently performed on the glass synthesized oligonucleotide, with the added benefit of extreme ease of handling.

Biotechnology↗
PubMed1997

Ventilatory response of the newborn infant to mild hypoxia.

The transition from an immature (biphasic) to a mature (sustained hyperpneic) response to a brief period of sustained hypoxia is believed to be well advanced by postnatal day 10 for newborn infants. However, a review of the supporting evidence convinced us that this issue warranted further, more systematic investigation. Seven healthy term infants aged 2 days to 8 weeks were studied. The ventilatory response (VR) elicited by 5 min breathing of 15% O2 was measured during quiet sleep. Arterial SaO2 (pulse oximeter) and minute ventilation (expressed as a change from control, delta V'i) were measured continuously. Infants were wrapped in their usual bedding and slept in open cots at room temperature (23 degrees-25 degrees). Infants aged 2-3 days exhibited predominantely a sustained hypopnea during the period of hypoxia (delta V'i = -2% at 1 min, -13% at 5 min). At 8 weeks of age, the mean response was typically biphasic (delta V'i = +9% at 1 min, -4% at 5 min). This age-related difference between responses was statistically significant (two-way ANOVA by time and age-group; interaction P < 0.05). These data reveal that term infants studied under ambient conditions during defined quiet sleep may exhibit an immature VR to mild, sustained hypoxia for at least 2 months after birth. This suggests that postnatal development of the O2 chemoreflex is slower than previously thought.

Aging↗