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H Refsum

Publications and source records attributed to H Refsum.

At least 19 recordsLinked to original sources
PubMed1992

[Routine determination of homocysteine in plasma. A new and improved possibility for risk evaluation and diagnosis of common diseases].

The performance of a rapid, fully automated HPLC assay for total homocysteine in plasma has made it possible to offer this analysis as a routine laboratory test. The reference interval in fasting individuals is 7-14 mumol/l. In EDTA-plasma, homocysteine remains stable for up to four days at room temperature. The most important indications for analysing homocysteine are deficiency of vitamin B12 or folate, premature cardiovascular disease and inherited homocystinuria. The clinical usefulness of the assay is based on the fact that the intracellular metabolism of homocysteine is dependent on vitamin B12, folate and vitamin B6. Moreover, homocysteine may be an atherogenic agent, and there is increasing evidence that a high level of homocysteine in plasma is an independent risk factor for developing premature atherosclerotic disease.

Adult↗
PubMed1992

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle.

The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). These changes were accompanied by a small shortening of APD90, but with an increase in ERP; i.e., the ERP/APD90 ratio was increased. Dofetilide also significantly lengthened APD90 at 10 mM [K+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.

Action Potentials↗
PubMed1992

Hemodynamic effects of d-sotalol in acute ischemic heart failure in dogs.

This study was designed to determine the hemodynamic effects of the class III antiarrhythmic agent d-sotalol in acute ischemic heart failure at concentrations that prolong ventricular repolarization. In pentobarbital-anesthetized open-chest dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 25 +/- 2 mm Hg was achieved. Embolization shortened the QT interval by 30 +/- 11 msec, while 1 and 2 mg/kg d-sotalol intravenously after embolization lengthened the QT interval by 23 +/- 7 and 39 +/- 7 msec, respectively (n = 7). Heart rate increased after embolization by 19 +/- 7 beats/min, while it decreased by 12 +/- 6 beats/min and by 21 +/- 5 beats/min after d-sotalol. The depressed LV function after embolization assessed by LV pressures, stroke volume, cardiac output, ultrasonometrically estimated LV volume, the pressure-volume relationship, and the time for isovolumic relaxation was not changed following infusion of 1 or 2 mg/kg d-sotalol. Plasma concentrations of d-sotalol were 1.55 +/- 0.33 and 2.58 +/- 0.50 micrograms/ml, respectively. In conclusion, d-sotalol at concentrations prolonging repolarization was devoid of cardiodepressive effects in acute ischemic heart failure in dogs.

Acute Disease↗
PubMed1992

Recurrent nerve/ansa cervicalis nerve anastomosis: a treatment alternative in unilateral recurrent nerve paralysis.

Sectioning of the right recurrent nerve was done in 5 mongrel dogs under general anaesthesia. The distal stump was anastomosed with the ansa cervicalis nerve branch to the sternothyroid muscle. Three to 5 months later the vocal cord movements during light and very light anaesthesia were videorecorded. Under light anaesthesia contraction and medial bulging of the reinnervated right vocal cord occurred in 4 of the dogs. Under very light anaesthesia there was also some adduction of the right vocal cord in these 4 dogs. The right recurrent nerve was then sectioned proximally to the anastomosis and stimulated electrically. In all 5 dogs we observed that electrical stimulation produced a strong adduction of the right vocal cord. Histochemistry of the right vocal and posterior cricoarytenoid muscles showed that reinnervation had taken place. The study indicates that in cases of unilateral vocal cord paralysis an anastomosis between the ansa cervalalis and the recurrent nerve will result in improved phonatory function of the affected vocal cord.

Anastomosis, Surgical↗
PubMed1992

Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.

OBJECTIVE: The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia. METHODS: Hypoxia was induced by superfusing guinea pig right ventricular papillary, muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [PO2 = 5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+ channels) in the absence (n = 6) and presence of dofetilide (n = 6) or glibenclamide (n = 4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer. RESULTS: During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p < 0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p < 0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p < 0.05), ERP by 48(4)% (p < 0.05) and developed force by 71(6)% (p < 0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p < 0.05), ERP by 44(6)% (p < 0.05), and developed force by 69(10)% (p < 0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, ERP, and developed force. CONCLUSIONS: Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia.

Action Potentials↗
PubMed1992

Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.

We studied the hemodynamic and metabolic effects of the novel class III antiarrhythmic agent dofetilide (UK-68,798) in acute ischemic heart failure. In pentobarbital-anesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 27 +/- 2 mm Hg was achieved. Embolization depressed LV systolic pressure, LV dP/dtmax, LV dP/dtmin, and cardiac output. None of these parameters were changed following i.v. infusion of dofetilide 5, 10, or 25 micrograms/kg, during spontaneous and paced cycle length of 300 ms (n = 9). Heart rate decreased by 12 +/- 8, 19 +/- 7, and 21 +/- 7 beats/min (p less than 0.05), while QT time increased by 23 +/- 7, 33 +/- 9, and 40 +/- 10 ms (p less than 0.05) after 5, 10, and 25 micrograms/kg, respectively. Ventricular effective refractory period increased from 128 +/- 10 to 153 +/- 11 ms after 25 micrograms/kg (n = 4). Arterial concentration and net myocardial uptake of glucose, lactate, and free fatty acids were not significantly influenced by dofetilide. In conclusion, dofetilide, at doses that prolonged repolarization, was devoid of cardiodepressive effects in acute ischemic heart failure.

Animals↗
PubMed1992

Electromechanical action of dofetilide and D-sotalol during simulated metabolic acidosis in isolated guinea pig ventricular muscle.

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group): (a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 microM). At normal extracellular pH (pH = 7.32 +/- 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18-20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization (Vmax), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 +/- 0.01) was simulated by reducing the bicarbonate concentration of the Tyrode's solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased Vmax and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in Vmax and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.

Acidosis↗
PubMed1992

Class III antiarrhythmic action and inotropy: effects of almokalant in acute ischaemic heart failure in dogs.

We studied the haemodynamic and metabolic effects of the novel class III antiarrhythmic agent almokalant (H 234/09) in acute ischaemic heart failure at a dose prolonging ventricular repolarization. In pentobarbital anaesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular end-diastolic pressure (LVEDP) of 32 +/- 2 mmHg was achieved. Embolization depressed LV dP/dt(max), LV dP/dt(min), left ventricular systolic pressure (LVSP) and cardiac output. After intravenous infusion of almokalant (0.35 micrograms/kg) LV dP/dt(max) and LV dP/dt(min) were not significantly changed at paced cycle length of 300 msec., whereas LVSP and aortic pressure decreased both at spontaneous and paced cycle length of 300 msec. LVEDP remained unchanged. Heart rate decreased from 185 +/- 7 to 167 +/- 5 beats/min., and corrected QT-time (QTc) increased from 9.5 +/- 0.3 to 10.4 +/- 0.5 msec. Arterial concentration and net myocardial uptake of glucose, lactate and free fatty acids were not significantly influenced by almokalant. In conclusion, almokalant at a dose prolonging ventricular repolarization had no negative inotropic effect in acute ischaemic heart failure.

Acute Disease↗
PubMed1992

Cell kinetics of the rat corneal epithelium.

In the rat corneal epithelium the mitotic rate (MR) is almost equal throughout the epithelium in the morning (Haaskjold et al. 1988). The labelling index (LI) shows a marked reduction in the central cornea, which could suggest a lack of uptake of tritiated thymidine via the salvage pathway (Haaskjold et al. 1989). In the present study we have used [3H]deoxycytidine, and [3H]thymidine after prior treatment with a methotrexate regimen to elucidate this discrepancy. Deoxycytidine is incorporated into DNA independent of thymidine kinase, while methotrexate, which depletes the cells of reduced folates, makes the cells completely dependent on the salvage pathway. With both techniques the same pattern of labelling was observed, confirming that in the morning the ratio between the MR and the LI differs throughout the cornea. Based on previous observations, an analysis of the MR/LI ratio during 24 h was performed, showing that these parameters were strongly correlated. This suggests that there may be different circadian variations in the cell proliferation parameters throughout the corneal epithelium. The methotrexate regimen may be a useful tool to investigate the salvage pathway.

Animals↗
PubMed1992

Palatopharyngoglossoplasty in the treatment of patients with obstructive sleep apnea syndrome.

A new technique (palatopharyngoglossoplasty (PPGP)) has been developed for surgical treatment of patients with the obstructive sleep apnea syndrome (OSAS). In 20 operated patients 18 reported immediate marked improvement of daytime sleepiness, alertness and vigilance during the day, and of working capacity. However, polysomnography carried out pre- and postoperatively showed that only 10 patients were "cured", defined as 50% or more reduction in apnea/hypopnea index (AHI). Cephalometric analysis pre- and postoperatively indicated that nonresponders had a long and narrow posterior airway space, and we suggest that during sleep this part of the upper airway collapses before as well as after the operation. The discrepancy between the subjective improvement observed after PPGP and the postoperative reduction in AHI may be due to reduced/eliminated snoring and/or improvement in sleep quality after the operation.

Adult↗
PubMed1992

The effect of the temperature of contrast media on cardiac electrophysiology and hemodynamics during coronary arteriography.

RATIONALE AND OBJECTIVES: The authors assess the effect of preheating ionic and nonionic contrast media on regional electrophysiologic and/or hemodynamic side effects during coronary arteriography. METHODS: The authors injected 6 mL of nonionic (iohexol) and ionic (ioxaglate) low-osmolality contrast media and NaCl 0.9% twice, at 20 degrees C and 37 degrees C, into the left coronary artery in eight open-chest dogs. To study regional electrophysiologic effects, the authors measured monophasic action potential duration (MAPD) using an epicardial suction electrode placed in the contrast-perfused area. Hemodynamic effects were studied by recording left ventricular systolic pressure (LVSP), mean aortic pressure, LV end diastolic pressure (LVEDP), LV dP/dtmax, and cardiac output. RESULTS: Ioxaglate and iohexol prolonged MAPD more at 20 degrees C than at 37 degrees C. NaCl 0.9% prolonged MAPD only when injected at 20 degrees C. The temperature of iohexol did not significantly influence LV pressures (LVPs) or LV dP/dtmax. Ioxaglate increased LVEDP and decreased LV dP/dtmax more at 20 degrees C than at 37 degrees C 10 seconds after injection. CONCLUSIONS: In dogs, contrast media, preheated to body temperature before selective injection during coronary arteriography, reduced dispersion of repolarization and reduced the risk of serious cardiovascular complications.

Action Potentials↗
PubMed1992

Homocysteine remethylation during nitrous oxide exposure of cells cultured in media containing various concentrations of folates.

Nitrous oxide irreversibly inactivates cob(I)alamin, which serves as a cofactor of the enzyme methionine synthase catalyzing the remethylation of homocysteine to methionine. In patients exposed to nitrous oxide, increase in plasma homocysteine is a responsive indicator of cob(I)alamin inactivation. In the present work, we measured the inactivation of methionine synthase and the concurrent homocysteine export rate of two murine and four human cell lines during nitrous oxide exposure. When cultured in a standard medium with high content (2.3 microM) of folic acid, the methionine synthase of all cell types was inactivated at an initial rate of 0.05 to 0.14 h-1. The inactivation curves leveled off, and a residual activity of 15 to 45% was observed after 48 h of nitrous oxide exposure. The rate and extent of the nitrous oxide-induced inactivation were markedly reduced when the cells were transferred and cultured (greater than 10 days) in a medium containing low concentration (10 nM) of 5-methyltetrahydrofolate. The methionine synthase inactivation increased in a dose-dependent manner when the 5-methyltetrahydrofolate content of the medium was increased from 3 nM to 2.3 microM. The inactivation of methionine synthase was associated with a marked enhancement of homocysteine export rate of murine fibroblasts and a moderate increase in export from two human glioma cell lines. In contrast, in three leukemic cell lines (murine T-lymphoma R 1.1 cells, human promyelocytic leukemia HL-60 cells and human acute myelogenous leukemia KG-1a cells), the homocysteine export rates were not increased during nitrous oxide exposure. In the responsive murine fibroblasts and the glioma cells, the homocysteine export rate varied inversely to the changes in methionine synthase activity induced by nitrous oxide exposure at different concentrations of folate in the medium. The enhancement of homocysteine export rate of some cell types during nitrous oxide exposure probably reflects inhibition of homocysteine remethylation in intact cells, and highlights the utility of extracellular homocysteine as an indicator of metabolic flux through the methionine synthase pathway. No enhancement of homocysteine export despite inactivation of methionine synthase in three leukemic cell lines questions the functional state of the enzyme in these cells.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

[Antiarrhythmic agents. Receptor hypothesis explains mechanisms of action].

Antiarrhythmic drugs are usually classified according to Vaughan Williams' classification I-IV. Class I includes the membrane stabilizers, class II includes the beta-blockers, drugs in class III lengthen the cardiac action potential and refractory period and class IV includes the calcium blockers. The effect of most antiarrhythmic drugs changes with heart rate and the level of myocardial depolarization, and these changes in effect can be explained by the modulated receptor hypothesis. Most class I antiarrhythmic drugs have greatest antiarrhythmic effect during periods of fast heart rate and in depolarized ischemic myocardium, and this might be attributed to greater affinity of the drugs for open or inactivated sodium channels. Most class III antiarrhythmic drugs have greatest effect during periods of slow heart rates, which may be attributed to greater affinity for closed potassium channels.

Anti-Arrhythmia Agents↗
PubMed1991

[Determination of homocysteine and methylmalonic acid in cobalamin deficiency. Diagnostic problem with a solution?].

Conditions with cobalamin deficiency are common and may represent a considerable diagnostic challenge. This deficiency state may result in a wide range of uncharacteristic symptoms, and the traditional laboratory assays may give inconclusive or even misleading results. This article briefly reviews the biochemistry, normal homeostasis, pathology, symptoms and signs resulting from cobalamin deficiency. Homocysteine and methylmalonyl-CoA are substrates in the two cobalamin-dependent pathways. Recent research suggests that measurements of homocysteine and methylmalonic acid in blood may constitute a simple, sensitive, and specific tool in the diagnosis and follow-up of the cobalamin-deficient patient.

Homocysteine↗
PubMed1991

Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate.

Plasma homocysteine was determined in 12 children with acute lymphoblastic leukemia. The patients were investigated prior to chemotherapy (stage I), during seven weeks of induction chemotherapy (stage II), and thereafter during intermittent high-dose methotrexate (HD-MTX) therapy (stage III). The patients were followed for a period of three to 15 months, and the study included a total of 80 HD-MTX courses. Before start of chemotherapy (stage I), the average plasma homocysteine level in the children with leukemia was 13.18 +/- 6.23 (SD) mumol/liter, which is significantly (P less than 0.001) higher than the level in control children (6.52 +/- 1.21 mumol/liter). The plasma homocysteine level in the patients was positively correlated with the peripheral white blood cell count (P less than 0.01) and negatively correlated with serum folate (P less than 0.02). The serum folate was normal or subnormal in these patients. During induction therapy with cytotoxic drugs such as vincristine, asparaginase, and intrathecal MTX (stage II), there was a drastic change in plasma homocysteine as a function of time. A reciprocal alteration in serum folate was observed, suggesting fluctuating intracellular folate status at this stage of therapy. At the end of stage II (about seven weeks), there was a significant (P less than 0.01) reduction in total homocysteine (to 7.08 +/- 3.84 mumol/liter). HD-MTX (8 g/m2) therapy with 5-formyltetrahydrofolate "rescue" (stage III) was usually begun about seven weeks after start of chemotherapy, and the patients were followed for two to eight courses separated by three to eight weeks. Plasma homocysteine showed a transient increase (26-64%) following each MTX infusion. After three MTX infusions, basal total plasma homocysteine was reduced to 5.56 +/- 1.12 mumol/liter. During most MTX infusions, there was a variable reduction (17-56%) in plasma methionine followed by a rebound increase. It is concluded that plasma homocysteine in children with acute lymphoblastic leukemia is elevated prior to therapy, probably because of occasional folate deficiency and increased burden of proliferating cells. During induction therapy, monitoring plasma homocysteine and serum folate both suggest a labile folate homeostasis, usually a deficiency state. HD-MTX induced a temporary intracellular folate depletion before 5-formyl-tetrahydrofolate was administered, as judged by a transient homocysteinemia. The methionine depletion may interfere with the antileukemic effect of MTX.

Adolescent↗
PubMed1991

Homocysteine export from cells cultured in the presence of physiological or superfluous levels of methionine: methionine loading of non-transformed, transformed, proliferating, and quiescent cells in culture.

Determination of the transient increase in plasma homocysteine following administration of excess methionine is an established procedure for the diagnosis of defects in homocysteine metabolism in patients. This so-called methionine loading test has been used for 25 years, but the knowledge of the response of various cell types to excess methionine is limited. In the present paper we investigated homocysteine export from various cell types cultured in the presence of increasing concentrations (15-1,000 microM) of methionine. For comparison of homocysteine export, the export rates per million cells were plotted versus cell density for proliferating cells, and versus time for quiescent cells. The homocysteine export from growing cells was greatest during early to mid-exponential growth phase, and then decreased as a function of cell density. The export rate was higher from phytohemagglutinin-stimulated than non-stimulated lymphocytes, and higher from proliferating than from quiescent fibroblasts. The hepatocytes showed highest export rate among the cell types investigated. The enhancement of homocysteine export by excess methionine ranged from no stimulation to marked enhancement, depending on cell type investigated, and three different response patterns could be distinguished: 1) quiescent fibroblasts and growing murine lymphoma cell showed no significant increase in homocysteine export following methionine loading; export from human lymphocytes was only slightly enhanced in the presence of excess methionine; 2) the homocysteine export from proliferating hepatoma cells and benign and transformed fibroblasts was stimulated three to eightfold by increasing the methionine concentration in the medium from 15 to 1,000 microM; and 3) the response to methionine loading was particularly increased (about 15-fold) in non-transformed primary hepatocytes in stationary culture. The results outline a potentially useful procedure for the comparison of homocysteine export during cell growth in the presence of various concentrations of methionine. The results are discussed in relation to the special feature of homocysteine metabolism in various cell types and tissues including liver, and to the possible source of plasma homocysteine following methionine loading in vivo.

Animals↗
PubMed1991

Class III antiarrhythmic action of d-sotalol during hypothermia.

To investigate whether changes in temperature influence the electrophysiologic effects of the class III antiarrhythmic agent d-sotalol, we studied its effects on propranolol-pretreated guinea pig papillary muscles at temperatures ranging from 37 degrees to 27 degrees C by means of conventional microelectrode techniques. We also examined the rate-dependent effect of d-sotalol at 37 degrees and 27 degrees C. Before the addition of d-sotalol, reducing the temperature from 37 degrees to 27 degrees C increased the action potential duration recorded at 50% repolarization (APD50) from 112 +/- 7 msec to 271 +/- 15 msec and action potential duration recorded at 90% repolarization (APD90) from 136 +/- 7 msec to 325 +/- 10 msec. d-Sotalol (50 mumol/L) lengthened APD50 and APD90 to a greater degree at low temperatures. Thus at 37 degrees C d-sotalol lengthened APD50 and APD90 by 12 +/- 6 msec and 19 +/- 5 msec, and at 27 degrees C by 37 +/- 5 msec and 52 +/- 7 msec, respectively. d-Sotalol produced its greatest effect on APD at long pacing cycle lengths, thus demonstrating reverse dependence. This rate-dependent effect was more marked at 27 degrees C than at 37 degrees C. The greater effect of d-sotalol on APD at long pacing cycle lengths may be explained by the modulated receptor hypothesis, assuming that the drug has a higher affinity for closed potassium channels. Such a mechanism may also explain the accentuated class III antiarrhythmic action of d-sotalol observed during hypothermia.

Action Potentials↗