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H Refsum

Publications and source records attributed to H Refsum.

At least 91 records · Page 5Linked to original sources
PubMed1997

Comparison of cardiovascular changes after administration of gadodiamide injection and gadopentetate dimeglumine in dogs.

RATIONALE AND OBJECTIVES: The authors compared the cardiovascular effects of gadodiamide injection and gadopentetate dimeglumine. METHODS: Gadodiamide injection or gadopentetate dimeglumine, each at doses of 0.3 or 1.5 mmol per kilogram of body weight, or saline volume control was administered intravenously in the cephalic vein of anesthetized dogs. Hemodynamic parameters, electrocardiographic parameters, and peripheral flow were measured. RESULTS: Neither the low or high dose of gadodiamide injection caused statistically significant (P < .05) changes in any of the measured cardiovascular parameters. High doses of gadopentetate dimeglumine, however, significantly decreased left ventricular and systemic blood pressure and significantly depressed left ventricular contractility (P < .05). CONCLUSION: Gadodiamide injection caused no observable cardiovascular effects, whereas high doses of gadopentetate dimeglumine caused cardio-depressive and hypotensive effects.

Animals↗
PubMed1997

Acute cardiotoxicity of gadolinium-based contrast media: findings in the isolated rat heart.

RATIONALE AND OBJECTIVE: The study was designed to compare acute and direct cardiotoxicity of gadopentetate dimeglumine, gadoteridol injection, and gadodiamide injection. METHODS: Two consecutive injections of contrast material (0.3 to 1.5 mmol/kg body weight) were given to spontaneously beating, isolated rat hearts. Cardiac function was assessed by measuring left ventricular developed pressure (LVDP), perfusion pressure, and electrocardiographic (ECG) parameters. RESULTS: Gadopentetate dimeglumine decreased LVDP, and its first derivatives (+/- dP/dt max) substantially more than gadodiamide injection. Gadoteridol increased these variables. PR and RT intervals lengthened after 1.5 mmol/kg gadopentetate dimeglumine and gadoteridol injection. Bradycardia and ventricular tachyarrhythmias were seen after injection of 1.5 mmol/kg gadopentetate dimeglumine. Except for isolated ventricular premature beats, gadodiamide injection and gadoteridol injection did not provoke any serious arrhythmia. CONCLUSION: Gadopentatate dimeglumine induced negative inotropy and more pronounced ECG disturbances. Gadoteridol injection and gadodiamide injection induced only small changes in left ventricular inotropy and minor electrophysiologic effects.

Animals↗
PubMed1997

Selective coronary artery perfusion in vitro: a method to study cardiac effects of contrast media.

RATIONALE AND OBJECTIVES: The authors evaluated selective perfusion of the coronary arteries in the isolated rat heart as a model for studying contrast medium-induced cardiac effects and compared the effects of iodixanol, iotrolan, and ioxaglate with this model. MATERIALS AND METHODS: Isolated, spontaneously beating rat hearts were used. Control hearts were perfused in the Langendorff or the selective perfusion mode receiving Krebs Henseleit buffer. Contrast media were injected selectively into the left coronary artery. Left ventricular pressure and electrocardiographic parameters were monitored continuously throughout the experiments. RESULTS: The stability of the selective perfusion preparation was similar to that of the conventional Langendorff preparation. Ioxaglate (0.3 g iodine per kilogram body weight) significantly (P < .05) depressed left ventricular contractility and decreased (P < .05) left ventricular pressure. Iodixanol and iotrolan had minor cardiac effects. CONCLUSION: Selective coronary artery perfusion seems to be a suitable model for studying direct cardiac effects of contrast media. The nonionic dimers, iodixanol and iotrolan, induce only minor changes in cardiac function.

Animals↗
PubMed1997

Assessment of homocysteine status.

Plasma total homocysteine (tHcy) determination is used in the diagnosis of homocystinuria, in cobalamin and folate deficiency and in cardiovascular risk assessment. However, determination of tHcy includes many pitfalls which complicate the assessment of homocysteine status. In the present article, we review basic knowledge for a rational use of plasma tHcy in diagnostic as well as scientific work. The subjects dealt with are procedures for sample handling and processing, the principles of tHcy analyses, and genetic and acquired determinants of the plasma tHcy concentration.

Animals↗
PubMed1997

Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure.

We investigated the elimination of total homocysteine (tHcy) from plasma after peroral homocysteine (Hcy) loading in eight patients with chronic renal failure. Data on bioavailability and distribution volume were obtained from two patients and two healthy controls by performing both intravenous and peroral Hcy loading. Response to high-dose folic acid was studied in six cases. Mean (SD) basal plasma tHcy was 27.4 (11.0) microM at inclusion. The half-life and the area under the curve were about four times higher, and clearance was reduced to 29.8% compared to controls. High-dose folic acid had no influence on half-life for tHcy, but the basal tHcy level declined by 26.8%. The reduction in tHcy was particularly pronounced in three patients with low-normal serum folate, and the enhanced methionine response to Hcy loading after folic acid suggested improved Hcy remethylation in tissues. In conclusion, patients with renal failure had markedly reduced clearance of tHcy from plasma, which probably accounts for their hyperhomocysteinemia. High-dose folic acid reduces fasting tHcy by improving tissue Hcy remethylation without affecting the low renal clearance of tHcy.

Adult↗
PubMed1997

NMR relaxation studies with MnDPDP.

PURPOSE: Our studies were designed to compare the efficacy of mangafodipir trisodium (MnDPDP, Teslascan) as a tissue-specific MR agent with that of manganese chloride (MnCl2), to compare the efficacy of different doses and rates of administration of MnDPDP, and to collect the data needed for predicting optimum pulse sequences. MATERIAL AND METHODS: The dose response for the relaxation rates R1 and R2 at 0.47 T, and the manganese (Mn) concentrations in rat liver and in the liver, pancreas, heart and adrenals of pigs was determined for both MnDPDP and MnCl2 administered i.v. Computer simulations were carried out to model the effects of different tissue Mn concentrations and TR on signal intensities and contrast-to-noise ratios. RESULTS: In rat liver and pig organs both compounds produced a positive dose-response in R1 and tissue Mn concentration, and only small or no response in R2. The Mn concentration in rat liver was positively correlated with R1, regardless of the form in which Mn was given, or the rate of administration. Optimal imaging parameters are therefore expected to be different pre- and post-MnDPDP administration. CONCLUSION: The added cardiovascular safety of MnDPDP compared with MnCl2 does not result in loss of efficacy in increasing RI at the intended clinical dose of 5 mumol/kg MnDPDP. The changes in R2 were too small to affect T2-weighted images. The data give the basis for choosing the appropriate pulse sequences for MnDPDP-enhanced MR imaging.

Animals↗
PubMed1997

Cardiovascular safety of MnDPDP and MnCl2.

PURPOSE: To investigate the apparent discrepancy between expected basic physiological responses at the cellular level and the in vivo behaviour of both MnDPDP and MnCl2 administered i.v. prompted parallel investigations of these substances. MATERIAL AND METHODS: Studies were performed in isolated perfused rat hearts, isolated bovine mesenteric arteries, conscious dogs, and dogs with acute ischaemic heart failure. RESULTS: These studies confirmed that Mn+2 at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn+2 at low concentrations was an effective superoxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn+2 maintained or elevated heart rate (HR) and blood pressure (BP), and did not worsen existing cardiac failure. MnDPDP was about 10 times less potent than MnCl2 in eliciting these cardiovascular responses. CONCLUSION: The ex vivo properties of Mn+2, inducing vasodilation and negative inotropy, are counter-balanced in vivo through the action of 2 mechanisms: extensive plasma protein binding reducing active M+2, and the release of catecholamines which maintain or even raise HR and BP. Taken together with pharmacokinetic factors, including maximal plasma concentrations in humans given the recommended 5 mumol/kg dose, it is concluded that MnDPDP in normal clinical use represents no safety risk to the cardiovascular system.

Animals↗
PubMed1997

Cardiovascular effects of MnDPDP and MnCl2 in dogs with acute ischaemic heart failure.

PURPOSE: To examine the cardiovascular effects of MnDPDP in a model of acute heart failure in the dog, and to compare these effects with those of MnCl2. MATERIAL AND METHODS: The study involved slow i.v. infusion of either 10, 60 and 300 mumol/kg of MnDPDP, or 1, 6 and 30 mumol/kg MnCl2, in increasing doses to groups of 5 dogs. Acute ischaemic heart failure was first induced by injection of polystyrene microspheres (50 +/- 10 microns) into the left coronary artery until a stable left ventricular end-diastolic pressure of approximately 20 mm Hg was achieved. The following test parameters were measured: left ventricular end-diastolic pressure; the first derivatives of maximum rate of left ventricular contraction and relaxation; mean aortic pressure; pulmonary artery pressure; right atrial pressure; cardiac output; heart rate; QT-time; PQ-time; QRS-width; and plasma catecholamines. RESULTS: Slow infusion of MnDPDP at doses up to and including 12 times the clinical dose was well tolerated in dogs without further depression of cardiovascular function during acute ischaemic heart failure. At 300 mumol/kg, i.e. 60 times the human dose, only minor haemodynamic and electrophysiological effects were seen, and these were similar to those seen after administration of 30 mumol/kg MnCl2. CONCLUSION: The present study suggests that slow infusion of MnDPDP should not cause further deterioration of cardiac function in patients with heart failure.

Acute Disease↗
PubMed1997

Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study.

The health consequences of coffee drinking remain controversial. We report on an association between coffee consumption and the concentration of total homocysteine (tHcy) in plasma, a risk factor for cardiovascular disease and for adverse pregnancy outcome. The study population consisted of 7589 men and 8585 women 40-67 y of age and with no history of hypertension, diabetes, ischemic heart disease, or cerebrovascular disease. They were recruited from Hordaland county of western Norway in 1992-1993. Daily use of coffee was reported by 89.1% of the participants, of whom 94.9% used caffeinated filtered coffee. There was a marked positive dose-response relation between coffee consumption and plasma tHcy, which was stronger than the relation between coffee and total serum cholesterol. In 40-42-y-old men, mean tHcy was 10.1 mumol/L for nonusers and 12.0 mumol/L for drinkers of > or = 9 cups of coffee/d. Corresponding tHcy concentrations in 40-42-y-old women were 8.2 and 10.5 mumol/L, respectively. Although coffee drinking was associated with smoking and lower intake of vitamin supplements and fruit and vegetables, the coffee-tHcy association was only moderately reduced after these variables were adjusted for. The combination of cigarette smoking and high coffee intake was associated with particularly high tHcy concentrations. A strong inverse relation between tea and tHcy concentration in univariate analysis was substantially attenuated after smoking and coffee drinking were adjusted for. The results of the present report should promote future studies on tHcy as a possible mediator of adverse clinical effects related to heavy coffee consumption.

Adult↗
PubMed1997

Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria.

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder which results in extremely elevated levels of total plasma homocysteine (tHcy) and high risk of thromboembolic events. About half of all patients diagnosed with CBS deficiency respond to pyridoxine treatment with a significant lowering of tHcy levels. We examined 12 CBS-deficient patients from 10 Norwegian families for mutations in the CBS gene and identified mutations in 18 of the 20 CBS alleles. Five of the seven patients classified as pyridoxine-responsive contain the newly identified point mutation, G797A (R266K). This point mutation is tightly linked with a previously identified 'benign' 68 bp duplication of the intron 7-exon 8 boundary within the CBS gene. We tested the effect of all of the mutations identified on human CBS function utilizing a yeast system. Five of the six mutations had a distinguishable phenotype in yeast, indicating that they were in fact pathogenic. Interestingly, the G797A allele had no phenotype when the yeast were grown in high concentrations of pyridoxine, but a severe phenotype when grown in low concentrations, thus mirroring the behavior in humans. These studies show that the G797A mutation is an important cause of pyridoxine-responsive CBS deficiency and demonstrate the utility of yeast functional assays in the analysis of human mutations.

Adolescent↗
PubMed1997

Elevated plasma total homocysteine and C677T mutation of the methylenetetrahydrofolate reductase gene in patients with spina bifida.

Total plasma homocysteine (tHcy) was significantly higher in 28 children with spina bifida (median 6.05 mumol/l) as compared with 76 controls (median 4.94 mumol/l). This difference was confined to a subgroup of patients (16/28) with one or two C677T-mutated alleles in the methylenetetrahydrofolate reductase gene. Since we found no significant difference between patients and controls in serum folate, erythrocyte folate, serum cobalamin or serum methylmalonic acid, which were within the normal range for both patients and controls, the elevated tHcy could not be attributed to vitamin deficiencies. Our findings point to an additional genetic defect involving folate-dependent enzymes in a subgroup of patients with neural-tube defects.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1997

Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis.

Epidemiological research has shown that elevated plasma total homocysteine (tHcy) is a risk factor for atherosclerotic disease. In the present case-control study, we investigated whether fasting or postmethionine-loading tHcy was a stronger predictor of risk of severe coronary atherosclerosis. Furthermore, we studied levels of B vitamins, which are involved in homocysteine metabolism. Subjects were recruited from men and women, aged 25 to 65 years, who underwent coronary angiography between June 1992 and June 1994 in a hospital in Rotterdam, The Netherlands. Cases (n=131) were defined as those with > or =90% occlusion in one and > or =40% occlusion in a second coronary artery, while control subjects (n=88) had <50% occlusion in only one coronary vessel. In addition, a population-based control group free from clinical cardiovascular disease (n=101) was studied. Coronary patients were studied at least 2.5 months after angiography or other acute illness, such as myocardial infarction. After adjusting for age and sex differences between the groups, cases had 9% (P=.01) higher geometric mean fasting and 7% (P=.04) higher geometric mean postload tHcy than the combined control groups. Despite higher levels of tHcy for cases, their geometric mean levels of red cell folate and pyridoxal 5'-phosphate were higher than for control subjects, whereas plasma vitamin B12 was only slightly lower in cases. The frequency distribution of tHcy values in cases was slightly shifted toward the right, across the entire range, compared with the distribution in the combined control group. This was somewhat more obvious for fasting than postload tHcy levels. The odds ratio (OR) for severe coronary atherosclerosis (case status) for each 1 SD increase in fasting tHcy (5 micromol/L) was 1.3 (95% confidence interval [CI], 1.0-1.6), similar to the OR for each 1 SD increase (12 micromol/L) in postmethionine-loading tHcy (1.3 [95 CI, 1.0-1.7]), after adjustment for sex, age, and other potential confounders. Furthermore, there was a significant linear trend of increasing fasting tHcy with increasing number of occluded arteries (P=.01), correcting for sex, age, and other potential confounders. Our data show a positive association between plasma tHcy and risk of severe coronary atherosclerosis, of similar strength for fasting and postload tHcy levels. The data suggest that the association exists over a wide range of tHcy levels, without a clear cutoff point below which there is no increased risk.

Adult↗
PubMed1997

Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease.

It is known that the metabolism of homocysteine (Hcy) depends on the vitamins B6, B12 and folate, and furthermore that metformin reduces serum vitamin B12 levels. In order to investigate whether metformin treatment affects serum total Hcy (tHcy) levels we performed an open, prospective, randomised study in 60 non-diabetic male patients with cardiovascular disease. After a 4-week run-in period with lovastatin 40 mg day-1, and diet and lifestyle advice, patients were randomised into two groups, both continuing the run-in treatment. One group received metformin up to 2000 mg day-1, whereas the control group got no additional treatment. After 12 and 40 weeks of metformin treatment, tHcy levels increased moderately but significantly by 7.2% (p < 0.05) and 13.8% (p < 0.05) in the metformin group relative to the control group, whereas serum vitamin B12 levels decreased by 13.4% (p < 0.0005) and 17.7% (p < 0.0005), respectively. Serum folate levels did not change after 12 weeks, but decreased by 8.0% after 40 weeks (p = 0.061) relative to the control group. Serum levels of total cysteine and methylmalonic acid (MMA) did not change. In conclusion, metformin treatment increased tHcy levels and decreased levels of vitamin B12 and folate. Since MMA levels were unchanged, it remains an open question whether the increase in tHcy levels is secondary to reduced vitamin B12 levels, folate levels or a combination of both.

Adult↗
PubMed1997

C677T mutation of methylenetetrahydrofolate reductase gene determined in blood or plasma by multiple-injection capillary electrophoresis and laser-induced fluorescence detection.

We constructed an assay to detect the common C677T mutation in the methylenetetrahydrofolate reductase gene. The mutation creates a Hinfl recognition site detected by restriction cleavage of a 198-bp fragment amplified in the polymerase chain reaction (PCR). Digested samples were subjected to capillary electrophoresis with laser-induced fluorescence detection (CE-LIF), with hydroxypropylmethylcellulose as the sieving matrix and SYBR Green I as the fluorescent dye. After amplification but before digestion, we added to the PCR mixture a fragment with the HinfI recognition site and a 15-bp truncation at the 3' end. Using this procedure, we could (a) verify completeness of digestion and monitor injection, (b) assign genotypes on the basis of pattern recognition, and (c) develop a multiple-injection mode with simultaneous separation of as many as eight samples. A seminested PCR protocol in combination with CE-LIF allowed genotyping of plasma/serum samples 20 years old.

Benzothiazoles↗
PubMed1997

Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide.

We compared the effects of methotrexate (MTX) and nitrous oxide on the methionine (Met) synthase system in two variants of a human glioma cell line. The cells were protected from cytotoxic effect of MTX by adding thymidine and hypoxanthine to the cell culture medium. MTX (0-1 microM) was associated with a dose- and time-dependent reduction in 5-methyltetrahydrofolate (5-methyl-THF) in both cell lines. Already after 3 hr of exposure, 5-methyl-THF was reduced by 50% and after additional 48 hr, the level was undetectable. In addition to reduction in folate level, homocysteine (Hcy) remethylation in intact cells was markedly inhibited as judged by an increased export of Hcy from the cells, and Met synthase activity in cell extracts and level of cellular methylcobalamin (CH3Cbl) declined. MTX reduced Hcy remethylation and CH3Cbl level more efficiently than nitrous oxide. In both cell variants, the inactivation of Met synthase by nitrous oxide was almost completely prevented in cells pre-exposed to MTX. This indicates that there is no catalytic turnover in cells exposed to MTX, and emphasizes the importance of the sequence of administration for synergistic effect of this drug combination. In conclusion, our data show that MTX through depletion of 5-methyl-THF reduces both the Met synthase activity and the cellular CH3Cbl level. Moreover, the effect of MTX on the Hcy remethylation is more pronounced than the inhibition caused by nitrous oxide. These observations should be taken into account in studies on MTX pharmacodynamics.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study.

From 1992-93, we screened 18,043 subjects, aged 40-67 yr, and found 67 cases (0.4%) with total plasma homocysteine (tHcy) > or = 40 micromol/liter. Compared to 329 controls, the cases had lower plasma folate and cobalamin levels, lower intake of vitamin supplements, consumed more coffee, and were more frequently smokers. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was observed in 73.1% of the cases and 10.2% of the controls. Only seven cases with cobalamin deficiency and one with homocystinuria received specific therapeutic instructions. 2 yr after the screening, 58 subjects were reinvestigated. 41 still had tHcy > 20 micromol/liter, and in 37 of these, intervention with low dose folic acid (0.2 mg/d) was started. Notably, 34 of 37 (92%) had homozygosity for the C677T mutation. Plasma tHcy was reduced in all but two after 7 wk, and became normal within 7 mo in 21 of 37 subjects. Most of the remaining subjects obtained a normal tHcy level with 5 mg/d of folic acid. We conclude that most subjects with hyperhomocysteinemia > or = 40 micromol/liter in the general population have the C677T mutation combined with low folate status. Daily supplement of low dose folic acid will reduce and often normalize their tHcy level.

Adult↗