Biomedical subjects
Publications and source records attributed to J Holm.
In a double-blind controlled clinical trial on 51 patients with subarachnoid hemorrhage, tranexamic acid, 4 gm per day for ten consecutive days, did not favorably affect the outcome. Neither mortality nor rebleeding rates were improved after a follow-up of three months.
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Human whey was subjected to gel chromatography. Two folate binding protein fractions wer eluted: a major one (Mr congruent to 30,000) and a minor one (Mr greater than 200,000). The former folate binding fraction (FB) could be isolated from whey by means of ion exchange chromatography. Equilibrium dialysis experiments with whey and isolated FB indicated the existence of cooperatively interacting sites in folate binding. The folate analogue methotrexate inhibited folate binding. Inhibition was apparently of a competitive type since methotrexate did not reduce maximum binding capacity. Cooperativity was lost in the presence of methotrexate. Binding affinity was inversely proportional to the concentration of FB suggesting involvement of a polymerizing protein system in binding. None of the other fractions eluted on the ion exchange column could bind folate.
Exit of 14C-tetraethylammonium (TEA) was studied in mouse kidney cortex slices incubated in Krebs-Ringer bicarbonate buffer (37 degrees C, pH 7.4) aerated with O2-CO295:5 v/v%. Substitution of Na+ in the wash out buffer by K+, Rb+ or the organic cations TEA and choline resulted in a stimulation of exit which, however, may be secondary to concomitant biochemical changes in the tissue (increase of water content and relative loss of K+) seen in the presence of these cations. However, enhancement of 14C-TEA exit although less pronounced was also produced of low organic cation concentrations having no effect on tissue water and K+. The latter specific effect on 14C-TEA exit may represent an interaction phenomenon in renal organic cation transport of accelerative exchange diffusion type.
In order to follow early metabolic adaptations in adipose tissue, which may lead to a decrease in fat cell size and body fat obtained by physical training, two sets of experiments were performed. Obese subjects and a control group exercised on a bicycle at two-thirds of maximal working capacity for one hour. Twenty-four hours thereafter, either on ad libitum diet, or on an isocaloric diet supplemented with calories corresponding to the expanded calories during the work load, an adipose tissue biopsy was taken and fat cell metabolism studied. In obese subjects on and ad libitum or on an isocaloric diet the lipolytic process was increased after the exercise but no significant effects were found on the rates of glucose metabolism. Furthermore, a relationship between cell surface and metabolism was found before, but not after, the work in all groups. No changes were seen in lipoprotein lipase activity. Obese subjects on a controlled diet showed a somewhat higher insulin and catecholamine responsiveness of adipocytes than was the case in the obese subjects on an ad libitum diet. This may well be due to the differences in carbohydrate intake, a factor of importance for hormonal responsiveness of fat cells. The increased basal lipolysis after exercise may be caused by the release of lipolytic hormones, and may well be the first sign of an adaption of the organism to diminish the fat stores as seen in physically trained subjects.
The enzyme pattern in gastrocnemius muscle tissue was studied in 39 patients with peripheral arterial insufficiency. Phosphofructokinase and glucose-6-phosphate-dehydrogenase were significantly increased in the skeletal muscles from these patients. The most pronounced changes were found in 3-OH-acyl-CoA-dehydrogenase, citrate synthase, and in cytochrome-c-oxidase. These enzyme activities were increased by 60, 40 and 25 per cent respectively. In patients with claudication as the only symptom, the metabolic capacity was generally increased in skeletal muscles affected by the low blood flow. With increasing severity of arterial insufficiency, all enzyme activities decreased and glycolytic enzymes were affected first. 3-OH-acyl-CoA-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities were still comparatively high in patients with gangrenous foot ulcers, indicating some maintenance of the muscle viability even in situations with very low blood flow.
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The activities (Vmax) of hexokinase, glycogen phosphorylase, glucose-6-phosphate dehydrogenase, phosphofructokinase, lactate dehydrogenase, citrate synthase, cytochrome c oxidase, and 3-OH-acyl-CoA dehydrogenase in human skeletal muscles were compared with the in vitro utilization of glucose and palmitic acid assessed under optimal conditions. Statistically significant correlations between substrate fluxes and enzyme activities were found suggesting that the substrate incorporation rate in vitro in some way reflects the capacity of metabolic pathways. The incorporation rate of leucine into muscle proteins was also statistically significantly correlated to the RNA concentration in the muscle tissue. Glycolytic and glycogenolytic enzymes correlated significantly to each other and correlations were also found between aerobic enzymes supporting the validity of constant proportions between certain key enzymes in human skeletal muscles.
The relationships between the carnitine concentration and enzyme activities representative of different metabolic pathways, glycogenolysis, glycolysis, beta-oxidation of fatty acids, citric acid cycle, and respiratory chain were studied in skeletal muscle tissue from 18 volunteering subjects. In addition, the in vitro incorporation rates of glucose-carbon and palmitate-carbon into different metabolites, and the concentration of glycogen, triglycerides, and phospholipids were determined in the same tissue specimen. The carnitine concentration correlated positively and statistically significantly with the activities of 3-OH-acyl-CoA dehydrogenase and citrate synthase, with the incorporation rate of palmitate-carbon into CO2, and the incorporation rate of glucose-carbon into lactate in the muscle tissue. The results indicate a coupling between the concentration of carnitine and the capacity for long-chained fatty acid oxidation in human skeletal muscles.
Twenty-three patients with intermittent claudication were submitted to physical training during 4-6 months. Eleven other patients with intermittent claudication served as a control group and were given placebo tablets during the same period. The aim of the investigation was to study the influence of physical training on the blood flow conditions in the calf. The effect of treatment on walking tolerance, on calf blood flow, blood flow resistance, and systolic blood pressure graident between the systemic circulation and the vascular bed in the calf was studied. Half a year after the end of the treatment period the patients were reexamined. The walking tolerance increased in both groups but more in the trained group. The increase in walking tolerance even in the control group was caused by the fact that the control group began to train to some extent. In neither group the maximal calf blood flow changed significantly compared with the pretreatment values. The maximal blood flow showed an increasing trend in the training group after a period fo 4 months compared with the control goupr (2p greater than 0.10). The blood flow resistance at maximal dilatation did not change significantly as compared with the initial values in any of the groups, but there was a significant difference (2p greater than 0.05) between the two groups with a decrease in the training group after 4 months. The changes in maximal calf blood flow and the changes in blood flow resistance at maximal dilatation were not related to the changes in walking tolerance. Half a year after the treatment period the walking tolerance had not decreased and there was no difference between the two groups. The maximal calf blood flow, the blood flow resistance, and the systolic pressure gradient were unchanged in comparison with the pretreatment values and there were no statistically significant differences between the two groups. The small changes in blood flow conditions observed after physical training cannot be the only factor explaining the well known improvement in walking tolerance. However, training may cause a redistribution of the blood flow in the working muscle.
In two patients with severe tetanus the skeletal muscle metabolism was studied. Muscle biopsies were taken 4-6 weeks after the development of tetanus. The patients were treated during this time with a neuromuscular blocking agent. In one of the patients a biopsy was also taken before treatment, 2 days after the first symptoms of the disease. Enzyme activities representative for glycogen synthesis, glycogen greakdown, glycolysis, fatty acid beta-oxidation and respiratory chain, and fluxes of glucose, palmitate and leusine in vitro, and the concentrations of glycogen, triglycerides, phospholipids, cholesterol, proteins and RNA were determined in the muscle tissue. The enzyme activities in the muscle tissue examined 2 days after the development of tetanus were close to normal, excep for decreased activities of phosphofructokinase and glycogen synthase. After 4-6 weeks of treatment the fluxes of glucose and palmitate and the corresponding enzyme activities were low in both patients. These findings are consistent with muscular inactivity. In contrast the activity of glucose-6-phosphate dehydrogenase, the incorporation rate of leucine-carbon into proteins and the RNA content were high, indicating a high protein synthesis as a probable manifestation of active repairative processes. It is concluded that the skeletal muscle metabolism in these patients was affected in a degenerative manner and that this effect was attributed more to the treatment than to the disease per se. Dynamic physical training under supervision is recommended for the period after the generalized spasms to overcome the "disuse" effects in the skeletal muscles.
In order to define specific metabolic abnormalities of adipose tissue metabolism in endogenous hypertriglyceridemia (EH) patients with this condition were compared with normolipidemic controls matched for body fat and fat cell size. In vitro the enlarged fat cells of EH were found to have an increased basal and noradrenaline-stimulated lipolysis in comparison with cells of the same size from normolipidemic controls. The insulin inhibition of noradrenaline-stimulated lipolysis was blunted. Lipoprotein lipase activity in these cells was clearly depressed. Basal triglyceride synthesis from labeled glucose was low in relation to plasma insulin. The reduction of insulin tolerance in vivo suggested that the depression of plasma glycerol and free fatty acid concentration was small in EH, suggesting that the more detailed findings in vitro were of relevance for in vivo conditions. It was suggested that the hyperinsulinemia and decreased glucose tolerance of EH may well be responsible for some of the aberrations of adipocyte metabolism in EH. The decreased responsiveness of lipolysis to insulin and the low lipoprotein lipase activity are, however, findings not typical for enlarged fat cells exposed chronically to insulin and might be characteristic for the fat cells of EH. It seems of importance to further define the factor(s) responsible for these metabolic aberrations, because the abnormalities of the acipocyte metabolism in EH may well offer a possible explanation to the pathogenesis of that condition.
An in vitro preparation of human skeltal muscle tissue aimed to be a model for clinical metabolic studies was functionally and structurally characterized. Muscle fibres from biopsy specimens obtained at surgical operations were teased away and collected in incubation vessels for the following determinations: exchangeable water content, extracellular space, potassium content, incorporation rate of labeled leucine into proteins, uptake of labeled cycloleucine, alpha-aminoisobutyric acid (AIB), and 3-o-methy1-glucose into the intracellular space, and the incorporation rate of glucose into various metabolites. After various times of incubation, muscle fibre samples were also taken for light and electron microscopy. During the incubation of the muscle fibres a transient intracellular oedema was demonstrated by electron microscopy and by determination of the exchangeable water content. The restitution of this oedema was associated with an increasing intracellular potassium concentration. Active transport of leucine, cycloleucine and AIB showing competitive inhibition was registered. The incorporation of labeled leucine into proteins was linear during 4 h of incubation and optimal stimulation of this incorporation was demonstrated in the presence of a complete amino acids mixture at a concentration corresponding to 10 times the normal plasma concentration in man. Insulin stimulated the incorporation rate of glucose-carbon into all metabolites and ouabain stimulated its incorporation in to glycogen. Monoidoacetate inhibited the incorporation of glucose into all metabolites.
A retrospective interhospital study of 171 surgically treated patients with atherosclerotic abdominal aortic aneurysm is presented (Orebro and Göteborg). Elective resection of the aneurysm was performed in 94 of the patients and emergency resection because of rupture or suspected rupture of the aneurysm in 77 cases. The mortality within the first postoperative month was 16% in the electively operated patients and 49% in the emergency operated patients. During the last 3 years, the mortality rate among electively operated patients was considerably lower (10%). The five-year survival rate was more than 50% in the electively operated patients. The main difference in long-term survival rate between emergency and electively operated patients was dependent on the primary mortality. The cause of late death was usually not related to the operation of the aneurysm, but to other manifestations of generalized atherosclerotic disease. The results seem to justify the conclusion that atherosclerotic abdominal aortic aneurysm should be resected irrespective of size and symptoms, unless the patient has symptoms of severe arterial hypertension and/or generalized atherosclerosis.
The metabolic capacity of leg muscles was determined in 12 patients with peripheral arterial insufficiency before and 6 months after vascular surgery. Succinic oxidase activity and the incorporation rates of glucose-carbon into glycogen, lipids, lacate, and CO2 were determined as a measure of metabolic capacity. Leg muscles from patients with intermittent claudication had high metabolic capacity, as shown previously. This capacity was reduced towards control values after successful revascularizations, while it remained unchanged if the surgery failed. In patients with gangrene the preoperative values of leg muscles' metabolic capacity were subnormal, and increased towards control values if surgery was successful. In 2 patients with limb gangrene the vascular surgery was only partially successful i.e. the gangrene threat was changed into intermittent claudication. In these 2 patients the metabolic capacity of leg muscles changed from sub- to supracontrol values. In 2 patients the vascular surgery failed, and the patients had no benefit from the operation. In these 2 patients the metabolic capacity of leg muscles remained unchanged. These results support the theory that changes in the amount of blood flow, i.e. the supply of oxygen and substrates to the leg, govern the level of metabolic capacity of the skeletal muscles. The results seem to justify the recommendation that reconstructive arterial surgery in patients with intermittent claudication ought to be followed by physical training to preserve the high metabolic capacity in the skeletal muscles.