Biomedical subjects
Publications and source records attributed to I Karlberg.
Abdominal aortic reconstruction was successfully performed in three kidney transplant patients without the use of any specific measures to protect the kidney transplant during aortic cross-clamping. The cases are discussed in relation to previously published case reports describing various surgical techniques to protect kidney transplants during abdominal aortic reconstruction.
Morphometric data on left ventricular papillary muscle structures have been determined in tumor-induced malnutrition and related to the maximum activities of key enzymes for energy production in the whole myocardium. Adult, nongrowing mice with a syngeneic sarcoma were used to represent a condition of cancer associated host tissue wasting. Hearts from mice 11 days after tumor implantation showed atrophy and a significantly reduced amount of myofibrillar, soluble, and collagen proteins than hearts from control animals. The cross-sectional area of myocardial cells was 33% smaller in tumor-bearing mice (p less than 0.025), but the total number of capillaries and the residual interstitial volume were similar in the two groups. The total number of subcellular structures per cell, such as mitochondria, myofibrils, and myosin filaments per myofiber, were significantly lower in the tumor-bearing animals (p less than 0.025). Conversely, the proportion of myofibrils was higher (p less than 0.05) in tumor-bearing animals while the proportion of mitochondria was lower. Maximum activities (Vmax) of selected regulatory key enzymes for energy production (glycogenolytic, glycolytic, and mitochondrial) were not significantly altered in hearts from tumor-bearing mice. The results support the conclusion that myocardial functional capacity is better preserved than overall structural components would imply in tumor-host associated malnutrition, which is probably secondary to deprived food intake. Teleologically, this may be a means by which functional deterioration of the heart is minimized during the induction of malnutrition.
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We demonstrate here that the carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one can cause sister chromatid exchange in human lymphocytes as well as it can cause mutation in bacterial cells and in V79 hamster cells. The non-methylated parent compound which has no tumorigenic action and yet significantly mutates both Salmonella typhimurium TA 100 and hamster V79 cells, has no effect on the frequency of sister chromatid exchange. These results support the idea that sister chromatid exchanges are a valuable additional indicator of tumorigenic potential.
1. Isotope and non-isotope methods were used to study hepatic metabolism of glucose in tumor-host livers. 2. Glycogen synthase, phosphofructokinase activities (Vmax) were decreased, while glucose-6-phosphate dehydrogenase and lactate dehydrogenase activities were increased in tumor-host livers. 3. Glycogen phosphorylase, glucokinase and several mitochondrial enzymes, had normal maximum activity in tumor-host livers. Net flux of glucose was decreased in the Embden-Meyerhof and the pentose phosphate pathway in tumor animals. 4. The hepatic cycling of glucose-carbons in tumor animals was significantly decreased as shown by different [14C] [3H] ratios of radioactivity in RNA and lactate, determined from simultaneous incorporation of [U-14C]glucose and [2-3H]glucose. 5. This study demonstrates that previous reports of increased activities of rate limiting enzymes of glucose metabolism in tumor-host livers do not represent a general finding of high glucose metabolism in tumor-host livers.
Oxygen consumption has been measured in sarcoma-bearing mice, liver cells and tumour tissue. The aim was to determine whether oxidative metabolism in tumour-host livers contributes to the negative energy balance in non-growing animals with a tumour due to insufficient hepatic adaptation of energy consumption. The oxygen uptake in isolated liver cells from freely fed and starved sarcoma-bearing mice showed a 50% decrease (depressed by 322 mumol O2/hr/g) compared to freely fed controls, while starvation of control animals reduced the oxygen uptake in the liver cells by 30-40%. In host tissues other than the liver, total oxygen uptake was depressed by an average 27% (depressed by 50 mumol O2/hr/g) 10-11 days after tumour implantation. In freely fed animals the ratio between oxygen uptake in the tumour-host liver and the host was 0.13 and 0.18 in sarcoma-bearing and control mice respectively. Depression of oxidative metabolism in tumour-host livers was not associated with ultrastructural alterations in the mitochondria or in other cellular organelles studied by electron microscopy. It is concluded that the negative energy balance in a non-growing tumour-bearing host is not explained by deficient adaptation of the hepatic oxidative metabolism, and that depression of activity metabolism in tumour-bearing animals accounts for depression of the metabolic rate in host tissues other than the liver.
This study was designed to ascertain whether the overall availability of whole-body lipids and nitrogen is a limiting factor for survival in tumor-bearing mice suffering from anorexia and cachexia. Three-month-old nongrowing mice (C57BL/6J) were given s.c. transplants of a methylcholanthrene-induced sarcoma. Freely fed, starved, and pair-fed animals were used. Body and lipid composition, tumor growth, and survival time were measured. Freely fed sarcoma-bearing mice died with profoundly altered body composition. This was not explained by the anorexia assessed in pair-feeding experiments. Starvation had caused a more severe depletion in body composition in both tumor-bearing and nontumor-bearing animals than the tumor alone did in freely fed tumor-bearing mice. Freely fed tumor-bearing animals had normal proportions of whole-body triglycerides, cholesterol, and polar lipids, but they lost palmitic acid quantitatively more than any other fatty acid. It is unlikely that any single fatty acid became limiting during tumor growth. The results show that the overall availability of lipids, nitrogen, and glucose precursors is not a limiting factor for survival in experimental tumor cachexia. Other factors considered to be more likely as determining factors for the death of tumor-bearing animals are discussed.
The time course of energy metabolism has been studied in weight-stable and nongrowing mice with a transplantable methylcholanthrene-induced sarcoma. Daily oxygen consumption and carbon dioxide production were measured in relation to the tumor growth from the time of tumor implantation. The time course of energy dynamics was related to the end-state changes in body composition. Freely fed sarcoma-bearing mice decreased their whole-body energy expenditure in proportion to the tumor growth. This was due to the accompanying anorexia. The alteration in oxygen consumption and carbon dioxide production was continuously evident 24 hr/day in sarcoma-bearing mice. The tumor-bearing mice lost body fat and had decreased respiratory quotient, while pair-fed controls maintained their body composition, and their respiratory quotients agreed with the food respiratory quotient. Loss of body lipids in freely fed sarcoma-bearing mice reflected a negative energy balance, accompanied with increased fat oxidation, while maintenance of body composition in pair-fed controls reflected a decreased metabolic rate. Sarcoma-bearing mice showed a significantly higher energy expenditure in relation to their food intake compared to that of pair-fed controls. Estimates of partition of oxygen uptake in sarcoma-bearing mice support that both the host and the tumor account for the elevated energy expenditure. This study has confirmed a small but significantly increased energy expenditure in sarcoma-bearing mice, which was continuously present 24 hr/day in spite of unlimited availability of food. This illustrates the fatal outcome of experimental cancer.
A double isotope method was used in patients with progressive malignancy and in control patients to measure: glucose turnover, conversion rate of carbon skeleton of glycerol into glucose, and the interorgan cycling of glucose carbons (Cori-cycle plus alanine-glucose cycle). [U-14C]glycerol and [6-3H]glucose were given intravenously as a single dose injection. The time course of the specific radioactivities of [6-3H] and [U-14C]glucose was followed in blood. The pool size and the turnover rate of glucose were increased in the cancer group as compared with the control patients. The net recycling of glucose carbons was not increased in the cancer group, despite the increased turnover of glucose. The alterations in the metabolism of glucose did not correlate with the plasma levels of insulin or thyroid hormones (T4, T3, rT3) neither in the entire cancer group nor in those cancer patients who were repeatedly investigated at different intervals of time. The turnover rate of glucose in the cancer patients correlated inversely to their body weight index. The gluconeogenesis rate, given as the fractional conversion rate of the injected radioactive dose of [14C]glycerol, or as mol glucose . kg body weight-1 . day-1, was increased in the cancer group, but still contributed only 3% of the glucose turnover rate in both cancer and control patients. We conclude that an increased gluconeogenesis from glycerol is not significant in terms of energy expenditure in patients with progressive malignancy, as has previously been concluded for the gluconeogenesis from alanine. It seems that increased turnover of glucose may contribute to inappropriately high energy expenditure in cancer patients.
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Reutilization of amino acid carbons was evaluated in relation to increased turnover of albumin in tumor-bearing mice. A methylcholanthrene-induced sarcoma (MCG 101) was used in nongrowing mice (C57BL/6J). Sarcoma-bearing mice developed hypoalbuminemia, but pair-fed controls did not. The hypoalbuminemia was caused by increased albumin degradation rate, measured by injection of Na214CO3, and by exponentially increased deposition of albumin into the tumor compartment. The fractional synthesis rate of albumin was doubled in tumor-bearing mice compared with controls. The translational capacity of albumin synthesis evaluated in vitro was maintained in tumor host livers. The recycling of [14C]leucine carbons was almost extinguished in plasma albumin of sarcoma-bearing mice, while that of control mice contributed to 30 to 40% of the total leucine carbon flux in turned over albumin. The recycling of arginine carbons was also different when measured after simultaneous injection of [guanido-14C]arginine and [2,3-3H]arginine. The hepatic pool of free leucine was increased by 22% in tumor-bearing mice. It is concluded that increased albumin degradation in cancer may be a disordered event and is earlier and of initially greater quantitative importance than is altered synthesis of albumin for the development of hypoalbuminemia in experimental cancer.
Rat-liver cells obtained through perfusion and collagenase treatment were frozen according to a fixed schedule and stored in liquid nitrogen at -196 degrees C. The metabolic capacity of the cells after thawing was tested by measuring their ability to achieve metabolic activation of cyclophosphamide, which in turn was measured as induction of sister-chromatid exchanges in human lymphocytes. The viability and metabolic efficiency of the frozen and thawed cells were comparable with those of fresh cells.
1. The protein degradation rate of human skeletal muscle was evaluated in vitro in isolated fibre bundles from the rectus abdominus muscle by measuring the tyrosine released from muscle tissue proteins. Protein metabolism in this semi-intact preparation was compared with that of the intact extensor digitorum longus muscles from rats under the same experimental conditions. 2. Protein balance was negative in both preparations, but protein synthesis and degradation were two to three times higher in the rat muscles. Tyrosine was released at a constant rate for at least 3 h of incubation independent of whether protein synthesis was inhibited or not. Disintegration of the muscle fibres more than doubled the tyrosine release rate. Human red gastrocnemius muscle showed 37% higher degradation rate compared with the predominantly white rectus abdominus muscle. The half-life of human skeletal muscle protein in vitro was estimated to be 20 days when calculated from the rate of tyrosine release. 3. The addition of leucine to the incubation medium decreased the rate of protein degradation, which was further decreased by the addition of other amino acids. Insulin did not influence the protein degradation rate during 2 h of incubation. This did not reflect a lack of sensitivity to insulin of the preparation, since protein synthesis responded to insulin. Calcium (5 mmol/l) stimulated and zinc (0.1 mmol/l) inhibited the protein degradation. 4. This experimental system may be suitable as an additional tool for evaluating protein degradation in human skeletal muscles.