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[Feeding-related disorders in medicine, with special reference to cancer anorexia-cachexia syndrome].

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life.

Adipose Tissue↗

Urinary excretion of carnitine in man.

A convenient assay procedure for urinary carnitine is described. Urinary excretion of carnitine is determined in human subjects in various experimental states. Average excretions by this procedure were 59.3+/-3.3 mg. per day in men and 44.1+/-2.9 mg. per day in women. Carnitine excretion had a wide variation in women during the menstrual cycle and reached a maximum at the time of ovulation, but the excretion was relatively constant in men. Marked increases in carnitine excretion were observed in the states with increased lipolysis induced by fasting or ACTH injection. This finding suggests that lipid mobilization might be reflected in the excretion of carnitine in urine.

Adolescent↗

Aldehyde fixation causes membrane vesiculation during platelet exocytosis: a freeze-substitution study.

Despite a plethora of reports on the ultrastructure of secretory granule release by exocytosis, the release of coagulant activity from stimulated platelets is still being attributed to membrane vesiculation. Membrane vesiculation and the formation of myelin figures have been shown to be artifacts of glutaraldehyde GA fixation. Cells fixed by direct osmium or rapid freezing are free of such structures. Yet there is still doubt that rapid freezing interferes with vesiculation process. This study has addressed this issue by examining: (1) whether freezing and freeze-substitution affects membrane vesiculation, (2) whether paraformaldehyde-fixation also induces the phenomenon, and (3) whether the aldehyde concentration is of influence. Aldehyde fixation was carried out prior to impact freezing and freeze-substitution. In thrombin-stimulated platelets, membrane vesiculation and myelin figures were found. Glutaraldehyde induced multivesicular structures, paraformaldehyde or low aldehyde concentrations only blebs on the platelet surface. The membrane vesicles were in continuity with the cytoplasmic matrix. Unstimulated platelets did not show vesiculation or myelin figures. Control samples, without aldehyde fixation, showed instead of membrane vesiculation, granule fusion with the plasmalemma, or, instead of myelin figures, compound granules. This confirms that membrane vesiculation and the formation of myelin figures are artifacts induced by the failure of aldehydes to arrest lipid mobility within membranes undergoing rapid changes in structure. Although the presence of membrane vesiculation and myelin figures in platelets indicates that exocytotic processes were occurring at the moment of aldehyde fixation, the finding of membrane vesiculation in aldehyde-fixed platelets does not indicate a separate type of exocytosis.

Aldehydes↗

[Lipolysis and lipid oxidation of weight stable patients with malignant tumors of the digestive system].

Tumor-caused weight loss is frequently associated with a high rate of lipolysis and fat oxidation. In order to differentiate the effect of weight-loss from the tumour-dependent regulation of fat metabolism, we studied weight-stable and well nourished patients (ideal body weight 109 +/- 4% (+/- SEM), body mass index 25.1 +/- 0.9 kg/m2). Parameters of lipolysis (glycerol-, fatty acid concentrations) and the calorimetric determined fat oxidation rate of five male tumor patients were examined before and during an euglycaemic insulinclamp (0.2 mU insulin/kg/min). Concomitant with a high rate of lipolysis (glycerol concentration 112 +/- 20 mumol/l, free fatty acid concentration 0.72 +/- 0.13 mmol/l) and fat oxidation (60% of energy expenditure) there was a low normal insulin level (5.9 +/- 0.5 mU/l). Insulin reduced lipolysis and fat oxidation and stimulated glucose oxidation. Weight-stable tumor patients have a high basal rate of lipolysis and fat oxidation; yet the insulin dependent regulation of the fat metabolism is intact, as we have already shown for weight-losing cancer patients.

Adult↗

Long-term effects on lipid metabolism of weight reduction on lactovegetarian and mixed diet.

The effects of two dietary weight reduction programmes (1200 kcal/day) on lipid metabolism were followed for one year in moderately obese subjects. The groups consisted of lactovegetarian (n = 31), mixed diet (n = 37) and control (n = 42) groups. Serum triglyceride levels decreased rapidly during the first two weeks (46 per cent on average) especially in the mixed diet group, and this change was still statistically significant at 6 and 12 months after the beginning of the study. Serum total cholesterol levels also decreased rapidly in the beginning, but at 6 and 12 months the change was no longer statistically significant. After a small initial decrease HDL cholesterol levels appeared to increase towards the end of the study year. This increase was more marked in men (18.6 per cent at 6 months) than in women, and in the mixed diet group than in the lactovegetarian group (P less than 0.05 between the groups). The HDL/total cholesterol ratio increased rapidly in the beginning of the weight reduction and practically remained at the elevated (12-16 per cent) level during the whole follow-up. This increase was also more apparent in men than in women, and in the mixed diet group than in the lactovegetarian group. The changes in HDL subfractions, HDL2 and HDL3, paralleled those seen in the HDL cholesterol levels. Similarly the alterations in apolipoproteins A-I and B resembled those of the HDL and total cholesterol levels. The activity of adipose tissue lipoprotein lipase decreased drastically (about 50 per cent) at the beginning of the weight reduction, while at 6 and 12 months the mean activities were higher than the initial levels. This was also seen in the LPL activity when measured in post-heparin plasma. The activity of post-heparin plasma hepatic lipase decreased clearly at both 6 (P less than 0.001) and 12 months (P less than 0.01) in the mixed diet group, whereas no change was found in the lactovegetarian group. The ratio of subscapular to triceps skinfold reduced significantly (P less than 0.01) in women but not in men during the intervention period. Our study shows that in moderately overweight subjects weight reduction with the aid of a low-calorie dietary programme results in favourable responses in lipid metabolism many months after the cessation of the weight reduction programme. These responses appear to be stronger in subjects following mixed diet than in those attempting to follow a lactovegetarian diet.

Adult↗

Classification of obese patients and complications related to the distribution of surplus fat.

The relation between obesity and noninsulin-dependent diabetes mellitus is established. The weak association between obesity and cardiovascular disease or stroke might be attributable to a risk present only in a subgroup of obesity patients. Recent prospective studies have shown such a group to be characterized by abdominal localization of adipose tissue, reviving old empiric observations of such links. The sex-linked adipose tissue distribution is probably dependent on a balance between glucocorticoids and sex steroid hormones. The former are active mainly on intraabdominal adipose tissues through the high density of a specific receptor expressing lipoprotein lipase activity. This effect is counteracted by female sex steroid hormones, mainly progesterone, which promote fat deposition in the gluteal-femoral regions, utilized mainly during pregnancy and lactation. Testosterone stimulates lipid mobilization through transcriptional expression of beta-adrenergic receptors via a specific androgen receptor and also inhibits lipoprotein lipase activity. Intraabdominal adipose tissues, drained by the portal vein, have a very sensitive lipolytic system in men, based on an increased beta-adrenoceptor activity. This is probably a testosterone effect via the mechanisms mentioned. With testosterone deficiency, these mechanisms are less active, permitting accumulation of fat that can be reversed by testosterone substitution. Abdominal distribution of fat in men thus is probably a sign of relative testosterone deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

Heterogeneity of human lipoprotein Lp[a]: cytochemical and biochemical studies on the interaction of two Lp[a] species with the LDL receptor.

Human Lp[a] can be fractionated into two species with different affinities for lysine-Sepharose. Forty to 81% of the total Lp[a] in the density fraction 1.055-1.15 g/ml from five individuals was retained by this affinity column. The remaining unretained Lp[a] species with no apparently functional lysine binding site was similar to the retained species in its electrophoretic mobility, lipid, protein, and apolipoprotein composition, and the heterogeneity was not related to apo[a] size polymorphism. Interaction of the two species with the low density lipoprotein (LDL) receptor was studied in human fibroblasts. Using gold-labeled lipoproteins and an immunochemical procedure, both Lp[a] species could be located in clusters on the cell surface, but the extent of labeling was far lower than that seen with LDL. Both Lp[a] variants were less effective than LDL in 1) down-regulation of LDL-receptor activity; 2) suppression of cellular sterol synthesis; and 3) stimulation of cholesteryl ester formation in human fibroblasts. Although degradation of both species of Lp[a] by the perfused rat liver was stimulated after estrogen induction of hepatic LDL-receptor activity, the stimulation amounted to only a quarter of that seen with LDL. The heterogeneity of Lp[a] with respect to the ability to bind epsilon-aminocarboxylic acid will need to be considered in studying the physiological role of this lipoprotein. Both Lp[a] species exhibited a similar interaction with the LDL-receptor in vitro, and confirmed previous investigations that Lp[a] is only a poor ligand for the LDL-receptor.

Affinity Labels↗

Adenosine deaminase and porcine meat quality. I. Effect of dipyridamole on plasma free fatty acids, glucose, lactate and c-AMP in pigs representing high and low red cell adenosine deaminase activity.

The effect of dipyridamole--an adenosine uptake inhibitor--on the plasma concentration of free fatty acids (FFA), glucose, lactate and cyclic adenosine monophosphate (cAMP) has been examined in 2 groups of Landrace pigs representing low (Ada 0) and high (Ada A) red cell adenosine deaminase (Ada) activity. Pigs fitted with a jugular vein catheter were given dipyridamole (0.16 mg/kg/min) over a period of 30 min. The infusions were performed 22 h after the last meal at a time where pigs were found to show steady increase and decline in rates of lipolysis and glycogenolysis, respectively. The results showed that lipid mobilization as identified by the plasma FFA concentration was markedly depressed. During the infusion of dipyridamole similar degree of inhibition was seen in Ada 0 and Ada A pigs, however, in the period following the infusion, a significantly stronger suppression persisted in the Ada 0 pigs. Both the blood glucose and lactate level rose distinctly as a result of the dipyridamole treatment. This stimulation of the glycolysis rate was significantly more expressed in Ada 0 pigs compared to that of the Ada A pigs. When theophylline, an antagonist of adenosine, was given together with dipyridamole, the rise in the lactate level was considerably diminished. Dipyridamole also produced a distinct rise in the plasma cAMP levels.

Adenosine Deaminase↗

Site-specific and sex differences in the rates of fatty acid/triacylglycerol substrate cycling in adipose, tissue and muscle of sedentary and exercised dwarf hamsters (Phodopus sungorus).

Site-specific and sex differences in fatty acid/triacylglycerol substrate cycling in adipose tissue and muscle were found in vivo in adult hamsters (Phodopus sungorus) fed ad libitum, both at rest and immediately after moderate exercise. In adipose tissue, rates of fatty acid/triacylglycerol cycling at rest were highest in two small intermuscular depots and lowest in the groin, behind forelimb, epididymal and kidney sites. Cycling rates were significantly higher in the groin and in the two depots around the forelimb in females. Following an hour of exercise in a hamster ball, the rates of fatty acid/triacylglycerol cycling rose significantly in the intermuscular and certain superficial adipose fatty depots of both sexes, but the increases were more uniform in males. In females only, cycling rates in the skeletal muscles also increased significantly. The rates of fatty acid/triacylglycerol cycling in adipose tissue correlate closely with the site-specific activities of hexokinase and phosphofructokinase, but not with mean adipocyte volume per se. The data are consistent with the hypotheses that adipose depots are depleted selectively during exercise and that there are sex differences in the pattern of lipid mobilization.

Adipose Tissue↗

[Secretion of fatty acids into milk as a function of the characteristics of the diet and the nutritional status of the goat at the onset of lactation].

The amounts of 11 milk fatty acids secreted by 210 individual goats during the 2nd week of lactation were explained by 4 variables: the intake of digestible organic matter and ether extracts, the organic matter digestibility and a lipid mobilization index. Significant effects varied according to the acids. About a quarter of the absorbed acetate equivalent appeared to be secreted as milk fat.

Animal Feed↗

All trans-retinol effects on human colon adenocarcinoma cultured cells: biological and nmr studies.

The effect of all-trans-retinol on tumor cell line HCT-8R from human colon adenocarcinoma has been examined. Growth inhibition in the absence of cytotoxic effect has been observed. T1 and T2 relaxation times of 1H NMR resonances from mobile lipid domains are shortened by adding the vitamin A to the culture medium. Furthermore, the 31P NMR phosphodiester signal, attributed to a RNA-proteolipid complex from plasma membrane, is affected by retinol treatment. A possible correlation between growth inhibition and NMR results is discussed.

Adenocarcinoma↗

The role of apolipophorin III in in vivo lipoprotein interconversions in adult Manduca sexta.

Sustained flight in the moth, Manduca sexta, necessitates lipid mobilization and transport to flight muscle, a process mediated by the adipokinetic hormone. An adult specific high density lipophorin (lipoprotein, HDLp-A, Mr = 7.68 X 10(5)) accepts diacylglycerol from the fat body, increasing in size and decreasing in density, to give a low density lipophorin (lipoprotein, LDLp, Mr = 1.56 X 10(6)). During this process, several molecules of the small apolipoprotein, apolipophorin III (apoLp-III), are added to the two molecules originally present in HDLp-A. A study of the time course of adipokinetic hormone-induced loading of diacylglycerol onto HDLp-A, using the analytical ultracentrifuge and gel filtration, suggests that a lipoprotein of density intermediate between HDLp-A and LDLp was formed transiently. Analysis of lipoproteins separated by density gradient ultracentrifugation in the course of the loading process indicates that apoLp-III is added more rapidly than diacylglycerol and that it changes its conformation on the surface as more diacylglycerol is added. Taken together with the known properties of apoLp-III, a prolate ellipsoid with an axial ratio of 3, we suggest that initially apoLp-III adds to the expanded hydrophobic surface of the lipoprotein with its short axis parallel to the surface and that apoLp-III subsequently unfolds to cover a greater area of hydrophobic surface. Exchange experiments with labeled apoLp-III showed that the two apoLp-III molecules in HDLp-A do not exchange with free apoLp-III, even when the lipoprotein passed through a loading and unloading cycle, suggesting a structural role for apoLp-III in HDLp-A.

Animals↗

[1H-NMR spectroscopy of the cell membranes of thymus lymphocytes in AKR mice].

360 MHz 1H NMR was used to monitor the changes of AKR mice thymus lymphocytes in cases of spontaneous and transplantable leukemia and vincristine administration. A comparison of relative signal intensities of methyl and methylene fatty acid chains protons and phosphatidylcholine headgroups protons enables to monitor leukemia development and vincristine effect. Spin-lattice relaxation curves of the same protons of leukemic thymi lymphocytes are well fitted by biexponential functions, bringing evidence for two regions with different lipid mobility.

AKR murine leukemia virus↗

Effect of 2-deoxy-D-glucose on lipolytic processes in blood and adipose tissue of rat.

The effect of 2-deoxy-D-glucose on lipolytic processes in the blood and adipose tissue was studied. Rats treated with this antimetabolite showed a significant increase in serum glucose, FFA and glycerol level, as well as in the lipid mobilizing activity. On the other hand, the lipolytic activity of rat serum decreased when compared to control group. From these results it may be concluded that during hypothermia induced by administration of 2-deoxy-D-glucose intracellular, but not intravascular, lipolysis is enhanced.

Adipose Tissue↗