Minimal clinically important difference module: summary, recommendations, and research agenda.
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Humans↗
Biomedical subjects
V A Welch
Publications and source records attributed to V A Welch.
Cyclosporine for rheumatoid arthritis.
OBJECTIVES: To estimate the short-term (up to one year) effects of cyclosporine for rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles. SELECTION CRITERIA: All randomized clinical trials (RCTs) and controlled clinical trials (CCTs) comparing cyclosporine against placebo in patients with rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: Two reviewers determined the trials to be included based on inclusion and exclusion criteria (GW, MSA). Data were independently abstracted by two reviewers (DH, GW),and checked by a third reviewer (BS) using a pre-developed form for the rheumatoid arthritis sub-group of the Cochrane Musculoskeletal Group. Methodological quality of the RCTs and CCTs was assessed by two reviewers (BS, DH). Rheumatoid arthritis outcome measures were extracted from the publications for change from baseline endpoints. Sufficient data were obtained to include in the pooled analysis the number of swollen joints, physician global assessment, patient global assessment and erythrocyte sedimentation rate (ESR). MAIN RESULTS: Three trials and 318 patients were included. A statistically significant decrease in the number of tender and swollen joints was observed for cyclosporine when compared to placebo. The standardized mean difference (SMD) for the change in the number of swollen joints was -0.969. Significant improvements in pain and the functional index were also found for cyclosporine. More side effects occurred in the cyclosporine group compared to placebo. REVIEWER'S CONCLUSIONS: Cyclosporine has an important clinical benefit int the short-term (up to one year) treatment of patients with progressive rheumatoid arthritis.
Antirheumatic Agents↗
Comparative effects on blood lipids and faecal steroids of five legume species incorporated into a semi-purified, hypercholesterolaemic rat diet.
The cholesterolaemic effects in rats of a diet (VS) containing Bambara groundnuts (Vigna subterranea), a popular legume eaten in Nigeria, were compared with diets PV, PS, LC and PL, containing baked beans (Phaseolus vulgaris), marrowfat peas (Pisum sativum), lentils (Lens culinaris Medik.) and butter beans (Phaseolus lunatus) respectively. Sixty Sprague-Dawley rats were fed on hypercholesterolaemic semi-purified diets supplemented with 10 g cholesterol and 5 g cholic acid/kg and formulated to provide 40% of energy from fat, as in a typical Western-type human diet. Legumes were substituted for 330 g/kg of the semi-purified diet on a dry-matter basis, which was modified to maintain the same contribution of energy sources as the control diet C3. Another ten rats were fed on control diet C2, which was similar to diet C3 but with no added cholesterol. The rats were fed for 8 weeks and plasma cholesterol levels were measured at weeks 4 and 8. The diets incorporating the five different legume species produced very different cholesterolaemic effects. Diets PV and PL were more potent at lowering raised plasma cholesterol levels than diets PS and LC. Inclusion of the Bambara groundnut into the semi-purified diet resulted in an exaggeration of hypercholesterolaemia. Differences in cholesterol-lowering capacity of the various legume diets in this experiment could not be related to concentrations of faecal bile acids or neutral sterols. However, there was evidence that the inclusion of legumes in the diets reduced the faecal excretion of secondary bile acids.
Analysis of Variance↗
Health implications of fatty acids.
1. Although dietary trans fatty acids can effect the fatty acid composition of tissues, they are not considered to be harmful, provided sufficient essential fatty acids are present in the diet. 2. A reduction in dietary saturated fatty acids (SFA) and dietary increases in mono- and polyunsaturated (PUFA) fatty acids are beneficial in reducing the risk of coronary heart disease. 3. There is only limited evidence of a beneficial effect on hypertension by reducing either total fat or SFA in the diet. 4. There is a little evidence of a role for dietary fat in the initiation of cancer but linoleic acid has been implicated in tumor promotion and chemical carcinogenesis. 5. Dietary PUFA might be beneficial in the treatment of certain autoimmune diseases such a multiple sclerosis.
Diet↗
Transport and cellular uptake of polychlorinated biphenyls (PCBs)--I. Association of individual PCB isomers and congeners with plasma lipoproteins and proteins in the pigeon.
Polychlorinated biphenyls (PCBs) are abundant and persistent pollutants in the ecosystem. Commercial mixtures (e.g. Aroclor 1254) can contain up to 80 different isomers and congeners, many of which accumulate in biological systems by the ingestion of PCB-contaminated lipid components of food chains. PCBs are lipophilic and lipid-rich lipoproteins provide an excellent system to transport PCBs to tissues. We report here the distribution of PCBs between plasma fractions in the pigeon. Twenty-four hours after injection, [14C]4-monochlorobiphenyl and [14C]2,2',5,5'-tetrachlorobiphenyl were associated with the protein-rich HDL fraction and the lipoprotein-poor fraction (predominantly albumin), rather than with the lipid-rich VLDL and LDL fractions. Five days after injection with the commercial PCB mixture Aroclor 1254, there was a distinctive distribution between the plasma fractions of the 41 congeners detected. Avian species have a poorly developed lymphatic system and dietary lipids are secreted into the portal vein. To emphasize this route of entry, the lipoprotein particles formed are termed portomicrons rather than chylomicrons. The most striking result was that the lipid-rich portomicron and the VLDL fraction was associated almost exclusively with only one congener (2,2',4,4'5,5'-hexachlorobiphenyl), whereas the other isomers and congeners were distributed amongst the LDL, HDL and the lipoprotein-poor (predominantly albumin) fractions. Thirteen of the congeners detected accounted for 74, 53 and 54%, respectively, of the total amount of PCBs in the LDL, HDL and lipoprotein-poor protein fractions. Five congeners that are highly toxic were enriched in the latter fraction. The distribution of PCBs is more complex than can be explained solely by their solubility in the lipid components of plasma fractions, and may suggest a complex association with apolipoproteins and plasma proteins that are important in transporting PCB to tissues. The identification of individual PCBs in lipoprotein fraction provides evidence for their role in the transport of lipophilic xenobiotics in blood and it is suggested that PCBs associated with lipoproteins are taken up by cells as lipoprotein-PCB complexes.
Animals↗
Transport and cellular uptake of polychlorinated biphenyls (PCBs)--II. Changes in vivo in plasma lipoproteins and proteins of pigeons in response to PCBs, and a proposed model for the transport and cellular uptake of PCBs.
The complex distribution of polychlorinated biphenyl (PCB) isomers and congeners amongst plasma fractions of the pigeon suggests that the lipid and apolipoprotein components of lipoproteins, as well as plasma proteins, may be important in transporting PCBs to tissues (Borlakoglu et al., Biochem. Pharmac. 40, 265 (1990]. Pigeons were injected with the commercial PCB mixture Aroclor 1254 (1.5 mmol/kg body weight). After 120 hr triacylglycerol-like droplets accumulated in hepatocytes ('fatty liver syndrome'), there was proliferation of the hepatic smooth endoplasmic reticulum, and plasma concentrations of triacylglycerol and total cholesterol increased. This was accompanied by significant decreases in plasma concentrations of total protein, total apolipoproteins of the low density lipoprotein (LDL) and the high density lipoprotein (HDL) fractions, and albumin and by a significant increase in that of urea, indicating increased protein breakdown. These results suggest that Aroclor 1254 increased hepatic lipid synthesis, but decreased hepatic production of albumin and apolipoproteins. This would explain the accumulation of triacylglycerol in the liver and the increase in the proportion of triacylglycerol to apolipoprotein in the total lipoproteins. From the evidence presented, a model is proposed based on the association of PCBs with hydrophobic domains of lipids and proteins for the transport of PCBs by plasma fractions, their uptake into cells and intracellular metabolism, and their accumulation in adipose tissue.
Animals↗
The effects of chemically modifying serum apolipoproteins on their ability to activate lipoprotein lipase.
Lipoprotein lipase activity was measured in an acetone-dried-powder preparation from rat epididymal adipose tissue using pig serum or pig serum lipoprotein, which had been chemically modified, as activator. Modification of acidic amino acids of lipoproteins with NN-dimethyl-1,3-diamine resulted in a complete loss of ability to activate lipoprotein lipase. Modification of 34% of lipoprotein arginine groups with cyclohexanedione resulted in the loss of 75% of the activation of lipoprotein lipase; approx. 42% of the original activity was recovered after reversal of the modification. This effect was dependent on the cyclohexanedione concentration. Modification of 48% of lipoprotein lysine groups with malonaldehyde decreased the maximum activation by 20%, but three times as much lipoprotein was required to achieve this. Non-enzymic glycosylation of lipoprotein with glucose, under a variety of conditions resulting in up to 28 nmol of glucose/mg of protein, had no effect upon the ability to activate lipoprotein lipase. In contrast non-enzymic sialylation resulted in a time-dependent loss of up to 60% of ability to activate lipoprotein lipase. Reductive methylation and acetoacetylation of serum did not affect the ability to activate lipoprotein lipase. The results are compared to the effects of similar modifications to low density lipoproteins on receptor-mediated endocytosis.
Amino Acids↗
Intermolecular specificity of pancreatic lipase in the lipolysis of triacylglycerols containing phytanic acid.
Treatment of mixtures of glycerol tripalmitate and rac-glycerol 1,2-dipalmitate 3-phytanate with pancreatic lipase demonstrated that phytanic acid retarded the release of palmitic acid esterified in the same triacylglycerol.
Eicosanoic Acids↗
Immunological properties of bovine serum lipoproteins and chemical analysis of their protein moieties.
Four classes of bovine serum lipoproteins were isolated by precipitation with dextran sulfate, ultracentrifugation, and preparative electrophoresis on polyacrylamide gel. Very low density lipoprotein (d less than 1.019 g/ml) was related immunologically to low density lipoprotein-two (d 1.039 to 1.060 g/ml) and high density lipoprotein (d 1.060 to 1.210 g/ml) was related immunologically to low density lipoprotein-one (d 1.019 to 1.039 g/ml), but the two pairs were immunologically distinct. The major N-terminal amino acid of both high density lipoprotein and low density lipoprotein-one was aspartic acid, and that of low density lipoprotein-two was glutamic acid. Very low density lipoprotein had both aspartic acid and glutamic acid as the major N-terminal amino acids. None of the lipoproteins was identical with any other with respect to amino acid composition, but high density lipoprotein and low density lipoprotein-one were similar to each other and different from low density lipoprotein-two. Very low density lipoprotein was similar to both low density lipoprotein-one and low density lipoprotein-two. It is concluded that the proteins of high density lipoprotein and of low density lipoprotein-one are related and are different from that of low density lipoprotein-two. The protein of very low density lipoprotein is related to that of low density lipoprotein-two but may contain polypeptides of high density lipoprotein or low density lipoprotein-one.
Amino Acids↗
Determination of physical properties of bovine serum lipoproteins by analytical ultracentrifugation.
Pure samples of low density lipoprotein-one (d 1.019 to 1.039 g/ml), low density lipoprotein-two (d 1.039 to 1.060 g/ml), and high density lipoprotein (d 1.060 to 1.210 g/ml) were isolated from bovine serum and their properties studied in the analytical ultracentrifuge. Approach-to-equilibrium experiments indicated that the lipoprotein classes were homogeneous. Molecular weights of the lipoproteins given by this method (low density lipoprotein-one, 1.14 x 10(6); low density lipoprotein-two, 2.37 x 10(6); high density lipoprotein, .576 x 10(6)) agreed well with those obtained by a high-speed-equilibrium method (1.03 x 10(6), 2.15 x 10(6), and .567 x 10(6)). Linear plots of flotation rate (corrected for viscosity) against the density of the medium were obtained in sedimentation velocity experiments and on extrapolation gave values for the hydrated density of 1.032 g/ml for low density lipoprotein-one, 1.044 g/ml for low density lipoprotein-two, and 1.071 g/ml for high density lipoprotein. The density of the material which would have to be added to high density lipoprotein to give it the physical properties of low density lipoprotein one was less than 1 g/ml, which suggested that it was predominantly lipid.
Animals↗
Effect of pregnancy and lactation on triglycerides of very-low-density lipoproteins of rat plasma.
Triglyceride in the blood of rats increased during pregnancy, decreased to control during lactation, and increased again on weaning. The triglyceride content of the very-low-density lipoproteins (d less than 1.006 g/ml) changed in parallel with that of the plasma, and its magnitude indicated that it was chiefly responsible for the transport of triglycerides in the blood. These changes were accompanied by changes in the electrophoretic pattern of the lipoproteins of rat plasma, but no such changes were observed in lipoproteins of ovine and caprine serum.
Animals↗
Lipid composition of bovine serum lipoproteins.
The four classes of lipoproteins (one of very low density, two of low density, and one of high density) were isolated from the serum of a lactating Friesian cow. The proportions of protein and of the different lipid classes were determined in each lipoprotein. Triglycerides predominated in the very low density lipoprotein, and cholesteryl esters and phospholipids in the others. The triglycerides of the very low density lipoprotein were richer in oleic acid than were those of the low density lipoproteins, but its cholesteryl esters were relatively poorer in linoleic and linolenic acid than were those of any of the others. Phytanic acid (3, 7, 11, 15-tetramethylhexadecan-1-oic acid) was in all lipoproteins except those of very low density; it was not in cholesteryl esters but was abundant in triglycerides, particularly in those of the low density lipoproteins. Hydrolysis of the triglycerides of very low density lipoprotein with pancreatic lipase showed that 82% of their stearic acid was esterified to the 1- and 3-positions of glycerol and that 64% of their palmitic acid was esterified to the 2-position.
Animals↗
Contribution of the fatty acids of three low density serum lipoproteins to bovine milk fat.
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Animals↗
Determination of the specific radioactivity of fatty acids separated as their methyl esters by gas-liquid chromatography.
Free or combined (3)H-labeled fatty acids are converted to their methyl-(14)C esters or, if labeled with (14)C, to their methyl-(3)H esters. For a given specific radioactivity of the methyl group, the nuclide ratio in the esters separated by GLC is a direct measure of the specific radioactivity of the fatty acids, and quantitative collection is unnecessary. Methods of methylation with minimum quantities of labeled methanol, and of deriving nuclide ratios from channel ratios in a scintillation spectrometer, are given.
Carbon Isotopes↗
Studies on the origin of milk fat. A further study of bovine serum lipoproteins and an estimation of their contribution to milk fat.
1. Tritium-labelled palmitic acid combined in olive-oil triglycerides was introduced into the rumen of a lactating cow and the specific radioactivity of the lipids of milk and of the lipoproteins of both jugular and mammary venous serum was measured. 2. As previously found in a similar experiment with [(3)H]stearic acid, the specific radioactivity of the triglyceride fraction of the dextran sulphate-precipitable lipoproteins reached a maximum earlier and greater than that of the milk fat. 3. This fraction was the only lipid separated that had a significant arteriovenous difference in concentration, and is therefore identified as the main circulating lipid precursor of milk fat. 4. Although the non-esterified fatty acids showed no arteriovenous difference in concentration, they showed a negative difference in specific radioactivity that could have occurred only at the expense of the triglycerides of the precipitable lipoproteins. 5. The mean specific radioactivity of the triglycerides immediately after removal from the blood is calculated and shown to be very close in value to that of the corresponding fraction in mammary venous serum. 6. By comparison of the mean specific radioactivities of milk fat and of this precursor, its contribution is calculated as 36%. 7. This value is discussed with reference to the concentration of C(16) and C(18) fatty acids in milk fat and it is concluded that substantial amounts of these acids must have been derived from a source other than preformed circulating lipids.
Animals↗
An investigation of serum lipoproteins and of their contribution to mild fat in the dairy cow.
1. Tritium-labelled olive-oil triglycerides were introduced into the rumens of lactating cows and the specific activities of the lipids of milk and plasma and of serum lipoproteins were measured. 2. On treatment of serum with dextran sulphate it was found that the lipid of the precipitated beta-lipoproteins consistently had a specific activity-time curve with a maximum comparable in value with, and occurring earlier than, that of the milk fat. 3. On fractionation of the lipids of these lipoproteins it was found that only the triglycerides and diglycerides had specific activity-time curves with maxima greater than that of milk fat, and on radioactivity data alone they are the only blood constituents studied that meet the requirements for being the precursor of milk fat. 4. From a consideration of abundances and the mean specific activities over the period of the experiment it is shown that the contribution of the diglycerides to the radioactivity in the milk fat must have been negligible and that only the triglycerides could have been responsible for all the radioactivity found in it. 5. Although no other fraction could alone have been responsible for all the radioactivity in the milk fat, at least one, the phospholipids, could have made some contribution. 6. It is calculated that 35-48% by weight of milk fat was derived from the beta-lipoprotein triglycerides, according to whether the phospholipids made an improbably large contribution or none at all.
Animals↗