Surface composition regulates clearance from plasma and triolein lipolysis of lipid emulsions

Sphingomyelin (SM) and cholesterol (Chol) are major surface lipid constituents of plasma lipoproteins. We investigated the effects of SM and Chol on the plasma clearance of lipid emulsions as a model for lipoprotein particles in rats. The presence of Chol facilitated the removal of emulsion particles from plasma, whereas SM delayed particle removal. Preinjection of lactoferrin, an inhibitor of the apolipoprotein E (apoE) receptor, revealed that the differences in clearance of emulsions were due to the differences in affinity for the apoE receptor. Measurement of apolipoprotein binding suggested that the balance of apoE and apoC (apoC-II and apoC-III) bound to emulsions caused the difference in plasma clearance of emulsion particles. That is to say, SM in the emulsion surface decreased binding of apoE, which led to a longer circulation of emulsion particles in plasma. Chol, on the other hand, decreased the ratio of apoC to apoE, which may have promoted emulsion uptake through the apoE receptor. We also examined in vitro lipolysis using immobilized lipoprotein lipase (LPL) in a heparin affinity column. Lipolysis rates were significantly reduced by the incorporation of SM into the emulsion surface, but not by the incorporation of Chol, indicating that SM in the lipoprotein surface is an important lipid component regulating LPL-mediated lipolysis. Our results suggest that the presence of SM and Chol in the lipoprotein surface plays an important role in the circulation behavior and LPL-mediated lipolysis of lipid emulsions through their effect on the selectivity of plasma protein binding.     

Effects of cholesterol and cholesteryl oleate on lipolysis and liver uptake of triglyceride/phosphatidylcholine emulsions in rats

Emulsions composed of soy bean triglyceride (TG), egg yolk phosphatidylcholine (PC), cholesterol (Chol) or cholesteryl-oleate (CO), labeled with a cholesteryl ether (3H-CHE) and a triglyceride (14C-TO), were injected into rats. 14C-TO was removed from plasma faster than 3H-CHE. The 14C-labeled moiety is cleaved by digestion of the TG in the emulsion in plasma and is removed to the endothelial cells (lipolysis). In contrast, the 3H-label remains stably associated and represents circulating emulsion particles. The majority (90%) of the 3H-label disappearing from the plasma accumulated in the liver for all types of emulsions. On the basis of these observations, the lipolysis and the removal of emulsion particles to organs (mainly liver) were determined: 30 mole percent of cholesterol (Chol) at the TG-PC emulsion surface markedly retarded organ uptake, but the effect on lipolysis was rather small; 20 mole percent of cholesteryl oleate (CO) in the TG-PC emulsion cores delayed both organ uptake and lipolysis, and induced a rapid increase in organ uptake rate after the initial delay accompanying the gradual progress of lipolysis. Lipolysis led to the enrichment of the cores with CO. Replacement of the core TG by CO, however, induced strong suppression of the liver uptake. These results show that the lipid composition at both surface and core of emulsion particles is a crucial factor in metabolism in the rat.     

The effects of anesthesia on the biodistribution of drugs in rats: a carboplatin study

PURPOSE: Anesthetics can alter the biodistribution profile of drugs and, consequently, the regional pharmacokinetics of antineoplastic drugs at the tumor site. The effect of coadministered anesthetics on the biodistribution profile of carboplatin was studied in rats. METHODS: Female Wistar rats were used to compare the effects of ketamine/xylazine, thiopental and pentobarbital on the biodistribution of 30 mg/kg radiolabelled 195mPt-carboplatin administered intravenously, with conscious rats as the control group. Blood and urine samples were collected between 5 and 120 min. RESULTS: The percentage values of the injected dose of platinum per ml (%ID/ml) in plasma at the final time-point were respectively, 0.557%, 0.156%, 0.115% and 0.086%, in pentobarbital-, ketamine/xylazine- and thiopental-injected rats, and in conscious animals. Following the same sequence of groups, the %ID/ml values of platinum in the cumulative urine were 0.001%, 0.619%, 0.184% and 0.118%, respectively. Urine output varied from very little in the pentobarbital group, to several milliliters in the other groups. CONCLUSIONS: There was an increase of almost 100-fold in total platinum uptake in the kidneys, cerebrum and cerebellum of rats receiving pentobarbital over the uptake in the control rats, whereas the biodistribution profile of the thiopental group had the least variance. These results demonstrate the importance of anesthetic selection in animal pharmacokinetic studies, as it influences the biodistribution and pharmacokinetic profile of the drug being studied.     

Lipid composition of high density lipoproteins in familial hyperlipoproteinemias

OBJECTIVE: Comparison of side effects (fever shivering and/or allergic reactions, collapse, symptomatic hypocalcaemia) of the different substitution fluids used during therapeutical plasmapheresis. DESIGN: Multicentric retrospective comparative study designed to explore the side effects due to the replacements fluids (albumin alone or associated with dextran 40, modified fluid gelatin, hydroxyethyl starch), and to determine the best combination in patients undergoing plasmapheresis. PATIENTS: 46,895 procedures were performed on 5,167 patients between 1990 and 1994. The analysis concerns 33,962 sessions, divided into two groups (group 1: 21,079 sessions from 1990 to 1992 comparing albumin alone versus combined albumin-macromolecules and the different combinations among these, group 2: 12,883 sessions in 1993-1994 comparing albumin alone versus albumin-hydroxyethyl starch). Because of the diversity of the products used, 13,029 sessions were not studied because groups of small sample sizes were formed. MEASUREMENTS AND RESULTS: In group 1, the comparison of albumin + macromolecules with albumin alone, shows the best haemodynamic tolerance, lower frequency of fever shivering and/or allergic reactions in the albumin alone subgroup. On the other hand, hypocalcaemia is significantly higher in this subgroup. The combinations albumin + dextran 40 (but after hapten inhibition) and albumin + hydroxyethyl starch are equivalent. Albumin + modified fluid gelatin is the combination presenting the highest incidence in terms of allergic manifestations. In group 2, albumin + hydroxyethyl starch versus albumin alone, the former is preferable in terms of the three side effects studied. CONCLUSION: The results of this study show a combination of albumin 4% hydroxyethyl starch to replace plasma during plasma exchange to be the method presenting the lowest morbidity and the best cost/effectiveness ratio.     

Lipid composition of wild and histamine-dependent strains of Candida tropicalis D-2

Lipid composition of prototropic and histidine-dependent strains of Candida tripicalis D-2 was studied by the method of gas and thin layer chromatography. Essential differences are shown in the quantitative composition of neutral lipids and fatty acids of the studied strains.     

Lipid and lipoprotein profiles in children with familial hypercholesterolaemia: effects of therapy

In 71 children with familial hypercholesterolaemia the effect of dietary and/or medical treatment was evaluated. Initial total cholesterol and low density lipoprotein (LDL)-cholesterol levels were significantly lower in children who were consecutively treated by diet (Step-One-Diet) than in those who received additional medication. By dietary treatment, the median total cholesterol level (236.5 mg/dl; range 210-510 mg/dl) was reduced by 7.4% and the median LDL-cholesterol level (162 mg/dl; range 126-423 mg/dl) by 9.9%. By dietary and medical therapy, the median total cholesterol level (330 mg/dl; range 270-424 mg/dl) was reduced by 29.7% and the median LDL-cholesterol level (263 mg/dl; 192-333 mg/dl) by 25.9%. High density lipoprotein (HDL)-cholesterol and HDL 3 remained unchanged. HDL 2 showed a significant decrease of 15.6% up to 27 mg/dl (13-42 mg/dl) on medical treatment. Apolipoprotein A I levels did not change during therapy. Initial apolipoprotein B levels were significantly higher in children who were treated by diet and medication and were reduced by 28.9% by combined therapy. In 28 patients (39.4%) an excess of lipoprotein (a) was detected. Regarding the apolipoprotein E phenotype, 32.2% of the patients carried the risk gene epsilon4 in a hetero- or homozygous form. CONCLUSION: Early dietary and/or medical treatment in hypercholesterolaemic children significantly ameliorates the lipoprotein status. The pretherapy lipoprotein status seems to prognosticate the effectiveness of therapy.     

Practice effects and composition: A reply to Anderson.

J. R. Anderson (see record 1989-24857-001) argues that our results (R. A. Carlson et al; see record 1989-24864-001) confirm several predictions of the ACT* account of skill acquisition, including the occurrence of composition. The ACT* theory does include mechanisms that can account for the major ordinal results of our experiment. However, the quantitative implications of the mechanisms that Anderson invokes to support the occurrence of composition result in unreasonable or inconsistent predictions for this data set. These mechanisms do not account for the observed effects in our control experiment, make the composition hypothesis difficult to falsify, and involve assumptions that negate the processing speed advantage that composition would provide. We also discuss several other points made by Anderson. Our results do provide weak support for some aspects of ACT*, while emphasizing the importance of quantitatively examining interrelations among mechanisms in complex models of skill acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies on segmented polyetherurethane for biomedical application: effects of composition and hard-segment content on biocompatibility

Segmented polyetherurethane (SPEU) materials based on polytetramethylene oxide (PTMO, Mw 1000 and 2000) with various hard-segment contents were synthesized and their biocompatibilities studied via different tests. The static contact angle data reveal that the higher hard-segment-content SPEU material possesses a lower contact angle, implying that the surface of the higher hard-segment-content SPEU is more hydrophilic than its low hard-segment-content SPEU counterpart. The catalyst- and additive-free PTMO-based SPEU materials in this study possess neither a hemolytic nor a cytotoxic response that could be considered non toxic for biomedical applications. By using L-929 cell lines, a cell-seeding test indicated that the higher hard-segment-content SPEU material possesses quicker cell attachment and proliferation behaviors. In vitro platelet adhesion tests indicated that the lower hard-segment-content SPEU possesses less platelet adhesion than the high hard-segment-content SPEU material. Both ex vivo canine artery-artery (A-A) and arterio-venous (A-V) shunting tests revealed that the extent of platelet adhesion reaction is less for lower hard-segment content SPEU. In addition, the blood compatibility of SPEU material synthesized from PTMO 1000 excels over PTMO 2000 SPEU material by near the same levels as the hard-segment-content SPEU.     

Lipid and fatty acid composition of different fractions from rat urinary transitional epithelium

Thyroid hormone action is mediated through its nuclear receptor (thyroid hormone receptor; TR). A mutation in the TR causes resistance to thyroid hormone (RTH) with autosomal dominant inheritance. Using T3 binding assay, gel shift assay and transfection study, the pathogenesis of this disorder was elucidated at a molecular level. Mutant TRs lose their T3 binding activity, and inhibit wild type TR action in a dominant negative manner. For this dominant negative inhibition, the preservation of DNA binding and dimerization activities are required. It is indicated that the mutant TR complex competes with wild type TR complex for the DNA binding site to exert dominant negative inhibition. Thus, the functional analyses of mutant TRs are useful to elucidate the molecular basis of this disorder.     

Lipid composition of bile in morbid obesity before and after jejunoileal bypass surgery

Bile cholesterol, phospholipids, total bile acids, individual bile acids, and fatty acid compositions of bile neutral lipids and phospholipids were analyzed before, at one month and at six months following jejunoileal bypass surgery in a series of morbidly obese patients. Preoperative mole percentages of cholesterol and lithogenic indices were high, indicating that biles were supersaturated with cholesterol and outside the micellar solubility zone when plotted on triangular coordinates. At the one month post-operative period percentages of cholesterol and lithogenic indices were significantly increased as compared to the pre-operative state. At six months post-operatively these values had decreased to approximately the pre-operative levels. No changes were observed in percentages of lithocholic acid, but deoxycholic acid decreased to markedly low levels at one month and remained low at the six month post-operative interval. Relative proportions of cholic acid increased, and the ratio of cholic to chenodeoxycholic acid was significantly increased at both post-operative intervals. No significant changes were noted in bile neutral lipid or phospholipid fatty acid composition, indicating that no depletion of essential fatty acids had occurred.     

Lipid composition of platelets in patients suffering from migraine without aura

Patients with migraine have a platelet hyperaggregability. As this alteration could be the consequence of an abnormal lipid composition of platelet membranes, we studied the phospholipid specimens and the cholesterol/phospholipid ratio in platelet of neuron patients suffering from migraine. The cholesterol/phospholipid ratio was 0.7 +/- 0.1 (normal 0.6 +/- 0.1, molar ratio). The proportion of five main platelet phospholipids components including phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, and phosphatidylinositol, were also normal. These data suggest that platelet hyperactivity in patients with migraine is not due to an altered lipid content of those cells.     

Pharmacokinetics and biodistribution of genetically-engineered antibodies

Monoclonal antibodies (MAbs), because of their inherent specificity, are ideal targeting agents. They can be used to deliver radionuclides, toxins or cytotoxic drugs to a specific tissue or malignant cell populations. Intact immunoglobulin (IgG) molecules have several practical limitations of their pharmacology; their relatively large size of approximately 150,000 daltons leads to a slow clearance from the blood pool and the body resulting in significant exposure to normal organs with limited quantities delivered to tumors. The IgG molecule shows a relatively poor diffusion from the vasculature into and through the tumor. Attempts to modify the pharmacology of the Ig molecule have classically involved the use of proteases to generate F(ab')2 and Fab' fragments with molecular weights of approximately 100,000 and 50,000 daltons, respectively. Fv fragments of IgG are one of the smallest size functional modules of antibodies that retain high affinity binding of an antigen. Their smaller size, approximately 25,000 daltons, enables better tumor penetration and makes them potentially more useful than a whole antibody molecule for clinical applications. Molecular cloning and expression of the variable region genes of IgG has greatly facilitated the generation of engineered antibodies. A single-chain Fv (scFv) recombinant protein, prepared by connecting genes encoding for heavy-chain and light-chain variable regions at the DNA level by an appropriate oligonucleotide linker, clears from the blood at much faster rate than intact IgG. The scFv fragment can retain an antigen-binding affinity similar to that of a monovalent Fab' fragment; this however, represents a relative decrease in binding affinity when compared to intact antibodies. The scFv with its faster clearance and lower affinity results in a lower percent-injected dose localizing in tumors when compared to the divalent IgG molecule. This may be adequate for imaging but probably not for therapy. The valency of the MAb fragment is critical for the functional affinity of an antibody to a cell surface or a polymeric antigen. In attempts to generate multivalent forms of scFv molecules, non-covalently linked scFv dimeric and trimeric molecules, disulfide linked dimeric scFvs, as well as covalently linked chimeric scFvs have been studied. These multivalent scFvs generally have a higher functional affinity than the monovalent form resulting in better in vivo targeting. Another way to alter the pharmacology of the scFvs is to modify its net charge. Charge-modified scFvs with desired isoelectric points (pI), have been prepared by inserting negatively charged amino acids on the template of the variable region genes. This can help to overcome undesirable elevations in renal uptake seen with most antibody fragments. In conclusion, genetic manipulations of the immunoglobulin molecules are effective means of altering stability, functional affinity, pharmacokinetics, and biodistribution of the antibodies required for the generation of the "magic bullet".     

Haemodynamic effects of eating: the role of meal composition

I have investigated 84 endometrial specimens (from 15 cases of normal endometrium, 20 cass of hyperplasia and 49 cases of endometrial carcinoma) to determine the relationship between three proteins (proliferating cell nuclear antigen (PCNA), p53 gene product and c-erB-2 gene product) and endometrial carcinoma by immuno-histochemical staining. In 49 cases of endometrial carcinoma, the positive rates for PCNA, p53 protein (mutant type) and c-erbB-2 protein were 65.3%, 59.2% and 22.4%. I could not find the expression of p53 protein besides endometrial carcinoma. And I could find the expression of c-erbB-2 protein in 11 cases of endometrial carcinoma and 1 case of atypical hyperplasia, but not in normal endometrium. p53 protein was more common in such a case, as with lymphnode metastasis, deep myometral invasion and undifferentiated adenocarcinoma. c-erbB-2 was also more common in a case with deep myometrial invasion. In conclusion, PCNA, p53 protein and c-erbB-2 protein are related to the proliferation of endometrial carcinoma. So they can be useful factors in making the prognosis.     

钢冷轧乳化液稳定性及对冷轧润滑的影响

研究了影响不同类型乳化液稳定性的因素,包括乳化剂的比例和总含量对阴离子乳化油稳定性的影响,乳化剂的HLB值(Hydrophile Lipophile Balance)和总量对非离子乳化油稳定性的影响.研究发现乳化剂的比例和乳化剂的HLB值对乳化油和乳化液的稳定性影响明显.通过研究不同浓度下乳化液的稳定性对其吸附性和摩擦系数的影响发现:乳化液的稳定性在一定范围内时,其润滑效果可达到最佳.在冷轧实验中也发现:应根据冷轧的实际规程和要求来选择乳化液的稳定性和合适的含量,以便使冷轧高效正常地进行.