Response of hypercholesterolemic subjects to administration of tocotrienols

The cholesterol-suppressive actions of Palmvitee and gamma-tocotrienol were assessed in hypercholesterolemic subjects after acclimation to the American Heart Association Step 1 dietary regimen for four and eight weeks, respectively. The four-week dietary regimen alone elicited a 5% decrease (P < 0.05) in the cholesterol level of the 36 subjects. Subjects continuing on the dietary regimen for a second four-week period experienced an additional 2% decrease in their cholesterol levels. Dietary assessments based on unanticipated recalls of 24-h food intake records suggest that significant reductions in energy and fat, predominantly in saturated fat, intakes are responsible. The subjects experienced significant Palmvitee- and gamma-tocotrienol-mediated decreases in cholesterol. The group of subjects acclimated to the dietary regimen for four weeks responded to Palmvitee (a blend of tocols providing 40 mg alpha-tocopherol, 48 mg alpha-tocotrienol, 112 mg gamma-tocotrienol, and 60 mg delta-to-cotrienol/day for four weeks) with a 10% decrease in cholesterol (P < 0.05). Dietary assessments showed no further change in energy and fat intakes. alpha-Tocopherol attenuated the cholesterol-suppressive action of the tocotrienols. The second group of subjects, acclimated to the dietary regimen for eight weeks, received 200 mg gamma-tocotrienol/d for four weeks. The cholesterol-suppressive potency of this alpha-tocopherol-free preparation was calculated to be equivalent to that of the mixture of tocotrienols (220 mg) used in the prior study. Cholesterol levels of the 16 subjects in the second group decreased 13% (P < 0.05) during the four-week trial. Plasma apolipoprotein B and ex vivo generation of thromboxane B2 were similarly responsive to the tocotrienol preparations, whereas neither preparation had an impact on high density lipoprotein cholesterol and apolipoprotein A-1 levels.     

Metabolism of methoxyphenamine and 2-methoxyamphetamine in P4502D6-transfected cells and cell preparations

1. Control and P4502D6-transfected human B-lymphoblastoid cell lines (cHol and h2D6v2 respectively) were used to study 2D6-mediated metabolism of methoxyphenamine (MPA) and 2-methoxyamphetamine (2MA). The main metabolites were products of O-dealkylation and aromatic hydroxylation at the 5-position. In addition, N-desmethyl-methoxyphenamine (NDMP) was also identified as a minor metabolite of MPA in extracts of these cells, confirming previous reports of 2D6-mediated N-demethylation of MPA. 2. An additional ring-hydroxylated metabolite of MPA and 2MA has been tentatively identified as the corresponding 3-hydroxy-2-methoxy derivative. 3. MPA metabolism in whole cells was time dependent, with approximately 30% of the MPA metabolized after 72 h. A 35% conversion of MPA was achieved on average with cell lysates. Only 18% 2MA was metabolized. By contrast, control cells (cHol) showed no evidence of any MPA or 2MA metabolites even after 96-h incubation. 4. Continuous presence of haemin/dimethylsulphoxide (DMSO) throughout the 4-day incubation with MPA resulted in a shift in the metabolite profile towards the production of NDMP at the expense of the other products. 5. In summary, h2D6v2 cells, lysates and microsomes can form all metabolites of MPA and can be used in drug interaction studies.     

Circulating and ovarian IGF binding proteins: potential roles in normo-ovulatory cycles and in polycystic ovarian syndrome

IGFs function as co-gonadotropins in the ovary, facilitating steroidogenesis and follicle growth. IGFBP-1 to -5 are expressed in human ovary and mostly inhibit IGF action in in vitro ovarian cell culture systems. In the clinical disorder of polycystic ovarian syndrome (PCOS), which is characterized by hyperandrogenemia, polycystic ovaries and anovulation, follicles have a higher androgen: estradiol (A : E2) content and growth is arrested at the small antral stage. In the PCOS follicle, follicle stimulating hormone (FSH) and IGF levels are in the physiologic range, and even in the face of abundant androstenedione (AD) substrate, aromatase activity and E2 production are low. When PCOS granulosa are removed from their ovarian environment, they respond normally or hyperrespond to FSH. It has been postulated that an inhibitor of IGF's synergistic actions with FSH on aromatase activity may be one (or more) of the IGFBPs, which contributes to the arrested state of follicular development commonly observed in this disorder. High levels of IGFBP-2 and IGFBP-4 are present in follicular fluid (FF) from androgen-dominant follicles (FFa) from normally cycling women and in women with PCOS. This is in marked contrast to the near absence of these IGFBPs in estrogen-dominant FF (FFe), determined by Western ligand blotting. Regulation of granulosa-derived IGFBPs is effected by gonadotropins and insulin-like peptides. In addition, an IGFBP-4 metallo-serine protease is present in FFe, but not in FFa in ovaries from normally cycling women and those with PCOS, although the IGFBP-4 protease is present in PCOS follicles hyperstimulated for in vitro fertilization. Recent studies demonstrate that IGF-II in FFe is higher than in FFa' whereas IGF-I, IGFBP-3 and IGFBP-1 levels do not differ, underscoring the importance of local IGF-II production by the granulosa and the importance of IGFBP-4 and IGFBP-2 in regulation of IGF-II action within the follicle during its developmental pathway as an E2- or A-dominant follicle. In the androgen-treated female-to-male transsexual (TSX) model for PCOS, IGF-I, IGF-II, IGFBP-3 and IGFBP-1 levels do not differ.     

A comparative study of blood pressure and sodium intake in Belgium and in Korea

A comparative blood pressure and sodium excretion were higher in Korea than in Belgium. By multiple regression and covariance analysis an independent positive association between sodium and blood pressure and a negative correlation between potassium and blood pressure were found in some population subgroups and in the total population studied in Korea. In Belgium a positive association between sodium and blood pressure was found when higher powers of age, height, weight and sodium were included in the analysis. The independent influence of sodium on blood pressure was relatively small, amounting to about 2 mm Hg of pressure rise for an increase in 24-h excretion of 100 mmol of sodium.     

Dorsal column inhibition of nociceptive thalamic cells mediated by gamma-aminobutyric acid mechanisms in the cat

Cells derived from mice homozygous for the severe combined immune deficiency (scid) mutation exhibit hypersensitivity to ionizing radiation, and defects in DNA double-strand break repair and V(D)J recombination. Using the technique of microcell-mediated chromosome transfer, we have introduced a number of dominantly marked human chromosomes into scid cells to localize the human homolog of the murine scid gene. Analysis of human-scid hybrid clones revealed that the presence of human chromosome 8 partially restored accurate V(D)J recombination and radioresistance to scid cells. Subsequent loss of the human chromosome 8 from human-scid hybrid clones rendered these cells sensitive to gamma-radiation and impaired their ability to catalyse V(D)J recombination. Introduction of chromosomes 2, 14, 16 and 19 that encode other repair genes did not result in the correction of these two scid defects. These observations demonstrate that the human homolog of the mouse scid gene resides on human chromosome 8.     

First established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone in polycystic ovary syndrome

This case report describes the first established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone (FSH) in a woman suffering from chronic clomiphene-resistant anovulation due to polycystic ovary syndrome (elevated serum luteinizing hormone and testosterone concentrations together with polycystic ovaries). Starting on day 3 of a progestagen withdrawal bleeding, 75 IU of rFSH was administered i.m. daily until a single preovulatory follicle was seen upon transvaginal ultrasound examination at day 13. Ovulation was induced by a single i.m. administration of 10,000 IU of human chorionic gonadotrophin, after which a viable singleton pregnancy was revealed at a gestational age of 6 weeks. The course of pregnancy and labour was uneventful and no abnormalities were found upon a paediatric examination.     

Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations

The application of cationic liposome reagents has advanced DNA and mRNA transfection research in vitro, and data are accumulating which show their utility for in vivo gene transfer. However, chemical structure-activity data leading to a better mechanistic understanding of their biological activity is still limited. Most of the cationic lipid reagents in use today for this application are formulated as liposomes containing two lipid species, a cationic amphiphile and a neutral phospholipid, typically dioleoylphosphatidylethanolamine (DOPE). The studies reported here examine the effects of some systematic chemical structural changes in both of these lipid components. Cationic and neutral phospholipids were formulated together as large multilamellar vesicles (MLV) or small sonicated unilamellar vesicles (SUV) in water, and each formulation was assayed quantitatively in 96-well microtiter plates under 64 different assay conditions using COS.7 cells and an RSV-beta-galactosidase expression plasmid. The cationic lipid molecules used for these studies were derived from a novel series of 2,3-dialkyloxypropyl quaternary ammonium compounds containing a hydroxyalkyl moiety on the quaternary amine. A homologous series of dioleylalkyl (C18:1) compounds containing increasing hydroxyalkyl chain lengths on the quaternary amine were synthesized, formulated with 50 mol % DOPE, and assayed for transfection activity. The order of efficacy was ethyl > propyl > butyl > pentyl > 2,3-dioleyloxypropyl-1-trimethyl ammonium bromide (DOTMA). DOTMA, which is commercially available under the trademark Lipofectin Reagent, lacks a hydroxyalkyl moiety on the quaternary amine. A homologous series of hydroxyethyl quaternary ammonium derivatives with different alkyl chain substitutions were synthesized, formulated with 50 mol % DOPE, and assayed in the transfection assay. The order of transfection efficacy was dimyristyl (di-C14:0) > dioleyl (di-C18:1) > dipalmityl (di-C16:0) > disteryl (di-C18:0). The addition of 100 microM chloroquine in the transfection experiment enhanced the activity of the dioleyl compound by 4-fold and decreased the activity of the dimyristyl compound by 70%. For each of the compounds and formulations examined in this report, large multilamellar vesicles (MLV; diameter 300-700 nm) were more active than small unilamellar vesicles (SUV; diameter 50-100 nm). The neutral phospholipid requirements for transfection activity in COS.7 cells with these cationic lipid molecules were examined.(ABSTRACT TRUNCATED AT 400 WORDS)     

A fast convergent rate preserving discontinuous Galerkin framework for rate-independent plasticity problems

In this paper a finite element framework based on the incomplete interior penalty Galerkin formulation, a non-symmetric discontinuous Galerkin method, is consistently formulated for modeling plasticity problems with small deformation. Because of its pure displacement-based framework, this proposed discontinuous Galerkin method is possibly able to completely preserve numerical integration algorithms efficiently developed in the traditional continuous Galerkin framework. Besides stresses on element interior quadrature points, stresses on element surface quadrature points are also required to return on yielding surfaces in this discontinuous Galerkin framework, which is able to provide more accurate material yielding profiles than the continuous Galerkin framework. The performance of the proposed discontinuous Galerkin framework has been evaluated in detail for J₂ and pressure-dependent plasticities using perfect plasticity, plasticity with hardening, and associative and non-associative material models. Quadratic convergent rates compatible to the tradition continuous Galerkin method for modeling plasticity problems have been achieved within a large penalty range in a nodal-based discontinuous Galerkin implementation.     

Dewatering of Biomaterials by Mechanical Thermal Expression

Dewatering by mechanical thermal expression (MTE) for a range of materials is explored using a laboratory-scale MTE compression-permeability cell. It is shown that MTE can be used to effectively dewater a range of biomaterials including lignite, biosolids, and bagasse. The underlying dewatering mechanisms relevant to MTE, namely (1) filtration of water expelled due to thermal dewatering, (2) consolidation, and (3) flash evaporation, are discussed. At lower temperatures, the dominating dewatering mechanism is consolidation, but with increasing temperature, thermal dewatering becomes more important. A major focus is an investigation of the effects of processing parameters, including temperature (20 to 200°C) and pressure (1.5 to 24 MPa), on material permeability, a fundamental dewatering parameter. It is illustrated that permeability is particularly dependent on the processing temperature, owing to changes in both the material structure and the water properties. In addition, a comparison of permeability in the direction of applied force (axial) and perpendicular to the direction of applied force (radial) is presented. It is shown that, due to alignment of particles under the applied force, the permeability and, hence, rate of water removal in the radial direction is greater than in the axial direction. SEM micrographs are presented to illustrate the particle alignment.