Plant-based sterols and stanols in health & disease: "Consequences of human development in a plant-based environment?"

Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.

Carpal bone titanium implant arthroplasty. 10 years' experience.

In 1984, in an effort to address the silicone wear particle problem, titanium implants were developed for the scaphoid, lunate, and trapeziometacarpal joint. The design of these implants closely resembled their silicone counterparts, though some modifications were made to accommodate the properties of unalloyed titanium and enhance their stability. Carpal bone implants act as articulating spacers to help maintain the relationship of adjacent carpal bones after local resection procedures. Their use allows carpal stabilization procedures and provides functional mobility with good strength and pain relief. Their surgical application began in 1985. The 10-year clinical experience seems very promising to date.

Isolation and characterization of heparan sulfate from crude porcine intestinal mucosal peptidoglycan heparin.

A method for the preparation of heparan sulfate from peptidoglycan heparin is described. The objective of this research was to provide a basis for the development and validation of an industrial process to support the preclinical development of heparan sulfate and/or heparan sulfate derivatives. In the preparation of heparan sulfate, heparin was recovered by alcohol fractionation and dermatan sulfate was isolated by selective precipitation. The remaining crude heparan sulfate was fractionated by anion-exchange chromatography into five subfractions. The biological activities of these subfractions were examined by anticoagulant and amidolytic assays. Molecular weight and molecular size were determined using capillary viscometry and polyacrylamide gel electrophoresis. Charge density and degree of sulfation were determined by cellulose acetate electrophoresis and elemental analysis. Oligosaccharide and disaccharide analysis relied on enzymatic depolymerization using heparin lyases followed by polyacrylamide gel and capillary electrophoresis. 1H NMR analysis provided detailed structural information on each subfraction. Crude heparin sulfate and its subfractions showed significant differences in physical, structural and biological properties.

New approaches for the preparation of hydrophobic heparin derivatives.

A heparin derivative sufficiently lipophilic to be bound to plastics, forming blood-compatible supports, or to be used as an anticoagulant by transdermal or oral routes would be of great pharmaceutical interest. For such applications, the functional groups within heparin's antithrombin III binding site, responsible for its anticoagulant activity, cannot be modified. Chemistry is described in which lipophilic substituents were attached to the reducing termini of heparin chains. Substituents introduced at this position had a minimal effect on the antithrombin III binding sites found in heparin's interior. These derivatives, with enhanced hydrophobicities, were prepared using two distinctly different approaches. First, octyl isocyanate and octadecyl isocyanate were coupled to the core peptide of peptidoglycan heparin to form octyl- and octadecyl-peptidoglycan heparin. These octyl- and octadecyl-peptidoglycan heparins were then purified by hydrophobic interaction chromatography on phenyl-Sepharose CL-4B, demonstrating their enhanced hydrophobicities. Second, the lipophilic acyl hydrazides of various long chain fatty acids were coupled to heparin's reducing end. Caprylic (C8), capric (C10), lauric (C12), and stearic (C18) hydrazide derivatives of heparin were prepared using this approach. Only the stearyl hydrazide derivative of heparin showed a measurable increase in lipophilicity. This result demonstrated that a single small linear C8, C10, or C12 aliphatic chain was ineffective in enhancing the hydrophobicity of the highly negative, polyanionic heparin molecule. Two lipophilic chains, lauryl (C12) and stearyl (C18), were then coupled to a single heparin chain, resulting in a heparin derivative having enhanced hydrophobicity. All the heparin derivatives prepared in this study maintained some of their anticoagulant activity.

Inositol uptake in rat aorta.

The purpose of this study was to investigate the mechanism of inositol uptake into rat thoracic aorta. 3H-inositol uptake into deendothelialized aorta was linear for at least 2 h and was composed of both a saturable, Na(+)-dependent, and a nonsaturable, Na(+)-independent component. The Na(+)-dependent component of inositol uptake had a Km of 50 microM and a Vmax of 289 pmol/mg prot/h. Exposure to LiCl, ouabain, or Ca2(+)-free Krebs-Ringer bicarbonate solution inhibited uptake. Metabolic poisoning with dinitrophenol, as well as incubation with phloretin, an inhibitor of carrier-mediated hexose transport, also inhibited uptake. Exposure to norepinephrine decreased inositol uptake, while phorbol myristate acetate was without effect. Isobutylmethylxanthine significantly increased inositol uptake, while the increased uptake due to dibutyryl cyclic AMP and forskolin were not statistically significant. Sodium nitroprusside, an activator of guanylate cyclase, and 8-bromo cyclic GMP, were without effect on uptake, as was methylene blue, an inhibitor of guanylate cyclase. Inositol uptake into the aorta was increased when the endothelium was allowed to remain intact, although this effect was likely due to uptake into both the endothelial and smooth muscle cells. These results suggest that the uptake of inositol into vascular smooth muscle is: (1) dependent upon an inward Na(+)-gradient; (2) carrier mediated, and (3) inhibited by alpha 1 adrenoceptor agonists.

Vasodilatory action of amlodipine on rat aorta, pig coronary artery, human coronary artery, and on isolated Langendorff rat heart preparations.

Amlodipine inhibited contractions of rat aortic rings induced by 40 mM KCl (IC50 = 7.5 x 10(-9) M). The time to attain the maximum inhibitory effect of KCl-induced contractions was long (hours) and dependent on the concentration of amlodipine. After 6 h of washing in drug-free normal Krebs-Ringer solution the contractions recovered only partially. The KCl-induced contractions appeared to be more sensitive to inhibition by amlodipine than were norepinephrine-induced contractions. CaCl2-induced contraction of KCl-depolarized aortic rings was inhibited by amlodipine in a complex manner. Amlodipine not only increased ED50 but also inhibited the maximal tension induced by CaCl2. Amlodipine also inhibited 35 mM KCl-induced contractions of pig coronary artery rings (IC50 = 2.2 x 10(-8) M) and human coronary artery rings (IC50 = 2.1 x 10(-8) M). In Langendorff rat heart preparations, low concentrations of amlodipine increased coronary flow (ED50, 10(-9) M) whereas higher concentrations (greater than 10(-7) M) decreased coronary flow. Amlodipine also decreased the rate of contraction (+ dP/dt, IC50 = 3 x 10(-7) M) and the rate of relaxation (-dP/dt, IC50 = 1.2 x 10(-7) M). Amlodipine decreased heart rate but only at high concentrations (greater than 300 nM). The results of this study indicate that amlodipine is a potent vasodilator with similar cardiovascular actions to other dihydropyridines except that its effects are slower in onset and longer lasting.