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PubMed2000

Diastereoselective vinyl addition to chiral hydrazones via tandem thiyl radical addition and silicon-tethered cyclization

A diastereoselective method for addition of a vinyl group to alpha-hydroxy hydrazones under neutral tin-free radical cyclization conditions, leading to substituted vinylglycinols, is presented. Tandem thiyl radical addition/cyclization upon a silicon-tethered vinyl group followed by treatment with potassium fluoride accomplishes a one-pot neutral vinyl addition process to afford acyclic allylic anti-hydrazino alcohols in good yield.

Journal Article↗
PubMed1999

Hyperactivation of mitogen-activated protein kinase increases phospho-tau immunoreactivity within human neuroblastoma: additive and synergistic influence of alteration of additional kinase activities.

Mitogen-activated protein (MAP) kinase phosphorylates tau in cell-free analyses, but whether or not it does so within intact cells remains controversial. In the present study, microinjection of MAP kinase into SH-SY-5Y human neuroblastoma cells increased tau immunoreactivity toward the phosphodependent antibodies PHF-1 and AT-8. In contrast, treatment with a specific inhibitor of MAP kinase (PD98059) did not diminish "basal" levels of these immunoreactivities in otherwise untreated cells. These findings indicate that hyperactivation of MAP kinase increases phospho-tau levels within cells, despite that MAP kinase apparently does not substantially influence intracellular tau phosphorylation under normal conditions. These findings underscore that results obtained following inhibition of kinase activities do not necessarily provide an indication of the consequences accompanying hyperactivation of that same kinase. Several studies conducted in cell-free systems indicate that exposure of tau to multiple kinases can have synergistic effects on the nature and extent of tau phosphorylation. We therefore examined whether or not such effects could be demonstrated within these cells. Site-specific phospho-tau immunoreactivity was increased in additive and synergistic manners by treatment of injected cells with TPA (which activates PKC), calcium ionophore (which activates calcium-dependent kinases), and wortmannin (which inhibits PIP3 kinase). Alteration in total tau levels was insufficient to account for the full extent of the increase in phospho-tau immunoreactivity. These additional results indicate that multiple kinase activities modulate the influence of MAP kinase on tau within intact cells.

Alzheimer Disease↗
PubMed1993

Selective amplification of additional members of the ADP-ribosylation factor (ARF) family: cloning of additional human and Drosophila ARF-like genes.

The ADP-ribosylation factor (ARF) family is one of four subfamilies of the RAS superfamily of low molecular weight GTP-binding proteins (G proteins). Highly degenerate oligonucleotides encoding two conserved regions were used in a PCR reaction to amplify cDNAs encoding each of the known ARF proteins and eight additional cDNA fragments encoding previously unreported human members of the ARF family. Additional sequences were obtained from yeast or fly libraries by using this technique. These oligonucleotides specifically amplify members of the ARF family but not the structurally related G protein alpha subunits or members of the other three subfamilies of the RAS superfamily. Fragments obtained by PCR were used to obtain full-length sequences encoding highly homologous ARF-like (ARL) gene products from human and Drosophila melanogaster libraries, termed ARL2 and Ar184F, respectively. The encoded proteins are each 184 amino acids long and are 76% identical, with 40-45% identity to human ARF1 and Drosophila arf-like (arl) proteins. These genes appear to be generally expressed in human tissues and during Drosophila development. The purified human ARL2 protein differed in several biochemical properties from human ARF proteins, including the complete absence of ARF activity. Thus, the ARF family of low molecular weight GTP-binding proteins includes at least 15 distinct but structurally conserved members, including both the functionally conserved ARF proteins and the functionally disparate ARL proteins. The latter proteins currently comprise two distinct gene products in Drosophila (arl and ARL84F) and one in man (ARL2).

ADP-Ribosylation Factor 1↗
PubMed1984

Additive by additive variance with inbreeding and linkage.

Two-locus coancestries, which provide the coefficients of the additive by additive component in the variance and covariance of relatives for a quantitative trait, were formulated generally in terms of two-locus probabilities of identity by descent for combinations of parental and recombinant gametes. Explicit expressions, with linkage, were developed for all relatives of self-fertilization, for selfed and outbred relatives and for full and half sibs from unrelated inbred parents. The relative effect of linkage on the two-locus coancestry decreases rapidly as inbreeding and relatedness of the relatives increase. It was concluded that the error caused by ignoring linkage would probably be small in the estimation of genetic variances or in the projection of selection response with self-fertilization.

Epistasis, Genetic↗
PubMed1991

Reading addition analysis of progressive addition lenses.

The optico-physical characteristics of four different designs of progressive addition lenses(PALs) were assessed using a computer-controlled automated focimeter. For each design and for the four designs taken together, reading addition power was shown to correlate positively with PAL progression corridor length and negatively with PAL progression corridor width. Empirical measurements from the four PALs measured showed each design to have more favourable characteristics when compared with a theoretical single power law model.

Equipment Design↗
PubMed2006

Impact of different hold time before addition of platelet additive solution on the in vitro quality of apheresis platelets.

BACKGROUND: The quality of platelets (PLTs) stored in PLT additive solution (PAS) is dependent on the type and proportion of the used PAS. No data are available as to whether a different hold time before the addition of PAS to hyperconcentrated PLT suspensions has an impact on PLT quality. The in vitro quality between single-donor PLT concentrates was compared with two different hold times with two PASs. STUDY DESIGN AND METHODS: On two occasions, 6x10(11) PLTs in 150 mL of plasma were collected from 20 blood donors. The units were split into two equal parts, and 140 mL of PAS-II or PAS-IIIM (randomized sequence) was added after 2 or 8 hours resulting in a PAS proportion of 65 percent. On Days 1, 5, and 7, glucose and lactate concentration, pH value, PLTs' P-selectin expression, response to hypotonic shock, and release of transforming growth factor-beta1 were determined. RESULTS: On all days, the lactate concentrations were higher and pH values were lower in units with an 8-hour hold time, whereas the results of in vitro tests relating to the in vivo viability and activation of PLTs were similar for both groups. PAS-IIIM-stored PLTs showed a lower glycolytic activity and better results in all performed in vitro tests than PAS-II-stored PLTs. CONCLUSIONS: Although the metabolism of glucose was enhanced during hold time, the differences between both hold time groups are not meaningful from a biological viewpoint. Therefore, an 8-hour hold time is feasible. PLT storage in PAS-IIIM results in a PLT in vitro quality superior to that of PLTs stored in PAS-II.

Blood Platelets↗
PubMed2005

Treatment of vascular smooth muscle cells with estradiol and beta-adrenergic agonists has an additive effect on cAMP levels, but no additive effect on inhibition of collagen synthesis.

Several studies have suggested that increased cell levels of cAMP result in decreased rates of collagen synthesis. Oestrogen treatment of vascular smooth muscle cells (VSMCs) has been shown to cause increased levels of cAMP and decreased rates of collagen synthesis. Beta-adrenergic agonists are also known to increase cellular levels of cAMP in VSMCs, although the effect of beta-adrenergic agonists on collagen synthetic rates in VSMCs is unknown. Since beta-agonists and oestrogens are commonly used clinical agents these studies were conducted to determine the potential of these agents to have an additive effect on cell cAMP levels and inhibition of collagen synthetic rates. When VSMCs were treated with both oestrogen and isoproterenol there was an additive effect on cellular cAMP levels although the observed decrease in collagen synthetic rates was the same as observed in cells treated with just oestrogen. Treatment of VSMCs with propranolol inhibited isoproterenol-induced changes in cAMP but had no effect on either oestrogen-induced increases in cAMP levels or inhibition of collagen synthesis. The cellular location of cAMP following beta-adrenergic agonist treatment was different from the distribution of cAMP in control or oestrogen-treated VSMCs. This difference in cellular distribution of cAMP may partially explain the absence of collagen synthesis inhibition following beta-adrenergic agonist treatment of VSMCs.

Adrenergic beta-Agonists↗
PubMed2006

[Comparison of the effectiveness of two treatment strategies in inpatients with a depressive disorder. A double-blind study of imipramine followed by lithium addition versus fluvoxamine followed by lithium addition].

BACKGROUND: There is still uncertainty regarding the best treatment optionfor depressed inpatients and the best strategy to follow if patient response is insufficient. AIM: To compare the efficacy of imipramine and fluvoxamine in depressed inpatients who subsequently received lithium supplement in case of poor response. METHOD: After a drug-free period and four days of placebo use, patients were randomised either to imipramine or to fluvoxamine (phase 1); the antidepressant dosage was fixed according to a predetermined plasma level. The efficacy of the antidepressant was evaluated four weeks after the predetermined plasma level had been attained. If patient response was inadequate, the antidepressant was augmented with lithium (phase 2). Patient response to the lithium addition was evaluated three weeks after an adequate lithium level had been attained. RESULTS: The study involved 138 inpatients. At the end of phase 1, imipramine was found to be superior tofluvoxamine according to the Clinical Global Impression of Improvement. Remission was achieved by 6 (23%) patients on imipramine and by 10 (15%) patients on fluvoxamine; this difference was not statistically significant. At the end of phase 2, 41 (9%) patients on imipramine and 27 (40%) patients on fluvoxamine achieved remission, this significant difference demonstrating the superiority of the imipramine strategy. CONCLUSION: Imipramine with subsequent lithium addition is superior to a similar strategy with fluvoxamine.

Adult↗
PubMed1987

Estimation of additive genetic, non-additive genetic, and permanent environmental sources of variation in preweaning traits in swine using the expectation-maximization algorithm for restricted maximum likelihood.

10188 growth records (performance up to weaning) of 283 Largewhite pigs were used to estimate various components of variance using a mixed linear model for the birth weight, litter size at birth, weaning weight, and litter size at weaning. Restricted maximum likelihood procedures were used. Object of the investigation were the respective additive genetic, non-additive genetic, and permanent environmental variation traits within the overall variation as well as the respective residual components. The results were tabulated and expressed specifically by way of the heritability and repeatability coefficients.

Animals↗
PubMed1996

Improved blood compatibility of segmented polyurethane by polymeric additives having phospholipid polar group. II. Dispersion state of the polymeric additive and protein adsorption on the surface.

To improve the blood compatibility of a segmented polyurethane (SPU), phospholipid polymer, i.e., 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymerized with cyclohexyl methacrylate or 2-ethylhexyl methacrylate, was blended into SPU as a polymeric additive. The blending was achieved by a solvent-evaporation technique from a homogeneous solution containing both the SPU and the MPC polymer. Surface analysis of the SPU membrane blended with the MPC polymer (SPU/MPC polymer membrane) revealed that the MPC polymer was concentrated at the surface of the SPU membrane which contacted the substrate, Teflon, compared with that which contacted air during the membrane-formation period. The dispersion state of the MPC polymer in the SPU membrane was evaluated in detail by staining the MPC unit with osmium tetraoxide. When sonication was applied during preparation of the mixed solution containing SPU and the MPC polymer, the dispersion of the MPC polymer in the SPU membrane was different from that without sonication. That is, the size of the domains of the MPC polymer became smaller but the number of the domains increased. The amount of the MPC polymer mixed with SPU affected the dispersion state. Plasma proteins adsorbed on the SPU/MPC polymer membrane surface after contact with human plasma were detected by gold-colloid-labeled immunoassay. Both albumin and fibrinogen were observed on the SPU membrane; however, the amount of these proteins was reduced on the SPU/MPC polymer membrane. Thus it was concluded that the blood compatibility of the SPU was effectively improved by the blending of the MPC polymer.

Adsorption↗
PubMed2002

The mechanism of 1,2-addition of disilene and silene: hydrogen halide addition.

The mechanism of 1,2-addition reactions of HF and HCl to Si=Si, Si=C, and C=C bonds has been investigated by ab initio quantum chemical methods. Geometries and relative energies of the stationary points and all the transition states were determined by using the MP2/6-311++G(d,p), B3LYP/6-311++G(d,p), and CBS-Q levels of theory. The investigated reactions can be characterized by two main thermodynamic profiles. The type in which the reagent molecule attacks a carbon atom is moderately exothermic with a high activation barrier. The second type in which a hydrogen halide attacks a silicon is strongly exothermic with a low activation energy. At the early stage of all the reactions a weakly bonded initial complex is found which indicates that the initial step of all the reactions is an electrophilic attack of hydrogen halide. The geometry and charge distribution of the transition state of the reactions indicate two main types of mechanism. If silicon is attacked, the halogen-silicon bond formation precedes the H-Y bond breaking. If, however, carbon is attacked, the first step is always an ionic dissociation of the hydrogen halide and a carbenium ion formation, which is stabilized by the C-Y bond formation in the final step of the reaction. The reaction diagrams and proposed mechanisms explain the experimentally found regioselectivity well.

Journal Article↗
PubMedDate not supplied

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study.

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.

Diabetes Mellitus, Type 2↗
PubMed1996

Some additional results about polymorphisms in models of an additive quantitative trait under stabilizing selection.

The existence of two stable, symmetric (allelic frequency 0.5 in each locus) polymorphic states is demonstrated for a two-locus model of an additive quantitative trait under strong Gaussian selection. Linkage disequilibrium at one of the states is negative whereas it is positive at the other state. For a three-locus model, it is shown that in order to maintain a stable polymorphism in all three loci, selection must be sufficiently but not excessively strong relative to recombination. Also, positive linkage disequilibrium can be maintained in a three-locus model under stabilizing selection that is not very strong.

Alleles↗
PubMed2001

The mechanism of 1,2-addition of disilene and silene. 1. Water and alcohol addition.

The mechanism of 1,2-addition reactions of water, methanol, and trifluoromethanol to Si=Si, Si=C, and C=C bonds has been investigated by ab initio quantum chemical methods. Geometries and relative energies of the stationary points and all the transition states were determined using the MP2/6-311++G(d,p), B3LYP/6-311++G(d,p), and CBS-Q levels of theory. The investigated reactions can be characterized by two main thermodynamical profiles. The type in which the reagent molecule attacks a carbon atom is moderately exothermic, with a high activation barrier. The second type, in which water or alcohol attacks a silicon, is strongly exothermic, with a small activation energy. At the early stage of all the reactions, a weakly bonded initial complex is found which determines the further mechanism of the reaction. On the basis of the HOMO, LUMO, and Laplacian of electron distribution of disilene and silene, several mechanisms have been assumed, depending on the substrate (disilene, substituted disilene, silene, or ethene) and the reagent (water, methanol, or trifluoromethanol). The reaction diagrams and proposed mechanisms explain the experimentally found regioselectivity and diastereoselectivity well.

Journal Article↗