The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status

Paraoxonase (PON1) is an HDL-associated enzyme. Low PON1 activity predicts vascular disease status and is a more reliable predictor of vascular disease than are functional PON1 genotypes. There is evidence that the relationship of PON1 to vascular disease is, in part, due to its antioxidant activity. However, the physical relationship of PON1 with HDL and the existence of cholesterol pathway regulatory elements at the PON1 locus suggest a further relationship of PON1 with lipoproteins, which may contribute to its role in vascular disease. We investigated the relationship of PON1 activity and genotype to lipid-related traits in 91 Caucasian men with severe carotid artery disease and 184 without vascular disease who were not on lipid-lowering medications. Prior studies of PON1 relationship to lipids have not stratified by disease status.. We found that PON1 activity was correlated with HDL traits in controls and with LDL- and VLDL-related traits in cases. We hypothesize differences in the joint regulation of PON1 and lipoproteins in cases and controls.     

Evaluation of the conformational switch model for alfalfa mosaic virus RNA replication

Key elements of the conformational switch model describing regulation of alfalfa mosaic virus (AMV) replication (R. C. Olsthoorn, S. Mertens, F. T. Brederode, and J. F. Bol, EMBO J. 18:4856-4864, 1999) have been tested using biochemical assays and functional studies in nontransgenic protoplasts. Although comparative sequence analysis suggests that the 3' untranslated regions of AMV and ilarvirus RNAs have the potential to fold into pseudoknots, we were unable to confirm that a proposed pseudoknot forms or has a functional role in regulating coat protein-RNA binding or viral RNA replication. Published work has suggested that the pseudoknot is part of a tRNA-like structure (TLS); however, we argue that the canonical sequence and functional features that define the TLS are absent. We suggest here that the absence of the TLS correlates directly with the distinctive requirement for coat protein to activate replication in these viruses. Experimental data are evidence that elevated magnesium concentrations proposed to stabilize the pseudoknot structure do not block coat protein binding. Additionally, covarying nucleotide changes proposed to reestablish pseudoknot pairings do not rescue replication. Furthermore, as described in the accompanying paper (L. M. Guogas, S. M. Laforest, and L. Gehrke, J. Virol. 79:5752-5761, 2005), coat protein is not, by definition, inhibitory to minus-strand RNA synthesis. Rather, the activation of viral RNA replication by coat protein is shown to be concentration dependent. We describe the 3' organization model as an alternate model of AMV replication that offers an improved fit to the available data.     

Novel antiglaucoma prodrugs and codrugs of ethacrynic acid

The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.     

The economics of drug abuse: a quantitative assessment of drug demand

Behavioral economic concepts have proven useful for an overall understanding of the regulation of behavior by environmental commodities and complements a pharmacological perspective on drug abuse in several ways. First, a quantitative assessment of drug demand, equated in terms of drug potency, allows meaningful comparisons to be made among drug reinforcers within and across pharmacological classes. Second, behavioral economics provides a conceptual framework for understanding key factors, both pharmacological and environmental, that contribute to reductions in consumption of illicit drugs. Finally, behavioral economics provides a basis for generalization from laboratory and clinical studies to the development of novel behavioral and pharmacological therapies.     

Proteomic analysis of primary cultures of human adipose-derived stem cells: modulation by Adipogenesis

Adipogenesis plays a critical role in energy metabolism and is a contributing factor to the obesity epidemic. This study examined the proteome of primary cultures of human adipose-derived adult stem (ADAS) cells as an in vitro model of adipogenesis. Protein lysates obtained from four individual donors were compared before and after adipocyte differentiation by two-dimensional gel electrophoresis and tandem mass spectroscopy. Over 170 individual protein features in the undifferentiated adipose-derived adult stem cells were identified. Following adipogenesis, over 40 proteins were up-regulated by > or = 2-fold, whereas 13 showed a > or = 3-fold reduction. The majority of the modulated proteins belonged to the following functional categories: cytoskeleton, metabolic, redox, protein degradation, and heat shock protein/chaperones. Additional immunoblot analysis documented the induction of four individual heat shock proteins and confirmed the presence of the heat shock protein 27 phosphoserine 82 isoform, as predicted by the proteomic analysis, as well as the crystallin alpha phosphorylated isoforms. These findings suggest that the heat shock protein family proteome warrants further investigation with respect to the etiology of obesity and type 2 diabetes.     

SYSTEMATIC IMPLICATIONS OF SEED COAT MORPHOLOGY IN NAMA (HYDROPHYLLACEAE)

Seeds from 37 species of Nama (Hydrophyllaceae) were examined by scanning electron microscopy in order to assess systematic implications of seed coat structure. Generally, seed coat morphology is species specific. Nevertheless, similarities among species in seed coat organization, particularly, outer testa anatomy and wall thickening-pitting patterns allow the recognition of six groups among examined taxa; furthermore, seed coat features often suggest both intra-group and inter-group relationships. Recognized groupings do not correspond well with the more classicial treatments of Nama; rather, they suggest that a restructuring of the infrageneric and even the generic taxonomy of Nama is in order.     

Glycosylated Triterpenoid Saponin: a Specific Inhibitor of Diguanylate Cyclase from Acetobacter xylinum. Biological Activity and Distribution

In a recent paper (Ohana et al. 1998), we described the purificationand structural characterization of a novel glycosidic triterpenoidsaponin (GTS), a specific inhibitor of diguanylate cyclase (dgc),the key regulatory enzyme of the cellulose synthesizing apparatusof the bacterium Acetobacter xylinum. This compound and an identicalor very similar one were isolated from pea (Pisum sativum),and A. xylinum respectively. We now present the effects of GTSon the kinetic properties of dgc. The observed inhibition isnon-competitive with respect to the substrate GTP, is decreasedby 50% in the presence of 20 µM c-di-GMP, and is not observedin the presence of various detergents. Photo-affinity labelingstudies using [³²P]c-di-GMP and purified enzyme showed thatthe inhibitor affects binding of c-di-GMP to dgc. It was ascertainedthat GTS, or at least a very similar compound, is present inother plant systems. The antibiotic Papulacandin B also inhibitsdgc, although less efficiently than GTS (Ki = 70 µM vs.5 µM). In in situ assays, highly purified GTS inhibitsbacterial cellulose synthesis and dgc activity. Similary, digitoninpermeabilized tobacco cell cultures display inhibition of glucansynthesis in the presence of GTS. (Received August 11, 1997; Accepted November 17, 1997)     

Incidence of Heart Disease in Children in the City of Toronto

A special registry of children with heart disease in the City of Toronto was set up (a) to provide for follow-up of all children with heart disease in that community, (b) to remove the “cardiac” label from children with functional murmurs, (c) to acquaint parents with facilities available for the management of children with heart disease, and (d) to record useful data regarding heart disease in children.The 1961-62 Cardiac Registry showed that 542 of 156,775 pre-school and school children had evidence of heart disease; 464 were congenital and 68 rheumatic in origin: 121 children with congenital heart defects had been treated surgically. Congenital cardiac disease ranked fifth in frequency among the causes of death in children. There was a diminution of acute rheumatic fever and rheumatic heart disease in children in 1961-62 when compared with data for previous years. Seventy-eight per cent of children in this series with a history of rheumatic fever were receiving continuous prophylaxis.     

Metal accumulation by chironomid larvae: the effects of age and body weight on metal body burdens

Age and body weight affected the extent of metal retention in larval chironomids. Elements differed with respect to age- and size-dependent metal uptake. The slopes of the regressions of metal burdens against age and size varied depending on the range in body size considered. Among fourth instar larvae, younger chironomids had higher concentrations of Cd, Mn, Ca, Ni, Fe, and Cu than older instars. When all instars were included, only concentrations of Cd and Ni were greater in young as compared to older larvae. Concentrations of Fe, Mn, Ca, and Ni were greater in larger chironomids than smaller larvae of similar age, but the effect of body weight on metal content was significant only when a wide range in biomass was considered. For the design of biological monitoring programs that use information on tissue residues of contaminants to assess contaminant bioavailability, individuals of different ages and sizes should be collected from each site in order to validate intersite comparisons. The advantages of considering metal burdens in addition to metal concentrations are emphasized.