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  1. Article: Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice

    Freeman, Lita / Amar, Marcelo J.A / Shamburek, Robert / Paigen, Beverly / Brewer, H. Bryan Jr / Santamarina-Fojo, Silvia / González-Navarro, Herminia

    Journal of lipid research JLR. 2007 Jan., v. 48, no. 1

    2007  

    Abstract: To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, ... ...

    Abstract To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KOxHL-KO). HL-WT and HL-S145G reduced (P < 0.05 for all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%), and apolipoprotein B (apoB; 34% vs. 16%) by enhancing the catabolism of autologous ¹²⁵I-apoB-intermediate density lipoprotein (IDL)/LDL (fractional catabolic rate in day⁻¹: 6.07 ± 0.25, LDLr-KOxHL-WT; 4.76 ± 0.30, LDLr-KOxHL-S145G; 3.70 ± 0.13, LDLr-KOxHL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of apoB-containing lipoproteins (apoB-Lps) and HDL. Importantly, consistent with the changes in apoB-Lps, atherosclerosis in LDLr-KOxHL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P < 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus ligand-binding functions of HL in apoB-Lp metabolism and atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of apoE, establish an antiatherogenic role of the ligand-binding function of HL in LDLr-deficient mice.
    Language English
    Dates of publication 2007-01
    Size p. 104-113.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
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  2. Article: Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

    Basso, Federica / Freeman, Lita A / Ko, Carol / Joyce, Charles / Amar, Marcelo J / Shamburek, Robert D / Tansey, Terese / Thomas, Fairwell / Wu, Justina / Paigen, Beverly / Remaley, Alan T / Santamarina-Fojo, Silvia / Brewer, H. Bryan Jr

    Journal of lipid research JLR. 2007 Jan., v. 48, no. 1

    2007  

    Abstract: We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss ... ...

    Abstract We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss from the body and reduce atherosclerosis. To evaluate this hypothesis, we fed low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/G8-transgenic (ABCG5/G8-Tg)xLDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing ezetimibe to reduce intestinal cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, and increased (4.4-fold) de novo hepatic cholesterol synthesis versus LDLr-KO mice. Plasma lipids decreased (total cholesterol, 32%; cholesteryl ester, 32%; free cholesterol, 30%), mostly as a result of reduced non-high density lipoprotein-cholesterol and apolipoprotein B (apoB; 36% and 25%, respectively). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/G8-TgxLDLr-KO mice. Kinetic studies revealed similar ¹²⁵I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-TgxLDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-TgxLDLr-KO versus LDLr-KO mice fed the Western/ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and atherosclerosis.
    Language English
    Dates of publication 2007-01
    Size p. 114-126.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Type III hyperlipoproteinemia: Defective metabolism of an abnormal apolipoprotein E

    Gregg, Richard E / Zech, Loren A / Schaefer, Ernst J / Brewer, H. Bryan Jr

    Science. Feb 6, 1981. v. 211 (4482)

    1981  

    Abstract: Abstract: Isoelectric focusing of apolipoprotein E isolated from the plasma of patients with type III hyperlipoproteinemia (HLP) indicates an abnormal biochemical pattern as compared to apoliprotein E from normal subjects. Metabolic studies using labeled ...

    Abstract Abstract: Isoelectric focusing of apolipoprotein E isolated from the plasma of patients with type III hyperlipoproteinemia (HLP) indicates an abnormal biochemical pattern as compared to apoliprotein E from normal subjects. Metabolic studies using labeled apolipoprotein from healthy (apoE3+) or type III HLP subjects (apoE3-) demonstrated that apoE3+ was cleared much more rapidly in both groups of subjects. In normal and HLP individuals, the residence time of apoE3+ was about half that of apoE3-. These data indicated a metabolic difference between the 2 apolipoproteins and suggest a decreased fractional catabolic rate of apoE3-, with delayed lipoprotein remnant catabolism in patients with type III hyperlipoproteinemia. This defect in metabolism may cause the plasma lipid and lipoprotein abnormalities which are characteristic of the disorder. The molecular basis for the defect is not yet known but may be alleviated by estrogen therapy.
    Keywords hyperlipoproteinemia ; lipoproteins ; lipid metabolism disorders ; lipid metabolism ; metabolic studies
    Language English
    Dates of publication 1981-0206
    Size p. 584-586., ill., charts.
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
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  4. Article: Normalization of plasma lipoprotein concentrations in patients with type II hyperlipoproteinemia by combined use of neomycin and niacin

    Hoeg, Jeffrey M / Maher, Martha B / Bou, Ernestina / Zech, Loren A / Bailey, Kent R / Gregg, Richard E / Sprecher, Dennis L / Susser, Jodi K / Pikus, Anita M / Brewer, H. Bryan Jr

    Circulation. Dec 1984. v. 70 (6)

    1984  

    Abstract: Abstract: A double-blind, randomized, placebo-controlled, cross-over clinical trial examined the effect of combined neomycin and niacin therapy in 25 type II hyperlipoproteinemia patients. The results indicated that elevated total and low density ... ...

    Abstract Abstract: A double-blind, randomized, placebo-controlled, cross-over clinical trial examined the effect of combined neomycin and niacin therapy in 25 type II hyperlipoproteinemia patients. The results indicated that elevated total and low density lipoprotein were normalized in most of these patients with neomycin or combined neomycin-niacin therapy. (wz)
    Keywords hyperlipoproteinemia ; niacin ; lipoproteins ; disease prevention ; diet therapy ; drug therapy ; patient care ; clinical trials ; diet study techniques
    Language English
    Dates of publication 1984-12
    Size p. 1004-1011., ill., charts.
    Document type Article
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
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  5. Article: Metabolism of high-density lipoprotein apolipoproteins in Tangier disease

    Schaefer, Ernst J / Blum, Conrad B / Levy, Robert I / Jenkins, Leslie L / Alaupovic, Petar / Foster, David M / Brewer, H. Bryan Jr

    New England journal of medicine Oct 26, 1978. v. 299 (17)

    1978  

    Abstract: Extract: Eleven normal subjects, two obligate heterozygotes, and two homozygotes were studied to define the metabolic defect in Tangier disease. Mean synthesis of apolipoproteins A-I and A-II was 8.24 mg per kilogram per day in the normal group, 7.94 in ... ...

    Abstract Extract: Eleven normal subjects, two obligate heterozygotes, and two homozygotes were studied to define the metabolic defect in Tangier disease. Mean synthesis of apolipoproteins A-I and A-II was 8.24 mg per kilogram per day in the normal group, 7.94 in heterozygotes and 3.86 in homozygotes. The mean plasma-residence time for both apolipoproteins was 5.21 days in the normal subjects, 3.41 days in heterozygotes, and 0.52 days in homozygotes. In normal subjects and heterozygotes the apolipoproteins were catabolized at similar rates, whereas in homozygotes apolipoprotein A-I was catabolized at a much greater fractional rate than apolipoprotein A-II. These findings indicate that the deficiency of these apolipoproteins in Tangier disease is largely due to rapid and altered catabolism.
    Keywords metabolism ; lipoproteins ; lipid metabolism disorders ; hematologic tests
    Language English
    Dates of publication 1978-1026
    Size p. 905-910., ill., charts.
    Document type Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
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  6. Article: The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease.

    Neufeld, Edward B / Stonik, John A / Demosky, Stephen J / Knapper, Catherine L / Combs, Christian A / Cooney, Adele / Comly, Marcella / Dwyer, Nancy / Blanchette-Mackie, Joan / Remaley, Alan T / Santamarina-Fojo, Silvia / Brewer, H Bryan

    The Journal of biological chemistry

    2004  Volume 279, Issue 15, Page(s) 15571–15578

    Abstract: ... Dwyer, N. K., Zhang, M., Blanchette-Mackie, J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) J ... surface (Neufeld, E. B., Remaley, A. T., Demosky, S. J., Jr., Stonik, J. A., Cooney, A. M., Comly, M ...

    Abstract We have previously established that the ABCA1 transporter, which plays a critical role in the lipidation of extracellular apolipoprotein acceptors, traffics between late endocytic vesicles and the cell surface (Neufeld, E. B., Remaley, A. T., Demosky, S. J., Jr., Stonik, J. A., Cooney, A. M., Comly, M., Dwyer, N. K., Zhang, M., Blanchette-Mackie, J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) J. Biol. Chem. 276, 27584-27590). The present study provides evidence that ABCA1 in late endocytic vesicles plays a role in cellular lipid efflux. Late endocytic trafficking was defective in Tangier disease fibroblasts that lack functional ABCA1. Consistent with a late endocytic protein trafficking defect, the hydrophobic amine U18666A retained NPC1 in abnormally tubulated, cholesterol-poor, Tangier disease late endosomes, rather than cholesterol-laden lysosomes, as in wild type fibroblasts. Consistent with a lipid trafficking defect, Tangier disease late endocytic vesicles accumulated both cholesterol and sphingomyelin and were immobilized in a perinuclear localization. The excess cholesterol in Tangier disease late endocytic vesicles retained massive amounts of NPC1, which traffics lysosomal cholesterol to other cellular sites. Exogenous apoA-I abrogated the cholesterol-induced retention of NPC1 in wild type but not in Tangier disease late endosomes. Adenovirally mediated ABCA1-GFP expression in Tangier disease fibroblasts corrected the late endocytic trafficking defects and restored apoA-I-mediated cholesterol efflux. ABCA1-GFP expression in wild type fibroblasts also reduced late endosome-associated NPC1, induced a marked uptake of fluorescent apoA-I into ABCA1-GFP-containing endosomes (that shuttled between late endosomes and the cell surface), and enhanced apoA-I-mediated cholesterol efflux. The combined results of this study suggest that ABCA1 converts pools of late endocytic lipids that retain NPC1 to pools that can associate with endocytosed apoA-I, and be released from the cell as nascent high density lipoprotein.
    MeSH term(s) ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Androstenes/pharmacology ; Anticholesteremic Agents/pharmacology ; Apolipoprotein A-I/metabolism ; Biological Transport ; Cell Membrane/metabolism ; Cholesterol/metabolism ; Detergents/pharmacology ; Endocytosis ; Endosomes/metabolism ; Fibroblasts/metabolism ; Green Fluorescent Proteins ; Humans ; Immunohistochemistry ; Lipid Metabolism ; Lipoproteins, HDL/metabolism ; Luminescent Proteins/metabolism ; Lysosomes/metabolism ; Microscopy, Confocal ; Models, Biological ; Sphingomyelins/metabolism ; Tangier Disease/genetics ; Tangier Disease/therapy
    Chemical Substances ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Androstenes ; Anticholesteremic Agents ; Apolipoprotein A-I ; Detergents ; Lipoproteins, HDL ; Luminescent Proteins ; Sphingomyelins ; Green Fluorescent Proteins (147336-22-9) ; 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one (3039-71-2) ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2004-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M314160200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Subregional neuroanatomical change as a biomarker for Alzheimer's disease

    Holland, Dominic / Brewer, James B / Hagler, Donald J / Fenema-Notestine, Christine / Dale, Anders M / Weiner, Michael / Thal, Leon / Petersen, Ronald / Jack, Clifford R. Jr / Jagust, William / Trojanowki, John / Toga, Arthur W / Beckett, Laurel / Green, Robert C / Gamst, Anthony / Potter, William Z / Montine, Tom / Anders, Dale / Bernstein, Matthew /
    Felmlee, Joel / Fox, Nick / Thompson, Paul / Schuff, Norbert / Alexander, Gene / Bandy, Dan / Koeppe, Robert A / Foster, Norm / Reiman, Eric M / Chen, Kewei / Shaw, Les / Lee, Virginia M.-Y / Korecka, Magdalena / Crawford, Karen / Neu, Scott / Harvey, Danielle / Kornak, John / Kachaturian, Zaven / Frank, Richard / Snyder, Peter J / Molchan, Susan / Kaye, Jeffrey / Vorobik, Remi / Quinn, Joseph / Schneider, Lon / Pawluczyk, Sonia / Spann, Bryan / Fleisher, Adam S / Vanderswag, Helen / Heidebrink, Judith L / Lord, Joanne L / Johnson, Kris / Doody, Rachelle S / Villanueva-Meyer, Javier / Chowdhury, Munir / Stern, Yaakov / Honig, Lawrence S / Bell, Karen L / Morris, John C / Mintun, Mark A / Schneider, Stacy / Marson, Daniel / Griffith, Randall / Badger, Beverly / Grossman, Hillel / Tang, Cheuk / Stern, Jessica / deToledo-Morrell, Leyla / Shah, Raj C / Bach, Julie / Duara, Ranjan / Isaacson, Richard / Strauman, Silvia / Albert, Marilyn S / Pedroso, Julia / Toroney, Jaimie / Rusinek, Henry / de Leon, Mony J / De Santi, Susan M / Doraiswamy, P. Murali / Petrella, Jeffrey R / Aiello, Marilyn / Clark, Christopher M / Pham, Cassie / Nunez, Jessica / Smith, Charles D / Given, Curtis A. II / Hardy, Peter / DeKosky, Steven T / Oakley, MaryAnn / Simpson, Donna M / Ismail, M. Saleem / Porsteinsson, Anton / McCallum, Colleen / Cramer, Steven C / Mulnard, Ruth A / McAdams-Ortiz, Catherine / Diaz-Arrastia, Ramon / Martin-Cook, Kristen / DeVous, Michael / Levey, Allan I / Lah, James J / Cellar, Janet S / Burns, Jeffrey M / Anderson, Heather S / Laubinger, Mary M / Bartzokis, George / Silverman, Daniel H.S / Lu, Po H / Fletcher, Rita / Parfitt, Francine / Johnson, Heather / Farlow, Martin / Herring, Scott / Hake, Ann M / van Dyck, Christopher H / MacAvoy, Martha G / Bifano, Laurel A / Chertkow, Howard / Bergman, Howard / Hosein, Chris / Black, Sandra / Graham, Simon / Caldwell, Curtis / Feldman, Howard / Assaly, Michele / Hsiung, Ging-Yuek R / Kertesz, Andrew / Rogers, John / Trost, Dick / Bernick, Charles / Gitelman, Darren / Johnson, Nancy / Mesulam, Marsel / Sadowsky, Carl / Villena, Teresa / Mesner, Scott / Aisen, Paul S / Johnson, Kathleen B / Behan, Kelly E / Sperling, Reisa A / Rentz, Dorene M / Johnson, Keith A / Rosen, Allyson / Tinklenberg, Jared / Ashford, Wes / Sabbagh, Marwan / Connor, Donald / Obradov, Sanja / Killiany, Ron / Norbash, Alex / Obisesan, Thomas O / Jayam-Trouth, Annapurni / Wang, Paul / Auchus, Alexander P / Huang, Juebin / Friedland, Robert P / DeCarli, Charles / Fletcher, Evan / Carmichael, Owen / Kittur, Smita / Mirje, Seema / Johnson, Sterling C / Borrie, Michael / Lee, T.-Y / Asthana, Sanjay / Carlsson, Cynthia M / Potkin, Steven G / Highum, Diane / Preda, Adrian / Nguyen, Dana / Tariot, Pierre N / Hendin, Barry A / Scharre, Douglas W / Kataki, Maria / Beversdorf, David Q / Zimmerman, Earl A / Celmins, Dzintra / Brown, Alice D / Gandy, Sam / Marenberg, Marjorie E / Rovner, Barry W / Pearlson, Godfrey / Blank, Karen / Anderson, Karen / Saykin, Andrew J / Santulli, Robert B / Pare, Nadia / Williamson, Jeff D / Sink, Kaycee M / Potter, Huntington / Ashok Raj, B / Giordano, Amy / Ott, Brian R / Wu, Chuang-Kuo / Cohen, Ronald / Wilks, Kerri L / Safirstein, Beth E

    Proceedings of the National Academy of Sciences of the United States of America. 2009 Dec. 8, v. 106, no. 49

    2009  

    Abstract: Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure ... ...

    Abstract Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.
    Keywords Alzheimer disease ; atrophy ; biomarkers ; brain ; clinical trials ; cognition ; early diagnosis ; magnetic resonance imaging ; neurodegenerative diseases ; neuroprotective effect ; therapeutics
    Language English
    Dates of publication 2009-1208
    Size p. 20954-20959.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0906053106
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  8. Article ; Online: Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

    Bakken, Trygve E / Roddey, J Cooper / Djurovic, Srdjan / Akshoomoff, Natacha / Amaral, David G / Bloss, Cinnamon S / Casey, B J / Chang, Linda / Ernst, Thomas M / Gruen, Jeffrey R / Jernigan, Terry L / Kaufmann, Walter E / Kenet, Tal / Kennedy, David N / Kuperman, Joshua M / Murray, Sarah S / Sowell, Elizabeth R / Rimol, Lars M / Mattingsdal, Morten /
    Melle, Ingrid / Agartz, Ingrid / Andreassen, Ole A / Schork, Nicholas J / Dale, Anders M / Weiner, Michael / Aisen, Paul / Petersen, Ronald / Jack, Clifford R / Jagust, William / Trojanowki, John Q / Toga, Arthur W / Beckett, Laurel / Green, Robert C / Saykin, Andrew J / Morris, John / Liu, Enchi / Montine, Tom / Gamst, Anthony / Thomas, Ronald G / Donohue, Michael / Walter, Sarah / Gessert, Devon / Sather, Tamie / Harvey, Danielle / Kornak, John / Dale, Anders / Bernstein, Matthew / Felmlee, Joel / Fox, Nick / Thompson, Paul / Schuff, Norbert / Alexander, Gene / DeCarli, Charles / Bandy, Dan / Koeppe, Robert A / Foster, Norm / Reiman, Eric M / Chen, Kewei / Mathis, Chet / Cairns, Nigel J / Taylor-Reinwald, Lisa / Trojanowki, J Q / Shaw, Les / Lee, Virginia M Y / Korecka, Magdalena / Crawford, Karen / Neu, Scott / Foroud, Tatiana M / Potkin, Steven / Shen, Li / Kachaturian, Zaven / Frank, Richard / Snyder, Peter J / Molchan, Susan / Kaye, Jeffrey / Quinn, Joseph / Lind, Betty / Dolen, Sara / Schneider, Lon S / Pawluczyk, Sonia / Spann, Bryan M / Brewer, James / Vanderswag, Helen / Heidebrink, Judith L / Lord, Joanne L / Johnson, Kris / Doody, Rachelle S / Villanueva-Meyer, Javier / Chowdhury, Munir / Stern, Yaakov / Honig, Lawrence S / Bell, Karen L / Morris, John C / Ances, Beau / Carroll, Maria / Leon, Sue / Mintun, Mark A / Schneider, Stacy / Marson, Daniel / Griffith, Randall / Clark, David / Grossman, Hillel / Mitsis, Effie / Romirowsky, Aliza / deToledo-Morrell, Leyla / Shah, Raj C / Duara, Ranjan / Varon, Daniel / Roberts, Peggy / Albert, Marilyn / Onyike, Chiadi / Kielb, Stephanie / Rusinek, Henry / de Leon, Mony J / Glodzik, Lidia / De Santi, Susan / Doraiswamy, P Murali / Petrella, Jeffrey R / Coleman, R Edward / Arnold, Steven E / Karlawish, Jason H / Wolk, David / Smith, Charles D / Jicha, Greg / Hardy, Peter / Lopez, Oscar L / Oakley, MaryAnn / Simpson, Donna M / Porsteinsson, Anton P / Goldstein, Bonnie S / Martin, Kim / Makino, Kelly M / Ismail, M Saleem / Brand, Connie / Mulnard, Ruth A / Thai, Gaby / Mc-Adams-Ortiz, Catherine / Womack, Kyle / Mathews, Dana / Quiceno, Mary / Diaz-Arrastia, Ramon / King, Richard / Weiner, Myron / Martin-Cook, Kristen / DeVous, Michael / Levey, Allan I / Lah, James J / Cellar, Janet S / Burns, Jeffrey M / Anderson, Heather S / Swerdlow, Russell H / Apostolova, Liana / Lu, Po H / Bartzokis, George / Silverman, Daniel H S / Graff-Radford, Neill R / Parfitt, Francine / Johnson, Heather / Farlow, Martin R / Hake, Ann Marie / Matthews, Brandy R / Herring, Scott / van Dyck, Christopher H / Carson, Richard E / MacAvoy, Martha G / Chertkow, Howard / Bergman, Howard / Hosein, Chris / Black, Sandra / Stefanovic, Bojana / Caldwell, Curtis / Ging-Yuek / Hsiung, Robin / Feldman, Howard / Mudge, Benita / Assaly, Michele / Kertesz, Andrew / Rogers, John / Trost, Dick / Bernick, Charles / Munic, Donna / Kerwin, Diana / Mesulam, Marek-Marsel / Lipowski, Kristina / Wu, Chuang-Kuo / Johnson, Nancy / Sadowsky, Carl / Martinez, Walter / Villena, Teresa / Turner, Raymond Scott / Johnson, Kathleen / Reynolds, Brigid / Sperling, Reisa A / Johnson, Keith A / Marshall, Gad / Frey, Meghan / Yesavage, Jerome / Taylor, Joy L / Lane, Barton / Rosen, Allyson / Tinklenberg, Jared / Sabbagh, Marwan / Belden, Christine / Jacobson, Sandra / Kowall, Neil / Killiany, Ronald / Budson, Andrew E / Norbash, Alexander / Johnson, Patricia Lynn / Obisesan, Thomas O / Wolday, Saba / Bwayo, Salome K / Lerner, Alan / Hudson, Leon / Ogrocki, Paula / Fletcher, Evan / Carmichael, Owen / Olichney, John / Kittur, Smita / Borrie, Michael / Lee, T-Y / Bartha, Rob / Johnson, Sterling / Asthana, Sanjay / Carlsson, Cynthia M / Potkin, Steven G / Preda, Adrian / Nguyen, Dana / Tariot, Pierre / Fleisher, Adam / Reeder, Stephanie / Bates, Vernice / Capote, Horacio / Rainka, Michelle / Scharre, Douglas W / Kataki, Maria / Zimmerman, Earl A / Celmins, Dzintra / Brown, Alice D / Pearlson, Godfrey D / Blank, Karen / Anderson, Karen / Santulli, Robert B / Schwartz, Eben S / Sink, Kaycee M / Williamson, Jeff D / Garg, Pradeep / Watkins, Franklin / Ott, Brian R / Querfurth, Henry / Tremont, Geoffrey / Salloway, Stephen / Malloy, Paul / Correia, Stephen / Rosen, Howard J / Miller, Bruce L / Mintzer, Jacobo / Longmire, Crystal Flynn / Spicer, Kenneth / Finger, Elizabether / Rachinsky, Irina / Drost, Dick / Jernigan, Terry / McCabe, Connor / Grant, Ellen / Ernst, Thomas / Kuperman, Josh / Chung, Yoon / Murray, Sarah / Bloss, Cinnamon / Darst, Burcu / Pritchett, Lexi / Saito, Ashley / Amaral, David / DiNino, Mishaela / Eyngorina, Bella / Sowell, Elizabeth / Houston, Suzanne / Soderberg, Lindsay / Kaufmann, Walter / van Zijl, Peter / Rizzo-Busack, Hilda / Javid, Mohsin / Mehta, Natasha / Ruberry, Erika / Powers, Alisa / Rosen, Bruce / Gebhard, Nitzah / Manigan, Holly / Frazier, Jean / Kennedy, David / Yakutis, Lauren / Hill, Michael / Gruen, Jeffrey / Bosson-Heenan, Joan / Carlson, Heatherly

    Proceedings of the National Academy of Sciences of the United States of America

    2012  Volume 109, Issue 10, Page(s) 3985–3990

    Abstract: Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors ... ...

    Abstract Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
    MeSH term(s) Adolescent ; Adult ; Aged ; Brain/pathology ; Brain Mapping/methods ; Cohort Studies ; Diagnostic Imaging/methods ; Female ; Genetic Variation ; Genome-Wide Association Study ; Genomics ; Genotype ; Humans ; Male ; Middle Aged ; Models, Genetic ; Phosphoric Diester Hydrolases/genetics ; Polymorphism, Single Nucleotide ; Saccharomyces cerevisiae/metabolism ; Visual Cortex/anatomy & histology ; Visual Cortex/pathology
    Chemical Substances Phosphoric Diester Hydrolases (EC 3.1.4.-) ; glycerophosphocholine phosphodiesterase (EC 3.1.4.2) ; glycerophosphodiester phosphodiesterase (EC 3.1.4.46)
    Language English
    Publishing date 2012-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1105829109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes

    Zeggini, Eleftheria / Ahmad, Tariq / Ardern-Jones, A / Attwood, Antony P / Ball, Stephen G / Balmforth, Anthony J / Ban, Maria / Barbour, Jamie / Barrett, Jeffrey C / Barrett, Jennifer H / Barton, Anne / Bentley, David / Berg, J / Bishop, D. Timothy / Boorman, James P / Bradbury, Linda A / Bradshaw, N / Brady, A / Braga Marcano, Carolina A /
    Braund, Peter S / Bredin, Francesca / Breen, Gerome / Brewer, C / Brice, G / Brown, Matthew A / Brown, Morris J / Bruce, Ian N / Bullman, B / Bumpstead, Suzannah J / Burke, Beverley / Burton, Paul R / Caesar, Sian / Campbell, J / Cant, Barbara / Cardin, Niall J / Cardon, Lon R / Castle, B / Caulfield, Mark / Cetnarsryj, R / Chaney, Amy / Chapman, C / Chu, C / Clayton, David G / Coates, N / Cole, T / Collier, David A / Compston, Alastair / Compston, Alistair / Connell, John / Conway, David / Craddock, Nick / Cummings, Fraser R / Davidson, R / Davison, Dan / Deloukas, Panos / Dixon, Richard J / Dobson, Richard / Dominiczak, Anna / Donaldson, A / Doney, Alex S.F / Donnelly, Peter / Donovan, Hannah / Dorkins, H / Douglas, F / Downes, Kate / Drummond, Hazel / Duncanson, Audrey / Dunger, David B / Easton, Doug / Eccles, D / Eeles, R / Elkin, Amanda / Ellard, Sian / Elliott, Katherine S / Elmslie, F / Evans, D.G / Evans, David / Everson, Ursula / Eyre, Steve / Farmer, Anne / Farrall, Martin / Farrar, Claire / Ferreira, Teresa / Ferrier, I. Nicol / Fisher, Sheila A / Forbes, Alastair / Franklyn, Jayne A / Fraser, Christine / Frayling, Timothy M / Freathy, Rachel M / Ghori, Mohammed J.R / Gilbert, Paul D / Goff, S / Goodman, S / Gordon-Smith, Katherine / Goris, An / Goudie, D / Gough, Stephen C.L / Gray, J / Green, Elaine K / Greenhalgh, L / Gregory, H / Groves, Christopher J / Grozeva, Detelina / Gungadoo, Johannie / Gwilliam, Rhian / Hall, Alistair S / Hallgrimsdóttir, Ingeleif B / Hamshere, Marian L / Harries, Lorna W / Hattersley, Andrew T / Heward, Joanne M / Hider, Samantha L / Hill, Adrian V.S / Hinks, Anne M / Hitman, Graham A / Hodgson, S.V / Holmans, Peter A / Homfray, T / Houlston, R.S / Howie, Bryan N / Hunt, Sarah E / Hussey, Judith M / Iles, Mark M / Inouye, Michael / Isaacs, John D / Izatt, L / Jackson, L / Jallow, Muminatou / Jeffers, L / Jewell, Derek P / John, Sally L / Johnson-Roffey, V / Jolley, Jennifer D / Jones, Ian R / Jones, Lisa / Jones, Richard W / Kavalier, F / Keniry, Andrew / King, Emma / Kirk, C / Kirov, George / Knight, Alexandra S / Knight, Beatrice / Koch, Kerstin / Kwiatkowski, Dominic P / Lalloo, F / Langman, C / Lango, Hana / Lathrop, G. Mark / Lee, Kate L / Lees, Charles W / Leung, Hin-Tak / Lewis, Cathryn M / Lindgren, Cecilia M / Locke, I / Longmuir, M / Lyons, Emily / Mackay, J / Magee, A / Mangino, Massimo / Mansfield, John C / Mansour, S / Maqbool, Azhar / Marchini, Jonathan L / Mathew, Christopher G / McArdle, Wendy L / McCarthy, Mark I / McGinnis, Ralph / McGuffin, Peter / Meech, Elizabeth / Miedzybrodzka, Z / Miller, J / Mohiuddin, M. Khalid / Morgan, Ann W / Morris, Andrew D / Morris, Andrew P / Morrison, P / Moskvina, Valentina / Munroe, Patricia B / Murday, V / Newhouse, Stephen J / Newport, Melanie / Nikolov, Ivan / Nimmo, Elaine R / Nutland, Sarah / O'Donovan, Michael C / Onipinla, Abiodun / Onnie, Clive M / Ouwehand, Nilesh J / Ouwehand, Willem H / Owen, Katharine R / Owen, Michael J / Parkes, Miles / Paterson, J / Pembrey, Marcus / Pereira-Gale, Joanne / Perry, John R.B / Pichert, G / Pointon, Jennifer J / Porteous, M / Potter, Catherine / Potter, Simon / Prescott, Natalie J / Prowse, Christopher V / Rahman, N / Rahman, Nazneen / Ravindrarajah, Rathi / Rayner, Nigel W / Ring, Susan M / Rockett, Kirk A / Rogers, M / Rowe, S / Saggar, A / Samani, Michael R / Samani, Nilesh J / Sanderson, Jeremy / Satsangi, Jack / Sawcer, Stephen J / Scott, G / Seal, Sheila / Shanley, S / Shields, Beverley / Side, L / Silman, Alan J / Simmonds, Matthew J / Sirugo, Giorgio / Snadden, L / Spencer, Chris C.A / St. Clair, David / Steel, M / Stevens, Helen E / Stevens, Suzanne / Strachan, David P / Stratton, Michael R / Su, Zhan / Symmons, Deborah P.M / Taylor, Niall C / Teo, Yik Ying / Thomas, M / Thomas, S / Thompson, John R / Thomson, Wendy / Timpson, Nicholas J / Tobin, Martin D / Todd, John A / Todhunter, Catherine E / Tremelling, Mark / Vannberg, Fredrik / Vukcevic, Damjan / Walker, Mark / Walker, Neil M / Wallace, Chris / Walters, Graham R / Watkins, Nicholas A / Webster, John / Weedon, Michael N / Whittaker, Pamela / Widden, Claire / Widmer, Barry / Williamson, Richard / Wilson, Gerry D / Winzer, Thilo / Withers, David / Wordsworth, Paul / Worthington, Jane / Xue, Mingzhan / Young, Allan H / Yuldasheva, Nadira

    Science. 2007 June 1, v. 316, no. 5829

    2007  

    Abstract: The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set ... ...

    Abstract The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
    Keywords etiology ; genes ; genotype ; islets of Langerhans ; loci ; noninsulin-dependent diabetes mellitus ; risk ; United Kingdom
    Language English
    Dates of publication 2007-0601
    Size p. 1336-1341.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1142364
    Database NAL-Catalogue (AGRICOLA)

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