Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study

BACKGROUND: Galactooligosaccharides are selectively fermented by the beneficial member of the colonic microflora contributing to the health of the host. OBJECTIVE: We assessed the prebiotic potential of a novel galactooligosaccharide produced through the action of β-galactosidases, originating from...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The American journal of clinical nutrition 2008-03, Vol.87 (3), p.785-791
Hauptverfasser: Depeint, Flore, Tzortzis, George, Vulevic, Jelena, I'Anson, Kerry, Gibson, Glenn R
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 791
container_issue 3
container_start_page 785
container_title The American journal of clinical nutrition
container_volume 87
creator Depeint, Flore
Tzortzis, George
Vulevic, Jelena
I'Anson, Kerry
Gibson, Glenn R
description BACKGROUND: Galactooligosaccharides are selectively fermented by the beneficial member of the colonic microflora contributing to the health of the host. OBJECTIVE: We assessed the prebiotic potential of a novel galactooligosaccharide produced through the action of β-galactosidases, originating from a probiotic Bifidobacterium bifidum strain, against a galactooligosaccharide produced through the action of an industrial β-galactosidase and a placebo. DESIGN: Fifty-nine healthy human volunteers participated in this study. Initially, the effect of the matrix on the prebiotic properties of a commercially available galactooligosaccharide (7 g/d) was assessed during 7-d treatment periods with a 7-d washout period in between. During the second phase, 30 volunteers were assigned to a sequence of treatments (7 d) differing in the amount of the novel galactooligosaccharide (0, 3.6, or 7 g/d). Stools were recovered before and after each intervention, and bacteria numbers were determined by fluorescent in situ hybridization. RESULTS: Addition of the novel galactooligosaccharide mixture significantly increased the bifidobacterial population ratio compared with the placebo (P < 0.05), whereas 7 g/d of the novel galactooligosaccharide significantly increased the bifidobacterial ratio compared with the commercial galactooligosaccharide (P < 0.05). Moreover, a significant relation (P < 0.001) between the bifidobacteria proportion and the novel galactooligosaccharide dose (0, 3.6, and 7 g/d) was observed. This relation was similar to the effect of the novel galactooligosaccharide on the prebiotic index of each dose. CONCLUSIONS: This study showed that galactooligosaccharide mixtures produced with different β-galactosidases show different prebiotic properties and that, by using enzymes originating from bifidobacterial species, an increase in the bifidogenic properties of the prebiotic product is achievable.
doi_str_mv 10.1093/ajcn/87.3.785
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_19912073</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1444960951</sourcerecordid><originalsourceid>FETCH-LOGICAL-c508t-5159cfd0ca3fa828849cb0ee4faf521c64a68c8d3f7613ccd184974f4cbdd6f13</originalsourceid><addsrcrecordid>eNpdksuO0zAUhiMEYkphyRYsJFg1HTvOxWHHVFxGGi4SzDo68aV15djFjisyb8xb4EwrkFhZx_78n_9csuw5wWuCW3oJe24vWbOm64ZVD7IFaSnLaYGbh9kCY1zkLamri-xJCHuMSVGy-nF2QRgt6pq0i-z3Ny977UbNkTyCiTBqZ5FTCJB1R2nQFgzw0Tmjty4A5zvwWkg06F9j9BIdvBORS4H6CY07iaS9mwaY5dIvfdTjNItdaaWF69OV9DoOqJ_jdH7ZXH--QiUhDVkhbdFOghl3E9rFAWx4m0x4sMIN-k6KFRIu9kbmvdE2Rdy7EJJFv0KHZFH2LufOjt4Zk-xom1Idpb0vJ4xRTE-zRwpMkM_O5zK7_fD-x-ZTfvP14_Xm3U3OK8zGvCJVy5XAHKgCVjBWtrzHUpYKVFUQXpdQM84EVU1NKOeCJKIpVcl7IWpF6DJ7c9JNrfkZZRi7QQcujQErXQwdaVuSxkMT-Oo_cO-it8lbV1DSFlVVz1B-gu7L9VJ1B68H8FNHcDcvQDcvQMeajnZpARL_4iwa-0GKf_R54gl4fQYgcDAqNZjr8JcrMGnLOfMye3niFLgOtj4xt9_TK8WY1awsS_oHxQfIaQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>231925563</pqid></control><display><type>article</type><title>Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Depeint, Flore ; Tzortzis, George ; Vulevic, Jelena ; I'Anson, Kerry ; Gibson, Glenn R</creator><creatorcontrib>Depeint, Flore ; Tzortzis, George ; Vulevic, Jelena ; I'Anson, Kerry ; Gibson, Glenn R</creatorcontrib><description>BACKGROUND: Galactooligosaccharides are selectively fermented by the beneficial member of the colonic microflora contributing to the health of the host. OBJECTIVE: We assessed the prebiotic potential of a novel galactooligosaccharide produced through the action of β-galactosidases, originating from a probiotic Bifidobacterium bifidum strain, against a galactooligosaccharide produced through the action of an industrial β-galactosidase and a placebo. DESIGN: Fifty-nine healthy human volunteers participated in this study. Initially, the effect of the matrix on the prebiotic properties of a commercially available galactooligosaccharide (7 g/d) was assessed during 7-d treatment periods with a 7-d washout period in between. During the second phase, 30 volunteers were assigned to a sequence of treatments (7 d) differing in the amount of the novel galactooligosaccharide (0, 3.6, or 7 g/d). Stools were recovered before and after each intervention, and bacteria numbers were determined by fluorescent in situ hybridization. RESULTS: Addition of the novel galactooligosaccharide mixture significantly increased the bifidobacterial population ratio compared with the placebo (P &lt; 0.05), whereas 7 g/d of the novel galactooligosaccharide significantly increased the bifidobacterial ratio compared with the commercial galactooligosaccharide (P &lt; 0.05). Moreover, a significant relation (P &lt; 0.001) between the bifidobacteria proportion and the novel galactooligosaccharide dose (0, 3.6, and 7 g/d) was observed. This relation was similar to the effect of the novel galactooligosaccharide on the prebiotic index of each dose. CONCLUSIONS: This study showed that galactooligosaccharide mixtures produced with different β-galactosidases show different prebiotic properties and that, by using enzymes originating from bifidobacterial species, an increase in the bifidogenic properties of the prebiotic product is achievable.</description><identifier>ISSN: 0002-9165</identifier><identifier>EISSN: 1938-3207</identifier><identifier>DOI: 10.1093/ajcn/87.3.785</identifier><identifier>PMID: 18326619</identifier><identifier>CODEN: AJCNAC</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Nutrition</publisher><subject>Adult ; beta-Galactosidase - metabolism ; Bifidobacterium - enzymology ; Bifidobacterium bifidum ; Biological and medical sciences ; Colon - metabolism ; Colon - microbiology ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Enzymes ; Feces - microbiology ; Feeding. Feeding behavior ; Female ; Fermentation ; Fluorescence in situ hybridization ; Functional foods &amp; nutraceuticals ; Fundamental and applied biological sciences. Psychology ; Galactose - biosynthesis ; Galactose - metabolism ; Humans ; In Situ Hybridization, Fluorescence - methods ; Male ; Oligosaccharides - biosynthesis ; Oligosaccharides - metabolism ; Probiotics ; Studies ; Vertebrates: anatomy and physiology, studies on body, several organs or systems</subject><ispartof>The American journal of clinical nutrition, 2008-03, Vol.87 (3), p.785-791</ispartof><rights>2008 INIST-CNRS</rights><rights>Copyright American Society for Clinical Nutrition, Inc. Mar 1, 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-5159cfd0ca3fa828849cb0ee4faf521c64a68c8d3f7613ccd184974f4cbdd6f13</citedby><cites>FETCH-LOGICAL-c508t-5159cfd0ca3fa828849cb0ee4faf521c64a68c8d3f7613ccd184974f4cbdd6f13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=20194556$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18326619$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Depeint, Flore</creatorcontrib><creatorcontrib>Tzortzis, George</creatorcontrib><creatorcontrib>Vulevic, Jelena</creatorcontrib><creatorcontrib>I'Anson, Kerry</creatorcontrib><creatorcontrib>Gibson, Glenn R</creatorcontrib><title>Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study</title><title>The American journal of clinical nutrition</title><addtitle>Am J Clin Nutr</addtitle><description>BACKGROUND: Galactooligosaccharides are selectively fermented by the beneficial member of the colonic microflora contributing to the health of the host. OBJECTIVE: We assessed the prebiotic potential of a novel galactooligosaccharide produced through the action of β-galactosidases, originating from a probiotic Bifidobacterium bifidum strain, against a galactooligosaccharide produced through the action of an industrial β-galactosidase and a placebo. DESIGN: Fifty-nine healthy human volunteers participated in this study. Initially, the effect of the matrix on the prebiotic properties of a commercially available galactooligosaccharide (7 g/d) was assessed during 7-d treatment periods with a 7-d washout period in between. During the second phase, 30 volunteers were assigned to a sequence of treatments (7 d) differing in the amount of the novel galactooligosaccharide (0, 3.6, or 7 g/d). Stools were recovered before and after each intervention, and bacteria numbers were determined by fluorescent in situ hybridization. RESULTS: Addition of the novel galactooligosaccharide mixture significantly increased the bifidobacterial population ratio compared with the placebo (P &lt; 0.05), whereas 7 g/d of the novel galactooligosaccharide significantly increased the bifidobacterial ratio compared with the commercial galactooligosaccharide (P &lt; 0.05). Moreover, a significant relation (P &lt; 0.001) between the bifidobacteria proportion and the novel galactooligosaccharide dose (0, 3.6, and 7 g/d) was observed. This relation was similar to the effect of the novel galactooligosaccharide on the prebiotic index of each dose. CONCLUSIONS: This study showed that galactooligosaccharide mixtures produced with different β-galactosidases show different prebiotic properties and that, by using enzymes originating from bifidobacterial species, an increase in the bifidogenic properties of the prebiotic product is achievable.</description><subject>Adult</subject><subject>beta-Galactosidase - metabolism</subject><subject>Bifidobacterium - enzymology</subject><subject>Bifidobacterium bifidum</subject><subject>Biological and medical sciences</subject><subject>Colon - metabolism</subject><subject>Colon - microbiology</subject><subject>Cross-Over Studies</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Enzymes</subject><subject>Feces - microbiology</subject><subject>Feeding. Feeding behavior</subject><subject>Female</subject><subject>Fermentation</subject><subject>Fluorescence in situ hybridization</subject><subject>Functional foods &amp; nutraceuticals</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Galactose - biosynthesis</subject><subject>Galactose - metabolism</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence - methods</subject><subject>Male</subject><subject>Oligosaccharides - biosynthesis</subject><subject>Oligosaccharides - metabolism</subject><subject>Probiotics</subject><subject>Studies</subject><subject>Vertebrates: anatomy and physiology, studies on body, several organs or systems</subject><issn>0002-9165</issn><issn>1938-3207</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdksuO0zAUhiMEYkphyRYsJFg1HTvOxWHHVFxGGi4SzDo68aV15djFjisyb8xb4EwrkFhZx_78n_9csuw5wWuCW3oJe24vWbOm64ZVD7IFaSnLaYGbh9kCY1zkLamri-xJCHuMSVGy-nF2QRgt6pq0i-z3Ny977UbNkTyCiTBqZ5FTCJB1R2nQFgzw0Tmjty4A5zvwWkg06F9j9BIdvBORS4H6CY07iaS9mwaY5dIvfdTjNItdaaWF69OV9DoOqJ_jdH7ZXH--QiUhDVkhbdFOghl3E9rFAWx4m0x4sMIN-k6KFRIu9kbmvdE2Rdy7EJJFv0KHZFH2LufOjt4Zk-xom1Idpb0vJ4xRTE-zRwpMkM_O5zK7_fD-x-ZTfvP14_Xm3U3OK8zGvCJVy5XAHKgCVjBWtrzHUpYKVFUQXpdQM84EVU1NKOeCJKIpVcl7IWpF6DJ7c9JNrfkZZRi7QQcujQErXQwdaVuSxkMT-Oo_cO-it8lbV1DSFlVVz1B-gu7L9VJ1B68H8FNHcDcvQDcvQMeajnZpARL_4iwa-0GKf_R54gl4fQYgcDAqNZjr8JcrMGnLOfMye3niFLgOtj4xt9_TK8WY1awsS_oHxQfIaQ</recordid><startdate>20080301</startdate><enddate>20080301</enddate><creator>Depeint, Flore</creator><creator>Tzortzis, George</creator><creator>Vulevic, Jelena</creator><creator>I'Anson, Kerry</creator><creator>Gibson, Glenn R</creator><general>American Society for Nutrition</general><general>American Society for Clinical Nutrition</general><general>American Society for Clinical Nutrition, Inc</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T7</scope><scope>7TS</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>7QL</scope><scope>7QO</scope></search><sort><creationdate>20080301</creationdate><title>Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study</title><author>Depeint, Flore ; Tzortzis, George ; Vulevic, Jelena ; I'Anson, Kerry ; Gibson, Glenn R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-5159cfd0ca3fa828849cb0ee4faf521c64a68c8d3f7613ccd184974f4cbdd6f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>beta-Galactosidase - metabolism</topic><topic>Bifidobacterium - enzymology</topic><topic>Bifidobacterium bifidum</topic><topic>Biological and medical sciences</topic><topic>Colon - metabolism</topic><topic>Colon - microbiology</topic><topic>Cross-Over Studies</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Enzymes</topic><topic>Feces - microbiology</topic><topic>Feeding. Feeding behavior</topic><topic>Female</topic><topic>Fermentation</topic><topic>Fluorescence in situ hybridization</topic><topic>Functional foods &amp; nutraceuticals</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Galactose - biosynthesis</topic><topic>Galactose - metabolism</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence - methods</topic><topic>Male</topic><topic>Oligosaccharides - biosynthesis</topic><topic>Oligosaccharides - metabolism</topic><topic>Probiotics</topic><topic>Studies</topic><topic>Vertebrates: anatomy and physiology, studies on body, several organs or systems</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Depeint, Flore</creatorcontrib><creatorcontrib>Tzortzis, George</creatorcontrib><creatorcontrib>Vulevic, Jelena</creatorcontrib><creatorcontrib>I'Anson, Kerry</creatorcontrib><creatorcontrib>Gibson, Glenn R</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Physical Education Index</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><jtitle>The American journal of clinical nutrition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Depeint, Flore</au><au>Tzortzis, George</au><au>Vulevic, Jelena</au><au>I'Anson, Kerry</au><au>Gibson, Glenn R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study</atitle><jtitle>The American journal of clinical nutrition</jtitle><addtitle>Am J Clin Nutr</addtitle><date>2008-03-01</date><risdate>2008</risdate><volume>87</volume><issue>3</issue><spage>785</spage><epage>791</epage><pages>785-791</pages><issn>0002-9165</issn><eissn>1938-3207</eissn><coden>AJCNAC</coden><abstract>BACKGROUND: Galactooligosaccharides are selectively fermented by the beneficial member of the colonic microflora contributing to the health of the host. OBJECTIVE: We assessed the prebiotic potential of a novel galactooligosaccharide produced through the action of β-galactosidases, originating from a probiotic Bifidobacterium bifidum strain, against a galactooligosaccharide produced through the action of an industrial β-galactosidase and a placebo. DESIGN: Fifty-nine healthy human volunteers participated in this study. Initially, the effect of the matrix on the prebiotic properties of a commercially available galactooligosaccharide (7 g/d) was assessed during 7-d treatment periods with a 7-d washout period in between. During the second phase, 30 volunteers were assigned to a sequence of treatments (7 d) differing in the amount of the novel galactooligosaccharide (0, 3.6, or 7 g/d). Stools were recovered before and after each intervention, and bacteria numbers were determined by fluorescent in situ hybridization. RESULTS: Addition of the novel galactooligosaccharide mixture significantly increased the bifidobacterial population ratio compared with the placebo (P &lt; 0.05), whereas 7 g/d of the novel galactooligosaccharide significantly increased the bifidobacterial ratio compared with the commercial galactooligosaccharide (P &lt; 0.05). Moreover, a significant relation (P &lt; 0.001) between the bifidobacteria proportion and the novel galactooligosaccharide dose (0, 3.6, and 7 g/d) was observed. This relation was similar to the effect of the novel galactooligosaccharide on the prebiotic index of each dose. CONCLUSIONS: This study showed that galactooligosaccharide mixtures produced with different β-galactosidases show different prebiotic properties and that, by using enzymes originating from bifidobacterial species, an increase in the bifidogenic properties of the prebiotic product is achievable.</abstract><cop>Bethesda, MD</cop><pub>American Society for Nutrition</pub><pmid>18326619</pmid><doi>10.1093/ajcn/87.3.785</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0002-9165
ispartof The American journal of clinical nutrition, 2008-03, Vol.87 (3), p.785-791
issn 0002-9165
1938-3207
language eng
recordid cdi_proquest_miscellaneous_19912073
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Adult
beta-Galactosidase - metabolism
Bifidobacterium - enzymology
Bifidobacterium bifidum
Biological and medical sciences
Colon - metabolism
Colon - microbiology
Cross-Over Studies
Dose-Response Relationship, Drug
Double-Blind Method
Enzymes
Feces - microbiology
Feeding. Feeding behavior
Female
Fermentation
Fluorescence in situ hybridization
Functional foods & nutraceuticals
Fundamental and applied biological sciences. Psychology
Galactose - biosynthesis
Galactose - metabolism
Humans
In Situ Hybridization, Fluorescence - methods
Male
Oligosaccharides - biosynthesis
Oligosaccharides - metabolism
Probiotics
Studies
Vertebrates: anatomy and physiology, studies on body, several organs or systems
title Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T04%3A59%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Prebiotic%20evaluation%20of%20a%20novel%20galactooligosaccharide%20mixture%20produced%20by%20the%20enzymatic%20activity%20of%20Bifidobacterium%20bifidum%20NCIMB%2041171,%20in%20healthy%20humans:%20a%20randomized,%20double-blind,%20crossover,%20placebo-controlled%20intervention%20study&rft.jtitle=The%20American%20journal%20of%20clinical%20nutrition&rft.au=Depeint,%20Flore&rft.date=2008-03-01&rft.volume=87&rft.issue=3&rft.spage=785&rft.epage=791&rft.pages=785-791&rft.issn=0002-9165&rft.eissn=1938-3207&rft.coden=AJCNAC&rft_id=info:doi/10.1093/ajcn/87.3.785&rft_dat=%3Cproquest_cross%3E1444960951%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=231925563&rft_id=info:pmid/18326619&rfr_iscdi=true