Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-30T20:01:35.328Z Has data issue: false hasContentIssue false
  • English
  • Français

UK Food Standards Agency α-linolenic acid workshop report

Published online by Cambridge University Press:  09 March 2007

Peter Sanderson ,
Yvonne E. Finnegan ,
Christine M. Williams ,
Philip C. Calder ,
Graham C. Burdge ,
Stephen A. Wootton ,
Bruce A. Griffin ,
D. Joe Millward ,
Nicholas C. Pegge  and
Wanda J. E. Bemelmans
Peter Sanderson*
Affiliation:
Nutrition Division, Food Standards Agency, Aviation House, 125 Kingsway, London WC2 6NH, UK
Yvonne E. Finnegan
Affiliation:
Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, Whiteknights, PO Box 226, Reading RG6 6AP, UK
Christine M. Williams
Affiliation:
Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, Whiteknights, PO Box 226, Reading RG6 6AP, UK
Philip C. Calder
Affiliation:
Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton SO16 7PX, UK
Graham C. Burdge
Affiliation:
Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton SO16 7PX, UK
Stephen A. Wootton
Affiliation:
Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton SO16 7PX, UK
Bruce A. Griffin
Affiliation:
Centre for Nutrition and Food Safety, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK
D. Joe Millward
Affiliation:
Centre for Nutrition and Food Safety, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK
Nicholas C. Pegge
Affiliation:
Department of Pharmacology, Therapeutics and Toxicology, University of Wales College of Medicine, Cardiff CF14 4XN, UK
Wanda J. E. Bemelmans
Affiliation:
University of Groningen, Department of General Practice, Anton Deusinglaan 4, 9713 AW, Groningen, The Netherlands
*
*Corresponding author: Dr Peter Sanderson, fax +44 20 7276 8906, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating whether n-3 polyunsaturated fatty acids (PUFA) from plant oils (α-linolenic acid; ALA) were as beneficial to cardiovascular health as the n-3 PUFA from the marine oils, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The workshop also aimed to establish priorities for future research. Dietary intake of ALA has been associated with a beneficial effect on CHD; however, the results from studies investigating the effects of ALA supplementation on CHD risk factors have proved equivocal. The studies presented as part of the present workshop suggested little, if any, benefit of ALA, relative to linoleic acid, on risk factors for cardiovascular disease; the effects observed with fish-oil supplementation were not replicated by ALA supplementation. There is a need, therefore, to first prove the efficacy of ALA supplementation on cardiovascular disease, before further investigating effects on cardiovascular risk factors. The workshop considered that a beneficial effect of ALA on the secondary prevention of CHD still needed to be established, and there was no reason to look further at existing CHD risk factors in relation to ALA supplementation. The workshop also highlighted the possibility of feeding livestock ALA-rich oils to provide a means of increasing the dietary intake in human consumers of EPA and DHA.

Keywords

α-Linolenic acidFish oilsCardiovascular diseaseNutrition research
Type
Research Article
Information
British Journal of Nutrition , Volume 88 , Issue 5 , November 2002 , pp. 573 - 579
Copyright
Copyright © The Nutrition Society 2002

References

Abelow, BJ, Holford, TR & Insogna, KL (1992) Cross-cultural association between dietary animal protein and hip fracture: a hypothesis. Calcified Tissue International 50, 14–18.Google Scholar
Albright, F, Smith, PH & Richardson, AM (1941) Postmenopausal osteoporosis. Journal of the American Medical Association 116, 2465–2474.CrossRefGoogle Scholar
Allen, LH, Oddoye, EA & Margen, S (1979) Protein-induced hypercalciuria: a longer term study. American Journal of Clinical Nutrition 32, 741–749.Google Scholar
Aspray, TJ, Prentice, A, Cole, TJ, Sawo, Y, Reeve, J & Francis, RM (1996) Low bone mineral content is common but osteoporotic fractures are rare in elderly rural Gambian women. Journal of Bone and Mineral Research 11, 1019–1025.CrossRefGoogle ScholarPubMed
Barzel, US (1995) The skeleton as an ion exchange system: implications for the role of acid–base imbalance in the genesis of osteoporosis. Journal of Bone and Mineral Research 10, 1431–1436.CrossRefGoogle ScholarPubMed
Barzel, US & Massey, LK (1998) Excess dietary protein can adversely affect bone. Journal of Nutrition 128, 1051–1053.Google Scholar
Bass, S, Delmas, PD, Pearce, G, Hendrich, E, Tabensky, A & Seeman, E (1999) The differing tempo of growth in bone size, mass, and density in girls is region-specific. Journal of Clinical Investigation 104, 795–804.CrossRefGoogle ScholarPubMed
Block, GD, Wood, RJ & Allen, LH (1980) A comparison of the effects of feeding sulfur amino acids and protein on urine calcium in man. American Journal of Clinical Nutrition 33, 2128–2136.Google Scholar
Bourrin, S, Ammann, P, Bonjour, JP & Rizzoli, R (2000a) Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats. Endocrinology 141, 3149–3155.Google Scholar
Bourrin, S, Toromanoff, A, Ammann, P, Bonjour, JP & Rizzoli, R (2000b) Dietary protein deficiency induces osteoporosis in aged male rats. Journal of Bone and Mineral Research 15, 1555–1563.CrossRefGoogle ScholarPubMed
Buclin, T, Cosma, M, Appenzeller, M, Jacquet, AF, Decosterd, LA, Biollaz, J & Burckhardt, P (2001) Diet acids and alkalis influence calcium retention in bone. Osteoporosis International 12, 493–499.CrossRefGoogle ScholarPubMed
Bushinsky, DA, Parker, WR, Alexander, KM & Krieger, NS (2001) Metabolic, but not respiratory, acidosis increases bone PGE (2) levels and calcium release. American Journal of Physiology 281, F1058–F1066.Google Scholar
Cadogan, J, Blumsohn, A, Barker, ME & Eastell, R (1998) A longitudinal study of bone gain in pubertal girls: anthropometric and biochemical correlates. Journal of Bone and Mineral Research 13, 1602–1612.Google Scholar
Cappola, AR, Bandeen-Roche, K, Wand, GS, Volpato, S & Fried, LP (2001) Association of IGF-I levels with muscle strength and mobility in older women. Journal of Clinical Endocrinology and Metabolism 86, 4139–4146.CrossRefGoogle ScholarPubMed
Caverzasio, J & Bonjour, JP (1989) Insulin-like growth factor I stimulates Na-dependent Pi transport in cultured kidney cells. American Journal of Physiology 257, F712–F717.Google Scholar
Chu, JY, Margen, S & Costa, FM (1975) Studies in calcium metabolism. II. Effects of low calcium and variable protein intake on human calcium metabolism. American Journal of Clinical Nutrition 28, 1028–1035.Google Scholar
Civitelli, R (1993) Dietary L-lysine and calcium metabolism in humans: background. Nutrition 9, 299–300.Google Scholar
Civitelli, R, Villareal, DT, Agnusdei, D, Nardi, P, Avioli, LV & Gennari, C (1992) Dietary L-lysine and calcium metabolism in humans. Nutrition 8, 400–405.Google Scholar
Clemmons, DR & Underwood, LE (1991) Nutritional regulation of IGF-I and IGF binding proteins. Annual Review of Nutrition 11, 393–412.CrossRefGoogle ScholarPubMed
Dawson-Hughes, B & Harris, SS (2002) Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. American Journal of Clinical Nutrition 75, 773–779.Google Scholar
Delmi, M, Rapin, CH, Bengoa, JM, Delmas, PD, Vasey, H & Bonjour, JP (1990) Dietary supplementation in elderly patients with fractured neck of the femur. Lancet 335, 1013–1016.Google Scholar
Department of Health (1998) Nutrition and Bone Health with Particular Reference to Calcium and Vitamin D. Report on Health and Social Subjects no. 49 London: The Stationery Office.Google Scholar
Draper, HH, Piche, LA & Gibson, RS (1991) Effects of a high protein intake from common foods on calcium metabolism in a cohort of postmenopausal women. Nutrition Research 11, 273–281.CrossRefGoogle Scholar
Feskanich, D, Willett, WC, Stampfer, MJ & Colditz, GA (1996) Protein consumption and bone fractures in women. American Journal of Epidemiology 143, 472–479.CrossRefGoogle ScholarPubMed
Food and Agriculture Organization/World Health Organization Expert Consultation (2002) Human Vitamin and Mineral Requirements, pp. 151–179. Rome: FAO.Google Scholar
Frassetto, LA, Todd, KM, MorrisRC, RC, Jr & Sebastian, A (1998) Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. American Journal of Clinical Nutrition 68, 576–583.Google Scholar
Frassetto, LA, Todd, KM, MorrisRC, RC, Jr & Sebastian, A (2000) Worldwide incidence of hip fracture in elderly women: relation to consumption of animal and vegetable foods. Journal of Gerontology 55A M585–M592.Google Scholar
Geinoz, G, Rapin, CH, Rizzoli, R, Kraemer, R, Buchs, B, Slosman, D, Michel, JP & Bonjour, JP (1993) Relationship between bone mineral density and dietary intakes in the elderly. Osteoporosis International 3, 242–248.Google Scholar
Hannan, MT, Tucker, KL, Dawson-Hughes, B, Cupples, LA, Felson, DT & Kiel, DP (2000) Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study. Journal of Bone and Mineral Research 15, 2504–2512.CrossRefGoogle Scholar
Heaney, RP (1993) Protein intake and the calcium economy. Journal of the American Dietetic Association 93, 1259–1260.Google Scholar
Hegsted, M & Linkswiler, HM (1981) Long-term effects of level of protein intake on calcium metabolism in young adult women. Journal of Nutrition 111, 244–251.Google Scholar
Hegsted, M, Schuette, SA, Zemel, MB & Linkswiler, HM (1981) Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake. Journal of Nutrition 111, 553–562.CrossRefGoogle ScholarPubMed
Holland, B, Welch, A, Unwin, I, Buss, D, Paul, A & Southgate, D (1991) McCance and Widdowson's The Composition of Food. Cambridge: Royal Society of Chemistry.Google Scholar
Hoppe, C, Molgaard, C & Michaelsen, KF (2000) Bone size and bone mass in 10-year-old Danish children: effect of current diet. Osteoporosis International 11, 1024–1030.Google Scholar
Juul, A, Bang, P, Hertel, NT, Main, K, Dalgaard, P, Jorgensen, K, Muller, J, Hall, K & Skakkebaek, NE (1994) Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. Journal of Clinical Endocrinology and Metabolism 78, 744–752.Google ScholarPubMed
Kerstetter, JE & Allen, LH (1990) Dietary protein increases urinary calcium. Journal of Nutrition 120, 134–136.Google Scholar
Kerstetter, JE, Caseria, DM, Mitnick, ME, Ellison, AF, Gay, LF, Liskov, TA, Carpenter, TO & Insogna, KL (1997) Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet. American Journal of Clinical Nutrition 66, 1188–1196.CrossRefGoogle ScholarPubMed
Kerstetter, JE, O'Brien, KO & Insogna, KL (2003) Low protein intake: the impact on calcium and bone homeostasis in humans. Journal of Nutrition 133, 855S–861S.Google Scholar
Kerstetter, JE, Svastisalee, CM, Caseria, DM, Mitnick, ME & Insogna, KL (2000) A threshold for low-protein-diet-induced elevations in parathyroid hormone. American Journal of Clinical Nutrition 72, 168–173.Google Scholar
Kim, Y & Linkswiler, HM (1979) Effect of level of protein intake on calcium metabolism and on parathyroid and renal function in the adult human male. Journal of Nutrition 109, 1399–1404.Google Scholar
Langdahl, BL, Kassem, M, Moller, MK & Eriksen, EF (1998) The effects of IGF-I and IGF-II on proliferation and differentiation of human osteoblasts and interactions with growth hormone. European Journal of Clinical Investigation 28, 176–183.Google Scholar
Langlois, JA, Rosen, CJ, Visser, M, Hannan, MT, Harris, T, Wilson, PW & Kiel, DP (1998) Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham Heart Study. Journal of Clinical Endocrinology and Metabolism 83, 4257–4262.Google Scholar
Lemann, J Jr, Litzow, JR & Lennon, EJ (1966) The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. Journal of Clinical Investigation 45, 1608–1614.CrossRefGoogle ScholarPubMed
Lutz, J (1984) Calcium balance and acid–base status of women as affected by increased protein intake and by sodium bicarbonate ingestion. American Journal of Clinical Nutrition 39, 281–288.Google Scholar
McCarthy, TL, Centrella, M & Canalis, E (1989) Insulin-like growth factor (IGF) and bone. Connective Tissue Research 20, 277–282.Google Scholar
Maiter, D, Fliesen, T, Underwood, LE, Maes, M, Gerard, G, Davenport, ML & Ketelslegers, JM (1989) Dietary protein restriction decreases insulin-like growth factor I independent of insulin and liver growth hormone binding. Endocrinology 124, 2604–2611.Google Scholar
Margen, S, Chu, JY, Kaufmann, NA & Calloway, DH (1974) Studies in calcium metabolism. I. The calciuretic effect of dietary protein. American Journal of Clinical Nutrition 27, 584–589.Google Scholar
Marsh, AG, Sanchez, TV, Chaffee, FL, Mayor, GH & Mickelsen, O (1983) Bone mineral mass in adult lacto-ovo-vegetarian and omnivorous males. American Journal of Clinical Nutrition 37, 453–456.CrossRefGoogle ScholarPubMed
Marsh, AG, Sanchez, TV, Michelsen, O, Chaffee, FL & Fagal, SM (1988) Vegetarian lifestyle and bone mineral density. American Journal of Clinical Nutrition 48, 837–841.Google Scholar
Marsh, AG, Sanchez, TV, Midkelsen, O, Keiser, J & Mayor, G (1980) Cortical bone density of adult lacto-ovo-vegetarian and omnivorous women. Journal of the American Dietetic Association 76, 148–151.Google Scholar
Meyer, HE, Pedersen, JI, Loken, EB & Tverdal, A (1997) Dietary factors and the incidence of hip fracture in middle-aged Norwegians. A prospective study. American Journal of Epidemiology 145, 117–123.Google Scholar
Mohan, S, Strong, DD, Lempert, UG, Tremollieres, F, Wergedal, JE & Baylink, DJ (1992) Studies on regulation of insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-4 production in human bone cells. Acta Endocrinologica 127, 555–564.Google Scholar
Muhlbauer, RC & Li, F (1999) Effect of vegetables on bone metabolism. Nature 401, 343–344.Google Scholar
Munger, RG, Cerhan, JR & Chiu, BC (1999) Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. American Journal of Clinical Nutrition 69, 147–152.Google Scholar
New, SA, Bolton-Smith, C, Grubb, DA & Reid, DM (1997) Nutritional influences on bone mineral density: a cross-sectional study in premenopausal women. American Journal of Clinical Nutrition 65, 1831–1839.Google Scholar
New, SA, Robins, SP, Campbell, MK, Martin, JC, Garton, MJ, Bolton-Smith, C, Grubb, DA, Lee, SJ & Reid, DM (2000) Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?. American Journal of Clinical Nutrition 71, 142–151.Google Scholar
Oh, MS (2000) New perspectives on acid-base balance. Seminars in Dialysis 13, 212–219.Google Scholar
Pannemans, DL, Schaafsma, G & Westerterp, KR (1997) Calcium excretion, apparent calcium absorption and calcium balance in young and elderly subjects: influence of protein intake. British Journal of Nutrition 77, 721–729.Google Scholar
Paul, AA, Southgate, DAT & Russell, J (1980) First Supplement to McCance and Widdowson's The Composition of Foods. London: H.M. Stationery Office.Google Scholar
Prentice, A, Parsons, TJ & Cole, TJ (1994) Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. American Journal of Clinical Nutrition 60, 837–842.Google Scholar
Prentice, A, Stear, SJ, Ginty, F, Jones, SC, Mills, L & Cole, TJ (2002) Calcium supplementation increases height and bone mass of 16–18 year old boys. Journal of Bone and Mineral Research 17, S397.Google Scholar
Promislow, JH, Goodman-Gruen, D, Slymen, DJ & Barrett-Connor, E (2002) Protein consumption and bone mineral density in the elderly: the Rancho Bernardo Study. American Journal of Epidemiology 155, 636–644.Google Scholar
Rapuri, PB, Gallagher, JC & Haynatzka, V (2003) Protein intake: effects on bone mineral density and the rate of bone loss in elderly women. American Journal of Clinical Nutrition 77, 1517–1525.CrossRefGoogle Scholar
Remer, T (2000) Influence of diet on acid–base balance. Seminars in Dialysis 13, 221–226.Google Scholar
Remer, T & Manz, F (1995) Potential renal acid load of foods and its influence on urine pH. Journal of the American Dietetic Association 95, 791–797.Google Scholar
Rizzoli, R (1998) Protein intake and osteoporosis. In Nutritional Aspects of Osteoporosis, pp. 141–154 [Burckhardt, P, Dawson-Hughes, B and Heaney, RP, editors]. New York: Springer-Verlag.Google Scholar
Roughead, ZK, Johnson, LK, Lykken, GI & Hunt, JR (2003) Controlled high meat diets do not affect calcium retention or indices of bone status in healthy postmenopausal women. Journal of Nutrition 133, 1020–1026.CrossRefGoogle ScholarPubMed
Rubin, J, Ackert-Bicknell, CL, Zhu, L, Fan, X, Murphy, TC, Nanes, MS, Marcus, R, Holloway, L, Beamer, WG & Rosen, CJ (2002) IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo. Journal of Clinical Endocrinology and Metabolism 87, 4273–4279.CrossRefGoogle ScholarPubMed
Schurch, MA, Rizzoli, R, Slosman, D, Vadas, L, Vergnaud, P & Bonjour, JP (1998) Protein supplements increase serum insulin-like growth factor-I levels and attenuate proximal femur bone loss in patients with recent hip fracture. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 128, 801–809.Google Scholar
Seeman, E, Karlsson, MK & Duan, Y (2000) On exposure to anorexia nervosa, the temporal variation in axial and appendicular skeletal development predisposes to site-specific deficits in bone size and density: a cross-sectional study. Journal of Bone and Mineral Research 15, 2259–2265.CrossRefGoogle ScholarPubMed
Sellmeyer, DE, Stone, KL, Sebastian, A & Cummings, SR (2001) A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group. American Journal of Clinical Nutrition 73, 118–122.Google Scholar
Spencer, H, Kramer, L, Osis, D & Norris, C (1978) Effect of a high protein (meat) intake on calcium metabolism in man. American Journal of Clinical Nutrition 31, 2167–2180.Google Scholar
Stear, SJ, Prentice, A, Jones, SC & Cole, TJ (2003) Effect of a calcium and exercise intervention on bone mineral status of 16–18 year old adolescent girls. American Journal of Clinical Nutrition 77, 985–992.Google Scholar
Sugimoto, T, Nishiyama, K, Kuribayashi, F & Chihara, K (1997) Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures. Journal of Bone and Mineral Research 12, 1272–1279.Google Scholar
Teegarden, D, Lyle, RM, McCabe, GP, McCabe, LD, Proulx, WR, Michon, K, Knight, AP, Johnston, CC & Weaver, CM (1998) Dietary calcium, protein, and phosphorus are related to bone mineral density and content in young women. American Journal of Clinical Nutrition 68, 749–754.Google Scholar
Thissen, JP, Davenport, ML, Pucilowska, JB, Miles, MV & Underwood, LE (1992) Increased serum clearance and degradation of 125I-labeled IGF-I in protein-restricted rats. American Journal of Physiology 262, E406–E411.Google ScholarPubMed
Thissen, JP, Ketelslegers, JM & Underwood, LE (1994) Nutritional regulation of the insulin-like growth factors. Endocrine Reviews 15, 80–101.Google Scholar
Thissen, JP, Underwood, LE, Maiter, D, Maes, M, Clemmons, DR & Ketelslegers, JM (1991) Failure of insulin-like growth factor-I (IGF-I) infusion to promote growth in protein-restricted rats despite normalization of serum IGF-I concentrations. Endocrinology 128, 885–890.CrossRefGoogle ScholarPubMed
Tkatch, L, Rapin, CH, Rizzoli, R, Slosman, D, Nydegger, V, Vasey, H & Bonjour, JP (1992) Benefits of oral protein supplementation in elderly patients with fracture of the proximal femur. Journal of the American College of Nutrition 11, 519–525.Google Scholar
Tucker, KL, Hannan, MT, Chen, H, Cupples, LA, Wilson, PW & Kiel, DP (1999) Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. American Journal of Clinical Nutrition 69, 727–736.Google Scholar
Tylavsky, FA & Anderson, JJ (1988) Dietary factors in bone health of elderly lactoovovegetarian and omnivorous women. American Journal of Clinical Nutrition 48, 842–849.CrossRefGoogle ScholarPubMed
Wang, J, Zhou, J & Bondy, CA (1999) IGF-1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB Journal 13, 1985–1990.CrossRefGoogle ScholarPubMed
Wolinsky, I & Fosmire, GJ (1982) Calcium metabolism in aged mice ingesting a lysine-deficient diet. Gerontology 28, 156–162.Google Scholar
Yakar, S, Rosen, CJ, Beamer, WG, Ackert-Bicknell, CL, Wu, Y, Liu, JL, Ooi, GT, Setser, J, Frystyk, J, Boisclair, YR & LeRoith, D (2002) Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation 110, 771–781.Google Scholar
Yan, L, Zhou, B, Prentice, A, Wang, X & Golden, MH (1999) Epidemiological study of hip fracture in Shenyang, People's Republic of China. Bone 24, 151–155.Google Scholar
Zhang, M, Xuan, S, Bouxsein, MLvon Stechow, D, Akeno, N, Faugere, MC, Malluche, H, Zhao, G, Rosen, CJ, Efstratiadis, A & Clemens, TL (2002) Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. Journal of Biological Chemistry 277, 44005–44012.CrossRefGoogle ScholarPubMed