Publications by authors named "Martin J Shearer"

42 Publications

Delivering neonatal vitamin K prophylaxis: the continuing need for surveillance and vigilance.

Authors:
Martin J Shearer

Arch Dis Child 2020 05 14;105(5):417-418. Epub 2020 Feb 14.

Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK

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http://dx.doi.org/10.1136/archdischild-2019-318117DOI Listing
May 2020

Plasma Response to Deuterium-Labeled Vitamin K Intake Varies by TG Response, but Not Age or Vitamin K Status, in Older and Younger Adults.

J Nutr 2019 01;149(1):18-25

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.

Background: Phylloquinone is the primary form of vitamin K in the diet and circulation. Large intra- and interindividual variances in circulating phylloquinone have been partially attributed to age. However, little is known about the nondietary factors that influence phylloquinone absorption and metabolism. Similarly, it is not known if phylloquinone absorption is altered by the individual's existing vitamin K status.

Objective: The purpose of this secondary substudy was to compare plasma response with deuterium-labeled phylloquinone intake in older and younger adults after dietary phylloquinone depletion and repletion.

Methods: Forty-two older [mean ± SD age: 67.2 ± 8.0 y; body mass index (BMI; in kg/m2): 25.4 ± 4.6; n = 12 men, 9 women] and younger (mean ± SEM age: 31.8 ± 6.6 y; BMI: 25.5 ± 3.3; n = 9 men, 12 women) adults were maintained on sequential 28-d phylloquinone depletion (∼10 µg phylloquinone/d) and 28-d phylloquinone repletion (∼500 µg phylloquinone/d) diets. On the 23rd d of each diet phase, participants consumed deuterated phylloquinone-rich collard greens (2H-phylloquinone). Plasma and urinary outcome measures over 72 h were compared by age group, sex, and dietary phase via 2-factor repeated-measures ANOVA.

Results: The plasma 2H-phylloquinone area under the curve (AUC) did not differ in response to phylloquinone depletion or repletion, but was 34% higher in older than in younger adults (P = 0.02). However, plasma 2H-phylloquinone AUC was highly correlated with the serum triglyceride (TG) AUC (r2 = 0.45). After adjustment for serum TG response, the age effect on the plasma 2H-phylloquinone AUC was no longer significant.

Conclusions: Plasma 2H-phylloquinone response did not differ between phylloquinone depletion and repletion in older and younger adults. The age effect observed was explained by the serum TG response and was completely attenuated after adjustment. Plasma response to phylloquinone intake, therefore, seems to be a predominantly lipid-driven effect and not dependent on existing vitamin K status. More research is required to differentiate the effect of endogenous compared with exogenous lipids on phylloquinone absorption. This trial was registered at clinicaltrials.gov as NCT00336232.
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http://dx.doi.org/10.1093/jn/nxy216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351140PMC
January 2019

Vitamin K epoxide reductase: moving closer to nature.

Authors:
Martin J Shearer

Blood 2018 11;132(18):1867-1869

ST THOMAS' HOSPITAL.

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http://dx.doi.org/10.1182/blood-2018-08-869578DOI Listing
November 2018

Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism.

Annu Rev Nutr 2018 08 1;38:127-151. Epub 2018 Jun 1.

Department of Hygienic Sciences, Kobe Pharmaceutical University, Kobe 658-8558 Japan; email:

Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in the maintenance of hemostasis. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we show how novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR. We also discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed.
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http://dx.doi.org/10.1146/annurev-nutr-082117-051741DOI Listing
August 2018

Prevalence and Predictors of Functional Vitamin K Insufficiency in Mothers and Newborns in Uganda.

Nutrients 2015 Oct 16;7(10):8545-52. Epub 2015 Oct 16.

Department of Pediatrics and Child Health, Mbarara University of Science and Technology, Plot 8-18 Mbarara-Kabale road, P.O. Box 1410, Mbarara, Uganda.

Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers delivering in a southwestern Uganda Hospital. We collected socio-demographic and dietary information, and paired samples of maternal venous and neonatal cord blood for the immunoassay of undercarboxylated prothrombin (PIVKA-II), a sensitive marker of functional vitamin K (VK) insufficiency. We used univariable and multivariable logistic regression models to identify predictors of VK insufficiency. We detected PIVKA-II of ≥0.2 AU (Arbitrary Units per mL)/mL (indicative of VK insufficiency) in 33.3% (47/141) of mothers and 66% (93/141) of newborns. Importantly, 22% of babies had PIVKA-II concentrations ≥5.0 AU/mL, likely to be associated with abnormal coagulation indices. We found no significant predictors of newborn VK insufficiency, including infant weight (AOR (adjusted odds ratio) 1.85, 95% CI (confidence interval) 0.15-22.49), gender (AOR 0.54, 95% CI 0.26-1.11), term birth (AOR 0.72, 95% CI 0.20-2.62), maternal VK-rich diet (AOR 1.13, 95% CI 0.55-2.35) or maternal VK insufficiency (AOR 0.99, 95% CI 0.47-2.10). VK insufficiency is common among mothers and newborn babies in southwestern Uganda, which in one fifth of babies nears overt deficiency. Lack of identifiable predictors of newborn VK insufficiency support strategies for universal VK prophylaxis to newborns to prevent VKDB.
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http://dx.doi.org/10.3390/nu7105408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632428PMC
October 2015

What's in a name? The pharmacy of vitamin K.

Br J Haematol 2016 09 22;174(6):989-90. Epub 2015 Oct 22.

Nutristasis Unit, Viapath, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.13828DOI Listing
September 2016

Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period.

Nutrients 2015 Sep 25;7(10):8308-20. Epub 2015 Sep 25.

The Centre for Haemostasis and Thrombosis, St. Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.

All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose of phylloquinone given at birth, and that derived from parenteral and/or enteral feeding. This observational study formed part of a prospective, multicentre, randomised, controlled trial that examined the vitamin K status of preterm infants after random allocation to one of three phylloquinone prophylactic regimens at birth (0.5 or 0.2 mg intramuscularly or 0.2 mg intravenously). In this nutritional sub-study we quantified the proportional and total phylloquinone intakes of preterm infants within the neonatal period from all sources. Almost all infants had average daily phylloquinone intakes that were in excess of the currently recommended amounts. In infants who did not receive parenteral nutrition, the bolus dose of phylloquinone given at birth was the major source of phylloquinone intake, whereas in infants who received parenteral nutrition, the intake from the parenteral preparation exceeded that from the bolus dose by a ratio of approximately 3:1. Our study supports the concern of others that preterm infants who receive current parenteral nutrition formulations may be receiving excessive vitamin K.
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http://dx.doi.org/10.3390/nu7105393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632413PMC
September 2015

Extreme warfarin hypersensitivity after oophorectomy.

Blood Coagul Fibrinolysis 2015 Dec;26(8):953-5

aUniversity of Manchester bDepartment of Haematology, Manchester Royal Infirmary cSerious Hazards of Transfusion UK National Haemovigilance Scheme, Manchester Blood Centre and the University of Manchester, Manchester dCentre for Haemostasis and Thrombosis, Guy's and St Thomas' NHS Foundation Trust, London, UK.

We report the case of a woman who developed unexplained warfarin hypersensitivity after undergoing surgery to remove her ovaries. Presurgery, the patient's international normalised ratios (INR) control was stable and uneventful but 11 days after her operation she presented with extremely high (frequently ≥10) INR. Warfarin was discontinued on day 24 postoperation but 11 days later the plasma warfarin concentration was high at 4.8 mg/l (therapeutic range 0.7-2.3 mg/l). After cessation of warfarin, she required frequent doses of oral and intravenous vitamin K1 (totalling 48 mg) as well as two doses of prothrombin complex concentrate to normalise the INR. The patient was switched from warfarin to heparin, then to dabigatran with no further thrombosis or bleeding. While on heparin, the kinetics of warfarin elimination and vitamin K status were found to be normal and the reason for the onset of the extreme sensitivity to warfarin remains unknown.
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http://dx.doi.org/10.1097/MBC.0000000000000347DOI Listing
December 2015

Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B 12 had been excluded.

Adv Hematol 2014 15;2014:465623. Epub 2014 Jan 15.

The Nutristasis Unit, The Centre for Haemostasis and Thrombosis, GSTS Pathology (Part of King's Healthcare Partners), St. Thomas' Hospital, London SE1 7EH, UK.

5-Methyltetrahydrofolate (5-MTHF) is the predominant form of folate and a strong determinant of homocysteine concentrations. There is evidence that suboptimal 5-MTHF availability is a risk factor for cardiovascular disease independent of homocysteine. The analysis of folates remains challenging and is almost exclusively limited to the reporting of "total" folate rather than individual molecular forms. The purpose of this study was to establish the reference intervals of 5-MTHF in plasma and red cells of healthy adults who had been prescreened to exclude biochemical evidence of functional deficiency of folate and/or vitamin B12. Functional folate and vitamin B12 status was assessed by respective plasma measurements of homocysteine and methylmalonic acid in 144 healthy volunteers, aged 19-64 years. After the exclusion of 10 individuals, values for 134 subjects were used to establish the upper reference limits for homocysteine (13  μ mol/L females and 15  μ mol/L males) and methylmalonic acid (430 nmol/L). Subjects with values below these cutoffs were designated as folate and vitamin B12 replete and their plasma and red cell 5-MTHF reference intervals determined, N = 126: 6.6-39.9 nmol/L and 223-1041 nmol/L, respectively. The application of these intervals will assist in the evaluation of folate status and facilitate studies to evaluate the relationship of 5-MTHF to disease.
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http://dx.doi.org/10.1155/2014/465623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914575PMC
February 2014

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis.

J Lipid Res 2014 Mar 31;55(3):345-62. Epub 2014 Jan 31.

Centre for Haemostasis and Thrombosis, Guy's and St. Thomas' NHS Foundation Trust, London SE1 7EH, UK; and.

In contrast to other fat-soluble vitamins, dietary vitamin K is rapidly lost to the body resulting in comparatively low tissue stores. Deficiency is kept at bay by the ubiquity of vitamin K in the diet, synthesis by gut microflora in some species, and relatively low vitamin K cofactor requirements for γ-glutamyl carboxylation. However, as shown by fatal neonatal bleeding in mice that lack vitamin K epoxide reductase (VKOR), the low requirements are dependent on the ability of animals to regenerate vitamin K from its epoxide metabolite via the vitamin K cycle. The identification of the genes encoding VKOR and its paralog VKOR-like 1 (VKORL1) has accelerated understanding of the enzymology of this salvage pathway. In parallel, a novel human enzyme that participates in the cellular conversion of phylloquinone to menaquinone (MK)-4 was identified as UbiA prenyltransferase-containing domain 1 (UBIAD1). Recent studies suggest that side-chain cleavage of oral phylloquinone occurs in the intestine, and that menadione is a circulating precursor of tissue MK-4. The mechanisms and functions of vitamin K recycling and MK-4 synthesis have dominated advances made in vitamin K biochemistry over the last five years and, after a brief overview of general metabolism, are the main focuses of this review.
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http://dx.doi.org/10.1194/jlr.R045559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934721PMC
March 2014

Vitamin K deficiency bleeding and early infant male circumcision in Africa.

Obstet Gynecol 2013 Aug;122(2 Pt 2):503-505

Division of Infectious Disease, Brigham and Women's Hospital, Boston, Massachusetts; Botswana-Harvard Partnership for HIV Research and Education, Gaborone, Botswana; the Department of Public Policy, Duke University, Durham, North Carolina; the Clinical Sciences Department, FHI 360, Durham, North Carolina; the Haemostasis Research Unit, Centre for Haemostasis & Thrombosis, St. Thomas' Hospital, London, United Kingdom; and the Department of Pediatrics and Child Health, Mbarara University of Science and Technology, Mbarara, Uganda.

Background: Early infant (1-60 days of life) male circumcision is being trialed in Africa as a human immunodeficiency virus prevention strategy. Postcircumcision bleeding is particularly concerning where most infants are breastfed, and thus these infants are at increased risk of vitamin K deficiency bleeding.

Case: During a circumcision trial, one infant bled for 90 minutes postprocedure. After discovering he had not received standard prophylactic vitamin K, we gave 2 mg phytomenadione (vitamin K1) intramuscularly; bleeding stopped within 30 minutes.

Conclusion: Vitamin K's extremely rapid action is not commonly appreciated. Neonatal vitamin K has been shown to be cost-effective. To increase availability and promote awareness of its importance, especially in low-resource settings where blood products and transfusions are limited, vitamin K should be included in the World Health Organization's Model List of Essential Medicines for Children.
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http://dx.doi.org/10.1097/AOG.0b013e31828b2f5cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773869PMC
August 2013

Vitamin K nutrition, metabolism, and requirements: current concepts and future research.

Adv Nutr 2012 Mar 1;3(2):182-95. Epub 2012 Mar 1.

Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas' NHS Foundation Trust, London, UK.

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.
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http://dx.doi.org/10.3945/an.111.001800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648719PMC
March 2012

Association of vitamin K status with adiponectin and body composition in healthy subjects: uncarboxylated osteocalcin is not associated with fat mass and body weight.

Br J Nutr 2012 Sep 5;108(6):1017-24. Epub 2011 Dec 5.

VitaK and Cardiovascular Research Institute CARIM, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.

Osteocalcin (OC) is a vitamin K-dependent protein found in bone and in circulation. High serum γ-carboxylated OC reflects a high, and high uncarboxylated OC (ucOC) reflects a low vitamin K status. A revolutionary hypothesis is that ucOC acts as a hormone improving glucose handling and reducing fat mass. The objective was to test the logical extrapolation of the ucOC hormone hypothesis to humans that elevated ucOC is associated with higher body weight, BMI and fat mass. In a cross-sectional analysis, the associations of vitamin K status with circulating adiponectin and body composition were investigated in 244 postmenopausal women (study I). The effects of vitamin K treatment on adiponectin, body weight and BMI were investigated in archived samples from forty-two young men and women who received varying doses of menaquinone-7 during 12 weeks (study II) and from a cohort of 164 postmenopausal women who participated in a 3-year placebo-controlled trial on 45 mg menaquinone-4 (MK-4) (study III). No association was found between vitamin K status and circulating adiponectin before or after vitamin K supplementation. A higher carboxylation of OC was significantly correlated with lower body weight, BMI and fat mass of the trunk. Women taking MK-4 maintained their baseline body weight and BMI, whereas women taking placebo showed significant increases in both indices. These findings demonstrate that a high vitamin K status of bone has no effect on circulating adiponectin in healthy people and long-term vitamin K supplementation does not increase weight in healthy postmenopausal women.
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http://dx.doi.org/10.1017/S000711451100626XDOI Listing
September 2012

The role of dietary vitamin K in the management of oral vitamin K antagonists.

Blood Rev 2012 Jan 13;26(1):1-14. Epub 2011 Sep 13.

Department of Clinical Pharmacology, Guy's & St Thomas' NHS Foundation Trust, London, UK.

Vitamin K antagonists (VKA) have been the mainstay of oral anticoagulant therapy for over 60years. In this review we critically assess the evidence for the importance of vitamin K nutrition during VKA therapy; the methodologies for measuring dietary intakes; the vitamin K intake data in patients on VKA and healthy people; and the experimental evidence for the influence of vitamin K intakes and biochemical measures of vitamin K status on VKA response. Several studies show that dietary intakes of phylloquinone (vitamin K1) are associated to the sensitivity and stability of anticoagulation during initiation and maintenance dosing with low habitual intakes associated with greater instability of the INR and risk of sub-therapeutic anticoagulation. Preliminary evidence suggests that the stability of anticoagulation therapy may be improved by daily vitamin K supplementation, but further studies are needed to find out whether this, or other dietary interventions, can improve anticoagulant control in routine clinical practice.
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http://dx.doi.org/10.1016/j.blre.2011.07.002DOI Listing
January 2012

Urinary excretion of vitamin K metabolites in term and preterm infants: relationship to vitamin K status and prophylaxis.

Pediatr Res 2010 Dec;68(6):508-12

The Nutristasis Unit, St Thomas' Hospital, London SE1 7EH, United Kingdom.

Little is known about the metabolic turnover and excretion of vitamin K in healthy newborn infants and the metabolic consequences of prophylactic regimens designed to protect against vitamin K deficiency bleeding (VKDB). We measured the excretion of two urinary metabolites (≤ 24 h) of vitamin K (5C- and 7C-aglycones) in term infants before (n = 11) and after (n = 5) a 1000 μg i.m. dose of vitamin K1 (K1) and in preterm infants after 200 μg i.m. (n = 4), 500 μg i.m. (n = 4), or 200 μg i.v. (n = 5). In preterm infants, we also measured serum K1, vitamin K1 2,3-epoxide, and PIVKA-II at 5 d postpartum. Before prophylaxis, the rate of 5C- and 7C-aglycone excretion was 25 times lower than adults, reflecting low vitamin K stores at birth. After prophylaxis, the excretion rate correlated to K1 dose (r = 0.6) but was two orders of magnitude lower than that in adults, probably reflecting the immaturity of neonatal catabolism. All term and 10 of 13 preterm infants mainly excreted 5C-aglycone. We present evidence that increased excretion of the 7C-aglycone was associated with metabolic overload because of the exposure to high-tissue K1 concentrations. Measurement of the 5C- and 7C-aglycones may facilitate longitudinal studies of vitamin K status in neonates and aid the development of improved prophylactic regimens.
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http://dx.doi.org/10.1203/PDR.0b013e3181f981c7DOI Listing
December 2010

Vitamin K in parenteral nutrition.

Authors:
Martin J Shearer

Gastroenterology 2009 Nov;137(5 Suppl):S105-18

Centre for Haemostasis and Thrombosis, St Thomas' Hospital, London, United Kingdom.

Vitamin K (as phylloquinone and menaquinones) is an essential cofactor for the conversion of peptide-bound glutamate to gamma-carboxy glutamic acid (Gla) residues in a number of specialized Gla-containing proteins. The only unequivocal deficiency outcome is a bleeding syndrome caused by an inability to synthesize active coagulation factors II, VII, IX, and X, although there is growing evidence for roles for vitamin K in bone and vascular health. An adult daily intake of about 100 microg of phylloquinone is recommended for the maintenance of hemostasis. Traditional coagulation tests for assessing vitamin K status are nonspecific and insensitive. Better tests include measurements of circulating vitamin K and inactive proteins such as undercarboxylated forms of factor II and osteocalcin to assess tissue and functional status, respectively. Common risk factors for vitamin K deficiency in the hospitalized patient include inadequate dietary intakes, malabsorption syndromes (especially owing to cholestatic liver disease), antibiotic therapy, and renal insufficiency. Pregnant women and their newborns present a special risk category because of poor placental transport and low concentrations of vitamin K in breast milk. Since 2000, the Food and Drug Administration has mandated that adult parenteral preparations should provide a supplemental amount of 150 microg phylloquinone per day in addition to that present naturally, in variable amounts, in the lipid emulsion. Although this supplemental daily amount is probably beneficial in preventing vitamin K deficiency, it may be excessive for patients taking vitamin K antagonists, such as warfarin, and jeopardize their anticoagulant control. Natural forms of vitamin K have no proven toxicity.
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http://dx.doi.org/10.1053/j.gastro.2009.08.046DOI Listing
November 2009

Prevalence of subclinical vitamin K deficiency in Thai newborns: relationship to maternal phylloquinone intakes and delivery risk.

Arch Dis Child Fetal Neonatal Ed 2010 Mar 11;95(2):F104-8. Epub 2009 Oct 11.

Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.

Background: Vitamin K deficiency bleeding (VKDB) in infants is a rare but serious worldwide problem, particularly in Southeast Asia. Apart from exclusive breast feeding, little is known of the maternofetal risk factors that predispose infants to VKDB.

Objectives: To assess (a) the relationships between functional vitamin K insufficiency in a large cohort of Thai mothers to that of their newborn infants and (b) the importance of delivery risk factors and maternal intakes of vitamin K as determinants of neonatal vitamin K status.

Methods: Vitamin K status was assessed by measuring undercarboxylated prothrombin (protein induced by vitamin K absence/antagonist-II (PIVKA-II)) in 683 mothers and in the cord blood of their babies by sensitive immunoassay. Dietary phylloquinone (vitamin K(1); K(1)) intakes were assessed in 106 of these mothers by food frequency questionnaire.

Results: Babies were categorised as 'normal' (n=590) or 'high risk' (n=93) according to birth weight and delivery type. PIVKA-II was detectable (>0.15 arbitrary units (AU)/ml) in 85 mothers (12.4%) and 109 babies (16.0%) with median levels of 0.78 and 1.04 AU/ml in mothers and babies, respectively. 'High-risk' babies had a higher median detectable PIVKA-II concentration than 'normal-risk' babies (3.1 vs 1.0 AU/ml, p=0.02) and a higher prevalence of clinically relevant (>5.0 AU/ml) concentrations (p=0.006). Mothers with K(1) intakes below the US recommended 'adequate intake' for pregnancy (<90 microg/day) had a higher prevalence of detectable PIVKA-II (18.8%) than those with adequate intakes (3.3%) (p=0.01).

Conclusions: Functional, clinically relevant, vitamin K insufficiency was more common in 'high-risk' than 'normal-risk' newborns. Vitamin K insufficiency in mothers was linked to lower dietary K(1) intakes during pregnancy.
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http://dx.doi.org/10.1136/adc.2009.173245DOI Listing
March 2010

Changes in vitamin biomarkers during a 2-year intervention trial involving increased fruit and vegetable consumption by free-living volunteers.

Br J Nutr 2009 Nov 19;102(10):1477-86. Epub 2009 Jun 19.

Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.

Trials in free-living populations involving increased consumption of fruit and vegetables are difficult to monitor. We evaluated biomarkers for assessing fruit and vegetable intake and compliance in a 2-year trial. Postmenopausal women were randomised to 300 g additional fruit and vegetables per d (n 66), placebo (n 70) or potassium citrate (n 140). They completed dietary checklists (3-monthly) and food diaries or FFQ (yearly). We measured whole-blood folate, plasma vitamin C and homocysteine (yearly), serum vitamin E and carotenoids (at 12 months) and urinary vitamin K metabolites (yearly). Plasma vitamin C was associated with fruit and vegetable intake at baseline (r +0.31; P < 0.01), remaining significant only for the non-fruit and vegetable group at 12 months (r +0.43; P < 0.01). For the fruit and vegetable group, vitamin C increased by 5.9 micromol/l (P = 0.07) but was not significantly associated with fruit and vegetable intake; vitamin E, beta-carotene and beta-cryptoxanthin were higher compared with the non-fruit and vegetable group (P < 0.05); and whole-blood folate and the urinary 5C-aglycone metabolite of vitamin K were associated with vegetable intake. For all participants plasma vitamin C increased with increasing fruit and vegetable intakes, reaching a plateau of 90-95 micromol/l at intakes>500 g/d, whereas whole-blood folate, beta-carotene and beta-cryptoxanthin continued to increase. Concentrations of vitamin C, folate and beta-cryptoxanthin were lower and the 7C-aglycone metabolite of vitamin K higher, in smokers compared with non-smokers. Suitable markers for monitoring fruit and vegetable compliance include beta-carotene and beta-cryptoxanthin. Plasma vitamin C and whole-blood folate may be suitable for monitoring intakes in populations but for monitoring compliance the former may be restricted to low intakes of fruit and vegetables and the latter to vegetable intake.
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http://dx.doi.org/10.1017/S0007114509990377DOI Listing
November 2009

The external quality assurance of phylloquinone (vitamin K(1)) analysis in human serum.

Biomed Chromatogr 2009 Dec;23(12):1276-82

The Centre for Haemostasis and Thrombosis (Nutristasis Unit), Guy's and St Thomas' NHS Foundation Trust, London, UK.

The vitamin K external quality assurance scheme (KEQAS) aims to assist in the harmonization of phylloquinone (vitamin K(1)) analysis in order to improve the comparability of clinical and nutritional studies. Serum samples were despatched to 17 groups from eight countries during 2000-2006. Using pilot data (1996-1999), an analytical performance target of 20% absolute difference from the all-laboratory trimmed mean (ALTM) was assigned and formed the basis for interlaboratory comparison. Assay specificity, analytical bias and assay performance were evaluated. From 21 batches of samples distributed, 414 results were reported of which 2.7% were outliers. The mean interlaboratory absolute difference from the ALTM was 21.7% with 47% of groups consistently meeting the performance target. The mean interlaboratory coefficient of variation was 29.6%. The false positive rate for phylloquinone depleted samples was high at 35%. Bias was found to be independent of HPLC-detector type (fluorescence vs electrochemical). Assay characteristics for the measurement of phylloquinone in human serum compare favourably with methods for analytes at equivalent concentrations. The high proportion of false positive results suggest that poor assay specificity at low phylloquinone concentrations is a common problem, which in the clinical setting could lead to underreporting of vitamin K deficiency.
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http://dx.doi.org/10.1002/bmc.1250DOI Listing
December 2009

Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin.

Blood Coagul Fibrinolysis 2009 Jun;20(4):297-302

Centre for Haemostasis and Thrombosis, St Thomas' Hospital, London, UK.

Dietary fluctuations of vitamin K are detrimental to oral anticoagulant control. Attempts to improve control through the avoidance of vitamin K-rich foods (mainly green vegetables) may inadvertently compromise folate status, itself a risk factor for thromboembolism. We evaluated the effect of a 6-month period of warfarin therapy on folate status in 114 patients using measurements of red-cell folate and 5-methyltetrahydrofolate and plasma folate and total homocysteine. Circulatory levels of phylloquinone, vitamin B12 and methylmalonic acid were also determined. A subset of 45 patients completed 7-day food diaries at the beginning and end of their treatment. There was a significant decrease in total erythrocyte folate (P = 0.005) and 5-methyltetrahydrofolate (P = 0.002) during the study. A concurrent increase in plasma phylloquinone (P = 0.003) was attributed to warfarin-induced perturbation of vitamin K metabolism. No other longitudinal changes were observed. Folate and phylloquinone intakes correlated with each other at baseline (P = 0.024) and after treatment (P = 0.011). Based on robust measurements of erythrocyte folates, patients showed a significant impairment in folate status after 6-month therapy with warfarin. The majority of patients had intakes of folate and phylloquinone below the national average or UK guidelines. The study highlights the need for improved dietary management of patients taking oral anticoagulants.
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http://dx.doi.org/10.1097/MBC.0b013e32832aa6a1DOI Listing
June 2009

Minerals and vitamins in bone health: the potential value of dietary enhancement.

Br J Nutr 2009 Jun 1;101(11):1581-96. Epub 2009 Apr 1.

Division of Bone Diseases, University Hospital, Rue Micheli-Du-Crest, 1211 Geneva, Switzerland.

Nutrition is important to bone health, and a number of minerals and vitamins have been identified as playing a potential role in the prevention of bone diseases, particularly osteoporosis. Despite this, there is currently no consensus on maximum levels to allow in food or as dietary supplements. The benefits of supplementation of populations at risk of osteoporosis with Ca and vitamin D are well established. Prolonged supplementation of Ca and vitamin D in elderly has been shown to prevent bone loss, and in some intervention studies to prevent fragility fractures. Although P is essential to bone health, the average intake is considered to be more than sufficient and supplementation could raise intake to adverse levels. The role of vitamin K in bone health is less well defined, though it may enhance the actions of Ca and vitamin D. Sr administered in pharmacological doses as the ranelate salt was shown to prevent fragility fractures in postmenopausal osteoporosis. However, there is no hard evidence that supplementation with Sr salts would be beneficial in the general population. Mg is a nutrient implicated in bone quality, but the benefit of supplementation via foodstuffs remains to be established. A consensus on dietary supplementation for bone health should balance the risks, for example, exposure of vulnerable populations to values close to maximal tolerated doses, against evidence for benefits from randomised clinical trials, such as those for Ca and vitamin D. Feedback from community studies should direct further investigations and help formulate a consensus on dietary supplementation for bone health.
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http://dx.doi.org/10.1017/S0007114509311721DOI Listing
June 2009

Metabolism and cell biology of vitamin K.

Thromb Haemost 2008 Oct;100(4):530-47

Centre for Haemostasis and Thrombosis, St Thomas' Hospital, Westminster Bridge Road, London, UK.

Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.
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October 2008

Vitamin K deficiency bleeding (VKDB) in early infancy.

Authors:
Martin J Shearer

Blood Rev 2009 Mar 19;23(2):49-59. Epub 2008 Sep 19.

The Centre for Haemostasis and Thrombosis, St. Thomas' Hospital, Westminster Bridge Road, London, UK.

Vitamin K deficiency bleeding (VKDB) is a rare and potentially life-threatening bleeding disorder of early infancy. Vitamin K stores are low at birth; thereafter breast-fed infants are at risk because of low concentrations in human milk. Classical VKDB occurs in the first week of life, is related to delayed or inadequate feeding and is readily prevented by small doses of vitamin K at birth. Late VKDB peaks at 3-8 weeks, typically presents with intracranial haemorrhage often due to undiagnosed cholestasis with resultant malabsorption of vitamin K. Diagnosis can be difficult but PIVKA-II measurements can provide confirmation even several days post-treatment. Without vitamin K prophylaxis, the incidence of late VKDB in Europe is 4-7 cases per 10(5) births; it is higher in SE Asia where in rural, low-income areas some 0.1% of affected infants may suffer intracranial bleeding. Late VKDB is largely preventable with parenteral vitamin K providing the best protection. The efficacy of oral prophylaxis is related to the dose and frequency of administration. Most multi-dose oral regimens provide protection for all except a small reservoir of infants with undetected hepatobiliary disease. Targeted surveillance of high-risk groups (e.g. biliary atresia) offers a novel approach to assess efficacy of prophylaxis.
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http://dx.doi.org/10.1016/j.blre.2008.06.001DOI Listing
March 2009

Excretion of the urinary 5C- and 7C-aglycone metabolites of vitamin K by young adults responds to changes in dietary phylloquinone and dihydrophylloquinone intakes.

J Nutr 2007 Jul;137(7):1763-8

The Centre for Haemostasis and Thrombosis, St. Thomas' Hospital, London SE1 7EH, UK.

The physiological function and putative health roles of vitamin K-dependent proteins now extend beyond their classical role in hemostasis and include bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. Current assessments of vitamin K status do not reflect the variety of molecular forms of vitamin K. We assessed whether urinary excretion of 2-methyl-3-(5'-carboxy-3'-methyl-2'-pentenyl)-1,4-naphthoquinone (7C-aglycone) and 2-methyl-3-(3'-3'-carboxymethylpropyl)-1,4-naphthoquinone (5C-aglycone), vitamin K metabolites common to both phylloquinone and the menaquinone series, reflect dietary vitamin K intake. In a randomized crossover study, 9 adults resided in a metabolic unit for two 30-d periods separated by a free-living period of > or = 4 wk. During each residency, subjects consumed 3 sequential diets: a control diet (93 microg phylloquinone/d) for 5 d, a phylloquinone-restricted diet (11 microg/d) for 15 d, followed by a randomly assigned repletion diet for 10 d with either phylloquinone (206 microg/d) or dihydrophylloquinone (240 microg/d). During the second residency, the alternative repletion diet was assigned. Urinary excretion of the 5C- and 7C-aglycones was measured in sequential 24-h collections. The 5C-aglycone accounted for approximately 75% of total excretion and declined in response to phylloquinone restriction (P = 0.001) to approximately 30% of that during the control diet period. Repletion with phylloquinone and dihydrophylloquinone doubled the excretion rate of the major 5C-aglycone by 24 h (P < 0.001), and tripled excretion by 4 d. There was a linear relationship between the logarithm of total urinary excretion and dietary vitamin K intake (r = 0.699, P < 0.001). We conclude that the urinary excretion of vitamin K metabolites reflects dietary phylloquinone intake and offers the first candidate marker of global vitamin K status.
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http://dx.doi.org/10.1093/jn/137.7.1763DOI Listing
July 2007

Vitamin K deficiency bleeding: the readiness is all.

Arch Dis Child 2007 Sep 23;92(9):741-3. Epub 2007 May 23.

Neonatal Unit, Norfolk and Norwich University Hospital NHS Trust, Norwich, UK.

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http://dx.doi.org/10.1136/adc.2007.116962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084018PMC
September 2007

Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.

J Bone Miner Res 2007 Apr;22(4):509-19

Nutrition Research Group, CVEU, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.

Unlabelled: Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.

Introduction: The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.

Materials And Methods: Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.

Results: Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).

Conclusions: These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.
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http://dx.doi.org/10.1359/jbmr.070116DOI Listing
April 2007

Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens.

Pediatrics 2006 Dec 13;118(6):e1657-66. Epub 2006 Nov 13.

Neonatal Unit, Hope Hospital, Salford, United Kingdom.

Objective: Preterm infants may be at particular risk from either inadequate or excessive vitamin K prophylaxis. Our goal was to assess vitamin K status and metabolism in preterm infants after 3 regimens of prophylaxis.

Methods: Infants <32 weeks' gestation were randomized to receive 0.5 mg (control) or 0.2 mg of vitamin K1 intramuscularly or 0.2 mg intravenously after delivery. Primary outcome measures were serum vitamin K1, its epoxide metabolite (vitamin K1 2,3-epoxide), and undercarboxylated prothrombin assessed at birth, 5 days, and after 2 weeks of full enteral feeds. Secondary outcome measures included prothrombin time and factor II concentrations.

Results: On day 5, serum vitamin K1 concentrations in the 3 groups ranged widely (2.9-388.0 ng/mL) but were consistently higher than the adult range (0.15-1.55 ng/mL). Presence of vitamin K1 2,3-epoxide on day 5 was strongly associated with higher vitamin K1 bolus doses. Vitamin K1 2,3-epoxide was detected in 7 of 29 and 4 of 29 infants from the groups that received 0.5 mg intramuscularly and 0.2 mg intravenously, respectively, but in none of 32 infants from group that received 0.2 mg intramuscularly. After 2 weeks of full enteral feeding, serum vitamin K1 was lower in the infants who received 0.2 mg intravenously compared with the infants in the control group. Three infants from the 0.2-mg groups had undetectable serum vitamin K1 as early as the third postnatal week but without any evidence of even mild functional deficiency, as shown by their normal undercarboxylated prothrombin concentrations.

Conclusions: Vitamin K1 prophylaxis with 0.2 mg administered intramuscularly maintained adequate vitamin K status of preterm infants until a median age of 25 postnatal days and did not cause early vitamin K1 2,3-epoxide accumulation. In contrast, 0.2 mg administered intravenously and 0.5 mg administered intramuscularly led to vitamin K1 2,3-epoxide accumulation, possibly indicating overload of the immature liver. To protect against late vitamin K1 deficiency bleeding, breastfed preterm infants given a 0.2-mg dose of prophylaxis should receive additional supplementation when feeding has been established.
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http://dx.doi.org/10.1542/peds.2005-2742DOI Listing
December 2006

Effect of calcium fortified milk supplementation with or without vitamin K on biochemical markers of bone turnover in premenopausal women.

Nutrition 2006 Nov-Dec;22(11-12):1120-8. Epub 2006 Oct 9.

Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand.

Objective: We compared the effect of supplementation with a fortified skimmed milk product (high calcium skim milk) with or without added phylloquinone (vitamin K(1)) on markers of bone formation and resorption in premenopausal women.

Methods: Eighty-two women 20 to 35 y of age were randomly allocated to three groups. Two groups received two daily servings of high calcium skim milk (1000 mg/d of extra calcium) with or without added phylloquinone (80 microg/d) for 16 wk, and a third control group received no supplementation. Bone density was assessed at baseline and the bone markers, total osteocalcin, type I N-terminal procollagen peptide, and cross-linked C-telopeptide of type I collagen were measured at baseline and at weeks 2, 12, and 16. Serum phylloquinone and undercarboxylated osteocalcin were measured in the control and vitamin K-supplemented groups at weeks 0 and 16.

Results: Baseline values for age, body mass index, and bone density did not differ across groups. In vitamin K-supplemented women, mean serum phylloquinone concentrations increased from 0.27 to 0.76 microg/L (P < 0.05) and undercarboxylated osteocalcin concentrations decreased from 9.68 to 4.46 microg/L (P < 0.05) over 16 wk. Plasma cross-linked C-telopeptide of type I collagen, total osteocalcin, and type I N-terminal procollagen peptide levels decreased significantly in both supplemented groups compared with the control group over 16 wk (cross-linked C-telopeptide of type I collagen >30%, total osteocalcin and type I N-terminal procollagen peptide >15%).

Conclusion: Fortified milk supplementation in premenopausal women reduced bone turnover significantly. Phylloquinone fortification substantially improved vitamin K status but had no demonstrable additive effect on bone turnover in this short-term study.
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http://dx.doi.org/10.1016/j.nut.2006.08.008DOI Listing
February 2007

Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials.

Arch Intern Med 2006 Jun;166(12):1256-61

York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, England.

Background: Observational and some experimental data suggest that low intake of vitamin K may be associated with an increased risk of fracture.

Objective: To assess whether oral vitamin K (phytonadione and menaquinone) supplementation can reduce bone loss and prevent fractures.

Data Sources: The search included the following electronic databases: MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), the Cochrane Library (issue 2, 2005), the ISI Web of Science (1945 to June 2005), the National Research Register (inception to the present), Current Controlled Trials, and the Medical Research Council Research Register.

Study Selection: Randomized controlled trials that gave adult participants oral phytonadione and menaquinone supplements for longer than 6 months were included in this review.

Data Extraction: Four authors extracted data on changes in bone density and type of fracture. All articles were double screened and double data extracted.

Data Synthesis: Thirteen trials were identified with data on bone loss, and 7 reported fracture data. All studies but 1 showed an advantage of phytonadione and menaquinone in reducing bone loss. All 7 trials that reported fracture effects were Japanese and used menaquinone. Pooling the 7 trials with fracture data in a meta-analysis, we found an odds ratio (OR) favoring menaquinone of 0.40 (95% confidence interval [CI], 0.25-0.65) for vertebral fractures, an OR of 0.23 (95% CI, 0.12-0.47) for hip fractures, and an OR of 0.19 (95% CI, 0.11-0.35) for all nonvertebral fractures.

Conclusions: This systematic review suggests that supplementation with phytonadione and menaquinone-4 reduces bone loss. In the case of the latter, there is a strong effect on incident fractures among Japanese patients.
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http://dx.doi.org/10.1001/archinte.166.12.1256DOI Listing
June 2006