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Papers by Martin Shearer

British journal of haematology, Jan 22, 2015

Nutrients, 2015

Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality o... more 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.

Methods in Enzymology

ABSTRACT

European Journal of Clinical Nutrition

There is limited information available on the vitamin K intake of lactating mothers, concentratio... more There is limited information available on the vitamin K intake of lactating mothers, concentration of vitamin K1 in breast milk, and the effect of long-term vitamin K1 supplementation of lactating mothers on the vitamin K1 concentration in breast milk. In a randomized study, we followed 20 mothers who received a daily oral vitamin K1 supplement (average 88 micrograms, supplemented group) and 16 mothers receiving no supplement (control group) from 4 throughout 91 days postpartum. Maternal vitamin K intakes (weighed dietary intake) at 4-6, 25-29 and 87-91 days postpartum ranged between 73 and 1735 micrograms/day. Differences between the groups were statistically not significant. Average intake exceeded the recommended dietary intake for lactating women of 55 micrograms/day by 670%. In the supplemented group, mean breast-milk vitamin K1 concentrations (HPLC) at 5, 26 and 88 days postpartum were 1.73 (SD 0.74), 1.36 (SD 0.81) and 1.67 (SD 2.01) ng/ml, respectively. Corresponding values in the control group were 1.44 (SD 0.57), 1.68 (SD 0.70) and 1.78 (SD 1.05) ng/ml. The latter were not statistically different from values in the supplemented group. Mean daily vitamin K1 intakes of infants breast-fed by supplemented mothers were 0.69 (SD 0.42), 0.93 (SD 0.51) and 1.25 (1.53) micrograms, respectively on days 5, 26 and 88. Corresponding values in the control group were 0.69 (SD 0.30), 1.07 (SD 0.58) and 1.31 (SD 0.95) micrograms and were statistically not different from values in the supplemented group. Average vitamin K1 intakes corresponded to 7-13% of the recommended dietary intake of 10 micrograms/d for infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Nutrition

in human and cows' milk and in infant formula foods has been assayed by a method based on highper... more in human and cows' milk and in infant formula foods has been assayed by a method based on highperformance liquid chromatography (HPLC). The method has three Chromatographie steps consisting of a preliminary purification of lipid extracts by conventional liquid chromatography, a further fractionation by semipreparative HPLC and a final analyt ical step by reversed-phase HPLC in which phylloquinone was resolved from the re maining contaminants and quantified by reference to an internal standard (phylloqui none 2,3-epoxide). The identity of the Chromatographie peak ascribed to phylloquinone (vitamin K!) was established by mass spectrometry. Mature human milk from 20 lactating mothers gave a mean concentration of phylloquinone of 2.1 /ig/liter, and colos trum from 9 mothers gave a mean value of 2.3 /ig/liter. These levels in human milk were significantly lower than those found in either Friesian (Holstein) cows' milk (mean 4.9 /ig/liter) or unsupplemented infant formula foods containing only cows' milk fat (mean 4.2 ¿tg/liter).The mean phylloquinone content of two unsupplemented infant formula foods containing only vegetable oils was 11.5 /ig/liter. After an oral dose of 20 mg phylloquinone, the concentration of KI in the breast milk of one mother rose to 140 /ig/liter after 12 hours and at 48 hours was still about twice the average endogenous level of human milk.

British Journal Of Nutrition

2002). Plasma phylloquinone (vitamin K 1 ) concentration and its relationship to intake in a nati... more 2002). Plasma phylloquinone (vitamin K 1 ) concentration and its relationship to intake in a national sample of British elderly people.

Introduction Prophylactic phytomenadione (vitamin K1) effectively prevents vitamin K deficiency b... more Introduction Prophylactic phytomenadione (vitamin K1) effectively prevents vitamin K deficiency bleeding of the newborn. However there are currently insufficient data to inform further dose optimisation which may be desirable, particularly for preterm infants. A non-invasive method to assess vitamin K status would be preferable. Our aims were: i) to devise a novel method for the measurement of the two major metabolites of vitamin K (5-carbon and 7-carbon side chain aglycone metabolites) in neonatal faecal matter; ii) apply this method to the comparison of patterns of excretion in term and preterm neonates. We hypothesised that vitamin K metabolite excretion in stool would be lower in preterm infants. Patients and Methods Meconium and subsequent stool samples were collected longitudinally from 21 infants (11 preterm, 10 term) during the first 6 months of life. All term neonates received 1 mg intramuscular (IM) vitamin K1, preterm neonates received ~0.4 mg/Kg IM. Data on type of milk ...

Background: Deficiency in B vitamins leads to hyperhomocysteinemia, a recognised cardiovascular r... more Background: Deficiency in B vitamins leads to hyperhomocysteinemia, a recognised cardiovascular risk factor. Objective: To assess prevalence of hyperhomocysteinemia (tHcy>15μmol/L) and intake of B vitamins in patients starting warfarin therapy (<14 days) and compare these intakes to the dietary reference values (DRVs). Design: Consecutive patients with thromboembolic disease or atrial fibrillation attending the Anticoagulation Clinic were recruited (n=182, mean age [sd]= 59 [16.2] years). Vitamin B status was assessed from plasma measurements of homocysteine, vitamin B12, methylmalonic acid, folate and 5-MTHF (also in red cells). A subset of patients completed a 7-day food diary. Dietary intakes without vitamin supplements were measured for folate, vitamin B2, B6 and B12 and are presented as mean [sd] per day and comparisons were made between patients, dietary reference value (DRV) and the National Diet and Nutrition Survey (NDNS) 2008-2012. Results: Hyperhomocysteinaemia was ...

Journal of Nutrition

The physiological function and putative health roles of vitamin K-dependent proteins now extend b... more 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 m...

Thrombosis and Haemostasis

Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-p... more Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained: Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22. Mothers: Clotting tests all within normal range; PIVKA I...

Advances in hematology, 2014

5-Methyltetrahydrofolate (5-MTHF) is the predominant form of folate and a strong determinant of h... more 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 m...

Journal of lipid research, 2002

Little is known of how the fat components of diets influence the absorption and metabolism of vit... more Little is known of how the fat components of diets influence the absorption and metabolism of vitamin K and the possible consequences to the synthesis of vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phylloquinone (K1) and triacylglycerols (TAG). One diet was enriched with corn oil (CO) (also rich in gamma-tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in alpha-tocopherol). Effects on gamma-carboxylation were assessed from coagulation assays and sensitive assays for undercarboxylated prothrombin (ucFII) and osteocalcin (ucOC). Total plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeks. Mean intakes of K1 during consumption of adjustment, O/SO, and CO diets were 225 microg/day, 291 microg/day, and 291 microg/day, respectively. Mean fasting levels of TAG and K1 were both ...

The British journal of nutrition, 2000

This paper reports the compilation of a food composition database for phylloquinone (vitamin K1) ... more This paper reports the compilation of a food composition database for phylloquinone (vitamin K1) derived from the direct analysis of foods, recipe calculation and the assignment of values based on food similarities. All the basic and other food items used in these calculations had been analysed by HPLC and about 170 of the items had been obtained and assayed in the UK. Recipe calculations took account of the cooking method and changes in water and fat content. Currently, approximately 1501 food items with Royal Society of Chemistry/Ministry of Agriculture, Fisheries and Food food codes have been allocated a vitamin K1 value, and a further 282 new recipe codes are included in the database. Representative values from each food group are reported together with an indication of the potential variation. Detailed examples of some recipe calculations are included, and also the impact of changing the type of fat in recipes. Vitamin K1 is associated with, and most abundant in, photosynthetic...

Clinical science (London, England : 1979), 1990

1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in r... more 1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides. 2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects. 3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay. 4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human. 5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8. 6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age. 7. In young normal subjects, th...

Advances in nutrition (Bethesda, Md.), 2012

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which t... more 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 end...

British Journal of Nutrition, 2009

Nutrition is important to bone health, and a number of minerals and vitamins have been identified... more 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.

OBJECTIVE. Preterm infants may be at particular risk from either inadequate or excessive vitamin ... more 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.

Thrombosis and Haemostasis, 2004

Thegeneencoding vitamin Kepoxider eductasecomplex subunit 1(VKORC1), acomponentofthe enzyme that ... more Thegeneencoding vitamin Kepoxider eductasecomplex subunit 1(VKORC1), acomponentofthe enzyme that is thetherapeutic targets ite forw arfarin,has recentlyb een identified.In ordertoinvestigate the relationship betweenVKORC1and warfarin dose response,westudiedtheVKORC1gene(VKORC1 )in patients withwarfarin resistance.Fromastudy group of 820patients, we identified 4individualswho required morethan 25 mg of warfarindailyfor therapeutic anticoagulation.Threeofthese had serumwarfarin concentrationswithin the therapeutic range of 0.7-2.3 mg/l and showed wild-type VKORC1 sequence.The fourth warfarinr esistant individual had consistentlyh igh ( ≥ 5.7 mg/l) serumw arfarin concentrations, yeth ad no clinicallyd iscernible cause forw arfarin resistance. VKORC1 showed ah et-

British journal of haematology, Jan 22, 2015

Nutrients, 2015

Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality o... more 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.

Methods in Enzymology

ABSTRACT

European Journal of Clinical Nutrition

There is limited information available on the vitamin K intake of lactating mothers, concentratio... more There is limited information available on the vitamin K intake of lactating mothers, concentration of vitamin K1 in breast milk, and the effect of long-term vitamin K1 supplementation of lactating mothers on the vitamin K1 concentration in breast milk. In a randomized study, we followed 20 mothers who received a daily oral vitamin K1 supplement (average 88 micrograms, supplemented group) and 16 mothers receiving no supplement (control group) from 4 throughout 91 days postpartum. Maternal vitamin K intakes (weighed dietary intake) at 4-6, 25-29 and 87-91 days postpartum ranged between 73 and 1735 micrograms/day. Differences between the groups were statistically not significant. Average intake exceeded the recommended dietary intake for lactating women of 55 micrograms/day by 670%. In the supplemented group, mean breast-milk vitamin K1 concentrations (HPLC) at 5, 26 and 88 days postpartum were 1.73 (SD 0.74), 1.36 (SD 0.81) and 1.67 (SD 2.01) ng/ml, respectively. Corresponding values in the control group were 1.44 (SD 0.57), 1.68 (SD 0.70) and 1.78 (SD 1.05) ng/ml. The latter were not statistically different from values in the supplemented group. Mean daily vitamin K1 intakes of infants breast-fed by supplemented mothers were 0.69 (SD 0.42), 0.93 (SD 0.51) and 1.25 (1.53) micrograms, respectively on days 5, 26 and 88. Corresponding values in the control group were 0.69 (SD 0.30), 1.07 (SD 0.58) and 1.31 (SD 0.95) micrograms and were statistically not different from values in the supplemented group. Average vitamin K1 intakes corresponded to 7-13% of the recommended dietary intake of 10 micrograms/d for infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Nutrition

in human and cows' milk and in infant formula foods has been assayed by a method based on highper... more in human and cows' milk and in infant formula foods has been assayed by a method based on highperformance liquid chromatography (HPLC). The method has three Chromatographie steps consisting of a preliminary purification of lipid extracts by conventional liquid chromatography, a further fractionation by semipreparative HPLC and a final analyt ical step by reversed-phase HPLC in which phylloquinone was resolved from the re maining contaminants and quantified by reference to an internal standard (phylloqui none 2,3-epoxide). The identity of the Chromatographie peak ascribed to phylloquinone (vitamin K!) was established by mass spectrometry. Mature human milk from 20 lactating mothers gave a mean concentration of phylloquinone of 2.1 /ig/liter, and colos trum from 9 mothers gave a mean value of 2.3 /ig/liter. These levels in human milk were significantly lower than those found in either Friesian (Holstein) cows' milk (mean 4.9 /ig/liter) or unsupplemented infant formula foods containing only cows' milk fat (mean 4.2 ¿tg/liter).The mean phylloquinone content of two unsupplemented infant formula foods containing only vegetable oils was 11.5 /ig/liter. After an oral dose of 20 mg phylloquinone, the concentration of KI in the breast milk of one mother rose to 140 /ig/liter after 12 hours and at 48 hours was still about twice the average endogenous level of human milk.

British Journal Of Nutrition

2002). Plasma phylloquinone (vitamin K 1 ) concentration and its relationship to intake in a nati... more 2002). Plasma phylloquinone (vitamin K 1 ) concentration and its relationship to intake in a national sample of British elderly people.

Introduction Prophylactic phytomenadione (vitamin K1) effectively prevents vitamin K deficiency b... more Introduction Prophylactic phytomenadione (vitamin K1) effectively prevents vitamin K deficiency bleeding of the newborn. However there are currently insufficient data to inform further dose optimisation which may be desirable, particularly for preterm infants. A non-invasive method to assess vitamin K status would be preferable. Our aims were: i) to devise a novel method for the measurement of the two major metabolites of vitamin K (5-carbon and 7-carbon side chain aglycone metabolites) in neonatal faecal matter; ii) apply this method to the comparison of patterns of excretion in term and preterm neonates. We hypothesised that vitamin K metabolite excretion in stool would be lower in preterm infants. Patients and Methods Meconium and subsequent stool samples were collected longitudinally from 21 infants (11 preterm, 10 term) during the first 6 months of life. All term neonates received 1 mg intramuscular (IM) vitamin K1, preterm neonates received ~0.4 mg/Kg IM. Data on type of milk ...

Background: Deficiency in B vitamins leads to hyperhomocysteinemia, a recognised cardiovascular r... more Background: Deficiency in B vitamins leads to hyperhomocysteinemia, a recognised cardiovascular risk factor. Objective: To assess prevalence of hyperhomocysteinemia (tHcy>15μmol/L) and intake of B vitamins in patients starting warfarin therapy (<14 days) and compare these intakes to the dietary reference values (DRVs). Design: Consecutive patients with thromboembolic disease or atrial fibrillation attending the Anticoagulation Clinic were recruited (n=182, mean age [sd]= 59 [16.2] years). Vitamin B status was assessed from plasma measurements of homocysteine, vitamin B12, methylmalonic acid, folate and 5-MTHF (also in red cells). A subset of patients completed a 7-day food diary. Dietary intakes without vitamin supplements were measured for folate, vitamin B2, B6 and B12 and are presented as mean [sd] per day and comparisons were made between patients, dietary reference value (DRV) and the National Diet and Nutrition Survey (NDNS) 2008-2012. Results: Hyperhomocysteinaemia was ...

Journal of Nutrition

The physiological function and putative health roles of vitamin K-dependent proteins now extend b... more 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 m...

Thrombosis and Haemostasis

Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-p... more Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained: Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22. Mothers: Clotting tests all within normal range; PIVKA I...

Advances in hematology, 2014

5-Methyltetrahydrofolate (5-MTHF) is the predominant form of folate and a strong determinant of h... more 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 m...

Journal of lipid research, 2002

Little is known of how the fat components of diets influence the absorption and metabolism of vit... more Little is known of how the fat components of diets influence the absorption and metabolism of vitamin K and the possible consequences to the synthesis of vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phylloquinone (K1) and triacylglycerols (TAG). One diet was enriched with corn oil (CO) (also rich in gamma-tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in alpha-tocopherol). Effects on gamma-carboxylation were assessed from coagulation assays and sensitive assays for undercarboxylated prothrombin (ucFII) and osteocalcin (ucOC). Total plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeks. Mean intakes of K1 during consumption of adjustment, O/SO, and CO diets were 225 microg/day, 291 microg/day, and 291 microg/day, respectively. Mean fasting levels of TAG and K1 were both ...

The British journal of nutrition, 2000

This paper reports the compilation of a food composition database for phylloquinone (vitamin K1) ... more This paper reports the compilation of a food composition database for phylloquinone (vitamin K1) derived from the direct analysis of foods, recipe calculation and the assignment of values based on food similarities. All the basic and other food items used in these calculations had been analysed by HPLC and about 170 of the items had been obtained and assayed in the UK. Recipe calculations took account of the cooking method and changes in water and fat content. Currently, approximately 1501 food items with Royal Society of Chemistry/Ministry of Agriculture, Fisheries and Food food codes have been allocated a vitamin K1 value, and a further 282 new recipe codes are included in the database. Representative values from each food group are reported together with an indication of the potential variation. Detailed examples of some recipe calculations are included, and also the impact of changing the type of fat in recipes. Vitamin K1 is associated with, and most abundant in, photosynthetic...

Clinical science (London, England : 1979), 1990

1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in r... more 1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides. 2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects. 3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay. 4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human. 5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8. 6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age. 7. In young normal subjects, th...

Advances in nutrition (Bethesda, Md.), 2012

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which t... more 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 end...

British Journal of Nutrition, 2009

Nutrition is important to bone health, and a number of minerals and vitamins have been identified... more 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.

OBJECTIVE. Preterm infants may be at particular risk from either inadequate or excessive vitamin ... more 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.

Thrombosis and Haemostasis, 2004

Thegeneencoding vitamin Kepoxider eductasecomplex subunit 1(VKORC1), acomponentofthe enzyme that ... more Thegeneencoding vitamin Kepoxider eductasecomplex subunit 1(VKORC1), acomponentofthe enzyme that is thetherapeutic targets ite forw arfarin,has recentlyb een identified.In ordertoinvestigate the relationship betweenVKORC1and warfarin dose response,westudiedtheVKORC1gene(VKORC1 )in patients withwarfarin resistance.Fromastudy group of 820patients, we identified 4individualswho required morethan 25 mg of warfarindailyfor therapeutic anticoagulation.Threeofthese had serumwarfarin concentrationswithin the therapeutic range of 0.7-2.3 mg/l and showed wild-type VKORC1 sequence.The fourth warfarinr esistant individual had consistentlyh igh ( ≥ 5.7 mg/l) serumw arfarin concentrations, yeth ad no clinicallyd iscernible cause forw arfarin resistance. VKORC1 showed ah et-