Supply Of Vitamin Research Articles

Understanding the physiology, pharmacology and therapeutic uses of vitamin D

Vitamin D was identified nearly a century ago as an important regulator in the absorption and transport of essential minerals (particularly calcium, phosphorus and magnesium), and as such is a key determinant of normal bone development. Vitamin D is now seen as a potentially key hormonal regulator in the cardiovascular, musculoskeletal, renal, nervous, adipose and immune systems. An adequate supply of vitamin D at all stages of life is essential for the maintenance of good health. It has, however, been estimated that upwards of 1 billion people, in both the developed and developing world, can be categorised as being vitamin D deficient. This article discusses some key aspects of the biochemistry, physiology and pharmacology of vitamin D.

VITAMIN D IN POSTMENOPAUSAL WOMEN IN NOVOSIBIRSK WITH A DIFFERENT STATE OF CARBOHYDRATE METABOLISM

The aim of the study was to evaluate the association of vitamin D status with carbohydrate metabolism and anthropometric status in postmenopausal Novosibirsk women.We analyzed correlations of carbohydrate metabolism parameters and body weight with hydroxyvitamin D [25(OH)D] levels using the Spearman test in 60 women. 25(OH)D levels correlations (p < 0.05) with a waist circumference (r = 0.51–0.64), blood glucose and HbA1c (r = 0.55–0.56), C-peptide (r = 0.53), duration of hypertension (r = –0.69) and diabetes (r = – 0.41) differed depending on the condition of carbohydrate metabolism. Insufficient supply of vitamin D through association with abdominal fat deposition, insulin secretion and duration of hypertension contributes to the formation of type 2 diabetes in postmenopausal Novosibirsk women.

Effects of an extra supply of vitamin D, calcium and phosphorus via drinking water on the calcium and phosphorus metabolism in growing chickens fed a conventional complete diet

Summary In spite of generous supply with vitamin D 3, Ca and P via complete diets non-infectious skeletal disorders are frequently observed in conventional broiler fattening. Especially fast-growing genotypes are affected. Because undersupply of nutrients for bone metabolism is generally suspected, vit D 3 and Ca/P containing drinking-water additives are administered preventively as well as therapeutically. Therefore, this study was conducted to test potential effects of this widespread procedure. 240 male broilers (Cobb 500 TM) were allotted to two subsequent trials with four groups each for a 35 day fattening period (day 1 till day 36). Broilers were housed on wood shavings and infrared lamps were initially used as heater. Water and feed were offered ad libitum. All animals were fed the same commercial starter, grower and finisher diets (215/205/195Â g XP, 10/8.5/8Â g Ca, 6.5/5.5/5Â g P, 5000/4400/5000 I.U. vit. D/kg). The groups (treatments) only differed in the kind of additional supply via drinking water; group I (control group): no additional supply; group II: vit. D 3 (1250 I.U./animal and day) at day 3 and 4; group III: Ca/P at day 5, 6, 15, 16, 23 and 24 (77Â mg P and 24Â mg Ca/l water); group IV: both vit. D and Ca/P. Six broilers of each group were sacrificed at day 6, 8, 16, 24 and 36 of the fattening period. Neither the extra supply of vit. D (doses: 200-fold of minimum requirement at both days) nor an additional intake of Ca and P clearly resulted in positive effects on performance or Ca and P metabolism or skeleton health throughout the whole trials. A subsequent trial (III), shortened to 7 days, was performed with 18 Ross 308 ® broilers. Calbindin, a protein which affects the active, vitamin D-dependent, transcellular Ca-transport, was examined in the small intestinal mucosa of these animals using a Western Blotting technique. Although applied via drinking water, absorption of vit. D was definitively demonstrated, subsequent increase of active Ca-absorption (calbindin D28 K) did not occur, indicating that there is no need for an active transport at dietary Ca and P levels that meet requirements.

Czy zwyczajowy sposób żywienia pacjentów z depresją wymaga suplementacji witaminami i składnikami mineralnymi?

Research on diet and nutrition of patients with depression show that their eating habits are frequently irrational and result in the inconsistent supply of nutrients, especially vitamins and minerals, the deficiency of which leads to nervous system dysfunction. The aim of the study was to evaluate the content of selected vitamins and minerals in daily food rations of patients suffering from recurrent depressive disorders. The study involved a group of 69 people (54 women and 15 men, aged 18-65 years, mean age of women 45.7 +/- 12.2 years, men 46.0 +/- 12.2 years), treated for recurrent depressive disorders. A questionnaire designed in the Department of Dietetics and Clinical Nutrition, Medical University of Bialystok was used to collect dietary data. The quantitative assessment of eating habits used a 24-hour diet recall including 3 weekdays and 1 weekend day. The study showed that the supply of most nutrients assessed was inconsistent with recommendations. The results indicate that the need for vitamin-mineral supplementation should be considered individually. Nutritional education related to the proper choice of groups of food products is indicated at the time of clinical improvement to ensure the optimum supply of vitamins and minerals.

Verticillium dahliae VdTHI4, involved in thiazole biosynthesis, stress response and DNA repair functions, is required for vascular disease induction in tomato

The vascular plant pathogen Verticillium dahliae colonizes the xylem fluid where only low nutrient concentrations are provided. Biosynthesis of the vitamin thiamine is connected to oxidative stress. The highly conserved VdThi4 protein is localized in fungal mitochondria and is required under vitamin B1 limiting conditions. Deletion of the corresponding VdTHI4 gene by Agrobacterium-mediated transformation resulted in strains which were impaired in growth on thiamine-free medium and could be rescued by additional vitamin supply or by complementation with the original gene after protoplastation. Furthermore, we show that VdThi4 increases fungal stress tolerance such as UV-damage or oxidative stress. The orthologous sti35 gene of Fusarium oxysporum, another vascular wilt fungus, was shown to be involved in stress response, however to be dispensable for pathogenicity on tomato. In contrast, VdTHI4 is required for fungal-induced tomato disease demonstrated by infection assays with a V. dahliae ΔVdTHI4 deletion strain which is still able to invade plants through the roots but is asymptomatic. Our results suggest remarkable differences between two vascular tomato pathogens where VdThi4 is required for pathogenicity of V. dahliae, whereas F. oxysporum still causes disease when the corresponding Sti35 protein is absent.

Preterm nutrition and the lung.

Experimental and clinical evidence show that fetal and neonatal nutrition and metabolism can markedly modulate pulmonary growth, development, and function, as well as long-term lung health and disease risks. Intrauterine growth restriction has been linked to an increased risk for respiratory distress syndrome and chronic lung disease, while excessive fetal growth reduced forced expiratory volume. Postnatal undernutrition adversely affected pulmonary function in animal models and was associated to a higher risk of chronic lung disease in very low birth weight infants. The supply of specific nutrients to very low birth weight infants, including fluids, protein, carbohydrates, inositol, docosahexaenoic acid, calcium, phosphorus and the vitamins A and E has been associated with lung development and function and deserves further evaluation. In infants with evolving or established chronic lung disease, excess fluid administration and high intravenous glucose infusion rates should be avoided and the provision of vitamin A be considered. Opportunities exist for further research relating to neonatal nutrition and lung health, for example exploring optimal strategies and effects of providing vitamin A, docosahexaenoic acid and intravenous lipid emulsions.

Food Consumption Pattern and Nutritional Health Status of Hill Farm Women

Diet composition plays an important role in nutritional status of an individual. An ample and diverse supply of calories, protein, vitamin and minerals is necessary for good nutrition. Balanced diet must include food items from the various food groups in sufficient quantities to meet the needs of an individual and for maintenance of good health throughout the life. The present study focuses on the health and well-being of farm women from four villages of district Kullu in Himachal Pradesh. The mean daily intake of nutrients was calculated by using the Food Composition Tables and was compared with the Recommended Dietary Allowances for adult women as recommended by Indian Council of Medical Research. The present study revealed that diet consumed by the farmwomen of the area was sufficient only in meeting the energy requirements whereas all other nutrients were deficient in their diet. A majority of the farm women suffer from iron-deficiency anemia.

Vitamin D and Alzheimer's disease: from an intriguing idea to a therapeutic option

Beyond the classically described regulation of calcium and bone metabolism, vitamin D is a neurosteroid hormone essential to neurophysiological function (regulation of neurotransmitters and neurotrophins) with anti-inflammatory and antioxidant neuroprotective action. In contrast, hypovitaminosis D, which is extremely frequent in the elderly, may result in neurological dysfunction and may explain part of the cognitive disorders in this population. Epidemiology is consistent with this notion and has repeatedly shown an association between hypovitaminosis D and cognitive decline, either in the general population or in Alzheimer's patients. Preliminary intervention trials confirm the causal relationship and quantify the cognitive effect of vitamin D supplementation in the elderly. This raises prospects for primary/secondary prevention of cognitive decline by exogenous supplies of vitamin D. In particular, although current anti-dementia drugs are only symptomatic, future treatment options could rely on drug combinations preventing several neurodegenerative mechanisms at once. As such, vitamin D enhances the efficacy of memantine in terms of neuronal protection and prevention of cognitive decline in Alzheimer's disease.

Parâmetros nutricionais de dietas anunciadas na imprensa leiga destinada ao público masculino e feminino

Objective: To analyze nutritional parameters of generic diets advertised in the press intended for male and female audience. Materials and Methods: This was a descriptive observational study. Four publications targeted to women and two for male public were selected based on the periodicity, circulation, readership and publication years. These publications were analyzed for one year, from July 2009 to June 2010. The nutrients evaluated were: carbohydrates, lipids, proteins, calcium, iron, vitamin C, vitamin A, vitamin E, and cholesterol, as well as information about the duration of the diet, fluid intake, physical activity and diet maintenance. Results: The duration of the diets were between 1 and 10 days and not much has been found concerning the use of fluids and maintenance diet. As for physical activity, emphasis was placed only on a male magazine. It was noted a wide variation in the energy content, as well as macronutrient and micronutrient between the diets analyzed, with the greatest inadequacy related to carbohydrates. The average caloric value to women's magazines and men were, respectively, 1113±151 and 1727±179 kcal. There was a shortfall of the micronutrients analyzed, highlighting the deficiencies in the supply of calcium, iron and vitamins A and E. Conclusions: Diets published in the lay press present short duration and come, only in some cases, accompanied by information on physical activity and fluid intake. In relation to the nutritional value, they present a reduced intake of energy and nutrients, particularly vitamins and minerals, if taken for a long period of time.

Hábitos saludables y prevención de la osteoporosis en mujeres perimenopáusicas de un ámbito rural

ObjectiveThe probability of developing osteoporosis decreases with an adequate supply of vitamin D, a balanced diet, and increased physical activity. In this study, we evaluated whether an educational intervention improves osteoporosis-related behavior in perimenopausal women from rural areas. MethodsA randomized experimental evaluation was performed of an educational intervention. The variables were physical activity, calcium intake and sun exposure in women from rural areas aged 45-54 years (n=216) at time 0 and 12 months after the educational intervention. In the control group (n=106), the information was sent by surface mail (month 0). In the intervention group (n=110), two interactive workshops were given (month 0). The topic of the workshops and the information sent by surface mail was healthy habits for osteoporosis prevention. ResultsAfter 12 months, the intervention group, but not the control group, had increased their physical activity (p=0.006), sun exposure (p=0.029), and calcium intake (53% to 64%). ConclusionA simple educational intervention in perimenopausal women from rural areas improved healthy habits for osteoporosis prevention.

Scientific Opinion on nutrient requirements and dietary intakes of infants and young children in the European Union

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on the nutrient requirements and dietary intakes of infants and young children in the European Union. This Opinion describes the dietary requirements of infants and young children, compares dietary intakes and requirements in infants and young children in Europe and, based on these findings, concludes on the potential role of young-child formulae in the diets of infants and young children, including whether they have any nutritional benefits when compared with other foods that may be included in the normal diet of infants and young children. The Panel concluded on the levels of nutrient and energy intakes that are considered adequate for the majority of infants and young children, and evaluated the risk of inadequate nutrient intakes in infants and young children in living Europe. Dietary intakes of alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), iron, vitamin D and iodine (in some European countries) are low in infants and young children living in Europe, and particular attention should be paid to ensuring an appropriate supply of ALA, DHA, iron, vitamin D and iodine in infants and young children with inadequate or at risk of inadequate status of these nutrients. No unique role of young-child formulae with respect to the provision of critical nutrients in the diet of infants and young children living in Europe can be identified, so that they cannot be considered as a necessity to satisfy the nutritional requirements of young children when compared with other foods that may be included in the normal diet of young children (such as breast milk, infant formulae, follow-on formulae and cow's milk).

The physiology and pharmacology of vitamin D

Vitamin D was identified nearly a century ago as an important regulator in the absorption and transport of essential minerals (particularly calcium, phosphorus and magnesium), and as such is a key determinant of normal bone development. Vitamin D is now seen as a potentially key hormonal regulator in the cardiovascular, musculoskeletal, renal, nervous, adipose and immune systems. An adequate supply of vitamin D at all stages of life is essential for the maintenance of good health. It has, however, been estimated that upwards of 1 billion people, in both the developed and developing world, can be categorised as being vitamin D deficient. This article discusses some of the key aspects of the biochemistry, physiology and pharmacology of vitamin D.

Efficacy of a one-year exercise program to prevent bone loss in postmenopausal women prescribed aromatase inhibitor therapy: An RCT.

e20533 Background: The aim of this single blinded RCT was to determine the effect of exercise on bone mineral density (BMD) in postmenopausal women prescribed an aromatase inhibitor (AI) for the treatment of breast cancer. Methods: 66 sedentary, postmenopausal women, median age of 54.5 years, with early breast cancer and receiving an aromatase inhibitor participated. Women were stratified for taking tamoxifen prior to AI, and randomised to either the exercise (n = 27) or control (n = 39) group. All participants received daily vitamin D (1000 IU) and calcium carbonate (1200 mg) supplements and a booklet from Osteoporosis Australia outlining the benefits of exercise in preventing osteoporosis. The exercise group attended a gym three times per week for one year, supervised at regular intervals by a personal trainer, and were contacted weekly regarding progress and progression. Training sessions comprised warm-up, impact training, and resistance training. The control group was contacted monthly to monitor health status and to receive their supply of vitamins. The primary outcome was total hip BMD measured with a dual-energy X-ray absorptiometer. The secondary outcomes included trochanteric, femoral neck, lumbar spine and whole body BMD and t-scores. Results: Intention-to-treat analysis revealed that the change in BMD was not significantly different between groups. At baseline, the mean (SD) total hip BMD in the control group was 0.892 (0.115) g/cm2 and 0.878 (0.112) g/cm2 at 1 yr. In contrast, hip BMD in the Exercise group was 0.918 (0.119) g/cm2 at baseline and 0.910 (0.113) g/cm2at 1 yr. The mean (SD) change for both groups was <1%. The mean T-score of the hip for Controls at baseline was -0.42 (0.94) and -0.53 (0.91) at 1 year. The baseline T-score for the Exercise group was -0.20 (0.95) and -0.26 (0.93) at one year. The average compliance with attendance for the exercise group was 71% but ranged from 20 to 100%. Compliance with vitamins for both groups was high. Conclusions: A one year exercise program did not provide additional benefit to bone density in women on AIs compared to receipt of calcium and vitamin D and advice to exercise. Clinical trial information: (ACTRN12608000220369).

Mutations of the trypsinogen activation peptide in hereditary pancreatitis

Mutations of the trypsinogen activation peptide in hereditary pancreatitis

Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus

Epigenetic modifications, including DNA methylation, contribute to the transcriptional regulation of developmental genes that control growth and differentiation during embryogenesis. The methyl donor, S-adenosylmethionine (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM biosynthesis requires a steady supply of nutrients, vitamins and cofactors obtained by the developing conceptus through histiotrophic nutrition pathways (HNPs). The visceral yolk sac (VYS) captures proteins and their substrate cargos by receptor-mediated endocytosis and degrades them using lysosomal proteases. We hypothesize that leupeptin, a protease inhibitor, reduces the availability of methionine and C1 substrates, restricting SAM biosynthesis and altering patterns of DNA methylation. Rat conceptuses were exposed to 50 and 100 μM leupeptin in whole embryo culture for periods of 26 h from gestational day (GD) 10 or 6 h on GD11. After 6 h on GD11, the 100-μM leupeptin treatment significantly decreased methionine in embryo (EMB) and VYS, reduced Mat2a protein levels and inhibited Mat2a specific activity, all of which produced a significant 52% reduction of SAM in the VYS. The 50- and 100-μM leupeptin treatments significantly decreased global methylation levels by 6%–9% in EMB and by 11%–15% in VYS following both 6- and 26-h exposure periods. This study demonstrates that HNP disruption alters C1 activity and significantly reduces global DNA methylation during organogenesis. Because epigenetic reprogramming is crucial for normal differentiation and growth, these findings suggest a possible mechanism through which nutrients and environmental factors may alter early developmental regulation.

Hormonal and biochemical parameters correlated with bone densitometric markers in prepubertal Hungarian children

BackgroundThe conditions that define bone development in prepuberty profoundly influence bone health later in life. We aimed to reveal important determinants of bone mass in Tanner stage I. MethodsWe studied 84 healthy children (43 girls and 41 boys) aged 7 to 11years. Serum estradiol (E2), 25-hydroxyvitamin D3-vitamin [25(OH)D3], intact parathyroid hormone (PTHi), osteocalcin (OC) and β-crosslaps (CTXs) were longitudinally analyzed (Roche Diagnostics System). Total and spine bone mineral content (tBMC and LBMC) and density (tBMD and LBMD) were assessed, and total fat body mass index (FBMi) was calculated (DXA Lunar Prodigy). ResultsThe serum PTHi, OC and LBMD values were significantly higher in girls than in boys. The mean 25(OH)D3 level was lower but not significantly in girls compared to boys. Significant negative correlation was found between PTHi and 25(OH)D3 levels (r=−0.28; p=0.011) when tested in all subjects, but no correlation was detected when the gender groups were separately tested. There was a trend for higher E2 levels in girls. Significant positive correlation (r=0.32; p=0.042) was detected between FBMi and E2 concentration in girls only. A significant negative correlation was found between E2 and 25(OH)D3 levels (r=−0.37, p<0.05) in girls with elevated (>3.6pmol/l) PTHi and with suboptimal (<75nmol/l) 25(OH)D3 levels. Furthermore, positive correlations were noted between E2 and CTXs and OC (r=0.54, p<0.01 and r=0.39, p<0.03) and a marginally significant positive correlation (r=0.33; p=0.06) was detected between OC and PTHi levels in girls. However, we detected no correlations when these markers were analyzed in boys. There was a significant correlation between E2 and all BMC and LBMD values in both genders. The tBMD, LBMD and tBMC values showed weak, but significant negative associations with 25OHD3 levels (β=−0.44 to −0.55; p<0.001) in girls only. All BMD and BMC values were positively predicted by OC levels, but not by CTXs, in both genders. Among the biochemical markers, E2 was the only factor correlating with all dependent variables (BMCs and BMDs) in both genders. Among all parameters analyzed, FBMi (β=0.64) showed the strongest influence on tBMC characteristically in girls only. ConclusionsOur results support that 1.) E2 levels play a key role in defining bone turnover and bone mass in both genders already in prepuberty; 2.) high PTHi levels in childhood should be evaluated with caution, because the normal range for serum PTHi in different Tanner stage groups is not well established; and 3.) the negative correlation between 25(OH)D and E2 and the positive correlation between PTHi and OC suggest that estrogens regulate PTHi indirectly and cause lower circulating 25(OH)D3 levels. We propose that the decreased levels of 25(OH)D3 reflect not the real vitamin supply, but may rather be the result of E2 regulation. Therefore, the actual serum 25OHD levels may underestimate the availability of factors supporting bone formation.

Trends in energy and nutrient supply in Trinidad and Tobago from 1961 to 2007 using FAO food balance sheets.

Trinidad and Tobago has experienced an epidemiological transition over recent decades characterised by reduced rates of communicable diseases but rapidly increasing rates of obesity and non-communicable chronic diseases. The objective of the present study was to investigate the changes in energy and nutrient supply that have taken place in Trinidad and Tobago between 1961 and 2007. Food balance sheets for each year between 1961 and 2007 were downloaded from the FAOSTAT database and daily per capita supply for seventeen food commodity groupings was calculated. After appropriate coding, energy and nutrient supply were determined using dietary analysis software. FAO food balance sheets for Trinidad and Tobago from 1961 to 2007. None. The food supply in 2007 provided an extra 1561 kJ (373 kcal)/capita per d than it did in 1961. Energy from carbohydrate as a percentage of total energy fell from 62% in 1961 to 57% in 2007, whereas energy from fat as a percentage of total energy increased from 26% to over 30% and now lies at the upper end of WHO recommendations. Sugars increased from 20% to over 26% of total energy and are well above WHO recommendations. When expressed on a nutrient density basis, supplies of vitamin A, folate and Ca are lower than WHO recommendations. Nutritional imbalances in the Trinidadian food supply need to be addressed to combat the rise in nutrition-related chronic disease that is projected to cause increased disability and premature death in the country in the coming years.

Ageing

Ageing

Therapeutic options in male osteoporosis

SummaryOsteoporosis in men is increasingly recognized as an important public health problem but affected patients are still under-diagnosed and -treated. As in women the diagnostic and therapeutic strategy has to be adapted to the individual case. In the practical management it is very important to detect possible causes of secondary osteoporosis, to explain the possibilities of basic therapy counteracting individual risk factors and communicate that osteoporosis is a chronic disease and adherence to a long-term treatment is crucial. In established severe osteoporosis a careful analgesic therapy is important to avoid further bone loss related to immobility. In elderly men with increased risk of falling insufficient Vitamin D supply or impaired activation of Vitamin D due to renal insufficiency must be taken into consideration. Specific medications available today for the treatment of male osteoporosis comprise among antiresorptive drugs the bis phosphonates alendronate, risedronate and zoledronic acid. Denosumab, the first biological therapy is approved for men with androgen deprivation therapy for prostate cancer. An important advantage of this potent antiresorptive drug is the increased adherence due to the comfortable application by sixmonthly subcutaneous injections. Study results from the 2-year multi-center randomized controlled ADAMO-Study will very soon allow the use of denosumab in all types of male osteoporosis. Teriparatide, the 34 N-terminal amino acid sequence of parathyroid hormone was approved for men with osteoporosis as an anabolic agent based on proven efficacy by different studies. Among drugs with other modes of action the D-hormone pro-drug alfacalcidol can be used in men alone or in combination with the advantage of pleiotropic effects on calcium absorption, parathyroids, bone and muscle. Recently also Strontium-ranelate was approved for male patients with the limitation to exclude men with clinical relevant cardiovascular risk factors. In general the possibilities to treat male osteoporosis have considerably improved during recent years. Today there is a choice of a spectrum of drugs from mild to strong potency with different modes of action on bone turnover to design strategies for individual male patients.

A Novel Mutation in VKORC1 and Its Effect on Enzymatic Activity in Japanese Warfarin-Resistant Rats

Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 µM. The Vmax values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The Km values of resistant rats (47 ± 32 µM) were similar to those of sensitive rats (59 ± 18 µM). Warfarin-sensitive rats exhibited enzyme efficiencies (Vmax/Km) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.