Antioxidant defense of children and adolescents with atopic dermatitis: Association with disease severity

Background: Atopic dermatitis (AD) is a relapsing, chronic cutaneous inflammatory disease with onset, in general, in early childhood. Chronic skin inflammation is associated with overproduction of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Oxidative stress, an imbalance between the production of free radicals and antioxidant defense, results in tissue inflammation due to the upregulation of genes that encode inflammatory cytokines. This condition plays an important role in the pathogenesis of AD. Objective: To compare the antioxidant defense in children and adolescents with AD with that of healthy individuals and to verify the association of antioxidant defense with disease severity and nutritional status. Methods: Cross-sectional study that evaluated 48 children and adolescents with AD and 25 controls for nutritional assessment (body mass index z score [BMIZ] and height for age z score [HAZ]) and levels of vitamins A, C, E, and D, zinc (Zn), copper (Cu), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx]), high-sensitivity C-reactive protein (CRP) and interleukin 33 (IL-33). Results: There was no significant difference in the comparison between AD and control groups for serum levels of vitamins (A, D, C, and E), copper, and antioxidant enzymes. Serum zinc levels were higher in the AD group (β = 24.20; 95% CI 13.95–34.91; P < 0.001) even after adjusting the BMIZ, HAZ, gender, IL-33, and CRP. Children and adolescents with moderate or severe AD compared to mild AD (SCORAD – 36.7±17.4 vs 11.8 ± 3.9; P < 0.001) had lower values of the vitamin E/total lipid ratio (3.68 [0.29;12.63] vs 5.92 [3.27;17.37]; P = 0.013) (AU)

[Serum vitamin K2 level and its association with bone metabolism markers in 1 732 children]. / 1 732ä¾‹å„¿ç«¥è¡€æ¸ ç»´ç”Ÿç´ K2ä¸´åºŠåˆ†æžåŠå ¶ä¸Žéª¨ä»£è°¢æ ‡å¿—ç‰©å ³ç³»çš„ç ”ç©¶.

OBJECTIVES: To study the level of serum vitamin K2 (VitK2) and its association with bone metabolism markers osteocalcin (OC), type I procollagen amino-terminal peptide (PINP), and type I collagen carboxy-terminal peptide (CTX) in children. METHODS: A prospective analysis was performed on 1 732 children who underwent routine physical examination from October 2020 to October 2021. The serum levels of VitK2 and 25-hydroxy vitamin D [25(OH)D] were measured. According to age, they were divided into four groups: <1 year, 1-3 years group, >3-6 years group, and >6-14 years. A total of 309 children with 25(OH)D≥50 nmol/L were screened out, and serum levels of OC, PINP, and CTX were measured to investigate the correlation of the serum levels of OC, PINP, and CTX with serum VitK2 levels in different age groups. RESULTS: The prevalence rate of serum VitK2 deficiency was 52.31% (906/1 732). The VitK2 deficiency group had higher prevalence rates of overweight/obesity and growth pain (≥3 years of age) than the normal VitK2 group (P<0.05). There were differences in the prevalence rate of serum VitK2 deficiency (P<0.0083) and the serum level of VitK2 (P<0.05) between the 1-3 years group and the >6-14 years group. The <1 year group had a higher serum level of CTX and a lower serum level of PINP than the >3-6 years group and the >6-14 years group (P<0.05). The <1 year group had a lower serum level of OC than the >6-14 years group (P<0.05). Serum VitK2 level was positively correlated with OC level (rs=0.347, P<0.01), and CTX level was negatively correlated with PINP level (rs=-0.317, P<0.01). CONCLUSIONS: Serum VitK2 deficiency may be associated with overweight/obesity. Serum VitK2 may affect the level of OC and even bone health.

Vitamins as Possible Cancer Biomarkers: Significance and Limitations.

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as 'hidden hunger'), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk.

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Low vitamin K status, high sclerostin and mortality risk of stable coronary heart disease patients.

Aim: We explored whether matrix Gla protein (MGP, natural calcification inhibitor) and sclerostin (glycoprotein responsible for osteoblast differentiation) interact in terms of mortality risk in coronary patients. Methods: 945 patients after myocardial infarction and/or coronary revascularization were followed in a prospective study. All-cause death, fatal or nonfatal cardiovascular events and heart failure hospitalizations were registered. Results: Either high desphospho-uncarboxylated MGP (dp-ucMGP) or high sclerostin were independently associated with 5-year all-cause/cardiovascular mortality. However, we observed an additional mortality risk in the coincidence of both factors. Concomitantly high dp-ucMGP (≥884 pmol/l) plus sclerostin (≥589 ng/l) were associated with increased all-cause mortality risk compared with 'normal' concentrations of both factors (HRR 3.71 [95% CI: 2.07-6.62, p < 0.0001]), or if only one biomarker has been increased. A similar pattern was observed for fatal, but not for nonfatal cardiovascular events. Conclusion: Concomitantly high MGP and sclerostin indicate increased mortality risk, which probably reflects their role in cardiovascular calcifications.

Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman's ρ 0.54, 0.60, and -0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

The Clinical Significance of Drug-Food Interactions of Direct Oral Anticoagulants.

Cardiovascular diseases are the most common cause of death in the world. For almost 60 years, vitamin K antagonists (VKAs) were the mainstay of anticoagulation therapy, but in recent years direct oral anticoagulants (DOACs) have become the anticoagulant treatment of choice. DOACs were initially considered drugs with no significant food interactions; however, clinical observations from daily practice have proved otherwise as interactions with food ingredients have been reported. Food, dietary supplements or herbs may contain substances that, when administered concomitantly with DOACs, can potentially affect the plasma concentration of the drugs. The aim of this paper was to evaluate the clinical significance of drug-food interactions of DOACs, such as dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. Patients treated with anticoagulants should avoid products containing St. John's wort and take special care with other food ingredients. As the interest in dietary supplements is on the rise, healthcare providers can contribute to the development of well-designed clinical trials on interactions between DOACs and food, and distribute sufficient knowledge about the proper use of these supplements among patients.

The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19.

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.

Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study.

Patients with chronic kidney disease (CKD) suffer from vitamin K deficiency and are at high risk of vascular calcification (VC) and premature death. We investigated the association of functional vitamin K deficiency with all-cause mortality and whether this association is modified by the presence of VC in CKD stage 5 (CKD G5). Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP), a circulating marker of functional vitamin K deficiency, and other laboratory and clinical data were determined in 493 CKD G5 patients. VC was assessed in subgroups by Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC). Backward stepwise regression did not identify dp-ucMGP as an independent determinant of VC. During a median follow-up of 42 months, 93 patients died. Each one standard deviation increment in dp-ucMGP was associated with increased risk of all-cause mortality (sub-hazard ratio (sHR) 1.17; 95% confidence interval, 1.01-1.37) adjusted for age, sex, cardiovascular disease, diabetes, body mass index, inflammation, and dialysis treatment. The association remained significant when further adjusted for CAC and AVC in sub-analyses (sHR 1.22, 1.01-1.48 and 1.27, 1.01-1.60, respectively). In conclusion, functional vitamin K deficiency associates with increased mortality risk that is independent of the presence of VC in patients with CKD G5.

The evaluation of vitamin K status in children with febrile seizure.

BACKGROUND: Febrile seizure is the most common neurological disorder in childhood. The exact pathophysiology of febrile seizures is unknown. Recent studies showed the role of vitamin K in nonhematological and inflammatory disorders. This study aimed to investigate the serum vitamin K levels in children with febrile seizures. AIMS: To evaluate vitamin K levels in children with febrile seizures. STUDY DESIGN: Prospective case-control study. METHODS: This multicenter study examined representative populations in 8 different cities in Turkey between April 1, 2018 and April 1, 2019. Blood samples were taken from all children at presentation. Vitamin K1, vitamin K2, tumor necrosis factor-alpha, interleukin 1 beta, and interleukin 6 levels were determined by enzyme-linked immunosorbent assay. RESULTS: A total of 155 children were included in the study-84 children with febrile seizures and 71 children in febrile control group. Serum vitamin K1 and vitamin K2 levels were also higher in children with febrile seizures than in the controls. The results of statistical analysis showed that vitamin K1 and vitamin K2 levels were correlated with tumor necrosis factor-alpha, interleukin 1 beta, and interleukin 6 levels. The median vitamin K1 and vitamin K2 levels of children experiencing their first febrile seizure were higher than those in children with recurrent febrile seizures. Type of febrile seizure has no effect on serum vitamin K1 and vitamin K2 levels. CONCLUSION: In children with febrile seizures, vitamin K levels are higher than those in the control group. These new findings may contribute to elucidating the etiopathogenesis of febrile seizures.

Regular Use of VKA Prior to COVID-19 Associated with Lower 7-Day Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Cohort Study.

BACKGROUND: Vitamin K concentrations are inversely associated with the clinical severity of COVID-19. The objective of this cohort study was to determine whether the regular use of vitamin K antagonist (VKA) prior to COVID-19 was associated with short-term mortality in frail older adults hospitalized for COVID-19. METHODS: Eighty-two patients consecutively hospitalized for COVID-19 in a geriatric acute care unit were included. The association of the regular use of VKA prior to COVID-19 with survival after 7 days of COVID-19 was examined using a propensity-score-weighted Cox proportional-hazards model accounting for age, sex, severe undernutrition, diabetes mellitus, hypertension, prior myocardial infarction, congestive heart failure, prior stroke and/or transient ischemic attack, CHA2DS2-VASc score, HAS-BLED score, and eGFR. RESULTS: Among 82 patients (mean ± SD age 88.8 ± 4.5 years; 48% women), 73 survived COVID-19 at day 7 while 9 died. There was no between-group difference at baseline, despite a trend for more frequent use of VKA in those who did not survive on day 7 (33.3% versus 8.2%, p = 0.056). While considering "using no VKA" as the reference (hazard ratio (HR) = 1), the HR for 7-day mortality in those regularly using VKA was 5.68 [95% CI: 1.17; 27.53]. Consistently, COVID-19 patients using VKA on a regular basis had shorter survival times than the others (p = 0.031). CONCLUSIONS: Regular use of VKA was associated with increased mortality at day 7 in hospitalized frail elderly patients with COVID-19.

Effect of Fat-Soluble Vitamins A, D, E and K on Vitamin Status and Metabolic Profile in Patients with Fat Malabsorption with and without Urolithiasis.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study.

BACKGROUND: A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited. OBJECTIVES: Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians. METHODS: We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000-2001 and 2007-2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)-high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders. RESULTS: Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status. CONCLUSIONS: A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk.

Intimal and medial calcification in relation to cardiovascular risk factors.

PURPOSE: To assess specific risk factors and biomarkers associated with intimal arterial calcification (IAC) and medial arterial calcification (MAC). METHODS: We conducted a cross-sectional study in patients with or at risk of vascular disease from the SMART study(n = 520) and the DCS cohort(n = 198). Non-contrast computed tomography scanning of the lower extremities was performed and calcification in the femoral and crural arteries was scored as absent, predominant IAC, predominant MAC or indistinguishable. Multinomial regression models were used to assess the associations between cardiovascular risk factors and calcification patterns. Biomarkers for inflammation, calcification and vitamin K status were measured in a subset of patients with IAC(n = 151) and MAC(n = 151). RESULTS: Femoral calcification was found in 77% of the participants, of whom 38% had IAC, 28% had MAC and 11% were scored as indistinguishable. The absolute agreement between the femoral and crural arteries was high(69%). Higher age, male sex, statin use and history of coronary artery disease were associated with higher prevalences of femoral IAC and MAC compared to absence of calcification. Smoking and low ankle-brachial-index (ABI) were associated with higher prevalence of IAC and high ABI was associated with less IAC. Compared to patients with IAC, patients with MAC more often had diabetes, have a high ABI and were less often smokers. Inactive Matrix-Gla Protein was associated with increased MAC prevalence, while osteonectin was associated with decreased risk of MAC, compared to IAC. CONCLUSIONS: When femoral calcification is present, the majority of the patients have IAC or MAC throughout the lower extremity, which have different associated risk factor profiles.

Vitamin K supplementation for cystic fibrosis.

BACKGROUND: Malabsorption and deficiency of fat-soluble vitamins K may occur in cystic fibrosis, a genetic disorder affecting multiple organs. Vitamin K is known to play an important role in both blood coagulation and bone formation, hence the role of supplementation of vitamin K in this category needs to be reviewed. This is an updated version of the review. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to investigate the hypotheses that vitamin K will decrease deficiency-related coagulopathy, increase bone mineral density, decrease risk of fractures and improve quality of life in people with CF. Also to determine the optimal dose and route of administration of vitamin K for people with CF (for both routine and therapeutic use). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 12 August 2019. SELECTION CRITERIA: Randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Three trials (total 70 participants, aged 8 to 46 years) assessed as having a moderate risk of bias were included. One trial compared vitamin K to placebo, a second to no supplementation and the third compared two doses of vitamin K. No trial in either comparison reported our primary outcomes of coagulation and quality of life or the secondary outcomes of nutritional parameters and adverse events. Vitamin K versus control Two trials compared vitamin K to control, but data were not available for analysis. One 12-month trial (n = 38) compared 10 mg vitamin K daily or placebo in a parallel design and one trial (n = 18) was of cross-over design with no washout period and compared 5 mg vitamin K/week for four-weeks to no supplementation for four-weeks. Only the 12-month trial reported on the primary outcome of bone formation; we are very uncertain whether vitamin K supplementation has any effect on bone mineral density at the femoral hip or lumbar spine (very low-quality evidence). Both trials reported an increase in serum vitamin K levels and a decrease in undercarboxylated osteocalcin levels. The cross-over trial also reported that levels of proteins induced by vitamin K absence (PIVKA) showed a decrease and a return to normal following supplementation, but due to the very low-quality evidence we are not certain that this is due to the intervention. High-dose versus low-dose vitamin K One parallel trial (n = 14) compared 1 mg vitamin K/day to 5 mg vitamin K/day for four weeks. The trial did report that there did not appear to be any difference in serum undercarboxylated osteocalcin or vitamin K levels (very low-quality evidence). While the trial reported that serum vitamin K levels improved with supplementation, there was no difference between the high-dose and low-dose groups. AUTHORS' CONCLUSIONS: There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed.

[Research progress of relationship between vitamin K and type 2 diabetes].

Objective: To systematically review research on the association between vitamin K and type 2 diabetes and diabetes-related biomarkers in humans, and evaluate the role of vitamin K in the prevention of type 2 diabetes. Methods: "Vitamin K", "type 2 diabetes" and related terms were searched in PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang Med Online up to November 2018. Results: A total of 1 Chinese and 12 English articles were included. Among 6 observational studies, 5 of them showed that higher dietary vitamin K intake and plasma vitamin K level were associated with the decrease of the risk of type 2 diabetes. Among 6 clinical intervention studies, 5 of them indicated that the supplementation of vitamin K(1) or K2 could have positive influence on insulin metabolism. One Mendelian randomization study showed higher circulation vitamin K level might reduce the risk of type 2 diabetes. Conclusion: Vitamin K plays an important role in the prevention and control of type 2 diabetes, which may be related to the improvement of insulin metabolism and blood glucose level.

Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (ß = -0.26, p = 0.045) after integrating effects of height (ß = -0.38, p = 0.01), insulin treatment (ß = 0.42, p = 0.002), retinopathy treated by laser (ß = 0.26, p = 0.02), and total cholesterol levels (ß = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy.

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases.

Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.

High dephospho-uncarboxylated matrix Gla protein concentrations, a plasma biomarker of vitamin K, in relation to frailty: the Longitudinal Aging Study Amsterdam.

PURPOSE: No previous study has evaluated the relationship between vitamin K and frailty. Thus, we assessed the relationship between vitamin K status and frailty over 13 years in the Longitudinal Aging Study Amsterdam (LASA). METHODS: Prospective cohort study with 644 community-dwelling adults ≥ 55 years from the LASA cohort. In 2002-2003, plasma desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) was measured as marker of vitamin K status through a sandwich ELISA. Frailty was measured at baseline and in four follow-up examinations with the LASA Frailty Index (LASA-FI), which was used as both a continuous and a dichotomous measure (FI ≥ 0.25), as indicator of the degree of frailty and frailty risk, respectively. Statistical analyses were performed with multivariable generalized estimating equations using the lowest dp-ucMGP tertile, reflecting a high vitamin K status, as reference. RESULTS: The mean (SD) age was 59.9 (2.9) years, and 54% were female. Compared with the lowest tertile, the medium and highest dp-ucMGP tertile were associated with a higher degree of frailty [1.40, 95% confidence interval (0.01-2.81) and 1.62, (0.18-3.06), respectively. P trend: 0.03]. Additionally, the medium and highest dp-ucMGP tertile had a higher odds ratio of frailty [1.75 (1.11-2.77) and 1.63 (1.04-2.57), respectively]. The degree of frailty increased over time, but the differences by dp-ucMGP tertiles existed since baseline and remained stable during follow-up. CONCLUSIONS: Baseline plasma low vitamin K status was associated with a greater degree of frailty and frailty risk in this cohort of older adults, which highlights the importance of ensuring an optimal nutritional status of this vitamin to prevent frailty in later life.

Joint association of vitamins D and K status with long-term outcomes in stable kidney transplant recipients.

BACKGROUND: Kidney transplant recipients (KTRs) experience substantial survival benefit compared with dialysis patients. However, their mortality and graft failure risk remain high. KTRs are often low in micronutrient status, including vitamins D and K. We investigated the association of both vitamins D and K status, and vitamin D treatment with all-cause mortality and death-censored graft failure. METHODS: We studied 461 KTRs from a single-centre study at median 6.1 years after transplantation. At baseline, vitamins D and K concentrations were measured by 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix gla protein (dp-ucMGP) and patients were categorized into: 25(OH)D <50/≥50 nmol/L and median dp-ucMGP <1057/≥1057 pmol/L. RESULTS: Mean age was 52 ± 12 years, and 122 KTRs (26%) had low vitamins D and K status. During median 9.8 years follow-up, 128 patients (28%) died and 48 (10%) developed death-censored graft failure. Low vitamins D and K status was associated with 2.33 (1.26-4.30) [hazard ratio (95% confidence interval)] increased mortality risk and 3.25 (1.17-9.08) increased graft failure risk compared with KTR with 25(OH)D ≥50 nmol/L and dp-ucMGP <1057 pmol/L. Dp-ucMGP was strongly associated with mortality (per 500 pmol/L increase): 1.41 (1.08-1.41) for vitamin D treatment versus no treatment 1.07 (0.97-1.18), and graft failure 1.71 (1.17-2.49) for vitamin D treatment versus 1.19 (1.05-1.36) no treatment, P-interaction <0.07 for vitamin D treatment (n = 44). CONCLUSIONS: Combined vitamins D and K deficiency are highly prevalent and are associated with increased mortality and graft failure risk compared with high vitamins D and K status. Low vitamin K status was strongly associated with an increased risk of premature mortality and graft failure for patients treated with vitamin D versus no vitamin D treatment.