Climatic variables are more effective on the spatial distribution of oak forests than land use change across their historical range.

The current research is conducted to model the effect of climate change and land use change (LUC) on the geographical distribution of Quercus brantii Lindl. (QB) forests across their historical range. Forecasting was done based on six general circulation models under RCP 2.6 and RCP 8.5 future climate change scenarios for the future years 2050 and 2070. In order to model the species distribution, different modeling methods were used. The results indicated that, in general, climatic variables had a higher influence on the distribution of QB than land use-related attributes. The mean diurnal range (bio2), the precipitation seasonality (bio15), and the mean temperature of the driest quarter (bio9) were the main predictors in the distribution of QB forests, while land use variables were less important in oak species distribution. The GBM, MaxEnt, and RF had higher accuracy and performance in modeling species distribution. The outputs also showed that in the current climate circumstances, 97,608.81 km2 of the studied area has high desirability for the presence of QB, and by 2070, under the pessimistic scenario, 96.29% of these habitats will be lost under the concomitant effect of LUC and climate change. By using the results of this research, it is possible to predict and identify the effective factors in changing the habitat of this oak species with more certainty. Based on the insights obtained from the results of such studies, the protection and restoration planning of the habitat of this key species, which supports diverse species, will be provided more efficiently.

The importance of vitamin B12 for individuals choosing plant-based diets.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Successful treatment of classic pyoderma gangrenosum with intralesional infliximab injection: A case report.

Pyoderma gangrenosum (PG) is a rare dermatological disease characterized by the rapid development of painful skin ulcers. While systemic infliximab is considered a standard treatment for patients with PG, herein, we report our success with the use of intralesional infliximab in a 40-year-old woman with systemic lupus erythematosus (SLE) and PG.

Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis.

The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health. It is therefore closely aligned with many of the recognised modifiable factors that influence bone mass accrual in the young, and bone maintenance and skeletal decline in older populations. While understanding of the relationship between micro-organisms and bone health is still in its infancy, two decades of broader microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and pathogenesis of osteoporosis as well as its prevention and treatment. Pre-clinical research has demonstrated biological interactions between the microbiome and bone metabolism. Furthermore, observational studies and randomized clinical trials have indicated that therapeutic manipulation of the microbiota by oral administration of probiotics may influence bone turnover and prevent bone loss in humans. In this paper, we summarize the content, discussion and conclusions of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in October, 2020. We provide a detailed review of the literature examining the relationship between the microbiota and bone health in animal models and in humans, as well as formulating the agenda for key research priorities required to advance this field. We also underscore the potential pitfalls in this research field that should be avoided and provide methodological recommendations to facilitate bridging the gap from promising concept to a potential cause and intervention target for osteoporosis.

Vitamin B12 status in health and disease: a critical review. Diagnosis of deficiency and insufficiency - clinical and laboratory pitfalls.

Vitamin B12 (cobalamin) is an essential cofactor for two metabolic pathways. It is obtained principally from food of animal origin. Cobalamin becomes bioavailable through a series of steps pertaining to its release from dietary protein, intrinsic factor-mediated absorption, haptocorrin or transcobalamin-mediated transport, cellular uptake, and two enzymatic conversions (via methionine synthase and methylmalonyl-CoA-mutase) into cofactor forms: methylcobalamin and adenosylcobalamin. Vitamin B12 deficiency can masquerade as a multitude of illnesses, presenting different perspectives from the point of view of the hematologist, neurologist, gastroenterologist, general physician, or dietician. Increased physician vigilance and heightened patient awareness often account for its early presentation, and testing sometimes occurs during a phase of vitamin B12 insufficiency before the main onset of the disease. The chosen test often depends on its availability rather than on the diagnostic performance and sensitivity to irrelevant factors interfering with vitamin B12 markers. Although serum B12 is still the most commonly used and widely available test, diagnostics by holotranscobalamin, serum methylmalonic acid, and plasma homocysteine measurements have grown in the last several years in routine practice. The lack of a robust absorption test, coupled with compromised sensitivity and specificity of other tests (intrinsic factor and gastric parietal cell antibodies), hinders determination of the cause for depleted B12 status. This can lead to incorrect supplementation regimes and uncertainty regarding later treatment. This review discusses currently available knowledge on vitamin B12, informs the reader about the pitfalls of tests for assessing its deficiency, reviews B12 status in various populations at different disease stages, and provides recommendations for interpretation, treatment, and associated risks. Future directions for diagnostics of B12 status and health interventions are also discussed.

Very high prevalence of 25-hydroxyvitamin D deficiency in 6433 UK South Asian adults: analysis of the UK Biobank Cohort.

Little research has assessed serum 25-hydroxyvitamin D (25(OH)D) concentration and its predictors in Western-dwelling South Asians in a relatively large sample size. This observational, cross-sectional analysis assessed baseline prevalence of 25(OH)D deficiency in UK-dwelling South Asians (aged 40-69 years, 2006-2010) from the UK Biobank Cohort. Serum 25(OH)D measurements were undertaken using the DiaSorin Liaison XL assay. Of 6433 South Asians with a 25(OH)D measurement, using commonly used cut-off thresholds, 55 % (n 3538) had 25(OH)D < 25 nmol/l (severe deficiency) and 92 % (n 5918) had 25(OH)D < 50 nmol/l (insufficiency). Of the participants with a measurement, 20 % (n 1287) had 25(OH)D concentration <15 nmol/l (very severe deficiency). When 824 participants with undetectable (<10 nmol/l) 25(OH)D measurements were included (total n 7257), 29 % (n 2105) had 25(OH)D < 15 nmol/l, 60 % (n 4354) had 25(OH)D < 25 nmol/l and 93 % (n 6749) had 25(OH)D < 50 nmol/l. Logistic regression predictors of 25(OH)D < 25 nmol/l included the following characteristics: being male; Pakistani; higher BMI; 40-59 years old; never consuming oily fish; summer sun exposure <5 h/d, not using a vitamin D-containing supplement, measurement in winter or spring and vegetarianism. In terms of region, median 25(OH)D concentration was 19-20 nmol/l in Scotland, Northern England, the Midlands and Wales. Across Southern England and London, it was slightly higher at 24-25 nmol/l. Our analyses suggest the need for increased awareness of vitamin D deficiency in South Asians as well as urgent public health interventions to prevent and treat vitamin D deficiency in this group.

Mapping the spatial and temporal variability of flood hazard affected by climate and land-use changes in the future.

The predicts current and future flood risk in the Kalvan watershed of northwestern Markazi Province, Iran. To do this, 512 flood and non-flood locations were identified and mapped. Twenty flood-risk factors were selected to model flood risk using several machine learning techniques: conditional inference random forest (CIRF), the gradient boosting model (GBM), extreme gradient boosting (XGB) and their ensembles. To investigate the future (year 2050) effects of changing climates and changing land use on future flood risk, a general circulation model (GCM) with representative concentration pathways (RCPs) of the 2.6 and 8.5 scenarios by 2050 was tested for impacts on 8 precipitation variables. In addition, future land uses in 2050 was prepared using a CA-Markov model. The performances of the flood risk models were validated with Receiver Operating Characteristic-Area Under Curve (ROC-AUC) and other statistical analyses. The AUC value of the ROC curve indicates that the ensemble model had the highest predictive power (AUC = 0.83) and was followed by GBM (AUC = 0.80), XGB (AUC = 0.79), and CIRF (AUC = 0.78). The results of climate and land use changes on future flood-prone areas showed that the areas classified as having moderate to very high flood risk will increase by 2050. Due to the changes occurring with land uses and in climates, the area classified as moderate to very high risk increased in the predictions from all four models. The areal proportion classes of the risk zones in 2050 under the RCP 2.6 scenario using the ensemble model have changed of the following proportions from the current distribution Very Low = -12.04 %, Low = -8.56 %, Moderate = +1.56 %, High = +11.55 %, and Very High = +7.49 %. The RCP 8.5 scenario has caused the following changes from the present percentages: Very Low = -14.48 %, Low = -6.35 %, Moderate = +4.54 %, High = +10.61 %, and Very High = +5.67 %. The results of current and future flood risk mapping can aid planners and flood hazard managers in their efforts to mitigate impacts.

Interaction between plasma homocysteine and the MTHFR c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans.

One-carbon metabolism provides a direct link among dietary folate/vitamin B12 exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR), and epigenetic regulation of the genome via DNA methylation. Previously, it has been shown that the common c.677C > T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with total homocysteine (tHcy) levels. To build on that and other more recent observations that have further highlighted associations among MTHFR c.677C > T, tHcy, and aberrations in DNA methylation, we investigated whether the interaction between mildly elevated plasma tHcy and the c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. We used data on plasma tHcy levels, c.677C > T polymorphism, and site-specific DNA methylation levels for a total of 915 white women and 335 men from the TwinsUK registry ( n = 610) and the Rotterdam study ( n = 670). We performed methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C > T genotypes on DNA methylation ß values. Our meta-analysis identified 13 probes significantly associated with rs1801133 × tHcy levels [false-discovery rate (FDR) < 0.05]. The most significant associations were with a cluster of probes at the AGTRAP-MTHFR-NPPA/B gene locus on chromosome 1 (FDR = 1.3E-04), with additional probes on chromosomes 2, 3, 4, 7, 12, 16, and 19. Our top 2 hits on chromosome 1 were functionally associated with variability in expression of the TNF receptor superfamily member 8 ( TNFRSF8) gene/locus on that chromosome. This is the first study, to our knowledge, to provide a direct link between perturbations in 1-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.-Nash, A. J., Mandaviya, P. R., Dib, M.-J., Uitterlinden, A. G., van Meurs, J., Heil, S. G., Andrew, T., Ahmadi, K. R. Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans.

The potential impact of future climate on the distribution of European yew (Taxus baccata L.) in the Hyrcanian Forest region (Iran).

The Hyrcanian Forest region is rich in relict species, and endemic and endangered species. Although there are concerns about climate change, its influence on tree species in the Hyrcanian forests in the north of Iran is still unidentified. Taxus baccata is among the few conifer species found in the region, and the present study aims to evaluate the potential impact of climate change on the distribution of T. baccata. For this purpose, we used ensemble species distribution modeling with ten algorithms and based on two geographic extents (global and regional) and climate data for different climate change scenarios. For the regional extent, we calibrated the models in Hyrcanian forests including the three provinces in the north of Iran. For the global extent, we calibrated the models on the whole range distribution of T. baccata. In both cases, we applied the models to predict the distribution of T. baccata in northern Iran under current, 2050, and 2070 climates. In regional extent modeling, precipitation of coldest quarter and in global extent modeling temperature seasonality emerged as the most important variables. Present environmental suitability estimates indicated that the suitable area for T. baccata in Hyrcanian forests is 5.89 × 103 km2 (regional modeling) to 9.74 × 103 km2 (global modeling). The modeling suggests that climate change under representative concentration pathways (RCP) 8.5 is likely to lead to strong suitability reductions in the region, with just between 0.63 × 103 km2 (regional modeling) and 0.57 × 103 km2 (global modeling) suitable area in 2070. Hence, T. baccata risks losing most currently suitable areas in the Hyrcanian forests under climate change. The results of the present study suggest there should be focus on conservation of areas predicted to remain suitable through near-future climate change and provide an estimate of the availability of suitable areas for the regeneration of T. baccata and its use in reforestation.

A critical evaluation of results from genome-wide association studies of micronutrient status and their utility in the practice of precision nutrition.

Rapid advances in 'omics' technologies have paved the way forward to an era where more 'precise' approaches - 'precision' nutrition - which leverage data on genetic variability alongside the traditional indices, have been put forth as the state-of-the-art solution to redress the effects of malnutrition across the life course. We purport that this inference is premature and that it is imperative to first review and critique the existing evidence from large-scale epidemiological findings. We set out to provide a critical evaluation of findings from genome-wide association studies (GWAS) in the roadmap to precision nutrition, focusing on GWAS of micronutrient disposition. We found that a large number of loci associated with biomarkers of micronutrient status have been identified. Mean estimates of heritability of micronutrient status ranged between 20 and 35 % for minerals, 56-59 % for water-soluble and 30-70 % for fat-soluble vitamins. With some exceptions, the majority of the identified genetic variants explained little of the overall variance in status for each micronutrient, ranging between 1·3 and 8 % (minerals), <0·1-12 % (water-soluble) and 1·7-2·3 % for (fat-soluble) vitamins. However, GWAS have provided some novel insight into mechanisms that underpin variability in micronutrient status. Our findings highlight obvious gaps that need to be addressed if the full scope of precision nutrition is ever to be realised, including research aimed at (i) dissecting the genetic basis of micronutrient deficiencies or 'response' to intake/supplementation (ii) identifying trans-ethnic and ethnic-specific effects (iii) identifying gene-nutrient interactions for the purpose of unravelling molecular 'behaviour' in a range of environmental contexts.

Vitamin D supplement use and associated demographic, dietary and lifestyle factors in 8024 South Asians aged 40-69 years: analysis of the UK Biobank cohort.

OBJECTIVE: Vitamin D deficiency (serum 25-hydroxyvitamin D<25nmol/L) is extremely common in western-dwelling South Asians but evidence regarding vitamin D supplement usage in this group is very limited. This work identifies demographic, dietary and lifestyle predictors associated with vitamin D supplement use. DESIGN: Cross-sectional analysis of baseline vitamin D supplement use data. SETTING: UK Biobank cohort. SUBJECTS: In total, n 8024 South Asians (Bangladeshi, Indian, Pakistani), aged 40-69 years. RESULTS: Twenty-three % of men and 39% of women (P<0.001) [22% of Bangladeshis, 32% of Indians, 25% of Pakistanis (P<0.001)] took a vitamin D containing supplement. Median vitamin D intakes from diet were low at 1.0-3.0 micrograms per day, being highest in Bangladeshis and lowest in Indians (P<0.001). Logistic regression modelling showed that females had a higher odds of vitamin D supplement use than males (odds ratio (OR) = 2.02; 95% confidence interval (CI) 1.79 to 2.28). A lower supplement usage was seen in younger persons (40-60 years) (OR=0.75; 95% CI 0.65 to 0.86 reference= >60 years), and those living outside of Greater London (OR=0.53 to 0.77), with borderline trends for a lower body mass index, higher oily fish intake and higher household income associated with increased odds of vitamin D supplement use. CONCLUSIONS: Vitamin D supplements were not used by most South Asians and intakes from diet alone are likely to be insufficient to maintain adequate vitamin D status. Public health strategies are now urgently required to promote the use of vitamin D supplements in these specific UK South Asian subgroups.

Effect of genetic variants associated with plasma homocysteine levels on stroke risk.

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection.

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)

A single-nucleotide polymorphism tagging set for human drug metabolism and transport.

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.

Potential distribution of Biscogniauxia mediterranea and Obolarina persica causal agents of oak charcoal disease in Iran's Zagros forests.

In Iran, native oak species are under threat from episodes of Charcoal Disease, a decline syndrome driven by abiotic stressors (e.g. drought, elevated temperature) and biotic components, Biscogniauxia mediterranea (De Not.) Kuntze and Obolarina persica (M. Mirabolfathy). The outbreak is still ongoing and the country's largest ever recorded. Still, the factors driving its' epidemiology in time and space are poorly known and such knowledge is urgently needed to develop strategies to counteract the adverse effects. In this study, we developed a generic framework based on experimental, machine-learning algorithms and spatial analyses for landscape-level prediction of oak charcoal disease outbreaks. Extensive field surveys were conducted during 2013-2015 in eight provinces (more than 50 unique counties) in the Zagros ecoregion. Pathogenic fungi were isolated and characterized through morphological and molecular approaches, and their pathogenicity was assessed under controlled water stress regimes in the greenhouse. Further, we evaluated a set of 29 bioclimatic, environmental, and host layers in modeling for disease incidence data using four well-known machine learning algorithms including the Generalized Linear Model, Gradient Boosting Model, Random Forest model (RF), and Multivariate Adaptive Regression Splines implemented in MaxEnt software. Model validation statistics [Area Under the Curve (AUC), True Skill Statistics (TSS)], and Kappa index were used to evaluate the accuracy of each model. Models with a TSS above 0.65 were used to prepare an ensemble model. The results showed that among the different climate variables, precipitation and temperature (Bio18, Bio7, Bio8, and bio9) in the case of O. persica and similarly, gsl (growing season length TREELIM, highlighting the warming climate and the endophytic/pathogenic nature of the fungus) and precipitation in case of B. mediterranea are the most important influencing variables in disease modeling, while near-surface wind speed (sfcwind) is the least important variant. The RF algorithm generates the most robust predictions (ROC of 0.95; TSS of 0.77 and 0.79 for MP and OP, respectively). Theoretical analysis shows that the ensemble model (ROC of 0.95 and 0.96; TSS = 0.79 and 0.81 for MP and OP, respectively), can efficiently be used in the prediction of the charcoal disease spatiotemporal distribution. The oak mortality varied ranging from 2 to 14%. Wood-boring beetles association with diseased trees was determined at 20%. Results showed that water deficiency is a crucial component of the oak decline phenomenon in Iran. The Northern Zagros forests (Ilam, Lorestan, and Kermanshah provinces) along with the southern Zagros forests (Fars and Kohgilouyeh va-Boyer Ahmad provinces) among others are the most endangered areas of potential future pandemics of charcoal disease. Our findings will significantly improve our understanding of the current situation of the disease to pave the way against pathogenic agents in Iran.

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency.

BACKGROUND: An increasing number of adult individuals are at risk of vitamin B12 deficiency, either from reduced nutritional intake or impaired gastrointestinal B12 absorption. OBJECTIVE: This study aims to review the current best practices for the diagnosis and treatment of individuals with vitamin B12 deficiency. METHODS: A narrative literature review of the diagnosis and treatment of vitamin B12 deficiency. RESULTS: Prevention and early treatment of B12 deficiency is essential to avoid irreversible neurological consequences. Diagnosis is often difficult due to diverse symptoms, marked differences in diagnostic assays' performance and the unreliability of second-line biomarkers, including holo-transcobalamin, methylmalonic acid and total homocysteine. Reduced dietary intake of B12 requires oral supplementation. In B12 malabsorption, oral supplementation is likely insufficient, and parenteral (i.e. intramuscular) supplementation is preferred. There is no consensus on the optimal long-term management of B12 deficiency with intramuscular therapy. According to the British National Formulary guidelines, many individuals with B12 deficiency due to malabsorption can be managed with 1000 µg intramuscular hydroxocobalamin once every two months after the initial loading. Long-term B12 supplementation is effective and safe, but responses to treatment may vary considerably. Clinical and patient experience strongly suggests that up to 50% of individuals require individualized injection regimens with more frequent administration, ranging from daily or twice weekly to every 2-4 weeks, to remain symptom-free and maintain a normal quality of life. 'Titration' of injection frequency based on measuring biomarkers such as serum B12 or MMA should not be practiced. There is currently no evidence to support that oral/sublingual supplementation can safely and effectively replace injections. CONCLUSIONS: This study highlights the interindividual differences in symptomatology and treatment of people with B12 deficiency. Treatment follows an individualized approach, based on the cause of the deficiency, and tailored to help someone to become and remain symptom-free.

Plain language titleDiagnosis and Treatment of Vitamin B12 DeficiencyPlain language summaryThe number of people who are at risk of developing a deficiency of vitamin B12 is steadily increasing. B12 deficiency can develop when people consume too few B12-containing foods of animal origin, or when they develop a form of B12 malabsorption. B12 deficiency can lead to serious complications so prevention and early treatment are essential. Diagnosing B12 deficiency can be challenging: the symptoms vary from patient to patient, and the methods used to measure B12 in the blood, or certain biomarkers associated with B12 metabolism, such as holo-transcobalamin, methylmalonic acid, and total homocysteine are unreliable. When people do not consume enough B12-containing foods, supplementation with B12 tablets is needed. In the case of B12 malabsorption, intramuscular injections of B12 are mandatory. The usual treatment with B12 is starting with injections of 1000 µg hydroxocobalamin twice weekly or on every other day for a period of up to 5 weeks or longer, until all symptoms have disappeared, and thereafter, the frequency of injections is gradually reduced. There is, however, a large group of people who require more frequent administration to become and remain symptom-free: this may range from daily or twice weekly to every 2 to 4 weeks.

Unravelling the basis of variability in cobalamin levels in the general population.

Cobalamin (Cbl) is an essential B vitamin involved in the normal functioning of the nervous system, the formation of key components of blood, DNA synthesis and methylation, and energy production. Physiological levels of Cbl vary greatly within populations, although the basis for this variability remains largely unknown. We conducted a twin study to characterise the basis of variation in plasma Cbl levels and to test whether common genetic polymorphisms in genes known to cause defects in inborn errors of Cbl metabolism and transport are also associated with mean plasma Cbl levels in the general population. The present results showed that plasma levels of Cbl were heritable, with genetic and phenotypic variance increasing with age, and levels significantly correlated with age, BMI, exercise, alcohol consumption, smoking status, social class and folate levels, which collectively accounted for up to 15 % of Cbl variation. Of eight genes responsible for the defects of the Cbl metabolic pathway (cblA-G and mut), MMAA, MMACHC, MTRR and MUT harboured polymorphisms that showed evidence of association with Cbl levels. Characterisation of the heritable component of variation in Cbl levels can facilitate the early diagnosis and prognosis of Cbl insufficiency/deficiency in individuals at a higher risk of associated diseases.

Genome-wide association study reveals a complex genetic architecture underpinning-induced CYP3A4 enzyme activity.

Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity-induced and inhibited-is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John's Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3-hydroxyquinine to quinine. We failed to detect any genome-wide significant associations (P < 1 × 10(-8)) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity.

Human metabolic profiles are stably controlled by genetic and environmental variation.

¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR-based biomarkers quantifying predisposition to disease.