Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Multiple Dietary Vitamin K Forms Are Converted to Tissue Menaquinone-4 in Mice.

BACKGROUND: Vitamin K is a term that comprises a family of structurally related quinones, phylloquinone (PK) and the menaquinones (MKn), that share a common naphthoquinone ring but vary in sidechain length (n) and saturation. Dietary PK is a biosynthetic precursor to tissue menaquinone-4 (MK4), but little is known about the absorption and metabolism of dietary MKn. OBJECTIVE: To characterize the absorption and metabolism of dietary MKn relative to PK. METHODS: In the 4-week diet study, 10-week-old male and female C57BL/6 mice were pair-fed a vitamin K deficient diet (control) or a diet supplemented with 5.0 µmol/kg total PK, MK4, and/or MK9 (separately and in combination). In the 1-week stable isotope study, 12-week-old mice were pair-fed diets containing 2.2 µmol/kg PK (unlabeled control), 2H7PK, 13C11MK4, 2H7MK7, or 2H7MK9. Vitamin K tissue content was quantified by HPLC and/or LC-MS, and concentrations were compared by sex and diet group using 2-factor ANOVA. RESULTS: Regardless of the form(s) of vitamin K provided in the diet, tissue MK4 concentrations did not differ across equimolar supplemented groups in the kidney, adipose, reproductive organ, bone, or pancreas in either males or females in the diet study (all P values > 0.05). Isotopic labeling confirmed the naphthoquinone ring of MK4 in tissues originated from the administered dietary PK or MKn. Despite equimolar supplementation, accumulation of the administered dietary form differed across diet groups in small intestinal segments (all P values < 0.002) and the liver (P < 0.001). Female mice had greater total vitamin K than males in every tissue examined (P < 0.05). CONCLUSIONS: Dietary PK, MK4, MK7, and MK9 all served as precursors to tissue MK4 in mice. This study expands our understanding of vitamin K metabolism and supports a common conversion mechanism of all dietary vitamin K forms to MK4. Further investigation of the metabolism and physiological roles of MK4 that may be independent of classical vitamin K function is warranted.

The Interval Between Matches Significantly Influences Injury Risk in Field Hockey.

Fixture congestion increases injury risk in football, but how it impacts other sports is unclear. The aim of this study was to identify associations between match density and injury incidence in field hockey players. Injury data from a prospective cohort study of professional and youth players was analysed in two ways. Inter-match intervals were clustered into<2424-hours, 3-7-days, and 13 + days, and injury rate ratios (IRR) were calculated to identify differences between clusters in match injuries. Separately, a Lasso-penalised Poisson regression model was used to determine the association between match load across the previous 24-hours, 3-days, 7-days and 14-days, and match and training injuries. Injury rates in matches within 24-hours of the previous match were mostly significantly higher when compared to matches after 3-7-days (IRRs: 3.78; 6.77, P = 0.003; 0.005). While a higher match exposure in the preceding 24-hour and 3-day periods was associated with higher combined match and training injury rates (ß̂ = 0.0001; 0.0018), a higher match exposure in the previous 7-and 14-day periods was associated with a reduced injury rate (ß̂ = -0.0001; -0.0005). Due to the increased injury risk in matches 3-days and especially 24-hours following the previous fixture, match distribution should be cautiously planned.

Tracking sleep in the field: sleep quality and sleep behaviours of elite track and field athletes during preparation and competition.

Elite athletes are susceptible to inadequate sleep, which may peak during competition and be exacerbated by poor sleep behaviours. This study sought to characterise and compare the sleep quality and sleep behaviours of elite track and field athletes during preparation and major competitions. Forty elite international track and field athletes (50% female, aged 25.1 ± 3.9 years) completed the Athlete Sleep Screening Questionnaire and the Athlete Sleep Behaviour Questionnaire on three separate occasions: during habitual training, during a pre-meet training camp and during a major international competition. Overall, 62.5% of athletes reported at least mild sleep difficulty during competition. Athletes reported higher sleep difficulty and poorer sleep behaviour during major competitions and the pre-meet training camp compared to habitual training (P = .001-.025). No significant differences were observed between the training camp and major competition. Global sleep behaviour scores were underpinned by unique characteristics at each timepoint. Sleep behaviour (R2 = .330, P = .017), injury status (R2 = .253, P = .003) and major championship experience (R2 = .113, P = .034) were associated with sleep difficulty during competition. Sleep quality and behaviours vary according to stage of the track and field season, providing a foundation for targeted intervention.

Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice.

BACKGROUND: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. OBJECTIVES: We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. METHODS: Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. RESULTS: HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. CONCLUSIONS: In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.

Tracking the corticospinal responses to strength training.

PURPOSE: The motor cortex (M1) appears to be a primary site of adaptation following both a single session, and repeated strength-training sessions across multiple weeks. Given that a single session of strength-training is sufficient to induce modification at the level of the M1 and corticospinal tract, this study sought to determine how these acute changes in M1 and corticospinal tract might accumulate across the course of a 2-week heavy-load strength-training program. METHODS: Transcranial magnetic stimulation (TMS) was used to infer corticospinal excitability (CSE), intracortical facilitation (ICF), short and long-interval intracortical inhibition (SICI and LICI) and silent period duration prior to and following each training session during a 2-week heavy-load strength-training period. RESULTS: Following 2-weeks of strength-training, increases in strength (15.5%, P = 0.01) were accompanied by an increase in CSE (44%, P = 0.006) and reductions in both silent period duration (14%, P < 0.0001) and SICI (35%, P = 0.0004). Early training sessions acutely increased CSE and ICF, and acutely reduced silent period duration and SICI. However, later training sessions failed to modulate SICI and ICF, with substantial adaptations occurring offline between training sessions. No acute or retained changes in LICI were observed. Co-contraction of antagonists reduced by 36% following 2-weeks of strength-training. CONCLUSIONS: Collectively, these results indicate that corticospinal plasticity occurs within and between training sessions throughout a training period in distinct early and later stages that are modulated by separate mechanisms of plasticity. The development of strength is akin to the previously reported changes that occur following motor skill training.

Modulation of intracortical inhibition and excitation in agonist and antagonist muscles following acute strength training.

PURPOSE: Transcranial magnetic stimulation (TMS) usually investigates the corticospinal responses of the agonist muscle to strength training, despite the role of the antagonist muscle in strength development. We examined the intracortical responses from an agonist and antagonist muscle following a single session of heavy-loaded strength training (dominant-arm only) to identify the early antagonistic responses to a single session that may accompany improvements in strength. METHODS: Corticospinal and motor cortical excitability and inhibition was collected from agonist and antagonist muscles prior to and following a single session of heavy-loaded wrist flexor training in 18 individuals. Training consisted of four sets 6-8 repetitions at 80% of 1-repetition maximum (1-RM). Recruitment curves for corticospinal excitability and inhibition of the right wrist flexor and wrist extensor muscles were constructed and assessed by examining the area under the recruitment curve. Intracortical measures were obtained using paired-pulse TMS. RESULTS: Following a single training session, increases in corticospinal excitability were observed in both the agonist and antagonist muscles. This was accompanied by decreases in corticospinal inhibition in both muscles. Intracortical inhibition was reduced and intracortical facilitation was increased for the agonist muscle only. Intracortical measures in the antagonist muscle remained unchanged after training. CONCLUSIONS: These findings indicate that the corticospinal responses to a single session of strength training are similar between agonist and antagonist muscles, but the intrinsic cortico-cortical circuitry of the antagonist remains unchanged. The corticospinal responses are likely due to increased involvement/co-activation of the antagonist muscle during training as the agonist muscle fatigues.

Determining the Corticospinal Responses to Single Bouts of Skill and Strength Training.

Mason, J, Frazer, AK, Jaberzadeh, S, Ahtiainen, JP, Avela, J, Rantalainen, T, Leung, M, and Kidgell, DJ. Determining the corticospinal responses to single bouts of skill and strength training. J Strength Cond Res 33(9): 2299-2307, 2019-Neuroplastic changes in the primary motor cortex accompany performance improvements following motor practice. Recent evidence suggests that the corticospinal responses to strength and skill training are similar, following both a single session and repeated bouts of training, promoting discussion that strength training is a form of motor learning. However, these findings are limited by the lack of a light-load strength training group. Therefore, the aim of the current study was to determine whether a single session of heavy-load strength training, light-load strength training or skill training differentially modulates the corticospinal pathway. Transcranial magnetic stimulation was used to assess the excitatory and inhibitory circuitry of the motor cortex following a single session of skill training, and following a single session of light-load and heavy-load strength training. Following a single session of training, participants in all groups experienced comparable increases in corticospinal excitability (ranging from 38 to 46%, all p < 0.05); however, disparity was observed in the inhibitory responses. Corticospinal inhibition was reduced in all 3 single-sessions, although to a greater magnitude in the heavy-load and skill-training sessions (22 and 18% respectively, compared with 11% following light-load training, all p < 0.05). Short-interval intracortical inhibition was reduced immediately following single sessions of heavy-load strength training (40% p < 0.05) and skill training (47% p < 0.05), but remained unchanged the following light-load strength training session. It appears that the corticospinal responses to single sessions of different types of strength and skill training are task-dependent. These findings reinforce the notion that strength training, at least when heavily-loaded, can be considered a form of motor learning, potentially because of the sensory feedback involved.

Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice.

Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1ß concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week-old male A/J mice were fed a low-fat (LF) diet, high-fat (HF) diet or HF+ whole freeze-dried Pd (HF + Pd, 0.04% wt/wt) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane. PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF + Pd mice (0 of 20) (p = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action.

Adaptations in corticospinal excitability and inhibition are not spatially confined to the agonist muscle following strength training.

PURPOSE: We used transcranial magnetic stimulation (TMS) to determine the corticospinal responses from an agonist and synergist muscle following strength training of the right elbow flexors. METHODS: Motor-evoked potentials were recorded from the biceps brachii and flexor carpi radialis during a submaximal contraction from 20 individuals (10 women, 10 men, aged 18-35 years; training group; n = 10 and control group; n = 10) before and after 3 weeks of strength training at 80% of 1-repetition maximum (1-RM). To characterise the input-output properties of the corticospinal tract, stimulus-response curves for corticospinal excitability and inhibition of the right biceps brachii and flexor carpi radialis were constructed and assessed by examining the area under the recruitment curve (AURC). RESULTS: Strength training resulted in a 29% (P < 0.001) increase in 1-RM biceps brachii strength and this was accompanied by a 19% increase in isometric strength of the wrist flexors (P = 0.001). TMS revealed an increase in corticospinal excitability AURC and a decrease in silent period duration AURC for the biceps brachii and flexor carpi radialis following strength training (all P < 0.05). However, the changes in corticospinal function were not associated with increased muscle strength. CONCLUSION: These findings show that the corticospinal responses to strength training of a proximal upper limb muscle are not spatially restricted, but rather, results in a change in connectivity, among an agonist and a synergistic muscle relevant to force production.

Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from heathy women.

Single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and BMI, was used to identify differentially-methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR, and TYMS (P <5.0 x 10-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r=-0.25, P=0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR, and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome-wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as cis-methylation quantitative trait loci.

Interactions between the colonic transcriptome, metabolome, and microbiome in mouse models of obesity-induced intestinal cancer.

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat (HF) consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and metabolome, and each has the potential to induce protumorigenic changes in the epithelial transcriptome. The physiological consequences and the degree to which these different biologic systems interact remain poorly defined. To understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of HF-fed and genetically obese (DbDb) mice with a genetic predisposition to intestinal tumorigenesis (Apc(1638N)); 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice, respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Regression analyses of coexpressed genes with the abundance of bacterial taxa identified three taxa, previously correlated with tumor burden, to be significantly correlated with a gene module enriched for Akt-related genes. Similarly, regression of coexpressed genes with metabolites found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that HF consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.

Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues.

p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.

Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations.

BACKGROUND: Folates are essential cofactors in metabolic pathways that facilitate biological methylation and nucleotide synthesis, and therefore have widespread effects on health and diseases. Although obesity is prevalent worldwide, few studies have investigated how obesity interacts with folate status. OBJECTIVE: Based on data from the NHANES, this study aims to examine the association between body mass index (BMI) and obesity-related metabolic factors with blood folate status. METHODS: A nationally representative sample of 3767 adults from the NHANES (2003-2006) was used as the study population. Regression analyses, with and without adjustment for demographic factors and dietary intakes, were performed to examine associations between BMI and metabolic factors with serum and RBC folate. RESULTS: The results indicate serum folate concentrations were lower in obese groups compared to the desirable BMI and overweight categories, paralleling lower intakes in this group. In contrast, RBC folate increased incrementally with BMI. Regression analyses demonstrated an inverse relation between BMI and serum folate but a positive relation for RBC folate (P < 0.01). Waist circumference, serum triglycerides, and fasting plasma glucose each displayed significant positive relations with RBC folate (P < 0.01), although relations with serum folate were not significant and consistent. CONCLUSIONS: In summary, obesity is associated with decreased serum folate, which parallels decreased folate intakes. In contrast, obesity is positively associated with RBC folate. Therefore, RBC folate, in addition to serum folate, should also be considered as a critical biomarker for folate status, especially in the obese population. Future research is needed to understand how obesity differentially alters serum and RBC folate status because they are associated with a variety of medical complications.

Can the recent sex-specific evolutions in elite running performances be attributed to advanced footwear technology?

Recent improvements in elite running performances across all distances have been largely attributed to the introduction of advanced footwear technology (AFT), which features a curved and stiff plate working synergistically with a new generation of midsole foams demonstrating enhanced resilience and compliance. These recent improvements appear to be considerably more pronounced in women's events, highlighted by improvements in road racing world records by an average of 3.7% (range: 2.6%-5.2%) compared to mean progressions of 1.5% (range: 1.3%-1.9%) in the same men's events. Although there is a growing body of research investigating the mechanisms underpinning running performance enhancements derived from AFT, there remains no explanation for potential sex-based differences in their benefits. We overview the currently available evidence and highlight why the recent direction of AFT research provides a barrier to progress by focusing primarily on male athletes. We subsequently provide our perspective on why women may be benefiting from the new generation of shoes more than men, suggest potential mechanisms leading to hypotheses that need to be further investigated in upcoming studies, and finally propose that factors outside of footwear innovation may have concurrently driven the recently observed performance evolutions.

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

BACKGROUND: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. OBJECTIVES: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. RESULTS: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. CONCLUSION: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Plain language titleExcess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?Plain language summaryIt has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12.

Baseline Characteristics of Adult Patients Treated and Never Treated with Teduglutide in a Multinational Short Bowel Syndrome and Intestinal Failure Registry.

The Short Bowel Syndrome (SBS) Registry (NCT01990040) is a multinational real-world study evaluating the long-term safety of teduglutide in patients with SBS and intestinal failure (SBS-IF) in routine clinical practice. This paper describes the study methodology and baseline characteristics of adult patients who have (ever-treated) or have never (never-treated) received teduglutide. A total of 1411 adult patients (679 ever-treated; 732 never-treated) were enrolled at 124 sites across 17 countries. The mean (standard deviation [SD]) age at enrollment was 55.4 (15.46) years, and 60.2% of patients were women. Crohn's disease was the most common cause of major intestinal resection in both ever-treated (34.1%) and never-treated patients (20.4%). A similar proportion of ever-treated and never-treated patients had a prior history of colorectal polyps (2.7% vs. 3.6%), whereas proportionally fewer ever-treated patients reported a history of colorectal cancer (1.8% vs. 6.2%) or any malignancy (17.7% vs. 30.0%) than never-treated patients. Never-treated patients received a numerically greater mean (SD) volume of parenteral nutrition and/or intravenous fluids than ever-treated patients (12.4 [8.02] vs. 10.1 [6.64] L/week). Ever-treated patients received a mean teduglutide dosage of 0.05 mg/kg/day. This is the first report of patient baseline characteristics from the SBS Registry, and the largest cohort of patients with SBS-IF to date. Overall, ever-treated and never-treated patients had similar baseline characteristics. Differences between treatment groups may reflect variations in patient selection and degree of monitoring.

Corrigendum: Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

[This corrects the article DOI: 10.3389/fnut.2023.1230061.].

Which trunk muscle parameter is the best predictor for physical function in older adults?

Background: Despite preliminary evidence demonstrating the relevance of trunk muscle strength for physical function in older adults, it is not clear which muscle-related trunk parameter is the best predictor for physical functions. Therefore, this study aimed to compare trunk muscle morphology or strength parameters regarding their predictive ability for physical functions. Methods: Seventy-four older adults (38 men, 36 women, mean age 76.85 years) were tested for maximum absolute and relative isokinetic trunk flexion and extension strength, trunk lean mass, and trunk muscle quality. Functional assessment included normal and fast walking speed, repeated sit-to-stand transfer, timed up and go, and postural sway during a closed-feet and a semi-tandem stance adjusted for body height. Pearson's correlations were used to compare relationship between trunk strength adjusted and unadjusted for body weight to physical functions. Linear regression analysis including sex and age as co-variables was performed between trunk muscle and functional test parameters. Results: Relative back extension strength was the most consistent significant predictor for all physical function tests (p = 0.004-0.04) except for postural sway. Relative trunk flexion strength was related to normal walking speed (p = 0.024). Trunk lean mass was related to timed up and go performance (p = 0.024). Conclusion: Relative back extension strength is associated with better performance in nearly all standard tests for physical function in older adults, while trunk flexion strength and lean mass seem to play a minor role. Our findings emphasize the importance of trunk muscle strength, especially the back extensor muscles, for physical function in older adults.

Asymmetries of foot strike patterns during running in high-level female and male soccer players.

BACKROUND: Foot strike pattern (FSP) is defined by the way the foot makes initial ground contact and is influenced by intrinsic and extrinsic factors. This study investigated the effect of running speed on asymmetries of FSP. METHODS: Seventeen female and nineteen male soccer players performed an incremental running test on an instrumented treadmill starting at 2.0 m/s until complete exhaustion. Force plate data were used to categorize foot strikes into rearfoot (RFS) and non-rearfoot strikes. Additionally, peak vertical ground reaction force (peakGRF) and stride time were calculated. The symmetry index (SI) was used to quantify lateral asymmetries between legs. RESULTS: The SI indicated asymmetries of the rate of RFS (%RFS) of approximately 30% at slow running speed which decreased to 4.4% during faster running speed (p = 0.001). There were minor asymmetries in peakGRF and stride time at each running stage. Running speed influenced %RFS (p < 0.001), peakGRF (p < 0.001) and stride time (p < 0.001). Significant interaction effects between running speed and sex were shown for %RFS (p = 0.033), peakGRF (p < 0.001) and stride time (p = 0.041). CONCLUSION: FSP of soccer players are asymmetric at slower running speed, but symmetry increases with increasing speed. Future studies should consider that FSP are non-stationary and influenced by running speed but also differ between legs.