Causes of Childhood Cancer: A Review of the Recent Literature: Part I-Childhood Factors.

PURPOSE: To review the childhood risk factors for pediatric cancer (diagnosis before age 20). METHODS: We conducted literature searches using Ovid Medline and Scopus to find primary research studies, review articles, and meta-analyses published from 2014 to 3 March 2021. RESULTS: Strong evidence indicates that an array of genetic and epigenetic phenomena, structural birth defects, and chromosomal anomalies are associated with an increased risk of various childhood cancers. Increased risk is also associated with prior cancer, likely due to previous treatment agents and therapeutic ionizing radiation. Convincing evidence supports associations between several pediatric cancers and ionizing radiation, immunosuppression, and carcinogenic virus infection both in healthy children and in association with immune suppression following organ transplantation. Breastfeeding and a childhood diet rich in fruits and vegetables appears to reduce the risk of pediatric leukemia but the evidence is less strong. Childhood vaccination against carcinogenic viruses is associated with a lower risk of several cancers; there is less strong evidence that other childhood vaccinations more broadly may also lower risk. Ultraviolet (UV) radiation is associated with increased melanoma risk, although most melanomas following childhood UV exposure occur later, in adulthood. Evidence is weak or conflicting for the role of body mass index, other childhood infections, allergies, and certain treatments, including immunomodulator medications and human growth therapy.

Analysis of Variation in Organizational Definitions of Primary Care Panels: A Systematic Review.

Importance: Primary care panel size plays an increasing role in measuring primary care provider (ie, physicians and advanced practice providers, which include nurse practitioners and physician assistants) workload, setting practice capacity, and determining pay and can influence quality of care, access, and burnout. However, reported panel sizes vary widely. Objective: To identify how panels are defined, the degree of variation in these definitions, the consequences of different definitions of panel size, and research on strengths of different approaches. Evidence Review: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, MEDLINE, Web of Science, Embase, and Dissertations and Theses Global databases were searched from inception to April 28, 2021, for subject headings and text words to capture concepts of primary care panel size. Article review and data abstraction were performed independently by 2 reviewers. Main outcomes reported included rules for adding or removing patients from panels, rules for measuring primary care provider resources, consequences of different rules on reported panel size, and research on advantages and disadvantages of different rules. Findings: The literature search yielded 1687 articles, with 294 potentially relevant articles and 74 containing relevant data. Specific practices were identified from 29 health care systems and 5 empanelment implementation guides. Patients were most commonly empaneled after 1 primary care visit (24 of 34 [70.6%]), but some were empaneled only after several visits (5 [14.8%]), enrollment in a health plan (4 [11.8%]) or any visit to the health care system (1 [3.0%]). Patients were removed when no visit had occurred in a specified look-back period, which varied from 12 to 42 months. Regarding primary care provider resources, half of organizations assigned advanced practice providers independent panels and half had them share panels with a physician, increasing the physician's panel by 50% to 100%. Analyses demonstrated that changes in individual rules for adding patients, removing patients, or estimating primary care provider resources could increase reported panel size from 20% to 100%, without change in actual primary care provider workload. No research was found investigating advantages of different definitions. Conclusions and Relevance: Much variation exists in how panels are defined, and this variation can have substantial consequences on reported panel size. Research is needed on how to define primary care panels to best identify active patients, which could contribute to a widely accepted standard approach to panel definition.

A systematic review of decision aids for gender affirming therapy.

BACKGROUND: Transgender and gender diverse (TGD) persons considering gender affirming therapy have to make many complex medical decisions, potentially without understanding the associated harms or benefits of hormonal and surgical interventions. Further, clinicians are often unaware of how best to communicate information to persons seeking gender affirming therapy. Patient decision aids have been developed to provide evidence-based information as a way to help people make decisions in collaboration with their clinicians. It is unclear whether such tools exist for persons seeking gender affirming therapy. The objective of our systematic review is to search for and determine the quality of any existing patient decision aids developed for TGD persons considering gender affirming therapy, and the outcomes associated with their use. METHODS: We adapted a search strategy for databases using two key concepts "decision support intervention/patient decision aid" and "transgender". We also conducted a brief online search of Google and abstracts from relevant conferences to identify any tools not published in the academic literature. Following study selection and data extraction, we used the International Patient Decision Aid Standards instrument (IPDASi) to assess the quality of patient decision aids, and the Standards for UNiversal reporting of patient Decision Aid Evaluations (SUNDAE) checklist to assess the quality of evaluations. RESULTS: We identified 762 studies; none were identified from Google or conference content. One tool met our inclusion criteria: an online, pre-encounter patient decision aid for transmasculine genital gender-affirming surgery developed in Amsterdam, translated in English and Dutch. The tool met all the IPDASi qualifying criteria, and scored a 17/28 on the certification criteria, and 57/112 on the quality criteria. The efficacy of the patient decision aid has not been evaluated. CONCLUSIONS: Despite multiple decisions required for gender affirming therapies, only one patient decision aid has been developed for transmasculine genital reconstruction. Further research is required to develop patient decision aids for the multiple decision points along the gender affirming journey.

A Systematic Review of Dietary Supplements and Alternative Therapies for Weight Loss.

OBJECTIVE: Dietary supplements and alternative therapies are commercialized as a panacea for obesity/weight gain as a result of the minimal regulatory requirements in demonstrating efficacy. These products may indirectly undermine the value of guideline-driven obesity treatments. Included in this study is a systematic review of the literature of purported dietary supplements and alternative therapies for weight loss. METHODS: A systematic review was conducted to evaluate the efficacy of dietary supplements and alternative therapies for weight loss in participants aged ≥18 years. Searches of Medline (PubMed), Cochrane Library, Web of Science, CINAHL, and Embase (Ovid) were conducted. Risk of bias and results were summarized qualitatively. RESULTS: Of the 20,504 citations retrieved in the database search, 1,743 full-text articles were reviewed, 315 of which were randomized controlled trials evaluating the efficacy of 14 purported dietary supplements, therapies, or a combination thereof. Risk of bias and sufficiency of data varied widely. Few studies (n = 52 [16.5%]) were classified as low risk and sufficient to support efficacy. Of these, only 16 (31%) noted significant pre/post intergroup differences in weight (range: 0.3-4.93 kg). CONCLUSIONS: Dietary supplements and alternative therapies for weight loss have a limited high-quality evidence base of efficacy. Practitioners and patients should be aware of the scientific evidence of claims before recommending use.

Community health worker interventions for older adults with complex health needs: A systematic review.

BACKGROUND/OBJECTIVES: The number of older adults with complex health needs is growing, and this population experiences disproportionate morbidity and mortality. Interventions led by community health workers (CHWs) can improve clinical outcomes in the general adult population with multimorbidity, but few studies have investigated CHW-delivered interventions in older adults. DESIGN: We systematically reviewed the impact of CHW interventions on health outcomes among older adults with complex health needs. We searched for English-language articles from database inception through April 2020 using seven databases. PROSPERO protocol registration CRD42019118761. SETTING: Any U.S. or international setting, including clinical and community-based settings. PARTICIPANTS: Adults aged 60 years or older with complex health needs, defined in this review as multimorbidity, frailty, disability, or high-utilization. INTERVENTIONS: Interventions led by a CHW or similar role consistent with the American Public Health Association's definition of CHWs. MEASUREMENTS: Pre-defined health outcomes (chronic disease measures, general health measures, treatment adherence, quality of life, or functional measures) as well as qualitative findings. RESULTS: Of 5671 unique records, nine studies met eligibility criteria, including four randomized controlled trials, three quasi-experimental studies, and two qualitative studies. Target population and intervention characteristics were variable, and studies were generally of low-to-moderate methodological quality. Outcomes included mood, functional status and disability, social support, well-being and quality of life, medication knowledge, and certain health conditions (e.g., falls, cognition). Results were mixed with several studies demonstrating significant effects on mood and function, including one high-quality RCT, while others noted no significant intervention effects on outcomes. CONCLUSION: CHW-led interventions may have benefit for older adults with complex health needs, but additional high-quality studies are needed to definitively determine the effectiveness of CHW interventions in this population. Integration of CHWs into geriatric clinical settings may be a strategy to deliver evidence-based interventions and improve clinical outcomes in complex older adults.

Does the use of patient decision aids lead to cost savings? a systematic review.

OBJECTIVES: To update a previous systematic review to determine if patient decision aid (PDA) interventions generate savings in healthcare settings, and if so, from which perspective (ie, patient, organisation providing care, society). DESIGN: Systematic review. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, Web of Science, Cochrane Library, Embase, Campbell Collaboration Library, EconLit, Business Source Complete, Centre for Reviews and Dissemination: NHS Economic Evaluations Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) from 15 March 2013 to 25 January 2019. The references of studies that met the eligibility criteria and any publications related to conference abstracts or registered clinical trials were reviewed to increase the sensitivity of the search. ELIGIBILITY CRITERIA: Full and partial economic evaluations with an experimental, quasi-experimental or randomised controlled design were included. The intervention had to satisfy the pre-determined minimum conditions necessary to be defined as a PDA, and (for full evaluations) provide details on the comparator used. DATA EXTRACTION AND SYNTHESIS: All study outcomes and economic data were extracted. The reporting and quality of the economic analyses were independently assessed by two health economists. RESULTS: Of 5066 studies, 22 studies were included, including the 8 studies from the previous review. Twelve studies reported cost-savings (range=US$10 to US$81 156; US dollars in 2020), primarily from the organisational or health system perspective, and 10 studies did not. However, due to the quality of the economic analyses, and the related issues with the interpretative validity of results it would be inappropriate to say that PDAs will generate savings, from any perspective. CONCLUSIONS: It is unclear whether PDAs will generate savings. Greater consensus on what constitutes a PDA and the need to compare them against usual care over a sufficient time horizon to allow valid assessment of costs and outcomes is required. PROSPERO REGISTRATION NUMBER: CRD42019118457.

Effectiveness of Ambulatory Telemedicine Care in Older Adults: A Systematic Review.

BACKGROUND: Disparities in healthcare access and delivery, caused by transportation and health workforce difficulties, negatively impact individuals living in rural areas. These challenges are especially prominent in older adults. DESIGN: We systematically evaluated the feasibility, acceptability, and effectiveness in providing telemedicine (TMed), searching the English-language literature for studies (January 2012 to July 2018) in the following databases: Medline (PubMed); Cochrane Library (Wiley); Web of Science; CINAHL; EMBASE (Ovid); and PsycINFO (EBSCO). PARTICIPANTS: Older adults (mean age = 65 years or older, and none were younger than 60 years). INTERVENTIONS: Interventions consisted of live, synchronous, two-way videoconferencing communication in nonhospital settings. All medical interventions were included. MEASUREMENTS: Quality assessment, using the Cochrane Collaboration's Risk-of-Bias Tool, was applied on all included articles, including a qualitative summary of all articles. RESULTS: Of 6616 citations, we reviewed the full text of 1173 articles, excluding 1047 that did not meet criteria. Of the 17 randomized controlled trials, the United States was the country with the most trials (6 [35%]), with cohort sizes ranging from 3 to 844 (median = 35) participants. Risk of bias among included studies varied from low to high. Our qualitative analysis suggests that TMed can improve health outcomes in older adults and that it could be used in this population. CONCLUSIONS: TMed is feasible and acceptable in delivering care to older adults. Research should focus on well-designed randomized trials to overcome the high degree of bias observed in our synthesis. Clinicians should consider using TMed in routine practice to overcome barriers of distance and access to care. J Am Geriatr Soc 67:1737-1749, 2019.

Bring on the Machines: Could Machine Learning Improve the Quality of Patient Education Materials? A Systematic Search and Rapid Review.

PURPOSE: Clear and trustworthy information is essential for people who are ill. People with cancer, in particular, are targeted with vast quantities of patient education material, but of variable quality. Machine learning technologies are popular across industries for automated tasks, like analyzing language and spotting readability issues. With the experience of patients with cancer in mind, we reviewed whether anyone has proposed, modeled, or applied machine learning technologies for the assessment of patient education materials and explored the utility of this application. METHODS: We systematically searched the literature to identify English-language articles published in peer-reviewed journals or as conference abstracts that proposed, used, or modeled the use of machine learning technology to assess patient education materials. Specifically, we searched MEDLINE, Web of Science, CINAHL, and Compendex. Two reviewers assessed study eligibility and performed study screening. RESULTS: We identified 1,570 publications in our search after duplicate removal. After screening, we included five projects (detailed in nine articles) that proposed, modeled, or used machine learning technology to assess the quality of patient education materials. We evaluated the utility of each application across four domains: multidimensionality (2 of 5 applications), patient centeredness (1 of 5 applications), customizability (0 of 5 applications), and development stage (theoretical, 1 of 5 applications; in development, 3 of 5 applications; complete and available, 1 of 5 applications). Combining points across each domain, the mean utlity score across included projects was 1.8 of 5 possible points. CONCLUSION: Given its potential, machine learning has not yet been leveraged substantially in the assessment of patient education materials. We propose machine learning systems that can dynamically identify problematic language and content by assessing the quality of patient education materials across a range of flexible, customizable criteria. Assessment may help patients and families decide which materials to use and encourage developers to improve materials overall.

Weight Loss Interventions in Older Adults with Obesity: A Systematic Review of Randomized Controlled Trials Since 2005.

OBJECTIVES: To identify geriatric obesity interventions that can guide clinical recommendations. DESIGN: Systematic review using Medline (PubMed), Cochrane Central Register of Controlled Trials, Web of Science, CINAHL, EMBASE (Ovid), and PsycINFO (Proquest) from January 1, 2005, to October 12, 2015, to identify English-language randomized controlled trials. PARTICIPANTS: Individuals aged 60 and older (mean age ≥65) and classified as having obesity (body mass index ≥30 kg/m2 ). INTERVENTIONS: Behavioral weight loss interventions not involving pharmacological or procedural therapies lasting 6 months or longer. MEASUREMENTS: Two investigators performed the systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria and achieved a high concordance rate (97.3%) in summarizing the primary outcomes. The three primary outcomes were weight loss, physical performance, and quality of life. RESULTS: Of 5,741 citations, 19 were included. (Six studies were unique, and the remaining 13 were based on the same study population.) Duration ranged from 6 to 18 months (n = 405 participants, age range 66.7-71.1). Weight loss in the intervention groups ranged from 0.5 to 10.7 kg (0.1-9.3%). Five studies had a resistance exercise program accompanying a dietary component. Greater weight loss was observed in groups with a dietary component than those with exercise alone. Exercise alone led to better physical function but no significant weight loss. Combined dietary and exercise components led to the greatest improvement in physical performance measures and quality of life and mitigated reductions in muscle and bone mass observed in diet-only study arms. Heterogeneous outcomes were observed, which limited the ability to synthesize the data quantitatively. CONCLUSIONS: The evidence supporting geriatric obesity interventions to improve physical function and quality of life is of low to moderate quality. Well-designed trials are needed in this population.

Associations between toenail arsenic concentration and dietary factors in a New Hampshire population.

BACKGROUND: Dietary factors such as folate, vitamin B12, protein, and methionine are important for the excretion of arsenic via one-carbon metabolism in undernourished populations exposed to high levels of arsenic via drinking water. However, the effects of dietary factors on toenail arsenic concentrations in well-nourished populations exposed to relatively low levels of water arsenic are unknown. METHODS: As part of a population-based case-control study of skin and bladder cancer from the USA, we evaluated relationships between consumption of dietary factors and arsenic concentrations in toenail clippings. Consumption of each dietary factor was determined from a validated food frequency questionnaire. We used general linear models to examine the associations between toenail arsenic and each dietary factor, taking into account potentially confounding effects. RESULTS: As expected, we found an inverse association between ln-transformed toenail arsenic and consumption of vitamin B12 (excluding supplements) and animal protein. Unexpectedly, there were also inverse associations with numerous dietary lipids (e.g., total fat, total animal fat, total vegetable fat, total monounsaturated fat, total polyunsaturated fat, and total saturated fat). Finally, increased toenail arsenic concentrations were associated with increased consumption of long chain n-3 fatty acids. CONCLUSION: In a relatively well-nourished population exposed to relatively low levels of arsenic via water, consumption of certain dietary lipids may decrease toenail arsenic concentration, while long chain n-3 fatty acids may increase toenail arsenic concentration, possibly due to their association with arsenolipids in fish tissue.

Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis have subnormal vitamin B6 status, both quantitatively and functionally. Abnormal vitamin B6 status in rheumatoid arthritis has been associated with spontaneous tumor necrosis factor (TNF)-alpha production and markers of inflammation, including C-reactive protein and erythrocyte sedimentation rate. Impaired vitamin B6 status could be a result of inflammation, and these patients may have higher demand for vitamin B6. The aim of this study was to determine if daily supplementation with 50 mg of pyridoxine for 30 days can correct the static and/or the functional abnormalities of vitamin B6 status seen in patients with rheumatoid arthritis, and further investigate if pyridoxine supplementation has any effects on the pro-inflammatory cytokine TNF-alpha or IL-6 production of arthritis. This was a double-blinded, placebo-controlled study involving patients with rheumatoid arthritis with plasma pyridoxal 5'-phosphate below the 25th percentile of the Framingham Heart Cohort Study. Vitamin B6 status was assessed via plasma and erythrocyte pyridoxal 5'-phosphate concentrations, the erythrocyte aspartate aminotransferase activity coefficient (alphaEAST), net homocysteine increase in response to a methionine load test (DeltatHcy), and 24 h urinary xanthurenic acid (XA) excretion in response to a tryptophan load test. Urinary 4-pyridoxic acid (4-PA) was measured to examine the impact of pyridoxine treatment on vitamin B6 excretion in these patients. Pro-inflammatory cytokine (TNF-alpha and IL-6) production, C-reactive protein levels and the erythrocyte sedimentation rate before and after supplementation were also examined. Pyridoxine supplementation significantly improved plasma and erythrocyte pyridoxal 5'-phosphate concentrations, erythrocyte alphaEAST, urinary 4-PA, and XA excretion. These improvements were apparent regardless of baseline B6 levels. Pyridoxine supplementation also showed a trend (p < 0.09) towards a reduction in post-methionine load DeltatHcy. Supplementation did not affect pro-inflammatory cytokine production. Although pyridoxine supplementation did not suppress pro-inflammatory cytokine production in patients with rheumatoid arthritis, the suboptimal vitamin B6 status seen in rheumatoid arthritis can be corrected by 50 mg pyridoxine supplementation for 30 days. Data from the present study suggest that patients with rheumatoid arthritis may have higher requirements for vitamin B6 than those in a normal healthy population.

Vitamin B-12 deficiency induces anomalies of base substitution and methylation in the DNA of rat colonic epithelium.

Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats. Weanling male Sprague-Dawley rats (n = 30) were divided into 2 groups and fed either a vitamin B-12-deficient diet or a similar diet containing adequate amounts of the vitamin. Rats from each group were killed at 6 and 10 wk. Uracil misincorporation into DNA was measured by GC/MS and genomic DNA methylation was measured by LC/MS. Plasma vitamin B-12 concentrations in deficient rats were below detectable limits at 6 and 10 wk; in control rats, concentrations were 0.46 +/- 0.07 and 0.42 +/- 0.10 nmol/L at those times. Although the colon total folate concentration did not differ between the groups, the proportion that was methylfolate was marginally greater in the deficient rats at 10 wk (P = 0.05) compared with control, consistent with the "methylfolate trap" that develops during vitamin B-12 deficiency. After 10 wk, the colonic DNA of the deficient rats displayed a 35% decrease in genomic methylation and a 105% increase in uracil incorporation (P < 0.05). This vitamin B-12-deficient diet, which was of insufficient severity to cause anemia or illness, created aberrations in both base substitution and methylation of colonic DNA, which might increase susceptibility to carcinogenesis.

Combined marginal folate and riboflavin status affect homocysteine methylation in cultured immortalized lymphocytes from persons homozygous for the MTHFR C677T mutation.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the synthesis of methionine from homocysteine. A common C677T mutation in the MTHFR gene renders the enzyme approximately 50% less active than the wild-type enzyme as shown in in vitro studies using cell extracts. We developed an immortalized cell culture model to determine whether the lower in vitro activity imparted by the homozygous (T/T) genotype is demonstrated in situ when exposed to adequate and marginal physiologic concentrations of folate and riboflavin. T/T MTHFR activity was compared with that of C/C genotype cell extracts by an in vitro assay and in intact cells by measuring the distribution of folate forms, the accumulation of homocysteine in the medium and the synthesis of methionine from formate and homocysteine. Under adequate nutrient conditions, the in vitro activity of the T/T MTHFR enzyme was approximately half that of the C/C genotype. Similarly, the proportion of 5-methyltetrahydrofolate in cells with the T/T genotype was approximately half that of the cells with wild-type MTHFR. In contrast, homocysteine accumulation in the culture medium was low and not different between genotypes, nor was there a difference in methionine synthetic capacity. Significant differences were observed between genotypes only when the supply of both folate and riboflavin was limited in the medium, which resulted in increased homocysteine accumulation and decreased methionine production in the T/T genotype. These data are consistent with the current understanding of the molecular interaction of the MTHFR mutant with folate substrates and the FAD prosthetic group.

Plasma pyridoxal 5'-phosphate concentration is correlated with functional vitamin B-6 indices in patients with rheumatoid arthritis and marginal vitamin B-6 status.

Many patients with rheumatoid arthritis (RA) have low plasma pyridoxal-phosphate (PLP) but a normal erythrocyte aspartate aminotransferase activity coefficient (alpha EAST), a measure of vitamin B-6 status in the erythrocytes, compared with healthy subjects. The goal of the present study was to examine the correlations of PLP levels in these two compartments (plasma and erythrocytes) with other established indices of vitamin B-6 status, and to determine which indicator better reflects functional status of vitamin B-6 in patients with RA. Multiple indices of vitamin B-6 status were measured in 33 patients with RA. Plasma PLP, urinary 4-pyridoxic acid (4-PA), net increase in plasma total homocysteine after a methionine load (DeltatHcy) and net increase in urinary xanthurenic acid after a tryptophan load (DeltaXA) were log-transformed to reach normality for statistical analyses. We found that log-plasma PLP levels were inversely correlated with both log-DeltatHcy (r = -0.368, P = 0.035) and log-DeltaXA (r = -0.333, P = 0.05). Plasma PLP was not correlated with alpha EAST or urinary 4-PA excretion. In contrast, erythrocyte PLP was inversely correlated with alpha EAST (r = -0.431, P = 0.012) and positively correlated with log-4-PA (r = 0.475, P = 0.005), but erythrocyte PLP was not correlated with the outcomes of a methionine or tryptophan load test. Erythrocyte PLP and log-4-PA, but not plasma PLP, were correlated with dietary intake of vitamin B-6 after adjusting for protein intake (r = 0.420, P = 0.015 and r = 0.333, P = 0.05, respectively). We suggest that in patients with RA, plasma PLP levels are a better diagnostic indicator of functional vitamin B-6 status than erythrocyte PLP levels.

Biochemical and molecular aberrations in the rat colon due to folate depletion are age-specific.

Elder adulthood and diminished folate status are each associated with an enhanced risk of colorectal carcinogenesis. We therefore examined whether these two factors are mechanistically related. Weanling male Sprague-Dawley rats (n = 44) and 1-y-old rats (n = 44) were each divided into three groups and fed diets containing 0, 4.5 or 18 micro mol folic acid/kg (deplete, replete and supplemented groups, respectively). Rats were killed at 0, 8 and 20 wk. The folate concentrations, the distribution of the different coenzymatic forms of folate, uracil incorporation into DNA and genomic DNA methylation were measured in the colonic mucosa. Folate-deplete and folate-replete elder rats had 30-45% lower colonic folate concentrations than young rats. Furthermore, 5-methyltetrahydrofolate was uniformly depleted in colons of the elder, folate-deplete rats, whereas this depletion occurred in only a minority of the younger rats. By the end of the experiment, the folate-deplete and folate-replete elder rats had approximately 50% more uracil incorporated into their colonic DNA than the corresponding young groups (P < 0.05). In elder rats, this uracil misincorporation was incremental across the three diet groups (P-test for trend < 0.05), whereas no excess uracil incorporation was observed in young rats. Neither age nor dietary folate affected genomic DNA methylation in the colon. In conclusion, the colon of elder rats is more susceptible to biochemical and molecular consequences of folate depletion than that of young rats. However, folate supplementation is as effective at sustaining adequate colonic folate status in elder rats as it is in the young.

Abnormal vitamin B(6) status is associated with severity of symptoms in patients with rheumatoid arthritis.

PURPOSE: Patients with rheumatoid arthritis have low plasma vitamin B(6) levels and elevated plasma homocysteine responses to a methionine load. We examined whether these abnormalities are associated with clinical and biochemical indicators of disease status. METHODS: We performed a cross-sectional study in 37 patients who met the American College of Rheumatology criteria for rheumatoid arthritis. Vitamin B(6) status was assessed by the plasma pyridoxal 5'-phosphate level and with the homocysteine response to a methionine load test. Clinical disease activity was assessed by joint counts, the Health Assessment Questionnaire disability score, and biochemical markers of the acute phase response. RESULTS: Plasma pyridoxal 5'-phosphate levels were inversely correlated with the erythrocyte sedimentation rate (r = -0.37, P = 0.02), C-reactive protein level (r = -0.52, P = 0.002), disability score (r = -0.37, P = 0.02), morning stiffness (r = -0.38, P = 0.02), and degree of pain (r = -0.33, P = 0.04). The increase in homocysteine levels after a methionine load correlated with the erythrocyte sedimentation rate (r = 0.39, P = 0.02), C-reactive protein level (r = 0.37, P = 0.03), disability score (r = 0.37, P = 0.04), degree of pain (r = 0.38, P = 0.02) and fatigue (r = 0.42, P = 0.01), number of painful joints (r = 0.43, P = 0.007), and number of swollen joints (r = 0.32, P = 0.05). CONCLUSION: Markers of vitamin B(6) status are associated with disease activity and severity, synovial burden, and pain in patients with rheumatoid arthritis, raising the possibility that impaired vitamin B(6) status in these patients is a result of inflammation.

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L-folinic or folic acid.

BACKGROUND: We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid. METHODS: Forty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12. Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection. RESULTS: Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in total folate and the remainder was unmethylated folic acid. CONCLUSIONS: Data from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients.

In the cystathionine beta-synthase knockout mouse, elevations in total plasma homocysteine increase tissue S-adenosylhomocysteine, but responses of S-adenosylmethionine and DNA methylation are tissue specific.

The cystathionine beta-synthase knockout mouse provides a unique opportunity to study biochemical consequences of a defective cystathionine beta-synthase enzyme. The present study was undertaken to assess the effect of elevated plasma total homocysteine caused by cystathionine beta-synthase deficiency on one-carbon metabolism in 10 homozygous mutant mice and 10 age- and sex-matched wild-type mice. Plasma total homocysteine levels, S-adenosylmethionine and S-adenosylhomocysteine concentrations in liver, kidney and brain were measured by HPLC. Tissue DNA methylation status was measured by in vitro DNA methyl acceptance. Plasma total homocysteine concentration in food-deprived homozygous mutant mice (271.1 +/- 61.5 micro mol/L) was markedly higher than in wild-type mice (7.4 +/- 2.9 micro mol/L) (P < 0.001). In liver only, S-adenosylmethionine concentrations were higher in the homozygous mutant mice (35.6 +/- 5.9 nmol/g) than in wild type mice (19.1 +/- 6.1 nmol/g) (P < 0.001) and tended to be lower in kidney (P = 0.07). In contrast, S-adenosylhomocysteine concentrations were significantly higher in homozygous mutant mice compared with wild-type mice in all tissues studied. Genomic DNA methylation status in homozygous mutant compared with wild-type mice was lower in liver (P = 0.037) and tended to be lower in kidney (P = 0.077) but did not differ in brain (P = 0.46). The results of this study are consistent with the predicted role of cystathionine beta-synthase in the regulation of plasma total homocysteine levels and tissue S-adenosylhomocysteine levels. However, the fact that the absence of the enzyme had differential effects on S-adenosylmethionine concentrations and DNA methylation status in different tissues suggests that regulation of biological methylation is a complex tissue-specific phenomenon.

A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.