Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase (AS3MT). Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena, including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for AS3MT, is differentially methylated as a function of arsenic exposure. In this study, we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989 to 1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean  % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation, and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene.     

Follicular dendritic cells inhibit human B-lymphocyte proliferation.

In germinal centers, B lymphocytes are intimately associated with follicular dendritic cells (FDCs). It has been hypothesized that FDCs are involved in the regulation of B-cell growth and differentiation through cell-cell interactions. In this study, highly enriched preparations of FDCs were isolated by cell sorting using the FDC restricted monoclonal antibody DRC-1. When irradiated FDCs were cultured with mitogen stimulated B cells, B cell 3H-TdR uptake was inhibited by up to 80%. This inhibitory effect was not seen when paraformaldehyde fixed FDCs were added to B-cell cultures, suggesting that the FDCs needed to be metabolically active. Moreover, supernatants from cultured FDCs were similarly able to inhibit B-cell proliferation. These results demonstrate that FDCs may downregulate the clonal expansion of B cells that occurs within lymphoid follicles as part of the normal physiologic immune response. Potentially, the loss of the inhibitory role of FDCs in vivo may be of importance in certain infectious and neoplastic processes in which germinal centers are affected.     

National Trends in Smoking Behaviors Among Mexican,Puerto Rican,and Cuban Men and Women in the United States

Objectives. We examined trends in smoking behaviors across 2 periods among Mexicans, Puerto Ricans, and Cubans in the United States.Methods. We analyzed data from the 1992–2007 Tobacco Use Supplements to the Current Population Survey. We constructed 2 data sets (1990s vs 2000s) to compare smoking behaviors between the 2 periods.Results. Significant decreases in ever, current, and heavy smoking were accompanied by increases in light and intermittent smoking across periods for all Latino groups, although current smoking rates among Puerto Rican women did not decline. Adjusted logistic regression models revealed that in the 2000s, younger Mexicans and those interviewed in English were more likely to be light and intermittent smokers. Mexican and Cuban light and intermittent smokers were less likely to be advised by healthcare professionals to quit smoking. Mexicans and Puerto Ricans who were unemployed and Mexicans who worked outdoors were more likely to be heavy smokers.Conclusions. Increases in light and intermittent smoking among Mexican, Puerto Rican, and Cuban Americans suggest that targeted efforts to further reduce smoking among Latinos may benefit by focusing on such smokers.Since 2000, Latinos have experienced the largest population growth of all US racial/ethnic groups, making Latinos the largest ethnic minority group in the country at 16.3% of the population.1 Mexicans, Puerto Ricans, and Cubans are the 3 largest Latino national and family background groups in the United States.1 The leading causes of death among Latinos are coronary heart disease and cancer, both of which are strongly associated with tobacco use.2,3 Although differences in smoking rates by Latino national origin groups have been found,4–6 very little research has examined trends in smoking behaviors for various Latino national origin groups by gender in the United States.The aggregation of smoking rates for various Latino national origin groups masks important variations within the population group.4 For example, smoking prevalence rates as determined by national data from 2008 are highest among Cubans (21.5%), followed by Mexicans (20.1%), and Puerto Ricans (18.6%).3 Puerto Ricans and Cubans are also more likely to be current smokers than are Mexicans.7 Furthermore, although research grounded on a nationally representative sample found that Latinos were approximately 4.5 times more likely to be light smokers than were non-Hispanic Whites,8 that study provided only aggregated rates for all Latinos and did not differentiate between national origin groups. Gender differences have also been reported among disaggregated Latino groups. A higher prevalence of smoking has been reported among Mexican (25.0%), Puerto Rican (27.6%), and Cuban (24.7%) men than among Mexican (10.4%), Puerto Rican (24.2%), and Cuban (12.4%) women.7 The lower rates of smoking among women have been consistent in surveys of Latinos.5,7,9 Results from these studies, although informative, have generally been determined by aggregated Latino data or data from a single survey time point. Although such data are valuable and can demonstrate existing gender differences, national-level trends from Latino nationality groups in the United States add valuable information that have not been previously reported.Previous research has also identified social and environmental factors associated with Latinos’ smoking behaviors. Acculturation to mainstream US culture plays a significant role in one’s health behaviors,10 and as Latinos acculturate, their smoking behaviors become similar to those of non-Hispanic Whites.7 Existing research has also revealed that Latinos are less likely to quit smoking,11 receive tobacco screening, and be advised to quit by a physician than are non-Hispanic Whites.12–15 A health professionals’ advice to quit smoking has been found to increase the likelihood that a smoker will successfully quit.16,17 Lastly, workplace smoking policies have also influenced smoking prevalence and intensity.18–20 Work environments adopting a smoke-free policy saw a 14% decrease in individuals’ smoking.21 When examining national-level smoking behaviors among Latinos, it is important to account for social and environmental factors such as acculturation, physician advice to quit smoking, and work environment smoking policies, as they may influence smoking behaviors.Existing research on smoking behaviors among Latino national origin groups has been predicated on data from specific regions of the United States.4,22–25 Although regional data are important for the development of community-level interventions,4 national-level data provide an overview of the country’s progress in tobacco control as well as remaining and emerging challenges for Latinos nationwide. We compared smoking behaviors across 2 periods, about a decade apart, among Mexicans, Puerto Ricans, and Cubans. Our goals in these analyses were (1) to compare Latino national origin groups across 2 periods to examine factors affecting changes in smoking behavior within and between groups, and (2) to evaluate demographic factors that influence current smoking behaviors within Latino national origin groups in the most recent period available. Examining long-term national trends in Latino smoking behaviors may prove vital to policymakers, public health officials, community workers, and interventionists as they address tobacco-related issues.     

Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples

Background: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989–1991 (visit 1) and 1998–1999 (visit 3).Methods: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation.Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population.Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies.Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. 2014. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect 122:946–954; http://dx.doi.org/10.1289/ehp.1306674     

Colon cancer screening in the ambulatory setting

BACKGROUND: Despite evidence of decreased mortality, recommendations for colon cancer screening have not been widely implemented by physicians. The objective of this study was to determine patient and clinician factors associated with screening for colon cancer. METHODS: A retrospective review of computerized medical records from primary care practices in an academic medical center was performed. Patients comprised men and women aged 50-74 with at least one visit between July 1, 1995 and June 30, 1997. Measurements included Fecal occult blood testing in the past 1 or 2 years, sigmoidoscopy in the previous 5 or 10 years, or colonoscopy in the past 10 years. RESULTS: A total of 6,039 patients were included in the analysis. Fecal occult blood testing had been performed in 44% of patients and sigmoidoscopy in 26%. Fifty-three percent of patients had undergone some type of colon cancer screening. In multivariate analysis, patient factors predictive of fecal occult blood testing included age (odds ratio (OR) per 5 years 1.05; 95% confidence interval 1.04, 1.06), Asian ethnicity (OR 1.23; 1.08, 1.41), number of visits during the study period (OR 1.05; 1.04, 1.06), recency of the last visit (OR 1.03; 1.02, 1.04), and having private insurance (OR 1.65; 1.04, 2.62). Predictors of sigmoidoscopy were similar except that patients with a family history of colon cancer and those with managed care insurance were also more likely to undergo sigmoidoscopy. Patients of nurse practitioners were less likely to receive fecal occult blood testing than were patients of physicians (OR 0.78; 0.65, 0.93). Patients of residents were less likely to undergo sigmoidoscopy than were patients of faculty (OR 0.79; 0.66, 0.94). CONCLUSIONS: Among patients seen in primary care practices, rates of colon cancer screening remain low, especially in patients who are younger, who have been seen less frequently, who are uninsured, or who do not have managed care insurance. Future research should explore these differences and should focus on increasing screening in all patient groups, especially in those who are underscreened.     

Fiblast (trafermin) in acute stroke: results of the European-Australian phase II/III safety and efficacy trial

BACKGROUND: Trafermin (basic fibroblast growth factor) has been shown to reduce infarct volume in acute ischemic stroke models, and to promote functional recovery and new synapse formation when given to animals with completed cerebral infarction. A previous study in acute stroke patients suggested that trafermin was safe and well tolerated when given over a 3-hour period over a wide dose range. METHODS AND RESULTS: Double-blind, parallel group, placebo-controlled trial of a single 24-hour intravenous infusion of trafermin. Patients having onset of stroke symptoms within 6 h and a baseline score of >/=7 on the NIH Stroke Scale (>/=2 motor) were randomized to receive 5 or 10 mg of trafermin or placebo intravenously infused over 24 h. The primary efficacy outcome was a categorized combination of the Barthel and Rankin scales assessed at 90 days. A total of 286 patients had been enrolled at 55 sites in 11 countries when the sponsor directed that enrollment be stopped because an interim analysis of efficacy data predicted too small a chance of demonstrating a statistically significant benefit after recruitment of the planned 900 patients. The 5-mg group showed a slight but nonsignificant advantage over placebo (OR 1.2, 95% CI 0.72-2.00, p = 0.48); the 10-mg group showed a nonsignificant disadvantage (OR 0.74, 95% CI 0.44-1.22, p = 0.24). Mortality rates at 90 days were 17% in the 5-mg group, 24% in the 10-mg group and 18% in the placebo group. Treatment with trafermin was associated with an increased leukocytosis and a decrease in blood pressure: mean decrease in systolic blood pressure from baseline was 19 mm Hg in the 5-mg group, 22 mm Hg in the 10-mg group and 8 mm Hg in the placebo group. In a post hoc subgroup analysis, patients in the 5-mg group treated more than 5 h after the onset of symptoms showed an apparent advantage over placebo (OR 2.1, 95% CI 1.00-4.41, p = 0.044; after age adjustment: OR 1.9, 95% CI 0.91-4.13, p = 0.08). CONCLUSIONS: With the proper treatment regimen, trafermin can likely be given safely to stroke patients. The 5-mg dose showed a trend toward a treatment advantage. The ideal time window for this agent may exceed 5 h. This may open new avenues for acute stroke therapy, aiming at enhancing recovery mechanisms rather than immediate neuroprotection.     

Receipt of preventive medical services at psychiatric visits by patients with severe mental illness

The authors used data from the National Ambulatory Medical Care Survey from 1992 to 1999 on 3,198 office visits to explore the extent to which psychiatrists provide clinical preventive medical services to patients with severe mental illness. Preventive services were provided during 11 percent of the visits. A multivariate analysis showed that preventive services were more likely to have been provided for patients with a chronic medical condition, for patients who were also seen by a nurse or other health provider during the visit, in rural areas, and during longer visits. Preventive services were less likely to have been provided during visits to health maintenance organizations and visits that took place later in the study period.