Indomethacin Reduces Lipid Peroxidation in Rat Brain Homogenate by Binding Fe2+

One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinergic neurons in the cerebral cortex and hippocampus. It is generally accepted that this neuronal degeneration is due to free-radical-induced damage. These free radicals attack vital structural components of the neurons. This implies that agents that reduce free radical generation could potentially delay the progression of AD. Free radical generation in the brain is assisted by the presence of iron, required by the Fenton reaction. Thus, agents that reduce iron availability for this reaction could potentially reduce free radical formation. Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the severity of AD, we investigated the possible mechanism by which indomethacin could afford neuroprotection. Our results show that indomethacin (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. In addition, our NMR data indicate that indomethacin binds the Fe²⁺/Fe³⁺ ion. This was confirmed by a study using UV/Vis spectrophotometry. The results imply that indomethacin provides a neuroprotective effect by binding to iron and thus making it unavailable for free radical production.     

Association Between Neighborhood-Level Smoking and Individual Smoking Risk: Maternal Smoking Among Latina Women in Pennsylvania

Objective

We examined whether or not high maternal smoking rates at the neighborhood level increase the likelihood of individual smoking by Latina women in the three months prior to and during pregnancy, independent of other individual and neighborhood factors.

Methods

This study was observational in nature, using linked vital statistics records for 24,443 Latina women in Pennsylvania (2009–2010) and U.S. Census data for 2,398 census tracts. We used multilevel logistic regression models to determine the individual odds of self-reported maternal smoking given different census tract-level rates of maternal smoking in the previous three years (2006–2008), adjusting for maternal and census-tract characteristics, including ethnic density, population density, and poverty.

Results

Higher levels of maternal smoking at the census-tract level were associated with increased individual odds of smoking among Latina mothers. In the fully adjusted model, a 10% increase in the neighborhood smoking rate was associated with a 1.28 (95% confidence interval 1.22, 1.34) increase in the individual odds of smoking.

Conclusion

Latina women living in census tracts where more women have smoked during or immediately prior to pregnancy are themselves at higher risk of smoking during this period.Tobacco control is a U.S. public health priority and maternal smoking is of particular importance.¹ Maternal smoking is associated with premature birth and low birthweight, birth defects, sudden infant death syndrome, and the exacerbation of childhood asthma and other respiratory disorders.² Furthermore, parental smoking increases the risk that children themselves will smoke as adults.³ In the United States, one in every seven women is estimated to smoke during pregnancy.⁴ Although women of Latina heritage are less likely to smoke than women from other ethnic/racial groups, Latina women account for approximately 23% of U.S. births each year.^5,6 A 1% absolute decrease in maternal smoking among Latina women would impact the health and well-being of more than 9,000 infants and mothers of Latina origin annually.Individual risk factors for prenatal and maternal smoking among Latina women in the United States include poverty, lower education levels, younger age, English language preference, and U.S. nativity.^7–9 Smoking behaviors also have been found to be contingent upon neighborhood characteristics, meaning the physical, demographic, or social characteristics of the relatively small geographic area surrounding one''s residential address. This research has predominantly focused on smoking among the general adult and adolescent populations.^10–14 For example, Xue et al. found that high co-ethnic density (i.e., a neighborhood characteristic defined at the level of census block groups) decreased the risk of tobacco use by African American adolescents independent of individual characteristics such as age, socioeconomic status (SES), and exposure to parental substance use.¹⁰ Similarly, Kandula et al. found that Asian American women living in “Asian enclaves” (i.e., census tracts with ≥50% Asian residents) in California were less likely to smoke than women not living in Asian enclaves, even after taking into account individual characteristics such as age, marital status, education, income, emotional well-being, duration of U.S. residency, and language spoken at home. Notably, neighborhood SES (a composite measure comprising concentrated affluence, concentrated poverty, percentage of college-educated residents, and percentage of home ownership) was not associated with increased or decreased odds of smoking in this minority population.¹⁵A limited but evolving literature has focused on neighborhood-level factors associated with smoking during pregnancy. Studies examining neighborhood-level associates of maternal smoking in Sweden, South Carolina, and California have found that neighborhood poverty is independently associated with risk of tobacco use during pregnancy.^16,17 In a nationwide analysis of U.S. natality files, Shoff and Yang found that after adjusting for individual-level characteristics such as age, education, and race/ethnicity, a one-unit increase in county-level SES (a composite measure comprising various county-level statistics for educational attainment, income, occupation, and household composition) was associated with a 21% decrease in the individual likelihood of smoking during pregnancy. They also found that women in rural counties were less likely than women in non-rural areas to smoke during pregnancy.¹⁸ Shaw et al. also found that as county-level co-ethnic density increases, Latina women are substantially less likely to smoke during pregnancy. For example, Latina women in U.S. counties with <1% Latino residents compared with Latina women in counties with 15% to <50% Latino residents had an adjusted odds ratio for smoking during pregnancy of 0.35 (95% confidence interval [CI] 0.28, 0.42). Among Latina women living in counties with ≥50% Latino residents, the adjusted odds ratio was 0.11 (95% CI 0.07, 0.17).¹⁹The relationships between neighborhood measures and individual behavior may be mediated by structural, spatially correlated factors, such as the availability of tobacco products and exposure to tobacco advertising. They may also be mediated by social factors, such as decreased chronic stress in neighborhoods in which high co-ethnic density results in greater social connectedness, support, or cohesion for members of the dominant ethnic group. It is also possible that this association is due to differences in social norms (i.e., shared beliefs about how people should behave).^20–22 In general, Latina women who live in neighborhoods with a high proportion of Latino residents are also living in neighborhoods where maternal smoking is infrequent. This environment may reinforce a perceived social norm—that women do not smoke during preconception or pregnancy (or smoke at all)—that may be a more important determinant of individual maternal smoking behavior than the neighborhood''s ethnic composition. This potential social norm that exists in Latino neighborhoods is suggested by an analysis completed by Shaw and Pickett, who demonstrated that non-Latina women living in U.S. counties with ≥50% Latino residents are also much less likely to smoke during pregnancy than women who live in less Latino-dense areas, independent of individual characteristics such as age, marital status, and education.²³ Shoff and Yang also found that the individual odds of smoking during pregnancy were lower for women living in counties with a higher proportion of Latino residents compared with women living in neighborhoods with lower proportions of Latino residents, adjusting for maternal race/ethnicity.¹⁸We sought to advance this literature by examining the relationship between peer smoking rates at the census-tract level and the individual-level probability of smoking in the three months prior to or during any trimester of pregnancy. We hypothesize that Latina women living in census tracts where more women smoke immediately prior to or during pregnancy will themselves be more likely to smoke prior to or during pregnancy, independent of other individual and census tract-level risk factors. Because residential Latino ethnic density has a strong relationship with maternal smoking, and because maternal smoking behaviors differ significantly among racial/ethnic groups, we focused our analysis on Latina women.^5,24     

Genetic Diversity of Enterovirus A71, India

We have identified circulation of 3 genogroups of enterovirus (EV) A71 in India. A new genogroup (proposed designation G) was discovered during this study. We isolated genogroups D and G in wide geographic areas but detected subgenogroup C1 only in 1 focus in western India. A systematic nationwide search for EV-A71 is warranted.     

A dose range finding study of novel oral insulin (IN‐105) under fed conditions in type 2 diabetes mellitus subjects

Aim: The objective of the study was to establish the dose response of IN‐105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin. Methods: The primary objective was to examine the effect of sequential single ascending doses of IN‐105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN‐105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C‐peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN‐105 administration were also compared against those of placebo. Results: Changes in glucose from baseline (mean ± s.d.) at 140 min (2 h postprandial) were 94.84 ± 22.3, 79.45 ± 43.00, 70.68 ± 35.71, 63.47 ± 42.75 and 53.06 ± 47.27 mg/dL, respectively, and exhibited linear dose–response. The insulin C_max values were found to be 50.8 ± 26.0 mU/L for placebo, 100.3 ± 66.7 with 10 mg IN‐105, 177.69 ± 150.3 with 15 mg IN‐105, 246.2 ± 245.2 with 20 mg IN‐105 and 352.5 ± 279.3 mU/L with 30 mg of IN‐105. Conclusions: IN‐105 absorption is proportional to the dose administered. The 2‐h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C‐peptide levels were found to be suppressed in proportion to the IN‐105 exposure. IN‐105 reduces glucose excursion despite lower endogenous insulin secretion. IN‐105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.     

Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

Background  

BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer.