Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Ideological Labels in America

This paper extends Ellis and Stimson’s (Ideology in America. New York: Cambridge UniversityPress, 2012) study of the operational-symbolic paradox using issue-level measures of ideological incongruence based on respondent positions and symbolic labels for these positions across 14 issues. Like Ellis and Stimson, we find that substantial numbers—over 30 %—of Americans experience conflicted conservatism. Our issue-level data reveal, furthermore, that conflicted conservatism is most common on the issues of education and welfare spending. In addition, we also find that 20 % of Americans exhibit conflicted liberalism. We then replicate Ellis and Stimson’s finding that conflicted conservatism is associated with low sophistication and religiosity, but also find that it is associated with being socialized in a post-1960s generation and using Fox News as a main news source. Finally, we show the important role played by identities, with both conflicted conservatism and conflicted liberalism linked with partisan and ideological identities, and conflicted liberalism additionally associated with ethnic identities

Rapid Chromosome Evolution in Recently Formed Polyploids in Tragopogon (Asteraceae)

Polyploidy, frequently termed "whole genome duplication", is a major force in the evolution of many eukaryotes. Indeed, most angiosperm species have undergone at least one round of polyploidy in their evolutionary history. Despite enormous progress in our understanding of many aspects of polyploidy, we essentially have no information about the role of chromosome divergence in the establishment of young polyploid populations. Here we investigate synthetic lines and natural populations of two recently and recurrently formed allotetraploids Tragopogon mirus and T. miscellus (formed within the past 80 years) to assess the role of aberrant meiosis in generating chromosomal/genomic diversity. That diversity is likely important in the formation, establishment and survival of polyploid populations and species.Applications of fluorescence in situ hybridisation (FISH) to natural populations of T. mirus and T. miscellus suggest that chromosomal rearrangements and other chromosomal changes are common in both allotetraploids. We detected extensive chromosomal polymorphism between individuals and populations, including (i) plants monosomic and trisomic for particular chromosomes (perhaps indicating compensatory trisomy), (ii) intergenomic translocations and (iii) variable sizes and expression patterns of individual ribosomal DNA (rDNA) loci. We even observed karyotypic variation among sibling plants. Significantly, translocations, chromosome loss, and meiotic irregularities, including quadrivalent formation, were observed in synthetic (S(0) and S(1) generations) polyploid lines. Our results not only provide a mechanism for chromosomal variation in natural populations, but also indicate that chromosomal changes occur rapidly following polyploidisation.These data shed new light on previous analyses of genome and transcriptome structures in de novo and establishing polyploid species. Crucially our results highlight the necessity of studying karyotypes in young (<150 years old) polyploid species and synthetic polyploids that resemble natural species. The data also provide insight into the mechanisms that perturb inheritance patterns of genetic markers in synthetic polyploids and populations of young natural polyploid species

Trophic Shifts of a Generalist Consumer in Response to Resource Pulses

Trophic shifts of generalist consumers can have broad food-web and biodiversity consequences through altered trophic flows and vertical diversity. Previous studies have used trophic shifts as indicators of food-web responses to perturbations, such as species invasion, and spatial or temporal subsidies. Resource pulses, as a form of temporal subsidies, have been found to be quite common among various ecosystems, affecting organisms at multiple trophic levels. Although diet switching of generalist consumers in response to resource pulses is well documented, few studies have examined if the switch involves trophic shifts, and if so, the directions and magnitudes of the shifts. In this study, we used stable carbon and nitrogen isotopes with a Bayesian multi-source mixing model to estimate proportional contributions of three trophic groups (i.e. producer, consumer, and fungus-detritivore) to the diets of the White-footed mouse (Peromyscus leucopus) receiving an artificial seed pulse or a naturally-occurring cicadas pulse. Our results demonstrated that resource pulses can drive trophic shifts in the mice. Specifically, the producer contribution to the mouse diets was increased by 32% with the seed pulse at both sites examined. The consumer contribution to the mouse diets was also increased by 29% with the cicadas pulse in one of the two grids examined. However, the pattern was reversed in the second grid, with a 13% decrease in the consumer contribution with the cicadas pulse. These findings suggest that generalist consumers may play different functional roles in food webs under perturbations of resource pulses. This study provides one of the few highly quantitative descriptions on dietary and trophic shifts of a key consumer in forest food webs, which may help future studies to form specific predictions on changes in trophic interactions following resource pulses

Risk of adenocarcinomas of the oesophagus and gastric cardia in patients hospitalized for asthma

In the first cohort study of the question we followed 92 986 (42 663 men and 50 323 women) adult patients hospitalized for asthma in Sweden from 1965 to 1994 for an average of 8.5 years to evaluate their risk of oesophageal and gastric cardia adenocarcinoma. Standardized incidence ratio (SIR) adjusted for gender, age and calendar year was used to estimate relative risk, using the Swedish nationwide cancer incidence rates as reference. Asthmatic patients overall had a moderately elevated risk for oesophageal adenocarcinoma (SIR = 1.5, 95% confidence interval CI, 0.9–2.5) and gastric cardia cancer (SIR = 1.4, 95% CI, 1.0–1.9). However, the excess risks were largely confined to asthmatic patients who also had a discharge record of gastro-oesophageal reflux (SIR = 7.5, 95% CI, 1.6–22.0 and SIR = 7.1, 95% CI, 3.1–14.0, respectively). No significant excess risk for oesophageal squamous-cell carcinoma or distal stomach cancer was observed. In conclusion, asthma is associated with a moderately elevated risk of developing oesophageal or gastric cardia adenocarcinoma. Special clinical vigilance vis-à-vis gastro-esophageal cancers seems unwarranted in asthmatic patients, but may be appropriate in those with clinically manifest gastro-oesophageal reflux.   http://www.bjcancer.com © 2001 Cancer Research Campaig

The CD4+ T-cell transcriptome and serum IgE in asthma: IL17RB and the role of sex

<p>Abstract</p> <p>Background</p> <p>The relationships between total serum IgE levels and gene expression patterns in peripheral blood CD4+ T cells (in all subjects and within each sex specifically) are not known.</p> <p>Methods</p> <p>Peripheral blood CD4+ T cells from 223 participants from the Childhood Asthma Management Program (CAMP) with simultaneous measurement of IgE. Total RNA was isolated, and expression profiles were generated with Illumina HumanRef8 v2 BeadChip arrays. Modeling of the relationship between genome-wide gene transcript levels and IgE levels was performed in all subjects, and stratified by sex.</p> <p>Results</p> <p>Among all subjects, significant evidence for association between gene transcript abundance and IgE was identified for a single gene, the interleukin 17 receptor B (IL17RB), explaining 12% of the variance (r²) in IgE measurement (p value = 7 × 10^-7, 9 × 10^-3after adjustment for multiple testing). Sex stratified analyses revealed that the correlation between IL17RB and IgE was restricted to males only (r²= 0.19, p value = 8 × 10^-8; test for sex-interaction p < 0.05). Significant correlation between gene transcript abundance and IgE level was not found in females. Additionally we demonstrated substantial sex-specific differences in IgE when considering multi-gene models, and in canonical pathway analyses of IgE level.</p> <p>Conclusions</p> <p>Our results indicate that IL17RB may be the only gene expressed in CD4+ T cells whose transcript measurement is correlated with the variation in IgE level in asthmatics. These results provide further evidence sex may play a role in the genomic regulation of IgE.</p

Childhood asthma and indoor allergens in Native Americans in New York

BACKGROUND: The objective of this study was to assess the correlation between childhood asthma and potential risk factors, especially exposure to indoor allergens, in a Native American population. METHODS: A case-control study of St. Regis Mohawk tribe children ages 2–14 years, 25 diagnosed with asthma and 25 controls was conducted. Exposure was assessed based on a personal interview and measurement of mite and cat allergens (Der p 1, Fel d 1) in indoor dust. RESULTS: A non-significant increased risk of childhood asthma was associated with self-reported family history of asthma, childhood environmental tobacco smoke exposure, and air pollution. There was a significant protective effect of breastfeeding against current asthma in children less than 14 years (5.2 fold lower risk). About 80% of dust mite and 15% of cat allergen samples were above the threshold values for sensitization of 2 and 1 μg/g, respectively. The association between current asthma and exposure to dust mite and cat allergens was positive but not statistically significant. CONCLUSION: This research identified several potential indoor and outdoor risk factors for asthma in Mohawks homes, of which avoidance may reduce or delay the development of asthma in susceptible individuals

Clinically diagnosed childhood asthma and follow-up of symptoms in a Swedish case control study

BACKGROUND: Childhood asthma has risen dramatically not only in the western societies and now forms a major and still increasing public health problem. The aims of this study were to follow up at the age of ten the patterns of asthma symptoms and associations among children with a clinically diagnosed asthma in a sizeable urban-rural community and to in compare them with demographic controls using a standardised questionnaire. METHODS: In a defined region in Sweden with a population of about 150 000 inhabitants, all children (n = 2 104) born in 1990 were recorded. At the age of seven all primary care and hospital records of the 1 752 children still living in the community were examined, and a group of children (n = 191) was defined with a well-documented and medically confirmed asthma diagnosis. At the age of ten, 86 % of these cases (n = 158) and controls (n = 171) completed an ISAAC questionnaire concerning asthma history, symptoms and related conditions. RESULTS: Different types of asthma symptoms were highly and significantly over-represented in the cases. Reported asthma heredity was significantly higher among the cases. No significant difference in reported allergic rhinitis or eczema as a child was found between cases and controls. No significant difference concerning social factors or environmental exposure was found between case and controls. Among the control group 4.7 % of the parents reported that their child actually had asthma. These are likely to be new asthma cases between the age of seven and ten and give an estimated asthma prevalence rate at the age of ten of 15.1 % in the studied cohort. CONCLUSION: A combination of medical verified asthma diagnosis through medical records and the use of self-reported symptom through the ISAAC questionnaire seem to be valid and reliable measures to follow-up childhood asthma in the local community. The asthma prevalence at the age of ten in the studied birth cohort is considerably higher than previous reports for Sweden. Both the high prevalence figure and allowing the three-year lag phase for further settling of events in the community point at the complementary roles of both hospital and primary care in the comprehensive coverage and control of childhood asthma in the community