A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

optiCall: a robust genotype-calling algorithm for rare, low-frequency and common variants.

MOTIVATION: Existing microarray genotype-calling algorithms adopt either SNP-by-SNP (SNP-wise) or sample-by-sample (sample-wise) approaches to calling. We have developed a novel genotype-calling algorithm for the Illumina platform, optiCall, that uses both SNP-wise and sample-wise calling to more accurately ascertain genotypes at rare, low-frequency and common variants. RESULTS: Using data from 4537 individuals from the 1958 British Birth Cohort genotyped on the Immunochip, we estimate the proportion of SNPs lost to downstream analysis due to false quality control failures, and rare variants misclassified as monomorphic, is only 1.38% with optiCall, in comparison to 3.87, 7.85 and 4.09% for Illuminus, GenoSNP and GenCall, respectively. We show that optiCall accurately captures rare variants and can correctly account for SNPs where probe intensity clouds are shifted from their expected positions. AVAILABILITY AND IMPLEMENTATION: optiCall is implemented in C++ for use on UNIX operating systems and is available for download at http://www.sanger.ac.uk/resources/software/opticall/.

Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors.

This study details the profile of 13 cell surface cluster differentiation markers on human reserve stem cells derived from connective tissues. Stem cells were isolated from the connective tissues of dermis and skeletal muscle derived from fetal, mature, and geriatric humans. An insulin/dexamethasone phenotypic bioassay was used to determine the identity of the stem cells from each population. All populations contained lineage-committed myogenic, adipogenic, chondrogenic, and osteogenic progenitor stem cells as well as lineage-uncommitted pluripotent stem cells capable of forming muscle, adipocytes, cartilage, bone, fibroblasts, and endothelial cells. Flow cytometric analysis of adult stem cell populations revealed positive staining for CD34 and CD90 and negative staining for CD3, CD4, CD8, CD11c, CD33, CD36, CD38, CD45, CD117, Glycophorin-A, and HLA DR-II.

Clonogenic analysis reveals reserve stem cells in postnatal mammals: I. Pluripotent mesenchymal stem cells.

Clonal populations of lineage-uncommitted pluripotent mesenchymal stem cells have been identified in prenatal avians and rodents. These cells reside in the connective tissue matrices of many organs and tissues. They demonstrate extended capabilities for self-renewal and the ability to differentiate into multiple separate tissues within the mesodermal germ line. This study was designed to determine whether such cells are present in the connective tissues of postnatal mammals. This report describes a cell clone derived by isolation from postnatal rat connective tissues, cryopreservation, extended propagation, and serial dilution clonogenic analysis. In the undifferentiated state, this clone demonstrates a high nuclear-to-cytoplasmic ratio and extended capacity for self-renewal. Subsequent morphological, histochemical, and immunochemical analysis after the induction of differentiation revealed phenotypic markers characteristic of multiple cell types of mesodermal origin, such as skeletal muscle, smooth muscle, fat cells, cartilage, and bone. These results indicate that this clone consists of pluripotent mesenchymal stem cells. This report demonstrates that clonal populations of reserve stem cells are present in mammals after birth. Potential roles for such cells in the maintenance, repair, and regeneration of mesodermal tissues are discussed.

Nonlinear components of age-related change in sleep initiation.

BACKGROUND: Although primary studies suggest that ability to initiate sleep declines as people age, no systematic literature review has addressed the age(s) at which adults experience the greatest change in their ability to initiate sleep. OBJECTIVE: To explore whether there are any points in time across the adult life span when the rate of change in ability to initiate sleep increases or decreases. METHODS: Mathematical modeling was used to generate data points from information about central tendency, variance, and correlations between age and time to sleep onset provided by seven research reports. The reports represent 258 subjects ages 17 to 91 years. Smoothing splines were used to identify inflection points suggestive of major changes in sleep initiation across the life span. RESULTS: Two mathematical models were generated. One model suggested that inflection points may exist around ages 30 and 50 years, respectively. With this model, the amount of time until sleep onset increased until the age of 30 years, but was unchanged from ages 30 to 50 years. Ability to initiate sleep appeared to decline steadily after the age of 50 years. The second model, with a p value of 0.05, lacked adequate power to identify a significant nonlinear trend. CONCLUSIONS: Decline in ability to initiate sleep may not occur at a steady rate over the adult life span. Further research is needed to pinpoint thresholds of change and possible gender differences in thresholds.

Creation and analysis of a computerized database of interventions to facilitate adult sleep.

BACKGROUND: Although sleep problems are a frequent complaint of ill and older adults, there is no ready source of continually updated scientific knowledge about sleep promotion interventions used by nurses. OBJECTIVES: To create a database of sleep promotion research and to describe the nature and strength of studies about nursing interventions used to promote sleep in adults. METHODS: Computer, hand, ancestry, and author searches were used to identify nursing and related-discipline studies of sleep promotion in adults. An experimental software program, arcs, was used to store, retrieve, examine, and summarize sleep research findings. RESULTS: Twelve interventions within the basic scope of nursing practice were identified. All were nonpharmacologic. Interventions were grouped according to their presumed mechanism of action: 1) to relax the sleeper, 2) to manage noise, 3) to re-pattern the sleep-wake schedule, or 4) to inform the sleeper about sleep hygiene. CONCLUSIONS: The research base underpinning sleep promotion practices in nursing is sparse. The use of relaxation approaches to promote sleep in those with chronic insomnia has the most support. Extensive research involving other interventions and populations is needed. As more studies become available, they can be added to the computer database, thus facilitating dissemination of scientific knowledge to guide nursing practice.

Age-related changes in initiation and maintenance of sleep: a meta-analysis.

The purpose of this meta-analysis was to determine the magnitude of change over the adult life span in four key sleep characteristics and to explore research design features that may account for variability in reported age-related sleep change. Forty-one published studies (combined N = 3293) provided 99 correlational effect sizes. Waking frequency and duration increased with age as previously concluded by narrative reviewers. Although narrative reviewers were less certain whether nighttime sleep amount or the ability to initiate sleep decreased with age, the meta-analysis suggested that both decreased. When sleep variables were measured by polysomnography rather than self-report, larger age-related changes were found. Few researchers who studied normal sleep controlled for important health moderators or studied women.

The use of the arcs software system to store and examine sleep research results.

Ready access to research results is essential if nurses are to keep current with the scientific knowledge available to guide practice. Sigma Theta Tau International has supported the development of a software system that facilitates ongoing storage of information from research reports and can be used to gain online access to continually updated databases of research results called "knowledgebases." One such experimental knowledgebase, the Sleep Promotion Knowledgebase, includes studies of correlates of poor sleep in adults as well as sleep interventions and outcomes. The authors describe the creation of the Sleep Promotion Knowledgebase using arcs BUILDER to store information about research reports and the scientific findings they contain. The use of arcs MAPPER to examine sleep promotion interventions also is described. The strengths and limitations of the software system are identified, and the potential uses of arcs to disseminate sleep research results are discussed.

Sleep promotion in adults.

Insomnia is among the most frequent health complaints brought to the attention of primary care providers. The prevalence estimates are highest in women, older adults, and patients with medical or psychiatric disorders. Clinical researchers have studied many barriers to sleep as well as some sleep promotion interventions for the ill and aging adult. Environmental, personal, and person-environment rhythm factors have been identified as correlates of poor sleep. All interventions studied by nurse researchers are non-pharmacological and have been classified as interventions that (a) create an environment more conductive to sleep, (b) relax the sleeper, or (c) entrain the circadian sleep-wake rhythm. This chapter summarizes results of published research on correlates of poor sleep and interventions to promote sleep. The chapter includes the relevant studies conducted by researchers in related disciplines as well as nurses' research. The arcs software package was used to facilitate summarization of intervention studies. It was concluded that correlates of poor sleep are well described, but theories of sleep promotion are not well explicated. Also, the research base for sleep promotion interventions for use with clinical populations other than those with chronic insomnia is sparse. Gaps in knowledge are identified and conceptual and methodological issues are discussed as the basis for future directions in sleep promotion research.

The use of across-method triangulation in the study of sleep concerns in healthy older adults.

Both qualitative and quantitative methods were used to study sleep concerns of 84 healthy adults ages 60 to 89. The combined use of methods in one study brought sampling, data-collection, and data-interpretation issues to the forefront. This article describes a sampling method that accommodates assumptions of both paradigms, reports results of an experimental approach to examining the effects of each method on the other, and identifies convergent and disparate findings regarding sleep concerns of older adults. Self-report measures affected qualitative interviews but not vice versa. Also, age-by-method and gender-by-method interactions were evident.

Nursing students' stress levels, attitude toward drugs, and drug use.

This study investigated relationships among nursing students' drug use and two variables usually assumed to contribute to the development of chemical dependency in nurses, i.e., stress and positive attitudes about drugs. Drug use was defined as the use of any psychoactive substance including prescription drugs, over-the-counter drugs, recreational drugs, nicotine, and alcohol. Questionnaires, were distributed to senior-year nursing students and a comparison group of seniors in liberal arts. The only significant difference in reported drug use was nursing students' more frequent use of over-the-counter analgesics. There were no significant differences between nursing and liberal arts majors with regard to three symptoms of stress. Nursing students reported more positive attitudes toward the use of some drugs than peers.