Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

The Getting-Out-of-Bed (GoB) scale: a measure of motivation and life outlook in older adults with cancer

OBJECTIVE: To develop and evaluate the psychometric properties of a measure of motivation and life outlook (Getting-Out-of-Bed [GoB]). DESIGN: Secondary analysis of baseline and 6-month data from a longitudinal follow-up study of older breast cancer survivors. PARTICIPANTS: Women (N = 660) diagnosed with primary breast cancer stage I-IIIA disease, age >or=65 years, and permission to contact from an attending physician in four geographic regions in the United States (city-based Los Angeles, California; statewide in Minnesota, North Carolina, and Rhode Island). MEASUREMENT: Data were collected over 6-months of follow-up from consenting patients' medical records and telephone interviews with patients. Data collected included the 4-item GoB, health-related quality of life (HRQoL), breast cancer, sociodemographic, and health-related characteristics. RESULTS: Factor analysis produced, as hypothesized, one principal component with eigen values of 2.74(baseline) and 2.91(6-months) which explained 68.6%(baseline) and 72.7%(6-months) of total variance. In further psychometric analyses, GoB exhibited good construct validity (divergent: low nonstatistically significant correlations with unrelated constructs; convergent: moderate statistically significant correlations with related constructs; discriminant: distinguished high HRQoL groups with a high level of significance), excellent internal reliability (Cronbach's alpha 0.84(baseline), 0.87(6-months)), and produced stable measurements over 6-months. Women with GoB scores >or=50 at baseline were more likely at 6-months to have good HRQoL, good self-perceived health, and report regular exercise, indicating good predictive ability. CONCLUSION: GoB demonstrated overall good psychometric properties in this sample of older breast cancer survivors, suggestive of a promising tool for assessing motivation and life outlook in older adults. Nevertheless, because it was developed and initially evaluated in a select sample, using measures with similar but not exact content overlap further evaluation is needed before it can be recommended for widespread use.