Associations between environmental stress, selection history, and quantitative genetic variation in Drosophila melanogaster

Stressful environments may increase quantitative genetic variation in populations by promoting the expression of genetic variation that has not previously been eliminated or canalized by natural selection. This “selection history” hypothesis predicts that novel stressors will increase quantitative genetic variation, and that the magnitude of this effect will decrease following continued stress exposure. We tested these predictions using Drosophila melanogaster and sternopleural bristle number as a model system. In particular, we examined the effect of high temperature stress (31°C) on quantitative genetic variation before and after our study population had been reared at 31°C for 15 generations. High temperature stress was found to increase both additive genetic variance and heritability, but contrary to the selection history hypothesis prediction, the magnitude of this effect significantly increased after the study population had been reared for 15 generations under high temperature stress. These results demonstrate that high temperature stress increases quantitative genetic variation for bristle number, but do not support the selection history hypothesis as an explanation for this effect.     

Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study

Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.     

Expression of IL-20 in synovium and lesional skin of patients with psoriatic arthritis: differential response to alefacept treatment

Introduction

Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.

Methods

Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.

Results

IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68⁺ macrophages and CD55⁺ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.

Conclusions

Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.     

Comparison of Doxycycline Delivery Methods for Tet-Inducible Gene Expression in a Subcutaneous Xenograft Model

Doxycycline (Dox) controlled Tet systems provide a powerful and commonly used method for functional studies on the consequences of gene overexpression/downregulation. However, whereas Dox delivery in tissue culture in vitro is relatively simple, the situation in vivo is more complex. Several methods of Dox delivery in vivo have been described-e.g., in drinking water containing alcohol, in drinking water containing various concentrations of sucrose, and in feed. Unfortunately there are no reports directly comparing the advantages and disadvantages of these diverse methods, and there is no generally accepted standard. We therefore compared four non-invasive methods of Dox delivery in vivo-in drinking water, by gavage, as a jelly, and in standard feed. To assess the delivery of Dox by these methods, we used a subcutaneous xenograft model based on colorectal carcinoma cells engineered for Dox-inducible expression of an activated mutant of c-Src and the luciferase reporter gene. Our results indicate that feed represents the most favorable method of Dox administration.     

Ancestral inbreeding reduces the magnitude of inbreeding depression in Drosophila melanogaster

The influence of natural selection on the magnitude of inbreeding depression is an important issue in conservation biology and the study of evolution. It is generally expected that the magnitude of inbreeding depression in small populations will depend upon the average homozygosity of individuals, as measured by the coefficient of inbreeding (F). However, if deleterious recessive alleles are selectively purged from populations during inbreeding, then inbreeding depression may differ among populations in which individuals have the same inbreeding coefficient. In such cases, the magnitude of inbreeding depression will partly depend on the ancestral inbreeding coefficient (fa), which measures the cumulative proportion of loci that have historically been homozygous and therefore exposed to natural selection. We examined the inbreeding depression that occurred in lineages of Drosophila melanogaster maintained under pedigrees that led to the same inbreeding coefficient (F = 0.375) but different levels of ancestral inbreeding (fa = 0.250 or 0.531). Although inbreeding depression varied substantially among individual lineages, we observed a significant 40% decrease in the median level of inbreeding depression in the treatment with higher ancestral inbreeding. Our results demonstrate that high levels of ancestral inbreeding are associated with greater purging effects, which reduces the inbreeding depression that occurs in isolated populations of small size.