Treatment of Rheumatoid Arthritis with Marine and Botanical Oils: Influence on Serum Lipids

The gap in mortality between patients with rheumatoid arthritis (RA) and the general population (1.5–3.0 fold risk) is increasing. This disparity is attributable mainly to cardiovascular disease (CVD), as the CVD risk is comparable to patients with diabetes mellitus. The purpose of this study is to determine whether borage seed oil rich in gamma-linolenic acid, fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or the combination of both oils are useful treatments for dyslipidemia in patients with RA. We randomized patients into a double blind, 18 month trial. Mixed effects models were used to compare trends over time in serum lipids. No significant differences were observed between the three groups: All three treatment groups exhibited similar meaningful improvement in the lipid profile at 9 and 18 months. When all groups were combined, these treatments significantly reduced total and LDL-cholesterol and triglycerides, increased HDL-cholesterol, and improved the atherogenic index. All improvements observed at 9 months persisted at 18 months (P < 0.001 verses baseline). Conclusion. Marine and botanical oils may be useful treatment for rheumatoid arthritis patients who are at increased risk for cardiovascular disease compared to the general population

Treatment of Rheumatoid Arthritis with Marine and Botanical Oils: Influence on Serum Lipids (poster)

Background: Over the past 30 years substantial progress has been made in the medical and surgical management of patients with rheumatoid arthritis (RA). Despite this progress, there is an increasing gap in mortality between patients with RA (1.5-3.0 fold risk) and the general population. This disparity is mainly attributable to cardiovascular disease (CVD) as the CVD risk is comparable in RA patients as to patients with diabetes mellitus. Although the reasons for this gap are not entirely clear, the traditional risk of abnormalities in lipid profiles appears to be enhanced by a chronic increase in inflammatory cytokines, resulting in accelerated atherosclerosis. Study Objective: The object of this study was to determine the effect of marine (fish oil) and botanical oils (borage oil) on lipids (TC, HDL, LDL, TG), a risk factor for cardiovascular disease in patients with RA. The main outcome (to be presented elsewhere) was to determine whether a combination of borage seed oil rich in gammalinolenic acid (GLA) and fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is superior to either oil alone for the treatment of RA. Population and Setting: The study was an 18 month randomized, double-masked comparison of borage seed oil, fish oil, and the combination of both oils in RA patients with active synovitis. Intervention: Patients received 3.5 gm omega-3 fatty acids daily in a 2.1gm EPA/1.4 gm DHA ratio (7 fish oil and 6 sunflower oil capsules daily); or 1.8 gm /d GLA (6 borage oil and 7 sunflower oil capsules /d); or 7 fish oil and 6 borage oil capsules daily (combination therapy). Discussion: Rheumatoid Arthritis (RA) is a chronic systemic inflammatory disease. Mediators of inflammation and prothrombotic factors contribute to endothelial dysfunction and development of cardiovascular disease in RA patients. Marine and botanical oils represent an excellent primary or secondary therapy for improvement of the cardiovascular risk management in RA. Patients taking these oils exhibit significant additional reductions in total and LDL-cholesterol, triglycerides, the TC/HDL ratio, and in the atherogenic index, and experience a significant increase in HDL-cholesterol. All of these improvements in the lipid profile were seen after 9 months of therapy, and increased after 18 months of oils administration. The overall dropout rate was 51%, and was similar across groups: 25 in the borage oil group, 28 in the fish oil group, and 22 in the combination group. Reasons for dropout were mainly gastrointestinal distress (belching, bloating, diarrhea, nausea, cramping), or an inability to swallow the large number of rather sizable capsules. This can be ameliorated by freezing the capsules and reducing their size. Among those evaluated for this study, compliance was 100%, assessed by pill counts. Learning Outcome: All treatments were safe, thus treatment of RA patients with one or a combination of these or similar oils should prove useful for reduction of cardiovascular risk in RA patients

Alternative Splicing Regulation During C. elegans Development: Splicing Factors as Regulated Targets

Alternative splicing generates protein diversity and allows for post-transcriptional gene regulation. Estimates suggest that 10% of the genes in Caenorhabditis elegans undergo alternative splicing. We constructed a splicing-sensitive microarray to detect alternative splicing for 352 cassette exons and tested for changes in alternative splicing of these genes during development. We found that the microarray data predicted that 62/352 (∼18%) of the alternative splicing events studied show a strong change in the relative levels of the spliced isoforms (>4-fold) during development. Confirmation of the microarray data by RT-PCR was obtained for 70% of randomly selected genes tested. Among the genes with the most developmentally regulated alternatively splicing was the hnRNP F/H splicing factor homolog, W02D3.11 – now named hrpf-1. For the cassette exon of hrpf-1, the inclusion isoform comprises 65% of hrpf-1 steady state messages in embryos but only 0.1% in the first larval stage. This dramatic change in the alternative splicing of an alternative splicing factor suggests a complex cascade of splicing regulation during development. We analyzed splicing in embryos from a strain with a mutation in the splicing factor sym-2, another hnRNP F/H homolog. We found that approximately half of the genes with large alternative splicing changes between the embryo and L1 stages are regulated by sym-2 in embryos. An analysis of the role of nonsense-mediated decay in regulating steady-state alternative mRNA isoforms was performed. We found that 8% of the 352 events studied have alternative isoforms whose relative steady-state levels in embryos change more than 4-fold in a nonsense-mediated decay mutant, including hrpf-1. Strikingly, 53% of these alternative splicing events that are affected by NMD in our experiment are not obvious substrates for NMD based on the presence of premature termination codons. This suggests that the targeting of splicing factors by NMD may have downstream effects on alternative splicing regulation

Control of ϕC31 integrase-mediated site-specific recombination by protein trans-splicing.

Serine integrases are emerging as core tools in synthetic biology and have applications in biotechnology and genome engineering. We have designed a split-intein serine integrase-based system with potential for regulation of site-specific recombination events at the protein level in vivo. The ϕC31 integrase was split into two extein domains, and intein sequences (Npu DnaEN and Ssp DnaEC) were attached to the two termini to be fused. Expression of these two components followed by post-translational protein trans-splicing in Escherichia coli generated a fully functional ϕC31 integrase. We showed that protein splicing is necessary for recombination activity; deletion of intein domains or mutation of key intein residues inactivated recombination. We used an invertible promoter reporter system to demonstrate a potential application of the split intein-regulated site-specific recombination system in building reversible genetic switches. We used the same split inteins to control the reconstitution of a split Integrase-Recombination Directionality Factor fusion (Integrase-RDF) that efficiently catalysed the reverse attR x attL recombination. This demonstrates the potential for split-intein regulation of the forward and reverse reactions using the integrase and the integrase-RDF fusion, respectively. The split-intein integrase is a potentially versatile, regulatable component for building synthetic genetic circuits and devices

Female Sexual Orientation: Behavior and Developmental History

The present study investigated female sexuality by examining a range of experiential, historical, attitudinal, and behavioral variables, and conceptualizing sexual orientation along several dimensions on a heterosexual/homosexual continuum. The focus was on determining what, if any, important etiological factors emerged, as well as differences in behavior, attitudes, and preferences among women with various sexual orientations. It was concluded that a nonconventionality factor could be interacting with certain experiential and situational variables to produce a bisexual or homosexual lifestyle. Consequently, the ideosyncratic variable nature of such a paradigm could partially explain inconsistencies in past research. Results of this study were comparable to previous ones indicating that the women were similar (across sexual orientations) in their emphasis on emotional aspects of a relationship, history of heterosexual dating and coitus, few (relative to males) sex partners, and a less (than males) actively assertive sexual pattern of behavior. Future research might include males in the investigation of the role of a nonconventionality factor in sexual orientation. Also, relationship between cognitive/perceptual styles and sexual orientation could be explored

Roles for Arabidopsis CAMTA Transcription Factors in Cold-Regulated Gene Expression and Freezing Tolerance[W][OA]

The Arabidopsis thaliana CBF cold response pathway plays a central role in cold acclimation. It is characterized by rapid cold induction of genes encoding the CBF1-3 transcription factors, followed by expression of the CBF gene regulon, which imparts freezing tolerance. Our goal was to further the understanding of the cis-acting elements and trans-acting factors involved in expression of CBF2. We identified seven conserved DNA motifs (CM), CM1 to 7, that are present in the promoters of CBF2 and another rapidly cold-induced gene encoding a transcription factor, ZAT12. The results presented indicate that in the CBF2 promoter, CM4 and CM6 have negative regulatory activity and that CM2 has both negative and positive activity. A Myc binding site in the CBF2 promoter was also found to have positive regulatory effects. Moreover, our results indicate that members of the calmodulin binding transcription activator (CAMTA) family of transcription factors bind to the CM2 motif, that CAMTA3 is a positive regulator of CBF2 expression, and that double camta1 camta3 mutant plants are impaired in freezing tolerance. These results establish a role for CAMTA proteins in cold acclimation and provide a possible point of integrating low-temperature calcium and calmodulin signaling with cold-regulated gene expression