Rheumatoid arthritis is associated with reduced adiposity but not with unfavorable major cardiovascular risk factor profiles and enhanced carotid atherosclerosis in black Africans from a developing population: a cross-sectional study

Introduction

Rheumatoid arthritis (RA) is characterized by inflamed joint-derived cytokine-mediated high-grade systemic inflammation that enhances cardiovascular metabolic risk and disease in developed populations. We investigated the potential impact of RA on cardiovascular risk factors including systemic inflammation and atherosclerosis, and their relationships in black Africans from a developing population.

Methods

We evaluated demographic features, adiposity indices, major traditional cardiovascular risk factors, circulating C-reactive protein and interleukin-6 concentrations and ultrasound determined carotid intima-media thickness (cIMT) in 274 black Africans; 115 had established RA. Data were analyzed in confounder-adjusted mixed regression models.

Results

The body mass index and waist-height ratio were lower in RA compared to non-RA subjects (29.2 (6.6) versus 33.7 (8.0), P < 0.0001 and 0.58 (0.09) versus 0.62 (0.1), P = 0.0003, respectively). Dyslipidemia was less prevalent in patients with RA (odds ratio (OR) (95% confidence interval (CI) = 0.54 (0.30 to1.00)); this disparity was no longer significant after further adjustment for reduced adiposity and chloroquine use. RA was also not associated with hypertension, current smoking and diabetes. The number of major traditional risk factors did not differ by RA status (1.1 (0.8) versus 1.2 (0.9), P = 0.7). Circulating C-reactive protein concentrations were similar and serum interleukin-6 concentrations reduced in RA (7.2 (3.1) versus 6.7 (3.1) mg/l, P = 0.7 and 3.9 (1.9) versus 6.3 (1.9) pg/ml, P < 0.0001, respectively). The cIMT was 0.700 (0.085) and 0.701 (0.111) mm in RA and non-RA subjects, respectively (P = 0.7). RA disease activity and severity parameters were consistently unrelated to systemic inflammation, despite the presence of clinically active disease in 82.6% of patients. In all participants, adiposity indices, smoking and converting angiotensin inhibitor non-use were associated with increased systemic inflammation, which related to more atherogenic lipid profiles, and circulating low density lipoprotein concentrations were associated with cIMT (partial R = 0.153, P = 0.032); RA did not impact on these relationships (interaction P ≥0.1).

Conclusions

Among black Africans, patients with established RA experience reduced overall and abdominal adiposity but no enhanced major traditional risk factor and atherosclerosis burden. This study further suggests that an absent interleukin-6 release by inflamed RA joints into the circulation may account for this unaltered cardiovascular disease risk.     

A new paradigm of quality of care in rheumatoid arthritis: how our new therapeutics have changed the game

Demonstrating the effectiveness of expensive new rheumatoid arthritis (RA) therapeutics is imperative to determine whether the quality of care has improved with the introduction of these agents. Our current RA quality measures are primarily process based, but they must become outcomes based to better demonstrate quality. New RA quality measures must be multidimensional, accounting for all of the important outcomes in RA: radiographic, functional status, and disease activity. To fully understand the potential benefits of new therapeutics in RA, outcome measures must be integrated with routine practice.New medications for rheumatoid arthritis (RA), combined with early, aggressive treatment strategies, have improved care. New biologic and small molecule therapies come with a hefty price tag, and demonstrating effectiveness is increasingly important: is the quality of care actually better for RA patients with newer therapies?To answer this question, we must first define quality. As described by the Institute of Medicine, quality of care is ''the degree to which healthcare services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge’ [1]. Quality of care can be evaluated using quality measures, which are tools that provide the ability to quantify an aspect of healthcare relative to an established criterion [2]. Other facets of quality include patient satisfaction and access to care. Quality of care in RA is currently largely based on the use of process-based quality measures. For example: the frequency of disease-modifying anti-rheumatic drug (DMARD) prescribing in RA; the use of disease activity and functional status measures in routine practice; and laboratory monitoring frequency according to established recommendations. These RA quality measures are primarily derived from the Arthritis Foundation Starter Set and the Physician Quality Reporting Database RA measure set, but the American College of Rheumatology is actively developing a new RA measure set [3]. Although the current RA quality measures provide a reasonable starting point, they do not fully capture the spectrum of care quality for patients with RA in the United States.Measures of quality of care are evolving to include concepts such as clinical outcomes. Some even argue that our primary goal should be to provide value: the health outcomes achieved per dollar spent [4]. This newer model incorporates the total cost of providing care to patients for a specific condition over a defined time period, relative to the health outcome achieved. For example, in RA the total cost of care would include nonbiologic and biologic DMARDs, office visits, physical therapy and inpatient hospitalizations. But the real question is how to best define outcomes in a chronic, complex condition such as RA? Outcomes can be multidimensional, accounting for all facets of care for a RA patient: radiographic progression, improvement in functional status score, or a decrease in disease activity score. Radiographic progression is often discussed as an important outcome in randomized controlled trials of RA therapeutics, but it is not a routine part of clinical practice. Measurement of functional status using a standardized, validated instrument is an important patient-reported outcome, capturing key information about how RA impacts activities of daily living. Patient-reported outcomes are not used regularly in many busy, office practices despite the correlation with disease outcomes and mortality [5,6].While professional groups such as the American College of Rheumatology have made recommendations on the measurement of disease activity through the use of tools such as the Disease Activity Score-28, the Clinical Disease Activity Index, or the Routine Assessment of Patient Disease Activity 3, documenting sustained low disease activity or remission requires multiple measurements [7]. Encouraging rheumatologists to treat to target and moving patients from high disease activity to remission is just one dimension of RA outcomes. Each potential clinical outcome has strengths and limitations and probably cannot serve as a standalone measure, but taken together they provide a more nuanced portrait of RA quality of care.Moving from thinking about quality measures as process based to outcomes based is a significant challenge. To achieve good outcomes in RA using the new therapeutics in RA, one needs to consider the timing of therapy, the duration of treatment, and the co-existence of other medical conditions. Some patients may delay initiation of DMARD therapy due to fear of toxicity or lack of understanding of the risk/benefit profile; other patients may not be fully adherent to the treatment plan due to financial issues, socioeconomic factors or language barriers; and still others may not have access to rheumatology care until after they have sustained radiographic or functional damage from their RA. Since quality is often measured at the level of the rheumatologist, how do we risk adjust for these complex patient-related factors when evaluating outcomes in RA? Some rheumatologists see tertiary-care referral patients with longer disease duration, more treatment failures, and multiple co-morbidities. Developing appropriate case-mix adjustment tools to allow for meaningful comparison across providers is a huge task. We have learned that even for a simple quality measure such as whether RA patients receive a DMARD, this case-mix adjustment matters. When evaluating the quality measure on receipt of DMARDs for patients with RA, case-mix adjustment identified age, race and socioeconomic status as negative predictors of DMARD receipt [8].Even though the road will be tough, we must determine how to best measure outcomes in RA to assess quality of care. The expenditures associated with biologic treatments raise important questions for how to demonstrate the effectiveness of medications for RA. However, there are emerging data on RA patients remaining in remission with fewer doses or even cessation of biologic drugs, raising the possibility that we can improve value for patients by simultaneously achieving good health outcomes and decreasing the overall cost of care [9]. An important first step to showing that new therapeutics are translating into better quality of care is incorporating the use of quantitative measurement of disease activity and functional status into routine clinical practice. By regularly measuring possible RA outcome measures, such as disease activity and functional status, we can identify patients who are achieving poor outcomes and create strategies to re-design care delivery for those patients. For example, the use of intensive nurse outreach between regularly scheduled rheumatologist visits to document medication adherence, side effects and education may improve outcomes faster and facilitate treating to target. Developing clinical risk-adjustment tools for RA can help offset differences in patient case mix among rheumatologists.However, measuring outcomes presents major challenges for the healthcare system in general. Collecting structured data to allow quality assessment is not routine in many practices and would place new burdens on the already stressed healthcare system, adding costs and frustration. Furthermore, accurately assessing quality of care requires adjusting for case-mix severity. This is especially true if outcomes become the focus of quality assessment. Collecting the dataset required for case-mix adjustment further taxes the healthcare provider. In addition, there are unanswered questions that remain: what is the current natural history of RA if diagnosed early and treated aggressively with combination nonbiologic and biologic DMARDs? To fully achieve the potential benefits of new therapeutics in RA, we first need RA quality measures that incorporate outcomes and these need to be easily integrated into typical practice.     

G-Octamer Formation from N9-Modified Guanine Derivatives

The properties of the self-assembly of two lipophilic guanine derivatives, 2′,3′,5′-O-tris(tert-butyldimethylsilyl)-guanosine and N⁹-(3,5-bis(tert-butyldimethylsilyloxy)-benzyl)-guanine, are described. In the presence of K⁺, both guanine derivatives self-associate into D ₄-symmetric octamers consisting of two G-quartets stacked around a central ion.     

Characterising the Role of GABA and Its Metabolism in the Wheat Pathogen Stagonospora nodorum

A reverse genetics approach was used to investigate the role of γ-aminobutyric acid metabolism in the wheat pathogenic fungus Stagonospora nodorum. The creation of mutants lacking Sdh1, the gene encoding succinic semialdehyde dehydrogenase, resulted in strains that grew poorly on γ-aminobutyric acid as a nitrogen source. The sdh1 mutants were more susceptible to reactive oxygen stress but were less affected by increased growth temperatures. Pathogenicity assays revealed that the metabolism of γ-aminobutyric acid is required for complete pathogenicity. Growth assays of the wild-type and mutant strains showed that the inclusion of γ-aminobutyric acid as a supplement in minimal media (i.e., not as a nitrogen or carbon source) resulted in restricted growth but increased sporulation. The addition of glutamate, the precursor to GABA, had no effect on either growth or sporulation. The γ-aminobutyric acid effect on sporulation was found to be dose dependent and not restricted to Stagonospora nodorum with a similar effect observed in the dothideomycete Botryosphaeria sp. The positive effect on sporulation was assayed using isomers of γ-aminobutyric acid and other metabolites known to influence asexual development in Stagonospora nodorum but no effect was observed. These data demonstrate that γ-aminobutyric acid plays an important role in Stagonospora nodorum in responding to environmental stresses while also having a positive effect on asexual development.     

Glycated collagen and altered glucose increase endothelial cell adhesion strength

Cell adhesion strength is important to cell survival, proliferation, migration, and mechanotransduction, yet changes in endothelial cell adhesion strength have not yet been examined in diseases such as diabetes with high rates of cardiovascular complications. We therefore investigated porcine aortic endothelial cell adhesion strength on native and glycated collagen‐coated substrates and in low, normal, and high glucose culture using a spinning disc apparatus. Adhesion strength increased by 30 dynes/cm² in cells on glycated collagen as compared to native collagen. Attachment studies revealed that cells use higher adhesion strength α_vβ₃ integrins to bind to glycated collagen instead of the typical α₂β₁ integrins used to bind to native collagen. Similarly, endothelial cells cultured in low and high glucose had 15 dynes/cm² higher adhesion strength than cells in normal glucose after 2 days. Increased adhesion strength was due to elevated VEGF release and intracellular PKC in low and high glucose cells, respectively. Thus glucose increased endothelial cell adhesion strength via different underlying mechanisms. These adhesion strength changes could contribute to diabetic vascular disease, including accelerated atherosclerosis and disordered angiogenesis. J. Cell. Physiol. 228: 1727–1736, 2013. © 2013 Wiley Periodicals, Inc.     

Neuroprotective Effects of Methyl-3-O-methyl gallate Against Sodium Fluoride-Induced Oxidative Stress in the Brain of Rats

Methyl-3-O-methyl gallate (M3OMG) is a rare natural product that showed promising in vitro antioxidant activities. In this study, the protective role of synthetic M3OMG against sodium fluoride (NaF)-induced oxidative stress in rat brain was evaluated. Animals were treated with either M3OMG (10 and 20 mg/kg i.p.), vitamin C (10 mg/kg i.p.) as the standard antioxidant or the vehicle (5 % dimethyl sulfoxide; 1 ml/kg) for 1 week. Oxidative stress was induced in the brain by adding 600 ppm NaF in the drinking water for 7 days. At the end of the treatment period, the levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione and the activities of antioxidant enzymes (superoxide dismutase and catalase) were evaluated in brain homogenates. M3OMG treatment mitigated the NaF-induced oxidative stress through normalization of the level of TBARS, reduced levels of glutathione and by the restoration of the diminished antioxidant enzyme activities. In conclusion, M3OMG could have a potential for treating neurotoxicity induced by fluoride or related environmental pollutants.     

Development,cross-species/genera transferability of novel EST-SSR markers and their utility in revealing population structure and genetic diversity in sugarcane

Sugarcane (Saccharum spp. hybrid) with complex polyploid genome requires a large number of informative DNA markers for various applications in genetics and breeding. Despite the great advances in genomic technology, it is observed in several crop species, especially in sugarcane, the availability of molecular tools such as microsatellite markers are limited. Now-a-days EST-SSR markers are preferred to genomic SSR (gSSR) as they represent only the functional part of the genome, which can be easily associated with desired trait. The present study was taken up with a new set of 351 EST-SSRs developed from the 4085 non redundant EST sequences of two Indian sugarcane cultivars. Among these EST-SSRs, TNR containing motifs were predominant with a frequency of 51.6%. Thirty percent EST-SSRs showed homology with annotated protein. A high frequency of SSRs was found in the 5′UTR and in the ORF (about 27%) and a low frequency was observed in the 3′UTR (about 8%). Two hundred twenty-seven EST-SSRs were evaluated, in sugarcane, allied genera of sugarcane and cereals, and 134 of these have revealed polymorphism with a range of PIC value 0.12 to 0.99. The cross transferability rate ranged from 87.0% to 93.4% in Saccharum complex, 80.0% to 87.0% in allied genera, and 76.0% to 80.0% in cereals. Cloning and sequencing of EST-SSR size variant amplicons revealed that the variation in the number of repeat-units was the main source of EST-SSR fragment polymorphism. When 124 sugarcane accessions were analyzed for population structure using model-based approach, seven genetically distinct groups or admixtures thereof were observed in sugarcane. Results of principal coordinate analysis or UPGMA to evaluate genetic relationships delineated also the 124 accessions into seven groups. Thus, a high level of polymorphism adequate genetic diversity and population structure assayed with the EST-SSR markers not only suggested their utility in various applications in genetics and genomics in sugarcane but also enriched the microsatellite marker resources in sugarcane.     

Optimization of selection for growth in Menz Sheep while minimizing inbreeding depression in fitness traits

The genetic trends in fitness (inbreeding, fertility and survival) of a closed nucleus flock of Menz sheep under selection during ten years for increased body weight were investigated to evaluate the consequences of selection for body weight on fitness. A mate selection tool was used to optimize in retrospect the actual selection and matings conducted over the project period to assess if the observed genetic gains in body weight could have been achieved with a reduced level of inbreeding. In the actual selection, the genetic trends for yearling weight, fertility of ewes and survival of lambs were 0.81 kg, –0.00026% and 0.016% per generation. The average inbreeding coefficient remained zero for the first few generations and then tended to increase over generations. The genetic gains achieved with the optimized retrospective selection and matings were highly comparable with the observed values, the correlation between the average breeding values of lambs born from the actual and optimized matings over the years being 0.99. However, the level of inbreeding with the optimized mate selections remained zero until late in the years of selection. Our results suggest that an optimal selection strategy that considers both genetic merits and coancestry of mates should be adopted to sustain the Menz sheep breeding program.     

Chromosomal Assignment of Six Genes (EIF4G3, HSP90, RBBP6, IL8, TERT,and TERC) in Four Species of the Genus Equus

We mapped six genes (EIF4G3, HSP90, RBBP6, IL8, TERT, and TERC) on the chromosomes of Equus caballus, Equus asinus, Equus grevyi, and Equus burchelli by fluorescence in situ hybridization. Our results add six type I markers to the cytogenetic map of these species and provide new information on the comparative genomics of the genus Equus.     

Photochemical characterization of a novel fungal rhodopsin from Phaeosphaeria nodorum

Eukaryotic microbial rhodopsins are widespread bacteriorhodopsin-like proteins found in many lower eukaryotic groups including fungi. Many fungi contain multiple rhodopsins, some significantly diverged from the original bacteriorhodopsin template. Although few fungal rhodopsins have been studied biophysically, both fast-cycling light-driven proton pumps and slow-cycling photosensors have been found. The purpose of this study was to characterize photochemically a new subgroup of fungal rhodopsins, the so-called auxiliary group. The study used the two known rhodopsin genes from the fungal wheat pathogen, Phaeosphaeria nodorum. One of the genes is a member of the auxiliary group while the other is highly similar to previously characterized proton-pumping Leptosphaeria rhodopsin. Auxiliary rhodopsin genes from a range of species form a distinct group with a unique primary structure and are located in carotenoid biosynthesis gene cluster. Amino acid conservation pattern suggests that auxiliary rhodopsins retain the transmembrane core of bacteriorhodopsins, including all residues important for proton transport, but have unique polar intramembrane residues. Spectroscopic characterization of the two yeast-expressed Phaeosphaeria rhodopsins showed many similarities: absorption spectra, conformation of the retinal chromophore, fast photocycling, and carboxylic acid protonation changes. It is likely that both Phaeosphaeria rhodopsins are proton-pumping, at least in vitro. We suggest that auxiliary rhodopsins have separated from their ancestors fairly recently and have acquired the ability to interact with as yet unidentified transducers, performing a photosensory function without changing their spectral properties and basic photochemistry.