Antimicrobial therapies for prevention of recurrent acute exacerbations of COPD (AECOPD): beyond the guidelines.

BACKGROUND: Unfortunately, many COPD patients continue to exacerbate despite good adherence to GOLD Class D recommended therapy. Acute exacerbations lead to an increase in symptoms, decline in lung function and increased mortality rate. The purpose of this review is to do a literature search for any prophylactic anti-microbial treatment trials in GOLD class D patients who 'failed' recommended therapy and discuss the role of COPD phenotypes, lung and gut microbiota and co-morbidities in developing a tailored approach to anti-microbial therapies for high frequency exacerbators. MAIN TEXT: There is a paucity of large, well-conducted studies in the published literature to date. Factors such as single-centre, study design, lack of well-defined controls, insufficient patient numbers enrolled and short follow-up periods were significant limiting factors in numerous studies. One placebo-controlled study involving more than 1000 patients, who had 2 or more moderate exacerbations in the previous year, demonstrated a non-significant reduction in exacerbations of 19% with 5 day course of moxifloxacillin repeated at 8 week intervals. In Pseudomonas aeruginosa (Pa) colonised COPD patients, inhaled antimicrobial therapy using tobramycin, colistin and gentamicin resulted in significant reductions in exacerbation frequency. Viruses were found to frequently cause acute exacerbations in COPD (AECOPD), either as the primary infecting agent or as a co-factor. However, other, than the influenza vaccination, there were no trials of anti-viral therapies that resulted in a positive effect on reducing AECOPD. Identifying clinical phenotypes and co-existing conditions that impact on exacerbation frequency and severity is essential to provide individualised treatment with targeted therapies. The role of the lung and gut microbiome is increasingly recognised and identification of pathogenic bacteria will likely play an important role in personalised antimicrobial therapies. CONCLUSION: Antimicrobial therapeutic options in patients who continue to exacerbate despite adherence to guidelines-directed therapy are limited. Phenotyping patients, identification of co-existing conditions and assessment of the microbiome is key to individualising antimicrobial therapy. Given the impact of viruses on AECOPD, anti-viral therapeutic agents and targeted anti-viral vaccinations should be the focus of future research studies.

The altered gut microbiota in adults with cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed. RESULTS: The CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (-0.383, Simpson's Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity. CONCLUSIONS: This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

The transcriptome of the arbuscular mycorrhizal fungus Glomus intraradices (DAOM 197198) reveals functional tradeoffs in an obligate symbiont.

• The arbuscular mycorrhizal symbiosis is arguably the most ecologically important eukaryotic symbiosis, yet it is poorly understood at the molecular level. To provide novel insights into the molecular basis of symbiosis-associated traits, we report the first genome-wide analysis of the transcriptome from Glomus intraradices DAOM 197198. • We generated a set of 25,906 nonredundant virtual transcripts (NRVTs) transcribed in germinated spores, extraradical mycelium and symbiotic roots using Sanger and 454 sequencing. NRVTs were used to construct an oligoarray for investigating gene expression. • We identified transcripts coding for the meiotic recombination machinery, as well as meiosis-specific proteins, suggesting that the lack of a known sexual cycle in G. intraradices is not a result of major deletions of genes essential for sexual reproduction and meiosis. Induced expression of genes encoding membrane transporters and small secreted proteins in intraradical mycelium, together with the lack of expression of hydrolytic enzymes acting on plant cell wall polysaccharides, are all features of G. intraradices that are shared with ectomycorrhizal symbionts and obligate biotrophic pathogens. • Our results illuminate the genetic basis of symbiosis-related traits of the most ancient lineage of plant biotrophs, advancing future research on these agriculturally and ecologically important symbionts.

Health-related quality of life, smoking and carotid atherosclerosis in white British women with systemic lupus erythematosus.

We tested the hypothesis that carotid atherosclerosis in systemic lupus erythematosus (SLE) is associated with poor health-related quality of life (HRQOL), which is independent of any association with traditional risk factors (TRFs), lifestyle and socioeconomic factors. Women with SLE completed the RAND Medical Outcome Study 36-Item Short-Form Health Survey version 1 (MOS SF-36). B-mode Doppler examination of the carotid arteries determined the presence of atherosclerotic plaque. The association between carotid plaque and HRQOL domains was analysed using logistic regression models with sequential adjustments for age, TRFs, education level and employment status. We studied 181 women, 47 (26%) of whom had carotid plaque. Carotid plaque was significantly associated with lower levels of physical functioning (p = 0.047), vitality (p = 0.04), role emotional (p = 0.04) and mental health subscales (p = 0.01) and lower mental component summary score (MCS) (p = 0.03). These associations were no longer significant after adjustment for age and TRFs, especially smoking. Smokers had lower physical functioning, vitality and mental health and more bodily pain. The association between carotid plaque and HRQOL was not independent of TRFs and smoking was a key mediator of the associations found. Poor HRQOL in smokers will need addressing as part of any smoking cessation strategies in SLE patients.

Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register.

BACKGROUND: Anti-tumour necrosis factor (TNF)alpha treatments improve outcome in severe rheumatoid arthritis (RA) and are efficacious in psoriasis and psoriatic arthritis. However recent case reports describe psoriasis occurring as an adverse event in patients with RA receiving anti-TNFalpha therapy. OBJECTIVES: We aimed to determine whether the incidence rate of psoriasis was higher in patients with RA treated with anti-TNFalpha therapy compared to those treated with traditional disease-modifying antirheumatic drugs (DMARDs). We also compared the incidence rates of psoriasis between the three anti-TNFalpha drugs licensed for RA. METHODS: We studied 9826 anti-TNF-treated and 2880 DMARD-treated patients with severe RA from The British Society for Rheumatology Biologics Register (BSRBR). All patients reported with new onset psoriasis as an adverse event were included in the analysis. Incidence rates of psoriasis were calculated as events/1000 person years and compared using incidence rate ratios (IRR). RESULTS: In all, 25 incident cases of psoriasis in patients receiving anti-TNFalpha therapy and none in the comparison cohort were reported between January 2001 and July 2007. The absence of any cases in the comparison cohort precluded a direct comparison; however the crude incidence rate of psoriasis in those treated with anti-TNFalpha therapy was elevated at 1.04 (95% CI 0.67 to 1.54) per 1000 person years compared to the rate of 0 (upper 97.5% CI 0.71) per 1000 person years in the patients treated with DMARDs. Patients treated with adalimumab had a significantly higher rate of incident psoriasis compared to patients treated with etanercept (IRR 4.6, 95% CI 1.7 to 12.1) and infliximab (IRR 3.5, 95% CI 1.3 to 9.3). CONCLUSIONS: Results from this study suggest that the incidence of psoriasis is increased in patients treated with anti-TNFalpha therapy. Our findings also suggest that the incidence may be higher in patients treated with adalimumab.

Activation tagging of the floral inducer FT.

FLOWERING LOCUS T (FT), which acts in parallel with the meristem-identity gene LEAFY (LFY) to induce flowering of Arabidopsis, was isolated by activation tagging. Like LFY, FT acts partially downstream of CONSTANS (CO), which promotes flowering in response to long days. Unlike many other floral regulators, the deduced sequence of the FT protein does not suggest that it directly controls transcription or transcript processing. Instead, it is similar to the sequence of TERMINAL FLOWER 1 (TFL1), an inhibitor of flowering that also shares sequence similarity with membrane-associated mammalian proteins.

The comparative responsiveness of the EQ-5D and SF-6D to change in patients with inflammatory arthritis.

PURPOSE: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). METHODS: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger's Z test. Treatment response and self-reported change were used as anchors of important change. RESULTS: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. CONCLUSIONS: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ-5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate.

Triggering of systolic arterial pressure alarms using statistics-based versus threshold alarms.

Threshold systolic arterial pressure alarms often use pre-operative values as a guide for intra-operative values. Recently, two systems (normalisation and principal component analysis) have been described that use the 'current' systolic arterial pressure and the change in systolic arterial pressure over a preceding time interval to generate an alarm based on units of standard deviation. Normalisation and principal component analysis techniques should prioritize alarms for clinically significant changes and hence reduce overall activation of alarms. Our aim was to measure the change in alarm activation using these techniques compared with standard threshold alarms. Systolic blood pressure data, collected from 10 patients (a total of 2177 min at 100 Hz), were cleaned and submitted to analysis using threshold alarms, normalisation and principal component analysis. With the threshold alarms set at 100 mmHg (low) and 140 mmHg (high), and a 5-min window, the alarms were activated for 557 min; using statistics-based thresholds the alarms were activated for 169 min (normalisation) and 155 min (principal component analysis), a reduction of approximately 70-72%.

Predictors of bone density testing in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk of low bone density and fractures. This study identifies predictors of initiation of dual energy X-ray absorptiometry (DXA) testing in RA. We identified RA patients from the CORRONA registry with >or=1 year follow-up without reported DXA at study entry. The primary outcome was report of DXA in the first year of follow-up (DXA initiation). Variables associated with DXA initiation were considered for the multivariate model. Stepwise logistic regression identified independent predictors. Of the 2,717 RA patients without DXA documented at enrollment, 297 (11%) reported DXA initiation. Independent predictors of DXA initiation included age, female sex, history of fracture, steroid use, and physician's assessment of RA activity. In conclusion, DXA initiation in RA patients in the CORRONA cohort is low despite increased risk of osteoporosis. Predictors of DXA initiation include fracture, common risk factors for osteoporosis, and RA-associated factors.

An update on UK rheumatology consultant workforce provision: the BSR/ARC Workforce Register 2005-07: assessing the impact of recent changes in NHS provision.

OBJECTIVES: To describe changes in the provision of rheumatology services, monitor the pattern of inequalities in UK rheumatology service provision since 2005, and to summarize the 3-yr impact of the new National Health Service (NHS) consultant contract and the Musculoskeletal Services Framework in England and Wales. METHODS: Questionnaires about timetable and working conditions were sent to all consultants on the BSR/ARC UK Workforce Register in January 2007, along with the personal and job-related details currently held about them on the register to update. The questionnaire included a visual analogue scale asking 'how concerned are you that your current post might be under threat' ranging from 0 'Not at all' to 100 'Extremely'. RESULTS: The response rate of the 2005 and 2007 surveys were 89 and 87%, respectively. Levels of optimal provision now exceed 70% in England and Wales, and 50% in Scotland and Northern Ireland. Levels of provision remain substantially higher in London than anywhere else. The median level of perceived job threat in the UK was 31 (interquartile range 11-61). Consultants in areas where provision is highest and a higher proportion of services are run in conjunction with Clinical Assessment and Treatment (CAT) centres report higher perceived job threat. CONCLUSIONS: Provision of rheumatology services has continued to expand over the past decade; however, inequalities persist at national and sub-national level. There is evidence of improvement in regions with the lowest provision, but there are indications of increased perceived job threat in areas with traditionally higher provision and where CAT centres have been introduced.

Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis.

Rheumatoid arthritis is both common and chronic, with significant consequences for multiple organ systems. Better understanding of its pathophysiology has led to the development of targeted therapies that have dramatically improved outcomes. The key to therapeutic success lies in identifying individuals who will have severe destructive disease as early as possible, so that effective treatment can be initiated before irreversible damage occurs. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing is particularly useful in the diagnosis of rheumatoid arthritis, with high specificity, presence early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, its sensitivity is low, and a negative result does not exclude disease. Anti-CCP antibodies have not been found at a significant frequency in other diseases to date, and are more specific than rheumatoid factor for detecting rheumatoid arthritis. We discuss anti-CCP antibody testing in rheumatoid arthritis, with an emphasis on diagnostic performance, prognostic capability, and relevance to pathogenesis and new treatment paradigms in rheumatoid arthritis.

Clostridium difficile carriage in adult cystic fibrosis (CF); implications for patients with CF and the potential for transmission of nosocomial infection.

Clostridium difficile is an anaerobic Gram-positive, spore-forming, toxin-producing bacillus transmitted among humans through the faecal-oral route. Despite increasing carriage rates and the presence of C. difficile toxin in stool, patients with CF rarely appear to develop typical manifestations of C. difficile infection (CDI). In this study, we examined the carriage, toxin production, ribotype distribution and antibiotic susceptibility of C. difficile in a cohort of 60 adult patients with CF who were pre-lung transplant. C. difficile was detected in 50% (30/60) of patients with CF by culturing for the bacteria. C. difficile toxin was detected in 63% (19/30) of C. difficile-positive stool samples. All toxin-positive stool samples contained toxigenic C. difficile strains harbouring toxin genes, tcdA and tcdB. Despite the presence of C. difficile and its toxin in patient stool, no acute gastrointestinal symptoms were reported. Ribotyping of C. difficile strains revealed 16 distinct ribotypes (RT), 11 of which are known to be disease-causing including the hyper-virulent RT078. Additionally, strains RT002, RT014, and RT015, which are common in non-CF nosocomial infection were described. All strains were susceptible to vancomycin, metronidazole, fusidic acid and rifampicin. No correlation was observed between carriage of C. difficile or any characteristics of isolated strains and any recorded clinical parameters or treatment received. We demonstrate a high prevalence of hypervirulent, toxigenic strains of C. difficile in asymptomatic patients with CF. This highlights the potential role of asymptomatic patients with CF in nosocomial transmission of C. difficile.

Development of the arbuscular mycorrhizal symbiosis.

The arbuscular mycorrhizal (AM) symbiosis formed between plant roots and fungi is one of the most widespread symbiotic associations found in plants, yet our understanding of events underlying its development are limited. The recent integration of biochemical, molecular and genetic approaches into analyses of the symbiosis is providing new insights into various aspects of its development. In the past year there have been advances in our understanding of the signals required for the formation of appressoria, the molecular changes in the root in response to colonisation, and components of the signal transduction pathways common to both the AM and Rhizobium symbioses.

GlycoSuiteDB: a new curated relational database of glycoprotein glycan structures and their biological sources.

GlycoSuiteDB is a relational database that curates information from the scientific literature on glyco-protein derived glycan structures, their biological sources, the references in which the glycan was described and the methods used to determine the glycan structure. To date, the database includes most published O:-linked oligosaccharides from the last 50 years and most N:-linked oligosaccharides that were published in the 1990s. For each structure, information is available concerning the glycan type, linkage and anomeric configuration, mass and composition. Detailed information is also provided on native and recombinant sources, including tissue and/or cell type, cell line, strain and disease state. Where known, the proteins to which the glycan structures are attached are reported, and cross-references to the SWISS-PROT/TrEMBL protein sequence databases are given if applicable. The GlycoSuiteDB annotations include literature references which are linked to PubMed, and detailed information on the methods used to determine each glycan structure are noted to help the user assess the quality of the structural assignment. GlycoSuiteDB has a user-friendly web interface which allows the researcher to query the database using mono-isotopic or average mass, monosaccharide composition, glycosylation linkages (e.g. N:- or O:-linked), reducing terminal sugar, attached protein, taxonomy, tissue or cell type and GlycoSuiteDB accession number. Advanced queries using combinations of these parameters are also possible. GlycoSuiteDB can be accessed on the web at http://www.glycosuite.com.

The Medicago Genome Initiative: a model legume database.

The Medicago Genome Initiative (MGI) is a database of EST sequences of the model legume MEDICAGO: truncatula. The database is available to the public and has resulted from a collaborative research effort between the Samuel Roberts Noble Foundation and the National Center for Genome Resources to investigate the genome of M.truncatula. MGI is part of the greater integrated MEDICAGO: functional genomics program at the Noble Foundation (http://www.noble.org ), which is taking a global approach in studying the genetic and biochemical events associated with the growth, development and environmental interactions of this model legume. Our approach will include: large-scale EST sequencing, gene expression profiling, the generation of M.truncatula activation-tagged and promoter trap insertion mutants, high-throughput metabolic profiling, and proteome studies. These multidisciplinary information pools will be interfaced with one another to provide scientists with an integrated, holistic set of tools to address fundamental questions pertaining to legume biology. The public interface to the MGI database can be accessed at http://www.ncgr.org/research/mgi.

Immigrant women family caregivers in Canada: implications for policies and programmes in health and social sectors.

Migration has become a profound global phenomenon in this century. In Canada, uncoordinated policies, including those related to immigration, resettlement, employment, and government funding for health and social services, present barriers to immigrant women caregivers. The purpose of this paper is to share relevant insights from individual and group interviews with immigrant women family caregivers, service providers and policy influencers, and discuss these in relation to immigration, health and social policy, and programme trends in Canada. The present authors conducted individual interviews with immigrant women family caregivers (n = 29) in phase 1, followed by two group interviews with women family caregivers (n = 7), and two group interviews with service providers and policy-makers (n = 15) in phase 2. Using an inductive approach, the authors employed thematic content data analysis. Immigrant women experienced barriers to health and social services similar to Canadian-born family caregivers, particularly those who have low incomes, jobs with limited flexibility and heavy caregiving demands. These immigrant women family caregivers avoided certain formal services for a variety of reasons, including lack of cultural sensitivity. However, their challenges were compounded by language, immigration and separation from family in the home country. The identified barriers to support reinforce the importance of modifying and expanding policies and programmes affecting immigrant women's ability to care for family members with illnesses or disabilities within the context of Canadian society. Participants recommended changes to policies and programmes to deal with information, transportation, language, attitudinal and network barriers. The various barriers to services and programmes which were experienced by immigrant women caregivers underscore the importance of reviewing policies affecting immigration, caregiving, and access to health and social services. Intersectoral collaboration among agencies is essential to reduce the barriers identified in the present study, and to establish services which are linguistically and culturally appropriate.

Methotrexate use in rheumatoid arthritis is associated with few clinically significant liver function test abnormalities.

OBJECTIVE: To determine the frequency of liver function tests (LFT) abnormalities associated with methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). METHODS: A retrospective chart review for demographic information, RA-specific history, medication history, complications of therapy, results of all available blood tests (specifically aspartate aminotransferase (AST), alanine aminotransferase (ALT), complete blood count (CBC), albumin, creatinine), and liver biopsy reports was conducted for RA patients, who were currently using or have used MTX in the past. RESULTS: A total of 2791 LFTs were performed among 182 RA patients with 94 abnormal results. 152 patients (83.5%) with 2007 LFT evaluations demonstrated no abnormal results, compared with 30 patients (16.5%) who had at least one abnormal LFT in 784 tests. Twenty-two of the 30 patients with at least one LFT abnormality (73.3%) continued treatment despite the elevation without further evaluation or change in therapy, and subsequent LFT assessments were within normal limits. 128 patients (70.3%) remained on MTX at the time of our study. The most common reason for discontinuation was inadequate response. CONCLUSIONS: MTX appears to be associated with very few clinically significant hepatic side effects. In view of these data, consideration as to revision of the current MTX monitoring guidelines in the direction of less frequent monitoring, especially in patients with no risk factors for liver disease, may be considered.