The enzymatic properties of Arabidopsis thaliana DNA polymerase λ suggest a role in base excision repair.

Base excision repair (BER) generates gapped DNA intermediates containing a 5'-terminal 2-deoxyribose-5-phosphate (5'-dRP) group. In mammalian cells, gap filling and dRP removal are catalyzed by Pol ß, which belongs to the X family of DNA polymerases. In higher plants, the only member of the X family of DNA polymerases is Pol λ. Although it is generally believed that plant Pol λ participates in BER, there is limited experimental evidence for this hypothesis. Here we have characterized the biochemical properties of Arabidopsis thaliana Pol λ (AtPol λ) in a BER context, using a variety of DNA repair intermediates. We have found that AtPol λ performs gap filling inserting the correct nucleotide, and that the rate of nucleotide incorporation is higher in substrates containing a C in the template strand. Gap filling catalyzed by AtPol λ is most efficient with a phosphate at the 5'-end of the gap and is not inhibited by the presence of a 5'-dRP mimic. We also show that AtPol λ possesses an intrinsic dRP lyase activity that is reduced by mutations at two lysine residues in its 8-kDa domain, one of which is present in Pol λ exclusively and not in any Pol ß homolog. Importantly, we also found that the dRP lyase activity of AtPol λ allows efficient completion of uracil repair in a reconstituted short-patch BER reaction. These results suggest that AtPol λ plays an important role in plant BER.

The C-terminal domain of Arabidopsis ROS1 DNA demethylase interacts with histone H3 and is required for DNA binding and catalytic activity.

Active DNA demethylation plays an important role in controlling methylation patterns in eukaryotes. In plants, the DEMETER-LIKE (DML) family of 5-methylcytosine DNA glycosylases initiates DNA demethylation through a base excision repair pathway. However, it is poorly understood how these DNA demethylases are recruited to their target loci and the role that histone marks play in this process. Arabidopsis REPRESSOR OF SILENCING 1 (ROS1) is a representative enzyme of the DML family, whose members are uniquely characterized by a basic amino-terminal domain mediating nonspecific binding to DNA, a discontinuous catalytic domain, and a conserved carboxy-terminal domain of unknown function. Here, we show that ROS1 interacts with the N-terminal tail of H3 through its C-terminal domain. Importantly, phosphorylation at H3 Ser28, but not Ser10, abrogates ROS1 interaction with H3. Conserved residues at the C-terminal domain are not only required for H3 interaction, but also for efficient DNA binding and catalytic activity. Our findings suggest that the C-terminal domain of ROS1 may function as a histone reader module involved in recruitment of the DNA demethylase activity to specific genomic regions.

Fibromyalgia in patients with ankylosing spondylitis: prevalence and utility of the measures of activity, function and radiological damage.

OBJECTIVES: To determine the prevalence of fibromyalgia (FM) in ankylosing spondylitis (AS). To evaluate the effect of FM on the measures of activity in AS. To analyse predictive factors in order to identify this group of patients. PATIENTS AND METHODS: A cross-sectional study based on 462 patients with definite ankylosing spondylitis included in the REGISPONSER. Sociodemographic data, clinical features, Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI), Bath AS radiology index (BASRI), Stoke modified index (Sasss-m), laboratory data, Short-Format 12 (SF-12), AS specific quality of life (ASQoL), Fibromyalgia Impact Questionnaire (FIQ) and treatments used were all documented. To diagnose FM, the ACR 1990 criteria had to be fulfilled. All statistical tests were performed using STATA. RESULTS: The prevalence of fibromyalgia in all AS was 4.11%. Among the women with AS, the prevalence of FM increased to 10.83%. The BASDAI, BASFI and total BASRI were strongly influenced by the presence of FM. The inverse relationship between BASDAI or BASFI and total BASRI was taken to generate a ratio. Accordingly, if the patient presented BASDAI/BASRI ≥1.5 or BASFI/BASRI ≥1.08, the probability of having FM was very high. CONCLUSIONS: There is an increased risk of FM in females with AS. The fact of having FM distorts the measures of activity and functional damage of AS. As a result, it is possible that some patients with AS and FM are being overtreated. The BASDAI/BASRI and BASFI/BASRI ratios are very useful to identify these patients.

Relationship between spinal mobility and disease activity, function, quality of life and radiology. A cross-sectional Spanish registry of spondyloarthropathies (REGISPONSER).

OBJECTIVE: To determine the relationship between anthropometric measurements and disease activity, functional capacity, quality of life and radiology in Spanish patients with ankylosing spondylitis (AS). PATIENTS AND METHODS: A cross-sectional study was made of 842 patients with definite ankylosing spondylitis (REGISPONSER). Sociodemographic data, spinal mobility measurements, Bath AS disease activity index (BASDAI), nocturnal pain, Bath AS radiology index (BASRI), Bath AS functional index (BASFI), the Short-Format 12 (SF-12) and the AS specific quality of life (ASQoL) questionnaire were applied. Pearson correlation coefficient analysis and regression models were constructed. RESULTS: There was moderate correlation between fingertip-to-floor distance and lateral cervical rotation with the BASFI (p<0.01). Good correlation was evident between wall-occiput distance and lateral cervical rotation with the BASRI (p<0.01). Moderate correlation was found between chest expansion, the Schober modified test and fingertip-to-floor distance with the total BASRI (p<0.01). The anthropometric measurement with the lowest correlation value was lateral lumbar flexion. Significant association was found between the Schober modified test and BASFI, BASDAI and BASRI (R(2) = 0.37; p<0.001); chest expansion and BASFI, BASDAI and BASRI (R(2) = 0.25; p<0.001); wall-occiput distance and BASFI, BASRI and ASQoL (R(2) = 0.44; p<0.001); fingertip-to-floor distance and BASFI and BASRI (R(2) = 0.30; p<0.001); and lateral cervical rotation and BASFI and BASRI (R(2) = 0.34; p<0.001). CONCLUSION: In our study, wall-occiput distance and lateral cervical rotation showed the strongest correlation to BASRI. Similarly, fingertip-to-floor distance and lateral cervical rotation exhibited the closest correlation to BASFI.

Adalimumab for treating rheumatoid arthritis.

BACKGROUND: Adalimumab is a fully human anti-TNFalpha monoclonal antibody. Published studies indicate that its use in patients with RA can be effective and safe. OBJECTIVES: The aim of this review was to assess the efficacy and safety of adalimumab in the treatment of RA. SEARCH STRATEGY: Electronic databases were searched up to August, 2004: MEDLINE, CINAHL, EBM Reviews (CDSR, ACP Journal Club, DARE and CENTRAL) and Health STAR. Conference proceedings were hand searched and pharmaceutical companies were contacted to obtain additional unpublished data from published trials. Adalimumab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing adalimumab alone or in combination with DMARDs to placebo or other DMARDs. DATA COLLECTION AND ANALYSIS: Two reviewers independently collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Outcome measures included ACR and EULAR responses, DAS 28 and components of ACR response and radiographic data. Safety data were also included. Continuous data were reported as weighted mean difference (WMD) with 95% confidence interval (95%CI), absolute benefit (AB) and relative difference (RD). Dichotomous outcomes were reported as relative risk (RR) with 95% CI, absolute risk difference (ARD) or risk difference (RDiff) with 95%CI and number needed to treat (NNT) or to harm (NNH). When significant heterogeneity was not found, data were pooled. MAIN RESULTS: Six studies with 2381 patients were included in this review. Two comparisons were done: A. adalimumab subcutaneously (sc) + methotrexate (or DMARDs) versus placebo sc + methotrexate (or DMARDs). B. adalimumab sc in monotherapy versus placebo sc. In the comparison A, with adalimumab 40 mg every other week (e.o.w.), the RR to achieve an ACR 20 response at 24 weeks ranged in the included studies from 1.52 to 4.63, and the NNT ranged from 1.9 to 5.4. The RR (95%CI) to achieve an ACR 50 response was 4.63 (3.04-7.05), and the NNT was 3.0 (95%CI 2.0-6.0). The RR (95%CI) to achieve an ACR 70 response was 5.14 (3.14-8.41) and the number needed to treat was 7.0 (95%CI 5.0-13.0). At 52 weeks, the RRs (95%CI) to achieve an ACR 20, 50, and 70 response were 2.46 (1.87-3.22), 4.37 (2.77-6.91), and 5.15 (2.60-10.22), with NNTs of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg e.o.w. and 20 mg every week (e.w.) significantly slowed the radiological progression including Sharp modified index, erosion score, and joint space score (only with 40 mg e.o.w.). In the comparison B, with adalimumab 40 mg e.o w. , the RRs to achieve an ACR 20, 50, and 70 response at 24/26 weeks were 1.91 (1.17-3.10), 2.84 (1.58-5.12), and 7.33 (2.25-33.90) with NNTs of 5.0 (95%CI 3.0-9.0), 7.0 (4.0-20.0), and 9.0 (3.0-38.0), respectively. In most of the analysed studies and comparisons, there were not significant differences in safety outcomes between adalimumab and control groups. The development of positive antinuclear antibodies was significantly more frequent in adalimumab patients than in placebo patients. Serious infections were significantly more frequent in adalimumab patients in only one study (Keystone 2004) with a RR (95%CI) of 7.64(1.02-57.18) and a NNH of 30.2. AUTHORS' CONCLUSIONS: On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.

Omega-3 fatty acids in rheumatoid arthritis: an overview.

OBJECTIVES: To review background, pharmacological properties, mechanisms of action, and published clinical experience using omega-3 fatty acids in rheumatoid arthritis. MATERIALS AND METHODS: English language publications were identified through a computerized search (using MEDLINE) between 1979 and 1995 using the terms "omega-3 fatty acids" and "fish oil". In addition, manual search and cross references were used to obtain published articles on the subject. Papers showing evidence of pharmacological properties and mechanisms of action were analyzed. For therapeutic efficacy, only randomized clinical trials are presented in this article. All papers were reviewed by a board certified rheumatologist with training in research methodology and critical appraisal skills. He was aware of study objectives. RESULTS: Main results are summarized in the text and presented in tables. Mean change from baseline is presented only for patients treated with omega-3 fatty acids. Omega-3 fatty acids are superior with respect to placebo in improving some outcome measures, and decrease the long-term requirements for nonsteroidal antiinflammatory drugs. Some of these effects are statistically significant, but their clinical significance remain to be established. CONCLUSIONS: Treatment with omega-3 fatty acids has been associated with improvement in some outcome measures in rheumatoid arthritis. Studies are needed to determine if they might represent an alternative to nonsteroidal antiinflammatory drugs in certain circumstances.

Direct-acting mutagenic activity in white, rosé, and red wines with the Ara test of Salmonella typhimurium.

Thirty-two commercially produced white, rosé, and red wines from Spain were assayed for genotoxicity. The Ara forward mutagenicity assay with Salmonella typhimurium served as the test system. All the wines were mutagenic in the absence of mammalian microsomal activation (S9 mix) and/or glycosidase activities with the exception of one rosé wine which gave a clear dose-response relationship, although its mutagenic potency was considered statistically nonsignificant. The mutagenic activity covered nearly a 30-fold range. Compared to white and rosé wines, red wines showed the highest levels of mutagenicity; this wine type included four "very potent" (greater than 3,000 AraR mutants/ml) mutagenic wines. The level of wine mutagenicity did not correlate with either the region or the year of production (vintage). Individual winery methods are suggested as primarily responsible for variations in mutagenic activity. The present study with the Ara test supports the possibility that wine components other than the flavonols quercetin and rutin are the major putative mutagens: (1) white wines, as well as rosé or red wines, were detected as being mutagenic; (2) in no case was activation required for the detection of mutagenicity; (3) mutagen(s) were detected mainly (red wine) when not exclusively (white and rosé wine) in the polar fraction from XAD-2 chromatography. The high sensitivity of the Ara test has allowed the screening of the mutagenicity of a variety of wines with no previous process of extraction or concentration. The comparison of the mutagenic activity of the entire complex mixture to that of its lyophilized residue has revealed a positive synergistic role for ethanol in the mutagenicity of certain wines. Finally, this work suggests that the Ara test is a useful tool for mutagenicity screening in wines. Thus, this test might play an important role in elucidating the genotoxic mechanism of action of alcoholic beverages, and for studying optional production methods to decrease the mutagenicity of commercial wines.

Direct costs of medical attention to Mexican patients with rheumatoid arthritis in a tertiary care center.

OBJECTIVE: Rheumatoid arthritis (RA) is a disease that often requires multiple drug treatment for long periods of time. The purpose of this study was to assess the direct costs of medical care for RA patients seen in a tertiary care center in Mexico City. METHODS: The clinical cases of 3 patients attending our Institution were studied. These represented: (i) one with a disease easily controlled with a disease modifying anti-rheumatic drug (DMARD) (mild disease), (ii) one adequately controlled with 2 or more DMARDs (moderate disease), and (iii) one poorly controlled in spite of multiple DMARDs (severe disease). The costs of the medical visits and of all laboratory and routine examinations during the last year were estimated according to local tabulators, considering the options of highest, intermediate and lowest costs. The costs of the prescribed medications were calculated from current price lists obtained from four drugstores near the Institution. RESULTS: Medical care to an RA patient costs between US $19 and US $221.70 monthly (US $228.08 and US $2,661.40 per year) depending on the socio-economic status of the patient and on variables related to the activity and severity of the disease in our setting. The number of medical visits represented 0.1% to 12.7% of the total costs, laboratory and routine examinations 0.1% to 7.1%, and medications 81.8% to 99.8%. For reference the minimum wage in Mexico is US $90.40 per month. CONCLUSIONS: The direct costs of medical care to RA patients in our setting can be high, and greatly depends on the prescribed medications.

Tru-cut needle biopsy of subcutaneous fat in the diagnosis of secondary amyloidosis in rheumatoid arthritis.

In order to investigate the presence of secondary amyloidosis in patients with rheumatoid arthritis (RA), we performed an abdominal subcutaneous fat biopsy with a tru-cut needle in 50 patients. The tissue was stained with Congo red and was observed with polarized light microscopy. We found amyloid deposits in 78% of our patients. We randomly selected ten patients with a positive biopsy and a second procedure was performed. Tissues were studied with electron microscopy. We found unbranched fibrils characteristic of amyloid in all of them. We found a direct correlation with rheumatoid factor titers: the more intense the amyloid deposit, the higher the rheumatoid factor titers (p < 0.001). We did not find any correlation between amyloid deposits and clinical manifestations of disease. Amyloid deposits in RA are more frequent than previously thought, and their clinical importance remains to be determined.

The involvement of reactive oxygen species in the direct-acting mutagenicity of wine.

The Ara forward mutagenicity assay with Salmonella typhimurium detected wine as a strong mutagen in the absence of mammalian microsomal activation and/or glycosidase activities, in agreement with previous findings. The standard amount (50 microliters) of S9 fraction in the preincubation mutagenesis test abolished most of the mutagenic activity of red wine in the Ara assay. The S9 fraction exerted the same inactivating capacity on hydrogen peroxide and coffee, a complex mixture generating H2O2. Catalase was identified as the putative S9 component responsible for its inactivating capacity. This specific scavenger for H2O2 abolished around 90% of the mutagenicity of red wine. The suppressing effect of catalase was much less noticeable in white and rose wines. Phenolics are proposed to be responsible for the direct-acting mutagenicity of wine through an auto-oxidative process leading to the production of H2O2.

Study of the causes of direct-acting mutagenicity in coffee and tea using the Ara test in Salmonella typhimurium.

The mutagenic activities of 6 of the chemicals identified in coffee solutions were assayed with the Salmonella Ara test, under experimental conditions optimized for coffee mutagenicity. Caffeine was the only non-mutagenic compound. Among the other 5 chemicals, hydrogen peroxide was the strongest mutagen and chlorogenic acid the weakest; methylglyoxal, glyoxal and caffeic acid exhibited intermediate mutagenicities. The minimal mutagenic doses of these components correlated negatively with their relative concentrations in coffee. It was concluded that chlorogenic acid, caffeic acid, glyoxal and methylglyoxal cannot contribute alone to the mutagenicity of coffee in the Ara test, since their minimal mutagenic concentrations were much higher than their respective levels in the coffee samples assayed. By contrast, 40-60% of the mutagenic activity in coffee and also in tea could be attributed to their H2O2 contents. Catalase abolished more than 95% of the mutagenic activity of coffee, as detected by the Ara test. A similar sensitivity to catalase has been reported by other authors in relation to the coffee mutagenicity identified by the Salmonella His test. Nevertheless, the results presented in this paper suggest that the Ara forward and the His reverse mutation tests are sensitive to the mutagenicity of different constituents in coffee solutions. We propose that the His test, sensitive at high coffee doses, mainly recognizes the mutagenicity of methylglyoxal, whilst the Ara test, sensitive at low coffee doses, mainly detects the mutagenic activity of hydrogen peroxide. The data reported also suggest that the direct-acting mutagenicity(ies) detected by the Ara test in tea solutions is (are) based on similar, if not identical, mechanisms.

[Cost-minimization analysis of subcutaneous abatacept in the treatment of rheumatoid arthritis in Spain]. / Análisis de minimización de costes de abatacept subcutáneo en el tratamiento de la artritis reumatoide en España.

OBJECTIVE: To compare the cost of treating rheumatoid arthritis patients that have failed an initial treatment with methotrexate, with subcutaneous abatacept versus other first-line biologic disease-modifying antirheumatic drugs. METHOD: Subcutaneous abatacept was considered comparable to intravenous abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab and tocilizumab, based on indirect comparison using mixed treatment analysis. A cost-minimization analysis was therefore considered appropriate. The Spanish Health System perspective and a 3 year time horizon were selected. Pharmaceutical and administration costs (Euros 2013) of all available first-line biological disease-modifying antirheumatic drugs were considered. Administration costs were obtained from a local costs database. Patients were considered to have a weight of 70 kg. A 3% annual discount rate was applied. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Subcutaneous abatacept proved in the base case to be less costly than all other biologic antirrheumatic drugs (ranging from Euros -831.42 to Euros -9,741.69 versus infliximab and tocilizumab, respectively). Subcutaneous abatacept was associated with a cost of Euros 10,760.41 per patient during the first year of treatment and Euros 10,261.29 in subsequent years. The total 3-year cost of subcutaneous abatacept was Euros 29,953.89 per patient. Sensitivity analyses proved the model to be robust. Subcutaneous abatacept remained cost-saving in 100% of probabilistic sensitivity analysis simulations versus adalimumab, certolizumab, etanercept and golimumab, in more than 99.6% versus intravenous abatacept and tocilizumab and in 62.3% versus infliximab. CONCLUSIONS: Treatment with subcutaneous abatacept is cost-saving versus intravenous abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab and tocilizumab in the management of rheumatoid arthritis patients initiating treatment with biological antirheumatic drugs.

OBJETIVO: Comparar, desde la perspectiva del Sistema Sanitario, el coste del tratamiento con abatacept subcutáneo en pacientes con artritis reumatoide tras fracaso a metotrexato, frente al resto de fármacos antirreumáticos modificadores de la enfermedad disponibles en España con indicación en primera línea de terapia biológica. MÉTODOS: Una comparación indirecta demostró eficacia y seguridad de abatacept subcutáneo comparables a abatacept intravenoso, adalimumab, certolizumab, etanercept, golimumab, infliximab y tocilizumab, por lo que se optó por una minimización de costes. El análisis incluyó costes farmacológicos y de administración (, 2013) para un paciente "tipo" de 70 kg y un horizonte temporal de tres años. Se aplicó una tasa anual de descuento del 3%. Se realizaron análisis de sensibilidad determinísticos y probabilísticos. RESULTADOS: Abatacept subcutáneo tuvo un coste anual de 10.760,41 durante el primer año, 10.261,29 en los años siguientes, y un coste total de 29.953,89 a los tres años, generando ahorros (rango -831,41 versus infliximab a -9.741,69 versus tocilizumab) frente a los demás antirreumáticos modificadores de la enfermedad. Las mayores diferencias entre fármacos se observaron durante el primer año de tratamiento. Abatacept subcutáneo se asoció a ahorros en el 100% de las simulaciones del análisis de sensibilidad probabilístico versus adalimumab, certolizumab, etanercept y golimumab, en más del 99,6% versus abatacept intravenoso y tocilizumab y en el 62,3% versus infliximab. CONCLUSIONES: En base a los resultados, el tratamiento con abatacept subcutáneo genera ahorros frente a abatacept intravenoso, adalimumab, certolizumab, etanercept, golimumab, infliximab y tocilizumab en pacientes con artritis reumatoide que inician tratamiento con fármacos antirreumáticos biológicos.

Dose escalation of the anti-TNF-alpha agents in patients with rheumatoid arthritis. A systematic review.

OBJECTIVE: To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation. METHODS: Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available. RESULTS: From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant. CONCLUSIONS: Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.

Neoliberalismo en salud: La tortura de trabajadoras y trabajadores del Instituto Materno Infantil de Bogotá / Neoliberalism in health: the torture of the health care workers of the Bogota s Instituto Materno Infantil (child and maternity hospital)

Objetivos Relacionar históricamente las transformaciones más significativas del Instituto Materno Infantil (IMI) en su proceso de crisis, cierre y liquidación con las experiencias de sus trabajadores/as. Encontrar elementos vivenciales y teóricos que interconecten el proceso de privatización de la salud con las experiencias de resistencia y dolor/sufrimiento de trabajadores/as. Métodos Etnografía inscrita en corrientes críticas y apoyada en trabajo de campo constante y colectivo, investigación histórica (fuentes primarias y secundarias) y entrevistas semiestructuradas con cinco mujeres que trabajaron por más de quince años en el IMI. Resultados Una línea del tiempo con cuatro periodos principales: Los años de gloria (hasta 1990), Llega el neoliberalismo (1990-2000), La crisis y las resistencias (2001-2005) y Liquidación (2006-). La narrativa de las mujeres entrevistadas devela múltiples agresiones que se intensificaron desde el 2006 generando dolor/ sufrimiento, relatos que ilustran violaciones a sus derechos humanos y laborales. Discusión Proponemos analizar las conexiones entre los diferentes tipos de violencia y el dolor/sufrimiento bajo la categoría tortura, entendida como acciones violentas que causan dolor físico-emocional, las cuales son ejecutadas por actores de poder sobre otros que desafían alterarlo. Enfatizamos en las burocracias, el confinamiento, los agentes torturadores y los resquebrajamientos a la unidad mente/cuerpo para argumentar que esta relación neoliberalismo y tortura pretende eliminar los últimos trabajadores/as de la salud del país con garantías laborales para avanzar en la acumulación de capital que genera la creciente sobreexplotación del trabajo y la mercantilización de la salud.

Objectives To link, from a historical point of view, the most significant transformations of the Instituto Materno Infantil (IMI) [the oldest child and maternity hospital of the country] during its process of crisis, closure and liquidation with the experiences of the hospital workers. To find experience-based and theoretical elements that can interconnect the process of health care privatization of the country with the workers' experiences of resistance and pain/suffering. Methods Critically-oriented ethnography based on continuous collective field work, historical research (primary and secondary sources) and semi-structured interviews with 5 women who worked at the IMI for more than 15 years.Results: A time line of 4 main periods: Los años de gloria [The golden years] (up to 1990); Llega el neoliberalismo [Neoliberalism arrives] (1990-2000); La crisis y las resistencias [Crisis and resistances] (2001-2005); and Liquidación [Liquidation (2006-20??)]. The narratives of the interviewed women unveil multiple aggressions that have intensified since 2006, have caused pain and suffering and are examples of violations of human and labour rights. Discussion We suggest to analyze the links between the different kinds of violence and pain and suffering as torture. This category is defined as the set of violent actions that cause physical and emotional pain, which are performed by actors in positions of power over other people who challenge that power and are part of modern States' ideological principles around a defined moral social order. For the IMI workers' case, the ideological principle that is being challenged is health care neoliberalism. From the analyses of bureaucracy, confinement, torturing agents, and the breaking-off of the body-mind unit we conclude that this relationship between neoliberalism and torture aims to eliminate the last health care workers of the country who had job stability and full-benefits through public labour contracts. Their elimination furthers the accumulation of capital generated by increasing over-exploitation of labour and commodification of health care.

[Cross-cultural adaptation and validation of a Spanish version of a specific instrument to measure health-related quality of life in patients with ankylosing spondylitis]. / Adaptación transcultural y validación de una versión en español de un instrumento específico para medir calidad de vida relacionada con la salud en pacientes con espondilitis anquilosante: el ASQoL.

OBJECTIVE: To make a cross-cultural adaptation and validation of a version in Spanish of the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) for assessing the health-related quality of life (HRQL) of patients with Ankylosing Spondylitis (AS). PATIENTS AND METHODS: A cross-sectional study with test-retest. AS patients (modified New York criteria) were included. Cross-cultural adaptation was done. Construct validity was assessed comparing the ASQoL scores with the SF-36 and EuroQol scores and diseaserelated variables. Internal consistency and reliability (test-retest) were assessed. Feasibility was assessed by the time spent to complete the questionnaire and the number of items without answer. Spearman correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis test were used in the statistical analysis. Cronbach́alpha coefficient and statistic kappa were used for assessing internal consistency and reliability. RESULTS: Fifty-four patients, 37 males (68.5%), with age (mean±SD) 40.5±10.5 years, were included. The ASQoL global score was 6.8±4.7 (median, 7; range, 0-17). The ASQoL scores had high correlations with physical (rho = 0.79) and mental (0.69) SF-36 components, the SF-36 domains pain (0.82), vitality (0.75), and role-physical (0.68), and the most of the disease-related variables. The ASQoL scores were significantly different between patients with different response levels in the health profile of the EuroQol. The Cronbach́alpha coefficient was 0.86. The reliability had kappa = 1 in 12 items and rho = 0.98. The time spent to complete the ASQoL was from 2 to 5 minutes and there only was a missing answer in one patient. CONCLUSION: The Spanish ASQoL is valid, reliable, and feasible instrument for assessing the HRQL of the AS patients.

[Resource utilization in a cohort of rheumatoid arthritis patients attended in rheumatology units in Spain]. / Utilización de recursos en una cohorte de pacientes con artritis reumatoide atendidos en área especializada de reumatología en España.

OBJECTIVE: To determine resource use over a 1-year period in patients with rheumatoid arthritis (RA) attended in rheumatology units in hospitals within the Spanish public health system. PATIENTS AND METHODS: An observational, longitudinal, prospective, multicenter, 1-year study was performed in randomly selected rheumatology units in hospitals of the Spanish public health system. Patients with RA were randomly selected in each hospital. Four visits (at baseline and every 4 months) were conducted by a rheumatologist not routinely involved in the care of the patient. Demographic and disease-related variables were collected. Patient diaries and systematic interviews were used to gather data on resource use. RESULTS: A total of 301 patients were included and 190 (83% females) completed the study. The mean age was 59 ± 13 years and the mean disease duration was 10 ± 10 years. The resources most heavily used were medical. All of the patients made medical visits with a median of four visits to rheumatologists (1-13). Ninetynine percent of the patients took at least one drug. The most frequent drugs were paracetamol (41%), deflaza-cort (32%), and methotrexate (24%). Laboratory tests were performed in all patients, and x-rays were performed in 59%. Sixty-one patients (32%) were hospitalized; 75% of these patients were non-surgical. The most frequently used non-medical direct resources were meals and home visits by non-medical staff (39%). Thirtyone patients (16%) had some type of work disability. CONCLUSIONS: AR is associated with substantial utilization of medical and non-medical resources related to the disease and work disability.

[Cost analysis in a cohort of rheumatoid arthritis patients managed in rheumatology units in Spain]. / Análisis de costes en una cohorte de enfermos con artritis reumatoide atendidos en área especializada de reumatología en España.

OBJECTIVE: To assess the annual costs of rheumatoid arthritis (RA) patients attended at rheumatology units in Spanish public hospitals. METHODS: A longitudinal, prospective, multicenter, observational, 1-year study was performed in the rheumatology units of randomly selected Spanish public hospitals. Randomly selected RA patients were included. The patients made four visits (at baseline and every 4 months). Resource use and costs were collected from patient diaries and structured questionnaires. RESULTS: A total of 301 patients were included and 190 (83% women) completed the study. The mean (± SD) age was 59±13 years and the mean disease duration was 10±10 years. The median annual cost per patient was 3,845 euros (318-36,783). The estimated total annual cost of the Spanish RA population managed in the rheumatology units of public hospitals was 590,110,000 euros. Of total costs, 74% were direct costs and 26% were indirect costs. Medical costs represented 81% of direct costs. The main components of medical costs were drugs (56%), medical visits (21%), complementary tests (12%), and hospitalizations (11%). Permanent work disability represented 66% of indirect costs. CONCLUSIONS: Direct costs were substantially higher than indirect costs. The main components of medical costs were drugs. There was high variability in resource use with a wide range of annual costs per patient.

Activation of multiple antibiotic resistance and binding of stress-inducible promoters by Escherichia coli Rob protein.

Multiple antibiotic resistance in Escherichia coli can be mediated by induction of the SoxS or MarA protein, triggered by oxygen radicals (in the soxRS regulon) or certain antibiotics (in the marRAB regulon), respectively. These small proteins (SoxS, 107 residues; MarA, 127 residues) are homologous to the C terminus of the XylS-AraC family of proteins and are more closely related to a approximately 100-residue segment in the N terminus of Rob protein, which binds the right arm of the replication origin, oriC. We investigated whether the SoxS-MarA homology in Rob might extend to the regulation of some of the same inducible genes. Overexpression of Rob indeed conferred multiple antibiotic resistance similar to that known for SoxS and MarA (against chloramphenicol, tetracycline, nalidixic acid, and puromycin), as well as resistance to the superoxide-generating compound phenazine methosulfate. The Rob-induced antibiotic resistance depended only partially on the micF antisense RNA that down-regulates the OmpF outer membrane porin to limit antibiotic uptake. Similar antibiotic resistance was conferred by expression of a Rob fragment containing only the N-terminal 123 residues that constitute the SoxS-MarA homology. Both intact Rob and the N-terminal fragment activated expression of stress genes (inaA, fumC, sodA) but with a pattern distinct from that found for SoxS and MarA. Purified Rob protein bound a DNA fragment containing the micF promoter (50% bound at approximately 10(-9) M Rob) as strongly as it did oriC, and it bound more weakly to DNA containing the sodA, nfo, or zwf promoter (50% bound at 10(-8) to 10(-7) M). Rob formed multiple DNA-protein complexes with these fragments, as seen previously for SoxS. These data point to a DNA-binding gene activator module used in different protein contexts.

Mutagenicity of red wine in the L-arabinose resistance test with Salmonella typhimurium.

The forward mutation assay to L-arabinose resistance (Ara test) in Salmonella typhimurium detected a Spanish red table wine (Rioja) as a direct-acting mutagen. The best mutagenic response was obtained by preincubating strain BA13 with the wine sample in the presence of sodium phosphate buffer and in the absence of any external metabolic activation. In fact, the S9 mixture abolished most of the mutagenic activity of red wine in the Ara test. Such an inactivating capacity seems to be independent of microsomal enzymes and mediated through some kind of heat-stable component(s) in the S9 fraction. Both regular wine (directly from the bottle) and lyophilized wine were strong mutagens in the Ara test, inducing 4914 and 2739 AraR mutants/ml. Both pKM101 and delta uvrB were critical factors in the detection of the mutagenicity of wine, exhibiting a synergic effect in strain BA13. The mutagenicity of red wine was somehow pH-dependent, increasing with the pH value of the preincubation mixture. In comparison with the Ara test, the His reverse mutation assay (Ames test) was much less sensitive to the mutagenicity of lyophilized red wine, TA102 being the most (448 His+/ml) and TA98 the least (38 His+/ml) sensitive strain. TA100, TA104 and TA97 manifested intermediate mutagenicities to red wine. Previous reports have identified strain TA98 as the His strain most sensitive to the apolar fraction (e.g. XAD-2-bound) of red wine. Based on these results we propose that TA98 mainly detects glycosides of mutagenic flavonols present in red wine (quercetin, rutin, etc.), which do not constitute the major direct-acting mutagens detected with the Ara test.(ABSTRACT TRUNCATED AT 250 WORDS)

Study on the mutagenicity of brandy with the Ara test.

The forward mutation assay to L-arabinose resistance (Ara test) in Salmonella typhimurium was used to demonstrate that evaporated residues of brandy had direct-acting mutagenic activity. The mutagenicity covered a 100-fold range, from 13482 to 127 AraR induced mutants/ml brandy equivalent. Rat liver S9 mix suppressed the mutagenic activity of brandy in the Ara test. The inactivating capacity was independent of microsomal monoxygenase enzymes and appeared to be mediated through a heat stable component of the S9 fraction. Catalase was identified as the putative S9 component responsible for its inactivating capacity. The implication of reactive oxygen species in the direct-acting mutagenicity of brandy was supported by the higher sensitivity of Escherichia coli bacterial strains deficient in two major cellular antioxidant defense (glutathione and/or catalase) compared to their parental wild-type. Phenolic compounds of a polar nature could be responsible for the mutagenicity through the production of reactive oxygen intermediates. Non-matured beverages (gin and non-matured rum) were non-mutagenic. It is conceivable that mutagenic phenolics might be extracted from the wood during maturation in the barrel. Autoxidation of phenolic compounds could be a common mechanism in the mutagenicity of complex mixtures of plant origin.