Smoking and response to rituximab in rheumatoid arthritis: results from an international European collaboration.

OBJECTIVES: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). METHOD: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. RESULTS: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). CONCLUSION: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.

Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the loss of immunological tolerance in Sjögren's syndrome.

Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant, characterized by low oestrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC)-mediated proinflammatory host responses. Expression of Toll-like receptors (TLRs)-7 and -9 and cytokine profiles was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-ß-oestradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles also contained another SS-autoantigen, hy1-RNA. These particles were internalized by pDCs in a size-dependent manner and affected TLR-7 and -9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle-stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS.

Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries.

OBJECTIVES: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. METHOD: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. RESULTS: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). CONCLUSION: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.

Sulfolobus islandicus meta-populations in Yellowstone National Park hot springs.

Abiotic and biotic forces shape the structure and evolution of microbial populations. We investigated forces that shape the spatial and temporal population structure of Sulfolobus islandicus by comparing geochemical and molecular analysis from seven hot springs in five regions sampled over 3 years in Yellowstone National Park. Through deep amplicon sequencing, we uncovered 148 unique alleles at two loci whose relative frequency provides clear evidence for independent populations in different hot springs. Although geography controls regional geochemical composition and population differentiation, temporal changes in population were not explained by corresponding variation in geochemistry. The data suggest that the influence of extinction, bottleneck events and/or selective sweeps within a spring and low migration between springs shape these populations. We suggest that hydrologic events such as storm events and surface snowmelt runoff destabilize smaller hot spring environments with smaller populations and result in high variation in the S. islandicus population over time. Therefore, physical abiotic features such as hot spring size and position in the landscape are important factors shaping the stability and diversity of the S. islandicus meta-population within Yellowstone National Park.

Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus.

BACKGROUND: Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high-affinity histamine H4 receptor (H4 R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4 R pattern, which is deranged in oral lichen planus (OLP). OBJECTIVES: To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP. METHODS: Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real-time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high-performance liquid chromatography. RESULTS: l-histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N-methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate-to-high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon-γ upregulated HDC-gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor-α. LPS induced a dose-dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins. CONCLUSIONS: HOKs are histamine-producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low-affinity H1 R and H2 R, but high enough to stimulate the high-affinity H4 R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.

Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis in Finland.

OBJECTIVE: A systematic review found that an average of 27% of rheumatoid arthritis (RA) patients using tumour necrosis factor (TNF) inhibitors discontinue their treatment within 1 year. The aim of this study was to assess drug survival on TNF inhibitors among patients with RA. METHODS: Patients were identified from the National Register for Biologic Treatment in Finland (ROB-FIN), which is a longitudinal cohort study established to monitor the effectiveness and safety of biologic drugs in rheumatic diseases. Inclusion was limited to TNF-inhibitor treatments started as the patient's first, second, or third biologic treatment between 2004 and 2014. Follow-up was truncated at 36 months. The results of a time-dependent Cox proportional hazards model were reported as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of the 4200 TNF-inhibitor treatment periods identified from ROB-FIN, 3443 periods from 2687 patients met the inclusion criteria. Twenty-seven per cent of the patients discontinued their treatment within 12 months. Infliximab (HR 1.8, 95% CI 1.3-2.5) and certolizumab pegol (HR 1.7, 95% CI 1.2-2.3) had lower drug survival compared to golimumab. A similar trend was seen with adalimumab (HR 1.2, 95% CI 0.90-1.7) and etanercept (HR 1.2, 95% CI 0.87-1.6). Concomitant use of methotrexate (MTX) was associated with improved drug survival (HR 0.76, 95% CI 0.64-0.90) in comparison with TNF-inhibitor monotherapy. CONCLUSIONS: Golimumab was better in terms of drug survival than infliximab or certolizumab pegol and at least as good as adalimumab and etanercept. Concomitant use of MTX improved drug survival on TNF inhibitors.

Infection and apoptosis associated with inflammation in periodontitis: An immunohistologic study.

OBJECTIVE: Evidence of increased apoptosis is observed in periodontitis and may be associated with destruction of the periodontal tissue caused by the increased cell death, with the release of danger signals and subsequent stimulation of the proinflammatory processes. However, the exact mechanisms associated with these processes remain unclear. This study aimed to investigate the presence of the periodontal pathogen Treponema denticola, apoptosis, high mobility group box 1 as a damage-associated molecular pattern, and several inflammatory markers in periodontitis and gingivitis subjects. MATERIALS AND METHODS: Soft tissue specimens from gingival tissues of periodontitis and gingivitis patients were used for immunohistochemical and immunofluorescence staining of T. denticola chymotrypsin-like proteinase (CTLP), apoptosis markers, high mobility group box 1, Toll-like receptor 4, inflammatory cell markers, and proinflammatory cytokines. RESULTS: Treponema denticola was detected in all periodontitis-affected tissues. This was associated with a significant increase in the number of apoptotic cells, including macrophages, alterations in the expression of high mobility group box 1 and its receptor, and increased levels of proinflammatory cytokines compared with gingivitis. CONCLUSIONS: In summary, the presence of T. denticola (especially its CTLP), apoptosis, high mobility group box 1, and inflammatory markers suggests their potential involvement in the pathogenesis of periodontitis.

Fluoride in thermal and non-thermal groundwater: Insights from geochemical modeling.

High fluoride (F) groundwaters (>1 mg/L) have been recognized as a water quality problem for nearly a century and occur in many countries worldwide. The affected aquifers can be sedimentary, metamorphic or igneous rocks, but the process giving rise to high-F concentrations has been studied with geochemical modeling and an examination of the rock sources. The association of high-F with silicic igneous rocks such as granites and rhyolites results from magmatic differentiation (fractional crystallization, fractional melting, and crustal assimilation) wherein F is enriched in the liquid phase because of its incompatibility in the mafic minerals that crystallize early during cooling. Further development of F-rich groundwaters occurs during the evolution of Na-HCO3 waters because of removal of Ca through ion-exchange and calcite precipitation, thereby raising the F concentration from minerals like fluorite and fluorapatite to maintain solubility equilibrium. Increasing temperatures enhance this effect because of the retrograde solubility of calcite. From geochemical modeling using the PhreeqcI code, the primary variables controlling F concentrations are DIC (dissolved inorganic carbon), salinity (ionic strength), PCO2, and temperature. Complexing is also important but plays a more secondary role. Considering these variables, an improved set of plotting parameters, F/Cl vs. HCO3/Cl, are shown to be effective in interpreting groundwater analyses. This approach is demonstrated by examining case studies from the Black Creek aquifer, South Carolina, USA, the Madison regional aquifer, midwestern USA, the Mizunami Underground Research Laboratory, Japan, New Zealand thermal waters, the San Luis Valley groundwaters, Colorado, USA, and the Aquia aquifer, Maryland, USA.

The biological activity of serum bacterial lipopolysaccharides associates with disease activity and likelihood of achieving remission in patients with rheumatoid arthritis.

BACKGROUND: Dysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients. METHODS: We measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays. RESULTS: The patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, p<0.001) at 12 months. Importantly, baseline LPS bioactivity correlated with disease activity (p=0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months (p=0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation. CONCLUSION: We describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor. A graphical summary of the conclusions of the study.

Ecological distribution and population physiology defined by proteomics in a natural microbial community.

An important challenge in microbial ecology is developing methods that simultaneously examine the physiology of organisms at the molecular level and their ecosystem level interactions in complex natural systems. We integrated extensive proteomic, geochemical, and biological information from 28 microbial communities collected from an acid mine drainage environment and representing a range of biofilm development stages and geochemical conditions to evaluate how the physiologies of the dominant and less abundant organisms change along environmental gradients. The initial colonist dominates across all environments, but its proteome changes between two stable states as communities diversify, implying that interspecies interactions affect this organism's metabolism. Its overall physiology is robust to abiotic environmental factors, but strong correlations exist between these factors and certain subsets of proteins, possibly accounting for its wide environmental distribution. Lower abundance populations are patchier in their distribution, and proteomic data indicate that their environmental niches may be constrained by specific sets of abiotic environmental factors. This research establishes an effective strategy to investigate ecological relationships between microbial physiology and the environment for whole communities in situ.

Failure of oral DHEA treatment to increase local salivary androgen outputs of female patients with Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is a female-dominant autoimmune disease characterized by androgen depletion and defective dehydroepiandrosterone (DHEA) processing enzymatic machinery in the salivary glands. We hypothesized that, because of these local failures, DHEA replacement therapy would be unable to improve the local androgen deficiency in SS salivary glands. METHODS: DHEA-deficient female SS patients (n = 12) were treated with placebo for 4 months followed by DHEA 50 mg q.d. for 4 months. Serum and saliva, collected in the morning before the trial and after both periods, were analysed for pro-hormones, androgens, and androgen metabolite using an enzyme-linked immunosorbent assay (ELISA). RESULTS: DHEA treatment increased serum DHEA-sulfate from 1.3 ± 0.1 to 6.4 ± 1.3 µM (p = 0.005), DHEA from 16.5 ± 2.8 to 34.8 ± 8.2 nM (p = 0.012), androstenedione from 3.1 ± 0.3 to 17.2 ± 1.9 nM (p = 0.002), free testosterone from 2.2 ± 0.1 to 7.7 ± 1.1 pM (p = 0.002), DHT from 275.5 ± 24.4 to 834.6 ± 122.8 pM (p = 0.002) and 3-α-diol-G from 3.8 ± 0.6 to 13.6 ± 2.0 nM (p = 0.001). However, only salivary DHEA and DHT outputs increased significantly and 25% of the patients showed no increases, except for DHEA itself. Outputs of active androgens (T, DHT) and 3-α-diol-G metabolite correlated with salivation. CONCLUSIONS: The local androgen deficiency in SS salivary glands is not only caused by low serum DHEA(-S) because restoration of systemic androgen levels by DHEA treatment did not correct local androgen depletion. This could be explained by low or no capacity of DHEA-substituted patients to convert the pro-steroid to active androgen metabolites. Such intracrine failures affect women in particular, who must produce their salivary T and DHT locally from DHEA.

Changes in healthcare workers' knowledge about tuberculosis following a tuberculosis training programme.

BACKGROUND: In resource-limited countries, health policy makers and practitioners need to know whether healthcare workers have sufficient knowledge of tuberculosis and its management. OBJECTIVES: We conducted a study to: (1) measure knowledge changes among healthcare workers who participated in a tuberculosis training programme; and (2) make recommendations about future tuberculosis training for healthcare workers in the KwaZulu-Natal Department of Health. METHODS: A cross-sectional study conducted in 2007 measured changes in tuberculosis knowledge of doctors, nurses and other healthcare workers after a training programme based on World Health Organization tuberculosis training modules. Data were collected before and after training using a self-administered, 98-item questionnaire covering eight components. RESULTS: A total of 267 healthcare workers, mean age 40.7 years, answered both pre- and post-training questionnaires. Mean total knowledge scores were low despite significant changes (p<0.001) from a pre-training score of 59.5% to a post-training score of 66.5%. Nurses showed significant improvements in mean total knowledge scores (p<0.001) but had the lowest mean total knowledge score post-training, 63.2%. Doctors had significantly better pre-training (p<0.001) and post-training (p<0.001) mean total knowledge scores compared to nurses. CONCLUSIONS: Improvement in healthcare workers' overall knowledge of tuberculosis during a training programme was not clinically significant. Periodic field training and supervision should be considered to ensure tuberculosis knowledge improvements.

Microbial oxidation of arsenite in a subarctic environment: diversity of arsenite oxidase genes and identification of a psychrotolerant arsenite oxidiser.

BACKGROUND: Arsenic is toxic to most living cells. The two soluble inorganic forms of arsenic are arsenite (+3) and arsenate (+5), with arsenite the more toxic. Prokaryotic metabolism of arsenic has been reported in both thermal and moderate environments and has been shown to be involved in the redox cycling of arsenic. No arsenic metabolism (either dissimilatory arsenate reduction or arsenite oxidation) has ever been reported in cold environments (i.e. < 10 degrees C). RESULTS: Our study site is located 512 kilometres south of the Arctic Circle in the Northwest Territories, Canada in an inactive gold mine which contains mine waste water in excess of 50 mM arsenic. Several thousand tonnes of arsenic trioxide dust are stored in underground chambers and microbial biofilms grow on the chamber walls below seepage points rich in arsenite-containing solutions. We compared the arsenite oxidisers in two subsamples (which differed in arsenite concentration) collected from one biofilm. 'Species' (sequence) richness did not differ between subsamples, but the relative importance of the three identifiable clades did. An arsenite-oxidising bacterium (designated GM1) was isolated, and was shown to oxidise arsenite in the early exponential growth phase and to grow at a broad range of temperatures (4-25 degrees C). Its arsenite oxidase was constitutively expressed and functioned over a broad temperature range. CONCLUSIONS: The diversity of arsenite oxidisers does not significantly differ from two subsamples of a microbial biofilm that vary in arsenite concentrations. GM1 is the first psychrotolerant arsenite oxidiser to be isolated with the ability to grow below 10 degrees C. This ability to grow at low temperatures could be harnessed for arsenic bioremediation in moderate to cold climates.

Rising arsenic concentrations from dewatering a geothermally influenced aquifer in central Mexico.

This study identifies causes of rising arsenic (As) concentrations over 17 years in an inter-montane aquifer system located just north of the Trans-Mexican-Volcanic-Belt in the Mesa central physiographic region that is extensively developed by long-screened production wells. Arsenic concentrations increased by more than 10 µg/L in 14% (3/22) of re-sampled wells. Similarly, in a larger scale analysis wherein As concentrations measured in 137 wells in 2016 were compared to interpolated, baseline concentrations from 246 wells in 1999, As concentrations rose more than 10 µg/L in 30% of wells. Between 1999 and 2016, the percentage of all wells sampled in each basin-wide sampling campaign exceeding the World Health Organization's 10 µg/L drinking water limit increased from 38 to 64%. Principal Components Analysis (PCA), step-wise multiple regression, and Random Forest modeling (RF) revealed that high As concentrations are closely associated with high pH and temperature, and high concentrations of fluoride (F), molybdenum (Mo), lithium (Li), sodium (Na) and silica (Si), but low calcium (Ca) and nitrate (NO3) concentrations. Pumping-induced mixing with hot, geothermally impacted groundwater generates alkaline water through hydrolysis of silicate minerals. The rising pH converts oxyanion sorption sites from positive to negative releasing As (and Mo) to pore waters. The negative correlation between nitrate and As concentrations can be explained by conservative mixing of shallow, young groundwater with geothermally influenced groundwater. Therefore water carrying an anthropogenic contaminant dilutes water carrying geogenic contaminants. This process is enabled by long well screens. Over-exploitation of aquifers in geothermal regions for agriculture can drive As concentrations in water from production wells to toxic levels even as the total dissolved solids remain low.

Methylmercury enters an aquatic food web through acidophilic microbial mats in Yellowstone National Park, Wyoming.

Microbial mats are a visible and abundant life form inhabiting the extreme environments in Yellowstone National Park (YNP), WY, USA. Little is known of their role in food webs that exist in the Park's geothermal habitats. Eukaryotic green algae associated with a phototrophic green/purple Zygogonium microbial mat community that inhabits low-temperature regions of acidic (pH approximately 3.0) thermal springs were found to serve as a food source for stratiomyid (Diptera: Stratiomyidae) larvae. Mercury in spring source water was taken up and concentrated by the mat biomass. Monomethylmercury compounds (MeHg(+)), while undetectable or near the detection limit (0.025 ng l(-1)) in the source water of the springs, was present at concentrations of 4-7 ng g(-1) dry weight of mat biomass. Detection of MeHg(+) in tracheal tissue of larvae grazing the mat suggests that MeHg(+) enters this geothermal food web through the phototrophic microbial mat community. The concentration of MeHg(+) was two to five times higher in larval tissue than mat biomass indicating MeHg(+) biomagnification occurred between primary producer and primary consumer trophic levels. The Zygogonium mat community and stratiomyid larvae may also play a role in the transfer of MeHg(+) to species in the food web whose range extends beyond a particular geothermal feature of YNP.

The geochemical behavior of aluminum in acidified surface waters.

Speciation calculations for aluminum, in water samples taken from a drainage basin containing acid mine waters, demonstrate a distinct transition from conservative behavior for pH below 4.6 to nonconservative behavior for pH above 4.9. This transition corresponds to the pK for the first hydrolysis constant of the aqueous aluminum ion and appears to be a consistent phenomenon independent of field location, ionic strength, and sulfate concentration. Nonconservative behavior is closely correlated with the equilibrium solubility of a microcrystalline gibbsite or amorphous aluminum hydroxide.

Origin, distribution, and geochemistry of arsenic in the Altiplano-Puna plateau of Argentina, Bolivia, Chile, and Perú.

Elevated concentrations of arsenic in water supplies represent a worldwide health concern. In at least 14 countries of South America, high levels have been detected relative to international standards and guidelines. Within these countries, the high plateau referred to as the "Altiplano-Puna", encompassing areas of Argentina, Bolivia, Chile, and Perú, exhibits high arsenic concentrations that could be affecting 3 million inhabitants. The origins of arsenic in the Altiplano-Puna plateau are diverse and are mainly natural in origin. Of the natural sources, the most important correspond to mineral deposits, brines, hot springs, and volcanic rocks, whereas anthropogenic sources are related to mining activities and the release of acid mine drainage (AMD). Arsenic is found in all water types of the Altiplano-Puna plateau over a wide range of concentrations (0.01 mg·L-1 < As in water > 10 mg·L-1) which in decreasing order correspond to: AMD, brines, saline waters, hot springs, rivers affected by AMD, rivers and lakes, and groundwater. Despite the few studies which report As speciation, this metalloid appears mostly in its oxidized form (As[V]) and its mobility is highly susceptible to the influence of dry and wet seasons. Once arsenic is released from its natural sources, it also precipitates in secondary minerals where it is generally stable in the form of saline precipitates and Fe oxides. In relation to human health, arsenic adaptation has been detected in some aboriginal communities of the Puna together with an efficient metabolism of this metalloid. Also, the inefficient methylation of inorganic As in women of the Altiplano might lead to adverse health effects such as cancer. Despite the health risks of living in this arsenic-rich environment with limited water resources, not all of the Altiplano-Puna is properly characterized and there exists a lack of information regarding the basic geochemistry of arsenic in the region.

Origin and geochemistry of arsenic in surface and groundwaters of Los Pozuelos basin, Puna region, Central Andes, Argentina.

Los Pozuelos is a closed basin in the Puna region of NW Argentina, Central Andes. This is a semi-arid region where closed basins are the most important feature for the hydrologic systems. The center of the basin is occupied by a fluctuating playa lake called Los Pozuelos lagoon, which constitutes a UNESCO Biosphere Reserve. This is one of the most populated closed basins in the Argentinian Puna and residents use groundwater for drinking and cooking. Lowest concentrations of As and dissolved solids are in the headwaters of the rivers (1.46-27 µg/L) and the highest concentrations are in the lagoon (43.7-200.3 µg/L). In groundwater, arsenic concentrations increase from the outer ring aquifer (3.82-29.7 µg/L) composed of alluvial-alluvial fan sediments to the inner lacustrine aquifer (10-113 µg/L) that surround the playa lake. Moreover, high concentrations of As during the dry season (90.2 and 113 µg/L), Na/K mass ratios (0.2 and 0.3), and formation of Na-rich efflorescent salts suggest that high evaporation rates increases As concentration, while rainwater dilutes the concentration during the wet season. As(V) is the dominant species in all the water types, except for the lagoon, where As(III) occasionally dominates because of organic matter buildup. There are at least three potential sources for As in water i) oxidation of As sulfides in Pan de Azúcar mine wastes, and acid mine drainage discharging into the basin; ii) weathering and erosion of mineralized shales; iii) weathering of volcanic eruptive non-mineralized rocks. Because it is a closed basin, the arsenic released from the natural and anthropogenic sources is transported in solution and in fluvial sediments and finally accumulates in the center of the basin where the concentration in water increases by evaporation with occasional enhancement by organic matter interaction in the lagoon.

Cost-effectiveness of infliximab in the treatment of rheumatoid arthritis in clinical practice.

OBJECTIVE: We evaluated the cost-effectiveness of infliximab therapy in Finnish RA patients in a real-life clinical setting and identified factors influencing it, using the national register of biological treatment (ROB-FIN). METHODS: A cost-utility analysis was performed, derived from EQ-5D, and related to HAQ score and disease activity using multiple regression. QALYs were calculated based on these utilities, using patient-level data up to the last control registered. Cost-effectiveness analyses included costs per ACR50 responder, and costs per low DAS28 score (<3.2) achieved, in combination with a clinically significant improvement (>1.2). The costs considered were direct medical costs of infliximab and cost of intravenous infusion. Patient-level costs were calculated based on dose and dosage frequency, and were related to the difference in QALYs resulting from infliximab therapy. RESULTS: The 297 patients had been treated with infliximab for an average of 21 months. The HAQ score and patient's global assessment improved significantly on infliximab therapy. More than two-thirds of the patients achieved a clinically important improvement in HAQ. A QALY gain occurred in 76%. 35% of these had an incremental cost-effectiveness ratio of < or =40,000 Euro/QALY gained, the median cost being 51,884 Euro. The cost per QALY gained was significantly lower for patients achieving an ACR50 response at 3, 12 and 24 months. CONCLUSION: Treatment with infliximab and aiming at ACR50 response appears cost-effective, remembering the restrictions of an observational study set up. Current Care guidelines, which require sufficient disease control when deciding on continuing biological therapy, get support from these findings.