Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Why do people use portable air purifiers? Evidence from occupant surveys and air quality monitoring in homes in three European cities

One of the most widely available technologies to clean the air in homes of particulate matter of less than 2.5 µm in diameter (PM2.5), known to have negative health impacts, are portable home air purifiers (HAPs). This paper presents research which (1) explored the effectiveness of HAPs in real-world conditions in 57 homes in three European cities; (2) examined if HAPs affect users’ perceptions of the indoor air quality (IAQ) at home; and (3) considered the motivations for occupants’ operation of HAPs. Results from this study found that PM2.5 concentrations in bedrooms were reduced by 45% to 69%; perceptions of IAQ were not correlated with measured high PM2.5 levels; occupants reported the HAPs to have a ‘cooling’ effect, which may explain why the predominant driver of HAP use was thermal comfort, rather than IAQ, in all three cities. The latter finding was supported by a statistically significant increase in the probability of HAP use with increasing indoor temperatures. If the operation of HAPs can be managed, or fully automated, to reflect indoor air pollution levels rather than thermal conditions, better pollutant reduction would be feasible and their use to reduce PM2.5 may help mitigate the negative health effects of exposure whilst at home

Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D

BACKGROUND: Hypovitaminosis D is well known in different populations, but may be under diagnosed in certain populations. We aim to determine the first diagnosis considered, the duration and resolution of symptoms, and the predictors of response to treatment in female asylum seekers suffering from hypovitaminosis D. METHODS: Design: A pre- and post-intervention observational study. Setting: A network comprising an academic primary care centre and nurse practitioners. Participants: Consecutive records of 33 female asylum seekers with complaints compatible with osteomalacia and with hypovitaminosis D (serum 25-(OH) vitamin D <21 nmol/l). Treatment intervention: The patients received either two doses of 300,000 IU intramuscular cholecalciferol as well as 800 IU of cholecalciferol with 1000 mg of calcium orally, or the oral treatment only. Main outcome measures: We recorded the first diagnosis made by the physicians before the correct diagnosis of hypovitaminosis D, the duration of symptoms before diagnosis, the responders and non-responders to treatment, the duration of symptoms after treatment, and the number of medical visits and analgesic drugs prescribed 6 months before and 6 months after diagnosis. Tests: Two-sample t-tests, chi-squared tests, and logistic regression analyses were performed. Analyses were performed using SPSS 10.0. RESULTS: Prior to the discovery of hypovitaminosis D, diagnoses related to somatisation were evoked in 30 patients (90.9%). The mean duration of symptoms before diagnosis was 2.53 years (SD 3.20). Twenty-two patients (66.7%) responded completely to treatment; the remaining patients were considered to be non-responders. After treatment was initiated, the responders' symptoms disappeared completely after 2.84 months. The mean number of emergency medical visits fell from 0.88 (SD 1.08) six months before diagnosis to 0.39 (SD 0.83) after (P = 0.027). The mean number of analgesic drugs that were prescribed also decreased from 1.67 (SD 1.5) to 0.85 (SD 1) (P = 0.001). CONCLUSION: Hypovitaminosis D in female asylum seekers may remain undiagnosed, with a prolonged duration of chronic symptoms. The potential pitfall is a diagnosis of somatisation. Treatment leads to a rapid resolution of symptoms, a reduction in the use of medical services, and the prescription of analgesic drugs in this vulnerable population

Salinity and Simulated Herbivory Influence Spartina alterniflora Traits and Defense Strategy

Sea level rise is expected to push saline waters into previously fresher regions of estuaries, and higher salinities may expose oligohaline marshes to invertebrate herbivores typically constrained by salinity. The smooth cordgrass, Spartina alterniflora (syn. Sporobolus alterniflorus), can defend itself against herbivores in polyhaline marshes, however it is not known if S. alterniflora’s defense varies along the mesohaline to oligohaline marsh gradient in estuaries. I found that S. alterniflora from a mesohaline marsh is better defended than plants from an oligohaline marsh, supporting the optimal defense theory. Higher salinity treatments lowered carbon content, C:N, and new stem biomass production, traits associated with a tolerance strategy, suggesting that salinity may mediate the defense response of S. alterniflora. Further, simulated herbivory increased the nitrogen content and decreased C:N of S. alterniflora. This indicates that grazing may increase S. alterniflora susceptibility to future herbivory via improved forage quality. Simulated herbivory also decreased both belowground and new stem biomass production, highlighting a potential pathway in which herbivory can indirectly facilitate marsh loss, as S. alterniflora biomass is critical for vertical accretion and marsh stability under future sea level rise scenarios

A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation

A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation

Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice

<p>Abstract</p> <p>Background</p> <p>Esophago-gastroduodenal anastomosis with rats mimics the development of human Barrett's esophagus and esophageal adenocarcinoma by introducing mixed reflux of gastric and duodenal contents into the esophagus. However, use of this rat model for mechanistic and chemopreventive studies is limited due to lack of genetically modified rat strains. Therefore, a mouse model of esophageal adenocarcinoma is needed.</p> <p>Methods</p> <p>We performed reflux surgery on wild-type, <it>p53</it>^{<it>A</it>135<it>V </it>}transgenic, and <it>INK4a/Arf</it>^+/-mice of A/J strain. Some mice were also treated with omeprazole (1,400 ppm in diet), iron (50 mg/kg/m, <it>i.p</it>.), or gastrectomy plus iron. Mouse esophagi were harvested at 20, 40 or 80 weeks after surgery for histopathological analysis.</p> <p>Results</p> <p>At week 20, we observed metaplasia in wild-type mice (5%, 1/20) and <it>p53</it>^{<it>A</it>135<it>V </it>}mice (5.3%, 1/19). At week 40, metaplasia was found in wild-type mice (16.2%, 6/37), <it>p53</it>^{<it>A</it>135<it>V </it>}mice (4.8%, 2/42), and wild-type mice also receiving gastrectomy and iron (6.7%, 1/15). Esophageal squamous cell carcinoma developed in <it>INK4a/Arf</it>^+/-mice (7.1%, 1/14), and wild-type mice receiving gastrectomy and iron (21.4%, 3/14). Among 13 wild-type mice which were given iron from week 40 to 80, twelve (92.3%) developed squamous cell carcinoma at week 80. None of these mice developed esophageal adenocarcinoma.</p> <p>Conclusion</p> <p>Surgically induced gastroesophageal reflux produced esophageal squamous cell carcinoma, but not esophageal adenocarcinoma, in mice. Dominant negative <it>p53 </it>mutation, heterozygous loss of <it>INK4a/Arf</it>, antacid treatment, iron supplementation, or gastrectomy failed to promote esophageal adenocarcinoma in these mice. Further studies are needed in order to develop a mouse model of esophageal adenocarcinoma.</p

Rapid End-Point Quantitation of Prion Seeding Activity with Sensitivity Comparable to Bioassays

A major problem for the effective diagnosis and management of prion diseases is the lack of rapid high-throughput assays to measure low levels of prions. Such measurements have typically required prolonged bioassays in animals. Highly sensitive, but generally non-quantitative, prion detection methods have been developed based on prions' ability to seed the conversion of normally soluble protease-sensitive forms of prion protein to protease-resistant and/or amyloid fibrillar forms. Here we describe an approach for estimating the relative amount of prions using a new prion seeding assay called real-time quaking induced conversion assay (RT-QuIC). The underlying reaction blends aspects of the previously described quaking-induced conversion (QuIC) and amyloid seeding assay (ASA) methods and involves prion-seeded conversion of the alpha helix-rich form of bacterially expressed recombinant PrPC to a beta sheet-rich amyloid fibrillar form. The RT-QuIC is as sensitive as the animal bioassay, but can be accomplished in 2 days or less. Analogous to end-point dilution animal bioassays, this approach involves testing of serial dilutions of samples and statistically estimating the seeding dose (SD) giving positive responses in 50% of replicate reactions (SD50). Brain tissue from 263K scrapie-affected hamsters gave SD50 values of 1011-1012/g, making the RT-QuIC similar in sensitivity to end-point dilution bioassays. Analysis of bioassay-positive nasal lavages from hamsters affected with transmissible mink encephalopathy gave SD50 values of 103.5–105.7/ml, showing that nasal cavities release substantial prion infectivity that can be rapidly detected. Cerebral spinal fluid from 263K scrapie-affected hamsters contained prion SD50 values of 102.0–102.9/ml. RT-QuIC assay also discriminated deer chronic wasting disease and sheep scrapie brain samples from normal control samples. In principle, end-point dilution quantitation can be applied to many types of prion and amyloid seeding assays. End point dilution RT-QuIC provides a sensitive, rapid, quantitative, and high throughput assay of prion seeding activity

A global corporate census: publicly traded and close companies in 1910

In 1910 the world had almost half a million corporations, only one-hundredth of today's total. About one-fifth—with over half of corporate capital—were publicly tradable, higher portions than today. Most publicly quoted corporations traded in Europe and the British Empire, but most close (private) corporations operated in the US, which, until the 1940s, had more corporations per capita than anywhere else. The 83 countries surveyed here differed markedly in company numbers, corporate capital/GDP ratios, and average corporate size. Enclave economies—dominated by quoted (and often foreign-owned) companies—had the largest average sizes, while other nations had more varied mixes of large quoted corporations and close company small and medium enterprises