Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

OBJECTIVES:

Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients.

METHODS:

Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients.

RESULTS:

We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine.

CONCLUSIONS

Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.     

Phylogeography of rabies virus isolated from herbivores and bats in the Espírito Santo State, Brazil

Rabies is enzootic in the State of Espírito Santo, Brazil. Every year, cattle and horses die from rabies that is transmitted by the vampire bat Desmodus rotundus. This paper describes the spread of the rabies virus by the continuous diffusion model using relaxed random walks with BEAST software. Forty-one (41) sequences of gene G from the rabies virus that was isolated from bats and domestic herbivores from several areas of the state between 2006 and 2010 were analyzed. The phylogenetic tree showed three main clusters as well as two sub-clusters under cluster 2. A spatial analysis showed that three strains of the rabies virus spread independently. In general, central Espírito Santo, which is mountainous, was the area where separation of the virus strains occurred. This physical barrier, however, was overcome at some point in time, as samples from different lineages were found in the same microarea.     

Age at menarche in rural France

Data upon age at menarche have been collected among 254 schoolgirls of a relatively endogamous rural population in central France. The median age at menarche estimated by probits was 13·05±0·18, SD1·42. This accords well with results obtained from urban samples in the years 1965–68. Both rural and urban samples give a median age 0·5 year earlier than data from a national survey performed in 1950.     

MSI-L gastric carcinomas share the hMLH1 methylation status of MSI-H carcinomas but not their clinicopathological profile

Sporadic gastric carcinomas (SGC) with microsatellite instability (MSI) exhibit mutations in target genes and display a particular clinicopathological profile. In SGC the MSI phenotype has been associated with hMLH1 promoter hypermethylation. Fifty-seven SGC, classified as high-frequency MSI (MSI-H), low-frequency MSI (MSI-L), and microsatellite stable (MSS), were analyzed for hMLH1 promoter methylation status and clinicopathological features. hMLH1 mutations and hMLH1 expression, as well as target gene mutations, were also evaluated. Our aims were to characterize the molecular and clinicopathological features of SGC, with and without hMLH1 promoter hypermethylation, and to compare the molecular and clinicopathological features of MSI-L, MSI-H, and MSS tumors in an attempt to clarify the place of MSI-L tumors in the mismatch repair (MMR) pathway. Hypermethylation of hMLH1 promoter occurred in 27 of 57 SGC (47.3%) and was significantly associated with MSI status, target gene mutations, and expansive pattern of growth of the tumors. Seventy-five percent of the MSI-H and 50% of MSI-L carcinomas showed hypermethylation (Met+) of hMLH1 in contrast to 0% in MSS carcinomas. No hMLH1 expression was observed in MSI-L/Met+ and MSI-H/Met+ cases. MSS and MSI-L tumors share the same clinicopathological profile regardless of the methylation status of the latter and are distinct from MSI-H tumors. We conclude that mutations in target genes, more than hypermethylation or absence of expression of hMLH1, are the link between MSI status and most of the clinicopathological features of SGC.     

Locomotive Syndrome is associated with chronic pain and poor quality of life in Brazilian oldest old: LOCOMOV Project

BackgroundIn 2007, the Japanese Orthopedic Association established the term “Locomotive Syndrome” (LS) for the concept of locomotor organ dysfunction with potential loss of independence. The purpose of this study was to identify characteristics of LS and establish a diagnostic cut-off for the Geriatric Locomotive Function Scale (GLFS 25-p) for the Brazilian population.MethodsA cross-sectional observational study of the LOCOMOV Project cohort of independent outpatients aged ≥80 years was conducted. Questionnaires on functional status in Basic and Instrumental Activities of Daily Living (Katz and Lawton, respectively) and quality of life (WHOQOL-Bref) were applied, together with the Geriatric Locomotive Function Scale (GLFS 25-p) to identify individuals with LS. Mobility was assessed using the five-times sit-to-stand test, 4-m gait speed, two-step test, one-leg standing time with eyes open and hand-grip test. The data were analyzed using Student's t-test, the Chi–Square test, and multiple logistic regression (stepwise). The significance level was set at 0.05 (5%).ResultsA sample of 102 individuals with mean age of 87.3 (±4.2) years and predominantly female (73.5%) was assessed. We determined a cut-off score of 19 (sensitivity of 0.86 and specificity of 0.67) for diagnosis of LS, as assessed by the GLFS 25-p, and a high prevalence (55%) of the syndrome was found in the sample. In the multiple regression analysis, LS was directly associated with chronic pain (OR 22.24, 95%CI 3.13–157.87), use of a walking device (OR 17.121, 95%CI 1.94–150.49), and inversely associated with gait speed ≥0.8 m/s (OR 0.42, 95%CI 0.006–0.278), perception of good health (OR 0.153, 95%CI 0.029–0.799) and male gender (OR 0.086, 95%CI 0.0105–0.714).ConclusionThe LS in the oldest old proved a very common condition in this survey, especially in women, and was strongly associated with chronic pain, worse performance on physical tests and poor quality of life.     

A biomechanical study of four different meniscal repair systems,comparing pull-out strengths and gapping under cyclic loading

Most studies comparing the biomechanical properties of different meniscal repair systems have simply investigated load to failure. Meniscal tissue is highly anisotropic, and far weaker under tension in the radial direction. Radially oriented loading to failure may not therefore be the most physiologically relevant in vitro test for repair of circumferential tears, and determining gapping across repair sites under cyclical loading at lower loads may be of greater importance. Using bovine menisci, vertical circumferential incisions were repaired using a simple vertical 2-0 PDS suture, Meniscal Arrow, Meniscal Fastener or T-Fix. Repairs were tested by simple loading to failure in a materials testing machine, and by cyclic loading between 5 and 10 N for 25 cycles. Initial gapping across the repairs was measured using a digital micrometer, and the increase in gapping under cyclic loading measured using a Differential Voltage Reluctance Transducer. The mean loads to failure for each of the repair groups were: sutures 72.7 N, Arrows 34.2 N, Fasteners 40.8 N and T-Fix 49.1 N. The load to failure was significantly greater with sutures than with Arrows or Fasteners. The mean gapping across the repairs for each of the repair groups after 25 loading cycles were: sutures 3.29 mm, Arrows 2.18 mm, Fasteners 3.99 mm and T-Fix 3.47 mm. The mean gapping was significantly less with Arrows than with Sutures, Fasteners or T-Fix. These results confirm that meniscal repair by suturing gives the highest load to failure, but show that Arrows give superior hold under lower loads, with the least gapping across repairs under cyclic loading of the four methods tested.     

A Two-Dimensional Second Order Conservative Front-Tracking Method with an Original Marker Advection Approach Based on Jump Relations

A two-dimensional front-tracking method is developed for handling complex shape interfaces satisfying the volume conservation. In order to validate the proposed front-tracking method, a complete convergence study is carried out on severalanalytical test cases for which the interface is widely stretched and deformed. Comparisons to different existing approaches show that our front-tracking method is secondorder accurate in space with lower errors than existing interface tracking techniques ofthe literature.We also propose an original marker advection method which takes into account thejump relations valid at interface in order to deal with the contrast of physical propertiesencountered in two-phase flow simulations. The conservative front-tracking methodcomputed in this work is shown to be able to describe interfaces with high accuracyeven for poorly resolved Eulerian grids.     

Esophageal involvement in congenital Chagas' disease. Report of a case with megaesophagus

A full-term infant developed dysphagia, vomiting, and regurgitation immediately after birth. On examination at 5 months of age, he was malnourished and had radiographically proven megaesophagus. On direct examination his blood was positive for Trypanosoma cruzi. Additionally an enzyme immunoassay for T. cruzi IgM antibodies was positive. He underwent corrective surgery for the megaesophagus but died post-operatively of aspiration pneumonia. At autopsy, the esophagus was markedly dilated. There was an extreme reduction of neurons in Auerbach's plexus, and inflammation of this plexus and the muscular layer of the esophagus. Nests of parasites were seen in the esophagus and bladder. It is suggested that this patient was not in the chronic phase of Chagas' disease but represents an acute digestive phase of this infection. This is the fourth case in the literature of congenital Chagas' disease with esophageal involvement and clinical signs, and the first in which megaesophagus was seen grossly at post-mortem examination.