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Introduction: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population., Methods: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus)., Results: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab., Conclusions: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

To assay new circulating markers related to macrovascular complications (MVC) in type 2 diabetes mellitus (T2DM), we carried out a descriptive cross-sectional study. We recruited 30 controls (CG), 34 patients with T2DM (DG), and 28 patients with T2DM and vascular complications (DG+C); among them, 22 presented MVC. Peripheral blood was used to determine redox status (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; glucose-6-phosphate dehydrogenase, G6PD) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid peroxidation, LPO), nitrite levels in plasma (NOx). Inflammatory markers (IL-1β, IL-6, IL-10, IL-18, MCP-1, TNF-α) and the relative expression of c-miRNAs were analyzed. The real-time PCR results showed that the expressions of miR-155-5p, miR-21-5p, miR-146a-3p, and miR-210-3p were significantly higher in the DG group compared to the CG. The DG+C group presented statistically relevant differences with CG for four miRs: the increased expression of miR-484-5p, miR-21-5p, and miR-210-3p, and decreased expression of miR-126a-3p. Moreover, miR-126a-3p was significantly less expressed in DG+C compared to DG. The application of binary logistic regression analysis and construction of receiving operator characteristic curves (ROC) revealed two models with high predictive values for vascular complications presence: (1) HbAc1, creatinine, total cholesterol (TC), LPO, GPx, SOD, miR-126, miR-484 (Exp(B) = 0.926, chi 2 = 34.093, p < 0.001; AUC = 0.913). (2) HbAc1, creatinine, TC, IL-6, LPO, miR-126, miR-484 (Exp(B) = 0.958, Chi 2 = 33.863, p < 0.001; AUC = 0.938). Moreover, our data demonstrated that gender, TC, GPx, CAT, and miR-484 were associated with MVC and exhibited higher predictive values (Exp(B) = 0.528, p = 0.024, Chi 2 = 28.214, AUC = 0.904) than classical variables (Exp(B) 0.462, p = 0.007, Chi 2 = 18.814, AUC = 0.850). miR-126, miR-484, IL-6, SOD, CAT, and GPx participate in vascular damage development in the studied diabetic population and should be considered for future studies.

The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a remarkable amount of studies about the consequences of pathological conditions on its development and functioning. This bibliographic review aims to cover mostly findings related to changes in the physical distribution of neurons and their connections-the connectome-both structural and functional, as well as their modelling approaches. It does not intend to offer an extensive description of all conditions affecting the brain; rather, it presents the most common ones. Thus, here, we highlight the need for accurate brain modelling that can subsequently be used to understand brain function and be applied to diagnose, track, and simulate treatments for the most prevalent pathologies affecting the brain.

A common denominator of metabolic diseases, including type 2 diabetes Mellitus, dyslipidemia, and atherosclerosis, are elevated oxidative stress and chronic inflammation. These complex, multi-factorial diseases are caused by the detrimental interaction between the individual genetic background and multiple environmental stimuli. The cells, including the endothelial ones, acquire a preactivated phenotype and metabolic memory, exhibiting increased oxidative stress, inflammatory gene expression, endothelial vascular activation, and prothrombotic events, leading to vascular complications. There are different pathways involved in the pathogenesis of metabolic diseases, and increased knowledge suggests a role of the activation of the NF-kB pathway and NLRP3 inflammasome as key mediators of metabolic inflammation. Epigenetic-wide associated studies provide new insight into the role of microRNAs in the phenomenon of metabolic memory and the development consequences of vessel damage. In this review, we will focus on the microRNAs related to the control of anti-oxidative enzymes, as well as microRNAs related to the control of mitochondrial functions and inflammation. The objective is the search for new therapeutic targets to improve the functioning of mitochondria and reduce oxidative stress and inflammation, despite the acquired metabolic memory.

Ovarian functions decrease with perimenopause. The ovary has extrinsic innervation, but the neural influence on ovarian functions and dysfunction is not well-studied. The present study aimed to biochemically and morphometrically characterize the intrinsic neurons in ovaries from young adult, middle-aged, and senescent Long Evans CII-ZV rats (3, 12, and 15 months old, respectively). Ovaries were extracted from four rats of each age group (n = 12 total), cryopreserved, and processed for immunofluorescence studies with the primary NeuN/β-tubulin and NeuN/tyrosine hydroxylase (TH) antibodies. The soma area and number of intrinsic neurons in the ovarian stroma, surrounding follicles, corpus luteum, or cyst were evaluated. The intrinsic neurons were grouped in cluster-like shapes in ovarian structures. In senescent rats, the intrinsic neurons were mainly localized in the ovarian stroma and around the cysts. The number of neurons was lower in senescent rats than in young adult rats (p < 0.05), but the soma size was larger than in young adult rats. Immunoreactivity to TH indicated the presence of noradrenergic neurons in the ovary with the same characteristics as NeuN/β-tubulin, which indicates that they are part of the same neuronal group. Taken together, the findings indicate that the intrinsic neurons may be related to the loss of ovarian functions associated with aging., (© 2022. The Author(s).)

Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients., Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice., Method: By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence., Results: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization., Conclusion: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD.

Objectives: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs., Methods: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring., Results: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3))., Conclusions: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Background: Canakinumab is a human anti-interleukin-1β (IL-1β) monoclonal antibody neutralizing IL-1β-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA)., Methods: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197., Results: Microarray analysis identified 984 probe sets differentially expressed (≥2-fold difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving ≥50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (≥2-fold difference; P < 0.05) on day 3 versus baseline, including IL-1β, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥1.5-fold decline, P ≤ 0.002)., Conclusions: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles., Trial Registration: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

Background: This study was done to evaluate the visual and anatomical outcomes of topical regenerating agents as a novel therapy for neutrophic corneal ulcer (NCU) secondary to acanthamoeba infection., Findings: A 20-year-old woman with a history of contact lens wear was referred to our hospital for keratitis after responding poorly to conventional treatment. In vivo confocal microscopy images suggested acanthamoeba keratitis with double-walled cysts in the anterior corneal stroma. Acanthamoeba infection was confirmed by laboratory findings. She was started on 0.1 % propamidine and 0.02 % chlorhexidine drops every hour. The antibiotic and antifungal drops were stopped when bacterial and fungal cultures proved negative. A central neurotrophic corneal ulcers (NCU) appeared, and despite treatment with artificial tears, bandage contact lens, and autologous serum, the ulcer worsened and she was treated with topical CACICOL20 (1 drop every 2 days) for 8 weeks. The corneal defect was completely repaired in 3 weeks. The treatment was well tolerated, and no local or systemic side effects were noted. Visual acuity remained 20/400. Two months later, the defect was still closed and the patient continued with 0.1 % propamidine and 0.02 % chlorhexidine drops, bandage contact lens, artificial tears, and autologous serum., Conclusions: Topical regenerating agents interact with components of the extracellular matrix, binding matrix proteins and protecting them from proteolysis, restoring the matrix environment, and improving tissue healing. In this case, CALCICOL20 was effective for vision stabilization, wound healing, and was well tolerated for NCU secondary to acanthamoeba infection.

Objective: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP., Methods: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution., Results: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively., Conclusion: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry., (Copyright © 2015 by the American College of Rheumatology.)

Background: While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution., Methods: A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn's disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications., Results: For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value., Conclusions: Simple clinical, biological and endoscopic tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed., (© 2014 S. Karger AG, Basel.)

Crohn's disease is characterised by recurrent and/or chronic inflammation of the gastrointestinal tract leading to cumulative intestinal tissue damage. Treatment tailoring to try to prevent this tissue damage as well as achieve optimal benefit/risk ratio over the whole disease course is becoming an important aspect of Crohn's disease management. For decades, clinical symptoms have been the main trigger for diagnostic procedures and treatment strategy adaptations. However, the correlation between symptoms and intestinal lesions is only weak. Furthermore, preliminary evidence suggests that a state of remission beyond the simple control of clinical symptoms, and including mucosal healing, may be associated with better disease outcome. Therefore monitoring the disease through the use of endoscopy and cross-sectional imaging is proposed. However, the degree of mucosal or bowel wall healing that needs to be reached to improve disease outcome has not been appropriately studied. Furthermore, owing to their invasive nature and cost, endoscopy and cross-sectional imaging are not optimal tools for the patients or the payers. The use of biomarkers as surrogate markers of intestinal and systemic inflammation might help. Two biomarkers have been most broadly assessed in Crohn's disease: C-reactive protein and faecal calprotectin. These markers correlate significantly with endoscopic lesions, with the risk of relapse and with response to therapy. They could be used to help make decisions about diagnostic procedures and treatment. In particular, with the use of appropriate threshold values, they could determine the need for endoscopic or medical imaging procedures to confirm the disease activity state.

Adults with psoriasis have a greater risk of developing metabolic syndrome (MetS) and cardiovascular disease (CVD), but few studies have investigated the prevalence of MetS and other risk factors for CVD in children with psoriasis. In an assessor-blinded study, 20 children ages 9-17 years with a current or previously documented history of psoriasis involving 5% or more of their body surface area or psoriatic arthritis were compared with a cohort of age- and sex-matched controls with benign nevi, warts, or acne. MetS, our primary endpoint, was defined by the presence of abnormal values in at least three of the following measures: triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), waist circumference, and blood pressure. Secondary endpoints included high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Thirty percent (6/20) of children with psoriasis met the criteria for MetS, compared with 5% (1/20) of the control group (p < 0.05). Subjects with psoriasis had higher mean FBG (91.1 mg/dL) than the control group (82.9 mg/dL) (p = 0.01). There were no statistically significant differences in the other four components of MetS, BMI, BMI percentile, hs-CRP, TC, or LDL-C. The results of this trial demonstrate that children with psoriasis have higher rates of MetS than age- and sex-matched controls. It may therefore be important to evaluate children with psoriasis for components of MetS to prevent future CVD morbidity and mortality., (© 2013 Wiley Periodicals, Inc.)

To examine the association between ethnicity and disease activity in patients with juvenile idiopathic arthritis (JIA), and to determine the association of ethnicity with disease severity and disability in this population. CARRAnet, a US database containing information (collected between May 2010 and June 2011) on almost 3,000 subjects with JIA, was used. Demographic variables were compared between Hispanic patients and non-Hispanic patients. Mann-Whitney and chi-square tests were used to compare indicators of disease activity, as well as imaging evidence of joint damage, and Childhood Health Assessment Questionnaire (CHAQ) scores between ethnicities. Two linear regression models were used to determine the association of ethnicity with number of active joints in JIA, and the association between ethnicity and disability (CHAQ scores). A total of 2,704 patients with JIA (277 Hispanic; 2,427 non-Hispanic) were included. Income and health insurance coverage were higher in non-Hispanics. RF-positive polyarticular JIA, positive RF and anti-CCP, as well as use of systemic steroids were more frequent in Hispanics. Imaging evidence of joint damage was present in 32 % of the Hispanic patients compared to 24 % of the non-Hispanic patients (p = 0.008). In multivariate linear regression analyses, the number of active joints was significantly higher in Hispanics than in non-Hispanics (p = 0.03), as well as CHAQ scores (p = 0.003), after adjusting for confounders. Hispanic patients with JIA had higher disease activity than non-Hispanic patients, as well as higher disease severity and disability. Since ethnicity influences disease activity, severity, and disability, different management and treatment plans should be planned accordingly.

Background: Collagen cross linking (CXL) of the cornea has been developed recently as a new treatment for multidrug-resistant infectious keratitis. The aim of this study is to summarize the previously published data and evaluate the effectiveness of this treatment., Results: The search identified 12 articles. The number of eyes was 104. The infectious keratitis was associated with bacteria in 58 eyes (57f%): Gram-positive bacteria in 44 (43%; 4 of which were infected with Mycobacterium (3.6%)) and Gram-negative bacteria in 14 eyes (13%), fungus in 13 eyes (12%), and Acanthamoeba in 7 eyes (7%). In 26 eyes (25%), the microbiological culture was negative or not performed. The mean time of re-epithelization after CXL was 20.7±28.1 days (minimum of 3, maximum of 145). Sixteen eyes underwent deep or lamellar keratoplasty. The pooled analysis suggested that CXL has a favorable effect on the block of corneal melting in 85% (95%; CI 0.77, 0.91) of eyes., Conclusion: Although randomized controlled trials are needed, the available evidence supports the use of CXL in the treatment of infectious keratitis.

Bacterial infections are one of the most frequent complications in cirrhosis and result in high mortality rates. Patients with cirrhosis have altered and impaired immunity, which favours bacterial translocation. Episodes of infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease. The most common and life-threatening infection in cirrhosis is spontaneous bacterial peritonitis followed by urinary tract infections, pneumonia, endocarditis and skin and soft-tissue infections. Patients with decompensated cirrhosis have increased risk of developing sepsis, multiple organ failure and death. Risk factors associated with the development of infections are severe liver failure, variceal bleeding, low ascitic protein level and prior episodes of spontaneous bacterial peritonitis (SBP). The prognosis of these patients is closely related to a prompt and accurate diagnosis. An appropriate treatment decreases the mortality rates. Preventive strategies are the mainstay of the management of these patients. Empirical antibiotics should be started immediately following the diagnosis of SBP and the first-line antibiotic treatment is third-generation cephalosporins. However, the efficacy of currently recommended empirical antibiotic therapy is very low in nosocomial infections including SBP, compared to community-acquired episodes. This may be associated with the emergence of infections caused by Enterococcus faecium and extended-spectrum β-lactamase-producing Enterobacteriaceae, which are resistant to the first line antimicrobial agents used for treatment. The emergence of resistant bacteria, underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of infections. Nosocomial infections should be treated with wide spectrum antibiotics. Further studies of early diagnosis, prevention and treatment are needed to improve the outcomes in patients with decompensated cirrhosis.

The aims of this study were to examine the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and disease activity in juvenile idiopathic arthritis (JIA), to determine the prevalence of vitamin D (VD) deficiency [25(OH)D ≤ 19 ng/ml] and insufficiency [25(OH)D 20-29 ng/ml], and to determine factors associated with lower serum levels of 25(OH)D in this population. In this cross-sectional study, disease activity was measured using JADAS-27, as well as its individual components (physician global assessment of disease activity, parent global assessment of child's well-being, count of joints with active disease, and erythrocyte sedimentation rate). Linear regression models were developed to analyze the association between serum 25(OH)D levels and JADAS-27 and to determine variables associated with serum 25(OH)D levels. A total of 154 patients (61% girls, 88% whites) were included. Mean age was 10.6. VD deficiency was detected in 13% and insufficiency in 42%. In univariate and multivariate analyses, 25(OH)D levels were not associated with JADAS-27, neither with its individual components. However, in a subset analysis including all new-onset JIA patients (n = 27), there was a nonsignificant negative correlation between serum 25(OH)D levels and JADAS-27 (r = -0.29, P = 0.14). In the univariate and multivariate analyses, age, ethnicity, BMI, and season were significantly associated with serum 25(OH)D levels, but not total VD intake. More than 1/2 of JIA patients had serum 25(OH)D levels below 29 ng/ml; however, there was no association between serum 25(OH)D levels and disease activity. Future larger, long-term studies with new-onset JIA patients are needed to further explore the association between serum 25(OH)D levels and disease activity.

In this brief, we present a novel model fitting procedure for the neuro-coefficient smooth transition autoregressive model (NCSTAR), as presented by Medeiros and Veiga. The model is endowed with a statistically founded iterative building procedure and can be interpreted in terms of fuzzy rule-based systems. The interpretability of the generated models and a mathematically sound building procedure are two very important properties of forecasting models. The model fitting procedure employed by the original NCSTAR is a combination of initial parameter estimation by a grid search procedure with a traditional local search algorithm. We propose a different fitting procedure, using a memetic algorithm, in order to obtain more accurate models. An empirical evaluation of the method is performed, applying it to various real-world time series originating from three forecasting competitions. The results indicate that we can significantly enhance the accuracy of the models, making them competitive to models commonly used in the field.

Non-adherence to treatments for chronic diseases may jeopardize patients' health, increase costs of care, and cause unnecessary clinic appointments and diagnostic studies, as well as additional treatments with potentially serious side effects. Little is known about adherence to methotrexate in pediatric rheumatology. Because this medication is commonly used in JIA, we assessed adherence among children receiving methotrexate in two countries. A total of 76 outpatients (M:F 21:55) with JIA seen in Rio de Janeiro (Brazil) and in Boston (US) taking methotrexate for >2 months were enrolled. Questionnaires were completed by the parents from both centers. Non-adherence was defined as omission of ≥3 prescribed doses in the previous 8 weeks. Patients' ages ranged from 1 to 17 years. Mean time on methotrexate was 20.5 months (±25). Overall rate of non-adherence was 18%. The rate of reported non-adherence was 8% in Boston and 24% in Rio de Janeiro (P = 0.012). The main reason for non-adherence in Boston was "child refused"; in Rio de Janeiro, the main reason was inability to obtain medication. Age had a negative association with adherence (P < 0.0001). Sex, time on methotrexate, route of administration, or concomitant use of other medications were not associated with adherence. Eighteen percent of children with JIA prescribed methotrexate were non-compliant. The difference in reasons for poor adherence between patients in Rio de Janeiro and Boston suggests that different strategies may be needed to improve adherence in these 2 settings. The rate of non-adherence warrants further investigation.

Background: Children with physical disabilities may have an increased risk for obesity and obesity might be a risk factor for inflammatory arthritis. The aims of this study were: to determine the prevalence of obesity in children and adolescents with juvenile idiopathic arthritis (JIA), and to examine the association between obesity and disease activity in this population., Findings: A cross-sectional analysis of all patients with JIA attending a pediatric rheumatology clinic, between October 2009 and September 2010, was performed. A linear regression model was used to explore the association between obesity and disease activity in patients with JIA. A total of 154 subjects were included in the analysis; median age was 10.6 years, 61% were female, and 88% were white. Obesity was found in 18%, 12% were overweight, and 3% were underweight. There was no association between obesity and JADAS-27 (Juvenile Arthritis Disease Activity Score 27), physician's assessment of disease activity, parent's assessment of child's well-being, erythrocyte sedimentation rate, number of active joints, or C-reactive protein (p-value range 0.10 to 0.95)., Conclusions: Although 18% of patients with JIA were obese, we did not find an association between obesity and disease activity. As obesity confers an additional health risk in children with arthritis, addressing this co-morbidity should be a health priority in patients with JIA. Future studies are necessary to further explore potential associations between obesity, development of JIA, and disease activity.

Objective: To evaluate the prevalence of vitamin D deficiency, as well as factors associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in children attending a pediatric rheumatology clinic, and to determine whether there was a difference in serum 25(OH)D levels and in vitamin D deficiency between children with autoimmune disorders and nonautoimmune conditions., Methods: Cross-sectional analysis of serum 25(OH)D levels of patients between the ages of 2 and 19 years, seen between November 2008 and October 2009., Results: A total of 254 patients were studied (169 autoimmune disorders, 85 nonautoimmune conditions). The mean age of study patients was 12.3 years; 67% were female and 80% were white. In the autoimmune disorders group, 23% had vitamin D deficiency [serum 25(OH)D < 20 ng/ml], and in the nonautoimmune conditions group 14% were vitamin D deficient. The average level of serum 25(OH)D was 28.6 (± 11) ng/ml (range 2 to 59). Age, ethnicity, body mass index, use of supplements, and season were significantly associated with serum levels of 25(OH)D (all p ≤ 0.02). The OR of patients with autoimmune disorders being vitamin D deficient was 2.3, in relation to patients with nonautoimmune conditions (p = 0.04)., Conclusion: Twenty percent of patients attending a pediatric rheumatology clinic were vitamin D deficient. Patients with autoimmune disorders were more likely to be vitamin D deficient than patients with nonautoimmune conditions. Screening of serum 25(OH)D levels should be performed for patients with autoimmune disorders.

After a 19-year-old female experienced several weeks of unrelieved fevers, an abdominal CT revealed multiple low-attenuation renal lesions. As the differential included lymphoma, infections and infarcts, a core biopsy of the kidney was performed, which revealed changes consistent with Churg-Strauss syndrome.

Soft computing (SC) emerged as an integrating framework for a number of techniques that could complement one another quite well (artificial neural networks, fuzzy systems, evolutionary algorithms, probabilistic reasoning). Since its inception, a distinctive goal has been to dig out the deep relationships among their components. This paper considers two wide families of SC models. On the one hand, the regime-switching autoregressive paradigm is a recent development in statistical time series modeling, and it includes a set of models closely related to artificial neural networks. On the other hand, we consider fuzzy rule-based systems in the framework of time series analysis. This paper discloses original results establishing functional equivalences between models of these two classes, and hence opens the door to a productive line of research where results and techniques from one area can be applied in the other. As a consequence of the equivalences presented in this paper, we prove the asymptotic stationarity of a class of fuzzy rule-based systems. Simulations based on information criteria show the importance of the selection of the proper membership function.

Background: More than 15 million people worldwide have rheumatic fever (RF) and rheumatic heart disease due to RF. Secondary prophylaxis is a critical cost-effective intervention for preventing morbidity and mortality related to RF. Ensuring adequate adherence to secondary prophylaxis for RF is a challenging task. This study aimed to describe the rates of recurrent episodes of RF, quantify adherence to secondary prophylaxis, and examine the effects of medication adherence to the rates of RF in a cohort of Brazilian children and adolescents with RF., Methods: This retrospective study took place in the Pediatric Rheumatology outpatient clinic at a tertiary care hospital (Instituto de Puericultura e Pediatria Martagão Gesteira) in Rio de Janeiro, Brazil, and included patients with a diagnosis of RF from 1985 to 2005., Results: 536 patients with RF comprised the study sample. Recurrent episodes of RF occurred in 88 of 536 patients (16.5%). Patients with a recurrent episode of RF were younger (p < 0.0001), more frequently males (p = 0.003), and less adherent (p < 0.0001) to secondary prophylaxis than patients without RF recurrence. Non-adherence to medication at any time during follow-up was detected in 35% of patients. Rates of non-adherence were higher in the group of patients that were lost to follow-up (42%) than in the group of patients still in follow-up (32%) (p = 0.027). Appointment frequency was inadequate in 10% of patients. Higher rates of inadequate appointment frequency were observed among patients who were eventually lost to follow-up (14.5%) than in patients who were successfully followed-up (8%) (p = 0.022). 180 patients (33.5%) were lost to follow up at some point in time., Conclusions: We recommend implementation of a registry, and a system of active search of missing patients in every service responsible for the follow-up of RF patients. Measures to increase adherence to secondary prophylaxis need to be implemented formally, once non-adherence to secondary prophylaxis is the main cause of RF recurrence. Detection of irregularity in secondary prophylaxis or in appointments should be an alert about the possibility of loss of follow-up and closer observation should be instituted.

Background: Cats are frequent carriers of Microsporum canis and veterinary students are at high risk of exposure and acquisition of the organism a la infección., Objectives: An outbreak of zoonotic ringworm carried by a litter of stray cats is described. Four veterinary students, four dogs, and six cats living in five separate locations were affected. All had direct or indirect contact with the infected kitten litter. We tried to identify the causal dermatophyte., Methods: Conventional and mycological culture methods were used., Results: Microscopic features of scrapings and hairs treated with 20% KOH strongly suggested a M. canis etiology, and a diagnosis of ringworm was empirically supported by successful treatment of humans and animals. Nevertheless, cultures failed to show the expected morphology., Conclusions: Culture features of our strain are compared with those described by other authors for dysgonic M. canis strains. Epidemiological features are also discussed., (Copyright 2009 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.)

Vitamin D levels depend on many variables, including sun exposure, age, ethnicity, body mass index, use of medications and supplements. A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. In addition to the traditional known metabolic activities, vitamin D has been shown to modulate the immune system, and its deficiency has been linked to the development of several autoimmune disorders including type 1 diabetes and multiple sclerosis. Experimental use of vitamin D has revealed a novel role in the immunopathogenesis of autoimmune diseases. Disorders such as systemic lupus erythematosus, rheumatoid arthritis, Behçet's, polymyositis/dermatomyositis and systemic scleroderma have all been associated to some extent to vitamin D deficiency. If vitamin D deficiency occurs at a higher rate in patients with autoimmune disorders, then appropriate supplementation may be indicated., (2010 Elsevier B.V. All rights reserved.)

We reviewed 53 patients referred to a pediatric rheumatology clinic in Asuncion, Paraguay. In 6 patients, a diagnosis of rheumatic fever was confirmed and in 47 patients other clinically significant diagnoses were made. Eighteen children had nonspecific findings and did not develop a rheumatologic condition on follow-up. Overdiagnosis of rheumatic fever can falsely inflate incidence and prevalence statistics and clinically significant diagnoses may be overlooked.

Purpose: To describe the presence of gold salt deposits in the corneal tissue of a patient treated with gold sodium thiomalate through confocal microscopy and to relate our findings to temporary corneal dynamics., Methods: A patient who had been treated with gold sodium thiomalate for 6 years was referred from the Rheumatology Unit of our center for an ophthalmologic examination. At the time of examination she had been treatment-free for 9 years. Besides visual acuity, the examination included slit-lamp biomicroscopy, intraocular pressure, and fundoscopy. Confocal microscopy performed using a Confoscan P4 instrument with a 40x lens to obtain 15 images per second on an S-VHS video system (Panasonic) for subsequent analysis., Results: The basic layered structure of the cornea was unaffected, but the presence of highly reflective particles was noted. These particles were interpreted as gold deposits in the corneal stroma, especially in the anterior and middle stroma., Conclusion: Confocal microscopy is a useful method of evaluating the deposition of gold salts in tissues, particularly the cornea. Its future use will help gain a deeper understanding of corneal metabolism.

This paper presents an extension of the method presented by Benitez et al (1997) for extracting fuzzy rules from an artificial neural network (ANN) that express exactly its behavior. The extraction process provides an interpretation of the ANN in terms of fuzzy rules. The fuzzy rules presented are in accordance with the domain of the input variables. These rules use a new operator in the antecedent. The properties and intuitive meaning of this operator are studied. Next, the role of the biases in the fuzzy rule-based systems is analyzed. Several examples are presented to comment on the obtained fuzzy rule-based systems. Finally, the interpretation of ANNs with two or more hidden layers is also studied.

Artificial neural networks are efficient computing models which have shown their strengths in solving hard problems in artificial intelligence. They have also been shown to be universal approximators. Notwithstanding, one of the major criticisms is their being black boxes, since no satisfactory explanation of their behavior has been offered. In this paper, we provide such an interpretation of neural networks so that they will no longer be seen as black boxes. This is stated after establishing the equality between a certain class of neural nets and fuzzy rule-based systems. This interpretation is built with fuzzy rules using a new fuzzy logic operator which is defined after introducing the concept of f-duality. In addition, this interpretation offers an automated knowledge acquisition procedure.