Search

Jaqueline de Cássia Proença-Assunção,1 Anna Paula Farias-de-França,2 Natalia Tribuiani,1 Jose Carlos Cogo,3 Rita de Cássia Collaço,4 Priscila Randazzo-Moura,5 Sílvio Roberto Consonni,6 Marco Vinicius Chaud,1 Carolina Alves dos Santos,2 Yoko Oshima-Franco1 1Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (Uniso), Sorocaba, SP, Brazil; 2Pharmacy Graduate Course, University of Sorocaba (Uniso), Sorocaba, SP, Brazil; 3Bioengineering and Biomedical Engineering Programs, Technological and Scientific Institute, Brazil University, São Paulo, Brazil; 4Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, SP, Brazil; 5Department of Surgery, Pontifícia Universidade Católica De São Paulo (PUCSP), Sorocaba, SP, Brazil; 6Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, SP, BrazilCorrespondence: Yoko Oshima-FrancoUniversity of Sorocaba (UNISO), Rodovia Raposo Tavares, Km 92.5, Sorocaba, 18023-000, SP, BrazilTel +55 15 2101-7197Fax +55 15-2101-7112Email yoko.franco@prof.uniso.brPurpose: A silver nanoparticle obtained by reducing salts with solid dispersion of curcumin (130 nm, 0.081 mg mL− 1) was used to counteract against the toxic – edematogenic, myotoxic, and neurotoxic – effects of Philodryas olfersii venom.Methods: The edematogenic effect was evaluated by plasma extravasation in rat dorsal skin after injection of 50 μg per site of venom alone or preincubated with 1, 10, and 100 μL of AgNPs; the myotoxicity was evaluated by measuring the creatine kinase released into the organ-bath before the treatment and at the end of each experiment; and neurotoxicity was evaluated in chick biventer cervicis using the conventional myographic technique, face to the exogenous acetylcholine (ACh) and potassium chloride (KCl) added into the bath before the treatment and after each experiment. Preliminarily, a concentration-response curve of AgNPs was carried out to select the concentration to be used for neutralizing assays, which consists of neutralizing the venom-induced neuromuscular paralysis and edema by preincubating AgNPs with venom for 30 min.Results: The P. olfersii venom-induced edema (n=6) and a complete neuromuscular blockade (n=4) that includes the total and unrecovered block of ACh and KCl contractures. AgNPs produced a concentration-dependent decrease the venom-induced edema (n=6) from 223.3% to 134.4% and to 100.5% after 10 and 100 μL AgNPs-preincubation, respectively. The preincubation of venom with AgNPs (1 μL; n=6) was able to maintain 46.5 ± 10.9% of neuromuscular response under indirect stimuli, 39.2 ± 9.7% of extrinsic nicotinic receptors functioning in absence of electrical stimulus and 28.3 ± 8.1% of responsiveness to potassium on the sarcolemmal membrane. The CK release was not affected by any experimental protocol which was like control.Conclusion: AgNPs interact with constituents of P. olfersii venom responsible for the edema-forming activity and neuromuscular blockade, but not on the sarcolemma membrane-acting constituents. The protective effect of the studied AgNPs on avian preparation points out to molecular targets as intrinsic and extrinsic nicotinic receptors.Keywords: chick biventer cervicis, opisthoglyphous snakes, Philodryas olfersii, neuromuscular blockade, silver nanoparticles

We establish new results concerning existence and asymptotic behavior of entire, positive, and bounded solutions which converge to zero at infinite for the quasilinear equation where are suitable functions and are not identically zero continuous functions. We show that there exists at least one solution for the above-mentioned problem for each for some . Penalty arguments, variational principles, lower-upper solutions, and an approximation procedure will be explored.

Abstract Background Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture. Results Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria. Conclusions Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

Abstract Background A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. Methods Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. Results Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. Conclusions This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

Large-vessel vasculitis (LVV) is a group of diseases characterized by inflammation of the aorta and its main branches, which includes giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and Takayasu’s arteritis (TAK). These conditions pose significant diagnostic and management challenges due to their diverse clinical presentations and potential for serious complications. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT) has emerged as a valuable imaging modality for the diagnosis and monitoring of LVV, offering insights into disease activity, extent, and response to treatment. 18F-FDG-PET-CT plays a crucial role in the diagnosis and management of LVV by allowing to visualize vessel involvement, assess disease activity, and guide treatment decisions. Studies have demonstrated the utility of 18F-FDG-PET-CT in distinguishing between LVV subtypes, evaluating disease distribution, and detecting extracranial involvement in patients with cranial GCA or PMR phenotypes. Additionally, 18F-FDG-PET-CT has shown promising utility in predicting clinical outcomes and assessing treatment response, based on the correlation between reductions in FDG uptake and improved disease control. Future research should focus on further refining PET-CT techniques, exploring their utility in monitoring treatment response, and investigating novel imaging modalities such as PET-MRI for enhanced diagnostic accuracy in LVV. Overall, 18F-FDG-PET-CT represents a valuable tool in the multidisciplinary management of LVV, facilitating timely diagnosis and personalized treatment strategies to improve patient outcomes.

BackgroundEarly diagnosis and treatment of Systemic lupus erythematosus (SLE) and Systemic sclerosis (SSc) present significant challenges for clinicians. Although various studies have observed changes in serum levels of selectins between healthy donors and patients with autoimmune diseases, including SLE and SSc, their potential as biomarkers has not been thoroughly explored. We aimed to investigate serum profiles of PSGL-1 (sPSGL-1), ADAM8 (sADAM8) and P-, E- and L-selectins (sP-, sE- and sL-selectins) in defined SLE and SSc patient cohorts to identify disease-associated molecular patterns.MethodsWe collected blood samples from 64 SLE patients, 58 SSc patients, and 81 healthy donors (HD). Levels of sPSGL-1, sADAM8 and selectins were analyzed by ELISA and leukocyte membrane expression of L-selectin and ADAM8 by flow cytometry.ResultsCompared to HD, SLE and SSc patients exhibited elevated sE-selectin and reduced sL-selectin levels. Additionally, SLE patients exhibited elevated sPSGL-1 and sADAM8 levels. Compared to SSc, SLE patients had decreased sL-selectin and increased sADAM8 levels. Furthermore, L-selectin membrane expression was lower in SLE and SSc leukocytes than in HD leukocytes, and ADAM8 membrane expression was lower in SLE neutrophils compared to SSc neutrophils. These alterations associated with some clinical characteristics of each disease. Using logistic regression analysis, the sL-selectin/sADAM8 ratio in SLE, and a combination of sL-selectin/sE-selectin and sE-selectin/sPSGL-1 ratios in SSc were identified and cross-validated as potential serum markers to discriminate these patients from HD. Compared to available diagnostic biomarkers for each disease, both sL-selectin/sADAM8 ratio for SLE and combined ratios for SSc provided higher sensitivity (98% SLE and and 67% SSc correctly classified patients). Importantly, the sADAM8/% ADAM8(+) neutrophils ratio discriminated between SSc and SLE patients with the same sensitivity and specificity than current disease-specific biomarkers.ConclusionSLE and SSc present specific profiles of sPSGL-1, sE-, sL-selectins, sADAM8 and neutrophil membrane expression which are potentially relevant to their pathogenesis and might aid in their early diagnosis.

Diarrhea is a prevalent and economically impactful ailment in cattle herds, resulting in substantial losses attributed to mortality, treatment expenses, and impaired calf growth. The aim of this study was to establish data about the occurrence of the main bacterial agents involved in diarrhea in dairy calves in the state of Maranhão, as well as to determine the most effective and/or resistant antibiotics, establishing a foundation for treatment and prevention protocols. The samples were collected with rectal swabs and initially cultivated on sheep blood agar (5%) and MacConkey agar and later on Salmonella-Shigella agar and eosin-methylene blue agar. Gram staining, biochemical tests, and antibiograms were performed on the obtained colonies. Ten municipalities were studied, with 230 calves evaluated from ten dairy farms. A total of 21 animals exhibited clinical signs of diarrhea, representing a frequency of 9.13%. The frequency of positive farms was 35%, and in 50% of municipalities. Bacteria isolated belonged to the Enterobacteriaceae family, with 71.4% Escherichia coli, 14.3% Enterobacter sp., 9.5% Proteus sp. and 4.8% Klebsiella sp. On the antibiogram, the bacteria that showed the highest resistance levels were those of the Proteus genus, followed by Enterobacter sp. and E. coli. The bacteria found are relevant for both animal and human health due to their zoonotic potential and serve as a public health alert since the isolates in this study showed in vitro resistance to several antibiotics, which predisposes them to the emergence of multidrug-resistant bacteria.

Los hongos micorrícicos arbusculares (HMA) y los endófitos septados oscuros (DSEF) tienen tal influencia en el desarrollo de las plantas y en las características edafológicas y nutrientes disponibles en el suelo, que cambios en estas comunidades pueden impulsar modificaciones en las variables bióticas y abióticas de un ecosistema, demostrando la sinergia entre especies. Dada su relevancia, el objetivo de este trabajo fue determinar el estado de colonización en las raíces de tres especies herbáceas representativas del sotobosque de una comunidad de Abies religiosa (Kunth Schltdl. et Cham.) y Pinus harwegii (Lindl), y contrastar la coexistencia de colonizadores en tres escenarios de conservación-perturbación que ejemplifican las situaciones de vulnerabilidad de un ecosistema forestal. Se constata una interacción tripartita AMF-HESO-planta por la aparición de hifas coenocíticas, vesículas, hifas septadas, células moniliformes y esclerocios. Los valores de micorrización arbuscular superan el 50% y son superiores a los encontrados para los endófitos (15.7-64.5%). La colonización de ambos tipos de hongos, como la esporulación de AMF (687 esporas 50 g-1 de suelo en la zona reforestada), parece estar relacionada con las condiciones microclimáticas derivadas del uso del suelo. Las variables edafológicas que permiten inferir el comportamiento de la colonización corresponden principalmente al fósforo disponible, calcio, pH, materia orgánica y capacidad de intercambio catiónico. Se concluye que las propiedades del suelo, su uso y el tipo de plantas son determinantes en el establecimiento de las comunidades fúngicas. Sin embargo, son necesarios más estudios sobre la interacción HESO-planta.

Abstract B and T cell responses were evaluated in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) after 1 or 2 weeks of methotrexate (MTX) withdrawal following each COVID-19 vaccine dose and compared with those who maintained MTX. Adult RA and PsA patients treated with MTX were recruited and randomly assigned to 3 groups: MTX-maintenance (n = 72), MTX-withdrawal for 1 week (n = 71) or MTX-withdrawal for 2 weeks (n = 73). Specific antibodies to several SARS-CoV-2 antigens and interferon (IFN)-γ and interleukin (IL)-21 responses were assessed. MTX withdrawal in patients without previous COVID-19 was associated with higher levels of anti-RBD IgG and neutralising antibodies, especially in the 2-week withdrawal group and with higher IFN-γ secretion upon stimulation with pools of SARS-CoV-2 S peptides. No increment of RA/PsA relapses was detected across groups. Our data indicate that two-week MTX interruption following COVID-19 vaccination in patients with RA or PsA improves humoral and cellular immune responses.

Introduction The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed.Methods Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment.Results After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (β coefficient: −1.2 (95% CI: −0.3 to −0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (β coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high–very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis.Conclusion Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.

Objective To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients.Methods Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3).Results Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

Polymyalgia rheumatica (PMR) is an inflammatory disease common in people aged 50 years and older. This condition is characterized by the presence of pain and stiffness involving mainly the shoulder and pelvic girdle. Besides the frequent association with giant cell arteritis (GCA), several conditions may mimic PMR or present with PMR features. Since the diagnosis is basically clinical, an adequate diagnosis of this condition is usually required. Positron emission tomography/computed tomography (PET-CT) has proved to be a useful tool for the diagnosis of PMR. The use of 18F-FDG-PET imaging appears promising as it provides detailed information on inflammatory activity that may not be evident with traditional methods. However, since PET-CT is not strictly necessary for the diagnosis of PMR, clinicians should consider several situations in which this imaging technique can be used in patients with suspected PMR.

Objective This study aimed to estimate the incidence of giant cell arteritis (GCA) in Spain and to analyse its clinical manifestations, and distribution by age group, sex, geographical area and season.Methods We included all patients diagnosed with GCA between 1 June 2013 and 29 March 2019 at 26 hospitals of the National Health System. They had to be aged ≥50 years and have at least one positive results in an objective diagnostic test (biopsy or imaging techniques), meet 3/5 of the 1990 American College of Rheumatology classification criteria or have a clinical diagnosis based on the expert opinion of the physician in charge. We calculated incidence rate using Poisson regression and assessed the influence of age, sex, geographical area and season.Results We identified 1675 cases of GCA with a mean age at diagnosis of 76.9±8.3 years. The annual incidence was estimated at 7.42 (95% CI 6.57 to 8.27) cases of GCA per 100 000 people ≥50 years with a peak for patients aged 80–84 years (23.06 (95% CI 20.89 to 25.4)). The incidence was greater in women (10.06 (95% CI 8.7 to 11.5)) than in men (4.83 (95% CI 3.8 to 5.9)). No significant differences were found between geographical distribution and incidence throughout the year (p=0.125). The phenotypes at diagnosis were cranial in 1091 patients, extracranial in 337 patients and mixed in 170 patients.Conclusions This is the first study to estimate the incidence of GCA in Spain at a national level. We found a predominance among women and during the ninth decade of life with no clear variability according to geographical area or seasons of the year.

Myrciaria dubia (Kunth) McVaugh (camu-camu) is a shrub native to the Amazon region that produces fruits with a high content of vitamin C and various bioactive compounds, making it a functional food with antioxidant, anti-inflammatory, and antimicrobial properties. However, it is unknown which microorganisms are associated with its root system and can influence its growth and productivity. Arbuscular mycorrhizal fungi (AMF) are associated with most plants and are essential for their establishment, survival, and productivity since they facilitate their nutrition, increase water absorption, and improve soil structure. Although the AMF association is already known in some species of Myrciaria, no report is available on its association in M. dubia. This study presents, for the first time, the symbiotic association between AMF and M. dubia from the INIA San Roque experimental station located in the Amazon region, Peru. For the morphological and molecular analyses of the AMF, samples of rhizospheric soil and roots from two native accessions of the National Germplasm Bank of M. dubia were collected. Eighteen AMF morphospecies were identified in rhizospheric soil, belonging to nine genera Acaulospora, Ambispora, Entrophospora, Diversispora, Gigaspora, Glomus, Paraglomus, Funneliformis, and Sclerocystis, being the first one the most frequent. The roots of M. dubia showed high colonization by AMF (mean = 91%), and characteristic structures of arbuscular mycorrhizae, such as vesicles, hyphae, and arbuscules, could be observed. Likewise, the molecular analysis detected the presence of genetic material (rDNA) corresponding to AMF in the roots of both accessions. Our results evidenced the symbiotic association between AMF and M. dubia, which encourages further investigation of the functional potential of these microorganisms in this economically crucial agricultural plant in Peru.

(1) Background: The diagnosis of lumbosacral radiculopathy involves anamnesis, an assessment of sensitivity and strength, diagnostic imaging—usually magnetic resonance imaging (MRI)—and electrodiagnostic testing (EDX), typically electromyography (EMG), and electroneurography (ENG). MRI evaluates the structures supporting the spinal cord, while EDX evaluates root functionality. The present study aimed to analyze the concordance of MRI and EDX findings in patients with clinically suspected radiculopathy. Additionally, we investigated the comparison between these two reference tests and various clinical variables and questionnaires. (2) Methods: We designed a prospective epidemiological study of consecutive cases with an observational, descriptive, cross-sectional, and double-blind nature following the STROBE guidelines, encompassing 142 patients with clinical suspicion of lumbosacral radiculopathy. (3) Results: Of the sample, 58.5% tested positive for radiculopathy using EDX as the reference test, while 45.8% tested positive using MRI. The comparison between MRI and EDX in the diagnosis of radiculopathy in patients with clinical suspicion was not significant; the overall agreement was 40.8%. Only the years with symptoms were comparatively significant between the positive and negative radiculopathy groups as determined by EDX. (4) Conclusion: The comparison between lumbar radiculopathy diagnoses in patients with clinically suspected pathology using MRI and EDX as diagnostic modalities did not yield statistically significant findings. MRI and EDX are complementary tests assessing different aspects in patients with suspected radiculopathy; degeneration of the structures supporting the spinal cord does not necessarily imply root dysfunction.

Novel mechanisms of COVID-19 vaccines raised concern about their potential immunogenicity in patients with rheumatoid arthritis (RA) undergoing immunomodulatory treatments. We designed a retrospective single-center study to investigate their effectiveness and safety in this population, analyzing data from the first vaccination program (December 2020–October 2021). Inclusion criteria were availability of post-vaccination serology and a minimum subsequent follow-up of 6 months. Binding antibody units (BAU/mL) ≥ 7.1 defined an adequate serological response. Post-vaccine COVID-19 incidence and its timing since vaccination, adverse events (AEs), and RA flares were recorded. Adjusted logistic and linear multivariate regression analyses were carried out to identify factors associated with vaccine response. We included 118 patients (87.2% women, age 65.4 ± 11.6 years, evolution 12.0 ± 9.6 years), of whom 95.8% had a complete vaccination schedule. Adequate humoral immunogenicity was achieved in 88.1% of patients and was associated with previous COVID-19 and mRNA vaccines, whereas smoking, aCCP, age, and DMARDs exerted a negative impact. Post-vaccine COVID-19 occurred in 18.6% of patients, a median of 6.5 months after vaccination. Vaccine AE (19.5%) and RA flares (1.7%) were mostly mild and inversely associated with age. Our results suggest that COVID-19 vaccines induce adequate humoral immunogenicity, with an acceptable safety profile in RA patients.

Dual targeted therapy (DTT) has emerged as a promising approach in patients with refractory spondyloarthritis (SpA) or psoriatic arthritis (PsA) and extra-musculoskeletal manifestations of both diseases, but its effectiveness/safety ratio still remains unclear. This is a retrospective, real-world multicenter study in refractory SpA and PsA patients with simultaneous use of two biological or synthetic targeted agents. Effectiveness was assessed using Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Disease Activity in Psoriatic Arthritis (DAPSA) Score. We identified 39 different DTT combinations in 36 patients (22 SpA; 14 PsA), 25 of them with concomitant inflammatory bowel disease. The most commonly used combinations were TNF inhibitor plus antagonist of the IL12/23 pathway, followed by TNF inhibitor plus IL-17 antagonist. During a median exposure of 14.86 months (IQR 8-20.2), DTT retention rate was 69.4% (n=25/36; 19 SpA, 6 PsA). Major clinical improvement (change in ASDAS-CRP > 2 or improvement > 85% in DAPSA) was achieved in 69.4% of patients (n=25/36 therapeutical combinations; 17/21 SpA, 8/15 PsA), with a 58.3% (n=21/36 combinations; 15/20 SpA, 6/13 PsA) low-activity/remission rate. Of the patients who were receiving glucocorticoids, 55% managed to withdraw them during follow-up. Interestingly, only four serious adverse events in three patients were observed, leading to DTT discontinuation.

A presente pesquisa apresenta como temática a aprendizagem cooperativa como estratégia para a diferenciação pedagógica em sala de aula cujo o objetivo é explicar a utilização da aprendizagem cooperativa como estratégia para a diferenciação pedagógica nas salas de aula das escolas primárias do Sumbe. Este tipo de aprendizagem tem a ver com aplicação de técnicas de ensinar e aprender na base da criação de grupos de trabalho na sala de aula, cujo fim é discutir, interagir em torno de uma temática tendo um objetivo comum, a partir desta criar situações que levam o aluno a diferenciação pedagógica que se apresenta na base de o professor utilizar vários métodos para fazer com que todos os alunos apreendam ao mesmo tempo e cada um da forma mais fácil, sem contar com as diferenças trazidas por eles, quer físicas ou psicológicas. Como é de conhecimento, na sala de aula todos alunos são diferentes, uns aprendem mais rápidos outros de forma mais lenta, cabe ao professor estar preparado, ter formação e informação para ensinar da maneira que cada um aprenda atendendo as suas particularidades. Esta investigação se apoia na variável, aprendizagem cooperativa bem como suas dimensões, a sua utilização no processo de ensino aprendizagem, promove a diferenciação pedagógica e o espirito de interajuda, pondo de parte a competição entre os alunos. Na realidade angolana ainda temos verificado em poucas vezes o uso desta estratégia por parte dos professores, tudo pelo desconhecimento da importância da sua utilização. Vale salientar que este, ajuda a atingir sucessos no processo de ensino-aprendizagem. Este estudo contou com uma metodologia centrada no paradigma qualitativo, e para a busca da informação foram aplicados métodos como: entrevista, inquerito por questionario e a triangulação de dados através do cruzamento das informações coletadas dos informantes.

IntroductionThe knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules.ObjectiveThis study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD.MethodsWe analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism.DiscussionOur results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Vertebral fragility fractures (VFF) pose a challenge for appropriate care. The aim of this study was to develop consensus recommendations for the management of VFF in older people from a multidisciplinary approach. Specialists in osteoporosis belonging to different scientific societies reviewed the main clinical practice guidelines published in Spain in 2014. Thirty-five recommendations for the management of VFF were evaluated by seven experts using an anonymous survey. Consensus was defined as 80% of responses of 8 (agree) and 9 (strongly agree) on a Likert scale. Consensus was achieved in 22 recommendations (62.8%). The experts agreed on the need for anamnesis, clinical assessment, and laboratory tests, including erythrocyte sedimentation rate, proteinography, and the assessment of levels of calcium, vitamin D, alkaline phosphatase, and thyroid-stimulating hormone. Optional tests, such as bone turnover markers (BTMs), magnetic resonance imaging, bone scintigraphy, or using a fracture risk assessment tool (FRAX®), did not achieve an agreed consensus. Also, there was consensus regarding the administration of calcium/vitamin D supplements, the withdrawal of toxic habits, and personalized physical exercise. Participants agreed on the administration of teriparatide for 24 months and then a switch to denosumab or bisphosphonates in patients at high risk of fracture. Specialists in osteoporosis, primary care physicians, and geriatricians should be involved in the follow-up of patients with VFF. Although there was multidisciplinary agreement on diagnostic tests and non-pharmacological and pharmacological treatment in frail older people, therapeutic objectives should be individualized for every patient. In addition to the specific recommendations, close collaboration between the geriatrician and the primary care physician is essential for the optimal chronic management of frail patients with fragility fractures.

The COVID-19 vaccination program has probably been the most complex and extensive project in history until now, which has been a challenge for all the people involved in the planning and management of this program. Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy have required special attention, not only because of the particular haste in carrying out the process but also because of the uncertainty regarding their response to the vaccines. We now have strong scientific evidence that supports the hypothesis that immunosuppressive therapy inhibits the humoral response to vaccines against other infectious agents, such as influenza, pneumococcus and hepatitis B. This has led to the hypothesis that the same could happen with the COVID-19 vaccine. Several studies have therefore already been carried out in this area, suggesting that temporarily discontinuing the administration of methotrexate for 2 weeks post-vaccination could improve the vaccine response, and other studies with various immunosuppressive drugs are in the same line. However, the fact of withholding or interrupting immunosuppressive therapy when dealing with COVID-19 vaccination remains unclear. On this basis, our article tries to compile the information available on the effect of immunosuppressant agents on COVID-19 vaccine responses in patients with IMIDs and proposes an algorithm for the management of these patients.

Abstract Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

In this paper, we consider the following modified quasilinear problem:

The individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.

Ocular disease, such as scleritis and peripheral ulcerative keratitis (PUK), may be a serious ocular complication. We present a patient with severe and refractory PUK treated with baricitinib. A review of the literature on Janus kinase inhibitors (JAKINIB) in refractory ocular surface pathology was also performed. For the literature review, the search in PubMed, Embase, and the Cochrane library was carried out from inception until 31 May 2021, including conference proceedings from four major rheumatology congresses. All original research articles studying JAKINIB treatment in patients with inflammatory eye disease were included. We present an 85-year-old woman with rheumatoid arthritis (RA) and secondary Sjögren’s syndrome refractory to methotrexate, leflunomide, certolizumab pegol, adalimumab, and tocilizumab (TCZ). However, 10 months after starting TCZ, the patient suffered a perforation secondary to PUK, requiring urgent surgical intervention. In the absence of infection, she was treated with boluses of intravenous methylprednisolone followed by oral prednisone at high doses in a decreasing pattern together with baricitinib at a dose of 2 mg/day with a very rapid and persistent favorable response to eye and joint symptoms. After 18 months of treatment, the patient had not presented serious side effects or signs of reactivation of her disease. In addition to this report, three other studies including one PUK associated with RA and two non-infectious scleritis treated with tofacitinib were included in this literature review. All three patients had experienced an insufficient response to conventional treatment, including biologic agents, before being switched to JAKINIB, leading to a complete or partial recovery in all of them without significant adverse effects so far. JAKINIBs (baricitinib and tofacitinib) may be an effective and safe therapy in patients with severe autoimmune and refractory ocular surface pathology, such as scleritis and PUK.

Abstract Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

Background: Visual involvement is the most feared complication of giant cell arteritis (GCA). Information on the efficacy of tocilizumab (TCZ) for this complication is scarce and controversial. Objective: We assessed a wide series of GCA treated with TCZ, to evaluate its role in the prevention of new visual complications and its efficacy when this manifestation was already present before the initiation of TCZ. Design: This is an observational multicenter study of patients with GCA treated with TCZ. Methods: Patients were divided into two subgroups according to the presence or absence of visual involvement before TCZ onset. Visual manifestations were classified into the following categories: transient visual loss (TVL), permanent visual loss (PVL), diplopia, and blurred vision. Results: Four hundred seventy-one GCA patients (mean age, 74 ± 9 years) were treated with TCZ. Visual manifestations were observed in 122 cases (26%), of which 81 were present at TCZ onset: PVL ( n = 60; unilateral/bilateral: 48/12), TVL ( n = 17; unilateral/bilateral: 11/6), diplopia ( n = 2), and blurred vision ( n = 2). None of the patients without previous visual involvement or with TVL had new episodes after initiation of TCZ, while only 11 out of 60 (18%) patients with PVL experienced some improvement. The two patients with diplopia and one of the two patients with blurred vision improved. Conclusion: TCZ may have a protective effect against the development of visual complications or new episodes of TVL in GCA. However, once PVL was established, only a few patients improved.