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ID PMID Title PublicationDate abstract
30621465 Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015-2018). 2019 Feb INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors. AREAS COVERED: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years. EXPERT OPINION: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.
30610331 Retro-odontoid Degenerative Pseudotumour Causing Spinal Cord Compression and Myelopathy: C 2019 BACKGROUND: A retro-odontoid pseudotumour compressing the spinal cord and causing myelopathy is often associated with an inflammatory condition such as rheumatoid arthritis. A degenerative non-inflammatory retro-odontoid pseudotumour responsible for clinically relevant spinal cord compression is a rare condition described in small clinical series and is likely associated with craniovertebral junction hypermobility or instability-like conditions. For several years, direct removal of the lesion through an anterior or lateral approach has been advocated as the best surgical option. However, in the last decade the posterior approach to the craniovertebral junction, to perform C1-C2 fixation and C1 laminectomy without removal of the retro-odontoid tissue, has demonstrated its efficacy in reducing retro-odontoid pannus as well as in obtaining improvement of myelopathy. METHODS: In this paper we analyse the clinical and radiological outcomes of seven patients (five males and two females) treated with posterior C1-C2 fixation and C1 laminectomy for a degenerative non-inflammatory retro-odontoid pseudotumour responsible for spinal cord compression. C1 laminectomy provided immediate spinal cord decompression. We also review the relevant literature focusing on associated cervical degenerative conditions that may contribute to triggering or acceleration of atlantoaxial hypermobility or 'instability', causing formation of the retro-odontoid tissue. RESULTS: The mean follow-up period (of six followed-up patients) was 55.8 months (range 10-96 months). In all cases the Nurick score at the latest follow-up visit demonstrated clinical improvement; magnetic resonance imaging during follow-up demonstrated progressive reduction of the retro-odontoid pseudotumour in all but one patient, who died of surgery-unrelated disease in the early postoperative period. No vascular or neural damage secondary to C1-C2 fixation was observed. CONCLUSION: C1-C2 fixation associated with C1 laminectomy is an effective surgical option to treat myelopathy secondary to a degenerative retro-odontoid pseudotumour. In these cases, direct removal of intracanalar tissue compressing the spinal cord is not required, as C1-C2 fixation is sufficient to cause its disappearance.
30261716 Cis-3-O-p-hydroxycinnamoyl Ursolic Acid Induced ROS-Dependent p53-Mediated Mitochondrial A 2019 Jan 1 Cis-3-O-p-hydroxycinnamoyl ursolic acid (HCUA), a triterpenoid compound, was purified from Elaeagnus oldhamii Maxim. This traditional medicinal plant has been used for treating rheumatoid arthritis and lung disorders as well as for its anti-inflammation and anticancer activities. This study aimed to investigate the anti-proliferative and apoptotic-inducing activities of HCUA in oral cancer cells. HCUA exhibited anti-proliferative activity in oral cancer cell lines (Ca9-22 and SAS cells), but not in normal oral fibroblasts. The inhibitory concentration of HCUA that resulted in 50% viability was 24.0 µM and 17.8 µM for Ca9-22 and SAS cells, respectively. Moreover, HCUA increased the number of cells in the sub-G1 arrest phase and apoptosis in a concentration-dependent manner in both oral cancer cell lines, but not in normal oral fibroblasts. Importantly, HCUA induced p53-mediated transcriptional regulation of pro-apoptotic proteins (Bax, Bak, Bim, Noxa, and PUMA), which are associated with mitochondrial apoptosis in oral cancer cells via the loss of mitochondrial membrane potential. HCUA triggered the production of intracellular reactive oxygen species (ROS) that was ascertained to be involved in HCUA-induced apoptosis by the ROS inhibitors YCG063 and N-acetyl-L-cysteine. As a result, HCUA had potential antitumor activity to oral cancer cells through eliciting ROS-dependent and p53-mediated mitochondrial apoptosis. Overall, HCUA could be applicable for the development of anticancer agents against human oral cancer.
28737645 Risk of Cancer Recurrence Among Individuals Exposed to Antitumor Necrosis Factor Therapy: 2019 Jan BACKGROUND: Patients with immune-mediated disorders such as ankylosing spondylitis, inflammatory bowel disease, psoriasis and rheumatoid arthritis are increasingly treated with tumor necrosis factor (TNF) inhibitors. The safety of anti-TNF therapy in patients with a history of cancer requires further evaluation. We conducted a systematic review and a meta-analysis of observational studies including patients with a history of cancer exposed to anti-TNF therapy assessing for a risk of new cancer or cancer recurrence. MATERIALS AND METHODS: A computerized literature search of MEDLINE, Google scholar, and Cochrane Database of Systematic Reviews was performed through September 1, 2015. Study characteristics, quality, and risk of bias were assessed. Random-effects model meta-analyses were used to estimate the risk of new cancer development or cancer recurrence. RESULTS: Nine English-language observational studies including patients with a history of cancer and exposed to anti-TNF therapy were idenitifed. The pooled incidence rate ratio of new or recurrent cancer among individuals with a history of cancer exposed to anti-TNF therapy was not significantly different compared with control therapies (incidence rate ratio, 0.90; 95% confidence interval, 0.59-1.37). Subgroup analyses were performed according to disease type, underlying cancer diagnosis, time to initiation of anti-TNF therapy and study quality. Heterogeneity of study populations, heterogeneity of the included cancer subtypes and utilization of observational studies limits the study quality. CONCLUSIONS: The risk of new cancer or cancer recurrence among patients with a history of cancer and use of anti-TNF therapy is similar to the risk with nonbiological disease modifying therapies. These results support the use of anti-TNF medications in select populations despite prior diagnosis of cancer.
31722123 Anti-TNF treatment negatively regulates human CD4(+) T-cell activation and maturation in v 2020 Mar TNF-blockade has shown clear therapeutic value in rheumatoid arthritis and other immune-mediated inflammatory diseases, however its mechanism of action is not fully elucidated. We investigated the effects of TNF-blockade on CD4(+) T cell activation, maturation, and proliferation, and assessed whether TNF-inhibitors confer regulatory potential to CD4(+) T cells. CyTOF and flow cytometry analysis revealed that in vitro treatment of human CD4(+) T cells with the anti-TNF monoclonal antibody adalimumab promoted IL-10 expression in CD4(+) T cells, whilst decreasing cellular activation. In line with this, analysis of gene expression profiling datasets of anti-TNF-treated IL-17 or IFN-γ-producing CD4(+) T cells revealed changes in multiple pathways associated with cell cycle and proliferation. Kinetics experiments showed that anti-TNF treatment led to delayed, rather than impaired T-cell activation and maturation. Whilst anti-TNF-treated CD4(+) T cells displayed some hyporesponsiveness upon restimulation, they did not acquire enhanced capacity to suppress T-cell responses or modulate monocyte phenotype. These cells however displayed a reduced ability to induce IL-6 and IL-8 production by synovial fibroblasts. Together, these data indicate that anti-TNF treatment delays human CD4(+) T-cell activation, maturation, and proliferation, and this reduced activation state may impair their ability to activate stromal cells.
35079707 Risk factors for dislocation after primary total hip replacement: meta-analysis of 125 stu 2019 Oct BACKGROUND: Dislocation following total hip replacement (THR) is associated with repeated hospitalisations and substantial costs to the health system. Factors influencing dislocation following primary THR are not well understood. We aimed to assess the associations of patient-, surgery-, implant- and hospital-related factors with dislocation risk following primary THR. METHODS: We did a systematic review and meta-analysis of all longitudinal studies reporting these associations. We searched MEDLINE, Embase, Web of Science, and Cochrane Library to March 8, 2019. Summary measures of association were calculated using relative risks (RRs) (with 95% confidence intervals, CIs). The review is registered on PROSPERO, number CRD42019121378. FINDINGS: We identified 149 articles based on 125 unique studies with data on 4 633 935 primary THRs and 35 264 dislocations. The incidence rates of dislocation ranged from 0·12% to 16·13%, with an overall pooled rate of 2·10% (1·83-2·38) over a weighted mean follow-up duration of 6 years. Using median year of data collection, there was a significant decline in dislocation rates from 1971 to 2015. Comparing males vs females, age ≥70 vs <70 years, and high vs low income, RRs (95% CIs) for dislocation were 0·97 (0·88-1·08), 1·27 (1·02-1·57), and 0·79 (0·74-0·85) respectively. White ethnicity, drug use disorder, and social deprivation were each associated with an increased dislocation risk. Comparing body mass index (BMI) ≥30 vs. <30 kg/m(2), the RR (95% CI) for dislocation was 1·38 (1·03-1·85). Medical and surgical history-related factors associated with dislocation risk included neurological disorder, psychiatric disease, comorbidity indices, previous surgery including spinal fusion, and surgical indications including avascular necrosis, rheumatoid arthritis, inflammatory arthritis, and osteonecrosis. Surgical factors such as the anterolateral, direct anterior, or lateral approach and posterior with short external rotator and capsule repair were each associated with reduced dislocation risk. At the implant level, larger femoral head diameters, elevated acetabular liners, dual mobility cups, cemented fixations and standard femoral neck lengths reduced the risk of dislocation. Hospital-related factors such as experienced surgeons and high surgeon procedure volume each reduced the risk of dislocation. INTERPRETATION: Dislocation following primary THR is on a temporal decline. Surgical approaches that reduce dislocation risk can be used by clinicians when performing primary THR. Alternative bearings such as dual mobility can be used in individuals at high risk of dislocation. Modifiable risk factors such as high BMI and comorbidities may be amenable to optimisation prior to surgery. FUNDING: National Institute for Health Research.
30760878 Correction: Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influen 2019 Dec The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.
31560728 Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian cloc 2019 Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1.
31248460 Health economic evaluation in orthotics and prosthetics: a systematic review protocol. 2019 Jun 27 BACKGROUND: Health economic evaluations are essential to support health care policy and investment decisions. To date, health economic evaluations in orthotics and prosthetics have focused on discrete components of an orthosis/prosthesis (e.g. a microprocessor controlled prosthetic knee joint) rather than the broader service provided by orthotist/prosthetists. As such, the contribution to orthotic/prosthetic policy and investment decisions is unclear. Whilst there are opportunities to conduct more informative health economic evaluations that describe the costs and benefits of the orthotic/prosthetic service, it is important that prospective research is informed by a critical review of the method design challenges and an understanding of how this research can be improved. The aim of this systematic review is to critically appraise the existing orthotic/prosthetic health economic evaluation literature and therefore determine evidence gaps, critical method design issues and the extent to which the literature informs orthotic/prosthetic policy and investment decisions. METHODS: A comprehensive range of databases-AMED, EMBASE, MEDLINE and PsychINFO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), ProQuest Nursing and Allied Health, Web of Science, Cochrane Database of Systematic Reviews (CDSR) and specialty health economic databases-will be searched using National Library of Medicine Medical Subject Headings (MeSH) terms as well as the title, abstract, and keyword terms. Search terms related to the intervention (e.g. orthosis), including variants used by varying professional disciplines (e.g. brace), will be used in preference to defining the populations that use orthotic and prosthetic services (e.g. people living with rheumatoid arthritis). Search terms related to health economic evaluations will be guided by previously developed and tested search strings and align with recommendations by the Canadian Agency for Drugs and Technologies in Health. Articles meeting the inclusion criteria will be hand-searched for relevant citations, and a forward citation search using Google Scholar will also be conducted to identify early online articles not yet indexed in traditional databases. Original research published in the English language and after 1 January 2000 will be included. The Checklist for Health Economic Evaluation Reporting Standards (CHEERS) and the Consensus on Health Economic Criteria (CHEC)-Extended list will be used to appraise the methodological quality and identify sources of bias. Data extraction and appraisal will be conducted by one reviewer independently using appraisal instrument guidelines and a content specific decision aid with exemplars. A subsequent review by a second researcher will be undertaken to confirm the accuracy of the extraction and appraisal, and a final review by a third where consensus cannot be reached. The data will be extracted to a purpose-built data extraction template with decision-making guidelines to support consistency. Where possible, the findings of the review will be reported as a meta-analysis, although the heterogeneity of the literature will likely mean a narrative review that illuminates method design issues that contribute to imprecision and variation will be more appropriate. DISCUSSION: This protocol has been purposefully designed to summarise the existing evidence and appraise the methodological approaches used and the quality of the health economic evaluations in orthotics and prosthetics. What we learn from this review will be used to guide further work in this area and design more rigorous health economic evaluations into the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018116910.
30968571 Overlap myositis, a distinct entity beyond primary inflammatory myositis: A retrospective 2019 Aug BACKGROUND: Inflammatory idiopathic myositis (IIM) comprises a heterogeneous group of systemic muscular diseases that can occur together with other connective tissue diseases (CTD), named overlap myositis (OM). The question of whether OM is a distinct entity still remains controversial. AIM: The present study was conducted to assess the clinical and prognostic differences between patients diagnosed with OM, primary polymyositis (PM) and primary dermatomyositis (DM). METHOD: The study consists of a retrospective longitudinal and multicenter series of IIM patients. Patients were classified as OM, PM and DM. Overlap myositis was defined as patients fulfilling criteria for IIM plus criteria for other CTD (namely systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and primary Sjögren's syndrome). RESULT: A total of 342 patients were included (98 OM, 137 PM and 107 DM). Overlap myositis patients, in comparison with PM and DM, showed significant differences, with more extramuscular involvement, particularly more arthritis (66%, 34.6% and 48.1%, respectively), puffy fingers (49.5%, 11.1% and 24.3%), sclerodactyly (45.4%, 2.2% and 2%), dysphagia (41.8%, 18.2% and 26.4%), Raynaud phenomenon (65.3%, 16.9% and 19.8%), leucopenia (28.9%, 2.2% and 8.4%), thrombocytopenia (8.2%, 2.2% and 1.9%), interstitial lung disease (ILD) (48%, 35% and 30.8%), renal manifestations (13.4%, 3.7% and 1.9%), and more severe infections (41.3%, 26.7% and 21%). No significant differences were found in survival between groups in log rank test (P = 0.106). Multivariate adjusted survival analyses revealed a worse prognosis for severe infections, ILD and baseline elevation of acute phase reactants. CONCLUSION: Overlap myositis stands out as a distinct entity as compared to PM and DM, featuring more extramuscular involvement and more severe infections. Close monitoring is recommended in this subset for early detection and treatment of possible complications.
30764869 Serum KL-6 levels reflect the severity of interstitial lung disease associated with connec 2019 Feb 14 BACKGROUND: Biomarkers have been actively investigated to supplement functional and imaging modalities to predict the severity, therapeutic responsiveness, and progression of connective tissue disease-associated interstitial lung disease (CTD-ILD). This study aimed to evaluate Krebs von den Lungen 6 (KL-6) as a potential biomarker reflecting the severity of CTD-ILD as assessed through computed tomography (CT) and pulmonary function test (PFT) parameters. METHODS: This retrospective study included 549 Korean patients with rheumatoid arthritis, systemic sclerosis, inflammatory myositis, and other CTDs with or without concurrent ILD. Serum KL-6 concentration (U/mL) was measured using the latex-enhanced immunoturbidimetric assay method. CT and PFT results were collected within 1 year of serum collection. A semiquantitative grade of ILD extent was evaluated through CT scan (grade 1, 0-25%; grade 2, 26-50%; grade 3, 51-75%; grade 4, 76-100%). RESULTS: CTD-ILD patients (n = 165) had elevated serum KL-6 levels compared to CTD patients without ILD (n = 384) (p < 0.001), and those findings were preserved after adjusting for age, sex, and CTD type. The semiquantitative grade of ILD on CT scan was significantly proportional to the KL-6 level, and the optimal cut-off KL-6 value effectively differentiated each ILD grade. The percent diffusing capacity of the lung for carbon monoxide (DLCO) (p < 0.001) and forced vital capacity (FVC) (p < 0.001) parameters had a moderate, negative correlation with the KL-6 level. CONCLUSION: Serum KL-6 levels were increased in CTD-ILD patients and had a positive correlation with CT grade and a negative correlation with FVC and DLCO. Serum KL-6 levels may reflect CTD-ILD severity.
30729703 Serum miR-214 as a novel biomarker for ankylosing spondylitis. 2019 Jul OBJECTIVE: Serum microRNA (miR) in ankylosing spondylitis (AS) patients has been rarely identified. The objective of this study was to find AS-specific miR in sera of patients with AS. METHODS: Total RNAs were isolated from whole sera of patients with AS, patients with rheumatoid arthritis (RA), and healthy controls (HC) using miRNeasy Serum/Plasma Kit. The presence of miR was assayed using Agilent 2100 Bioanalyzer Small RNA assay. Each RNA sample was used for miR microarray. To verify microarray results, candidate circulating miRs were validated by quantitative polymerase chain reaction (qPCR) using samples from patients with AS (n = 65), patients with RA (n = 25), and HCs (n = 39). Cycle threshold values were converted to copy numbers by drawing a standard curve using a synthetic chemical standard. All clinical values were also evaluated at the time of miR isolation. RESULTS: A total of 887 miRs were screened for three groups. Lower expression of miR-214 in AS than in HC and RA was observed after normalization of raw data. Finally, lower expression of serum miR-214 was confirmed in AS after validation by qPCR. Correlation analysis showed that the level of miR-214 of AS was significantly associated with Ankylosing Spondylitis Disease Activity Score-C-reactive protein (r = 0.299, P = 0.02). However, other disease-specific variables showed no statistical significance: gender (P = 0.286), peripheral arthritis (P = 0.634), enthesitis (P = 0.464), dacylitis (P = 0.750), psoriasis (P = 0.552), inflammatory bowel disease (P = 0.369), human leukocyte antigen-B27 positivity (P = 0.473), use of non-steroidal anti-inflammatory drugs (P = 0.448), and use of tumor necrosis factor-blocker in the last 3 months (P = 0.505). CONCLUSION: miR-214 may serve as a noninvasive biomarker for diagnosis of AS. In addition, expression level of miR-214 was associated with disease activity.
31993307 Solute carrier transporters: the metabolic gatekeepers of immune cells. 2020 Jan Solute carrier (SLC) transporters meditate many essential physiological functions, including nutrient uptake, ion influx/efflux, and waste disposal. In its protective role against tumors and infections, the mammalian immune system coordinates complex signals to support the proliferation, differentiation, and effector function of individual cell subsets. Recent research in this area has yielded surprising findings on the roles of solute carrier transporters, which were discovered to regulate lymphocyte signaling and control their differentiation, function, and fate by modulating diverse metabolic pathways and balanced levels of different metabolites. In this review, we present current information mainly on glucose transporters, amino-acid transporters, and metal ion transporters, which are critically important for mediating immune cell homeostasis in many different pathological conditions.
31193495 Inyección Intraarticular Única de Ácido Hialurónico en la Artrosis de Rodilla: Estudio 2019 INTRODUCCIÓN: La viscosuplementación del líquido sinovial mediante la inyección intraarticular (IA) de ácido hialurónico (AH) es un tratamiento sintomático ampliamente utilizado en la artrosis de rodilla (AR). Además de los productos diseñados para realizar inyecciones múltiples (normalmente de 3 a 5 inyecciones, en intervalos de 1 semana), se presta especial atención a los productos de una única inyección, ya que ofrecen ventajas específicas, como son un menor número de visitas al médico y de intervenciones invasivas con sus riesgos asociados. Sin embargo, aún existen dudas sobre la eficacia de estas inyecciones únicas, en comparación con los regímenes de inyecciones múltiples. MÉTODOS: Se realizó un estudio multicéntrico, abierto, prospectivo, post-mercado (ART-ONE 75) con el producto de inyección única ARTHRUM 2,5% (3 ml, 75 mg AH), en 214 pacientes que sufrían de AR. Los pacientes fueron seguidos en D30, D60, D120 y D180 (días). El perfil promedio de los pacientes en el momento de la inclusión fue de 62,9 años, 56% mujeres, grados I-III de Kellgren-Lawrence (46% KL III), IMC de 27,2 kg/m(2) y 4 años desde el diagnóstico de AR. Se realizó una comparación post-hoc con una inyección IA única de placebo (326 pacientes, agrupados de 3 estudios ECA), que proporcionaron un perfil de paciente similar. RESULTADOS: el criterio principal fue la variación desde el inicio de la puntuación de la escala WOMAC A (dolor, escala 0-100) en D60, que se redujo en 28,9 (17,4) para la población por intención de tratar (ITT, por sus siglas en inglés) (199 pacientes), 28,0 (17,8) para la población por protocolo (PP) en la inclusión (175 pacientes), y en 27,7 (16,8) para la población PP al finalizar (143 pacientes).Los criterios secundarios y accesorios incluyeron WOMAC A en otras ocasiones, WOMAC B (rigidez), WOMAC C (función), calidad de vida y discapacidad en cada momento de seguimiento. Todos los índices mejoraron significativamente y continuaron mejorando al final del estudio. La evaluación terapéutica en D180 mostró que más del 75% de los pacientes se encontraban satisfechos con la reducción del dolor, la mejora de la movilidad, y la reducción de analgésicos y AINE. El porcentaje de pacientes definidos como respondedores de OMERACT-OARSI fue superior al 86%, a partir de D60 y en adelante. La tolerancia general fue buena, sin que ocurriera ningún evento adverso grave. El resultado de la comparación post-hoc para la escala WOMAC A mostró un tamaño del efecto [IC 95%] desde TE = 0,33 [0,15; 0,51] en D60 a TE = 0,65 [0,45; 0,85] en D180 (p <0,001), frente a la inyección de placebo (solución salina), lo cual es un resultado clínicamente relevante a favor de ARTHRUM 2,5%. CONCLUSIÓN: El presente estudio confirma la eficacia clínica de una única inyección IA de 3 ml de solución de AH conteniendo 75 mg de AH nativo de alto PM (> 2 MDa).
31737644 Targeted Metabolomic Analysis of Serum Fatty Acids for the Prediction of Autoimmune Diseas 2019 Autoimmune diseases (ADs) are rapidly increasing worldwide and accumulating data support a key role of disrupted metabolism in ADs. This study aimed to identify an improved combination of Total Fatty Acids (TFAs) biomarkers as a predictive factor for the presence of autoimmune diseases. A retrospective nested case-control study was conducted in 403 individuals. In the case group, 240 patients diagnosed with rheumatoid arthritis, thyroid disease, multiple sclerosis, vitiligo, psoriasis, inflammatory bowel disease, and other AD were included and compared to 163 healthy individuals. Targeted metabolomic analysis of serum TFAs was performed using GC-MS, and 28 variables were used as input for the predictive models. The primary analysis identified 12 variables that were statistically significantly different between the two groups, and metabolite-metabolite correlation analysis revealed 653 significant correlation coefficients with 90% level of significance (p < 0.05). Three predictive models were developed, namely (a) a logistic regression based on Principal Component Analysis (PCA), (b) a straightforward logistic regression model and (c) an Artificial Neural Network (ANN) model. PCA and straightforward logistic regression analysis, indicated reasonably well adequacy (74.7 and 78.9%, respectively). For the ANN, a model using two hidden layers and 11 variables was developed, resulting in 76.2% total predictive accuracy. The models identified important biomarkers: lauric acid (C12:0), myristic acid (C14:0), stearic acid (C18:0), lignoceric acid (C24:0), palmitic acid (C16:0) and heptadecanoic acid (C17:0) among saturated fatty acids, Cis-10-pentadecanoic acid (C15:1), Cis-11-eicosenoic acid (C20:1n9), and erucic acid (C22:1n9) among monounsaturated fatty acids and the Gamma-linolenic acid (C18:3n6) polyunsaturated fatty acid. The metabolic pathways of the candidate biomarkers are discussed in relation to ADs. The findings indicate that the metabolic profile of serum TFAs is associated with the presence of ADs and can be an adjunct tool for the early diagnosis of ADs.
31677330 Secreted Frizzled-related proteins (sFRPs) in osteo-articular diseases: much more than sim 2019 Dec Osteo-articular diseases are characterized by a dysregulation of joint and/or bone homeostasis. These include diseases affecting the joints originally, such as osteoarthritis and rheumatoid arthritis, or the bone, such as osteoporosis. Inflammation and the involvement of Wingless-related integration site (Wnt) signaling pathways are key pathophysiological features of these diseases resulting in tissue degradation by matrix-degrading enzymes, namely matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTs), secreted by the joint resident cells and/or by infiltrating immune cells. Activation of Wnt signaling pathways is modulated by different families of proteins, including Dickkopfs and the secreted Frizzled-related proteins (sFRPs). The sFRP family is composed of five secreted glycoproteins in mammals that regulate Wnt signaling in the extracellular compartment. Indeed, sFRPs are able to bind both to the soluble Wnt ligands and to their cell membrane receptors, the Frizzled proteins. Their expression profile is altered in osteo-articular diseases, suggesting that they could account for the abnormal activation of Wnt pathways. In the present article, we review how sFRPs are more than simple antagonists of the Wnt signaling pathways and discuss their pathophysiological relevance in the context of osteo-articular diseases. We detail their Wnt-dependent and their Wnt-independent roles, with a particular emphasis on their ability to modulate the inflammatory response and extracellular matrix (ECM) remodeling. We also discuss their potential therapeutic use with a focus on bone remodeling, osteo-articular cancers, and tissue engineering.
31464584 A novel homozygous frame-shift mutation in the SLC29A3 gene: a new case report and review 2019 Aug 29 BACKGROUND: The SLC29A3 gene, encoding a nucleoside transporter protein, is found in intracellular membranes. Based on the literatures, mutations in this gene cause a wide range of clinical manifestations including H syndrome, pigmented hypertrichosis with insulin dependent diabetes, Faisalabad histiocytosis, and dysosteosclerosis. However, all these disorders with their different names and terminologies are actually the same entity termed H syndrome. CASE PRESENTATION: We report four GJB2 and GJB6 negative deaf patients from two Iranian related families who present the associated symptoms of SLC29A3-disorder. Whole Exome Sequencing (WES) using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in one of studied patients. A novel homozygous frame-shift mutation c.307-308delTT (p.Phe103fs) in exon 3 of SLC29A3 gene was identified in a 35 years old man with profound hearing loss, camptodactyly, rheumatoid arthritis and delayed puberty without any skin changes, short stature and insulin dependent diabetes mellitus. The mutation found was also confirmed by Sanger sequencing in other studied patients and their healthy parents. In compared to proband, however the clinical manifestations of these patients were different, indicating variable expressivity of mutant SLC29A3 gene as well as possible involvement of other modifier genes. CONCLUSION: The present study uncovered a rare novel homozygous frame-shift mutation c.307-308delTT in SLC29A3 gene of four related patients with various manifestation of SLC29A3-disorder. Such studies can help to conduct genetic counseling and subsequently, prenatal diagnosis more accurately for individuals at the high risk of these types of genetic disorders.
31379350 Pregnancy in autoimmune diseases in the sub-Saharan zone: the experience of the University 2019 May 1 Autoimmune diseases are a group of heterogeneous conditions responsible for polymorphic clinical and biological manifestations. Because pregnancy activates them and promotes gestational complications, it is difficult for women with these diseases. Pregnancy and autoimmune diseases have rarely been studied in sub-Saharan Africa. We report the experience of the Internal Medicine Department of the University Hospital of Libreville. Conducted retrospectively for 2008 through 2011, and prospectively from 2012 through August 31, 2018, this descriptive and analytical study examined the records at the Department of Internal Medicine of the University Hospital Center of Libreville of women with a known autoimmune disease, receiving regular care there, and who became pregnant after the diagnosis. During pregnancy, women were monitored and manÂged simultaneously in the departments of obstetrics and internal medicine. Data considered for this study were demographic data (Âge, sex, social status), type of autoimmune disease, including the diagnosis, the therapies used, extent of disease control, and time from diagnosis to each pregnancy. Obstetric data include the number of fetuses, obstetric complications, gestational Âge at and route of delivery, fetal sex, and Apgar score to 5 minutes (normal ≥ 7). Women had the following autoimmune diseases : systemic lupus erythematosus (SLE) (n = 16), Sjögren's disease (n = 3), inflammatory myopathy (n = 2), rheumatoid arthritis (n = 1), primary antiphospholipid syndrome (APS) (n = 1), and Still disease (n = 1).The overall averÂge Âge at diagnosis was 26.6 years (range : 13-40). The 24 women had 32 pregnancies. The mean interval from diagnosis to first pregnancy was 3.3 years, to the second pregnancy also 3.3 years (n = 6), and to the third (n = 2), 5 years. Disease was controlled for at least 2 years (n = 23) except for one woman with primary APS. Therapeutically, corticosteroids were used alone (n = 2) or combined with other immunomodulatory therapies (n = 32). Gestational complications included spontaneous abortions in the first trimester (n =2), in utero deaths (n = 2), perinatal death on day 12 (n = 1), and eclampsia (n = 2), one of which was complicated by a pulmonary embolism in the first pregnancy. The mean gestational Âge at delivery was 37 weeks. Intrauterine growth restriction affected 11 fetuses, and preterm delivery 18. There were 11 cesarean deliveries and 16 vaginal. Mean birth weight was 2353.3 grams, Apgar was ≥ 7 for all neonates except in one case of dermatomyositis complicating a neonatal death. The sex ratio was 13 male infants per 17 females. Women with optimal disease control can become pregnant and have positive pregnancy outcomes. This possibility has been little explored in sub-Saharan Africa; mystical-religious notions of conceptions persist and can prevent women from attempting to become prégnant . This experience with a short series of viable fetuses of women with autoimmune diseases is therefore encouraging and deserves to be continued.
31359626 Minimal Clinically Important Difference of Four Commonly Used Balance Assessment Tools in 2020 Mar BACKGROUND: Although balance is commonly assessed during the recovery of total knee arthroplasty (TKA), the minimal clinically important difference (MCID) values of frequently used balance assessment tools have not been established previously in this population. OBJECTIVE: To determine the MCID of four balance tests-ie, the Balance Evaluation Systems Test (BESTest), Mini-BESTest, Brief-BESTest, and the Berg Balance Scale (BBS)-in individuals post-TKA. DESIGN: Prospective cohort. SETTING: Outpatient rehabilitation. PARTICIPANTS: Inclusion criteria: (1) first primary TKA with diagnosed knee osteoarthritis; (2) aged 50-85 years. EXCLUSION CRITERIA: (1) TKA due to rheumatoid arthritis of the knee or traumatic injury; (2) known medical conditions that influence balance ability. One hundred forty-six participants were recruited, and 134 of them with complete data were included in the analysis. INTERVENTIONS: Participants received individualized physiotherapy, consisting of electrotherapy for pain and edema control, mobilization and strengthening exercises, and gait and balance training, once or twice per week between assessments. MAIN OUTCOME MEASUREMENTS: Participants were assessed on the BESTest, Mini-BESTest, Brief-BESTest, BBS, and Functional Gait Assessment (FGA) 2 and 4 weeks after surgery. The FGA was used as the anchor reference measure to calculate the MCID of the other four balance tests. A distribution-based approach was also employed to derive the MCID (ie, standardized effect size of 0.5). RESULTS: The BESTest (area under curve [AUC] = 0.811, 95% confidence interval [CI] 0.739-0.883) had the highest accuracy in detecting clinically important improvements on the FGA (≥4 points), followed by the Mini-BESTest (AUC = 0.782, 95% CI 0.704-0.860), Brief-BESTest (AUC = 0.701, 95% CI 0.618-0.795), and BBS (AUC = 0.586, 95% CI 0.490-0.682). The anchor- and distribution-based MCIDs were 6-8 for the BESTest, 1-2 for the Mini-BESTest, and 2-3 for the Brief-BESTest. CONCLUSIONS: Improvements exceeding MCIDs established above are indicative of significant progress in balance function post-TKA. The BBS is not a recommended tool due to its low AUC value.
31288216 Functionalized aptamer with an antiparallel G-quadruplex: Structural remodeling, recogniti 2019 Oct 1 Connective tissue growth factor (CTGF), a widely used biomarker, is involved in many diseases, such as diabetic retinopathy, diabetic nephropathy, and rheumatoid arthritis, and it is often over-expressed in human malignant tumors. Therefore, sensitive, specific and efficient detection methods for CTGF are needed for the early diagnosis and assessment of prognosis. In this study, an aptamer, APT1, that specifically binds to CTGF was obtained by SELEX technology. Circular dichroism spectroscopy indicated that APT1 formed interconvertible parallel and antiparallel G-quadruplexes. Mutation and truncation strategies optimized APT1 and improved its functions, yielding APT1M6T, which folded into an antiparallel G-quadruplex with higher targeting affinity. A stable APT1M6T-CTGF complex model was established by molecular simulation, which helped elucidate the molecular recognition mechanism of APT1M6T and CTGF and also provided experimental guidance for rational site-directed modification of APT1M6T. A locked nucleic acid sequence was then integrated into APT1M6T to generate APT1M6TL, which had higher structural stability. A BLI-based enzyme-linked aptamer sandwich assay (BLI-ELASA) was successfully developed. The method exhibited a broad detection range from 0.05 to 50 nM with a low detection limit of 0.02 nM. The method showed high selectivity, reproducibility, and stability for analysis of CTGF in spiked serum and urine samples. This developed BLI-ELASA is promising and enables real-time, sensitive and rapid detection of the disease-specific biomarker CTGF.