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BACKGROUND: In this randomized controlled trial (RCT) comparing current acupuncture with carbamazepine for trigeminal neuralgia, meta- and sequential analyses were utilized. AIM: To guide clinical decision making regarding the treatment of trigeminal neuralgia with carbamazepine. METHODS: The RCT literature on needle comparison was searched in various Chinese biomedical databases including Chinese Biomedical Literature Database, Wanfang Data, VIP Database, as well as international databases such as Excerpt Medica Database, Cochrane Library, PubMed, and Web of Science, along with related clinical registration platforms such as World Health Organization International Clinical Trial Registry Platform, ChiCTR, and Clinical Trials up to 1 April 2020. Risk of bias was evaluated using the Cochrane Collaborative Risk Bias tool, primary outcome measures (pain reduction) were analyzed using STATA meta-analysis, outcome measures were analyzed using trial sequential analysis 0.9.5.10 Beta sequential analysis, GRADE was used to assess the evidence, and adverse reactions were documented. RESULTS: This study analyzed 16 RCTs with a total of 1231 participants. The meta-analysis revealed a statistically significant difference in pain reduction between acupuncture and carbamazepine [standardized mean difference (SMD) = 1.47; 95% confidence interval (CI): 0.99-1.95], although the quality of evidence was deemed to be of extremely low quality. Cumulative meta-analysis based on the year of publication indicated that carbamazepine treatment first demonstrated a statistically significant difference in pain reduction in 2014 and remained relatively stable over time [SMD = 1.84; 95%CI: 0.22-3.47]. Additionally, the number of adverse events associated with acupuncture was significantly lower compared to carbamazepine. CONCLUSION: Acupuncture for trigeminal neuralgia is better than analgesia and safer than carbamazepine; however, firm conclusions still require a high-quality, multicenter, large-sample RCT to confirm these findings.
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Skin cutaneous melanoma (SKCM), a form of skin cancer, ranks among the most formidable and lethal malignancies. Exploring tumor microenvironment (TME)-based prognostic indicators would help improve the efficacy of immunotherapy for SKCM patients. This study analyzed SKCM scRNA-seq data to cluster non-malignant cells that could be used to explore the TME into nine immune/stromal cell types, including B cells, CD4 T cells, CD8 T cells, dendritic cells, endothelial cells, Fibroblasts, macrophages, neurons, and natural killer (NK) cells. Using data from The Cancer Genome Atlas (TCGA), we employed SKCM expression profiling to identify differentially expressed immune-associated genes (DEIAGs), which were then incorporated into weighted gene co-expression network analysis (WGCNA) to investigate TME-associated hub genes. Discover candidate small molecule drugs based on pivotal genes. Tumor immune microenvironment-associated genes (TIMAGs) for constructing TIMAS were identified and validated. Finally, the characteristics of TIAMS subgroups and the ability of TIMAS to predict immunotherapy outcomes were analyzed. We identified five TIMAGs (CD86, CD80, SEMA4D, C1QA, and IRF1) and used them to construct TIMAS. In addition, five potential SKCM drugs were identified. The results showed that TIMAS-low patients were associated with immune-related signaling pathways, high MUC16 mutation frequency, high T cell infiltration, and M1 macrophages, and were more favorable for immunotherapy. Collectively, TIMAS constructed by comprehensive analysis of scRNA-seq and bulk RNA-seq data is a promising marker for predicting ICI treatment outcomes and improving individualized therapy for SKCM patients.
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Imunoterapia , Melanoma , RNA-Seq , Neoplasias Cutâneas , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Melanoma/genética , Melanoma/imunologia , Melanoma/terapia , Melanoma/tratamento farmacológico , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Prognóstico , Melanoma Maligno Cutâneo , Masculino , Transcriptoma , Feminino , Resultado do Tratamento , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Natural deep eutectic solvents (NADESs), as emerging green solvents, can efficiently extract natural products from natural resources. However, studies on the extraction of phenolic compounds from celtuce (Lactuca sativa var. augustana) leaves (CLs) by NADESs are still lacking. This study screened the NADES L-proline-lactic acid (Pr-LA), combined it with ultrasound-assisted extraction (UAE) to extract phenolic compounds from CLs, and conducted a comparative study on the extraction effect with traditional extraction solvents. Both SEM and FT-IR confirmed that Pr-LA can enhance the degree of fragmentation of cell structures and improve the extraction rate of phenolic compounds. Molecular dynamics simulation results show that Pr-LA can improve the solubility of phenolic compounds and has stronger hydrogen bonds and van der Waals interactions with phenolic compounds. Single-factor and Box-Behnken experiments optimized the process parameters for the extraction of phenolic compounds from CLs. The second-order kinetic model describes the extraction process of phenolic compounds from CLs under optimal process parameters and provides theoretical guidance for actual industrial production. This study not only provides an efficient and green method for extracting phenolic compounds from CLs but also clarifies the mechanism of improved extraction efficiency, which provides a basis for research on the NADES extraction mechanism.
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Solventes Eutéticos Profundos , Lactuca , Fenóis , Folhas de Planta , Fenóis/química , Fenóis/isolamento & purificação , Folhas de Planta/química , Lactuca/química , Solventes Eutéticos Profundos/química , Extratos Vegetais/química , Ondas Ultrassônicas , Espectroscopia de Infravermelho com Transformada de Fourier , Simulação de Dinâmica Molecular , Solventes/químicaRESUMO
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Others and our studies have shown that mechanical stresses (forces) including shear stress and cyclic stretch, occur in various pathological conditions, play significant roles in the development and progression of CVDs. Mitochondria regulate the physiological processes of cardiac and vascular cells mainly through adenosine triphosphate (ATP) production, calcium flux and redox control while promote cell death through electron transport complex (ETC) related cellular stress response. Mounting evidence reveal that mechanical stress-induced mitochondrial dysfunction plays a vital role in the pathogenesis of many CVDs including heart failure and atherosclerosis. This review summarized mitochondrial functions in cardiovascular system under physiological mechanical stress and mitochondrial dysfunction under pathological mechanical stress in CVDs (graphical abstract). The study of mitochondrial dysfunction under mechanical stress can further our understanding of the underlying mechanisms, identify potential therapeutic targets, and aid the development of novel treatments of CVDs.
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Doenças Cardiovasculares , Mitocôndrias , Estresse Mecânico , Humanos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Animais , Mitocôndrias/metabolismoRESUMO
Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.
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In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the 'grey zone' between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases.
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Predisposição Genética para Doença , Doenças Reumáticas , Humanos , Doenças Reumáticas/genética , Doenças Reumáticas/diagnóstico , Mutação , Variação Genética , Testes Genéticos/métodosRESUMO
BACKGROUND: Restorative proctocolectomy with IPAA improves the quality of life in patients with ulcerative colitis by the removal of diseased large bowel and preservation of the natural route of defecation. Although the surgery may improve preexisting extraintestinal manifestations in the joints, skin, and eyes, extraintestinal manifestations, particularly primary sclerosing cholangitis, can persist after colectomy. OBJECTIVES: A systematic review of diagnosis and treatment of liver, joint, skin, and eye manifestations in patients with restorative proctocolectomy and IPAA for ulcerative colitis. DATA SOURCES: PubMed, Google Scholar, and Cochrane database. STUDY SELECTION: Relevant articles on primary sclerosing cholangitis and extraintestinal manifestations in ileal pouches published between January 2001 and July 2023 in English were included on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. INTERVENTION: Diagnosis and treatment of primary sclerosing cholangitis and extraintestinal manifestations in patients with restorative proctocolectomy and IPAA were included. MAIN OUTCOME MEASURES: Association between primary sclerosing cholangitis, extraintestinal manifestations, and inflammatory disorders of the pouch and their management. RESULTS: Primary sclerosing cholangitis and extraintestinal manifestations are associated with pouchitis, particularly chronic pouchitis. Primary sclerosing cholangitis is associated with chronic pouchitis, enteritis, and possible pouch neoplasia. However, the disease severity and course of primary sclerosing cholangitis and pouchitis do not appear to be parallel. Despite the fact that oral vancomycin or budesonide have been used to treat primary sclerosing cholangitis-associated pouchitis, their impact on the disease course of primary sclerosing cholangitis is not known. Biological therapy for chronic inflammatory disorders of the pouch may also be beneficial for the concurrent extraintestinal manifestations of the joints, skin, and eyes. However, studies on the correlation between the severity of inflammatory pouch disorders and the severity of joint, skin, and eye diseases are lacking. LIMITATIONS: This is a qualitative, not quantitative, review of case series and case reports. CONCLUSIONS: Primary sclerosing cholangitis and extraintestinal manifestations of the joints, skin, and eyes appear to be associated with inflammatory disorders of the ileal pouch. Although the treatment of pouchitis does not seem to affect the disease course of primary sclerosing cholangitis, effective therapy of inflammatory pouch disorders, particularly with biologics, likely benefits concurrent disorders of the joints, skin, and eyes. See video from the symposium .
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Colangite Esclerosante , Colite Ulcerativa , Pouchite , Proctocolectomia Restauradora , Colangite Esclerosante/complicações , Colangite Esclerosante/cirurgia , Humanos , Proctocolectomia Restauradora/efeitos adversos , Proctocolectomia Restauradora/métodos , Pouchite/etiologia , Pouchite/terapia , Pouchite/diagnóstico , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Bolsas Cólicas/efeitos adversos , Oftalmopatias/etiologia , Dermatopatias/etiologiaRESUMO
Neointimal hyperplasia is a pathological vascular remodeling caused by abnormal proliferation and migration of subintimal vascular smooth muscle cells (VSMCs) following intimal injury. There is increasing evidence that tRNA-derived small RNA (tsRNA) plays an important role in vascular remodeling. The purpose of this study is to search for tsRNAs signature of neointima formation and to explore their potential functions. The balloon injury model of rat common carotid artery was replicated to induce intimal hyperplasia, and the differentially expressed tsRNAs (DE-tsRNAs) in arteries with intimal hyperplasia were screened by small RNA sequencing and tsRNA library. A total of 24 DE-tsRNAs were found in the vessels with intimal hyperplasia by small RNA sequencing. In vitro, tRF-Glu-CTC inhibited the expression of fibromodulin (FMOD) in VSMCs, which is a negative modulator of TGF-ß1 activity. tRF-Glu-CTC also increased VSMC proliferation and migration. In vivo experiments showed that inhibition of tRF-Glu-CTC expression after balloon injury of rat carotid artery can reduce the neointimal area. In conclusion, tRF-Glu-CTC expression is increased after vascular injury and inhibits FMOD expression in VSMCs, which influences neointima formation. On the other hand, reducing the expression of tRF-Glu-CTC after vascular injury may be a potential approach to prevent vascular stenosis.
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Lesões das Artérias Carótidas , Lesões do Sistema Vascular , Animais , Ratos , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Fibromodulina/metabolismo , Hiperplasia/complicações , Hiperplasia/metabolismo , Hiperplasia/patologia , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Neointima/patologia , Neointima/prevenção & controle , Ratos Sprague-Dawley , RNA/metabolismo , RNA de Transferência/metabolismo , Remodelação Vascular , Lesões do Sistema Vascular/metabolismoRESUMO
Environmental factors, particularly dietary habits, play an important role in cardiovascular disease susceptibility and progression through epigenetic modification. Previous studies have shown that hyperplastic vascular intima after endarterectomy is characterized by genome-wide hypomethylation. The purpose of this study was to investigate whether methyl donor diet affects intimal hyperplasia and the possible mechanisms involved. Intimal hyperplasia was induced in SD rats by carotid artery balloon injury. From 8 d before surgery to 28 d after surgery, the animals were fed a normal diet (ND) or a methyl donor diet (MD) supplemented with folic acid, vitamin B12, choline, betaine, and zinc. Carotid artery intimal hyperplasia was observed by histology, the effect of MD on carotid protein expression was analyzed by proteomics, functional clustering, signaling pathway, and upstream-downstream relationship of differentially expressed proteins were analyzed by bioinformatics. Results showed that MD attenuated balloon injury-induced intimal hyperplasia in rat carotid arteries. Proteomic analysis showed that there were many differentially expressed proteins in the common carotid arteries of rats fed with two different diets. The differentially expressed proteins are mainly related to the composition and function of the extracellular matrix (EMC), and changes in the EMC can lead to vascular remodeling by affecting fibrosis and stiffness of the blood vessel wall. Changes in the levels of vasculotropic proteins such as S100A9, ILF3, Serpinh1, Fbln5, LOX, HSPG2, and Fmod may be the reason why MD attenuates intimal hyperplasia. Supplementation with methyl donor nutrients may be a beneficial measure to prevent pathological vascular remodeling after injury.
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Lesões das Artérias Carótidas , Lesões do Sistema Vascular , Ratos , Animais , Hiperplasia , Ratos Sprague-Dawley , Proteômica , Remodelação Vascular , Dieta , Lesões das Artérias Carótidas/metabolismoRESUMO
NOD-like receptors (NLRs) are intracellular sensors associated with systemic autoinflammatory diseases (SAIDs). We investigated the largest monocentric cohort of patients with adult-onset SAIDs for coinheritance of low frequency and rare mutations in NOD2 and other autoinflammatory genes. Sixty-three patients underwent molecular testing for SAID gene panels after extensive clinical workups. Whole exome sequencing data from the large Atherosclerosis Risk in Communities (ARIC) study of individuals of European-American ancestry were used as control. Of 63 patients, 44 (69.8%) were found to carry combined gene variants in NOD2 and another gene (Group 1), and 19 (30.2%) were carriers only for NOD2 variants (Group 2). The genetic variant combinations in SAID patients were digenic in 66% (NOD2/MEFV, NOD2/NLRP12, NOD2/NLRP3, and NOD2/TNFRSF1A) and oligogenic in 34% of cases. These variant combinations were either absent or significantly less frequent in the control population. By phenotype-genotype correlation, approximately 40% of patients met diagnostic criteria for a specific SAID, and 60% had mixed diagnoses. There were no statistically significant differences in clinical manifestations between the two patient groups except for chest pain. Due to overlapping phenotypes and mixed genotypes, we have suggested a new term, "Mixed NLR-associated Autoinflammatory Disease ", to describe this disease scenario. Gene variant combinations are significant in patients with SAIDs primarily presenting with mixed clinical phenotypes. Our data support the proposition that immunological disease expression is modified by genetic background and environmental exposure. We provide a preliminary framework in diagnosis, management, and interpretation of the clinical scenario.
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Doenças Hereditárias Autoinflamatórias , Proteína Adaptadora de Sinalização NOD2 , Adulto , Humanos , Genótipo , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , Pirina/genéticaRESUMO
OBJECTIVES: Whipple's disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defense against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. METHODS: A multicenter, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. RESULTS: All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms, and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or hydroxychloroquine, symptoms were largely controlled, though mild relapses occurred in follow up. CONCLUSION: Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin rich repeat-associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.
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ABSTRACT: Factitious disorder, a disorder characterized by the falsification of symptoms to obtain primary gain, continues to be one of the more challenging cases that psychiatrists encounter. We describe a case of a woman we treated on the medical unit who falsified several of her symptoms but also was diagnosed with Yao syndrome, a disease that can also cause unexplained symptoms such as abdominal pain and fever. We navigate the difficulties in managing this type of patient and comanaging her with medicine and rheumatology. Although the prevalence of factitious disorder is anywhere from 1% to 2% of patients on the medical floor, they typically utilize a disproportionate number of resources. Despite this, the literature is still inconclusive when it comes to the management and treatment approaches. More study is warranted on this complex and burdensome illness.
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Transtornos Autoinduzidos , Doenças Hereditárias Autoinflamatórias , Feminino , Humanos , Transtornos Autoinduzidos/diagnóstico , Transtornos Autoinduzidos/terapia , Prevalência , Dor AbdominalRESUMO
Purpose: Neutrophil extracellular traps (NETs) play an important role in ischemia-reperfusion injury (IRI) of the hindlimb. The aim of this study was to investigate the effect of recombinant DNase I and sivelestat in eliminating NETs and their effects on IRI limbs. Patients and Methods: An air pump was used to apply a pressure of 300 mmHg to the root of the right hindlimb of the rat for 2 h and then deflated to replicate the IRI model. The formation of NETs was determined by the detection of myeloperoxidase (MPO), neutrophil elastase (NE), and histone H3 in the skeletal muscles of the hindlimbs. Animals were administered 2.5 mg/kg bw/d DNase I, 15 or 60 mg/kg bw/d sivelestat by injection into the tail vein or intramuscularly into the ischemic area for 7d. Elimination of NETs, hindlimb perfusion, muscle fibrosis, angiogenesis and motor function were assessed. Results: DNase I reduced NETs, attenuated muscle fibrosis, promoted angiogenesis in IRI area and improved limb motor function. Local administration of DNase I improved hindlimb perfusion more than intravenous administration. Sivelestat at a dose of 15 mg/kg bw/d increased perfusion, counteracted skeletal muscle fibrosis, promoted angiogenesis and enhanced motor function. However, sivelestat at a dosage of 60 mg/kg bw/d had an adverse effect on tissue repair, especially when injected locally. Conclusion: Both DNase I and moderate doses of sivelestat can eliminate IRI-derived NETs. They improve hindlimb function by improving perfusion and angiogenesis, preventing muscle fibrosis. Appropriate administration mode and dosage is the key to prevent IRI by elimination of NETs. DNase I is more valid when administered topically and sivelestat is more effective when administered intravenously. These results will provide a better strategy for the treatment of IRI in clinical.
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Traditional classification of genetic diseases as monogenic and polygenic has lagged far behind scientific progress. In this opinion article, we propose and define a new terminology, genetically transitional disease (GTD), referring to cases where a large-effect mutation is necessary, but not sufficient, to cause disease. This leads to a working disease nosology based on gradients of four types of genetic architecture: monogenic, polygenic, GTD, and mixed. We present four scenarios under which GTD may occur; namely, subsets of traditionally Mendelian disease, modifiable Tier 1 monogenic conditions, variable penetrance, and situations where a genetic mutational spectrum produces qualitatively divergent pathologies. The implications of the new nosology in precision medicine are discussed, in which therapeutic options may target the molecular cause or the disease phenotype.
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Medicina Genômica , Herança Multifatorial , Humanos , Fenótipo , Mutação , Herança Multifatorial/genética , Predisposição Genética para DoençaRESUMO
Objectives: Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance. Both diseases are rare, primarily reported in the pediatric population, and are thought to be phenotypically indistinguishable. We provide the largest cohort of adult-onset patients and compared these diseases and the gene variant frequency to population controls. Methods: A cohort of adult patients with AIDs were retrospectively studied. All underwent molecular testing for periodic fever syndrome gene panels after extensive and negative workups for systemic autoimmune and other related diseases. Patients were divided into Group 1- NLRP3-AID patients with NLRP3 variants (N=15), Group 2- NLRP12-AID with NLRP12 variants (N=14) and Group 3- both NLRP3 and NLRP12 (N=9) variants. Exome sequence data of two large control populations including the ARIC study were used to compare gene variant distribution and frequency. Results: All 38 patients were Caucasian with women accounting for 82%. Median age at diagnosis was 41 ± 23 years and the disease duration at diagnosis was 14 ± 13 years. We identified statistically significant differences between the groups, notably that gastrointestinal symptoms as well as evaluations for same were significantly more frequent in patients with NLRP12 variants, and headaches/dizziness were less common among the NLRP12 patients. Livedo reticularis was noted in four patients, exclusively among NLRP12 carriers. Over 50% of patients in Groups 1 and 2 carry low-frequency disease-associated variants, while the remaining carry rare variants. We unprecedently identified digenic variants, i.e., the coexistence of NLRP3 and NLRP12, which were either both low frequency or low frequency/rare. Allele frequencies of all variants identified in our cohort were either absent or significantly lower in the control populations, further strengthening the evidence of susceptibility of these variants to SAID phenotypes. Conclusion: Our comparative study shows that both NLRP3-AID and NLRP12-AID share similar clinical phenotypes, yet there are significant differences between them with regard to gastrointestinal and neurological symptoms. A spectrum of high to low genetic variations in both genes can contribute to SAID individually or in combination.
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Síndromes Periódicas Associadas à Criopirina , Doenças Hereditárias Autoinflamatórias , Adulto , Humanos , Criança , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Estudos Retrospectivos , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Variação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
Inflammatory bowel disease (IBD) is a chronic inflammatory disease primarily affecting the gastrointestinal (GI) tract and other organs. In this article, we provide a comprehensive review of IBD, particularly in the context of enteropathic arthritis and its therapeutic advances. Patients with IBD present with intestinal and extraintestinal manifestations (EIMs). Enteropathic arthritis or arthritis associated with IBD (Crohn's disease [CD] and ulcerative colitis [UC]) is the most common EIM and can involve both peripheral and axial joints with some overlaps. Furthermore, peripheral arthritis can be divided into two subcategories. Due to its varied inflammatory presentations and association with NOD2 mutations, CD can mimic other autoimmune and autoinflammatory diseases. Differential diagnosis should be extended to include another NOD2-associated disease, Yao syndrome. Therapy for IBD entails a myriad of medications and procedures, including various biologics targeting different pathways and Janus kinase (JAK) inhibitors. A better understanding of the therapeutic efficacy and mechanism of each drug aids in proper selection of more effective treatment for IBD and its associated inflammatory arthritis.
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Rationale: Neointimal hyperplasia caused by dedifferentiation and proliferation of venous smooth muscle cells (SMCs) is the major challenge for restenosis after coronary artery bypass graft. Herein, we investigated the role of Lamtor1 in neointimal formation and the regulatory mechanism of non-coding RNA underlying this process. Methods: Using a "cuff" model, veins were grafted into arterial system and Lamtor1 expression which was correlated with the activation of mTORC1 signaling and dedifferentiation of SMCs, were measured by Western blot. Whole transcriptome deep sequencing (RNA-seq) of the grafted veins combined with bioinformatic analysis identified highly conserved circSlc8a1 and its interaction with miR-20a-5p, which may target Lamtor1. CircSlc8a1 was biochemically characterized by Sanger sequencing and resistant to RNase R digestion. The cytoplasmic location of circSlc8a1 was shown by fluorescence in situ hybridization (FISH). RNA pull-down, luciferase assays and RNA immunoprecipitation (RIP) with Ago2 assays were used to identify the interaction circSlc8a1 with miR-20a-5p. Furthermore, arterial mechanical stretch (10% elongation) was applied in vitro. Results:In vivo, Lamtor1 was significantly enhanced in grafted vein and activated mTORC1 signaling to promote dedifferentiation of SMCs. Arterial mechanical stretch (10% elongation) induced circSlc8a1 expression and positively regulated Lamtor1, activated mTORC1 and promoted SMC dedifferentiation and proliferation. Local injection of circSlc8a1 siRNA or SMC-specific Lamtor1 knockout mice prevented neointimal hyperplasia in vein grafts in vivo. Conclusions: Our study reveals a novel mechanobiological mechanism underlying the dedifferentiation and proliferation of venous SMCs in neointimal hyperplasia. CircSlc81/miR-20a-5p/Lamtor1 axis induced by arterial cyclic stretch may be a potential clinical target that attenuates neointimal hyperplasia in grafted vessels.