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ID PMID Title PublicationDate abstract
31187641 In-hospital mortality among adults with autism spectrum disorder in the United States: A r 2020 Jan A retrospective data analysis using 2004-2014 Healthcare Cost and Utilization Project Nationwide Inpatient Sample was conducted to examine in-hospital mortality among adults with autism spectrum disorders in the United States compared to individuals in the general population. We modeled logistic regressions to compare inpatient hospital mortality between adults with autism spectrum disorders (n = 34,237) and age-matched and sex-matched controls (n = 102,711) in a 1:3 ratio. Adults with autism spectrum disorders had higher odds for inpatient hospital mortality than controls (odds ratio = 1.44, 95% confidence interval: 1.29-1.61, p < 0.001). This risk remained high even after adjustment for age, sex, race/ethnicity, income, number of comorbidities, epilepsy and psychiatric comorbidities, hospital bed size, hospital region, and hospitalization year (odds ratio = 1.51, 95% confidence interval: 1.33-1.72, p < 0.001). Adults with autism spectrum disorders who experienced in-hospital mortality had a higher risk for having 10 out of 27 observed Elixhauser-based medical comorbidities at the time of death, including psychoses, other neurological disorders, diabetes, hypothyroidism, rheumatoid arthritis collagen vascular disease, obesity, weight loss, fluid and electrolyte disorders, deficiency anemias, and paralysis. The results from the interaction of sex and autism spectrum disorders status suggest that women with autism spectrum disorders have almost two times higher odds for in-hospital mortality (odds ratio = 1.95, p < 0.001) than men with autism spectrum disorders. The results from the stratified analysis also showed that women with autism spectrum disorders had 3.17 times higher odds (95% confidence interval: 2.50-4.01, p < 0.001) of in-hospital mortality compared to women from the non-autism spectrum disorders matched control group; this difference persisted even after adjusting for socioeconomic, clinical, and hospital characteristics (odds ratio = 2.75, 95% confidence interval: 2.09-3.64, p < 0.001). Our findings underscore the need for more research to develop better strategies for healthcare and service delivery to people with autism spectrum disorders.
31181444 A review for the neuroprotective effects of andrographolide in the central nervous system. 2019 Sep Andrographolide is compound extracted from Andrographis paniculata (A. paniculata), a traditional herb that has been used in ancient China and other parts of eastern Asia to treat an array of disorders, such as cancer, rheumatoid arthritis, diarrhea, upper respiratory tract infection, and laryngitis, for a very long history. The mechanisms of action of andrographolide in disease prevention and/or therapy include anti-inflammation, anti-oxidative stress, anti-apoptosis, and/or pro-apoptosis. Pharmacodynamic studies have shown that andrographolide can cross the blood brain barrier and distribute into different brain regions, and therefore its pharmacological effects in the central nervous system (CNS) have begun to be revealed in recent years. For example, andrographolide has been reported to reduce brain infarct volume in several models of cerebral ischemia. In models of Alzheimer's disease (AD), andrographolide not only reduces Aβ aggregation, but suppresses neuroinflammatory response and synaptic dysfunction, which could be evidenced by the reversal of microglia-mediated production of pro-inflammatory cytokines as well as AD-associated decreases in synaptic proteins, such as postsynaptic membrane dense substance-95. Andrographolide may also inhibit the onset and/or progression of Parkinson's disease, multiple sclerosis, and surgery- or diabetes-induced cognitive impairment. Further, andrographolide has been shown to inhibit chronic stress-induced abnormalities in serum corticosterone levels, mood-associated behavior, and hippocampal neurogenesis, suggesting that andrographolide may have a potential to treat psychiatric disorders, such as anxiety and depression. In this review, we summarize and discuss the pharmacological effects of andrographolide in the CNS in hope of revealing more possibilities of andrographolide in disease prevention and/or therapy.
31172701 Korean Guidelines for Diagnosis and Management of Interstitial Lung Diseases: Part 5. Conn 2019 Oct Connective tissue disease (CTD) is a collection of disorders characterized by various signs and symptoms such as circulation of autoantibodies in the entire system causing damage to internal organs. Interstitial lung disease (ILD) which is associated with CTD is referred to as CTD-ILD. Patients diagnosed with ILD should be thoroughly examined for the co-occurrence of CTD, since the treatment procedures and prognosis of CTD-ILD are vary from those of idiopathic interstitial pneumonia. The representative types of CTD which may accompany ILD include rheumatoid arthritis, systemic sclerosis (SSc), Sjögren's syndrome, mixed CTD, idiopathic inflammatory myopathies, and systemic lupus erythematous. Of these, ILD most frequently co-exists with SSc. If an ILD is observed in the chest, high resolution computed tomography and specific diagnostic criteria for any type of CTD are met, then a diagnosis of CTD-ILD is made. It is challenging to conduct a properly designed randomized study on CTD-ILD, due to low incidence. Therefore, CTD-ILD treatment approach is yet to been established in absence of randomized controlled clinical trials, with the exception of SSc-ILD. When a patient is presented with acute CTD-ILD or if symptoms occur due to progression of the disease, steroid and immunosuppressive therapy are generally considered.
31136883 Pregnancy outcome in women after total hip replacement: A population-based study. 2019 Jul OBJECTIVE: Only a few small studies have been published on pregnancies after total hip replacement (THR), and they have reported no adverse pregnancy outcomes after THR. The aim of our study was to evaluate whether maternal THR affects pregnancy outcomes on a population-based level. STUDY DESIGN: Data for this nationwide register-based cohort study have been collected from four national registries in Finland from 1980 to 2007. All females who had undergone THR during that period formed the patient group, and three controls for each patient without THR were selected. Patient group comprised 2429 women, 719 (29.6%) of whom had 1190 pregnancies ending in singleton deliveries. Of those births, 986 were before THR and 204 after THR. The control group comprised 7276 women, 2805 (38.6%) of whom had 5112 pregnancies ending in singleton deliveries, 3695 occurred before the index date (time point when THR took place within the patient group) and 1417 after. Logistic regression model was used to analyze univariable and adjusted odds ratios (aOR) for adverse neonatal outcomes after maternal THR compared with controls. Data were adjusted using the following variables: maternal age, smoking, rheumatoid arthritis. RESULTS: Stillbirth was more common in the patient group compared with control group 4 (2.0%) vs 8 (0.6%) p = 0.02. Moreover, neonates in the patient group were more likely to be born preterm (aOR 3.58, p=<0.001), small for gestational age (aOR 2.83, p = 0.006) and low birthweight (aOR 4.79, p=<0.001), compared to control group. Trial of labor more likely ended in emergency cesarean section in the patient group than in the control group 39 (28.9%) vs 150 (11.6%), p=<0.001. Adverse pregnancy outcome was more common after THR also when compared to pregnancies before THR. CONCLUSIONS: Neonates born after maternal total hip replacement have an increased risk of stillbirth, small for gestational age, low birthweight and preterm birth. Trial of labor is more likely to end in emergency cesarean section.
32500047 Xanthoma disseminatum with extensive respiratory involvement effectively treated with clad 2020 Apr Xanthoma disseminatum (XD) is a rare and benign proliferative systemic disease that usually affects the skin and mucosal membranes with variable extent. Extensive systemic involvement can be associated with higher morbidity. There is paucity in the literature describing this rare pathological entity, and the ideal management remains controversial. In this article, we report our experience with cladribine in treating a case of XD. We documented the clinical and pathological manifestations of a 24-year-old woman who was initially diagnosed with rheumatoid arthritis. She presented to our institute with respiratory compromise and was found to have XD affecting skin, mucosal membranes, joints, and bone marrow. The patient received six cycles of cladribine for 6 months, during which she showed a remarkable response in relation to the respiratory lesions. Her hemoglobin also normalized and inflammatory markers gradually decreased to reach normal values. However, her skin lesions did not respond to treatment but no new lesions appeared. With our experience with cladribine, we believe that it could be a promising treatment option for XD. However, more work has to be conducted to determine the efficacy and safety in the long term.
30598166 Human-Disease Phenotype Map Derived from PheWAS across 38,682 Individuals. 2019 Jan 3 Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project. We computed associations between 632,574 common variants and 541 diagnosis codes. Using these associations, we constructed a "disease-disease" network (DDN) wherein pairs of diseases were connected on the basis of shared associations with a given genetic variant. The DDN provides a landscape of intra-connections within the same disease classes, as well as inter-connections across disease classes. We identified clusters of diseases with known biological connections, such as autoimmune disorders (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and cardiovascular disorders. Previously unreported relationships between multiple diseases were identified on the basis of genetic associations as well. The network approach applied in this study can be used to uncover interactions between diseases as a result of their shared, potentially pleiotropic SNPs. Additionally, this approach might advance clinical research and even clinical practice by accelerating our understanding of disease mechanisms on the basis of similar underlying genetic associations.
31650390 IRAK2 is associated with systemic lupus erythematosus risk. 2020 Feb INTRODUCTION: Interleukin-1 receptor-associated kinases (IRAKs) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways. They play a key role in inflammation and innate immunity. IRAKs have been previously incriminated in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis and inhibition of IRAKs has been recently regarded as a potential therapeutic strategy for SLE. OBJECTIVES: The aim of the present study was to test the association between IRAK2 rs708035 and rs3844283 with SLE. MATERIAL AND METHODS: IRAK2 rs708035 and rs3844283 were genotyped by mutagenically separated polymerase chain reaction (MS-PCR) in 142 SLE patients and 149 age- and gender-matched controls. RESULTS: The hyperfunctional IRAK2 rs708035 A allele was more frequent among SLE patients than controls (62.9% versus 54.7%, p = 0.046). IRAK2 rs3844283 C allele was present in 66.5% of patients and 75.5% of controls. The CC genotype was the most frequently exhibited genotype. It was carried by 45.1% of patients with SLE and 57.7% of controls. The G allele was associated with an increased risk of SLE (OR = 1.54, 95%, CI = 1.07-2.22, p = 0.017). IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium (D' = 0.64). The AG haplotype was more frequently observed in SLE patients than in controls (0.292 versus 0.194, p = 0.008). CONCLUSION: This study for the first time ever reveals the association of IRAK2 rs708035 and IRAK2 rs3844283 and the corresponding haplotypes with SLE. Our findings give additional rationale to target IRAKs in the treatment of SLE.Key Points• IRAK2 rs708035 A allele is more frequent in SLE patients than in controls and IRAK2 rs3844283 G allele is associated with SLE susceptibility.• These two alleles are in linkage disequilibrium.• The AG haplotype is associated with SLE.
31595160 Umbelliferone Prevents Lipopolysaccharide-Induced Bone Loss and Suppresses RANKL-Induced O 2019 Excessive bone resorption plays a central role in the development of inflammatory bone diseases, including osteoporosis and rheumatoid arthritis. Thus, identification of agents that can effectively suppress excessive osteoclast formation and function is crucial for the prevention and treatment of inflammatory bone loss. Umbelliferone (Umb), a derivative of coumarin, is a natural bioactive compound with anti-inflammatory and antioxidant properties. However, the effect of Umb on metabolic bone diseases is unknown. In this study, we found that Umb exhibited a strong inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo. Histological analysis confirmed that Umb prevented trabecular bone matrix degradation and osteoclast formation in bone tissue. In addition, Umb suppressed RANKL-induced osteoclast differentiation and abrogated bone resorption. We found that the anti-osteoclastic and anti-resorptive activities of Umb are mediated via suppression of the RANKL-induced Akt-c-Fos-NFATc1 signaling pathway and the attenuation of osteoclast-specific genes, such as TRAP, OSCAR, ATP6v0d2, and CtsK. In particular, Umb downregulated the stability of c-Fos and NFATc1 proteins, but did not suppress the expression of their mRNAs. These results indicate that Umb may be a potential therapeutic agent for inflammatory bone diseases associated with abnormal osteoclast formation and function.
31401320 Evaluation of the toxicity potential of acute and sub-acute exposure to the aqueous root e 2019 Nov 15 ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochia ringens Vahl. (Aristolochiaceae) is used traditionally in Nigeria for managing a number of ailments including gastrointestinal disturbances, rheumatoid arthritis, pile, insomnia, oedema, and snake bite venom. Some studies in our laboratory have demonstrated a scientific justification for some of such uses. This study aims at investigating the toxicological actions of the aqueous root extract of Aristolochia ringens (AR). MATERIALS AND METHODS: Brine shrimp lethality assay was carried out using 10, 100 and 1000 μg/ml of the extract. Oral and intraperitoneal acute toxicity tests were carried out using mice. The effect of sub-acute (30 days) repeated oral exposure to the extract at 10, 50 and 250 mg/kg in rats was also evaluated via weekly assessments of body weights and general observations as well as end of exposure haematological, biochemical and histological examinations of blood and tissue samples of treated rats. Phytochemical analyses to determine the presence of aristolochic acid I in the extract was also carried out using high performance liquid chromatography (HPLC). RESULTS: The aqueous root extract of A. ringens showed potential for biological activity and cytotoxicity with an LC(50) of 175 μg/ml in brine shrimps. AR was found to be relatively safe on acute oral exposure with LD(50) estimated to be greater than 10 g/kg, while its LD(50) on intraperitoneal administration was 407.38 mg/kg. Upon 30 days sub-chronic exposure, AR induced significant weight loss in female rats, enlargement of male rats' stomach, oxidative stress in male and female rats' kidney and liver tissues and disruption of leukocytes level in female rats. It also showed evidence of kidney and liver injuries inducible by oxidative damage and the potential to cause male sterility. HPLC revealed the presence of 0.003 mg/1 g of aristolochic acid in AR. CONCLUSION: These results show that AR contains detectible aristolochic acid I and has potential to induce toxic responses. Caution must therefore be exercised in its medicinal application especially when required for a prolonged use.
31115919 The effectiveness and safety of infliximab compared with biosimilar CT-P13, in 3112 patien 2019 Aug BACKGROUND: CT-P13, a biosimilar of the reference product infliximab, has been approved for the treatment of ulcerative colitis on the basis of the results of trials conducted in patients with spondyloarthritis and rheumatoid arthritis. AIM: To compare the effectiveness and safety of CT-P13 and the reference product in infliximab-naive patients with ulcerative colitis METHODS: A comparative real-life equivalence cohort study was conducted using the French nationwide health administrative database. Infliximab-naive patients with ulcerative colitis over 15 years of age who started infliximab with no other indications for infliximab were included. The primary outcome was a composite endpoint (death, ulcerative colitis-related surgery, all-cause hospitalisation and reimbursement for other biologics). Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 vs the reference product, in a multivariable marginal Cox model situated within prespecified margins of (0.80-1.25). RESULTS: A total of 3112 patients were included between 1 January 2015 and 30 June 2017: 1434 received the reference product, 1678 received CT-P13. Overall, 710 patients in the reference product group and 743 patients in the CT-P13 group met the composite endpoint. In multivariable analysis of the primary outcome, CT-P13 was equivalent to the reference product (HR 1.04; 95% CI: 0.94-1.15). The number of serious infections was lower in the CT-P13 group (HR 0.65; 95% CI: 0.48-0.88). There was no difference in the incidence of solid or haematologic malignancy (HR 0.81; 95% CI: 0.41-1.60). CONCLUSIONS: The effectiveness of CT-P13 is equivalent and the risk of serious infections could be lower than that of the reference product for infliximab-naive patients with ulcerative colitis.
34841075 An automated mass spectrometric blood test for therapeutic drug monitoring of infliximab. 2019 Apr Infliximab is a monoclonal antibody therapy used to treat several chronic immune-mediated diseases, including Crohn's disease, ulcerative colitis, and rheumatoid arthritis. Infliximab acts by binding to tumor necrosis factor and, thus, inhibiting the inflammatory cascade. While it is a highly effective therapy, a subset of patients on infliximab will develop a loss of response to therapy. In these circumstances, therapeutic drug monitoring of infliximab offers a rational approach to clinical decision making and is associated with improved outcomes. While infliximab has most commonly been measured by immunometric approaches, mass spectrometric approaches offer the opportunity to improve test accuracy and reduce test costs. Herein, we describe a simple, bottom-up high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) approach for quantitation of infliximab in serum. Method development included pre-digestion and digestion experiments to determine critical sample preparation steps, optimization of the workflow and selection of rapidly produced proteolytic peptide(s) for quantitation. The workflow was further improved by automating all sample preparation steps on a robotic liquid handler, facilitating implementation in routine clinical use. A method comparison was performed against a Health Canada and US Food and Drug Administration licensed enzyme-linked immunosorbent assay. Our LC-MS/MS assay accurately reported concentrations based on drug manufacturer targets and demonstrated no interference from endogenous antibodies to infliximab; immunoassay methods did not share these performance characteristics. This LC-MS/MS method provides a workflow amenable to implementation in a clinical laboratory and desired performance characteristics for guiding clinical decision making.
31862695 Lipid rafts in glial cells: role in neuroinflammation and pain processing. 2020 May Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.
31808359 Proximal Medial Gastrocnemius Release Versus Open Plantar Fasciotomy for the Surgical Trea 2020 Mar BACKGROUND: Plantar fasciitis is a common cause of foot pain. If conservative treatment fails, there is no consensus as to the best surgical management for recalcitrant plantar fasciitis (RPF). The aim of this study was to compare the results obtained from proximal medial gastrocnemius release (PMGR) with those obtained from open plantar fasciotomy (OPF) in terms of pain, satisfaction, health-related quality of life, and American Orthopaedic Foot & Ankle Society (AOFAS) score. METHODS: This is a prospective randomized trial conducted between 2012 and 2016. Patients with RPF for at least 9 months were included. Diagnosis was clinically made. The exclusion criteria were neuropathic heel pain; a history of previous foot fracture, surgery, or deformity; rheumatoid arthritis; or the need for long-term analgesic administration. After ruling out other conditions with magnetic resonance or ultrasound imaging, patients were randomized to be operated on with OPF or PMGR independently of the Silfverskjold test. Follow-up was carried out for up to 1 year. The AOFAS, visual analog scale (VAS) for pain, SF-36, and Likert scale for satisfaction were used to evaluate the results obtained. The analysis was done with 21 patients in the OPF group and 15 in the PMGR group. The demographic data (age, sex, body mass index, duration of symptoms, and positivity to the Silfverskjold test) of the groups were comparable. RESULTS: No differences were found in terms of the AOFAS (P = .24), VAS (P = .14), or any item of the SF-36. Satisfaction was very good in 85.8% of the PMGR group and 89.5% of the OPF group (P = .27). Faster recovery was observed in the PMGR group. CONCLUSION: OPF and PMGR provided good results for patients with RPF. Neither was superior to the other relative to pain, AOFAS score, satisfaction, or the SF-36. We recommend PMGR as the first option in RPF surgical management in order to avoid potential biomechanical complications related to OPF. LEVEL OF EVIDENCE: Level I, therapeutic randomized controlled trial.
31799834 De Novo-Designed Near-Infrared Nanoaggregates for Super-Resolution Monitoring of Lysosomes 2019 Dec 24 As the cleaners of cells, lysosomes play an important role in circulating organic matter within cells, recovering damaged organelles, and removing waste via endocytosis. Because lysosome dysfunction is associated with various diseases-lysosomal storage diseases, inherited diseases, rheumatoid arthritis, and even shock-it is vital to monitor the movement of lysosomes in cells and in vivo. To that purpose, a method of optical imaging, super-resolution imaging technology (e.g., SIM and STORM), can overcome the limitations of traditional optical imaging and afford a range of possibilities for fluorescence imaging. However, the short wavelength excitation and easy photobleaching of super-resolution fluorescence probes somewhat problematize super-resolution imaging. As described herein, we designed a low-toxicity, photostable, near-infrared small molecule fluorescence probe HD-Br for use in the super-resolution imaging of lysosomes. The interaction of lysosomes and mitochondria was dynamically traced while using the probe's properties to label the lysosomes. Because the probe has the optimal near-infrared excitation and emission wavelengths, liver organoid 3D imaging and Caenorhabditis elegans imaging were also performed. Altogether, our findings indicate valuable approaches and techniques for super-resolution 3D and in vivo imaging.
31755595 The role of Interleukin 1 receptor antagonist in mesenchymal stem cell-based tissue repair 2020 Mar Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1β in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1β in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1β-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
31688984 Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa. 2020 Jan Complement inhibition has been identified as a potential therapeutic target for multiple inflammatory disorders including Hidradenitis Suppurativa (HS). It is currently unclear how complement integrates into our current model of molecular pathogenesis in HS and whether it represents a central component of pathogenesis, or a neutrophil-associated bystander. Levels of C5a in serum and tissue correlate with disease activity and degree of neutrophilic infiltrates in HS. C5a has been associated with Th17 immune axis activation in psoriasis, rheumatoid arthritis and Crohn's disease with strong similarities to TH17 activation in HS. Porphyromonas species (which are identified in the HS microbiome) are able to cleave inactive C5 into C5a implicating the cutaneous microbiome as an activator of complement. C3a and C5a are associated with activation of the NLRP3 inflammasome, implicated in the inflammatory drive in HS. Complement receptors are present upon dendritic cells, monocytes, fibroblasts and adipocytes, which may broaden the potential contribution of complement to multiple aspects of HS pathogenesis. Dysregulation of complement receptor pathways has been documented in obesity, insulin resistance and polycystic ovarian syndrome leading to the possibility that complement may explain the epidemiological associations between these conditions and HS. The therapeutic potential of complement inhibitors in HS may be related to the therapeutic target (complement receptor or complement subunit) and the presence of alternate receptors (such as C5aR2) or ligands (including C3a, PAMPs and DAMPs). Integrating complement into the known pathogenesis of HS may aid in explaining the contradictory results between Phase 2 studies of C5a antagonists. It also allows for the identification of existing knowledge gaps to target further clinical investigation and research.
31602922 [Long-term effect of Tripterygium Glycosides Tablets combined with traditional Chinese med 2019 Aug To preliminarily investigate the effect of Tripterygium Glycosides Tablets( TGT) combined with traditional Chinese medicine( TCM) on the fertility and female menstruation on persons who have took during childhood. The children with henoch-schonlein purpura( HSP) or henoch-schonlein purpura nephritis( HSPN) who treated with TGT under 18 years old and now older than 18 years old( including 18 years old) during January 1998 to December 2010 were selected in our research. The content of follow-up visit included marriage,marriage age,fertility and child health; and unmarried female patients were asked whether they had menstrual abnormalities. The data of the unmarried female patients,including age,clinical classification,TCM syndrome type,initial dose and other related factors that may affect menstrual cycle,was analyzed by using binary logistic regression analysis. A total of 195 patients who met the criteria were followed up in this study,and 26 patients married for more than 1 year. Among the 26 married patients,1 HSP patient had no birth planning due to rheumatoid arthritis,and the remaining 25 patients all had given birth or were pregnant. The 169 unmarried patients included 89 female patients. Among the 89 female patients,4 cases refused to tell the menstrual situations,72 cases had normal menstruation( 84. 7%),13 cases had abnormal menstruation( 15. 3%),and there was no case of amenorrhea. Logistic regression analysis results showed that the age,clinical classification,TCM syndrome type and initial dose had no correlation with abnormal menstruation. Our results demonstrated that TGT has no effect on adulthood fertility among patients who took TGT combined with traditional Chinese medicine during childhood.
31371481 Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fen 2019 Oct Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C (max) on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C (max) for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.
31354747 CD4(+)CD25(+)LAG3(+) T Cells With a Feature of Th17 Cells Associated With Systemic Lupus E 2019 Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cell subsets. We analyzed immune cell subsets in human peripheral blood mononuclear cells (PBMC) in order to identify the cells that are significantly associated with SLE disease activity and treatment. The frequencies of various subsets of CD4(+) T cells, B cells, monocytes and NK cells in PBMC were assessed in 30 healthy controls (HC), 30 rheumatoid arthritis (RA) patients and 26 SLE patients using flow cytometry. The correlations between subset frequencies in SLE and clinical traits including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were examined. Changes in subset frequencies after the treatment in SLE patients were investigated. We focused on CD25(+)LAG3(+) T cells and investigated their characteristics, including cytokine secretion, mRNA expression and suppression capacity. We assessed correlations between CD25(+)LAG3(+) T cells and SLEDAI by Spearman's rank correlation coefficient. CD25(+)LAG3(+) T cells were significantly increased in SLE whereas there were few in RA and HC groups. CD25(+)LAG3(+) T cell frequencies were significantly correlated with SLEDAI and were increased in patients with a high SLEDAI score (> 10). CD25(+)LAG3(+) T cells produced both IL-17 and FOXP3, expressed mRNA of both FOXP3 and RORC and lacked suppressive capacity. CD25(+)LAG3(+) T cells were associated with disease activity of SLE. CD25(+)LAG3(+) T cells had features of both CD25(+)FOXP3(+) regulatory T cells (CD25(+) Treg) and Th17. CD25(+)LAG3(+) T cells could be associated with the inflammatory pathophysiology of SLE.
30815434 Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constrai 2019 Interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and is a key cytokine mediator of inflammasome activation. IL-1β signaling leads to parturition in preterm birth (PTB) and contributes to the retinal vaso-obliteration characteristic of oxygen-induced retinopathy (OIR) of premature infants. Therapeutics targeting IL-1β and IL-1R are approved to treat rheumatoid arthritis; however, all are large proteins with clinical limitations including immunosuppression, due in part to inhibition of NF-κB signaling, which is required for immuno-vigilance and cytoprotection. The all-D-amino acid peptide 1 (101.10, H-d-Arg-d-Tyr-d-Thr-d-Val-d-Glu-d-Leu-d-Ala-NH(2)) is an allosteric IL-1R modulator, which exhibits functional selectivity and conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Peptide 1 has proven effective in experimental models of PTB and OIR. Seeking understanding of the structural requirements for the activity and biased signaling of 1, a panel of twelve derivatives was synthesized employing the various stereochemical isomers of α-amino-γ-lactam (Agl) and α-amino-β-hydroxy-γ-lactam (Hgl) residues to constrain the D-Thr-D-Val dipeptide residue. Using circular dichroism spectroscopy, the peptide conformation in solution was observed to be contingent on Agl, Hgl, and Val stereochemistry. Moreover, the lactam mimic structure and configuration influenced biased IL-1 signaling in an in vitro panel of cellular assays as well as in vivo activity in murine models of PTB and OIR. Remarkably, all Agl and Hgl analogs of peptide 1 did not inhibit NF-κB signaling but blocked other pathways, such as JNK and ROCK2 phosphorylation contingent on structure and configuration. Efficacy in preventing preterm labor correlated with a capacity to block IL-1β-induced IL-1β synthesis. Furthermore, the importance of inhibition of JNK and ROCK2 phosphorylation for enhanced activity was highlighted for prevention of vaso-obliteration in the OIR model. Taken together, lactam mimic structure and stereochemistry strongly influenced conformation and biased signaling. Selective modulation of IL-1 signaling was proven to be particularly beneficial for curbing inflammation in models of preterm labor and retinopathy of prematurity (ROP). A class of biased ligands has been created with potential to serve as selective probes for studying IL-1 signaling in disease. Moreover, the small peptide mimic prototypes are promising leads for developing immunomodulatory therapies with easier administration and maintenance of beneficial effects of NF-κB signaling.