Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
32902896 Differing Progression to Posterior Glottic Stenosis in Autoimmune and Idiopathic Subglotti 2021 Aug OBJECTIVES/HYPOTHESIS: We sought to characterize rates of progression to posterior glottic stenosis (PGS) from autoimmune or idiopathic subglottic stenosis. STUDY DESIGN: This was a retrospective review. METHODS: Patients from a tertiary-care laryngology practice over a 10-year period with autoimmune or idiopathic subglottic stenosis (SGS) were included. Patients with a history of prolonged intubation or other causes of iatrogenic stenosis were excluded. PGS was confirmed on videostrobolaryngoscopy recordings by a fellowship-trained laryngologist. PGS type (1-4) was also recorded. Demographic information was recorded, and if applicable, autoimmune disease type was specified. Time until PGS was recorded along with the number of interventions. Chi-squared analysis was used to compare PGS in autoimmune and idiopathic SGS. RESULTS: A total of 77 patients were identified with autoimmune (32 patients) or idiopathic (45 patients) subglottic stenosis. Autoimmune pathologies included systemic lupus erythematosus, granulomatosis with polyangiitis (GPA), rheumatoid arthritis, relapsing polychondritis, and sarcoidosis, with GPA the most common (14/32). Patients with autoimmune SGS had a higher rate of PGS (10 of 32) compared to idiopathic subglottic stenosis (1 of 45) for an odds ratio of 20 (95% CI: 2.4-166.4, P = .006). Patients with idiopathic SGS were more likely to be female (all 45 compared to 29/32 autoimmune, P = .07) and older (mean 53 (range 29-75) compared to 46 (20-82), P = .02). CONCLUSIONS: In this large patient cohort, autoimmune SGS patients were found to have a higher likelihood of developing PGS compared to their idiopathic counterparts, suggesting that counseling for this progression may be warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1816-1820, 2021.
32880072 Estimating the relative contribution of comorbidities in predicting health-related quality 2021 Feb BACKGROUND: Little is known about the relative contribution of comorbidities in predicting the health-related quality of life (HRQoL) of people with Multiple Sclerosis (PwMS). OBJECTIVE: To determine the associations between the number of and individual comorbidities and HRQoL and estimate the relative contribution of different comorbidities on HRQoL. METHODS: Cross-sectional analysis of data on self-reported presence of 30 comorbidities and HRQoL from the Australian MS Longitudinal Study (AMSLS) participants (n = 902). HRQoL was measured using the Assessment of Quality of Life-8 Dimensions (AQoL-8D). Linear regression and general dominance analysis were used. RESULTS: Higher number of comorbidities was associated with lower HRQoL (p trend p < 0.01). Comorbidities accounted for 18.1% of the variance in HRQoL. Mental health and musculoskeletal disorders were the strongest contributors to lower HRQoL. Of individual comorbidities, systemic lupus erythematosus (SLE) [β = - 0.16 (- 0.27, - 0.05)] and depression [β = - 0.15(- 0.18, - 0.13)] were most strongly associated with overall HRQoL, depression [β = - 0.14(- 0.16, - 0.11)] and anxiety [β = - 0.10 (- 0.13, - 0.07)] with psychosocial HRQoL, and SLE [β = - 0.18 (- 0.29, - 0.07)], rheumatoid arthritis [β = - 0.11 (- 0.19, - 0.02)] and hyperthyroidism [β = - 0.11 (- 0.19, - 0.03)) with physical HRQoL. CONCLUSION: Comorbidities potentially make important contributions to HRQoL in PwMS. Our findings highlight groups of and individual comorbidities that could provide the largest benefits for the HRQoL of PwMS if they were targeted for prevention, early detection, and optimal treatment.
32626768 Study on Genotyping Polymorphism and Sequencing of N-Acetyltransferase 2 (NAT2) among Al-A 2020 One of the well-studied phase II drug metabolizing enzymes is N-acetyltransferase 2 (NAT2) which has an essential role in the detoxification and metabolism of several environmental toxicants and many therapeutic drugs like isoniazid (antituberculosis, TB) and antimicrobial sulfonamides. According to the variability in the acetylation rate among different ethnic groups, individuals could be classified into slow, intermediate, and fast acetylators; these variabilities in the acetylation rate are a result of single nucleotide polymorphisms (SNPs) in the coding sequence of NAT2. The variety of NAT2 acetylation status is associated with some diseases such as bladder cancer, colorectal cancer, rheumatoid arthritis, and diabetes mellitus. The main objectives of this research are to describe the genetic profile of NAT2 gene among the people of the Al-Ahsa region, to detect the significant SNPs of this gene, to determine the frequency of major NAT2 alleles and genotypes, and then categorize them into fast, intermediate, and slow acetylators. Blood samples were randomly collected from 96 unrelated people from Al-Ahsa population, followed by DNA extraction then amplifying the NAT2 gene by polymerase chain reaction (PCR); finally, functional NAT2 gene (exon 2) was sequenced using the Sanger sequencing method. The well-known seven genetic variants of NAT2 gene are 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, and 857G>A were detected with allele frequencies 1%, 35.4%, 42.7%, 41.1%, 29.2%, 51%, and 5.7%, respectively. The most common NAT2 genetic variant among Al-Ahsa population was 803A>G with a high frequency 0.510 (95% confidence interval 0.44-0.581) followed by 341T>C 0.427 (95% confidence interval 0.357-0.497). The most frequent two haplotypes of NAT2 were NAT2∗6C (25.00%) and NAT2∗5A (22.92%) which were classified as a slow acetylators. According to trimodal distribution of acetylation activity, the predicted phenotype of Al-Ahsa population was found to be 5.21% rapid acetylators, 34.38% intermediate acetylators, and 60.42% were slow acetylators. In addition, this study found four novel haplotypes NAT2∗5TB, NAT2∗5AB, NAT2∗5ZA, and NAT2∗6W which were slow acetylators. This study revealed a high frequency of the NAT2 gene with slow acetylators (60.42%) in Al-Ahsa population, which might alter the drug's efficacy and vulnerability to some diseases.
32595567 Evaluation of Self-Assessed State of Health and Vitamin D Knowledge in Emirati and Interna 2020 INTRODUCTION: Globally, vitamin D deficiency is one of the most common deficiencies, affecting nearly half the world's population. The objective of this survey was to assess and compare the knowledge about vitamin D and the perceived state of health in Emirati and international tourist female students in Dubai, United Arab Emirates (UAE). METHODS: This is a cross-sectional study that took place in universities in Dubai, United Arab Emirates. This survey consisted of 17 multiple choice questions and was adapted from a study recently conducted in Poland. The first part of the survey assessed levels of supplementation, diet and UV exposure. Another section evaluated the participants' self-assessed state of health in terms of vitamin D testing, symptoms related to vitamin D deficiency and general welbeing. The collected data were statistically analyzed using SPSS statistics for windows version 26.0 (SPSS Inc., Chicago, IL, United States). Statistical significance was set at P < 0.05. RESULTS: 105 respondents were Emiratis and 65 were international students. The average age was 21, with an average BMI 23.3 kg/m(2). Almost one-third of each group reported using Vitamin D supplements once weekly. The vast majority of both groups reported rarely getting tanned. Almost all participants in both groups reported regular consumption of Vitamin D rich foods. In both groups, more than half reported consuming milk and cheese regularly and up to one-third reported consuming fish in a regular manner. Although more than half of the students rated their health as good; more than two-thirds reported experiencing muscle pain; only half reported having their blood Vitamin D levels measured once; half reported experiencing problems with concentration and more than three-quarters reported experiencing bad mood in the past month. The prevalence of these symptoms was almost similar across different categories of vitamin D supplementation, tanning habits, dietary intake, or nationality. No statistically significant differences were noted between the Emirati and International tourist students regarding any of the studied variables. CONCLUSION: Notably, more Emirati students were aware of the association between vitamin D and osteoporosis than International tourist students (40% vs. 21.9%, respectively; p < 0.05). On the other hand, both groups had lower knowledge about the relationship between vitamin D deficiency and depression, Rheumatoid Arthritis and Hypertension, and the optimal vitamin D level; however, no statistically significant differences were noted regarding this knowledge of Emiratis and international students.
32564401 LPS-Induced Inflammation Prior to Injury Exacerbates the Development of Post-Traumatic Ost 2020 Nov Osteoarthritis (OA) is a debilitating and painful disease characterized by the progressive loss of articular cartilage. Post-traumatic osteoarthritis (PTOA) is an injury-induced type of OA that persists in an asymptomatic phase for years before it becomes diagnosed in ~50% of injured individuals. Although PTOA is not classified as an inflammatory disease, it has been suggested that inflammation could be a major driver of PTOA development. Here we examined whether a state of systemic inflammation induced by lipopolysaccharide (LPS) administration 5-days before injury would modulate PTOA outcomes. RNA-seq analysis at 1-day post-injury followed by micro-computed tomography (μCT) and histology characterization at 6 weeks post-injury revealed that LPS administration causes more severe PTOA phenotypes. These phenotypes included significantly higher loss of cartilage and subchondral bone volume. Gene expression analysis showed that LPS alone induced a large cohort of inflammatory genes previously shown to be elevated in synovial M1 macrophages of rheumatoid arthritis (RA) patients, suggesting that systemic LPS produces synovitis. This synovitis was sufficient to promote PTOA in MRL/MpJ mice, a strain previously shown to be resistant to PTOA. The synovium of LPS-treated injured joints displayed an increase in cellularity, and immunohistological examination confirmed that this increase was in part attributable to an elevation in type 1 macrophages. LPS induced the expression of Tlr7 and Tlr8 in both injured and uninjured joints, genes known to be elevated in RA. We conclude that inflammation before injury is an important risk factor for the development of PTOA and that correlating patient serum endotoxin levels or their state of systemic inflammation with PTOA progression may help develop new, effective treatments to lower the rate of PTOA in injured individuals. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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.
32244454 A Hydrophilic Interaction Liquid Chromatography-Tandem Mass Spectrometry Quantitative Meth 2020 Mar 31 Baricitinib, is a selective and reversible Janus kinase inhibitor, is commonly used to treat adult patients with moderately to severely active rheumatoid arthritis (RA). A fast, reproducible and sensitive method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of baricitinib in rat plasma has been developed. Irbersartan was used as the internal standard (IS). Baracitinib and IS were extracted from plasma by liquid-liquid extraction using a mixture of n-hexane and dichloromethane (1:1) as extracting agent. Chromatographic separation was performed using Acquity UPLC HILIC BEH 1.7 µm 2.1 × 50 mm column with the mobile phase consisting of 0.1% formic acid in acetonitrile and 20 mM ammonium acetate (pH 3) (97:3). The electrospray ionization in the positive-mode was used for sample ionization in the multiple reaction monitoring mode. Baricitinib and the IS were quantified using precursor-to-production transitions of m/z 372.15 > 251.24 and 429.69 > 207.35 for baricitinib and IS, respectively. The method was validated according to the recent FDA and EMA guidelines for bioanalytical method validation. The lower limit of quantification was 0.2 ng/mL, whereas the intra-day and inter-day accuracies of quality control (QCs) samples were ranged between 85.31% to 89.97% and 87.50% to 88.33%, respectively. Linearity, recovery, precision, and stability parameters were found to be within the acceptable range. The method was applied successfully applied in pilot pharmacokinetic studies.
32141102 Dibutyltin alters immune cell production of the pro-inflammatory cytokines interleukin (IL 2020 Aug Dibutyltin (DBT) is used to stabilize plastics and as a deworming agent in some poultry. It is found in human blood (levels as high as 0.3 μM). Interleukin (IL) 1β (IL-1β) and IL-6 are pro-inflammatory cytokines produced by lymphocytes, monocytes, and other cells. Elevated levels of IL-1β and IL-6 have been associated with pathologies including rheumatoid arthritis and cancers. DBT was shown to decrease IL-1β and IL-6 secretion from immune cells at higher concentrations while causing increases at lower concentrations. However, it was not clear if these changes were due to DBT's alteration of the secretory process or due its ability to change cellular synthesis/production of these proteins. This study addresses this question, as well as mechanisms for any observed changes in synthesis/production. Monocyte-depleted peripheral blood mononuclear cells (MD-PBMCs) were exposed to DBT at concentrations of 5, 2.5, 1, 0.5, 0.25, 0.1, and 0.05 μM for 1, 6, and 24 h and the production (combination of secreted and intracellular levels from the same cells) of both IL-1β and IL-6 were measured. Effects of selected DBT exposures on cytokine production were also examined in PBMCs and DBT's effects were similar when monocytes were present. The 24-h exposures to DBT decreased production of both IL-1β and IL-6 at the two highest concentrations but increased production at lower concentrations. Both decreases and increases in cytokine production appear to be explained by DBT-induced changes in mRNA levels. DBT-induced increases in cellular production of the cytokines appear to require p38 and ERK1/2 MAPK pathways.
31933400 Prevalence of Iron Deficiency (ID) without anemia in the general population presenting to 2020 Apr OBJECTIVES: There are no evidence-based recommendations to screen for iron deficiency in non-anemic patients, even though symptoms may be present. The aim of this study is to measure the prevalence of iron deficiency (ID) without anemia in the general population aged 18-50 presenting to primary care along with the incidence and time to develop anemia in the iron-deficient population. METHODS: A single-center retrospective chart review of patients who presented to family medicine clinics between June 2010 and March 2018 at the American University of Beirut Medical Center (AUBMC). Adults 18-50 years old, who had a CBC and ferritin levels ordered with the proximity of maximum four weeks, with an absence of current or previously documented anemia (back to 2007) defined as MCV less than 80 or hemoglobin (Hb) less than 12 in females and 13 in males were included. ID was defined as serum ferritin level below 30 ng/mL. RESULTS: A total of 1,784 adults aged 18-50 years were included. The prevalence of iron deficiency without anemia was 57.5% [95% confidence interval, 55.08% to 59.92%] among females and 7.6% [95% confidence interval, 3.77% to 11.43%] among males. Iron deficiency without anemia was significantly associated with the level of hemoglobin (Hb) among females (Chi-square, p < 0.001). Overt iron deficiency anemia developed within the 5 years follow up in 14% of females and 0.5% of males. There was a statistically significant association between iron deficiency and menorrhagia (Chi-square, P-value = 0.004), dizziness (Chi-square, P-value = 0.018), dyspnea/shortness of breath (Chi-square, P-value = 0.020), polycystic ovarian syndrome (Chi-square, P-value = 0.0256) and rheumatoid arthritis (Chi-square, P-value = 0.00278). CONCLUSION: Iron deficiency without anemia in childbearing females is common but only one-seventh of females developed anemia within 5 years. Guidelines should consider incorporating ferritin levels with CBC in the workup of patients presenting with symptoms suggestive of iron deficiency or anemia.
31908072 Rapid discrimination of Notopterygium incisum and Notopterygium franchetii based on charac 2020 May INTRODUCTION: The herbs Notopterygium incisum (NI) and N. franchetii (NF) are referred to as "Qianghuo" in the Chinese Pharmacopeia and are popular for treatment of certain conditions, including headaches, rheumatoid arthritis and the common cold. Recently, several adulterations of NI and NF have been found in the Chinese herbal market. OBJECTIVE: The aim of this study was to rapidly identify the unique characteristic compounds of NI and NF, to discriminate Qianghuo from its adulterations. METHODOLOGY: Twenty-four batches of NI and NF samples with different origins were collected and extracted with methanol. The extracts were analysed using ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). Principal component analysis (PCA) and orthogonal partial squared discriminant analysis (OPLS-DA) were then used to distinguish between NI and NF and to identify their potential characteristic markers. RESULTS: Fifty compounds were identified or tentatively characterised according to the retention time, m/z value and MS/MS fragment analysis. Six compounds were selected as potential markers of NI and NF by PCA and OPLS-DA. They were successfully applied to authenticate 17 kinds of Chinese patent medicines containing Qianghuo. The markers could not be detected in three of the Chinese patent medicines, indicating that they were counterfeit products. CONCLUSION: The UHPLC-QTOF-MS/MS coupled with the multivariate analysis method could discriminate NI and NF from their adulterations. Moreover, the data clearly demonstrated significant differences in the chemical compositions of NI and NF. Further research is needed to examine the relationship between therapeutic efficacy and the chemical constituents of NI and NF.
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.
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.
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.
33301474 The transcriptomic profiling of SARS-CoV-2 compared to SARS, MERS, EBOV, and H1N1. 2020 The SARS-CoV-2 (COVID-19) pandemic is a global crisis that threatens our way of life. As of November 18, 2020, SARS-CoV-2 has claimed more than 1,342,709 lives, with a global mortality rate of ~2.4% and a recovery rate of ~69.6%. Understanding the interaction of cellular targets with the SARS-CoV-2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of SARS-CoV-2 compared to other respiratory viruses (EBOV, H1N1, MERS-CoV, and SARS-CoV), to determine a unique anti-SARS-CoV-2 gene signature. We identified for the first time that molecular pathways for heparin-binding, RAGE, miRNA, and PLA2 inhibitors were associated with SARS-CoV-2 infection. The NRCAM and SAA2 genes, which are involved in severe inflammatory responses, and the FGF1 and FOXO1 genes, which are associated with immune regulation, were found to be associated with the cellular gene response to SARS-CoV-2 infection. Moreover, several cytokines, most significantly IL-8 and IL-6, demonstrated key associations with SARS-CoV-2 infection. Interestingly, the only response gene that was shared among the five viral infections was SERPINB1. The protein-protein interaction (PPI) analysis shed light on genes with high interaction activity that SARS-CoV-2 shares with other viral infections. The findings showed that the genetic pathways associated with rheumatoid arthritis, the AGE-RAGE signaling system, malaria, hepatitis B, and influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of SARS-CoV-2 and EBOV were more similar than to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against SARS-CoV-2.
33292350 An anti-CD6 monoclonal antibody (itolizumab) reduces circulating IL-6 in severe COVID-19 e 2020 Nov 14 BACKGROUND: Since the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients. RESULTS: We show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn't rise as compared to their low baseline levels. CONCLUSION: These findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients. TRIAL REGISTRATION: CECMED IIC RD-EC 179, RPCEC00000311. Registered 4 May 2020 - Retrospectively registered, http://rpcec.sld.cu/ensayos/RPCEC00000311-Sp or http://rpcec.sld.cu/trials/RPCEC00000311-En.
33066186 Immunomodulatory and Anti-Inflammatory Effects of Fucoidan: A Review. 2020 Oct 13 Inflammation is the initial response of the immune system to potentially harmful stimuli (e.g., injury, stress, and infections). The process involves activation of macrophages and neutrophils, which produce mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory and anti-inflammatory cytokines. The pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) are considered as biomarkers of inflammation. Even though it occurs as a physiological defense mechanism, its involvement in the pathogenesis of various diseases is reported. Rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, and cardiovascular diseases are only a part of the diseases, in which pathogenesis the chronic inflammation is involved. Fucoidans are complex polysaccharides from brown seaweeds and some marine invertebrates, composed mainly of L-fucose and sulfate ester groups and minor amounts of neutral monosaccharides and uronic acids. Algae-derived fucoidans are studied intensively during the last years regarding their multiple biological activities and possible therapeutic potential. However, the source, species, molecular weight, composition, and structure of the polysaccharides, as well as the route of administration of fucoidans, could be crucial for their effects. Fucoidan is reported to act on different stages of the inflammatory process: (i) blocking of lymphocyte adhesion and invasion, (ii) inhibition of multiple enzymes, and (iii) induction of apoptosis. In this review, we focused on the immunemodulating and anti-inflammatory effects of fucoidans derived from macroalgae and the models used for their evaluation. Additional insights on the molecular structure of the compound are included.
32997846 Molecular basis and therapeutic potential of myostatin on bone formation and metabolism in 2020 Sep 30 Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is a key autocrine/paracrine inhibitor of skeletal muscle growth. Recently, researchers have postulated that myostatin is a negative regulator of bone formation and metabolism. Reportedly, myostatin is highly expressed in the fracture area, affecting the endochondral ossification process during the early stages of fracture healing. Furthermore, myostatin is highly expressed in the synovium of patients with rheumatoid arthritis (RA) and is an effective therapeutic target for interfering with osteoclast formation and joint destruction in RA. Thus, myostatin is a potent anti-osteogenic factor and a direct modulator of osteoclast differentiation. Evaluation of the molecular pathway revealed that myostatin can activate SMAD and mitogen-activated protein kinase signaling pathways, inhibiting the Wnt/β-catenin pathway to synergistically regulate muscle and bone growth and metabolism. In summary, inhibition of myostatin or the myostatin signaling pathway has therapeutic potential in the treatment of orthopedic diseases. This review focused on the effects of myostatin on bone formation and metabolism and discussed the potential therapeutic effects of inhibiting myostatin and its pathways in related orthopedic diseases.
32679784 Immunologic Effects of Vitamin D on Human Health and Disease. 2020 Jul 15 Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.
32581890 Efficacy of the Whole-Body Cryotherapy as Add-on Therapy to Pharmacological Treatment of D 2020 INTRODUCTION: Accumulating evidence indicates the effectiveness of cryogenic temperature interventions in rheumatoid arthritis, ankylosing spondylitis, fibromyalgia, multiple sclerosis, and chronic low back pain. The application of whole-body cryotherapy (WBC) in psychiatric aspects of medicine was also noted. Nevertheless, the exact mechanisms explaining the beneficial effect of WBC on mood disorders remain unclear. The study aimed to assess the efficacy of repetitive short exposure to extremely low temperatures (WBC) on mood, quality of life as well as on biochemical measures among people diagnosed with depressive episode undergoing pharmacological treatment. MATERIALS AND METHODS: Prospective randomized, double-blind sham-controlled protocol was used. The study enrolled 92 medically stable adults (aged 20-73 years) with a diagnosis of a depressive episode. The participants were randomly allocated and exposed to 10 whole-body cryotherapy (WBC) sessions (-110°C till -160°C [the experimental group (EG)] or to low, but not cryogenic temperatures -50°C [the control group (CG)]. Thirty participants in the EG and 26 in CG completed the whole study. The primary outcome measures were depressive symptoms evaluated with the Beck Depression Inventory-II (BDI-II) as well as the Hamilton Depression Rating Scale (HAM-D 17). The quality of life, quality of sexual life, acceptance of the disease and self-reported mood, vitality, and sleep quality were assessed as secondary outcome measures. The study was registered at Australian New Zealand Clinical Trials Registry (ACTRN12619001600134). RESULTS: The results show evidence for a statistically significant difference in the clinical assessment of depressive symptoms according to HAM-D 17 scale (T4 by group interaction p=0.02), BDI-II (T2 time by group interaction p=0.01), cognitive-affective BDI dimension (T4 by group interaction p=0.00), and somatic BDI dimension (T4 by group interaction p=0.028). Significant improvement was also noticed in life quality (p < 0.05), self-assessed mood (p=0.035), and disease acceptance (p=0.007). There were no statistically significant changes related to sexual satisfaction, self-assessed vitality, and sleep (p > 0.05). CONCLUSIONS: Whole-body cryotherapy is a useful method to improve standard pharmacological treatment. The WBC intervention reduces mental health deterioration, especially in mood disorders, such as depression, and can be beneficial for well-being and quality of life.
32571993 Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resol 2020 Jun BACKGROUND: Immune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%-20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients. CASE PRESENTATION: We provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes. CONCLUSIONS: A deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.