HBV reactivation in HBsAg-/HBcAb+ rheumatoid arthritis patients receiving biologic/targeted synthetic DMARDs.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population. METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed. RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation. CONCLUSION: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy.

Design of carbazole-based platinum complexes with steric hindrance for efficient organic light-emitting diodes.

The construction of platinum complexes with high steric hindrance is expected to suppress triple-triplet annihilation and π-π stacking to achieve high-performance organic light-emitting diodes (OLEDs) with low efficiency roll-off. Herein, two large steric hindrance platinum complexes (N-CzPhPtacac and N-CzCF3PhPtacac) were prepared by taking advantage of steric hindrance between the phenyl group on carbazole and the functional group (phenyl and trifluoromethyl substituted phenyl) at the 3-position of a pyridine moiety. Due to the similar electron cloud distribution and gap difference between the HOMO and LUMO, the two complexes showed similar orange-red emission peaks at 590 and 596 nm with high PL quantum yields of 90% and 92% and short excited state lifetimes of 2.77 and 3.08 µs in doped films, respectively. Consequently, OLEDs based on N-CzPhPtacac and N-CzCF3PhPtacac showed maximum external quantum efficiency (EQEmax) values of 15.4% and 18.9%, respectively. Importantly, benefitting from the more stretched spatial configuration from the -CF3 effect, the corresponding OLED exhibited a lower efficiency roll-off, with an EQE of 18.1% at 1000 cd m-2.

Increased Expression of Long Noncoding RNA LOC100506314 in T cells from Patients with Nonsegmental Vitiligo and Its Contribution to Vitiligo Pathogenesis.

This study aimed to identify the abnormal expression of long noncoding RNAs (lncRNAs) in T cells from patients with vitiligo and to investigate their functional roles in the immune system. Using microarray analysis, the expression levels of RNA transcripts in T cells from patients with vitiligo and controls were compared. We identified several genes and validated their expression levels in T cells from 41 vitiligo patients and 41 controls. The biological functions of the lncRNAs were studied in a transfection study using an RNA pull-down assay, followed by proteomic analysis and western blotting. The expression levels of 134 genes were significantly increased, and those of 142 genes were significantly decreased in T cells from vitiligo patients. After validation, six genes had increased expression, and three genes had decreased expression in T cells from patients with vitiligo. T-cell expression of LOC100506314 was increased in vitiligo, especially CD4+, but not CD8+ T cells. The expression levels of LOC100506314 in CD4+ T cells was positively and significantly associated with the severity of vitiligo. LOC100506314 was bound to the signal transducer and activator of transcription 3 (STAT3) and macrophage migration inhibitory factor (MIF). Enhanced expression of LOC100506314 inhibited the phosphorylation of STAT3, protein kinase B (AKT), and extracellular signal-regulated protein kinases (ERK), as well as the levels of nuclear protein of p65 and the expression of IL-6 and IL-17 in Jurkat cells and T cells from patients with vitiligo. In conclusion, this study showed that the expression of LOC100506314 was elevated in CD4+ T cells from patients with vitiligo and associated the severity of vitiligo. LOC100506314 interacted with STAT3 and MIF and inhibited IL-6 and IL-17 expression by suppressing the STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), AKT, and ERK pathways. Enhanced expression of LOC100506314 in T cells may be a potential treatment strategy for vitiligo.

Significant Functional Differences Between Dopamine D4 Receptor Polymorphic Variants Upon Heteromerization with α1A Adrenoreceptors.

The functional role of the dopamine D4 receptor (D4R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D4R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α2A adrenoceptor (α2AR) and with the D2R, localized in their cortical somato-dendritic region and striatal nerve terminals, respectively. By using biophysical and cell-signaling methods and heteromer-disrupting peptides in mammalian transfected cells and rat brain slice preparations, here we provide evidence for a new functionally relevant D4R heteromer, the α1AR-D4R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α1AR with the D4.4R and D4.7R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α1AR and D4R ligands could be demonstrated for both α1AR-D4.4R and α1AR-D4.7R heteromers on G protein-independent signaling, but only for α1AR-D4.4R on G protein-dependent signaling. From these functional differences, it is proposed that the D4.4R variant provides a gain of function of the α1AR-mediated noradrenergic stimulatory control of cortico-striatal glutamatergic neurotransmission, which could result in a decrease in the vulnerability for impulse control-related neuropsychiatric disorders and increase in the vulnerability for posttraumatic stress disorder.

Integration of Chinese Herbal Medicine into Routine Care Was Related to Lower Risk of Chronic Kidney Disease in Patients with Rheumatoid Arthritis: A Population-Based Nested Case-Control Study in Taiwan.

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as the first-line agents for the symptomatic relief of rheumatoid arthritis (RA), but it may insidiously provoke the onset of renal diseases, especially chronic kidney disease (CKD). While Chinese herbal medicine (CHM) has become an increasingly popular adjunctive therapy among RA groups, there are currently no available data on the effect of CHM use towards risk of CKD. This study aimed to explore on a population-level whether CHM use decreases sequent CKD risk among them. Methods: In this nested case-control study retrieved from the nationwide insurance database of Taiwan from 2000 to 2012, we looked at the association between CHM use and the likelihood of developing CKD, with a focus on usage intensity. Cases with CKD claims were defined and matched to one randomly selected control case. Conditional logistic regression was then applied to estimate odds ratio (OR) of CKD from CHM treatment measured before the index date. For each OR, we calculated a 95% confidence interval for CHM use relative to the matched control. Results: This nested case-control study included 5464 patients with RA, where after matching comprised 2712 cases and 2712 controls. Among them, there were 706 and 1199 cases that ever received CHM treatment, respectively. After the adjustment, CHM use in RA individuals was related to a lower likelihood of CKD, with an adjusted OR of 0.49 (95% CI: 0.44-0.56). Additionally, a dose-dependent, reverse association was found between the cumulative duration of CHM use and risk of CKD. Conclusion: Integrating CHM into conventional therapy may reduce the likelihood of developing CKD, which could be a reference in instituting novel preventive strategies to improve treatment outcomes and reduce related fatalities for RA subjects.

Relationship between Chinese Herbal Medicine Use and Risk of Sjögren's Syndrome in Patients with Rheumatoid Arthritis: A Retrospective, Population-Based, Nested Case-Control Study.

Background and Objectives: Sjögren's Syndrome (SS) is a common extra-articular feature among subjects with rheumatoid arthritis (RA). While Chinese herbal medicine (CHM) has been used to treat symptoms of RA for many years, few studies have examined its efficacy in guarding against the SS onset. This study aimed to compare risk of SS for RA patients with and without use of CHM. Materials and Methods: Data obtained for this nested case-control study were retrieved from Taiwanese nationwide insurance database from 2000-2013. Cases with SS claims were defined and matched to two randomly selected controls without SS from the recruited RA cohorts. Risk of SS in relation to CHM use was estimated by fitting multiple conditional logistic regression. Results: Patients aged between 20 and 80 years were included and 916 patients with incident SS were matched to 1832 non-SS controls by age, sex and index year. Among them, 28.1% and 48.4% cases ever received CHM therapy, respectively. After adjusting for baseline characteristics, CHM use was found to be related to a lower risk of SS among them (adjusted odds ratio = 0.40, 95% confidence interval: 0.34-0.47). A dose-dependent, reverse association, was further detected between the cumulative duration of CHM use and SS risk. Those receiving CHM therapy for more than 730 days showed a significantly reduced risk of SS by 83%. Conclusions: Findings of this study indicated that the add-on CHM formula, as part of RA care, may be a beneficial treatment for prevention against the incident SS.

Health-related quality of life improvement by adalimumab therapy in patients with rheumatoid arthritis in Taiwan: A nationwide prospective study.

BACKGROUND: To determine the effects of adalimumab on health-related quality of life (HRQoL) in Taiwanese patients with moderate-to-severe rheumatoid arthritis (RA) (NCT02616380). METHODS: During a 24-week observational period, 100 biologic-naive patients with RA received 40 mg adalimumab subcutaneously, every 2 weeks. The primary endpoint was a change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at 24 weeks. The secondary endpoints included change in HAQ-DI at week 12, number and percentage of patients achieving a meaningful improvement in HAQ-DI at weeks 12 and 24, and changes in the 36-Item Short Form Health Survey (SF-36), EuroQol 5-dimension 3-level version (EQ-5D-3L) index, and Work Productivity and Activity Impairment (WPAI) questionnaire scores at weeks 12 and 24. RESULTS: At weeks 12 and 24, mean changes in HAQ-DI from baseline were -0.34 ± 0.46 and -0.44 ± 0.59 (both p < 0.001), and clinically meaningful improvement in HAQ-DI was achieved by 60.4% and 59.6% of patients, respectively. SF-36, EQ-5D-3L index, and WPAI scores significantly improved ( p < 0.001) from baseline to weeks 12 and 24. Exploratory analyses showed diabetes was significantly associated with changes in HAQ-DI, EQ-5D-3L, and WPAI scores whereas peptic ulcer correlated with changes in the SF-36 physical component summary T-score. CONCLUSION: HRQoL improved after initiation of adalimumab therapy in Taiwanese patients with moderate-to-severe RA.

Increased risk of hospital admissions in patients with active systemic lupus erythematosus (SLE) classified according to two different SLE disease activity indices: a prospective cohort study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the risk of hospital admissions within one year in patients with active systemic lupus erythematosus (SLE), classified according to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) or the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). METHODS: This study was conducted in adult patients with SLE recruited from the rheumatology outpatient department in a regional hospital in southern Taiwan. SLE disease activity was measured with SLE-DAS and SLEDAI-2K. The computerised patient record database was accessed to identify patients' hospital admissions. Cox regression analyses were used to estimate the hazard ratio (HR) for all-cause and SLE-related hospital admission in SLE patients classified by SLE-DAS and SLEDAI-2K. RESULTS: A total of 326 adult patients with SLE completed this study. All-cause and SLE-related hospital admissions within one year occurred in 17.5% and 12.6% of the patients, respectively. Results of the Cox regression analysis indicated that SLE patients with moderate/severe disease activity classified by the SLE-DAS (HR=2.43, p=0.005) but not moderate/severe disease activity classified by the SLEDAI-2K (HR=1.84, p=0.057) was significantly associated with the risk of SLE-related admissions. However, only moderate/severe disease activity classified by the SLE-DAS was significantly associated with the risk of all-cause admissions (HR=1.94, p=0.016). When steroid dosage was considered, only the steroid dosage was significantly associated all-cause and SLE-related admissions. CONCLUSIONS: In this study, SLE disease activity classified by SLE-DAS was significantly associated with an increased risk for both all-cause and SLE-related hospital admissions. Rheumatologists should be vigilant for increased risk of hospital admissions in patients with moderate/high SLE disease activity as classified by SLE-DAS.

Novel strategy in Dengzhan Shengmai capsule metabolites analysis based on the prediction database / 药学学报

Dengzhan Shengmai capsule, as a compound Chinese patent medicine, consists of four herbs: Herba Erigerontis, Ginseng, Ophiopogon, and Schisandrae Chinensis Fructus, and contains significant components of flavonoids, lignans, saponins, and organic acids. It is widely used clinically to treat cerebrovascular diseases such as chronic cerebral hypoperfusion and dementia with remarkable efficacy. This study proposes a research strategy for multi-component traditional Chinese medicine metabolites based on prediction databases and unfolds the analysis using Dengzhan Shengmai capsule as an example. Using the UPLC-Q-TOF/MS method, the analytical method was established and detected biological samples such as urine, feces, and bile of rats before and after administration based on the prediction of theoretical metabolites of Dengzhan Shengmai capsule. The possible secondary fragment ion information of metabolites was identified by comparing the detected results with prediction databases. The metabolites were identified based on the archetypal component mass spectrometric cleavage law and multistage mass spectrometric data. 51 metabolites, mainly flavonoid, organic acid, and lignan constituents, were finally identified from rat biosamples based on 306 theoretical metabolites of Dengzhan Shengmai capsule. This study provides a new strategy for the identification of metabolites in vivo and the analysis of metabolic pathways of TCM. The study complied with the procedures established by the Animal Experiment Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and passed the animal experiment ethics examine (No. 00003645).

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants.

The functional and pharmacological significance of the dopamine D4 receptor (D4R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human DRD4 gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D4R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D4.4R and D4.7R). DRD4 polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D4.7R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D4R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D4R. We review the evidence conveying a significant and differential role of D4.4R and D4.7R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α2A receptor (α2AR)-D4R heteromers and dopamine D2 receptor (D2R)-D4R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D4R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.

Pharmacological targeting of G protein-coupled receptor heteromers.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

HLA-B*27 Heavy Chain Homo-Oligomers Promote the Cytotoxicity of NK Cells via Activation of PI3K/AKT Signaling.

Background and Objectives: Ankylosing spondylitis (AS) is a chronic inflammatory disease and is highly linked with the expression of the human leukocytic antigen-B*27 (HLA-B*27) genotype. HLA-B*27 heavy chain (B*27-HC) has an innate characteristic to slowly fold, resulting in the accumulation of the misfolded B*27-HC and the formation of homo-oligomeric B*27-HC molecules. The homo-oligomeric B*27-HC can act as a ligand of KIR3DL2. Interaction of the homo-oligomeric B*27-HC molecules with KIR3DL2 will trigger the survival and activation of KIR3DL2-positive NK cells. However, the effects of homo-oligomeric B*27-HC molecules associated with KIR3DL2 on the cytotoxic activity of NK cells and their cytokine expressions remain unknown. Materials and Methods: HLA-B*-2704-HC was overexpressed in the HMy2.C1R (C1R) cell line. Western blotting and quantitative RT-PCR were used to analyze the protein expression and cytokine expression, respectively, when C1R-B*-2704 cells that overexpress B*2704-HC were co-cultured with NK-92MI cells. Flow cytometry was used to analyze the cytotoxicity mediated by NK-92MI cells. Results: Our results revealed that NK-92MI cells up-regulated the expression of perforin and enhanced the cytotoxic activity via augmentation of PI3K/AKT signaling after co-culturing with C1R-B*2704 cells. Suppression of the dimerized B*27-HC formation or treatment with an inhibitor of PI3K, LY294002, or with an anti-B*27-HC monoclonal antibody can reduce the perforin expression of NK-92MI after co-culturing with C1R-B*-2704. Co-culturing with C1R-B*-2704 cells suppressed the TNF-α and IL6 expressions of NK-92MI cells. Conclusion: Stimulation of NK cell-mediated cytotoxicity by homo-oligomeric B*27-HC molecules may contribute to the pathogenesis of AS.

Preferential Gs protein coupling of the galanin Gal1 receptor in the µ-opioid-Gal1 receptor heterotetramer.

Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.

A Comparison of the Risk of Fracture in Rheumatoid Arthritis Patients with and without Receiving Chinese Herbal Medicine.

OBJECTIVE: Patients with rheumatoid arthritis (RA) often suffer from bone complications due to persistent joint inflammation, especially incident fracture. Nowadays, Chinese herbal medicines (CHMs) have provided safe and effective therapy for treating skeletal conditions, but it is unclear whether CHMs can prevent fracture onset among RA individuals. This study aimed to determine the association between the use of CHMs and the risk of fracture among them. METHODS: This retrospective, population-based study retrieved administrative health data from the Taiwan National Health Insurance (NHI) database to identify patients with newly diagnosed RA between 2000 and 2009. Of the 6178 incident RA patients, 2495 matched pairs of CHMs users and non-CHMs users were identified by propensity score matching. Enrollees with hip fractures prior to RA onset were excluded. Included subjects were followed until the end of 2013. Incidence and adjusted hazard ratios (HR) of new-onset bone fracture in the multivariable Cox proportional hazard model were measured with 95% confidence interval (CI). RESULTS: Fracture incidence was lower in CHMs users than in the comparison cohort (26.91 vs 32.94 per 1000 person-years, respectively), with an adjusted HR of 0.82 (95% CI: 0.73-0.92). Subjects receiving CHMs for more than 2 years had a much lower risk of fracture onset by more than 50%. Some CHMs prescriptions (Yan Hu Suo, Bei Mu, Da Huang, Dang Shen, Fu-Zi, Shu-Jing-Huo-Xue-Tang, Dang-Gui-Nian-Tong-Tang, Jia-Wei-Xiao-Yao-San, Gan-Lu-Yin, and Gui-Zhi-Shao-Yao-Zhi-Mu-Tang) were associated with reduced fracture risk. CONCLUSION: Adding CHMs to routine treatment was found to be related to lower fracture risk in RA patients.

[Tree-ring reconstruction of March-August drought variability over the past 567 years in the Yajiang region of West Sichuan Plateau, China]. / å·è¥¿é› æ±Ÿåœ°åŒºè¿‡åŽ»567å¹´3­8æœˆå¹²æ—±å˜åŒ–çš„æ ‘è½®é‡å»º.

We constructed standard tree-ring-width chronology of Picea likiangensis var. rubescens for the Larima sampling site in the Ganzi Prefecture, Sichuan Province, by the single-free detren-ding method. The results showed that there was significant and positive correlation between the tree-ring chronology and March-August 1-month scale standardized precipitation and evapotranspiration index (SPEI1) of Yajiang region. The variation of the March-August SPEI1 sequence for 1942-2008 was reconstructed based on the current and last year sequences of the tree-ring chronology, with an explained variation of 42.8%. The newly reconstructed series mainly represented the variation of SPEI1 in the low-frequency domain over the historical period. Three wet periods were found in 1442-1465, 1516-1601 and 1836-2008, while the two intervals were dry periods for the March-August SPEI1 reconstruction in the Yajiang region of West Sichuan Plateau. There was a significant drying trend in 1456-1762 for the reconstructed sequence, a significant wetting trend in 1455-1762, while the wetting trend was the most significant in 1959-2008. Mutation test showed that the sudden changes from dry to wet for the March-August SPEI1 reconstructions occurred in 1512, 1733, 1767, 1831, 1941, 1957 and 1975, while that in 1684 and 1961 was the opposite. The comparison with surrounding region showed a good coherence of variations in the low-frequency domain among the SPEI1 reconstruction for the Yajiang region, the annual precipitation reconstruction for the northeastern Tibetan Plateau, and the SPEI05 reconstruction for the northern slope of the eastern Qilian Mountains. The reconstructed sequence well represented the variation of the March-August SPEI1 in the northeastern Tibetan Plateau and the southern Qinhai Province.

Association between clinical phenotypes of dermatomyositis and polymyositis with myositis-specific antibodies and overlap systemic autoimmune diseases.

ABSTRACT: The aim of this study was to evaluate the association between clinical phenotypes of dermatomyositis (DM) and polymyositis (PM) with myositis-specific antibodies (MSAs), and overlap diagnosis of systemic autoimmune diseases.This cross-sectional study was conducted on 67 patients with DM and 27 patients with PM recruited from a regional hospital in southern Taiwan. Clinical phenotypes of DM and PM were assessed and MSAs were measured using a commercial line blot assay. The association of clinical phenotypes of DM and PM with MSAs and overlap diagnosis of systemic autoimmune diseases was performed using univariate and multiple logistic regression analyses.Clinically, patients with DM and PM and overlap diagnosis of systemic sclerosis were associated with a higher risk of interstitial lung diseases (ILDs) (odds ratio [OR] = 6.73; P = .048), Raynaud phenomenon (OR = 7.30; P = .034), and malignancy (OR = 350.77; P = .013). The risk of malignancy was also associated with older age (OR 1.31; P = .012), and male patients were associated with a higher risk of fever. For MSAs, anti-aminoacyl-tRNA synthetase antibodies were associated with ILD, antinuclear antibody were associated with a lower risk of arthritis, anti-transcription intermediary factor 1-gamma antibodies were associated with milder symptoms of muscle weakness, anti-Ku antibodies were associated with overlap diagnosis of systemic lupus erythematosus, and anti-Ro52 antibodies were associated with the development of Raynaud phenomenon and Sjögren syndrome.MSAs and overlap diagnosis of systemic sclerosis were significantly associated with clinical phenotypes of DM and PM. Physicians should be vigilant for malignancy in older DM and PM patients with overlap diagnosis of systeic sclerosis. The possibility of developing ILD in patients with overlap diagnosis of systemic sclerosis or serum positivity of anti-aminoacyl-tRNA synthetase antibodies should be considered.

Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib.

OBJECTIVES: The aim of this study was to investigate hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving tofacitinib. METHOD: This was a retrospective study performed in a regional teaching hospital in southern Taiwan. During January 2017 and December 2020, patients with a clinician-confirmed diagnosis of RA using tofacitinib for at least 3 months were enrolled. Serum HBV DNA levels and serum alanine aminotransferase were followed up around every 3 to 6 months to assess HBV reactivation. RESULTS: A total of 98 patients with RA were enrolled, and eight were hepatitis B surface antigen positive (HBsAg+) (8.1%), 64 were HBsAg-negative (HBsAg-)/hepatitis B core antibody positive (HBcAb+) (65.3%). In the HBsAg+ patients, two patients received antiviral prophylaxis, and none of them had HBV reactivation or hepatitis flare-up. The HBV reactivation rate was 33.3% (2/6) in the HBsAg+ RA patient without antiviral prophylaxis. Among the HBsAg-/HBcAb+ patients, the HBV reactivation rate was 3.1% (2/64). The incidence rate of HBV reactivation was 153.8 per 1000 person-years for overall HBsAg+ patients and 250 per 1000 person-years after excluding patients receiving antiviral prophylaxis. The incidence rate was 11.2 per 1000 person-years for HBsAg-/HBcAb+ patients with RA receiving tofacitinib. CONCLUSION: Tofacitinib could induce HBV reactivation in both HBsAg+ and HBsAg-/HBcAb+ RA patients. HBsAg+ patients receiving tofacitinib have a high incidence rate of HBV reactivation, which could be prevented by antiviral prophylaxis. Although the risk of reactivation is low in HBsAg-/HBcAb+ patients, closely monitoring HBV DNA and alanine aminotransferase should be suggested.

Association of Traditional Chinese Medicine Body Constitution and Health-Related Quality of Life in Female Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study.

BACKGROUND: Traditional Chinese medicine (TCM) body constitution has been studied in many diseases, but few have focused on systemic lupus erythematosus (SLE) and particularly their association with disease-specific quality of life (QoL). Therefore, the aim of this study was to investigate the association of TCM body constitution and QoL in female patients with SLE. METHODS: A cross-sectional study was conducted on adult female patients with a clinician-confirmed diagnosis of SLE in a regional hospital in Taiwan. TCM body constitution types were determined using the Constitution in Chinese Medicine Questionnaire (CCMQ). Disease-specific QoL of the participants was assessed using the LupusQoL. Multiple linear regression analyses were conducted to assess the associations between TCM body constitution types with the score of each of the eight domains of LupusQoL and between the numbers of multiple unbalanced body constitution types and score of each of the eight domains of LupusQoL. RESULTS: Of the 317 female patients with SLE, 22 (6.9%) were classified to have a gentleness balanced body constitution type. Among the remaining 295 patients with unbalanced body constitution types, Qi-deficiency was the most common (64.4%), followed by Yin-deficiency (57.6%). Multiple linear regression analyses showed that Qi-deficiency was significantly associated with the emotional, pain, and fatigue domains of the LupusQoL, whereas Yin-deficiency was significantly associated with the emotional and fatigue domains of the LupusQoL. In addition, all domains of the LupusQoL showed a general pattern of poorer QoL with increasing numbers of unbalanced body constitution types. CONCLUSIONS: Different TCM body constitution types were significantly associated with various domains of the LupusQoL. A high prevalence of multiple body constitution types in patients with SLE was observed. A consistent pattern of poorer LupusQoL with increasing numbers of unbalanced body constitution types was evident.

[Evaluation of Air Pollution Characteristics and Air Quality Improvement Effect in Beijing and Chengdu].

In recent years, China's air quality has been improving, and the concentration of atmospheric particulate matter has decreased significantly. In this study, the pollution characteristics and trends of two typical representative cities (Beijing and Chengdu) were analyzed. The geographical locations, pollution emissions, and meteorological diffusion conditions of the two cities were compared, to evaluate the relative contribution of meteorological conditions and pollution reduction regulations in decreasing fine particulate matter (PM2.5) concentrations. The results showed that the number of heavily polluted days and pollution episodes in Beijing and Chengdu decreased significantly from 2013 to 2018, and the concentration of SO2 and PM2.5 decreased substantially. Compared to 2013, SO2 concentration in Beijing and Chengdu has decreased by 77.8% and 70.9%, whereas PM2.5 concentration has decreased by 42.7% and 48.5%, respectively. The largest reduction appeared in winter, when PM2.5 decreased at an annual rate of 13.5 µg ·m-3 for Beijing and 14.1 µg ·m-3 for Chengdu. During the study period, the wind speed in Chengdu was less than that in Beijing, temperature was approximately 3℃ higher, and static wind in winter was more frequent. A significantly lower mixed-layer height, atmospheric capacity index, and ventilation coefficient in Chengdu resulted in more unfavorable atmospheric diffusion conditions. The static and stable weather index and the environmental meteorological index (EMI) also showed that the atmospheric diffusion conditions were better in Beijing than in Chengdu. The EMI of the two cities showed a decreasing trend during the study period, and the decline in EMI in Chengdu was the most significant in 2018, indicating an evident improvement in meteorological conditions. In 2018, emission reductions are estimated to have contributed 33.5% and 24% to the decrease in PM2.5 in Beijing and Chengdu, respectively, and meteorological conditions contributed 7.2% and 11.1% to the reduction in these two cities. In winter, emission reductions respectively contributed 31.7% and 32.5% to reduction in Beijing and Chengdu, while meteorological conditions made a larger contribution.

Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.