Astragaloside IV protects against autoimmune myasthenia gravis in rats via regulation of mitophagy and apoptosis.

Astragaloside IV (AS­IV) has various pharmacological effects, including antioxidant and immunoregulatory properties, which can improve myasthenia gravis (MG) symptoms. However, the potential mechanism underlying the effects of AS­IV on MG remains to be elucidated. The present study aimed to investigate whether AS­IV has a therapeutic effect on MG and its potential mechanism of action. By subcutaneously immunizing rats with R97­116 peptide, an experimental autoimmune (EA) MG rat model was established. AS­IV (40 or 80 mg/kg/day) treatment was then applied for 28 days after modeling. The results demonstrated that AS­IV significantly ameliorated the weight loss, Lennon score and pathological changes in the gastrocnemius muscle of EAMG rats compared with the model group. Additionally, the levels of acetylcholine receptor antibody (AChR­Ab) were significantly decreased, whereas mitochondrial function [ATPase and cytochrome c (Cyt­C) oxidase activities] and ultrastructure were improved in the AS­IV treated rats. Moreover, the mRNA and protein expression levels of phosphatase and tensin homolog­induced putative kinase 1, Parkin, LC3II and Bcl­2, key signaling molecules for mitophagy and apoptosis, were upregulated, whereas the mRNA and protein expression levels of p62, Cyt­C, Bax, caspase 3 and caspase 9 were downregulated following AS­IV intervention. In conclusion, AS­IV may protect against EAMG in a rat model by modulating mitophagy and apoptosis. These findings indicated the potential mechanism underlying the effects of AS­IV on MG and provided novel insights into treatment strategies for MG.

PINK1/Parkin pathway-mediated mitophagy by AS-IV to explore the molecular mechanism of muscle cell damage.

BACKGROUND: Functional disorders of mitochondria are closely related to muscle diseases. Many studies have also shown that oxidative stress can stimulate the production of a large number of reactive oxygen species (ROS), which have various adverse effects on mitochondria and can damage muscle cells. PURPOSE: In this study, based on our previous research, we focused on the PINK1/Parkin pathway to explore the mechanism by which AS-IV alleviates muscle injury by inhibiting excessive mitophagy. METHODS: L6 myoblasts were treated with AS-IV after stimulation with hydrogen peroxide (H2O2) and carbonyl cyanide m-chlorophenylhydrazone (CCCP). Then, we detected the related indices of oxidative stress and mitophagy by different methods. A PINK1 knockdown cell line was established by lentiviral infection to obtain further evidence that AS-IV reduces mitochondrial damage through PINK1/Parkin. RESULTS: After mitochondrial damage, the expression of malondialdehyde (MDA) and intracellular ROS in L6 myoblasts significantly increased, while the expression of superoxide dismutase (SOD) and ATP decreased. The mRNA and protein expression levels of Tom20 and Tim23 were decreased, while those of VDAC1 were increased. PINK1, Parkin, and LC3 II mRNA and protein expression increased, and P62 mRNA and protein expression decreased·H2O2 combined with CCCP strongly activated the mitophagy pathway and impaired mitochondrial function. However, abnormal expression of these factors could be reversed after treatment with AS-IV, and excessive mitochondrial autophagy could also be reversed, thus restoring the regulatory function of mitochondria. However, AS-IV-adjusted function was resisted after PINK1 knockdown. CONCLUSION: AS-IV is a potential drug for myasthenia gravis (MG), and its treatment mechanism is related to mediating mitophagy and restoring mitochondrial function through the PINK1/Parkin pathway.

Risk of gout attack not increased in patients with thalassemia: a population-based cohort study.

The incidence of gout arthritis in patients with thalassemia and the association between them was indefinite. We aimed to give epidemiological evidence regarding the association between thalassemia and gout arthritis. This retrospective cohort study extracted data relating to the risk of gout arthritis from patients diagnosed with thalassemia between 2000 and 2013. We selected the control group at a ratio of 1:4 by propensity score matching (PSM). Univariable and multivariable Cox proportional hazard regression models were performed to analyze the association between thalassemia and gout arthritis and to evaluate the hazard ratio (HR) of gout arthritis after exposure with thalassemia. The sensitivity analysis was performed to avoid the mislabeled thalassemia disease, the transfusion-dependent thalassemia was classified to compare the risk of gout arthritis. The secondary outcome for the risk of gout arthritis with antigout drugs treatment was also evaluated between study groups. In the age and sex matched cohort, the majority of thalassemia patients were women (62.03%) and aged younger than 30 years old (44.79%). There were 138 (4.2%) and 500 (3.8%) incident cases of gout arthritis in the thalassemia and non-thalassemia group. After PSM, the incidence rate, per 100 person-years, of gout arthritis was 0.48 (95% CI 0.42 to 0.56) and 0.60 (95% CI 0.51 to 0.72) in non-thalassemia individuals and patients with thalassemia, respectively. In the Cox proportional hazard regression, patients with thalassemia had no significant increase in the risk of gout arthritis (adjusted HR, 1.00; 95%CI: 0.80 to 1.25) after adjusting demographic variables and comorbidities. The Kaplan-Meier curve showed that the cumulative incidence of gout arthritis was not a significant difference in the thalassemia group than in the comparison group (p > 0.05). The sensitivity analysis showed the consistent results about the risk of gout arthritis in patients with thalassemia. Our study indicated that there was no significant increase in the risk of gout arthritis in subjects with thalassemia.Future research needs to clarify the biological mechanisms behind this connection.

Sanfu herbal patch applied at acupoints in patients with bronchial asthma: statistical analysis plan for a randomised controlled trial.

BACKGROUND: Sanfu herbal patch (SHP) is widely used in the prevention and treatment of bronchial asthma in China, but its efficacy and mechanism of action are not completely clear. This trial aims to determine the efficacy of SHP and the underlying mechanism. METHODS/DESIGN: We will conduct a multi-centre parallel randomised controlled trial consisting of 72 participants with bronchial asthma recruited and randomly allocated at a ratio of 1:1 into two groups. The patients in one group will receive three courses of SHP treatment, and the patients in the other group will receive placebo treatment, with 24 weeks of follow-up evaluation for both groups. The primary outcome, i.e. forced expiratory volume in the first second (FEV1), which refers to the change in FEV1 from the beginning of the baseline to the end of 3 treatment sessions (TSs), will be assessed and compared via Student's t test or the Mann-Whitney U test. Other outcomes will include questionnaire surveys and laboratory indicators. Detailed and complete statistical analyses in a double-blinded fashion will be provided for evaluating this trial. DISCUSSION: The data we obtain will be examined based on the above statistical analysis, which will help to reduce the risk of external reporting bias and data-driven results. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR1900024616. Registered on 19 July 2019.

A rare radiotherapy-sensitive primitive neuroectodermal tumor with APC gene amplification in an adult: a case report and literature review.

Primitive neuroectodermal tumor (PNET) of the lung is rare in adults, and treatment options vary. We herein describe the disease course and follow-up of PNET in an adult. A 27-year-old man was admitted to our hospital because of cough and headache, and whole-exome sequencing revealed positive expression of the EWSR1-FLI1 fusion gene and amplification of the APC gene. Although the patient received multidisciplinary treatment including chemotherapy regimens of etoposide plus cisplatin; focal radiotherapy focusing on the cerebrum, lung, and kidneys; and a subsequent palliative gastrointestinal operation, he eventually died of multiple organ functional failure. His overall survival period was 18 months, and his progression-free survival period was 4 months. During the treatment, the patient showed remarkable sensitivity to radiotherapy. In conclusion, PNET of the lung in adult patients is extremely rare, and the prognosis is very poor. Involvement of a multidisciplinary team in the development of personalized therapeutic strategies is essential. This patient with APC gene amplification showed excellent sensitivity to radiotherapy for intrapulmonary and intracranial lesions, suggesting that APC gene amplification may be related to radiotherapy sensitivity. However, further clinical research is needed.

Tofacitinib Treatment of Refractory Cutaneous Leukocytoclastic Vasculitis: A Case Report.

Introduction: To date, there is no treatment with proven efficacy for cutaneous leukocytoclastic vasculitis (CLV). Several reports have suggested that CLV responds favorably to corticosteroids, colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), azathioprine, and hydroxychloroquine (HCQ). To the best of our knowledge, the oral small molecule Janus kinase inhibitor, tofacitinib, plays an important role in the treatment of autoimmune and inflammatory diseases. Therefore, tofacitinib may be a prospective therapy in patients with CLV. Case Presentation: A 29-year-old woman presented to our hospital with a 5-year history of symmetric skin lesions mainly affecting both lower extremities. The results for anti-neutrophil cytoplasmic antibodies (ANCA), anti-extracted nuclear antigens (ENA) autoantibodies, anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies, and antinuclear antibodies (ANA) were all negative. The definite diagnosis of CLV was determined by a skin biopsy. However, the patient exhibited a poor response to prednisone, HCQ, methotrexate, colchicine, azathioprine, and tripterygium wilfordii polyglycoside tablets (TGTs) treatments. She was then treated with oral tofacitinib (5 mg twice daily) and oral prednisone (25 mg daily). Outcomes: Her skin lesions gradually improved over a period of 4 weeks. Two months later, the skin ulcers completely resolved. No evidence of recurrence of skin ulcers was observed during a 6-month follow-up. Conclusion: We present the first case of a female patient receiving short-term tofacitinib therapy for refractory CLV. Tofacitinib may be a promising oral alternative for patients with CLV. However, its efficacy and safety require further appraisal through clinical trials.

Association between neutrophils and renal impairment of rheumatoid arthritis: A retrospective cross-sectional study.

OBJECTIVE: Previous studies have shown that increased neutrophils, as a manifestation of oxidative stress, may be involved in the progression of kidney disease. To our knowledge, little is known about the relationship between neutrophils and renal impairment in rheumatoid arthritis (RA). Therefore, we aim to investigate whether neutrophil is associated with renal impairment in RA patients. METHODS: We retrospectively investigated the renal function of 602 RA patients in the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine by estimated glomerular filtration rate (eGFR) from September 2018 and September 2019. The exposure variable was neutrophils, and the main outcome was eGFR. General data (gender, age, duration, hypertension, diabetes, hobbies, and medication history), whole blood markers, lipid indexes, and inflammatory indexes were collected as much as possible. We used multivariable logistic regression analysis to evaluate the association between neutrophils and renal impairment in RA participants. RESULTS: A total of 89 cases (14.8%) had renal impairment with eGFR < 60 ml/min/1.73 m2 , and 75 cases (84.3%) were female. Subgroup analysis showed that female (odds ratio [OR] = 0.523, 95% confidence interval [CI]: 0.318-0.867, p = .011), neutrophils greater thsn 7.5 × 109 /L (OR = 2.314, 95% CI: 1.310-4.087, p = .004), NLR > 3.53 (OR = 1.757, 95% CI: 1.104-2.799, p = .018), hemoglobin less than 120 g/L (OR = 2.413, 95% CI: 1.418-4.118, p = .001), and UA > 360 µmol/L (OR = 6.052, 95% CI: 3.708-9.878, p < .001) was related to renal damage in RA. Adjusted for several confounders, the multivariable analysis indicated that neutrophils greater than 7.5 × 109 /L (OR = 1.784, 95% CI: 1.164-3.288, p = .031) was independently associated with an increased risk of renal impairment in RA. CONCLUSION: Our study demonstrated that neutrophils greater than 7.5 × 109 /L was associated with a high risk of renal impairment in RA, suggesting that neutrophil may be a biomarker for renal impairment in RA.

Camrelizumab-Related Myocarditis and Myositis With Myasthenia Gravis: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have substantially changed the treatment of a variety of malignant tumors. With the increasing of their usage, the unique immune-mediated toxicity profile of ICIs has become apparent. We report a case of esophageal squamous cell carcinoma in a patient who received anti-programmed cell death protein 1 (PD-1) (camrelizumab) therapy and the occurrence of sequential immune-related adverse events (irAEs). Although many irAEs have been reported, severe myositis caused by camrelizumab with simultaneous involvement of multiple organs, including the myocardium, respiratory muscles, and skeletal muscles, has rarely been described in literature. This 69-year-old male patient developed a grade 4 camrelizumab-induced adverse reaction according to the Common Terminology Criteria for Adverse Events (CTCAE) and was successfully treated with methylprednisolone and immunoglobulins. The early identification of irAEs, immediate discontinuation of immunotherapy, use of steroids and/or immunosuppressants, and adjuvant supportive treatment are critical to the clinical prognosis of patients. It should be aware that autoimmune complications can occur even when ICI treatment is ceased.

Need for Greater Attention to Joint Damage in Rhupus Patients: Results from an Ultrasound Study.

BACKGROUND The aim of this study was to evaluate the prevalence of inflammation and bone destruction of hand joints in rhupus patients through ultrasound examination. MATERIAL AND METHODS Ten rhupus patients and 33 systemic lupus erythematosus (SLE) patients with hand arthropathy were recruited in this single-center study, and the clinical features and ultrasound manifestations of these patients were analyzed. RESULTS We discovered that rhupus patients were older (47.31±4.35 years vs. 38.58±2.50 years, P=0.040), had longer duration of disease (median 72 months vs. median 12 months, P=0.040), had a higher positive rate (70% vs. 10.71%, P<0.001), and had higher titers of anti-CCP antibody (42.633±14.520 vs. 2.121±0.970, P<0.001) than SLE patients with arthropathy. More importantly, the prevalence rates of synovial hyperplasia (90% vs. 42.42%, P=0.008), synovitis (90% vs. 18.18%, P<0.001), synovial hyperplasia (70% vs. 10.71%, P<0.001), and bone destruction (70% vs. 6.06%, P<0.001) were higher in rhupus patients than in SLE patients with arthropathy. CONCLUSIONS Rhupus patients are more prone to develop synovitis, synovial hyperplasia, and bone destruction. Therefore, more attention should be paid to protection of the joints in rhupus patients.

Use of the Gout Impact Scale to Evaluate Quality of Life in Chinese Subjects with Gout: A Cross-Sectional Study.

BACKGROUND To use a gout-specific quality of life (QoL) tool, the Gout Impact Scale (GIS), to evaluate characteristics of gout affecting QoL in subjects with gout. MATERIAL AND METHODS In this cross-sectional study, 169 individuals with gout completed the 24-item GIS and a general questionnaire regarding gout characteristics. The reliability and validity of the GIS were verified by Cronbach's a and exploratory factor analysis, respectively. The impact of gout characteristics on the QoL of subjects with gout was assessed by stepwise multiple regression analysis. RESULTS The 169 subjects with gout included 149 (88.2%) men and 20 (11.8%) women, of median age 43 years. The reliability of the GIS was appropriate (0.84-0.90), except for Gout Medication Side Effects (0.69) and Unmet Gout Treatment Need (0.59). Exploratory factor analysis showed that construct validity was acceptable, with a cumulative variance contribution rate of 5 common factors of 70.09% and factor loading >0.5 between each pair of items of the GIS. Univariate analysis showed that male sex was positively correlated with Well-being During Attack (p<0.05), and that source of medical expenses, current cigarette use and drinking were significantly correlated with Unmet Gout Treatment Need (p<0.05 each). A family history of gout, gout flares, and attack frequency were significantly correlated with total GIS, Well-being During Attack, and Gout Concern during Attack (p<0.05 each). Multivariate analysis suggested that history of gouty arthritis, acute attack and attack frequency had a considerable impact on QoL (p<0.05 each). CONCLUSIONS The GIS showed acceptable reliability and validity in identifying associations between poor QoL and gout characteristics.

Chinese Herbal Medicines and Conventional Chronic Heart Failure Treatment for the Management of Chronic Heart Failure Complicated with Depression: A Systematic Review and Meta-Analysis.

BACKGROUND: Combination therapy with Chinese herbal medicines (CHMs) and conventional medical treatment (CMT) was proposed as a therapeutic strategy for chronic heart failure (CHF) patients complicated with depression. Therefore, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess effects of this combination therapy on CHF complicated with depression. METHODS: RCTs comparing the combination of CHMs and CMT to CMT were retrieved in seven electrical databases till March 30, 2019. The effective rate of cardiac function and Hamilton depression scale (HAMD) were marked as the primary outcomes. Left ventricular ejection fraction (LVEF) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) were marked as the secondary outcomes. The methodological quality of eligible RCTs used the Cochrane bias risk assessment tool. Stata 13.0 and Review Manager 5.3 were preferred for synthesizing the results if the results were appropriate. RESULTS: Thirteen RCTs enrolling 1022 subjects met the inclusion criteria. The majority of the retrieved RCTs were evaluated to be of low methodological quality. The pooled results of the meta-analysis showed that CHMs plus CMT group created better outcomes compared to CMT alone therapy, as evidenced by the fact that the overall effects of combination therapy strategy were significantly greater than the control group in increasing effective rate of cardiac function (risk ratio (RR) = 1.28; 95% CI: 1.16 to 1.42), in improving depressive symptoms (HAMD) (standard mean difference (SMD) = -1.31; 95% CI: -1.68 to -0.95) and quality of life (MLHFQ) (weighted mean difference (WMD) = -8.42; 95% CI: -10.08 to -6.76), in increasing LVEF scores (WMD = 5.33; 95% CI: 4.30 to 6.35). CONCLUSION: The combination of CHMs and CMT increased the effective rate of cardiac function and LVEF scores and reduced HAMD and MLHFQ scale scores, which was a potential therapeutic strategy that improved the management of CHF patients complicated with depression. Future trials were needed to verify the above results since abnormal heterogeneity and poor quality of literature have existed in the included studies.

Serum Uric Acid Shows Inverted "U" Type Correlation with Osteoporosis in Chinese Ankylosing Spondylitis Patients: A Retrospective Study.

BACKGROUND This study was to investigate the correlation between osteoporosis and serum uric acid in ankylosing spondylitis (AS) patients, and to further identify potential factors that might be associated with osteoporosis in AS patients. MATERIAL AND METHODS We included 182 AS patients, consisted of 143 male patients and 39 female patients, who visited our hospital from January 1, 2014 to December 31, 2018. We used dual-energy x-ray absorptiometry to measure bone mineral density (BMD) of orthotopic lumbar vertebrae in patients with AS. The gender, age, disease duration, BMD, T-score, Z-score, uric acid, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood platelet (PLT), and status of treatment with biologics of the patients were collected. Then, the Spearman correlation coefficient and multivariate liner regression analysis were applied to identify the relationship between the factors and BMD, T-score, and Z-score in AS patients. RESULTS Male AS patients between the ages of 16 and 30 years old had a higher risk of osteoporosis (P<0.05). AS patients with uric acid value between 300-360 µmol/L had the highest BMD, T-score, and Z-score. The BMD had a positive correlation with age and disease duration (P<0.01) while had a negative correlation with PLT (P<0.05). BMD in AS patients with elevated ESR was significantly (P<0.05) lower than in AS patients with normal ESR. There were no significant differences in BMD between AS patients with elevated CRP and the patients with normal CRP and PLT. Treatment with TNFi (tumor necrosis factor alpha inhibitor) did not improve BMD in AS patients. CONCLUSIONS The relationship between uric acid and BMD in AS patients was observed as inverted "U"-type. Keeping uric acid within 300-360 µmol/L might be helpful in preventing AS patients from developing osteoporosis.