Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies.

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.

Contribution of relapse-associated worsening to overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis.

OBJECTIVE: The neurological disability accumulation in patients with relapsing-onset multiple sclerosis (MS) is commonly attributed to relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Using a mediation model, this research aimed to investigate and quantify the contributions of RAW and PIRA to the overall disability accrual. METHODS: Clinical data, containing Expanded Disability Status Scale (EDSS) scores, duration, attack number, and demographics, were collected from 121 patients with relapsing-onset MS in China and included in the mediation model. Two phases were defined: an early phase, from the clinical onset to EDSS 3, and a later phase, greater than EDSS 3. RESULTS: Clinical attack number partly mediated the relationship between duration and neurological disability (Duration â†’ Attack â†’ EDSS score) only in the early phase, with the ratio of indirect (RAW) to total effect of 0.414; while this mediator effect became negligible (<10%) in the later phase, with a predominating direct effect (PIRA). Onset age positively correlated with EDSS scores during the early stage, independent of the clinical attack number (the direct effect was significant, but the indirect effect was not), while this association was insignificant later. Besides, compared to females, male patients appeared to relapse less frequently before reaching EDSS 3 but were vulnerable to an accelerated progression after that. CONCLUSIONS: In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course, albeit RAW is also partly involved during the early stage. The correlations between the disabled outcome and the onset age or sex vary in different phases.

Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.

OBJECTIVE: The immunological features between neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), lacked systemic comparisons. Accordingly, we aimed to investigate immunological differences between NMOSD, MS, and MOGAD. METHODS: Patients with MOGAD, MS, and NMOSD who received immunological tests including cytokine profiles and cytometry analysis of the lymphocyte subgroups were retrospectively reviewed and divided into training and validation sets. Discriminatory models based on immunological data were established to identify optimal classifiers using orthogonal partial least square discriminant analysis (OPLS-DA). Constructed models were tested in another independent cohort. RESULTS: OPLS-DA of the immunological data from 50 patients (26 NMOSD, 14 MS, and 10 MOGAD) demonstrated the discriminatory values of a relatively low level of T-lymphocyte subsets, especially the CD4+ T cells, in MOGAD; a decreased NK cell, eosinophil, and lymphocyte level; an elevated neutrophil-to-lymphocyte ratio in NMOSD; and a declined IFN-γ-producing CD4+ T cells/Th with an increased IL-8 concentration in MS. All the models (NMOSD vs. MS, NMOSD vs. MOGAD, and MS vs. MOGAD) exhibited a significant predictive value and accuracy (>85%). CONCLUSIONS: NMOSD, MS, and MOGAD may be different in pathogenesis, and several immunological biomarkers can serve as potential classifiers clinically.

Characteristics of immune and inflammatory responses among different age groups of pediatric patients with COVID-19 in China.

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) among pediatric patients are more common in children less than 1 year of age. Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients. METHODS: We recruited pediatric patients confirmed of moderate COVID-19 symptoms, admitted to Wuhan Children's Hospital from January 28th to April 1st in 2020. Patients were divided into four age groups (≤ 1, 1-6, 7-10, and 11-15 years). Demographic information, clinical characteristics, laboratory results of lymphocyte subsets test, immune and inflammation related markers were all evaluated. RESULTS: Analysis included 217/241 (90.0%) of patients with moderate clinical stage disease. Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years (P = 0.001). Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old (P < 0.01). CD19+ B cells were the only significantly elevated immune cells, especially among patients under 1 year old (cell proportion: n = 12, 30.0%, P < 0.001; cell count: n = 13, 32.5%, P < 0.001). While, low levels of immune related makers, such as immunoglobulin (Ig) G (P < 0.001), IgA (P < 0.001), IgM (P < 0.001) and serum complement C3c (P < 0.001), were also mostly found among patients under 1 year old, together with elevated levels of inflammation related markers, such as tumor necrosis factor γ (P = 0.007), interleukin (IL)-10 (P = 0.011), IL-6 (P = 0.008), lactate dehydrogenase (P < 0.001), and procalcitonin (P = 0.007). CONCLUSION: The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.

Clinical characteristics of sleep disorders in patients with Parkinson's disease.

In order to investigate the sleep quality and influencing factors in patients with Parkinson's disease (PD), 201 PD patients were enrolled and underwent extensive clinical evaluations. Subjective sleep evaluation was assessed using the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). It was found that poor sleep quality (77.11%) and excessive daytime sleepiness (32.34%) were commonly seen in PD patients and positively correlated with disease severity. Then 70 out of the 201 PD patients and 70 age- and sex-matched controls underwent a polysomnographic recording. The parameters were compared between PD group and control group and the influencing factors of sleep in PD patients were analyzed. The results showed that sleep efficiency (SE) was significantly decreased (P<0.01), and sleep latency (SL) and the arousal index (AI) were increased (P<0.05) in the PD group as compared with those in the control group. SE and total sleep time (TST) were positively correlated with the Hoehn and Yahr (H&Y) stage. There was significant difference in the extent of hypopnea and hypoxemia between the PD group and the control group (P<0.05). Our results indicate that PD patients have an overall poor sleep quality and a high prevalence of sleep disorder, which may be correlated with the disease severity. Respiratory function and oxygen supply are also affected to a certain degree in PD patients.

Clinical Characteristics of Sleep Disorders in Patients with Parkinson's Disease / 华中科技大学学报（医学）（英德文版）

In order to investigate the sleep quality and influencing factors in patients with Parkinson's disease (PD),201 PD patients were enrolled and underwent extensive clinical evaluations.Subjective sleep evaluation was assessed using the Pittsburgh Sleep Quality Index (PSQI),and the Epworth Sleepiness Scale (ESS).It was found that poor sleep quality (77.11％) and excessive daytime sleepiness (32.34％) were commonly seen in PD patients and positively correlated with disease severity.Then 70 out of the 201 PD patients and 70 age-and sex-matched controls underwent a polysomnographic recording.The parameters were compared between PD group and control group and the influencing factors of sleep in PD patients were analyzed.The results showed that sleep efficiency (SE) was significantly decreased (P＜0.01),and sleep latency (SL) and the arousal index (AI) were increased (P＜0.05) in the PD group as compared with those in the control group.SE and total sleep time (TST) were positively correlated with the Hoehn and Yahr (H&Y) stage.There was significant difference in the extent of hypopnea and hypoxemia between the PD group and the control group (P＜0.05).Our results indicate that PD patients have an overall poor sleep quality and a high prevalence of sleep disorder,which may be correlated with the disease severity.Respiratory function and oxygen supply are also affected to a certain degree in PD patients.

αν and ß1 Integrins mediate Aß-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

αν and ß1 integrins mediate Aß-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 µg/mL 17E6 and 5 µg/mL ab58524, which are specific αν and ß1 integrin antagonists, respectively, for 42 h prior to 10 µM Aß treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 µg/mL polybrene. Under these conditions, the neurons were transfected and the apoptosis of different cell types was detected. Moreover, we used real-time PCR and Western blotting analyses to detect the expression of FAK and ρFAK genes in different cell types and investigated the underlying mechanism and signal pathway by which αν and ß1 integrins mediate Aß-induced neurotoxicity in hippocampal neurons. An MTT assay showed that both 17E6 and ab58524 significantly increased cell viability compared with the Aß-treated neurons (P<0.01 and P<0.05, respectively). However, this protective effect was markedly attenuated after transfection with silencing FAK (siFAK). Moreover, TUNEL immunostaining and flow cytometry indicated that both 17E6 and ab58524 significantly protected hippocampal neurons against apoptosis induced by Aß (P<0.05) compared with the Aß-treated cells. However, this protective effect was reversed with siFAK treatment. Both the gene and protein expression of FAK increased after Aß treatment. Interestingly, as the gene and protein levels of FAK decreased, the ρFAK protein expression markedly increased. Furthermore, both the gene and protein expression of FAK and ρFAK were significantly diminished. Thus, we concluded that both αν and ß1 integrins interfered with Aß-induced neurotoxicity in hippocampal neurons and that this mechanism partially contributes to the activation of the Integrin-FAK signaling pathway.