Long-term and low-dose rituximab treatment for chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To evaluate the efficacy and safety of a low-dose, long-term rituximab regimen in the treatment of idiopathic CIDP. METHODS: This study included 15 CIDP patients treated with rituximab. Patients were administered 600 mg of rituximab intravenously every 6 months. Baseline evaluation was conducted before the initiation of rituximab treatment and subsequent evaluations were conducted 6 months after each rituximab infusion at on-site visits. Clinical improvement was objectively determined by improvement of scale score at least decrease ≥1 INCAT or mRS or increase ≥4 MRC or ≥8 cI-RODS after each infusion compared to baseline evaluation. RESULTS: Fifteen CIDP patients were included and 10 of them were typical CIDP and five were distal CIDP. Nine in 15 (60%) patients after first infusion and three in six (50%) patients after second infusion exhibited significant clinical improvement compared to baseline evaluation. Additionally, rituximab facilitated a reduction or cessation of other medications in 73% of patients at last visit. The safety profile was favorable, with no reported adverse events. CONCLUSION: Rituximab presents a promising therapeutic option for idiopathic CIDP, offering both efficacy and safety with a low-dose, long-term regimen.

Insights into refractory chronic inflammatory demyelinating polyneuropathy: a comprehensive real-world study.

Background: Refractory chronic inflammatory demyelinating polyneuropathy (CIDP) is a challenging subset of CIDP. It does not respond well to immune therapy and causes substantial disability. A comprehensive understanding of its clinical profile, electrophysiological characteristics and potential risk factors associated with refractoriness remains to be further elucidated. Methods: Data in this cross-sectional study was collected and reviewed from the Huashan Peripheral Neuropathy Database (HSPN). Included patients were categorized into refractory CIDP and non-refractory CIDP groups based on treatment response. The clinical and electrophysiological characteristics were compared between refractory and non-refractory CIDP groups. Potential risk factors associated with refractory CIDP were explored with a multivariate logistic regression model. Results: Fifty-eight patients with CIDP were included. Four disease course patterns of refractory CIDP are described: a relapsing-remitting form, a stable form, a secondary progressive form and a primary progressive form. Compared to non-refractory CIDP patients, refractory CIDP exhibited a longer disease duration (48.96 ± 33.72 vs. 28.33 ± 13.72 months, p = 0.038) and worse functional impairment (MRC sum score, 46.08 ± 12.69 vs. 52.81 ± 7.34, p = 0.018; mRS, 2.76 ± 0.93 vs. 2.33 ± 0.99, p = 0.082; INCAT, 3.68 ± 1.76 vs. 3.03 ± 2.28, p = 0.056, respectively). Electrophysiological studies further revealed greater axonal impairment (4.15 ± 2.0 vs. 5.94 ± 2.77 mv, p = 0.011, ulnar CMAP) and more severe demyelination (5.56 ± 2.86 vs. 4.18 ± 3.71 ms, p = 0.008, ulnar distal latency, 7.94 ± 5.62 vs. 6.52 ± 6.64 ms, p = 0.035, median distal latency; 30.21 ± 12.59 vs. 37.48 ± 12.44 m/s, p = 0.035, median conduction velocity; 58.66 ± 25.73 vs. 42.30 ± 13.77 ms, p = 0.033, median F-wave latency), compared to non-refractory CIDP. Disease duration was shown to be an independent risk factor for refractory CIDP (p < 0.05, 95%CI [0.007, 0.076]). Conclusion: This study provided a comprehensive description of refractory CIDP, addressing its clinical features, classification of clinical course, electrophysiological characteristics, and prognostic factors, effectively elucidating its various aspects. These findings contribute to a better understanding of this challenging subset of CIDP and might be informative for management and treatment strategies.

Effectiveness and safety of rituximab in autoimmune nodopathy: a single-center cohort study.

Autoimmune nodopathy is a peripheral neuropathy characterized by acquired motor and sensory deficit with autoantibodies against the node of Ranvier or paranodal region in the peripheral nervous system. The clinical and pathological characteristics of the disease are distinct from that of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and the standard treatment for CIDP is partially effective. Rituximab is a chimeric monoclonal antibody which binds and depletes B cells in peripheral blood. This prospective observational study included 19 patients with autoimmune nodopathy. Participants received intravenous rituximab treatment 100 mg the first day and 500 mg the next day and given every 6 months. The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, Inflammatory Rasch-Built Overall Disability Scale (I-RODS), Medical Research Council (MRC) sum score, and Neuropathy Impairment Score (NIS) were collected at entry and before the rituximab infusion every 6 months. At the last visit, 94.7% (18/19) of the patients showed clinical improvement on either the INCAT, I-RODS, MRC, or NIS scale. After the first infusion, 9 patients (47.7%) showed improvement on the INCAT score, and 11 patients (57.9%) on cI-RODS. In patients who received more than one rituximab infusion, the improvement of INCAT score and cI-RODS at the last assessment was higher than that after the first infusion. We also observed tapered or withdrawn concomitant oral medications in these patients.

Bone Marrow Mesenchymal Stem Cell Exosome Attenuates Inflammasome-Related Pyroptosis via Delivering circ_003564 to Improve the Recovery of Spinal Cord Injury.

Bone marrow mesenchymal stem cell (BMSC) is previously reported to present a certain effect on treating spinal cord injury (SCI), while the underlying mechanism is largely uncovered. Therefore, the current study aimed to investigate the involvement of exosome-delivered circRNA profile in the BMSC's effect on pyroptosis for SCI treatment. H2O2 treated rat primary neurons were cultured with normal medium, BMSC, BMSC plus GW4869, and BMSC-derived exosome, respectively, then inflammasome-related pyroptosis markers, and circRNA profiles were detected. Subsequently, circ_003564-knockdown BMSC exosome was transfected into H2O2 treated rat primary neurons and NGF-stimulated PC-12 cells. Furthermore, in vivo validation was conducted. BMSC and BMSC-derived exosome both decreased inflammasome-related pyroptosis markers including cleaved caspase-1, GSDMD, NLRP3, IL-1ß, and IL-18 in H2O2-treated neurons, while exosome-free BMSC (BMSC plus GW4869) did not obviously reduce these factors. Microarray assay revealed that BMSC (vs. exosome-free BMSC) and BMSC-derived exosome (vs. normal medium) greatly regulated circRNA profiles, which were enriched in neuroinflammation pathways (such as neurotrophin, apoptosis, and TNF). Among three functional candidate circRNAs (circ_015525, circ_008876, and circ_003564), circ_003564 was most effective to regulate inflammasome-related pyroptosis. Interestingly, circ_003564-knockdown BMSC exosome showed higher expression of inflammasome-related pyroptosis markers compared to negative-control-knockdown BMSC exosome in H2O2 treated primary neurons/NGF-stimulated PC-12 cells. In vivo, BMSC exosome improved the function recovery and decreased tissue injury and inflammasome-related pyroptosis in SCI rats, whose effect was attenuated by circ_003564 knockdown transfection. BMSC exosome attenuates inflammasome-related pyroptosis via delivering circ_003564, contributing to its treatment efficacy for SCI.

MiR-487b suppressed inflammation and neuronal apoptosis in spinal cord injury by targeted Ifitm3.

Spinal cord injury (SCI) was a serious nerve injury, which involves complex genetic changes. This paper was intended to investigate the function and mechanism of differentially expressed genes in SCI. The three datasets GSE92657, GSE93561 and GSE189070 of SCI from GEO database were used to identify differentially expressed genes (DEGs). We identified the common DEGs in the three datasets GSE92657, GSE93561 and GSE189070 of SCI from GEO database. Next, a protein-protein interaction (PPI) network of DEGs was constructed. Subsequently, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were significantly enriched in immune response, inflammatory response. The expression level of immune-related genes (Arg1, Ccl12, Ccl2, Ifitm2, Ifitm3, and et al.) at different time points of SCI were analyzed in GSE189070 dataset. Next, differentially expressed miRNAs (DE-miRNAs) were identified in SCI compared with normal based on GSE158194 database. DE-miRNA and targeted immune-related genes were predicted by miRwalk, including miR-487b-5p targeted Ifitm3, miR-3072-5p targeted Ccl3, and et al. What's more, the miR-487b was identified and verified to be down-regulated in Lipopolysaccharide (LPS)-induced BV-2 cell model. Further, the miR-487b inhibited cell inflammation and apoptosis in LPS-induced BV2 cell by targeted Ifitm3. For the first time, our results revealed that miR-487b may play an important regulatory role in SCI by targeted Ifitm3 and provide further evidence for SCI research.

Peptidomics Analysis Reveals Serum Biomarkers in Spinal Cord Injury Patients.

Spinal cord injury (SCI) is a severe traumatic disease, always resulting in neuronal injury. In this study, we aimed to exhibit a peptidome profile of serum from patients with SCI. A label-free peptidomics strategy was used to analyze the differentially expressed peptides (DEPs). Then, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses was used to evaluate the function of the peptides precursors proteins. Also, the protein-protein interaction networks were mapped using STRING database. Finally, parallel reaction monitoring assays were used to validate the expression of candidate peptides. We identified 217 DEPs including 29 upregulated peptides and 188 downregulated peptides in SCI group. Many pathways such as Platelet activation, Complement and coagulation cascades, Focal adhesion were enriched. Seven peptides including PSPRPSP, RPPGFSP, DKPDMAEIEKFDKSKLK, STTAVVTNPKE, GHAGAQGPPGPPG, SMPPAQQQITS and SKVLPIQDNVSK were significantly changed between SCI patients and healthy people. Peptidomics provide a powerful tool to find the variation of SCI. RPPGFSP, DKPDMAEIEKFDKSKLK and SMPPAQQQITS may play important roles in SCI. However, the specific function of these peptides and whether they can be used as therapeutic targets for SCI need to be further investigated.

Circ-Usp10 promotes microglial activation and induces neuronal death by targeting miRNA-152-5p/CD84.

Spinal cord injury (SCI) is a traumatic disease resulting in neuronal injury. circRNAs are closely associated with human diseases. Nevertheless, the potential mechanism by which circRNAs impact SCI remains to be elucidated. The aim of this study was to investigate the regulatory roles of Circular RNAs (circRNAs) in SCI. The SCI mouse model and integrated bioinformatics analysis were used to identify the differentially expressed genes (DEGs). Functional enrichment analysis was conducted to study the related pathways. The circRNA-mediated ceRNA network and subnetwork was constructed based on circMir, TargetScan and miRanda. qRT-PCR, ELISA, flow cytometry, and luciferase reporter assays were carried out to validate the role of circ_0014637 (circ-Usp10) and microRNA(miR)-152-5p /CD84 in microglia. In all, 23 DE-circRNAs, 127 DE-miRNAs and 1327 DE-mRNAs were identified. We integrated these DEGs to construct a circRNA-miRNA-mRNA network. The circ-Usp10/miR-152-5p/CD84 axis was found to function in microglial activation. We also found that circ-Usp10 inhibited the secretion of proinflammatory factors in microglial BV2 cells. In addition, silencing circ-Usp10 significantly reduced the death of the neuronal cell line HT22. Taken together, we concluded that circ-Usp10 may function as a competing endogenous RNA (ceRNA) to promote microglial activation and induce neuronal death by targeting miR-152-5p/CD84. The circ-Usp10 may be a diagnostic biomarker and potential target for SCI therapy.

MR neurography of lumbosacral nerve roots: Diagnostic value in chronic inflammatory demyelinating polyradiculoneuropathy and correlation with electrophysiological parameters.

PURPOSE: MR neurography(MRN) is an advanced imaging technique to visualize peripheral nerves. Our aim was to determine the value of morphological features of lumbosacral nerve roots on MRN in diagnosing chronic inflammatory demyelinating polyradiculoneuropathy(CIDP) and analyze their correlations with electrophysiological parameters. METHODS: MRN of lumbosacral plexus was performed in 21 CIDP patients and 21 healthy volunteers. The cross-sectional areas(CSAs) and signal intensities(SI) of L3 to S1 nerve roots were measured and compared between two groups. Receiver operating characteristic(ROC) curves were plotted to assess the diagnostic accuracy. All patients also underwent nerve conduction studies. Correlations between CSAs and SI of lumbosacral nerve roots and electrophysiological parameters were analyzed. RESULTS: Compared with control group, CIDP patients showed significantly increased CSAs and SI from L3 to S1 nerve root (P < 0.001 and P < 0.05 respectively for all nerve roots). The CSAmean and SImean were 28.04 ± 8.55mm2, 1.314 ± 0.199 for patient group and 14.91 ± 2.36mm2,1.155 ± 0.094 for control group. ROC analysis revealed the best diagnostic accuracy for the CSAmean with an area under the curve of 0.968 and optimal cut-off value of 19.20 mm2. CSAs of L5 or S1 nerve root correlated positively with central latency and negatively with conduction velocity of tibial nerve. SI of L5 also had a positive correlation with latency of sural nerve. CONCLUSIONS: Evaluation of lumbosacral nerve roots on MRN in a quantitative manner may serve as an important tool to support the diagnosis of CIDP.

Effect of fasudil on experimental autoimmune neuritis and its mechanisms of action

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.

Effect of fasudil on experimental autoimmune neuritis and its mechanisms of action.

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.

Comparing the role of Ginkgolide B and Ginkgolide K on cultured astrocytes exposed to oxygen­glucose deprivation.

Ginkgolide B (GB) and ginkgolide K (GK) are two main active monomers of ginkgolides that present a unique group of diterpenes found naturally in the leaves of the Ginkgo biloba tree. Astrocytes are the most abundant cell type within the central nervous system (CNS) and serve essential roles in maintaining healthy brain function. The present study compared the biological effects of GB and GK on astrocytes exposed to oxygen­glucose deprivation (OGD). The results demonstrated that GB and GK exhibit many different actions. The level of the platelet­activating factor (PAF) was elevated on astrocytes exposed to OGD, and inhibited by GB and GK treatment. Although GB and GK inhibited the expression of p­NF­κB/p65, GK exerted stronger anti­inflammatory and antioxidant effects on astrocytes exposed to OGD than GB by inhibiting interleukin (IL)­6 and tumor necrosis factor­α, and inducing IL­10 and the nuclear factor­erythroid 2­related factor 2/HO­1 signaling pathway. When compared with GB treatment, GK treatment maintained high levels of phosphoinositide 3­kinase/phosphorylated­protein kinase B expression, and induced a marked upregulation of Wnt family member 1 and brain derived neurotrophic factor, indicating that GK, as a natural plant compound, may have more attractive prospects for clinical application in the treatment of neurological disorders than GB.

Prognostic factors of Guillain-Barré syndrome: a 111-case retrospective review.

BACKGROUND: To identify the predictive factors associated with worse prognosis in the Guillain-Barré syndrome (GBS), which can be helpful to fully evaluate the disease progression and provide proper treatments. METHODS: Clinical data of 111 GBS patients who were diagnosed from 2010 to 2015 were collected and retrospectively analyzed. RESULTS: Patients with diabetes (P=0.031), high blood pressure at admission (P=0.034), uroschesis (P=0.028), fever (P<0.001), ventilator support (P<0.001) during hospitalization, disorder of consciousness (p=0.007) and absence of preceding respiratory infection(P=0.016) were associated with worse outcome at discharge, while abnormal sensation, ataxia, weakness and decrease of tendon reflex seemed not correlated with the Medical Research Council(MRC) score at discharge. Compared with the subtype of acute inflammatory demyelinating polyneuropathy, prognosis of Miller-Fisher syndrome (p<0.001) and cranial nerve variant (p<0.038) were better, but prognosis of acute motor axonal neuropathy(AMAN) was worse (p<0.032). Laboratory examinations at admission showed that hyperglycemia (P=0.002), high leukocyte count (P=0.010), hyperfibrinogenemia (P=0.001), hyponatremia (P=0.020), hypoalbuminemia (P=0.005), abnormal hepatic (P=0.048) and renal (P=0.009) functions were associated with poorer prognosis at discharge, while albuminocytologic dissociation in cerebrospinal fluid, GM1 and GQ1b antibody showed no correlation with the MRC score at discharge. γ-Globulin and glucocorticoid therapies showed no difference in the MRC score at the discharge. CONCLUSIONS: AMAN, diabetes, high blood pressure, uroschesis, high body temperature, ventilator support, consciousness disorder, absence of upper respiratory tract preceding infection, hyperglycemia, hyponatremia, hypoalbuminemia, high leukocyte count, hyperfibrinogenemia, abnormal hepatic and renal function were demonstrated as poor prognostic factors.

TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation.

Vinpocetine has long been used for cerebrovascular disorders and cognitive impairment. Based on the evidence that the translocator protein (TSPO, 18 kDa) was expressed in activated microglia, while Vinpocetine was able to bind TSPO, we explored the role of Vinpocetine on microglia treated with lipopolysaccharide (LPS) and oxygen-glucose deprivation (OGD) in vitro. Our results show that both LPS and OGD induced the up-regulation of TSPO expression on BV-2 microglia by RT-PCR, western blot and immunocytochemistry. Vinpocetine inhibited the production of nitrite oxide and inflammatory factors such as interleukin-1ß (IL-1ß), IL-6 and tumour necrosis factor-α (TNF-α) in BV-2 microglia, in which cells were treated with LPS or exposed to OGD, regardless of the time Vinpocetine was added. Next, we measured cell death-related molecules Akt, Junk and p38 as well as inflammation-related molecules nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Vinpocetine did not change cell death-related molecules, but inhibited the expression of NF-κB and AP-1 in LPS-stimulated microglia, indicating that Vinpocetine has an anti-inflammatory effect by partly targeting NF-κB/AP-1. Next, conditioned medium from Vinpocetine-treated microglia protected from primary neurons. As compared with in vitro, the administration of Vinpocetine in hypoxic mice also inhibited inflammatory molecules, indicating that Vinpocetine as a unique anti-inflammatory agent may be beneficial for the treatment of neuroinflammatory diseases.

A resonance Raman spectroscopic and CASSCF investigation of the Franck-Condon region structural dynamics and conical intersections of thiophene.

Resonance Raman spectra were acquired for thiophene in cyclohexane solution with 239.5 and 266 nm excitation wavelengths that were in resonance with ∼240 nm first intense absorption band. The spectra indicate that the Franck-Condon region photodissociation dynamics have multidimensional character with motion mostly along the reaction coordinates of six totally symmetry modes and three nontotally symmetry modes. The appearance of the nontotally symmetry modes, the C-S antisymmetry stretch +C-C=C bend mode ν(21)(B(2)) at 754 cm(-1) and the H(7)C(3)-C(4)H(8) twist ν(9)(A(2)) at 906 cm(-1), suggests the existence of two different types of vibronic-couplings or curve-crossings among the excited states in the Franck-Condon region. The electronic transition energies, the excited state structures, and the conical intersection points (1)B(1)/(1)A(1) and (1)B(2)/(1)A(1) between 2 (1)A(1) and 1 (1)B(2) or 1 (1)B(1) potential energy surfaces of thiophene were determined by using complete active space self-consistent field theory computations. These computational results were correlated with the Franck-Condon region structural dynamics of thiophene. The ring opening photodissociation reaction pathway through cleavage of one of the C-S bonds and via the conical intersection point (1)B(1)/(1)A(1) was revealed to be the predominant ultrafast reaction channel for thiophene in the lowest singlet excited state potential energy hypersurface, while the internal conversion pathway via the conical intersection point (1)B(2)/(1)A(1) was found to be the minor decay channel in the lowest singlet excited state potential energy hypersurface.