A predictive nomogram for short-term outcomes of myasthenia gravis patients treated with low-dose rituximab.

BACKGROUND: This study aims to establish and validate a predictive nomogram for the short-term clinical outcomes of myasthenia gravis (MG) patients treated with low-dose rituximab. METHODS: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC-ROC) and Hosmer-Lemeshow test, respectively. RESULTS: Disease duration (OR = 0.987, p = 0.032), positive anti-muscle-specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post-rituximab patients. The nomogram identified MG patients with clinical response with an AUC-ROC (95% CI) of 0.875 (0.798-0.952) in the derivation cohort and 0.741(0.501-0.982) in the validation cohort. Hosmer-Lemeshow test showed a good calibration (derivation: Chi-square = 3.181, p = 0.923; validation: Chi-square = 8.098, p = 0.424). CONCLUSIONS: The nomogram achieved an optimal prediction of short-term outcomes in patients treated with low-dose rituximab.

Berberine attenuates experimental autoimmune myasthenia gravis via rebalancing the T cell subsets.

Myasthenia Gravis (MG) is a T cell-driven, autoantibody-mediated disease. Here we show that oral Berberine (BBR) ameliorated clinical symptoms of experimental autoimmune myasthenia gravis(EAMG) rat model via decreasing the frequencies of Th1, Th17, Th1/17 cell subsets. JAK-STAT pathway was highlighted by transcriptomic analysis with EAMG mononuclear cells (MNCs). Surface plasmon resonance identified ligand binding interaction between BBR and JAK2, and electrostatic interaction was proposed by molecular dynamic simulation. Reduced phosphorylated JAK1/2/3 and STAT1/3 in MNCs from BBR-fed EAMG rats were demonstrated. These results suggest that BBR might improve EAMG by rebalancing T cell subsets through targeting JAK-STAT pathway.

Anthocyanin and Phenolic Acids Contents Influence the Color Stability and Antioxidant Capacity of Wine Treated With Mannoprotein.

Wine is consumed by humans worldwide, but the functional components are lost and the color changes during its production. Here, we studied the effects of mannoprotein (MP) addition (0, 0.1, and 0.3 g/L) upon crushing and storage. We measured anthocyanins, phenolic acids profiles, color characteristics, and antioxidant activities of wine. The results showed that the addition of MP before fermentation significantly increased the total phenolic content (TPC), total anthocyanin content, total tannin content (TTC), total flavonoid content, and total flavanol content in wine, whereas the addition of MP during storage had the opposite effect. The addition of MP before alcohol fermentation significantly increased the amount of individual anthocyanins and individual phenolic acids, maintained the color, and increased the antioxidant capacity of wine. In addition, the addition of 0.3 g/L MP during storage increased the content of individual phenolic acids and TPC of wine. However, the addition of 0.1 g/L MP during storage significantly reduced the TPC, TAC, TTC, and individual anthocyanin content (except for malvidin-3-glucoside and malvidin-3-acetly-glucoside); meanwhile, the treatment attenuated the color stability and antioxidant capacity of wine. The results demonstrated that the addition of MP before alcohol fermentation could increase the functional components and improve the color stability and antioxidant capacity of wine.

A Case Report of Adult-Onset Alexander Disease with a Tumor-Like Lesion in the Lateral Ventricle.

Adult-onset Alexander disease (AOAD) is an autosomal dominant progressive astrogliopathy caused by pathogenic variants in glial fibrillary acidic protein (GFAP). Individuals with this disorder often present with a typical neuroradiologic pattern, including frontal white matter abnormality with contrast enhancement, atrophy and signal intensity changes of the medulla oblongata and upper cervical cord on MRI. Focal lesions are rarely seen in AOAD, which causes concern for primary malignancies. This study aimed to present the case of a 37-year-old male patient initially diagnosed with an astrocytoma in the lateral ventricle that was later identified as GFAP mutation-confirmed AOAD. GFAP sequencing revealed a heterogeneous missense mutation point c.236G>A. Hence, AOAD should be considered in patients with tumor-like lesion brain lesion in association with atrophy of medulla oblongata and upper cervical spinal cord, and frontal white matter abnormality with contrast enhancement.

Therapeutic and Immunoregulatory Effects of Tacrolimus in Patients with Refractory Generalized Myasthenia Gravis.

OBJECTIVES: The aim of this study wasto investigate the efficacy of tacrolimus treatment in patients with refractory generalized myasthenia gravis (MG) and explore its impact on lymphocytic phenotypes and related cytokines mRNA expression. METHODS: A total of 24 refractory generalized MG patients were enrolled. Before treatment and at 2, 6, and 12 months after tacrolimus treatment, the therapeutic effect was evaluated by the quantitative MG score of the Myasthenia Gravis Foundation of America (QMG), Manual Muscle Test (MMT), MG-specific Activities of Daily Living (MG-ADL), 15-item Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and changes of prednisone dosage. Also, we used the flow cytometer for the lymphocytic immunophenotyping and real-time PCR for the qualification of cytokine mRNA in peripheral blood mononuclear cells (PBMCs) at different time points during the treatment. RESULTS: Significantly decreased QMG, MMT, MG-ADL, and MG-QOL15 were observed at all time points during the tacrolimus treatment. The dosage of prednisone also reduced at the end of the observation period with only 6 adverse events reported. The immunological impact of tacrolimus was revealed by reduced percentages of Tfh, Breg, CD19+BAFF-R+ B cells, and increased percentages of Treg cells as well as down-regulated expression of IL-2, IL-4, IL-10, and IL-13 mRNA levels in PBMCs during the treatment. CONCLUSION: Our study indicated the clinical efficacy of tacrolimus in patients with refractory generalized MG. The underlying immunoregulatory mechanism of tacrolimus may involve alterations in the phenotypes of peripheral blood lymphocytes and Th1/Th2-related cytokine expression of PBMCs.

Low-dose rituximab lowers serum Exosomal miR-150-5p in AChR-positive refractory myasthenia gravis patients.

Two potentially related microRNAs (miRNAs; miR-150-5p and miR-146a-5p) were examined after low-dose rituximab (RTX) treatment in patients with acetylcholine receptor antibody (AChR)-positive refractory myasthenia gravis (MG). In this prospective, open-label, and self-controlled pilot trial, 12 AChR-positive refractory MG patients were administrated a single, low dose of RTX and followed up at six months. Results showed that RTX decreased the serum exosomal miR-150-5p, scores on three clinical indices (MGFA, MMT, ADL), and patients' prednisolone requirement. Additionally, CD19+ and CD27+ B cells decreased, showing a strong correlation with miR-150-5p. In conclusion, low-dose RTX is effective for AChR-positive refractory MG treatment. Furthermore, our data support the role of miR-150-5p as a potential biomarker for MG.

Low-dose rituximab every 6 months for the treatment of acetylcholine receptor-positive refractory generalized myasthenia gravis.

INTRODUCTION: In this prospective, open-label study we explore the effectiveness of low-dose rituximab every 6 months in treating refractory generalized myasthenia gravis (GMG). METHODS: Twelve patients with acetylcholine receptor (AChR)-positive refractory GMG were enrolled for the study. The primary endpoint was the change in quantitative myasthenia gravis (QMG) score from baseline to the study end. Secondary endpoints included changes in manual muscle testing (MMT), MG-Related Activities of Daily Living (MG-ADL), and 15-item Quality-of-Life (MGQOL-15) scores, as well as prednisolone reduction. RESULTS: MG decreased from 18.25 ± 4.03 to 8.42 ± 3.99 (P = .0001), MMT from 27.50 ± 17.78 to 4.58 ± 4.34 (P = .0001), ADL from 8.50 ± 2.84 to 1.17 ± 1.27 (P < .0001), MGQOL-15 from 37.25 ± 13.78 to 17.50 ± 9.73 (P = .0015), and prednisolone dose from 29.38 ± 11.92 mg/day to 8.86 ± 1.88 mg/day (P ≤ .01). DISCUSSION: Low-dose rituximab every 6 months is effective in treating refractory GMG patients.

Effect of low-dose rituximab treatment on T- and B-cell lymphocyte imbalance in refractory myasthenia gravis.

We aimed to explore the effects of low-dose rituximab (RTX) on circulating T- and B-cell lymphocytes and the improvement of clinical symptoms in refractory myasthenia gravis (MG) patients. Fifteen patients with refractory MG were treated with a low dose of 600 mg RTX and were evaluated by serial-clinical scales, flow cytometry of peripheral blood T and B cells, and antibody titer before and after six months of RTX treatment. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were significantly improved and the average steroid-dosage reduction was 40% (p = .001) in refractory MG patients at six months after RTX infusion. Compared to eighteen non-refractory MG patients and eighteen Healthy controls, our study showed that the frequencies of circulating regulatory B cells (Bregs) and regulatory T cells (Tregs) were significantly lower and the expression of B-cell activating factor receptors (BAFF-Rs) was greater in refractory MG patients without RTX treatment. Importantly, 600-mg RTX was sufficient to deplete B cells and maintain low B-cell counts for up to six months after infusion. Additionally, a low dose of RTX further increased the frequencies of Tregs. Hence, there is an immune imbalance in circulating T- and B-cell lymphocytes in refractory MG patients compared to non-refractory MG patients. We conclude that remarkable T- and B-cell lymphocyte imbalance exists in refractory MG. Low-dose RTX can improve myasthenic symptom and deplete B cells and increase Tregs%.

Oxidant and Transition-Metal-Free Photoinduced Direct Oxidative Annulation of 1-Aryl-2-(furan/thiophen-2-yl)butane-1,3-diones.

A photoinduced direct oxidative annulation of 1-aryl-2-(furan/thiophen-2-yl)butane-1,3-diones and ethyl-2-(furan-2-yl)-3-oxo-3-(aryl-2-yl)propanoates in EtOH without the need for any transition metals and oxidants provided access to highly functionalized polyheterocyclic 1-(5-hydroxynaphtho[2,1-b]furan-4-yl)ethanones and 1-(5-hydroxyfuran/thieno/pyrrolo[3,2-e]benzofuran-4-yl)ethanones. The phenomenon of excited-state intramolecular proton transfer (ESIPT) was observed for both 1-(5-hydroxynaphtho[2,1-b]furan-4-yl)ethanone and 1-(5-hydroxy furan/thieno/pyrrolo[3,2-e]benzofuran-4-yl)ethanone analogues.

Responsiveness to low-dose rituximab in refractory generalized myasthenia gravis.

We aim to investigate the effect of a low dose of rituximab (RTX) in improving the clinical symptoms of refractory generalized myasthenia gravis (MG). Eight patients with refractory generalized MG were treated with a low dose of 600mg RTX. Patients were evaluated by serial clinical scales, flow cytometry of peripheral blood B, T and NK cells, immunoglobulin, complement levels and antibody titer. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were recorded at baseline as well as 1, 3, and 6months after RTX infusion. The initial improvement was recorded at 1month after treatment. QMGS, MMT and MG-ADL were significantly improved and the average steroid dosage reduction was 43% (p=0.018) at 6months. 600mg RTX was sufficient to deplete B cells and maintain low B-cell counts until 6months after infusion. Treatment with RTX did not result in a significant change in the percentage of CD4+, CD8+ T-cells while an average increase in the percentage of NK cells. Our study found successful B cell depletion was parallel to symptoms remission and change in serum C3 and C4 levels. Serum AChR antibody levels were independent of clinical response and not influenced by RTX. Therefore, low dose of 600mg RTX may be sufficient in depleting B cells, maintaining low B-cell counts and improving the clinical symptoms of MG in 6months.

Isaacs syndrome with CASPR2 antibody: A series of three cases.

Isaacs syndrome is a form of peripheral nerve hyperexcitability, characterized by spontaneous muscle twitching and stiffness. Some patients are reported to be positive for CASPR2 antibody that may be one of the pathogenic autoantibodies in Isaacs syndrome. We reported a series of three patients with Isaacs syndrome, including their clinical features, electrophysiologic findings, laboratory parameters and therapeutic responses. All the three patients were positive for CASPR2 antibodies examined on transfected human embryonic kidney 293 cells by indirect immunofluorescence method. One patient had invasive thymoma. Symptomatic treatment was not sufficient for them, while immunotherapies including corticosteroids, double filtration plasmapheresis and rituximab provided favorable outcomes. The titers of CASPR2 antibody decreased after immune modulating therapy in parallel to clinical improvements in two patients.

Synthesis and biological evaluation of arylpyrazoles as fungicides against phytopathogenic fungi.

3-phenol-1H-pyrazoles (2), 4-halogeno-3-phenol-1H-pyrazoles (3) and 2-(1-phenol-1H-pyrazol-5-yl)phenols (4) were prepared by the condensation of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-ones and hydrazine hydrate or phenylhydrazine in good yields. They were evaluated against five phytopathogens fungi, namely Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and Fusarium solani in vitro. Most of the above-mentioned compounds exhibited activities. For example, 4-chloro-2-(1H-pyrazol-3-yl)phenol (3k) and 4-bromo-3-phenol-1H-pyrazole (3b) showed good and broad-spectrum antifungal properties against Cytospora sp., C. gloeosporioides, Botrytis cinerea, Alternaria solani and F. Solani with [Formula: see text] values ranging from 4.66 to 12.47 [Formula: see text]g/mL. The results showed that pyrazoles with one aryl group at 3-position (2 and 3) exhibited better antibacterial activity than those with two aryl substituents (4). In addition, the existence of an electron-withdrawing group, a substituent on the ortho-position of phenol ring or a halogen atom at the 4-position of the pyrazole enhanced the antifungal activity of pyrazoles 2 and 3. A series of arylpyrazole derivatives was facilely prepared and was evaluated against five phytopathogens fungi including Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani in vitro. Most of those compounds exhibited remarkable antifungal activities and were superior to the positive control hymexazol.