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BACKGROUND: Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease, associated with CGG repeat expansions in the 5' untranslated region of LRP12, GIPC1, NOTCH2NLC and RILPL1. However, the genetic cause of a proportion of pathoclinically confirmed cases remains unknown. METHODS: A total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions in LOC642361/NUTM2B-AS1 in all 26 patients. RESULTS: We identified CGG repeat expansion in the non-coding transcripts of LOC642361/NUTM2B-AS1 in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts. CONCLUSIONS: We identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of the LOC642361/NUTM2B-AS1 gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion in LOC642361/NUTM2B-AS1.
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Distrofias Musculares , Adulto , Humanos , Distrofias Musculares/genética , Fenotipo , Cuerpos de Inclusión Intranucleares/genética , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment.
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Interleucina-6 , Miastenia Gravis , Humanos , Estudios Prospectivos , Estudios de Cohortes , Calidad de Vida , Miastenia Gravis/tratamiento farmacológicoRESUMEN
INTRODUCTION/AIMS: GNE myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. Although over 300 GNE variants have been reported, some patients remain undiagnosed with monoallelic pathogenic variants. This study aims to analyze the entire GNE genomic region to identify novel pathogenic variants. METHODS: Patients with clinically compatible GNE myopathy and monoallelic pathogenic variants in the GNE gene were enrolled. The other GNE pathogenic variant was verified using comprehensive methods including exon 2 quantitative polymerase chain reaction and nanopore long-read single-molecule sequencing (LRS). RESULTS: A deep intronic GNE variant, c.862+870C>T, was identified in nine patients from eight unrelated families. This variant generates a cryptic splice site, resulting in the activation of a novel pseudoexon between exons 5 and 6. It results in the insertion of an extra 146 nucleotides into the messengerRNA (mRNA), which is predicted to result in a truncated humanGNE1(hGNE1) protein. Peanut agglutininï¼PNAï¼ lectin staining of muscle tissues showed reduced sialylation of mucin O-glycans on sarcolemmal glycoproteins. Notably, a third of patients with the c.862+870C>T variant exhibited thrombocytopenia. A common core haplotype harboring the deep intronic GNE variant was found in all these patients. DISCUSSION: The transcript with pseudoexon activation potentially affects sialic acid biosynthesis via nonsense-mediated mRNA decay, or resulting in a truncated hGNE1 protein, which interferes with normal enzyme function. LRS is expected to be more frequently incorporated in genetic analysis given its efficacy in detecting hard-to-find pathogenic variants.
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Exones , Intrones , Complejos Multienzimáticos , Trombocitopenia , Humanos , Masculino , Femenino , Complejos Multienzimáticos/genética , Exones/genética , Intrones/genética , Adulto , Trombocitopenia/genética , Miopatías Distales/genética , Adulto Joven , Adolescente , Niño , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Linaje , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.
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Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Resultado del Tratamiento , Receptores Colinérgicos/inmunologíaRESUMEN
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.
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Factores Inmunológicos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Rituximab , Humanos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Resultado del TratamientoRESUMEN
Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.
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BACKGROUND: Myasthenia gravis (MG) is the most prevalent autoimmune disorder affecting the neuromuscular junction. A rapid deterioration in respiratory muscle can lead to a myasthenic crisis (MC), which represents a life-threatening condition with high mortality in MG. Multiple CD4+ T subsets and hypercytokinemia have been identified in the peripheral pro-inflammatory milieu during the crisis. However, the pathogenesis is complicated due to the many types of cells involved, leaving the underlying mechanism largely unexplored. METHODS: We conducted single-cell transcriptomic and immune repertoire sequencing on 33,577 peripheral blood mononuclear cells (PBMCs) from two acetylcholine receptor antibody-positive (AChR +) MG patients during MC and again three months post-MC. We followed the Scanpy workflow for quality control, dimension reduction, and clustering of the single-cell data. Subsequently, we annotated high-resolution cell types utilizing transfer-learning models derived from publicly available single-cell immune datasets. RNA velocity calculations from unspliced and spliced mRNAs were applied to infer cellular state progression. We analyzed cell communication and MG-relevant cytokines and chemokines to identify potential inflammation initiators. RESULTS: We identified a unique subset of monocytes, termed monocytes 3 (FCGR3B+ monocytes), which exhibited significant differential expression of pro-inflammatory signaling pathways during and after the crisis. In line with the activated innate immune state indicated by MC, a high neutrophil-lymphocyte ratio (NLR) was confirmed in an additional 22 AChR + MC patients in subsequent hemogram analysis and was associated with MG-relevant clinical scores. Furthermore, oligoclonal expansions were identified in age-associated B cells exhibiting high autoimmune activity, and in CD4+ and CD8+ T cells demonstrating persistent T exhaustion. CONCLUSIONS: In summary, our integrated analysis of single-cell transcriptomics and TCR/BCR sequencing has underscored the role of innate immune activation which is associated with hypercytokinemia in MC. The identification of a specific monocyte cluster that dominates the peripheral immune profile may provide some hints into the etiology and pathology of MC. However, future functional studies are required to explore causality.
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Síndrome de Liberación de Citoquinas , Miastenia Gravis , Humanos , Transcriptoma/genética , Linfocitos T CD8-positivos , Leucocitos Mononucleares , Miastenia Gravis/genéticaRESUMEN
BACKGROUND AND PURPOSE: Treatment options for chronic inflammatory demyelinating polyneuropathy (CIDP) are intravenous immunoglobulin, plasmapheresis, corticosteroids and immunosuppressive drugs. However, a substantial proportion of patients with CIDP remain refractory to treatment and develop severe functional disability. A systematic review and a meta-analysis of the efficacy of hematopoietic stem cell transplantation (HSCT) treatment in refractory CIDP patients was performed. METHODS: The study is based on queries in the PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science and clinicaltrials.gov databases on 4 December 2022. Articles that met our eligibility criteria were included after screening. Patients' characteristics, treatment regime and outcome measures were extracted. RESULTS: Eighty-nine patients in 11 studies were included. The pooled estimate of responsiveness amongst the four included studies was 87.04% (95% confidence interval 66.7%-99.5%) and the pooled estimate of freedom of all immune modulating or suppressive drugs was 80.75% (95% confidence interval 71.2%-90.2%). CONCLUSION: This meta-analysis and systematic review suggested that HSCT can be effective in the treatment of refractory CIDP. Whilst there are risks involved, HSCT may be a beneficial and viable therapy for refractory CIDP when carefully evaluated.
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Trasplante de Células Madre Hematopoyéticas , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.
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Varicela , Herpes Labial , Herpes Zóster , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/genética , Acuaporina 4/genética , Varicela/complicaciones , Estudio de Asociación del Genoma Completo , Herpes Labial/complicaciones , Análisis de la Aleatorización Mendeliana , Autoanticuerpos , Herpes Zóster/complicaciones , Antígenos HLA-BRESUMEN
BACKGROUND AND PURPOSE: The aim was to evaluate the potential of retinal nerve fiber layer thickness (RNFLT) measured with optical coherence tomography in predicting disease progression in relapsing-remitting multiple sclerosis (RRMS). METHODS: Analyses were conducted post hoc of this 24-month, phase III, double-blind study, in which RRMS patients were randomized (1:1:1) to once daily oral fingolimod 0.5 mg, 1.25 mg or placebo. The key outcomes were the association between baseline RNFLT and baseline clinical characteristics and clinical/imaging outcomes up to 24 months. Change of RNFLT with fingolimod versus placebo within 24 months and time to retinal nerve fiber layer (RNFL) thinning were evaluated. RESULTS: Altogether 885 patients were included. At baseline, lower RNFLT was correlated with higher Expanded Disability Status Scale score (r = -1.085, p = 0.018), lower brain volume (r = 0.025, p = 0.006) and deep gray matter volume (r = 0.731, p < 0.0001), worse visual acuity (r = -19.846, p < 0.0001) and longer duration since diagnosis (r = -0.258, p = 0.018). At month 12, low baseline RNFLT (<86 µm) versus high baseline RNFLT (≥99 µm) was associated with a greater brain volume loss (percentage change -0.605% vs. -0.315%, p = 0.035) in patients without optic neuritis history. At month 24, low baseline RNFLT versus high baseline RNFLT was associated with a higher number of new or newly enlarged T2 lesions (mean number 4.0 vs. 2.8, p = 0.014) and a higher risk of subsequent RNFL thinning (hazard ratio 2.55; 95% confidence interval 1.84-3.53; p < 0.001). The atrophy of the RNFL in the inferior quadrant was alleviated with fingolimod 0.5 mg versus placebo at month 24 (Δ(least squares mean) = 1.8, p = 0.047). CONCLUSION: Retinal nerve fiber layer thickness could predict disease progression in RRMS. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00355134, https://clinicaltrials.gov/ct2/show/NCT00355134.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/complicaciones , Clorhidrato de Fingolimod/uso terapéutico , Fibras Nerviosas/patología , Retina/diagnóstico por imagen , Retina/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Progresión de la Enfermedad , Tomografía de Coherencia Óptica/métodosRESUMEN
BACKGROUND: Charcot-Marie-Tooth disease 2C (CMT2C) and scapuloperoneal spinal muscular atrophy (SPSMA) are different clinical phenotypes of TRPV4 mutation. The mutation of p.R316C has been reported to cause CMT2C and SPSMA separately. CASE PRESENTATION: Here, we reported a Chinese family harboring the same p.R316C variant, but with an overlap syndrome and different clinical manifestations. A 58-year-old man presented with severe scapula muscle atrophy, resulting in sloping shoulders. He also exhibited distinct muscle atrophy in his four limbs, particularly in the lower limbs. The sural nerve biopsy revealed severe loss of myelinated nerve fibers with scattered regenerating clusters and pseudo-onion bulbs. Nerve conduction study showed axon damage in both motor and sensory nerves. Sensory nerve action potentials could not be evoked in bilateral sural or superficial peroneal nerves. He was diagnosed with Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome, whereas his 27-year-old son was born with clubfoot and clinodactyly. Electromyogram examination indicated chronic neurogenic changes and anterior horn cells involvement. Although there was no obvious weakness or sensory symptoms, early SPSMA could be considered for him. CONCLUSIONS: A literature review of the clinical characteristics in CMT2C and SPSMA patients with TRPV4 mutation suggested that our case was distinct due to the overlap syndrome and phenotype variation. Altogether, this case broadened the phenotype spectrum and provided the nerve biopsy pathological details of TRPV4-related neuropathies.
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Enfermedades Autoinmunes , Enfermedad de Charcot-Marie-Tooth , Enfermedades del Tejido Conjuntivo , Atrofia Muscular Espinal , Humanos , Masculino , Enfermedad de Charcot-Marie-Tooth/genética , Atrofia Muscular , Atrofia Muscular Espinal/genética , Canales Catiónicos TRPV/genética , Persona de Mediana EdadRESUMEN
Polygonum cuspidatum is a homology of traditional medicine and functional food widely distributed around the world. Our previous study on the hyperlipidemic animal model demonstrated that Polygonum cuspidatum was effective in ameliorating hyperlipidemia, which is characterized by lipid disorders. Herein, the regulatory effect of Polygonum cuspidatum on lipid metabolism needs to be known if its hypolipidemic mechanism is desired to clarify. In this study, an ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry-based lipidomic strategy was first applied to investigate the lipidomic patterns of high-fat diet-induced hyperlipidemic hamsters when treated with Polygonum cuspidatum. The results showed that Polygonum cuspidatum improved the lipidomic profile of hyperlipidemia. A total of 65 differential lipids related to the hypolipidemic effect of Polygonum cuspidatum were screened out and identified, and these differential lipids covered various categories, such as phosphatidylcholines, phosphatidylethanolamines, triacylglycerols, sphingomyelins and so on. Orally administrated Polygonum cuspidatum restored these differential lipids back to normal or nearly normal levels. This study adopted lipidomics to reveal the key lipid molecules as potential therapeutic targets of Polygonum cuspidatum against hyperlipidemia, which would provide a scientific basis for its clinical application.
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Fallopia japonica , Hiperlipidemias , Animales , Cricetinae , Hiperlipidemias/tratamiento farmacológico , Lipidómica , Cromatografía Líquida de Alta Presión , Espectrometría de Masas , LípidosRESUMEN
BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. Cytokines play important roles in facilitating the immune response and augmenting the pathogenic antibody production. The current study aims to sensitively characterize the serum levels of cytokines with very low concentration in generalized MG (gMG). METHODS: Using ultrasensitive single-molecule arrays (SIMOA), we measured serum IL-2, IL-4, IL-5 and IL-12p70 in 228 participants including 152 immunotherapy-naïve anti-acetylcholine receptor (AChR) subtype gMG from Huashan MG registry and 76 age-matched healthy controls. Subgroup analysis was then performed by stratifying patients according to the onset ages, MGFA classification, disease duration at baseline. RESULTS: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were significantly elevated in gMG compared to controls (0.179 pg/mL versus 0.011 pg/mL, P < 0.0001; 0.029 pg/mL versus 0.018 pg/mL, P = 0.0259; 0.215 pg/mL versus 0.143 pg/mL, P = 0.0007; 0.132 pg/mL versus 0.118 pg/mL, P = 0.0401). Subgroup analysis revealed that IL-2 levels were slightly elevated in gMG with MGFA II compared to MGFA III/IV (0.195 pg/mL versus 0.160 pg/mL, P = 0.022), as well as elevated levels of IL-2 (0.220 pg/mL versus 0.159 pg/mL, P = 0.0002) and IL-5 (0.251 pg/mL versus 0.181 pg/mL, P = 0.004) in late-onset gMG compared with the early-onset gMG. gMG patients with a long duration had a significant increased serum IL-12p70 than those with a short duration (0.163 pg/mL versus 0.120 pg/mL, P = 0.011). CONCLUSION: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were increased in AChR subtype gMG using ultrasensitive measurement. Serum cytokines with very low concentrations may provide as potential biomarkers in stratifying gMG patients in future prospective cohort studies.
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Miastenia Gravis , Receptores Colinérgicos , Citocinas , Humanos , Interleucina-12 , Interleucina-2 , Interleucina-4 , Interleucina-5RESUMEN
Myasthenic crisis (MC) is a life-threatening state with respiratory failure in patients with myasthenia gravis (MG). The fast-acting immunomodulatory therapies for treating MC included plasma exchange (PE) and intravenous immunoglobulin (IVIG). However, the efficacy and the impact on antibody changes remained unknown. We prospectively followed 40 anti-acetylcholine receptors (AChR) antibody-positive MC patients who received either PE (n = 12) or IVIG (n = 28) at crisis. PE was associated with a reduced ICU stay length (p = 0.018) and an early response by the average changes in MGFA-QMG (p = 0.003), MMT (p = 0.020), and ADL (p = 0.011) at one-week off-ventilation. However, the clinical efficacy was equally comparable in both groups after 1 month. Post-treatment hemoglobin drop was significant in both groups, while IVIG was associated with a significant reduction in anti-AChR antibody titers (p < 0.001). This analysis provides real-world evidence in supporting the use of PE as a fast-acting therapy for shortening the ICU stay in AChR-associated MC.
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Inmunoglobulinas Intravenosas , Miastenia Gravis , Autoanticuerpos , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Intercambio Plasmático , Estudios Prospectivos , Receptores ColinérgicosRESUMEN
BACKGROUND AND PURPOSE: This study aimed to evaluate the clinical characteristics and prognosis of late onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), and compare them with those of early onset (<50 years) NMOSD (EO-NMOSD) and NMOSD with various antibody serostatuses. METHODS: From January 2015 to December 2020, 360 anti-aquaporin 4 antibody (AQP4-ab)-positive and 130 anti-myelin oligodendrocyte glycoprotein antibody (MOG-ab)-positive patients presented to the Huashan Hospital, China. We retrospectively reviewed their medical records, including the Expanded Disability Status Scale (EDSS) score at each visit and the annualized relapse rate (ARR). Prognostic outcomes included the time to first relapse, blindness, motor dysfunction, severe motor dysfunction, and death. Correlations between the age at onset, lesion location, and clinical parameters were analyzed. RESULTS: This study included 122 (24.9%) patients with LO-NMOSD, 101 with AQP4-ab and 21 with MOG-ab. Compared with EO-NMOSD patients, those with LO-NMOSD had higher EDSS scores and more frequent disease onset with transverse myelitis, blindness, motor dysfunction, and severe motor dysfunction. Compared with LO-NMOSD patients with MOG-ab, those with AQP4-ab had a worse prognosis. Age at disease onset had a significantly positive correlation with EDSS score at the last follow-up of all NMOSD patients, but a negative correlation with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up) in NMOSD patients with AQP4-ab. CONCLUSIONS: Patients with LO-NMOSD, especially those with AQP4-ab, had a worse prognosis compared with patients with EO-NMOSD. Age at disease onset and antibody serostatus predicted blindness and motor dysfunction.
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Neuromielitis Óptica , Acuaporina 4 , Autoanticuerpos , Humanos , Glicoproteína Mielina-Oligodendrócito , Recurrencia Local de Neoplasia , Neuromielitis Óptica/patología , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort. METHODS: Patients with aquaporin 4 (AQP4) antibody-positive NMOSD with AZA (n = 167), MMF (n = 131), or RTX (n = 55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events. RESULTS: The median follow-up time of the 353 patients was 30.3 months. The regimen of RTX was 100 mg on Day 1 and 500 mg on Day 2, followed by 500 mg every 6 months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR] = 4.40, 95% confidence interval [CI] = 1.41-13.80, p = 0.011) or MMF (HR = 5.20, 95% CI = 1.60-16.86, p = 0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34-3.66, p = 0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%, p < 0.001). CONCLUSIONS: We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody-positive NMOSD.
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Azatioprina , Neuromielitis Óptica , Autoanticuerpos , Azatioprina/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Recurrencia Local de Neoplasia , Neuromielitis Óptica/tratamiento farmacológico , Estudios Retrospectivos , Rituximab/efectos adversosRESUMEN
Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5' UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy.
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Proteínas Adaptadoras Transductoras de Señales/genética , Distrofias Musculares/genética , Expansión de Repetición de Trinucleótido , Regiones no Traducidas 5' , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofias Musculares/patología , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Secuenciación del ExomaRESUMEN
BACKGROUND: Limb-girdle muscular dystrophy type R1 (LGMDR1) can be caused by recessive CAPN3 mutations accounting for the majority of LGMD. To date, no systemic evaluation has been performed to analyse the detrimental and normal mutations on CAPN3 and its hotspots. METHODS: CAPN3 variants (n=112) from a total of 124 patients with LGMDR1 recruited in four centres in China were retrospectively analysed. Then external CAPN3 variants (n=2031) from online databases were integrated with our Chinese cohort data to achieve a worldwide perspective on CAPN3 mutations. According to their related phenotypes (LGMDR1 or normal), we analysed consequence, distribution, ethnicity and severity scores of CAPN3 mutations. RESULTS: Two hotspot mutations were identified including c.2120A>G in Chinese population and c.550del in Europe. According to the integrated dataset, 521 mutations were classified as LGMDR1-related and converged on exons 1, 10, 5, 22 and 13 of CAPN3. The remaining 1585 variants were classified as normal-population related. The deleterious ratio of LGMDR1-relevant variants to total variants in each population was 0.26 on average with a maximum of 0.35 in Finns and a minimum of 0.21 in South Asians. Severity evaluation showed that Chinese LGMDR1-related variants exhibited a higher risk (Combined Annotation Dependent Depletion score +1.10) than that from database patients (p<0.001). CONCLUSIONS: This study confirmed two hotspots and LGMDR1-related CAPN3 variants, highlighting the advantages in using a data-based comprehensive analysis to achieve a genetic landscape for patients with LGMDR1.
Asunto(s)
Calpaína/genética , Proteínas Musculares/genética , Distrofia Muscular de Cinturas/genética , Mutación , Adulto , Pueblo Asiatico/genética , Exones , Femenino , Humanos , Masculino , Distrofia Muscular de Cinturas/etiología , Población Blanca/genéticaRESUMEN
BACKGROUND: A growing number of studies show that integrated health care provides comprehensive and continuous care to patients with hypertension or diabetes. However, there is still no consensus about the effect of integrated health care on patients with hypertension or diabetes. The objective of this study was to verify the effectiveness of integrated health care for patients with hypertension or diabetes by using a systematic review and meta-analysis. METHODS: The study searched multiple English and Chinese electronic databases. The search period was from database inception to 31 October 2020. Systematic reviews and meta-analyses were conducted after assessing the risk of bias of each study. RESULTS: Sixteen studies that involved 5231 patients were included in this study. The results of the systematic review revealed that systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and glycosylated haemoglobin (HbA1c) are commonly used indicators for patients with hypertension or diabetes. Individual models and group- and disease-specific models are the most commonly used models of integrated health care. All the studies were from high-income and middle-income countries. Meta-analysis showed that integrated health care significantly improved SBP, DBP and HbA1c but not BMI. A comparison of interventions lasting 6 and 12 months for diabetes was conducted, and HbA1c was decreased after 12 months. The changes in SBP and DBP were statistically significant after using group- and disease-specific model but not individual models. HbA1c was significantly improved after using group- and disease-specific models and individual models. CONCLUSION: Integrated health care is a useful tool for disease management, and individual models and group- and disease-specific models are the most commonly used models in integrated health care. Group- and disease-specific models are more effective than individual models in the disease management of hypertension patients. The duration of intervention should be considered in the disease management of patients with diabetes, and interventions longer than 12 months are recommended. The income level may affect the model of integrated health care in selecting which disease to intervene, but this point still needs support from more studies.
Asunto(s)
Diabetes Mellitus , Hipertensión , Presión Sanguínea , Atención a la Salud , Diabetes Mellitus/terapia , Hemoglobina Glucada , Humanos , Hipertensión/terapiaRESUMEN
BACKGROUND: Telemedicine has been widely used for long-term care and self-management in patients with chronic disease, but there is no consensus regarding the effect of telemedicine on chronic disease management. The aim of this study is to review and analyse the effect of telemedicine on the management of chronic diseases such as hypertension, diabetes, and rheumatoid arthritis using a systematic review and meta-analysis. METHODS: We performed a comprehensive literature search of the Web of Science, PubMed, MEDLINE, EMBASE, CNKI (Chinese database), VIP (Chinese database), WanFang (Chinese database), and SinoMed (Chinese database) databases from their inception until December 31, 2021. The retrieved literature was screened and assessed independently by two authors. We used the risk-of-bias assessment tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions 5.0.2 for assessing literature quality and Revman 5.3 software to conduct the meta-analysis. RESULTS: Fifteen articles were included in this study. The results of the systematic review indicated that telemedicine consultation and telemonitoring are the most commonly used intervention methods. Telemedicine is helpful for improving self-management in patients with rheumatoid arthritis. The results of the meta-analysis showed patients' index of glycosylated hemoglobin (HbA1c) improved after 12 months of intervention (MD = - 0.84; 95% CI = - 1.53, - 0.16; Z = 2.42; P = 0.02), and no significant differences in fasting blood glucose (FBG) levels were observed after 6 months of intervention (MD = - 0.35; 95% CI = - 0.75,0.06; Z = 1.69; P = 0.09). The results also showed that systolic blood pressure (MD = - 6.71; 95% CI = - 11.40, - 2.02; Z = 2.81; P = 0.005) was reduced after 6 months of intervention. CONCLUSION: Telemedicine had a positive effect on the management of diabetes, hypertension, and rheumatoid arthritis, especially when telemedicine consultation and telemonitoring method were used. When telemedicine was used as a disease management tool for patients with diabetes, the optimal intervention time is 12 months. Telemedicine improved the systolic blood pressure in hypertensive patients while also reducing negative emotions and enhancing medication adherence in rheumatoid arthritis patients.