Clinical spectrum and gene mutations in a Chinese cohort with anoctaminopathy

Recessive mutations in anoctamin-5 (ANO5) are causative for limb-girdle muscular dystrophy (LGMD) 2L and non-dysferlin Miyoshi-like distal myopathy (MMD3). ANDS mutations are highly prevalent in European countries; however it is not common in patients of Asian origin, and there is no data regarding the Chinese population. We retrospectively reviewed the clinical manifestations and gene mutations of Chinese patients with anoctaminopathy. A total of five ANDS mutations including four novel mutations and one reported mutation were found in four patients from three families. No hotspot mutation was found. Three patients presented with presymptomatic hyperCKemia and one patient had limb muscle weakness. Muscle imaging of lower limbs showed preferential adductor magnus and medial gastrocnemius involvement. No hotspot mutation has been identified in Chinese patients to date. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Prevalence estimation of ATTRv in China based on genetic databases

Introduction: Amyloid transthyretin (ATTR) is divided into either hereditary (ATTRv) or sporadic (ATTRwt) and ATTRv is a rare hereditary disease transmitted as an autosomal dominant manner. Its global prevalence is traditionally estimated as 5,000 to 10,000 persons. However, it may be underestimated and the exact prevalence of ATTRv in China mainland remains unknown.Methods: The Genome Aggregation database (gnomAD) database (containing 125,748 exomes) and two genomic sequencing databases——China Metabolic Analytics Project (ChinaMAP) (containing 10588 individuals) and Amcarelab gene database (containing 45392 exomes), were integrated to estimate the prevalence of ATTRv in the world and mainland Chinese populations. Pathogenic variants allele frequency and the prevalence of ATTRv was calculated.Results: Six variants, counting 470 alleles, were defined as pathogenic variants in gnomAD. The prevalence of ATTRv in the world population was 57.4/100,000. Two variants (2 allele counts) and 15 variants (34 individuals) were defined as pathogenic variants in the ChinaMAP database and the Amcarelab exome database, respectively. Thus, the estimated prevalence interval of ATTRv in mainland China was 18.9/100,000-74,9/100,000.Conclusion: The present study demonstrated that the previous prevalence was greatly underestimated using traditional methods. Therefore, raising awareness of the disease is essential for recognizing ATTRv in its early stage

Dietary supplementation with Dendrobium officinale leaves improves growth, antioxidant status, immune function, and gut health in broilers

BackgroundThe Dendrobium officinale leaves (DOL) is an underutilized by-product with a large biomass, which have been shown to exhibit immunomodulatory and antioxidant functions. The purpose of this research was to investigate the effects of DOL on broiler growth performance, antioxidant status, immune function, and gut health.MethodsOne hundred and ninety-two 1-day-old chicks were selected and divided into 4 groups at random, 6 replicates for each group and 8 in each. Chicks were given a basal diet supplemented with different amounts of DOL: 0% (control group, NC), 1% (LD), 5% (MD), or 10% (HD). During the feeding trial (70 days), broiler body weight, feed intake, and residual feeding were recorded. On d 70, 12 broilers from each group were sampled for serum antioxidant and immune indexes measurement, intestinal morphological analysis, as well as 16S rRNA sequencing of cecal contents and short-chain fatty acid (SCFA) determination.ResultsIn comparison to the NC group, the LD group had greater final body weight and average daily gain, and a lower feed conversion ratio (p < 0.05, d 1 to 70). However, in MD group, no significant change of growth performance occurred (p > 0.05). Furthermore, DOL supplementation significantly improved the levels of serum total antioxidant capacity, glutathione peroxidase, superoxide dismutase, and catalase, but reduced the level of malondialdehyde (p < 0.05). Higher serum immunoglobulin A (IgA) content and lower cytokine interleukin-2 (IL-2) and IL-6 contents were observed in DOL-fed broilers than in control chickens (p <0.05). Compared to the NC group, duodenal villus height (VH) and villus height-to-crypt depth (VH:CD) ratio were considerably higher in three DOL supplementation groups (p < 0.05). Further, 16S rRNA sequencing analysis revealed that DOL increased the diversity and the relative abundance of cecal bacteria, particularly helpful microbes like Faecalibacterium, Lactobacillus, and Oscillospira, which improved the production of SCFA in cecal content. According to Spearman correlation analysis, the increased butyric acid and acetic acid concentrations were positively related to serum antioxidant enzyme activities (T-AOC and GSH-Px) and immunoglobulin M (IgM) level (p < 0.05).ConclusionOverall, the current study demonstrated that supplementing the dies with DOL in appropriate doses could enhance growth performance, antioxidant capacity, and immune response, as well as gut health by promoting intestinal integrity and modulating the cecal microbiota in broilers. Our research may serve as a preliminary foundation for the future development and application of DOL as feed additive in broiler chicken diets

Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Objective: To expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment. Methods: Whole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays. Results: Common clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that de- fective KARS function is responsible for the phenotypes in these individuals. Conclusions: Our results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease

Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients

BackgroundDespite the efficacy of efgartigimod demonstrated in ADAPT phase 3 trial, data specifically derived from Chinese participants are not available. Therefore, we aimed to evaluate the efficacy and safety of efgartigimod in Chinese patients with generalized myasthenia gravis (gMG).MethodsThis is a prospective cohort study conducted in 8 hospitals across China. gMG patients received weekly intravenous infusions of efgartigimod (10 mg/kg) under a named patient program (NPP). The present study is an 8-week study, consisting of 4 consecutive doses of efgartigimod administered over 3 weeks (one cycle), followed by a 5-week follow-up period to assess the tolerability of efgartigimod’s therapeutic effects. The primary outcome was the mean change in MG activities of daily living (MG-ADL) total score from baseline to 4 weeks. MG-ADL responder was defined as a ≥ 2-point improvement that persisted for 4 weeks, starting by week 4. Safety evaluations encompassed the monitoring of adverse events (AE) and serious AE (SAE) throughout the study.ResultsBetween 5 July 2022 and 25 August 2023, a total of 14 gMG patients were included. The mean age was 57.7 years, with a mean MG-ADL score of 10.86 ± 3.32. At week 4, MG-ADL scores showed a mean reduction of 6 points, reaching a maximum decline of 13 points. Among the patients, 85.7% (12/14) achieved MG-ADL responder status after one cycle of treatment. The most significant reduction in quantitative MG (QMG) scores also occurred at week 4, with a mean decrease of 7 points. Notably, the improvements in MG-ADL and QMG scores persisted until week 8. During treatment and follow-up period, only two mild neck rashes occurred and resolved promptly. No infections or SAE were reported.DiscussionA single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients

Real-world experience of teriflunomide in relapsing multiple sclerosis: paramagnetic rim lesions may play a role

ObjectivesThe aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing–remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden.MethodsThis is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated.ResultsOver a treatment period of 19.7 (3.1–51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0–11.5) mL, accounting for 2.3% (0.0%–49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study.ConclusionTeriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision

Current Advances in Virus-Like Particles as a Vaccination Approach against HIV Infection

HIV-1 virus-like particles (VLPs) are promising vaccine candidates against HIV-1 infection. They are capable of preserving the native conformation of HIV-1 antigens and priming CD4+ and CD8+ T cell responses efficiently via cross presentation by both major histocompatibility complex (MHC) class I and II molecules. Progress has been achieved in the preclinical research of HIV-1 VLPs as prophylactic vaccines that induce broadly neutralizing antibodies and potent T cell responses. Moreover, the progress in HIV-1 dendritic cells (DC)-based immunotherapy provides us with a new vision for HIV-1 vaccine development. In this review, we describe updates from the past 5 years on the development of HIV-1 VLPs as a vaccine candidate and on the combined use of HIV particles with HIV-1 DC-based immunotherapy as efficient prophylactic and therapeutic vaccination strategies