Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.

OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS. METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms. RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio. INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024.

Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI- and Age-Dependent Manner.

OBJECTIVE: Peripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS. METHODS: A total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets, and CRP) and its derived metrics (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and systemic immune-inflammation index [SII]) were analyzed in relation to the following incident ALS by Cox proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further. RESULTS: After adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR and SII) were associated with an increased risk of ALS incidence (per SD increment hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02-1.29 for neutrophils; HR = 1.15, 95% CI = 1.03-1.28 for NLR; and HR = 1.17, 95% CI = 1.05-1.30 for SII). Subgroup and interaction analyses revealed that body mass index (BMI) and age had specific effects on this association. In participants with BMI ≥ 25 or age < 65 years, higher neutrophil counts, and their metrics increased the risk of incident ALS; however, in participants with BMI < 25 or age ≥ 65 years, neutrophils had no effect on incident ALS. INTERPRETATION: Our study provides evidence that increased neutrophil levels and neutrophil-derived metrics (NLR and SII) are associated with an increased risk of developing ALS. ANN NEUROL 2023;94:942-954.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

Lipids, Apolipoproteins, Statins, and Intracerebral Hemorrhage: A Mendelian Randomization Study.

OBJECTIVE: To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease. METHODS: Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH. RESULTS: Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH. INTERPRETATION: Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399.

Mutation-specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage. METHODS: A total of 60 presymptomatic ALS mutation carriers and 70 age- and gender-matched controls (non-mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein. RESULTS: All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 (C9ORF72) gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6-26.1 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p = 0.007), lower systolic blood pressure (120, IQR 110-130 mmHg vs. 128, IQR 120-140 mmHg; p = 0.02), lower fasting serum glucose (89.0, IQR 85.0-97.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p = 0.005) and higher HDL (1.6, IQR 1.3-1.8 mmol/l vs. 1.2, IQR 1.0-1.4 mmol/l; p = 0.04). However, presymptomatic superoxide dismutase 1 (SOD1) gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0, IQR 26.1-31.5 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p = 0.02), higher fasting serum glucose (100.0, IQR 94.0-117.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p = 0.04) and lower HDL (1.2, IQR 1.0-1.4 mmol/l vs. 1.4, IQR 1.2-1.7 mmol/l; p = 0.01). These features were most prominent in patients carrying SOD1 gene mutations associated with slow disease progression. CONCLUSIONS: This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

Lipids and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

OBJECTIVE: Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis. METHODS: Using genome-wide association study summary-level data for total cholesterol (TC) (n = 188,578), high-density lipoprotein cholesterol (HDL-C) (n = 403,943), low-density lipoprotein cholesterol (LDL-C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL-C is a potential mediator on the pathway from traits of LDL-C-related polyunsaturated fatty acids (PUFAs) to ALS risk. RESULTS: We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL-C had the most potent effect (OR 1.028, 95% CI 1.008-1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL-C-modifying lifestyles and ALS. The mediation analysis revealed that LDL-C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009. CONCLUSIONS: We provided high-level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL-C in the pathway from PUFAs to ALS.

Corneal confocal microscopy in the evaluation of immune-related motor neuron disease syndrome.

BACKGROUND: To investigate the sensitivity and specificity of corneal confocal microscopy (CCM) in the diagnosis of immune-related motor neuron disease syndrome and evaluation of the response to immunosuppressive therapy. METHODS: Seventy-two patients with clinical manifestations of motor neuron disease (MND) were analysed. According to whether they had concomitant rheumatic immune disease or rheumatic immune antibody abnormalities, they were divided into an MND group (33 patients) and an immune-related MND syndrome group (39 patients). Another 10 healthy adults were selected as the control group. All individuals were examined by CCM. RESULTS: For Langerhans cell(LC) density, the area under the receiver operating characteristic(ROC)curve was 0.8, the best cut-off was 67.7 cells/mm2, the sensitivity was 79.5%, and the specificity was 72.7%. For inferior whorl length (IWL), the area under the ROC curve was 0.674, the best cut-off was 17.41 mm/mm2, the sensitivity was 69.2%, and the specificity was 66.7%. After immunosuppressive therapy in 5 patients with immune-related MND syndrome, the LCD was significantly reduced (P < 0.05), and there was no statistically significant change in the IWL (P > 0.05). CONCLUSION: The LC density and IWL are ideal for distinguishing MND from immune-related MND syndrome. The LC density reflects the immunotherapy response sensitively.

Assessment of bidirectional relationships between 98 genera of the human gut microbiota and amyotrophic lateral sclerosis: a 2-sample Mendelian randomization study.

BACKGROUND: Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. OBJECTIVES: To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. RESULTS: Using the inverse variance-weighted method, OTU10032 unclassified Enterobacteriaceae species-level OTU and unclassified Acidaminococcaceae were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01-1.07; P = 0.011 and OR, 1.02; 95% CI, 1.01-1.04; P = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50-2.55; P = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of OTU4607_Sutterella (per 1-unit higher log odds: ß, 2.23; 95% CI, 1.27-3.18; P = 0.020) and Lactobacillales_ORDER (per 1-unit higher log odds: ß, 0.51; 95% CI, 0.09-0.94; P = 0.019). CONCLUSIONS: Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials.

Plasma repressor element 1-silencing transcription factor levels are decreased in patients with Alzheimer's disease.

BACKGROUND: Repressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer's disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy. METHODS: Participants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis. RESULTS: The plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02). CONCLUSION: The plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

Effect of racial background on motor cortical function as measured by threshold tracking transcranial magnetic stimulation.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

MiR-142-5p serves as a tumor suppressor in retinoblastoma cells by regulating MYCN.

Retinoblastoma is an intraocular malignant tumor and generally occurred in childhood. Here, we intended to appraise the functional influence of microRNA-142-5p (miR-142-5p) in retinoblastoma. MiR-142-5p was declined, and MYCN was upregulated in retinoblastoma tissues and cells. Moreover, miR-142-5p restricted cell proliferation, migration, invasion, and enhanced cell apoptosis in retinoblastoma cells. MYCN was adversely controlled by miR-142-5p. Besides, the inhibition of miR-142-5p-mediated effects on retinoblastoma progression were blocked by MYCN overexpression in retinoblastoma cells. This research illustrated that miR-142-5p restricted retinoblastoma progression via interacting with MYCN.

Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

OBJECTIVE: Observational studies have indicated that life course adiposity is associated with amyotrophic lateral sclerosis (ALS). However, whether such an association reflects causality remains unclear. We aimed to determine whether life course adiposity such as birth weight (BW), childhood body mass index (BMI), adult BMI, body fat percentage (BF%), and waist-to-hip ratio (WHR) have causal effects on ALS. METHODS: Single nucleotide polymorphisms (SNPs) significantly associated with life course adiposity were used as instrumental variables to estimate the causal effects on ALS. We used summary-level data from a cohort of 20,806 cases and 59,804 controls in a Mendelian randomization (MR) framework. RESULTS: Genetically predicted one standard deviation (1-SD) increase in BF% was associated with lower risk of ALS (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.54-0.83, p = 3.25E-04) after Bonferroni correction (p < 0.05/5). Genetically predicted 1-SD higher childhood BMI was suggestively associated with lower risk of ALS (OR = 0.88, 95% CI = 0.78-0.99, p = 0.031). The weighted median method indicated a suggestive association between BMI and ALS (OR = 0.86, 95% CI = 0.69-0.96, p = 0.016). Neither a genetically predicted 1-SD increase in BW (inverse variance weighted [IVW]: OR = 1.01, 95% CI = 0.87-1.17, p = 0.939) nor WHR adjusted for BMI (IVW: OR = 0.90, 95% CI = 0.76-1.05, p = 0.178) was associated with ALS. INTERPRETATION: Our findings provide novel evidence supporting a causal role of higher adiposity, taken as a whole, on lower risk of ALS. A deeper understanding of the energy metabolism of ALS is more likely to identify feasible nutritional interventions and even novel therapeutic targets that might improve the survival of ALS patients. Ann Neurol 2020;87:434-441.

Chinese validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale.

BACKGROUND AND PURPOSE: The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) was developed using Rasch methodology. This scale has been demonstrated as a reliable outcome measure of amyotrophic lateral sclerosis (ALS) trials. To date, there are no similar interval-weighted scales to assess disability in ALS patients. The current study aimed to validate a Chinese version of the ROADS via Rasch methodology. METHODS: The Chinese version of the ROADS was obtained through a standardized forward-backward translation and cultural adaptation. ALS patients were recruited from the Department of Neurology of Peking University Third Hospital in Beijing, China to complete the ROADS and the revised ALS Functional Rating Scale (ALSFRS-R). Overall, 254 participants with ALS finished the Chinese scale. Rasch analysis was performed on the ROADS for validation and the ALSFRS-R for comparison. RESULTS: The Chinese version of the ROADS was modified according to the statistical results. A final 28-question scale was constructed that fulfilled all the requirements of the Rasch model with proper validity and reliability. Furthermore, the ROADS showed improved item targeting compared to the ALSFRS-R. Conversely, the ALSFRS-R did not fit the Rasch model expectations due to misfit values and disordered thresholds for all 12 items. CONCLUSIONS: The Chinese adaptation of the ROADS is a linearly weighted scale that specifically captures overall disability in ALS patients. This scale indicates a wider range of item difficulties and better responsiveness than the ALSFRS-R. The ROADS could be used as a valuable tool for use in ALS trials and in the clinic in Chinese settings.

Urban prevalence of multiple sclerosis in China: A population-based study in six provinces.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a rare neurological disease addressed by only few epidemiological studies in China. This population-based study aimed to estimate the prevalence of MS in China by using national medical insurance databases. METHODS: Data from the Urban Employee Basic Medical Insurance database and the Urban Residence Basic Medical Insurance database, which were collected during 2012 to 2016 and included approximately 0.20 billion residents in six provinces, were used in this population-based study. The prevalent patients with MS were identified via diagnostic text or disease codes. RESULTS: The crude prevalence in 2016 was 2.44 per 100,000 population (95% confidence interval (CI) 2.18-2.72), with the prevalence in females being higher than that in males. The standardized prevalence (based on 2010 Chinese census data) was 2.29 (95% CI 2.21-2.38). The prevalence in both sexes in 2016 increased up to the age range of 30-34 years. Subsequently, the female prevalence declined with increasing age, but male prevalence stabilized with increasing age. During the 5-year time period, prevalence ranged from 2.32 (95% CI 2.06-2.60) in 2015 to 2.91 (95% CI 2.39-3.47) in 2012. CONCLUSIONS: The prevalence of MS in China was lower than that in Europe and North America. The temporal trend of prevalence in China was also observed to be stable. As the first prevalence study of MS in mainland China, this population-based study can provide useful information for worldwide healthcare services and prevention of MS.

Trends in the clinical features of amyotrophic lateral sclerosis: A 14-year Chinese cohort study.

BACKGROUND AND PURPOSE: The aim was to determine the transitional patterns in the clinical characteristics, treatments and comorbidities in amyotrophic lateral sclerosis (ALS) patients over the past 14 years using data from a large clinical cohort in mainland China. METHODS: Sporadic ALS patients who visited the Peking University Third Hospital from January 2005 to December 2018 were included in this study. The 14 years were divided into three periods, and changes in the baseline characteristics of the participants were analyzed at 5-year intervals. RESULTS: In total, 3410 patients with sporadic ALS were recruited: 2181 were men and 1229 were women. The proportion of patients with bulbar-onset ALS increased from 13.0% in 2005-2009 to 19.5% in 2015-2018 (p < 0.001). The mean (standard deviation) age at onset increased from 49.5 (11.4) years in 2005-2009 to 53.0 (11.0) years in 2015-2018 (p < 0.001). ALS patients with diabetes or hypertension showed a delay in ALS onset, and the delay was even more apparent when the patients had both comorbidities. The proportion of riluzole users in 2015-2018 was approximately 2.5-fold of that in 2005-2009 (p < 0.001). CONCLUSIONS: In the context of a lack of clinical data on ALS in mainland China, this study evaluated a large cohort of patients diagnosed over a 14-year period. The age at onset and percentage of patients who used riluzole both increased over the study period. Additionally, it was found that patients with comorbidities such as diabetes and hypertension had a delayed age of ALS onset.

Disease duration of progression is helpful in identifying isolated bulbar palsy of amyotrophic lateral sclerosis.

BACKGROUND: Compared with typical bulbar onset amyotrophic lateral sclerosis (ALS), isolated bulbar palsy (IBP), an often under-understood variant of ALS, is characterized by symptoms confined to bulbar region for extended periods and relative preservation of limb and ventilation function. To find a cutoff value of disease duration that can distinguish IBP from typical bulbar onset ALS well, the association of survival with disease progression in bulbar onset ALS patients was analyzed. METHODS: Clinical data of bulbar onset ALS patients were collected from January 2009 to December 2013. The duration from bulbar onset to first significant limb involvement was analyzed by a cutoff point analysis with maximally selected log-rank statistics and dichotomized to categorize patient outcomes. The patients were divided into two groups, the IBP and typical bulbar onset ALS groups, according to the cutoff value. Clinical features were compared. RESULTS: 115 bulbar onset ALS patients were recruited, and the duration from bulbar onset to first significant limb involvement was associated with survival (P < 0.001). The cutoff duration was 20 months. 19 patients were identified as IBP and 96 patients as typical bulbar onset ALS using 20 months as the cutoff duration. Female was more common, limb weakness was less frequent and pure upper motor neuron (UMN) bulbar signs were more frequent in the IBP group than in the typical bulbar onset ALS group (P = 0.047; P = 0.004; P = 0.031). The median survival time of the IBP group was significantly longer than that of the typical bulbar onset ALS group (64 months and 26 months, respectively; P < 0.001). CONCLUSIONS: A cutoff duration of 20 months from bulbar onset to first significant limb involvement may be used to specifically distinguish IBP from typical bulbar onset ALS. IBP was characterized by female predominance, relative preservation of limb function, more pure UMN bulbar signs and a relatively benign prognosis.

The long non-coding RNA ILF3-AS1 increases the proliferation and invasion of retinoblastoma through the miR-132-3p/SMAD2 axis.

A great deal of evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of retinoblastoma (RB). However, the roles of lncRNA ILF3-AS1 in RB are still unclear. In the present study, our work revealed that the lncRNA ILF3-AS1 was increased in both RB tissues and cell lines. Repression of ILF3-AS1 suppressed both RB cell proliferation and invasion in vitro. ILF3-AS1 also promoted tumor growth in vivo. While exploring the mechanisms behind ILF3-AS1 in RB, we identified that ILF3-AS1 sponges with miR-132-3p that is expressed at low levels in RB tissues as well as attenuates RB progression. Furthermore, SMAD2 was confirmed to be a miR-132-3p target. Finally, we found that SMAD2 overexpression or miR-132-3p inhibitors recover the inhibitory effects of ILF3-AS1 suppression on RB progression. Collectively, these data indicate that ILF3-AS1 is involved in RB progression through the miR-132-3p/SMAD2 axis, providing a novel and promising biomarker that can be used for the treatment of RB.

Using arthroscopy combined with fluoroscopic technique for accurate location of the bone tunnel entrance in chronic ankle instability treatment.

BACKGROUND: Minimally invasive reconstruction techniques are used for anatomical ligament construction of the lateral collateral ligament complex of the ankle, but the two key elements, the bone tunnel and the appropriate graft tension, for the identification of the anatomic location during the surgery are not clearly stated. METHODS: The patients with chronic ankle instability who received arthroscopic anatomic lateral ligament complex reconstruction were retrospectively analyzed. The anatomical location of the bone tunnel was performed under arthroscopy combined with fluoroscopy for accurate location of the bone tunnel entrance. The graft tension and routing were controlled under arthroscopic visualization. The clinical outcomes were assessed using the Karlsson-Peterson score, Sefton articular stability scale, and Visual Analogue Scale (VAS). The complications were recorded during the follow-up. RESULTS: A total of 18 patients were enrolled in this study. The mean follow-up was 33.33 ± 3.69 (range from 24 to 36) months. No patient had recurrence of ankle instability after the operation. According to the Sefton articular stability scale, 94.5% of the patients had excellent/good function. The mean value of the anterior drawer tests and the talar tilt angle examination were decreased. The mean of the Karlsson-Peterson score and the Visual Analogue Scale(VAS) score were both improved significantly. CONCLUSIONS: The anatomic reconstruction of the ankle lateral ligament complex to treat chronic ankle instability using the arthroscopy combined with the fluoroscopic technique could improve the clinical functions, satisfaction, and reduced pain of patients.

Evaluation of chemical similarity among rhizome, pseudo stem and leaf of Musa basjoo by UPLC-ELSD fingerprint combined with chemo metrics methods.

Rhizoma Musa (the Rhizome of Musa basjoo Sied.et Zucc.) is used as a traditional medical herb of Miao nationality in Guizhou province, in China. It has the efficacy of clearing heat and detoxifying, quenching thirst, diuresis, etc. Modern pharmacological studies have shown that it has hypoglycemic, inhibition of α-glucosidase, and anti-inflammatory activity. However, when the rhizomes of Musa basjoo are dug up, the rhizomes are unable regenerate, and the pseudostem and leaf are discarded, which not only pollutes the environment, but also causes a huge waste of herb resources. In this study, a UPLC-ELSD fingerprint analysis with chemometric method was applied for the evaluation of chemical similarity among rhizome, pseudostem and leaf of Musa Basjoo. The results indicated that the combined method could efficiently analyze and compare the chemical similarity among rhizome, pseudostem, and leaf of Musa Basjoo. The proposed method provides the foundation for the resource substitution of the rhizome, pseudostem, and leaf of Musa Basjoo.

Incidence and prevalence of amyotrophic lateral sclerosis in urban China: a national population-based study.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease and information on disease burden of ALS in mainland China was limited. We aimed to estimate the prevalence and incidence of ALS in China. METHODS: We used 2012-2016 data from China's Urban Employee Basic Medical Insurance and Urban Residence Basic Medical Insurance, covering approximately 0.43 billion individuals. ALS cases were identified by the primary diagnosis (International Classification of Diseases code or text of diagnosis) in the insurance database. RESULTS: The crude prevalence and incidence in 2016 were 2.91 per 100 000 person-years (95% CI 2.31 to 3.58) and 1.65 (95% CI 1.33 to 2.01), respectively. The standardised prevalence and incidence based on 2010 Chinese census data were 2.97 (95% CI 2.91 to 3.03) and 1.62 (95% CI 1.58 to 1.67), respectively. The annual prevalence between 2013 and 2016 remained relatively constant, ranging from 2.91 (95% CI 2.31 to 3.58) in 2016 to 3.29 (95% CI 2.51 to 4.17) in 2014 (linear regression: ß=-0.129, p=0.104). Both rates peaked in the group aged 75-79 years. CONCLUSIONS: The prevalence and incidence of ALS in mainland China were lower than those in developed countries, and maintained a relatively stable trend. The age at onset and age at diagnosis for ALS patients were younger than those in developed countries. Further research is expected to clarify the potential pathophysiological mechanism of ALS.