Quantitative association between lead exposure and amyotrophic lateral sclerosis: a Bayesian network-based predictive study.

BACKGROUND: Environmental lead (Pb) exposure have been suggested as a causative factor for amyotrophic lateral sclerosis (ALS). However, the role of Pb content of human body in ALS outcomes has not been quantified clearly. The purpose of this study was to apply Bayesian networks to forecast the risk of Pb exposure on the disease occurrence. METHODS: We retrospectively collected medical records of ALS inpatients who underwent blood Pb testing, while matched controlled inpatients on age, gender, hospital ward and admission time according to the radio of 1:9. Tree Augmented Naïve Bayes (TAN), a semi-naïve Bayes classifier, was established to predict probability of ALS or controls with risk factors. RESULTS: A total of 140 inpatients were included in this study. The whole blood Pb levels of ALS patients (57.00 µg/L) were more than twice as high as the controls (27.71 µg/L). Using the blood Pb concentrations to calculate probability of ALS, TAN produced the total coincidence rate of 90.00%. The specificity, sensitivity of Pb for ALS prediction was 0.79, or 0.74, respectively. CONCLUSION: Therefore, these results provided quantitative evidence that Pb exposure may contribute to the development of ALS. Bayesian networks may be used to predict the ALS early onset with blood Pb levels.

Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival.

OBJECTIVE: Currently, it is unclear whether serum Cystatin C can be used to evaluate the prognosis of ALS. We aim to study the relationship between serum Cystatin C and survival in ALS. METHODS: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, and the Chinese PLA General Hospital from January 2016 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. According to the levels of serum Cystatin C, the participants were divided into high and low Cystatin C levels groups. The comparison between groups was performed with parametric or non-parametric test. Kaplan-Meier method and Cox regression model were used to calculate survival analysis. RESULTS: Three hundred fifty-six sporadic ALS patients were enrolled in this study, including 203 males and 153 females. Among all ALS patients, 26 cases (7.3%) were lost to follow-up, 226 cases (63.5%) died, and 104 cases (29.2%) were still alive at the last follow-up. The median survival time of all ALS patients was 42.0 months. Patients with high Cystatin C levels had shorter median survival than those with lower Cystatin C levels (38.0 months vs. 48.0 months, P = 2.58 × 10-4). In multivariate Cox regression analysis, onset form, age of onset, diagnostic delay, disease progression rate, creatinine, and serum Cystatin C levels were associated with ALS survival. CONCLUSIONS: Our study found that serum Cystatin C was associated with ALS survival, and serum Cystatin C level might be an independent predictor of ALS survival.

Genetically proxied antidiabetic drugs targets and stroke risk.

BACKGROUND: Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk. METHODS: We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification. RESULTS: Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data. CONCLUSIONS: Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.

Sporadic adult-onset neuronal intranuclear inclusion disease without high-intensity signal on DWI and T2WI: a case report.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in cells in the central and peripheral nervous system. High-intensity signal in the corticomedullary junction on diffusion-weighted imaging (DWI) is supportive to the diagnosis of NIID. We describe a patient with sporadic adult-onset NIID but without any high-intensity signal on DWI and T2-weighted imaging (T2WI). CASE PRESENTATION: A 58-year-old woman without special family history developed mild persistent tremor in the right hand and deteriorated 2 years later. At 60 years of age, the patient began to conceive the bank, police and internet being deceptive, further presented apathy and confusion after two and a half years, as well as fabrication of non-existent things. Despite the treatment of antipsychotic drugs due to a diagnosis of mental disorder, the patient appeared weakness in the right limbs. Neurological examination revealed mutism, resting tremor, cogwheel-like rigidity in upper limbs, and weakness in all limbs. Brain magnetic resonance imaging displayed no cerebral atrophy initially but atrophy of frontal, temporal and parietal lobes 5 years later. No any high-intensity signal on DWI and T2WI was revealed. However, hypometabolism in the cortexes with atrophy and the right putamen nucleus were showed on 18F-fluoro-deoxy-glucose positron emission tomography/magnetic resonance. On the basis of 107 GGC repeats (normal number <40) in NOTCH2NLC gene and intranuclear inclusions with p62 immunoreactivity in the adipocyte of cutaneous sweat duct by skin biopsy, NIID was finally diagnosed. The symptomatic treatment was given but the patient had no evident improvement. CONCLUSIONS: Our case highlights that despite the lack of high-intensity signal on DWI and T2WI, NIID is still considered for patients with parkinsonism and mental impairment.

Time of symptoms beyond the bulbar region predicts survival in bulbar onset amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Spreading pattern and time interval of spreading are getting more and more attention. The aim of present study was to investigate spreading pattern in bulbar onset ALS patients and to explore the relationship between time interval of spreading and survival. METHODS: ALS patients with bulbar onset diagnosed at Chinese PLA General Hospital from January 2015 to December 2018 were recruited. Clinical features including gender, onset age, diagnostic delay, the second involved region (SIR), time of symptoms beyond the bulbar region, forced vital capacity (FVC), ALSFRS-R score, electromyography results, and survival time were retrospectively collected. RESULTS: A total of 96 bulbar onset ALS patients were collected. Overall patients showed female predominance. Median age at onset was 56 years. Median diagnostic delay was 8.5 months. Median time of symptoms beyond the bulbar region (TBBR) was 7 months. Median ALSFRS-R score at baseline was 40. Fifty-six (58.3%) patients' SIR were upper limb, 6 (6.3%) patients' SIR were lower limb, 3 (3.1%) patients' SIR were upper and lower limbs, and 5 (5.2%) patients' SIR were thoracic region. Twenty-six (27.1%) patients did not report SIR. The median survival time of patients with TBBR ≥ 7 months was significantly longer than that with TBBR < 7 month. Multivariate Cox regression showed that onset age and TBBR were prognostic factors. CONCLUSIONS: In bulbar onset ALS patients, cervical region is the second most common SIR. TBBR is an independent prognostic factor.

Characteristics of Late-Onset Amyotrophic Lateral Sclerosis in a Chinese Cohort.

OBJECTIVE: This retrospective study analyzed the clinical characteristics and prognosis of the elderly amyotrophic lateral sclerosis (ALS) population in a large sample. METHODS: The study included 1,005 patients with sporadic ALS admitted to Chinese PLA General Hospital between March 2011 and March 2021. We stratified the ALS patients into young and old groups using 2 cutoffs for the age at disease onset (≥65 or ≥70 years old) and compared their demographic, clinical, and survival data. RESULTS: The mean onset age of all patients was 52.79 ± 10.55 years, with 123 (12.24%) having a disease onset ≥65 years and 44 (4.38%) having an onset ≥70 years. There were 624 (62.1%) male patients. More bulbar-onset cases were in the late-onset group (p = 0.001). The sex distribution, time from onset to diagnosis, and the time of symptom spread from spinal or bulbar localization to a generalized localization did not differ between groups. Late-onset patients progressed more rapidly and had a significantly shorter survival. CONCLUSIONS: Chinese ALS patients have an earlier age at onset and a relatively smaller proportion of old onset than European and Japanese patients. Elderly patients are more likely to have bulbar onset, which is related to rapid progression and a shorter survival.

Inflammatory Cytokine Levels in Patients with Sporadic Amyotrophic Lateral Sclerosis.

OBJECTIVES: In the present study, inflammatory factors, including interleukin (IL) and tumor necrosis factor-α (TNF-α) in the peripheral blood of patients with sporadic amyotrophic lateral sclerosis (sALS), were evaluated, and the issue of whether these variables were associated with the progression and severity of the disease examined. METHODS: Data on inflammatory factors, including IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α, were retrospectively collected from 248 sALS patients admitted to the Chinese PLA General Hospital between March 2018 and March 2021. The relationships between the variables and clinical features, including gender, age at onset, site of onset, time from onset to hospital admission, ALS functional rating scale score, and diagnostic category were analyzed. RESULTS: IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α levels were elevated in 43.75%, 7.04%, 16.42%, 25.35%, 1.41%, and 50.72% of ALS patients, respectively, compared with the normal value range. IL-2 and IL-6 levels were inversely associated with the ALS functional rating scale score (r = -0.280, p = 0.004 and r = -0.198, p = 0.048). CONCLUSION: Elevated levels of inflammatory cytokines support the hypothesis of an inflammatory response in ALS, and IL-2 and IL-6 may be used as an inflammation-related biomarker for disease severity.

Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy.

BACKGROUND: Adrenoleukodystrophy is a rare neurogenetic disease, AMN is the most common adult phenotype, such patients in China have not gotten enough attention. This article aims to study the features of AMN in Chinese patients and expand the gene spectrum of Chinese X-linked adrenoleukodystrophy (X-ALD) patients. METHODS: We applied clinical analysis, radiology, plasma levels of very long chain fatty acids (VLCFA) and genetic analysis to test the 6 Chinese AMN patients. RESULTS: All 6 patients are men. Ages of neurological symptom onset are distributed between 21 and 38. Sexual dysfunction occurred in 5 of 6 patients. Three patients had positive family history. Five patients had Addison's disease. Four patients were diagnosed as pure AMN, while the other two patients were with cerebral involvement. Four patients had abnormalities of nerve conduction studies. There were four patients with central conduction defects in somatosensory evoked potential tests. All 6 patients were found diffuse cord atrophy in spinal MRI. Brain MRI showed abnormal signals in 2 of the 6 tested patients, which indicated the clinical phenotypes. Plasma levels of VLCFA, as well as C24:0/C22:0 and C26:0/C22:0 ratios were elevated in 5 tested patients. Five different ABCD1 mutations were identified in 5 tested patients, one of which was a de novo mutation, and the other four have been reported previously. CONCLUSION: This research described the clinical, neuroimaging, biochemical, and genetic sides of Chinese AMN patients. A de novo mutation in the ABCD1 gene sequence was identified. Emotional trauma may trigger or aggravate the development of cerebral demyelination in AMN patients. Regular evaluation of brain MRI is important for AMN patients, especially for 'pure AMN' patients. When encountering patients with 'myeloneuropathy-only', neurologists should not ignore the tests of VLCFA or/and the ABCD1 gene.

Molecular identification of species of Physalis (Solanaceae) using a candidate DNA barcode: the chloroplast psbA-trnH intergenic region.

Physalis L., an important genus of the family Solanaceae, includes many commercially important edible and medicinal species. Traditionally, species identification is based on morphological traits; however, the highly similar morphological traits among species of Physalis make this approach difficult. In this study, we evaluated the feasibility of using a popular DNA barcode, the chloroplast psbA-trnH intergenic region, in the identification of species of Physalis. Thirty-six psbA-trnH regions of species of Physalis and of the closely related plant Nicandra physalodes were analyzed. The success rates of PCR amplification and sequencing of the psbA-trnH region were 100%. MEGA V6.0 was utilized to align the psbA-trnH sequences and to compute genetic distances. The results show an apparent barcoding gap between intra- and interspecific variations. Results of both BLAST1 and nearest-distance methods prove that the psbA-trnH regions can be used to identify all species examined in the present study. In addition, phylogenetic analysis using psbA-trnH data revealed a distinct boundary between species. It also confirmed the relationship between species of Physalis and closely related species, as established by previous studies. In conclusion, the psbA-trnH intergenic region can be used as an efficient DNA barcode for the identification of species of Physalis.

Evaluation of Next-Generation Sequencing for the Diagnosis of Infections of the Central Nervous System Caused by the Neurotropic Herpes Viruses: A Pilot Study.

BACKGROUND: There are sparse and limited studies on small sample size reporting the application of next-generation sequencing (NGS) in the detection of central nervous system (CNS) viral infections. We assessed the diagnostic performance of NGS of cerebrospinal fluid (CSF) for predicting viral infections of the CNS caused by the neurotropic herpes viruses in a pilot population. MATERIALS AND METHODS: We prospectively collected CSF samples from 24 patients with CNS viral infection from April 2017 to October 2018. Of the 24 patients, 19 patients were infected with herpes simplex virus 1 (HSV-1), 1 patient with HSV-2, and 4 patients with varicella-zoster virus (VZV). All CSF samples were screened for viral DNA using NGS technologies to detect viral CNS infections. RESULTS: Of the 24 patients with confirmed viral CNS infection caused by the neurotropic herpes viruses, 10 (10/24, 41.67%) patients exhibited positive NGS results. With the help of NGS, HSV-1 DNA was detected in the CSF of 6 patients (6/19; 31.58%). HSV-2 DNA was detected in 1 patient (1/1; 100%) and VZV DNA was detected in 3 patients (3/4; 75%). The positive rate of virus detected by NGS decreased with time. The positive rates of NGS of CSF in the first, second, and third weeks were 54.5% (6/11), 44.4% (4/9), and 0% (0/4), respectively. CONCLUSIONS: NGS method is a promising pathogen detection tool for identifying viral CNS infections. It should be recommended to sequence viral DNA of CSF in the early stage of CNS viral infections.

[The value of electromyography in differentiating intramedullary tumor from inflammatory demyelinating disease of cervical region].

OBJECTIVE: To investigate the value of needle electromyography (EMG) in differentiating intramedullary tumor from inflammatory demyelinating disease of cervical region. METHODS: Patients hospitalized in the Chinese PLA General Hospital from March 2008 to June 2013 with abnormalities on MRI of cervical vertebra and preliminary diagnosed as intramedullary tumor or inflammatory demyelinating disease of cervical region were enrolled in the study. Electrophysiological examination was performed before any treatment. Pathological findings were analyzed and prognosis was evaluated in all the subjects. RESULTS: A total of fifty-five patients were enrolled in the study with 33 cases of inflammatory demyelinating disease and 22 cases of intramedullary tumor defined by the postoperative pathological findings. In all the 33 cases with demyelinating disease, only one case (3.03%) presented as neurogenic damage by needle EMG. While in all the 22 cases with intramedullary tumor, needle EMG revealed neurogenic damage in 15 cases (68.18%) and the spinal segments of muscles with neurogenic damage were all within the spinal lesions demonstrated by MRI. The diagnostic sensitivity of EMG for intramedullary tumor was 68.18% and the diagnostic specificity was 96.97%, while the diagnostic sensitivity and specificity for intramedullary tumor by the medical history, symptoms and signs were 59.09% and 75.76% respectively. CONCLUSION: Needle EMG might play an important role in distinguishing intramedullary tumor from inflammatory demyelinating disease of cervical spinal cord.

[Clinical, magnetic resonance imaging and neuroelectrophysiological characteristics of 14 patients with lumbosacralradiculitis].

OBJECTIVE: To improve the understanding of lumbosacralradiculitis by analyzing the clinical, magnetic resonance imaging (MRI) and neuroeletrophysiological characteristics of disease. METHODS: The clinical, MRI and neuroeletrophysiological data of 14 patients diagnosed as lumbosacralradiculitis were retrospectively analyzed. RESULTS: The predominant age of onset was in the forth decade. Each patient had bilateral or unilateral lower extremity numbness and weakness of variable severity, including muscle atrophy (n = 5) and decreased sensation in L4-S1 nerve root territory (n = 9). Lower extremity tendon reflexes decreased or became absent in all patients. Urinary and defecation disorders were seen in 3 patients. Lumbosacral MRI showed lumbosacral meninges and nerve root enhancement in 4 patients. Cerebrospinal fluid analysis revealed elevated white blood cell (30×10(6)/L) (n = 1) and increased protein content (n = 12) (450-1 000 mg/L, n = 7; 1 000-2 000 mg/L, n = 3; 2 000-3 000 mg/L, n = 2). Needle electromyography (EMG) demonstrated neurogenic damage in 13 patients. Motor nerve conduction study showed decreased motor never conduction velocity (MCV) (n = 5), decreased compound muscle action potential (CMAP) amplitude (n = 12), CMAP absent at right side (n = 2) and left side (n = 1) among 22 peroneal nerves; decreased MCV (n = 6), decreased CMAP amplitude (n = 6), CMAP absent at right side (n = 2) and left side (n = 1) among 23 tibial nerves. F-wave was performed for 11 patients and abnormal in 6 patients, with prolonged latency and reduced occurrence rate in right common peroneal nerve (n = 2), left prolonged latency (n = 3) and right tibial nerve (n = 1) respectively. Bilateral sural nerve conduction study revealed no abnormality. CONCLUSION: Diagnosing lumbosacralradiculitis is not easy based on lumbosacral MRI. And neuroelectrophysiological study may provide more valuable information in verifying the location of lesions and judging the damage extent of lumbosacralradiculitis.

Prognostic value of geriatric nutritional risk index in patients with amyotrophic lateral sclerosis.

BACKGROUND: The geriatric nutritional risk index (GNRI) is a prognostic indicator for several diseases, meanwhile, nutrition and inflammation play important roles in the disease progression of amyotrophic lateral sclerosis (ALS). However, the association between the GNRI and ALS remains unknown. METHODS: 443 patients diagnosed with ALS were divided into two groups based on the GNRI levels. Associations between GNRI and survival time were analyzed using Kaplan-Meier curves and compared by the log-rank test. Univariate and multivariate analyses were used to assess their prognostic values for survival time. Spearman correlation analysis was used to evaluate the correlation coefficients between GNRI and other clinical variables. RESULTS: No significant differences were found in diagnostic delay between the two groups. The onset age and disease progression rate (DPR) were significantly lower in high GNRI group while forced vital capacity (FVC), revised version of the ALS functional rating scale (ALSFRS-R), serum albumin and body mass index (BMI) were significantly lower in low GNRI group. Lower GNRI levels were linked with shorter ALS patients' survival time by Kaplan-Meier curves. The univariate and multivariate analysis identified the onset age, gender, onset site, diagnostic delay, DRP and GNRI as predictors of survival time in patients with ALS. CONCLUSION: Nutritional status was closely corelated with ALS progression. The GNRI may be used as a potential prognostic indictor for ALS patients.

microRNA-mRNA expression profiles in the skeletal muscle of myotonic dystrophy type 1.

OBJECTIVES: Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, yet there are currently no disease-modifying treatments. Disrupted miRNA expressions may lead to dysregulation of target mRNAs and dysfunction involved in DM1 pathogenic mechanism. METHODS: We used microarray platforms to examine the miRNA/mRNA expression profiles in skeletal muscle biopsies derived from DM1 patients and matched controls. Bioinformatics analysis and dual-luciferase reporter assay were conducted to provide insight into miRNA-mRNA regulatory networks altered in DM1. RESULTS: Twenty-three differentially expressed miRNAs and 135 differentially expressed genes were identified. qPCR confirmed that miR-3201, myogenic factor 5 (MYF5), myogenic differentiation 1 (MYOD1), CUGBP, Elav-like family member 1 (CELF1), and CELF2 were significantly up-regulated, while miR-196a, miR-200c, and miR-146a were significantly down-regulated. Enriched functions and pathways such as multicellular organismal development, RNA splicing, cell differentiation, and spliceosome are relevant to DM1. The miRNA-mRNA interaction network revealed that miR-182, miR-30c-2, and miR-200c were the critical nodes that potentially interacted with hub genes. Luciferase reporter assay confirmed the direct interaction between miR-196a and CELF2. CONCLUSION: Those results implied that the observed miRNA/mRNA dysregulation could contribute to specific functions and pathways related to DM1 pathogenesis, highlighting the dysfunction of miR-196a and CELF2.

Repetitive nerve stimulation on survival in amyotrophic lateral sclerosis.

Objective: No previous studies investigated the association between decrement of low-frequency repetitive nerve stimulation (LF-RNS) and amyotrophic lateral sclerosis (ALS) survival. We aim to study the relationship between decrement and survival in ALS. Methods: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, Chinese PLA General Hospital from January 2018 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. A decremental response of 10% or greater at least in one muscle was considered positive. According to the decrement, the participants were divided into LF-RNS (+) and LF-RNS (-) groups. Results: One hundred and eighty-one sporadic ALS patients were recruited in our study, including 100 males and 81 females. Among them, 10 cases (5.5%) were lost to follow-up, 99 cases (54.7%) died, and 72 patients (39.8%) were still alive at the last follow-up. The median survival time of all ALS patients in this study was 42.0 months. There was no significant difference of median survival in LF-RNS(+) group and LF-RNS(-) group (p = 0.159, Kaplan-Meier method). In multivariate Cox regression analysis, age of onset, diagnostic delay, and ALS Functional Rating Scale-Revised (ALSFRS-R) score were associated with ALS survival, but the decrement was not correlated with ALS survival (p = 0.238). Conclusion: The decrement in accessory and ulnar nerves was not associated with the survival of ALS. The decrement of LF-RNS could not be an electrophysiological marker to predict ALS survival.

Mendelian Randomization Identifies Genetically Supported Drug Targets for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Currently, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have no effective treatments. Drug repurposing offers a rapid method to meet therapeutic need for ALS and FTD. To identify therapeutic targets associated with ALS and FTD, Mendelian randomization (MR) analysis and colocalization were performed. Genetic instruments were based on transcriptomic and proteomic data for 422 actionable proteins targeted by approved drugs or clinical drug candidates. The publicly available ALS GWAS summary data (including a total of 20,806 ALS cases and 59,804 controls) and FTD GWAS summary data (including a total of 2154 patients with FTD and 4308 controls) were used. Using cis-expression quantitative trait loci and cis-protein quantitative trait loci genetic instruments, we identified several drug targets for repurposing (ALS: MARK3, false-discovery rate (FDR) = 0.043; LTBR, FDR = 0.068) (FTD: HLA-DRB1, FDR = 0.083; ADH5, FDR = 0.056). Our MR study analyzed the actionable druggable proteins and provided potential therapeutic targets for ALS and FTD. Future studies should further elucidate the underlying mechanism of corresponding drug targets in the pathogenesis of ALS and FTD.

Gender-specific association of uric acid and survival in sporadic amyotrophic lateral sclerosis patients.

OBJECTIVE: To investigate the relationship between serum uric acid (UA) and survival in sporadic amyotrophic lateral sclerosis (sALS) patients. METHOD: A total of 801 sporadic amyotrophic lateral sclerosis (sALS) patients fulfilled the revised El Escorial criteria were enrolled and followed up in the study. Baseline clinical data and laboratory variables including gender, age, age of onset, site of onset, disease duration, body mass index (BMI), uric acid (UA), creatinine (Cr), and creatine kinase (CK) were collected during enrollment. Multivariate Cox regression models were used to evaluate the survival-related factors after adjustment for confounders. RESULTS: The serum UA level was significantly lower in female patients than that in male patients (243.5 vs 314.9 µmol/L, p < 0.001). Gender, BMI, Cr, CK were significantly associated with the level of uric acid according to the linear regression analysis. In the multivariate Cox regression analysis, higher serum UA level (>268.0 µmol/L) was an independent protective factor for prolonged survival among female patients (HR = 0.69, P = 0.042) after adjustment for confounders. CONCLUSION: The present study provided further support that higher UA was a protective factor for survival in sALS patients, especially in female.

The protective role of mesencephalic astrocyte-derived neurotrophic factor in endoplasmic reticulum stress in RT4-D6P2T schwannoma sells with the S63del MPZ mutation.

BACKGROUND: Endoplasmic reticulum stress (ERS) occurred in S63del mutant CMT1B mice model, and few drugs has been studied. Mesencephalic astrocyte-derived neurotrophic factor (MANF) can inhibit ERS. This study aimed at investigating the effect of MANF on ERS of RT4-D6P2T schwannoma cells with S63del MPZ Mutation. METHODS: Experimental grouping: blank control group, blank control + MANF group, lentivirus group, lentivirus + MANF group, S63del MPZ group, S63del MPZ + MANF group. CCK8 and Annexin-FITC/PI were used to detect cell proliferation and apoptosis. JC-1 was used to detect ΔΨm. MANF, GRP78 and CHOP mRNA and protein were detected by using RT-qPCR, western blotting and immunofluorescence. ER-Tracker and mito-tracker were used to observe the morphology of endoplasmic reticulum (ER) and mitochondria. RESULTS: Cell proliferation decreased (p < 0.001) and apoptosis increased (p < 0.001) in S63del MPZ group; cell proliferation increased (p = 0.005) and apoptosis decreased (p < 0.001) in S63del MPZ + MANF group. ΔΨm decreased (p < 0.001), MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 increased (p < 0.001) and Bcl2 decreased (p < 0.001) in S63del MPZ group. MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 decreased (p < 0.001) and Bcl2 increased (p < 0.001) in S63del MPZ group. CONCLUSIONS: ERS occurred in RT4-D6P2T cells with S63del MPZ mutation, and MANF exerted protective effect in RT4-D6P2T cells with S63del MPZ mutation.

Association between Genetically Proxied Inhibition of HMG-CoA Reductase and Age at Onset of Huntington's Disease.

BACKGROUND: Previous studies have found that statins may play a potential role in the age at onset (AAO) of Huntington's disease (HD). We performed this Mendelian randomization (MR) study to assess the association between genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and low-density lipoprotein (LDL) cholesterol with age at onset of HD. METHODS: Single-nucleotide polymorphisms (SNPs) in HMG-CoA reductase associated with LDL cholesterol in a genome-wide association study (GWAS) analysis were used. The summary data of residual AAO of HD were obtained from a GWAS meta-analysis (n = 9064 HD patients). MR estimates representing lifelong inhibition of drug targets were generated using random-effects inverse-variance weighted analysis. RESULTS: Genetically proxied plasma LDL cholesterol (ß = 0.039, 95% CI = -0.454 to 0.531) and HMG-CoA reductase inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL cholesterol (ß = -2.228, 95% CI = -4.830 to 0.374) were not associated with age at onset of HD. CONCLUSION: The plasma LDL cholesterol levels and the reduction of plasma LDL cholesterol levels by the inhibition of HMG-CoA reductase (i.e., statins) were not associated with the age of HD onset.