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Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease preferentially affects the optic nerve and the spinal cord. The first attack usually occurs in the third or fourth decade, though patients with disease onset in the fifties or later are not uncommon. This study aimed to investigate the clinical characteristics and prognosis in patients with different age of onset and to explore the correlations between age of onset and clinical characteristics and prognostic outcomes. We retrospectively reviewed the medical records of 298 NMOSD patients diagnosed according to the 2015 updated version of diagnostic criteria. Patients were divided into early-onset NMOSD (EO-NMOSD) (<50 years at disease onset) and late-onset NMOSD (LO-NMOSD) (≥50 years at disease onset) based on the age of disease onset. LO-NMOSD patients were divided into two subgroups: relative-late-onset NMOSD (RLO-NMOSD) (50~70 years at disease onset) and very-late-onset NMOSD (≥70 years at disease onset). Clinical characteristics, laboratory findings, neuroimaging features, and prognostic outcomes were investigated. Compared to EO-NMOSD patients, patients with LO-NMOSD showed more frequent transverse myelitis (TM) (58.20% vs. 36.00%, = 0.007) while less frequent optic neuritis (ON) (23.10% vs. 34.80%, = 0.031) and brainstem/cerebral attacks (7.50% vs. 18.30%, = 0.006) as the first attack. Patients with LO-NMOSD showed less frequent relapses, higher Expanded Disability Status Scale (EDSS) score at the last follow-up, fewer NMOSD-typical brain lesions, and longer segments of spinal cord lesions. Patients with older onset age showed a higher proportion of increased protein levels in cerebrospinal fluid during the acute phase of attacks. Age at disease onset positively correlated with length of spinal cord lesions at first attack and at last follow-up, negatively correlated with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up), irrespective of AQP4-IgG serostatus. Patients with older age at disease onset progressed to severe motor disability sooner, and age of onset positively correlated with EDSS score at the last follow-up, irrespective of AQP4-IgG serostatus. Age of disease onset affects clinical characteristics and prognosis outcomes of patients with NMOSD.

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The presence of Lewy bodies is a major pathological change of PD. α-synuclein is the main component of Lewy bodies and is encoded by the SNCA gene. Mutations in the SNCA gene mainly result in rare familial forms of PD, while genetic variability in the SNCA gene modulates susceptibility to sporadic PD. Recent studies have suggested that levels of α-synuclein in extracellular biological fluid are associated with PD and implicated α-synuclein as a potential biomarker for PD diagnosis and severity. We studied serum α-synuclein concentration and two polymorphic variants of SNCA (Rep1 and rs11931074) in 110 sporadic PD patients and 136 controls. We further explored the influence of the two polymorphisms on the expression levels of serum α-synuclein. Soluble α-synuclein was detected in serum in all subjects, with no statistically significant difference between PD patients and controls ( p  = 0.611). Different Rep1 alleles and genotypes did not influence the expression of serum α-synuclein. The frequency of allele T of rs11931074 was significantly elevated in PD patients ( p  = 0.041), and was correlated with decreased serum α-synuclein in both dominant ( p  = 0.011) and additive ( p  = 0.008) models of association.

BackgroundAbnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.MethodsPatients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.ResultsIn the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.ConclusionsNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo . A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of Lewy bodies is a major pathological change of PD. α-synuclein is the main component of Lewy bodies and is encoded by the SNCA gene. Mutations in the SNCA gene mainly result in rare familial forms of PD, while genetic variability in the SNCA gene modulates susceptibility to sporadic PD. Recent studies have suggested that levels of α-synuclein in extracellular biological fluid are associated with PD and implicated α-synuclein as a potential biomarker for PD diagnosis and severity. We studied serum α-synuclein concentration and two polymorphic variants of SNCA (Rep1 and rs11931074) in 110 sporadic PD patients and 136 controls. We further explored the influence of the two polymorphisms on the expression levels of serum α-synuclein. Soluble α-synuclein was detected in serum in all subjects, with no statistically significant difference between PD patients and controls (p = 0.611). Different Rep1 alleles and genotypes did not influence the expression of serum α-synuclein. The frequency of allele T of rs11931074 was significantly elevated in PD patients (p = 0.041), and was correlated with decreased serum α-synuclein in both dominant (p = 0.011) and additive (p = 0.008) models of association.[PUBLICATION ABSTRACT]

Background Acute myeloid leukemia (AML) is a highly malignant hematopoietic disease, with low remission and high relapse rates, and there is currently no effective treatment except for acute promyelocytic leukemia. DExH-Box Helicase 9, a member of the DExD/H-box family of helicases, is highly expressed in some solid tumors and associated with poor prognosis. However, its role in AML has not been reported. This study aimed to investigate the clinical significance and biological roles of DHX9 in AML. Methods Specific gene primers and TaqMan probes were prepared to construct absolute quantitative methods for DHX9. Receiver operating characteristic curves were constructed to evaluate the diagnostic and prognostic value of DHX9. Series of shRNA-mediated DHX9 knockdown experiments to assess the functional roles of DHX9 such as proliferation, cell cycle, apoptosis and differentiation ability. In addition, bioinformatic analysis was used to find out which potential pathways DHX9 participated in. Results A detection method for DHX9 was successfully established. DHX9 was highly expressed in the AML patients with aberrant myeloid blasts. Significant differences were found among patients with different risk levels, with high levels of DHX9 related to a poor prognosis. shRNA-mediated DHX9 knockdown significantly inhibited the proliferation and cell cycle, and induced apoptosis and differentiation in THP-1 and MOLM-13 cells. Further bioinformatic analysis showed that DHX9 expression was significantly associated with metabolism pathways, suggesting that DHX9 may be involved in the metabolic reprogramming of AML blasts. Conclusions Our study discovers that DHX9 promotes AML development and may serve as a biomarker for AML, holding a better prospect for clinical application.

This study aimed to investigate the efficacy and safety of a novel balloon catheter in dilation intervention for patients with cricopharyngeus achalasia after stroke. Thirty-four patients with cricopharyngeus achalasia after stroke received routine swallowing rehabilitation training and were randomly assigned to an experimental group (Exp, n = 17) that received dilation therapy using the novel balloon catheter once daily for 5 days per week or a control group (Con, n = 17) that received dilation therapy with a 14-Fr ordinary urinary catheter once daily for 5 days per week. The intervention duration, Eating Assessment Tool (EAT)-10 scores, and Functional Oral Intake Scale (FOIS) scores were recorded at baseline and each day during intervention. The time for a patient’s FOIS score to be ≥ 3 as well as the recovery time for oral intake of water, liquid food, mushy food, and solid food were recorded or estimated. Complications were also recorded during intervention. The intervention duration was shorter in the Exp group than in the Con group (p = 0.005). The Exp group patients improved faster than the Con group patients, with a shorter recovery time for oral intake of liquid food (p = 0.002), mushy food (p = 0.001), and solid food (p = 0.001). At the time of intervention termination, EAT-10 scores were lower in the Exp group than in the Con group (p = 0.005). The Exp group had a similar incidence of complications as the Con group but with better tolerability (p = 0.028). Compared with the urinary catheter, the novel balloon catheter for dilation in patients with cricopharyngeus achalasia after stroke may lead to a better and more rapid recovery.