Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.

BACKGROUND: It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. METHODS AND RESULTS: In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%. A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% versus 5.6%) and dementia (2.9% versus 0.8%) compared with noncarriers. After adjustment for associated risk factors, the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio [OR], 2.697 [95% CI, 1.266-5.745]; P=0.040) and dementia (OR, 8.498 [95% CI, 1.727-41.812]; P=0.032). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There was no statistical difference in the change in longitudinal cognitive scale scores. CONCLUSIONS: Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.

Association Between Wnt Target Genes and Cortical Volumes in Alzheimer's Disease.

The disproportionate cortical atrophy is an established biomarker for the pathophysiological process of Alzheimer's disease (AD). However, the genetic basis underlying the cortical atrophy remains poorly defined. Herein, we aim to illustrate the effect of the Wnt target genes on the cortical volumes of AD patients. 82 sporadic AD patients were recruited. All the subjects had history survey, blood biochemical examination, cognitive assessment, MRI morphometry and whole exome sequencing. This report focused on 84 common variants (minor allele frequency > 0.01) of 32 Wnt target genes, including the APC, DAAM1, DACT1, DISC1, LATS2, TLR2, WDR61, and the AXIN, DVL, FZD, LRP, TCF/LEF, WNT family genes. The Wnt target genes showed asymmetric effects on the cortical volumes of AD patients. The right temporal/parietal/occipital cortices were more affected than left temporal/parietal/occipital cortices. Nevertheless, the reverse applied to the frontal cortex. The DACT1 affected the cortical thickness most, followed by the TCF3 and APC. The DACT1 rs698025-GG genotype displayed greater right temporal pole and left medial orbito-frontal gyrus than rs698025-GA genotype (2.4 ± 0.4 vs. 2.0 ± 0.6, P = 0.005; 5.2 ± 0.6 vs. 5.0 ± 0.6, P = 0.001). The brain region most influenced by the Wnt target genes was the right calcarine cortex. In conclusion, the common variants of the Wnt target genes exert asymmetric effects on the cortical volumes of AD patients. The Wnt signaling pathway may play a role in the cortical atrophy of AD patients.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.

BACKGROUND: The pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders. METHODS: The participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2-3. RESULTS: Among the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration. CONCLUSION: There is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Astrocytic purinergic signalling contributes to the development and maintenance of neuropathic pain via modulation of glutamate release.

Although activation of astrocytes is critical in developing neuropathic pain (NP) following nerve injury, the underlying mechanisms of NP and therapeutic management for NP are still vague. Importantly, the decreases in the levels of astrocytic glutamate transporter-1 (GLT-1) in the spinal dorsal horn result in enhanced excitatory transmission and cause persistent pain. P2Y1 purinergic receptor (P2Y1R) has been shown to enhance many inflammatory processes. The up-regulated expression of astrocytic P2Y1R is crucial to participate in pain transduction under conditions of nerve injury and peripheral inflammation considering that P2Y1R is potentially involved in glutamate release and synaptic transmission. This study indicates that the expression of P2Y1R in the spinal cord was increased accompanied by the activation of A1 phenotype astrocytes in the rat model of spinal nerve ligation (SNL). Astrocyte-specific knockdown of P2Y1R alleviated SNL-induced nociceptive responses and mitigated A1 reactive astrocytes, which subsequently increased GLT-1 expression. Conversely, in naïve rats, P2Y1R over-expression induced a canonical NP-like phenotype and spontaneous hypernociceptive responses and increased the concentration of glutamate in the spinal dorsal horn. Besides, our in vitro data showed that the proinflammatory cytokine tumour necrosis factor-alpha contributes to A1/A2 astrocyte reactivity and Ca2+ -dependent release of glutamate. Conclusively, our results provide novel insights that as a significant regulator of astrocytic A1/A2 polarization and neuroinflammation, P2Y1R may represent a potential target for the treatment of SNL-induced NP.

Iron metabolism in non-anemic myasthenia gravis patients: A cohort study.

BACKGROUND: The association of iron metabolism parameters with disease severity and outcome in myasthenia gravis (MG) patients has not been reported. This study was conducted to determined clinical factors including iron metabolism parameters correlated with disease severity and future outcome in non-anemic immunotherapy-naïve MG patients first receiving immunotherapy. MATERIAL AND METHODS: One hundred and ten patients were included at baseline to explore predictor variables associated with disease severity represented by variables derived from MG activities of daily living (MG-ADL) score using multivariate logistic regression, after which 103 and 98 patients were included respectively in multivariate survival analyses at 6-month and 12-month follow-up to identify predictors for minimal manifestation status (MMS) after starting immunotherapy. RESULTS: Higher ferritin level was independently associated with higher risk of severe generalized disease in non-anemic immunotherapy-naïve MG patients. Total iron binding capacity <250 µg/dL and the interval between onset and immunotherapy <1 year were independent predictors for MMS at 6-month and 12-month follow-up after initiating immunotherapy. Transferrin <2.00 g/L was an independent predictor for MMS at 12-month follow-up. CONCLUSION: Iron metabolism parameters might be promising biomarkers for evaluating disease severity and guiding therapeutic decision in MG patients.

Autoimmune Cerebellar Ataxia: Etiology and Clinical Characteristics of a Case Series from China.

Autoimmune cerebellar ataxia (ACA) is an important and potentially treatable cause of sporadic cerebellar syndrome, but studies with large sample size are limited. This study reported a large ACA series in China and described its etiology and clinical characteristics. We reviewed all ACA patients from our hospital (2013-2021) and analyzed their clinical and paraclinical features, treatment, and outcome. ACA subtypes investigated included paraneoplastic cerebellar degeneration (PCD), primary autoimmune cerebellar ataxia (PACA), anti-glutamate decarboxylase (GAD)-associated cerebellar ataxia, opsoclonus-myoclonus syndrome (OMS), Miller Fisher syndrome (MFS), and ACA-associated with autoimmune encephalitis. A total of 127 patients were identified and 40.9% were male. The median onset age was 47.0 years. Gait ataxia was the most prevalent feature followed by limb ataxia, dizziness, and dysarthria/dysphagia. Extracerebellar manifestations included pyramidal signs (28.3%) and peripheral neuropathy/radiculopathy (15.0%). ACA subtypes were PCD (30.7%), PACA (37.8%), ACA associated with autoimmune encephalitis (12.6%), anti-GAD-associated ACA (8.7%), MFS (7.1%), and OMS (3.1%). Neuronal antibodies were positive in 67.7% of patients. Brain magnetic resonance imaging was unremarkable (55.7%) or showed atrophy (18.3%) or abnormal signal intensity (26.1%, most of which was extracerebellar). Although most patients received immunotherapy, the modified Rankin scale at last follow-up was ≤ 2 in only 47.3% patients. Thirteen patients died and 24 relapsed. Compared with PACA, PCD patients were older and had poorer outcome. This study illustrates the heterogeneity in the clinical features of ACA and suggests the importance of neuronal antibody testing in ACA diagnosis. PCD and PACA are the dominant ACA subtypes, and the former has a less favorable prognosis.

Clinical-neuroimaging-pathological relationship analysis of adult onset Neuronal Intranuclear Inclusion Disease (NIID).

BACKGROUND: Neuronal Intranuclear Inclusion Disease (NIID) is a degenerative disease with heterogeneous clinical manifestations. We aim to analysis the relationship between clinical manifestations, neuroimaging and skin pathology in a Chinese NIID cohort. METHODS: Patients were recruited from a Chinese cohort. Detail clinical information were collected. Visual rating scale was used for evaluation of neuroimaging. The relationship between clinical presentations and neuroimaging, as well as skin pathology was statistically analyzed. RESULTS: Thirty-two patients were recruited. The average onset age was 54.3 y/o. 28.1% had positive family history. Dementia, autonomic nervous system dysfunction, episodic attacks were three main presentations. CSF analysis including Aß42 and tau level was almost normal. The most frequently involved on MRI was periventricular white matter (100%), frontal subcortical and deep white matter (96.6%), corpus callosum (93.1%) and external capsule (72.4%). Corticomedullary junction DWI high intensity was found in 87.1% patients. Frontal and external capsule DWI high intensity connected to form a "kite-like" specific image. Severity of dementia was significantly related to leukoencephalopathy (r = 0.465, p = 0.0254), but not cortical atrophy and ventricular enlargement. Grey matter lesions were significantly associated with encephalopathy like attacks (p = 0.00077) but not stroke like attacks. The density of intranuclear inclusions in skin biopsy was not associated with disease duration, severity of leukoencephalopathy and dementia. CONCLUSIONS: Specific distribution of leukoencephalopathy and DWI high intensity were indicative. Leukoencephalopathy and subcortical mechanism were critical in pathogenesis of NIID. Irrelevant of inclusion density and clinical map suggested the direct pathogenic factor need further investigation.

Recurrent headache and visual symptoms in a young man: a rare neuronal intranuclear inclusion disease case report.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease. Patients with NIID may present with heterogeneous clinical symptoms, including episodic encephalopathy, dementia, limb weakness, cerebellar ataxia, and autonomic dysfunction. Among the NIID cases reported in China, patients often have complicated and severe manifestations. Therefore, many clinicians do not consider the disease when the patient presents with relatively minor complaints. CASE PRESENTATION: We present the case of a 39-year-old man showing migraine-aura-like symptoms for the past 3 years. Brain magnetic resonance imaging (MRI) revealed hyperintense signals in the splenium of the corpus callosum and corticomedullary junction on diffusion-weighted imaging (DWI) over time. In addition, brain atrophy that was not concomitant with the patient's age was detected while retrospectively reviewing the patient's imaging results. Genetic analysis and skin biopsy confirmed a diagnosis of NIID. The patient was treated with sibelium, and the symptoms did not recur. DISCUSSION AND CONCLUSIONS: Migraine-aura-like symptoms may be the predominant clinical presentation in young patients with NIID. Persistent high-intensity signals on DWI in the brain and early-onset brain atrophy might be clues for the diagnosis of NIID.

Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study.

BACKGROUND AND PURPOSE: Although inflammation has been proposed to be a candidate risk factor for cerebral small vessel disease (CSVD), previous findings remain largely inconclusive and vary according to disease status and study designs. The present study aimed to investigate possible associations between inflammatory biomarkers and MRI markers of CSVD. METHODS: A group of 15 serum inflammatory biomarkers representing a variety of those putatively involved in the inflammatory cascade was grouped and assessed in a cross-sectional study involving 960 stroke-free subjects. The biomarker panel was grouped as follows: systemic inflammation (high-sensitivity C reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α), endothelial-related inflammation (E-selectin, P-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), CD40 ligand, lipoprotein-associated phospholipase A2, chitinase-3-like-1 protein and total homocysteine (tHCY)) and media-related inflammation (matrix metalloproteinases 2, 3 and 9, and osteopontin). The association(s) between different inflammatory groups and white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), enlarged perivascular space (PVS) and the number of deep medullary veins (DMVs) were investigated. RESULTS: High levels of serum endothelial-related inflammatory biomarkers were associated with both increased WMH volume (R2=0.435, p=0.015) and the presence of lacunes (R2=0.254, p=0.027). Backward stepwise elimination of individual inflammatory biomarkers for endothelial-related biomarkers revealed that VCAM-1 was significant for WMH (ß=0.063, p=0.005) and tHCY was significant for lacunes (ß=0.069, p<0.001). There was no association between any group of inflammatory biomarkers and CMBs or PVS. Systemic inflammatory biomarkers were associated with fewer DMVs (R2=0.032, p=0.006), and backward stepwise elimination of individual systemic-related inflammatory biomarkers revealed that hsCRP (ß=-0.162, p=0.007) was significant. CONCLUSION: WMH and lacunes were associated with endothelial-related inflammatory biomarkers, and fewer DMVs were associated with systemic inflammation, thus suggesting different underlying inflammatory processes and mechanisms.

NLRC4 Gene Single Nucleotide Polymorphisms Are Associated with the Prognosis of Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: To analyze and study the correlation between NLR family CARD domain-containing 4 (NLRC4) gene single nucleotide polymorphisms and the prognosis of patients with hemophagocytic lymphohistiocytosis (HLH). METHODS: In this study, we retrospectively studied the clinical data of 62 HLH patients, including 40 males and 22 females. The genomic DNA was extracted, and the genotypes at rs385076 locus and rs479333 locus of the NLRC4 gene were analyzed. The level of blood interleukin-18 (IL-18) was analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the TT genotype at the NLRC4 gene rs385076 locus, the mortality of HLH patients with TC genotype and CC genotype was higher (RR = 3.205, 95% CI: 1.277-4.788, p = 0.012; RR = 3.052, 95% CI: 1.098-4.753, p = 0.031). Taking the CC genotype at rs479333 of the NLRC4 gene as a reference, HLH patients with CG genotype and GG genotype had a higher risk of death (RR = 3.475, 95% CI: 1.488-5.775, p = 0.003; RR = 2.986, 95% CI: 1.014-5.570, p = 0.047). NLRC4 gene rs385076 T>C and rs479333 C>G were significantly related to the poor prognosis of HLH patients. The area under the curve (AUC) of the receiver operating curve (ROC) for the prognostic outcome of HLH with serum IL-18 level was 0.6813 (95% CI: 0.5365-0.8260, p = 0.0189). NLRC4 gene rs385076 T>C and rs479333 C>G were related to higher serum IL-18 levels. CONCLUSION: NLRC4 gene rs385076 T>C and rs479333 C>G are related to the poor prognosis of HLH patients.

The non-canonical effects of heme oxygenase-1, a classical fighter against oxidative stress.

The role of heme oxygenase-1 in resisting oxidative stress and cell protection has always been a hot research topic. With the continuous deepening of research, in addition to directly regulating redox by catalyzing the degradation of heme, HO-1 protein also participates in the gene expression level in a great diversity of methods, thereby initiating cell defense. Particularly the non-canonical nuclear-localized HO-1 and HO-1 protein interactions play the role of a warrior against oxidative stress. Besides, HO-1 may be a promising marker for disease prediction and detection in many clinical trials. Especially for malignant diseases, there may be new advances in the treatment of HO-1 by regulating abnormal ROS and metabolic signaling. The purpose of this review is to systematically sort out and describe several aspects of research to facilitate further detailed mechanism research and clinical application promotion in the future.

Differential Expression of miRNA in the Peripheral Blood Mononuclear Cells in Myasthenia Gravis with Muscle-Specific Receptor Tyrosine Kinase Antibodies.

To determine if differential profile of miRNAs in peripheral blood mononuclear cells (PBMCs) could be identified in muscle-specific receptor tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) and linked to disease stage, a case-control method was used to compare the difference in miRNA expression profiles of PBMCs using next generation sequencing (NGS) in MuSK-MG patients and healthy controls (HCs). Six significant miRNAs from the discovery set were then validated using RT-qPCR in 11 MuSK-MG patients and 10 HCs. A unique miRNA prediction algorithm was used to predict the target genes of differentially expressed miRNAs and a network of miRNA gene pathways. Compared with HCs, 101 differentially expressed miRNAs were screened in MuSK-MG, of which 5 miRNAs were upregulated, and 96 miRNAs were downregulated. The top six differentially expressed molecules were selected for verification; four of them (miR-340-5p, miR-106b-5p, miR-27a-3p, and miR-15a-3p) were significantly different. The network analysis of miRNA gene pathways revealed that differentially expressed miRNAs were involved in a complex set of biological processes. Clinically, the four miRNAs that were validated are not correlated to MuSK antibody titers and quantitative myasthenia gravis score. Four miRNAs that were validated in this study have specificity to distinguish MuSK-MG from HCs.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

Right ventricular systolic function is associated with health-related quality of life: a cross-sectional study in community-dwelling populations.

BACKGROUND: Considerable evidence has been presented that heart and health-related quality of life are directly linked in patients with various diseases. This exploratory study investigated whether cardiac structure and function were associated with health-related quality of life in the general population. METHODS: This cross-sectional study was performed in five villages of Shunyi, a suburban district of Beijing, from June 2013 to April 2016. All inhabitants aged 35 years or older living in five villages of Shunyi were invited to participate. Exclusion criteria were individuals who declined participation, who had incomplete Health-related quality of life (HRQoL) data, and who had suboptimal echocardiograms. HRQoL was evaluated by the Mandarin version of SF-36. The association between the echocardiography-derived cardiac structure and function and each domain of SF-36 was analyzed by the multivariate linear regression analysis after adjusted for conventional risk factors affecting HRQoL. RESULTS: The baseline data of 990 individuals were analyzed. The median age of the participants was 57 (50-63) years, and 367 (37.1%) were male, the average physical and mental component summary scores were 89.3 (79.8-94.3) and 90 (83.5-95) respectively. Tricuspid annular plane systolic excursion, an echocardiography-derived right ventricular parameter, was associated with all the subscales and summarized scores of SF-36 (all P<0.05). The independent association between tricuspid annular plane systolic excursion and physical/mental component summary scores remained after adjusting for age, gender, body mass index, education level, annual personal income, smoking and drinking status, and comorbidities (ß=0.65, 95% confidence interval 0.30-1.01, P<0.01 and ß=0.49, 95% confidence interval 0.23-0.76, P<0.01 for physical and mental component summary scores respectively). Compared with the participants with tricuspid annular plane systolic excursion ≥21 mm, the participants with tricuspid annular plane systolic excursion <21 mm had lower adjusted scores of physical and mental component summary scores (81.8 vs. 84.5, P=0.015, and 85.5 vs. 88.1, P<0.01 for physical and mental component summary scores respectively). CONCLUSIONS: In this population-based study, right ventricular systolic function assessed by tricuspid annular plane systolic excursion was independently associated with health-related quality of life assessed by SF-36.

Increased Premature Cerebral Small Vessel Diseases in Dialysis Patients: A Retrospective Cross-Sectional Study.

BACKGROUND: Growing data indicate a higher prevalence of cerebrovascular diseases in patients with ESRD. Cerebral small-vessel disease (CSVD) is an important risk factor of stroke and dementia. A comprehensive assessment of CSVD in a dialysis population is needed. METHODS: In this retrospective cross-sectional study, we enrolled 179 dialysis patients and 351 controls matched by sex and age with normal serum creatinine. The presence and locations of 3 main features of CSVD in dialysis patients, including lacunes, cerebral microbleeds (CMBs), and white matter hyperintensities (WMHs), were evaluated with brain magnetic resonance imaging and compared with controls. Univariate and multivariate analyses were performed to identify risk factors. RESULTS: Compared with controls, the prevalence of CSVD was significantly increased in dialysis patients (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.26-5.62). Among them, risks of CMBs and WMHs were increased in dialysis (OR 4.01, 95% CI 1.78-9.42; 3.91, 95% CI 1.67-9.15), except for lacunes. The age of subjects with CSVD detected was significantly younger in the dialysis group (p = 0.002). Unlike controls, basal ganglia were most affected by lacunes and CMBs in dialysis patients. In dialysis patients, multivariate analysis further revealed that aging, smoking, and hyperlipidemia were significantly associated with CSVD, while dialysis modality was not significant. CONCLUSION: We demonstrated a higher prevalence and early-onset tendency of CSVD in dialysis patients, especially for CMBs and WMHs. Dialysis patients showed different patterns and associated factors for CSVD.

Peripheral nerve hyperexcitability syndrome: A clinical, electrophysiological, and immunological study.

INTRODUCTION: Peripheral nerve hyperexcitability syndrome (PNHS) is characterized by muscle fasciculations and spasms. Nerve hyperexcitability and after-discharges can be observed in electrophysiological studies. Autoimmune mechanisms play a major role in the pathophysiology of primary PNHS. METHODS: We retrospectively conducted a case-control study recruiting patients with clinical and electrophysiological features of PNHS. Control patients were diagnosed with other neuronal or muscular diseases. Contactin-associated protein2 (CASPR2) and leucine-rich glioma-inactivated1 (LGI1) antibodies were examined. RESULTS: A total of 19 primary PNHS patients and 39 control patients were analyzed. The most common symptoms for the case group were fasciculations (11/19) and muscle spasms (13/19). Case group patients were likely to demonstrate electrodiagnostic findings of nerve hyperexcitability (17/19) and after-discharges in the tibial nerve (19/19). We found high prevalence of CASPR2 (9/19) and LGI1 (6/19) antibodies in the case group. DISCUSSION: Primary PNHS patients were likely to show after-discharges in the tibial nerve. The pathogenesis of PNHS is autoimmune CASPR2 and LGI1 antibodies are possible pathogenic antibodies for primary PNHS.

A phase III, randomized, double-blind, controlled trial of carboxyamidotriazole plus chemotherapy for the treatment of advanced non-small cell lung cancer.

BACKGROUND: Carboxyamidotriazole (CAI), a calcium channel blocker, inhibits tumor cell proliferation, metastasis, and angiogenesis. This trial aimed to determine whether CAI combined with conventional chemotherapy could prolong progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients. METHODS: Patients were assigned into groups (3:1 ratio) to receive either chemotherapy + CAI or chemotherapy alone. Cisplatin (25 mg/m2) was administered by intravenous infusion on days 1, 2, and 3, and vinorelbine (25 mg/m2) on days 1 and 8 of each 3-week cycle for four cycles. CAI was administered at 100 mg daily with concomitant chemotherapy; this treatment was continued after chemotherapy was ceased until serious toxicity or disease progression had occurred. PFS was the primary endpoint, and the secondary endpoints were objective response rate (ORR), disease control rate, overall survival (OS), and quality of life. RESULTS: In total, 495 patients were enrolled in the trial: 378 in the chemotherapy + CAI group and 117 in the chemotherapy + placebo group. PFS was significantly greater in the chemotherapy + CAI [median, 134 days; 95% confidence interval (CI) 127-139] than in the chemotherapy + placebo (median, 98 days; 95% CI: 88-125) group, with a hazard ratio of 0.690 (95% CI: 0.539-0.883; p = 0.003). There was no difference in the OS rates of both groups. The ORR was greater in the chemotherapy + CAI group than in the chemotherapy + placebo group (34.6% versus 25.0%, p = 0.042). Adverse events of ⩾grade 3 occurred more frequently in the CAI group [256 (68.1%) versus 64 (55.2%); p = 0.014]. CONCLUSION: CAI + platinum-based chemotherapy prolonged PFS and could be a useful therapeutic option to treat NSCLC. CLINICAL TRIAL REGISTRATION: chinadrugtrials.org.cn identifier: CTR20160395.

Strategy for screening cognitive impairment in Chinese patients with amyotrophic lateral sclerosis.

BACKGROUND: It is an economical strategy to design a screening method to decide which patients with amyotrophic lateral sclerosis/ motor neuron disease (ALS/MND) should enter into the stage for further comprehensive neuropsychological investigation. METHODS: 59 patients (including 8 with frank dementia) were recruited. They underwent the extensive neuropsychological evaluation and short screening batteries, namely the Mini-Mental State Examination (MMSE), the Peking Union Medical College Hospital version of Montreal Cognitive Assessment (MoCA-P) and the Frontal Assessment Battery (FAB). Results of the extensive neuropsychological evaluation were set as the gold standard to diagnose cognitive impairment, and the effectiveness of screening tests were measured against them. RESULTS: By comparing the sensitivity and specificity, we found that the combination of FAB plus both or either of the other 2 short batteries provided a satisfactorily high sensitivity, but none of these screening batteries was significantly associated with quantitative behavioral measurements among non-demented subjects, the Frontal Behavioral Inventory-ALS version (FBI-ALS). CONCLUSIONS: The combination of the FBI-ALS, the FAB, and the MMSE or the MoCA-P or both could effectively screen comorbid dementia, cognitive and behavioral impairment in ALS but this implicates a limited specificity. And the FAB needed to be validated in large Chinese sample.

Study of B Cell Repertoire in Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antibody-mediated encephalitis. There are several studies on B cell repertoire of anti-NMDAR encephalitis in Caucasians. Here, the cerebrospinal fluid (CSF) samples of 12 Chinese patients with first-episode anti-NMDAR encephalitis were collected to investigate the B cell receptor (BCR) binding to NMDAR by single cell amplification of BCR and Sanger sequencing. BCR data of healthy persons, and of patients with anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis, multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) from the public databases were used as control. A heavy chain common clone IGHV1-18*04,IGHD1-26*01/ IGHD2-2*03/IGHD2-8*01, IGHJ3*02_(CDR3) ARVGSKYGFETFDI was found in 11 of 12 enrolled patients but not in the comparison data set. In addition, 4 shared clonotypes were found among these patients, and three of them contained the common clone. This study also revealed that the antibody gene family usage preference between patients and healthy controls were different, while they had similar antibody mutation rate. Our findings may have potential clinical implications for the diagnosis of anti-NMDAR encephalitis.

Spinal Intrathecal Actinomycosis Causes Multisegmental Root Failure: A Case Report.

Actinomycosis is a slowly progressing infection caused by Actinomyces species, which consists of filamentous gram-positive bacteria. Intraspinal actinomycosis is very rare and most of the previous cases presented with epidural lesions. Only two cases of intrathecal actinomycosis have been described. We reported a case of intrathecal actinomycosis in a 46-year-old woman. Our patient presented with multisegmental root failure, which was different from previous intrathecal cases mainly involving the spinal cord. The manifestations, cervical MR imaging results, biopsy and histopathological features, and treatment history of the patient were reviewed. Clinical features of this disease resemble intraspinal neoplasms, other infectious processes, and granulomatous diseases, thus being difficult to diagnose preoperatively. Histopathological evidence from the biopsy is important for timely diagnosis. Early diagnosis and treatment may greatly improve the prognosis.