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Sinomenine (SIN) is commonly used as part of rheumatoid arthritis (RA) therapy in China, but there is still no published evidence of the efficacy of SIN monotherapy. This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients. In this 24 week, randomized, placebo-controlled, double-blind clinical trial, people with mild to moderate RA were randomly assigned (1:1:1, stratified by hospital) to receive SIN (120 mg, twice daily), methotrexate (MTX) (10 mg per week), or SIN + MTX therapy. The primary outcome was the proportion of patients who achieved a 50% improvement in the American College of Rheumatology (ACR) criteria at week 24 and who showed improvement according to the clinical disease activity index (CDAI). In this prospective subgroup analysis, we also assessed whether the 24 week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine. Of the 135 enrolled participants, 38, 39, and 36 patients were treated with SIN, MTX, and SIN + MTX, respectively. In the SIN-treated group, 52.63% of patients achieved ACR50 after 24 weeks of treatment, which was comparable to the results in the MTX-treated and SIN + MTX-treated groups. Hepatic and gastrointestinal disorders were the main adverse events; however, the ratio of patients suffering from hepatic disorder in the SIN group (1/38) was much lower than that in the MTX (10/39) and SIN + MTX (8/36) groups. A total of 221 serum samples were collected at the four follow-up time points in the three treatments, and the levels of ornithine, citrulline, and arginine were obtained through ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The serum ornithine level decreased after the 24 week treatment along with a decrease in disease activity, and may reflect therapeutic responses with a sensitivity value of 80%. In conclusion, SIN revealed a comparable efficacy to MTX for treating RA patients, but with fewer side effects. In addition, the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA, which shows the value of this measure as an assessment indicator of drugs in treating RA.

Litter-leached dissolved organic carbon (DOC) plays an essential role in regulating biogeochemical cycles in forests. However, it is unclear how tree litter-leached DOC amounts and biodegradation vary with mycorrhizal types and leaf habits. We collected leaf litter from 14 common tree species belonging to different mycorrhizal types (arbuscular mycorrhizal, AM; and ectomycorrhizal, ECM) and leaf habits (deciduous broadleaf, evergreen broadleaf, and evergreen coniferous) in subtropical forests of southern China. We used a soaking experiment to determine litter-leached DOC, dissolved total nitrogen (DTN), and dissolved total phosphorus (DTP) amounts, and DOC aromaticity and molecular weight, and then assessed leaf litter-leached DOC biodegradation using a 42-day incubation experiment. AM broadleaf tree litter produced greater amounts of DOC with lower aromatic content and molecular weight than ECM broadleaf tree litter. In contrast, AM evergreen coniferous litter leached lower amounts of DOC with greater aromaticity than ECM evergreen coniferous litter. In the litter leachates, AM broadleaf trees often had higher DOC:DTN ratio than ECM broadleaf trees, while AM evergreen coniferous species had a lower DOC:DTP ratio than ECM evergreen coniferous species. For both deciduous and evergreen broadleaf trees, AM species had greater DOC biodegradation than ECM species due to the lower aromatic content and molecular weight. However, litter-leached DOC biodegradation did not differ between AM and ECM evergreen coniferous trees. Tree mycorrhizal associations can indicate the interspecific variations of litter-leached DOC amounts and biodegradation, but such tree mycorrhizal effect is highly dependent on leaf habit in subtropical forests.

OBJECTIVES Cardiovascular dysautonomia can be present at early, late and even prodromal stages of Parkinson's disease. This study aimed to describe the characteristics of 24-h ambulatory blood pressure (BP) monitoring and investigate the frequency of cardiovascular dysautonomia in Parkinson's disease without an abnormal BP history. METHODS Parkinson's disease patients without history of abnormal BP were consecutively enrolled from three Chinese centres, on whom office BP measurement, neurological evaluations and 24-h ambulatory BP monitoring were performed. RESULTS Totally, 101 Parkinson's disease patients (42.6% women) with an average age of 66.6 ± 8.2 years were included in our cohort, and data analysis revealed that 26 (25.74%) patients suffered from orthostatic hypotension, among whom 18 (69.23%) were symptomatic. Patients with orthostatic hypotension compared with those without had significantly higher nocturnal SBP level, and more severe nonmotor symptoms, autonomic dysfunction and cognitive impairment. Further, 54 out of 101 (53.47%) individuals had a reverse dipping pattern in SBP and/or DBP. Reverse dippers had more cases of orthostatic hypotension (P

Background:Identifying risk factors and mortality of individuals with Alzheimer’s disease (AD) could have important implications for the clinical management of AD.Objective:This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases.Methods:One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated.Results:Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944–1.563). Employing Cox’s proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort.Conclusion:This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.

Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the

Background There is rare reports about opinions and clinical practice of functional movement disorders (FMD) in China. The present survey aimed to investigate the views of FMD in Chinese clinicians. Methods The Chinese version survey of FMD were conducted in nationwide practitioners by means of an online questionnaire. Results Four hundred and thirty-four Chinese clinicians completed a 21-item questionnaire probing diagnostic and management issues in FMD. More than 80% of respondents considered that atypical movement disorder, multiple somatizations, and emotional disturbance were essential or absolutely necessary for clinically definite diagnosis of FMD. About three quarters of respondents requested standard neurological investigations to rule out organic causes. Over half believed that prior diagnosis of an organic disorder (59.9%), lack of associated non-physiologic deficits (51.8%), and evidence of physical injury (50.0%) were ‘very influential’ or ‘extremely influential’ for a non-FMD diagnosis. The majority (77.4%) of the respondents may refer patients to a neuropsychiatrist or psychiatrist experienced in FMD, followed by psychologist or psychotherapist experienced in FMD (53.2%). However, lack of guidelines, physician knowledge, and training often limited clinicians’ ability in managing patients with FMD. Early diagnosis of FMD, identification and management of concurrent psychiatric disorder, and acceptance of the diagnosis by the patient were considered most important for predicting a favorable prognosis. Conclusions Opinions and clinical practice of Chinese practitioners not only varied among Chinese neurologists, but also differed from international peers. Combined efforts are needed to promote related research and establish practice guidelines in China in the future.

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron‐specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD‐associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA‐425 (miR‐425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque‐associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR‐425, a neuronal‐specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR‐425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR‐425‐deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR‐425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal‐specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s)., The present study demonstrates that miR‐425 loss is responsible for PI3K‐Akt signaling suppression and impaired NPC proliferation. Moreover, miR‐425 loss induces dendritic spine defects and impaired synaptic plasticity. Taken together, miR‐425 loss following initial plaque deposition is the opening of the floodgates that mediates the ability of the APAM to cascade into a cellular phase of AD.

Introduction We investigated the association between Alzheimer's disease (AD) and the risk of cancer in the Chinese population. Methods In this retrospective cohort study, multivariate Cox proportional hazard regression analysis was used to determine the correlation between AD and the risk of various cancers, as shown by hazard ratios (HRs) with 95% confidence intervals (CIs). Results Of 8097 AD patients, the HR for all subsequent cancers was 0.822 (95% CI, 0.728-0.928; P = .002). Among them, three specific cancers were associated with AD: lung cancer (HR, 0.656; 95% CI, 0.494- 0.871; P = .004), prostate and testicular cancer (HR, 0.414; 95% CI, 0.202-0.847; P = .016), and lymphoma (HR, 2.202; 95% CI, 1.005-4.826; P = .049). Conclusion Patients with AD might have a lower chance of developing several cancers, including lung cancer and prostate and testicular cancer. Meanwhile, a positive association between AD and a higher incident rate of lymphoma was observed.

Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer’s Disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE e4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 (5.6%, 95% CI (1.8%, 12.5%)), and followed by coding variants of TREM2 (4.4%, 95%CI (1.2%,10.9%)) and novel mutations of ACE (3.3%, 95%CI (0.7%, 9.4%)). Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE e4 status. Evidence from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.

AIM: To explore the functions of Chordin-like 2, which is encoded by CHRDL2, in the process of retinal pigmented epithelium (RPE) differentiation and damage repair. METHODS: The fetal RPE cells (fRPE) was obtained from aborted fetus which obeyed medical ethics. Real-time quantitative polymerase chain reaction was used to measure expression quantity of CHRDL2 and other functional genes expression. Knocking down and overexpression was used to analyze the functions about Chordin-like 2. Enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of bone morphogenetic proteins 4 (BMP4). Flow cytometry was used to analyze cell cycle. Cell morphology was observed by phase contrast microscope (PCM). RESULTS: In normal RPE cells, CHRDL2 was firstly upregulated and followed a downregulation but eventually, it was expressed higher than the cells which undergone epithelial-mesenchymal transition (EMT). After knocking down CHRDL2, the secretion of BMP4 was decreased, RPE-related genes (OTX2, MITF, RPE65) were downregulated while EMT-related genes (SNAI1, VIM) were upregulated. However, the expression of these related genes after overexpression of CHRDL2 had contrary results. Chordin-like 2 also regulated the cell cycle by regulating BMP pathway. When CHRDL2 was knocked down, more fRPE cells stayed in S phase of cell cycle, while adding BMP4 reduced the proportion of the cells in S phase. However, overexpression of CHRDL2 increased more BMP4 secretion, this effect decreased the number of cells in S phase, but exogenous BMP inhibitor also could change this effect. At last, in the process of RPE cells differentiation, adding BMP4 at early stage could intervene normal RPE differentiation. Compared with BMP4, inhibiting BMP pathway had no significant negative effect at early stage, but suppressed differentiation at late stage. CONCLUSION: BMP pathway can be activated in a correct temporal order, otherwise, the cells have incorrect differentiation orientation. And Chordin-like 2 plays a role in dynamic regulation of BMP pathway and it also regulates the differentiation of RPE cells. Therefore, this research enlightens a new direction to inhibit EMT and promote cell redifferentiation after injury.

Citri reticulatae pericarpium (CRP) shows multiple bioactivities, including antioxidant, anti-tumor, and anti-inflammation. The folk proverb “CRP, the older, the better” means storing for longer time would improve its quality, which attributed to the influence of bioactive compounds. The aim of this work was to study which compounds are the factors that long storage would influence the quality of CRP. 161 compounds, including 65 flavonoids, 51 phenolic acids, 27 fatty acids, and 18 amino acids were identified through derivatization and non-derivatization liquid chromatography mass spectrometry approaches. Their dynamic changes indicated phenolic acids, which were reported to have various activities, were the main increased components. Furthermore, the representative phenolic acids were quantified and correlation analysis between their contents and antioxidant activity implicated they were the possible indicators that long storage would improve CRP quality. The results would provide basis for quality control of CRP during storage.

BACKGROUND Language dysfunction is a frequently reported symptom in Alzheimer's disease (AD). However, computer-assisted analysis of spontaneous speech in AD and mild cognitive impairment (MCI) is rarely used to date. OBJECTIVE To characterize the language impairment in AD and amnestic MCI (aMCI) with computer-based automatic analysis via the "Automatic Speech Recognition (ASR) software for cognitive impairment V1.3". METHODS A total of 64 subjects, including 20 AD patients, 20 aMCI patients, and 24 healthy controls were recruited. All subjects underwent neuropsychological tests, and spontaneous speech samples were recorded through the description of the "Cookie-Theft Picture" and then analyzed by the computerized software. Subsequently, we compared the speech parameters between the subjects and the controls. RESULTS We identified seven spontaneous speech parameters (percentage of silence duration, average duration of phrasal segments, average duration of silence segments, number of speech segments, number of long pauses, ratio of hesitation/speech counts and ratio of short pause/speech counts) demonstrating significant differences between the three groups (p