Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population.

OBJECTIVE: Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimer's disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1). These studies have been conducted almost exclusively in white populations and it is unclear whether these observations generalize to populations with different ethnicities. METHODS: We recruited 1224 unrelated northern Han Chinese subjects comprising 612 patients with a clinical diagnosis of late-onset AD (LOAD) according to the criteria of the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association and 612 healthy age- and sex-matched control subjects. Because of our previous study investigating CLU, CR1, and PICALM in the Han population, we limited the current analysis to BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1. RESULTS: In a multivariate analysis, associations of MS4A6A (rs610932; odds ratio = 0.632, Bonferroni corrected P = .019) and CD33 (rs3865444; odds ratio = 1.492, Bonferroni corrected P = .017) with LOAD were replicated successfully. When these data were stratified by apolipoprotein E (APOE) ε4 status, both rs610932 and rs610932 were evident only among subjects without the APOE ε4 allele. For BIN1, assuming a dominant model of inheritance, a positive association for rs7561528 in APOE ε4 carriers was observed. This association, however, did not remain significant after Bonferroni correction. As for ABCA7, CD2AP, and EPHA1 single nucleotide polymorphisms from recent GWAS, despite the similar directional effects, no significant differences in genotype and estimated allele frequency distribution between patients and control subjects were observed. CONCLUSIONS: This study provides the first independent evidence that MS4A and CD33 loci are associated with the risk of LOAD in northern Han Chinese population. Genotypes at the two loci confer risk predominantly in APOE ε4-negative subjects.

A randomized, parallel control and multicenter clinical trial of evidence-based traditional Chinese medicine massage treatment VS External Diclofenac Diethylamine Emulgel for the treatment of knee osteoarthritis.

BACKGROUND: Both massage and topically administered NSAIDs are safe and effective treatments for knee osteoarthritis (KOA); however, different massage technique sects in China caused assessment difficulties for the treatment of KOA. In order to standardize the massage techniques and procedures, we organized multi-disciplinary experts in China to acquire an evidence-based traditional Chinese medicine massage treatment of knee osteoarthritis. The purposes of this study will be to provide clinicians a complementary and alternative therapy for patients and to evaluate the efficacy and safety of evidence-based traditional Chinese medicine massage treatment of KOA compared to External Diclofenac Diethylamine Emulgel. METHODS AND DESIGN: A randomized controlled trial in which 300 participants diagnosed with KOA will be recruited and randomly allocated to either the experimental group or the control group in a ratio of 2:1. Two hundred participants will receive evidence-based traditional Chinese medicine massage 2 sessions per week for 10 weeks as the experimental group, and 100 participants will receive External Diclofenac Diethylamine Emulgel 3-4 times per day for 10 weeks as the control group. The patients in the two groups will receive follow-up at two time points at 5 weeks and 10 weeks from the beginning of treatment, respectively. The MRI scans and X-ray will be performed at baseline and at the end of the intervention. The primary outcome will be the changes in the Western Ontario and McMaster Osteoarthritis Index (WOMAC). Secondary outcomes will be measured by the PRO scale for knee osteoarthritis based on the concept of traditional Chinese medicine (Chinese scale for knee osteoarthritis (CSKO)), X-ray evaluation, and MRI scan evaluation. The data of WOMAC and CSKO will be analyzed at the baseline, 5 weeks, and 10 weeks from the beginning of treatment. The data from MRI scans and X-rays will be analyzed at baseline and at the end of the intervention. The significance level sets as 5%. The safety of interventions will be evaluated after each treatment session. DISCUSSION: This study will provide clinicians with much-needed knowledge for the treatment of KOA through a controlled trial. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800014400 . Registered on 10 January 2018.

[The evaluation of hydrocarbon potential generation for source rocks by near-infrared diffuse reflection spectra].

Near-infrared (NIR) and mid-infrared (MIR) diffuse reflection spectra were compared and evaluated for hydrocarbon potential generation of source rocks. Near-infrared diffuse reflectance often exhibits significant differences in the spectra due to the non-homogeneous distribution of the particles, so the signal-to-noise ratio of NIR is much lower than MIR It is too difficult to get accurate results by NIR without using a strong spectral preprocessing method to remove systematic noise such as base-line variation and multiplicative scatter effects. In the present paper, orthogonal signal correction (OSC) and an improved algorithm of it, i.e. direct orthogonal signal correction (DOSC), are used as different methods to preprocess both the NIR and MIR spectra of the hydrocarbon source rocks. Another algorithm, wavelet multi-scale direct orthogonal signal correction (WMDOSC), which is a combination of discrete wavelet transform (DWT) and DOSC, is also used as a preprocessing method. Then, the calibration model of hydrocarbon source rocks before and after pretreatment was established by interval partial least square (iPLS). The experimental results show that WMDOSC is more successfully applied to preprocess the NIR spectra data of the hydrocarbon source rocks than other two algorithms, and NIR performed as good as MIR in the analysis of hydrocarbon potential generation of source rocks with WMDOSC-iPLS pretreatment calibration model.

[DWT-iPLS applied in the infrared diffuse reflection spectrum of hydrocarbon source rocks].

Infrared spectroscopy is useful to monitor the quality of products on-line, or to quality multivariate properties simultaneously. The IR spectrometer satisfies the requirements of users who want to have quantitative product information in real-time because the instrument provides the information promptly and easily. However, Samples that are measured using diffuse reflectance often exhibit significant differences in the spectra due to the non-homogeneous distribution of the particles. In fact, multiple spectral measurements of the same sample can look completely different. In many cases, the scattering can be an overpowering contributor to the spectrum, sometimes accounting for most of the variance in the data. Although the degree of scattering is dependent on the wavelength of the light that is used and the particle size and refractive index of the sample, the scattering is not uniform throughout the spectrum. Typically, this appears as a baseline shift, tilt and sometimes curvature, where the degree of influence is more pronounced at the longer-wavelength end of the spectrum. The diffuse reflection spectrum is unsatisfactory and the calibration may provide unsatisfactory prediction results. So we must use some methods to remove the effects of the scattering for multivariate calibration of IR spectral signals. Discrete wavelet transform (DWT) is a good method to remove the effects of the scattering for multivariate calibration of IR spectral signals. By using DWT on individual signals as a preprocessing method in regression modeling on IR spectra, good compression is achieved with almost no loss of information, the low-frequency varying background and the high-frequency noise be removed simultaneously. In this report, we use the iPLS method to establish the calibration models of hydrocarbon source rocks. iPLS is a new regression method and the authors can get better results by using DTW- iPLS.

[The orthogonal polynomial regression method of multi-wavelength radiation thermometry].

For the problem of multi-wavelength radiation thermometry, the traditional data processing methods are the least squares techniques, the multiple linear regression fitting, and the stepwise regression fitting. There are some shortages in these methods, resulting in a certain error between the fitting result and the true temperature of the object surface. A new data processing method of multi-wavelength radiation thermometry--the orthogonal polynomial regression method was brought forward in this article on the base of variable emissivity. The mathematic principle of orthogonal polynomial regression method was expounded and according to the surface emissivities of tungsten, the true temperature of tungsten surface was simulated by the stepwise regression method and the orthogonal polynomial regression method. By comparing the fitting results, the authors found that the orthogonal polynomial regression method has the merit of simple principle and small operation, and the relative error between the fitting result and the surface true temperature is smaller. So the authors can draw the conclusion that using the orthogonal polynomial regression method to process the data of the multi-wavelength radiation thermometry, the fitting result has smaller error, it can fit the true temperature of object faster, and the result is more accurate than the traditional data processing methods.

[The measurement of the ratio of primary hydroxyl group to second hydroxyl group in polyether polyol by near infrared spectrum].

The method of near infrared spectrum, combined with derivative spectrum and multiple linear regression was applied to measure the ratio of primary hydroxyl group to second hydroxyl group in polyether polyol. The authors obtained good predictive results by using the method in this experiment. The work is very helpful for the on-line measurement of polyether polyol.

[Application of cross-correlation analysis to model transfer of near infrared spectrum].

Model transfer was studied by cross-correlation in near infrared spectrum. The hypothesis is that there exists an inherent proportional constant between the two spectra for model building measured by two different spectrometers after cross-correlation analysis is put forward and approved. The compatibility of the two models is enhanced after using the proportional constant. So the good results were obtained.

Activation of adenosine receptor potentiates the anticonvulsant effect of phenytoin against amygdala kindled seizures.

Drug resistance in epilepsy is considered as a complicated and multifactorial problem. Poor penetration of antiepileptic drugs (AEDs) across blood-brain barrier (BBB) into the brain, which results in insufficient level of the drugs at the targeted brain region, has been discussed as one mechanism contributing to pharmacoresistance of epilepsies. Therefore, modulating permeability of BBB is the effective treatment strategy since it facilitates the entry of AEDs into the central nervous system (CNS). Recently, signaling through receptors for the adenosine has been identified as a potent modulator of BBB permeability. This paper aimed to investigate the effects of auxiliary application of adenosine receptor (AR) agonist on amygdala-kindled seizures in adult male Wistar rats. When fully kindled seizures were achieved by daily electrical stimulation of the amygdala, rats were randomly divided into three groups: control, phenytoin, and phenytoin (PHT)+5'-N-ethylcarboxamidoadenosine (NECA) groups. NECA (0.08 mg/kg, i.v.) was applied to the PHT+NECA group after the administration of PHT (75 mg/kg, i.p. on the first day; 50mg/kg, i.p. on the following 9 days). Intravenous infusion of NECA resulted in a significant increase in brain PHT levels as compared with the PHT treatment alone. On the other hand, the auxiliary application of NECA dramatically decreased the frequency of generalized seizures and seizure stage, shortened duration of afterdischarge and generalized seizures, as well as the elevated the afterdischarge threshold and generalized seizures threshold. Our study demonstrated that auxiliary application of AR agonist enhanced brain antiepileptic drug levels and strengthened the anticonvulsant properties of PHT against amygdala kindled seizures.

[Adopting the method of principal components analysis combined with correlation coefficient to increase the predicted concentration's accuracy of benzene and its homology mixture].

The concentrations of benzene and its homology mixture were measured by near infrared spectra, and the emphasis was put on the character of the principal component and its physical significance. It is pointed out that the anterior principal components are very similar to the correlation coefficient of the multi-component solution and the theoretical proof for the right condition is given. The high frequency noise of the system can be checked out by principal component combined with the correlation coefficient. Removing the noise can greatly increase the accuracy of the prediction model.

[Study on the degradation of polymer light-emitting diodes by in-situ micro-Raman spectroscopy].

The authors report Raman degradation study of polymer light-emitting devices under ambient conditions. In order to investigate the chemical degradation reaction in polymer light-emitting diode (PLEDs) devices, the chemical structure of the poly (2-(4-Ethylhexyl) phenyl-1, 4-phenylene vinylene) (P-PPV) polymer was analyzed by micro-Raman spectroscopy during the lifetime of the devices. The evidence for the reduction of conjugation length is provided by Raman spectroscopy. This reduction of theconjugation length, which dramatically increases the resistance and cuts off the current density, was the main reason for the failure of lighting. These findings provide an important insight into the intrinsic degradation mechanisms of the polymer LEDs and help in the development of even more stable devices.

Targeting the mTOR signaling network for Alzheimer's disease therapy.

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that can sense environmental stimuli such as growth factors, energy state, and nutrients. It is essential for cell growth, proliferation, and metabolism, but dysregulation of mTOR signaling pathway is also associated with a number of human diseases. Encouraging data from experiments have provided sufficient evidence for the relationship between the mTOR signaling pathway and Alzheimer's disease (AD). Upregulation of mTOR signaling pathway is thought to play an important role in major pathological processes of AD. The mTOR inhibitors such as rapamycin have been proven to ameliorate the AD-like pathology and cognitive deficits effectively in a broad range of animal models. Application of mTOR inhibitors indicates the potential value of reducing mTOR activity as an innovative therapeutic strategy for AD. In this review, we will focus on the recent process in understanding mTOR signaling pathway and the vital involvement of this signaling pathway in the pathology of AD, and discuss the application of mTOR inhibitors as potential therapeutic agents for the treatment of AD.

Clusterin in Alzheimer's disease.

Clusterin, also known as apolipoprotein J, is a ubiquitous multifunctional glycoprotein. Following its identification in 1983, clusterin was found to be clearly increased in Alzheimer's disease (AD). Later research demonstrated that clusterin could bind amyloid-beta (Abeta) peptides and prevent fibril formation, a hallmark of AD pathology. In addition to preventing excessive inflammation, intracellular clusterin was found to reduce apoptosis and oxidative stress. Although early studies were inconclusive, two recent large-scale genome-wide association studies (GWAS) independently identified variants within the clusterin gene as risk factors for developing AD. This review focuses on the characteristics of clusterin and possible mechanisms of its relationship to AD.

Anticonvulsant effect of unilateral anterior thalamic high frequency electrical stimulation on amygdala-kindled seizures in rat.

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. In this study, we examined the effect of unilateral high frequency stimulation (HFS) of the ANT on amygdala-kindled seizures in Wistar rats. When fully-kindled seizures were achieved by daily amygdala kindling, HFS (15 min train of 100 µs pulses at 200 Hz and 450-800 µA) was delivered to the ipsilateral or contralateral ANT immediately before the kindling stimulation for 15 days. HFS of the ipsilateral ANT significantly decreased the incidence of generalized seizures and the mean behavioral seizure stage and afterdischarge duration (ADD), and shortened cumulative ADD and cumulative generalized seizure duration. Furthermore, HFS of the ipsilateral ANT significantly increased the afterdischarge threshold (ADT). Our data suggest that unilateral HFS of the ANT may be an effective method of inhibiting kindled seizures by suppressing the susceptibility to seizures and generating long lasting anti-epileptic effect preventing the recurrence of kindled seizures, providing an alternative to bilateral ANT DBS for refractory epilepsy.

Common variants in toll-like receptor 4 confer susceptibility to Alzheimer's disease in a Han Chinese population.

Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-ß (Aß) plaque formation and Aß clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5'-untranslated region (UTR) to approximately 6 kb of the predicted 3'- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3'-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7x10-6, Pc s1.0x10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.

Replication of the MTHFD1L gene association with late-onset Alzheimer's disease in a Northern Han Chinese population.

We conducted a replication study of the 2 genetic variants, rs11754661 and rs2073067, in MTHFD1L that have been recently reported to be associated with late-onset Alzheimer's disease (LOAD) in a genome-wide study in Caucasians. The associations were evaluated in a case-control sample comprising 1,189 Northern Han-Chinese individuals. The rs11754661 polymorphism is associated with LOAD (OR = 1.727; p = 0.016). For rs2073067, LOAD association was found only in APOEε4 carriers (OR = 0.400; p < 0.001). Haplotype analysis revealed the "AC" haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of MTHFD1L gene in LOAD.

Genetic association of SLC2A14 polymorphism with Alzheimer's disease in a Han Chinese population.

Glucose uptake and metabolism are impaired in Alzheimer's disease (AD) brain, which appear to be a cause, rather than a consequence of neurodegeneration. Recently, the gene of the 14th isoform of subfamily A of solute carrier family 2 (SLC2A14), encoding glucose transporter 14 (GLUT14), was identified for the association in vivo with AD pathology of Tau, and rs10845990 within SLC2A14 showed association with AD in Caucasians. In order to evaluate the involvement of the SLC2A14 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (597 LOAD cases and 605 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.015, allele P = 0.039). The G-carrying genotype (GT + GG) individuals showed a 1.41-fold increased risk compared with the TT genotype carriers (odds ratio (OR) = 1.41, 95 % confidence interval (CI) = 1.11-1.79, P = 0.005, Power = 83.6 %). After stratification by ApoE ε4-carrying status, rs10845990 polymorphism was only significantly associated with LOAD in non-ApoE ε4 allele carriers (P < 0.001). Multivariate logistic regression analysis also conferred this positive association between the SNP rs10845990 and LOAD in the dominant and additive model after adjustment for age, gender, and the ApoE ε4 carrier status. These results suggested that SLC2A14 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.

Lack of association between rs597668 polymorphism near EXOC3L2 and late-onset Alzheimer's disease in Han Chinese.

Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimer's disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P=0.653; allele: P=0.603), even after stratification for apolipoprotein E (APOE) ɛ4 status and statistical adjustment for age, gender and APOE ɛ4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population.

Blood clusterin levels, rs9331888 polymorphism, and the risk of Alzheimer's disease.

Variants in the clusterin gene have been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease.

Interleukin-33 (IL-33), a newly described member of the IL-1 family, is located on chromosome 9p24, a chromosomal region of interest in Alzheimer's disease (AD) defined by many genome-wide studies. Three intronic rs1157505, rs11792633, and rs7044343 single nucleotide polymorphisms (SNPs) within IL-33 have recently been reported to be associated with risk of AD in Caucasian populations. In order to assess the involvement of the IL-33 polymorphisms in the risk of developing late onset AD (LOAD), we analyzed the genotype and allele distributions of these 3 polymorphisms in 704 Han Chinese subjects. The minor alleles of the rs11792633 polymorphism within IL-33 was significantly associated with a reduced risk of LOAD (odds ratio [OR] = 0.73, p = 0.005). Furthermore, rs11792633 polymorphism was still strongly associated with LOAD (dominant model: OR = 0.67, p = 0.015; recessive model: OR 0.57, p = 0.021; additive model: OR = 0.71, p = 0.004) after adjusting for age, gender, and the apolipoprotein E (APOE) ε4 status. Our results support the evidence that genetic variants of IL-33 affect susceptibility to LOAD in Han Chinese.

Genetic association of TLR4/11367 polymorphism with late-onset Alzheimer's disease in a Han Chinese population.

The amyloid beta-protein (A-ß) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 4 (TLR4) is thought to contribute to Aß clearance. Studies have reported the presence and functional significance of the TLR4/11367 polymorphism in a Han Chinese population. To evaluate the involvement of the TLR4/11367 polymorphism in the risk of late-onset Alzheimer's disease (LOAD), we performed a case-control study to analyze the genotype and allele distributions of the TLR4/11367 polymorphism in a Han Chinese population (137 LOAD cases and 137 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P<0.001, allele P<0.001). After stratification by APOE ε4-carrying status, the C allele of the TLR4/11367 polymorphism was still significantly associated with LOAD in APOE ε4 non-carriers (OR=5.77, 95% CI=3.03-11.00, P<0.001) and carriers (OR=2.03, 95% CI=1.03-3.98, P=0.04). In addition, a logistic regression analysis also conferred positive association between TLR4/11367C and LOAD (dominant model: ORa=3.08, 95% CI=1.60-5.93, P=0.001; recessive model: ORa=8.79, 95% CI=3.31-23.36, P<0.001; additive model: ORa=2.75, 95% CI=1.73-4.37, P<0.001) after adjustment for age, gender, and the APOE ε4 carrier status. This study gives the first evidence that the TLR4/11367 polymorphism was associated with LOAD in a Han Chinese population.