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The diagnosis of metabolic-associated fatty liver disease is based on the detection of liver steatosis together with the presence of metabolic dysfunction. According to this new definition, the diagnosis of metabolic-associated fatty liver disease is independent of the amount of alcohol consumed. Actually, alcohol and its metabolites have various effects on metabolic-associated abnormalities during the process of alcohol metabolism. Studies have shown improved metabolic function in light to moderate alcohol drinkers. There are several studies focusing on the role of light to moderate alcohol intake on metabolic dysfunction. However, the results from studies are diverse, and the conclusions are often controversial. This review systematically discusses the effects of alcohol consumption, focusing on light to moderate alcohol consumption, obesity, lipid and glucose metabolism, and blood pressure., Competing Interests: The authors have no conflict of interest related to this publication., (© 2021 Authors.)

Gilbert's syndrome is a kind of benign inherited disease of bilirubin binding disorder, mainly due to the homozygous polymorphism A(TA)7TAA in the promoter of the gene for uridine diphosphate -glucuronosyltransferase 1A1 (UGT1A1), which is a TA insertion into the promoter, designated as UGT1A1*28, with UGT activity reduction to 30% of the normal value. Therefore, circulating fat-soluble unconjugated bilirubin cannot be converted into water-soluble conjugated bilirubin, leading to unconjugated hyperbilirubinemia. Bilirubin has a strong affinity for erythrocyte phospholipids, which interferes with membrane composition and dynamics, resulting in increased erythrocytes fragility, easy rupture, and gradual shortening of survival time. However, there are no obvious sign of hemolysis or abnormal iron metabolism, erythrocytes and bone marrow morphology. A small amount of chronic hemolysis stimulates extramedullary (normal bone marrow morphology) hematopoiesis, ensuing compensatory increase in circulating erythrocytes and hemoglobin. Hyperbilirubinemia may also weaken gastrointestinal motility, increase passive diffusion and absorption across the intestinal mucosal epithelium by 1.5 to 2 times, thereby aggravating or worsening hyperbilirubinemia mainly with unconjugated bilirubin circulation, which indicates that there is a causal relationship between the circulating bilirubin concentration and rapid erythrocytes turnover and hemolysis rate in patients with Gilbert's syndrome. Interestingly, bilirubin also has significant antioxidant and anti-mutagenic activities, and the potential health benefits of mild hyperbilirubinemia in Gilbert's syndrome include reduced prevalence of cardiovascular disease, type 2 diabetes mellitus (and related risk factors), certain cancers, and cardiovascular-related and all-cause mortality. Exogenous bilirubin and biliverdin supplements in intestinal epithelial cells can be absorbed and may increase circulating concentration of these antioxidant compounds. With this information, we hope to raise awareness of the potentially harmful and beneficial effects of benign hyperbilirubinemia, and explore and develop beneficial medical interventions.

Cerebrospinal fluid (CSF) progranulin (PGRN) is related to various neurodegeneration diseases. And sleep problems can cause abnormality in protein metabolism in vivo. We aim to explore the potential associations between the self-reported sleep characteristics and CSF PGRN in cognitively intact older adults. Our study recruited 747 participants (mean (standard deviation (SD)) age, 61.99 (10.52) years, 329 (42.89%) females) who had normal cognition from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF PGRN and sleep characteristics measured. The multiple linear regression and nonlinear regression adjusted for age, gender, education, and apolipoprotein E-epsilon 4 gene (APOE4) status were used to assess the associations between sleep characteristics and PGRN. Interaction effects were explored between APOE4 status and sleep characteristics on CSF PGRN level. Sleep disturbances indicated lower CSF PGRN (β = - 0.0186, p = 0.0160). For detailed items in sleep disturbances, lower CSF PGRN was found in males who woke up during sleep (β = - 0.0121, p = 0.0062) and in females who had breathing difficulties (β = - 0.0258, p = 0.0271). Meanwhile, sleep efficiency was associated with CSF PGRN (β = - 0.0512, p = 0.0497). No significant interaction effects between sleep characteristics and APOE4 status were found. Meanwhile, we did not find a nonlinear relationship between nocturnal sleep duration and CSF PGRN. Sleep problems may influence the metabolism of PGRN, thus attenuating the protective effects of PGRN on neurodegeneration diseases.

Background: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population., Methods: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS., Results: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001)., Conclusions: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Background: Metabolic healthy obesity (MHO) is a unique subgroup of overweight and obese individuals with normal metabolic characteristics. Its association with the risk of stroke remains unclear. We aimed to examine the risk of stroke in MHO individuals and the further associations between stroke and metabolic abnormalities under different bodyweight conditions., Methods: We systematically searched PubMed, Embase and Cochrane Library from December 1946 to January 2019, and only included prospective cohort studies. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of incident stroke., Results: A total of eight studies comprising 4,256,888 participants were included in the meta-analysis. MHO individuals had an increased risk of stroke compared with metabolically healthy normal weight (MH-NW) individuals (RR =1.17, 95% CI: 1.11-1.23). However, the stroke risk of metabolically healthy overweight individuals was the same (RR =1.02, 95% CI: 0.84-1.23). All groups with unhealthy metabolism had a similarly elevated risk: normal weight (RR =1.83, 95% CI: 1.57-2.14), overweight (RR =1.93, 95% CI: 1.44-2.58), and obesity (RR =2.00, 95% CI: 1.40-2.87)., Conclusions: The meta-analysis confirms a positive association between MHO phenotype and the risk of stroke. Individuals with metabolic abnormalities under different bodyweight conditions are at elevated risk., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4387). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear., Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD., Methods: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models., Results: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them., Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

It has been increasingly evident that pulse pressure (PP) is associated with Alzheimer's disease (AD) but whether PP increases AD risk and the mechanism responsible for this association remains unclear. To investigate the effects of PP in the process of AD, we have evaluated the cross-sectional and longitudinal associations of PP with AD biomarkers, brain structure and cognition and have assessed the effect of PP on AD risk in a large sample (n= 1,375) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Multiple linear regression and mixed-model regression were employed in cross-sectional and longitudinal analyses respectively. Clinical disease progression was assessed using Cox proportional hazards models. High PP was associated with lower β-amyloid 42 (Aβ 42 ) ( P = .015), and higher total tau (T-tau) ( P = .011), phosphorylated tau (P-tau) ( P = .003), T-tau/Aβ 42 ( P = .004) and P-tau/Aβ 42 ( P = .001), as well as heavier cortical amyloid-beta burden ( P = .011). Longitudinally, baseline high PP was significantly associated with hippocampal atrophy ( P = .039), entorhinal atrophy ( P = .031) and worse memory performance ( P = .058). Baseline high PP showed more rapid progression than those with normal PP ( P <.001). These results suggest PP elevation could increase AD risk, which may be driven by amyloid plaques and subclinical neurodegeneration.

Objective: The aim of this study was to investigate the mechanism of simvastatin-induced apoptosis in nasopharyngeal carcinoma (NPC) cells., Materials and Methods: CNE1 and HK1 cell lines were treated with different concentrations of simvastatin for different time course. Subsequently, Cell Counting Kit-8 (CCK-8), colony formation assay, and flow cytometry were conducted to evaluate cell activity, colony formation ability, as well as cell cycle of NPC cells, respectively. The mRNA expressions of p21, Bim, and cyclin D1 were examined by qPCR. Meanwhile, the protein expression levels of apoptosis-related proteins (including caspase-3, Bax, Bcl-2) were detected by Western blot. Caspase-3 activity was determined to estimate cell apoptosis. An NPC xenotransplantation model was constructed to further determine the role of simvastatin in vivo. In addition, NF-κB activity was assessed through Luciferase reporter gene assay and Western blot., Results: Simvastatin treatment lead to significantly reduced viability of NPC cells and the number of cell colonies dose-dependently and time-dependently. Meanwhile, simvastatin treatment caused cell cycle arrest in G0/G1 phase, remarkably downregulated expression of cyclin D1, and upregulated expressions of p21 and Bim. In addition, simvastatin induced apoptosis of NPC cells and enhanced the Luciferase activity of caspase-3. Western blot results indicated that simvastatin promoted the protein level of Bax and caspase-3, whereas suppressed the protein expression of Bcl-2. In vivo experiments showed that simvastatin was able to suppress the growth of NPC cells. Further studies demonstrated that simvastatin remarkably attenuated the Luciferase activity of pNF-κB-Luc, thereby specifically inhibiting the NF-κB signaling pathway., Conclusions: Simvastatin inhibits proliferation and promotes apoptosis of NPC cells by inhibiting the NF-κB pathway.

Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.

Background: This article reports the effects of proenkephalin (PENK) on osteosarcoma (OS) cell migration., Methods: A Gene Expression Omnibus (GEO) dataset was used to identify differentially expressed genes (DEGs) in OS tumor samples and normal human osteoblasts. Tumor tissue and adjacent normal tissue were collected from 40 OS patients. MG63 cells were transfected with si-PENK. Transwell migration assays and wound healing assays were performed to compare the effect of PENK on migration. Moreover, LY294002 was used to identify the potential mechanism. Gene expression was examined via qRT-PCR and Western blotting., Results: Bioinformatic analysis revealed that PENK was downregulated in OS tumor samples compared with normal human osteoblasts. Moreover, PENK was identified as the hub gene of the DEGs. The PI3K/Akt signaling pathway was significantly enriched in the DEGs. Moreover, PENK was downregulated in OS and MG63 cells compared with the corresponding control cells. Silencing PENK promoted MG63 cell migration; however, treatment with LY294002 partially attenuated PENK silencing-induced OS cell migration., Conclusion: PENK inhibits OS cell migration by activating the PI3K/Akt signaling pathway.

Elevated serum uric acid (SUA) has been reported to be associated with an increased risk of cardiovascular diseases, but the role of SUA in intracranial atherosclerosis remains unclear. To investigate the association between SUA and intracranial atherosclerotic stenosis (ICAS), we evaluated 1522 subjects (305 with ICAS, 1217 without ICAS) with magnetic resonance angiography (MRA). Subjects were classified into ten groups according to the deciles of the SUA level. The rate of ICAS reached a minimum in the seventh decile (6.0-6.3 mg/dL; reference group). After adjusting for confounding factors, multivariate logistic regression analysis demonstrated that both low SUA level (≤ 3.8 mg/dL; OR, 2.34; 95% CI, 1.29-4.39; p = 0.006) and high SUA level (≥ 7.8 mg/dL; OR, 2.10; 95% CI, 1.15-3.92; p = 0.017) conferred greater risk for ICAS. In multivariable analysis with a quadratic model which used SUA as a continuous variable, a U-shaped association between SUA and the rate of ICAS was confirmed (α > 0; p < 0.001). The estimated SUA level associated with the lowest rate of ICAS was 6.2 mg/dL. In conclusion, our findings suggest a U-shaped association between ICAS and SUA.

Non-alcoholic fatty liver disease and alcohol (ethanol)-related liver disease is a global epidemic of chronic liver disease and the main cause of fatty liver. Non-alcoholic fatty liver patients sometimes ingest different types of alcohol. Therefore, when obesity coexist with alcohol consumption, it is more difficult to diagnose the cause of fatty liver. The amount of alcohol consumption and alcohol drinking pattern and chronic liver injury, type 2 diabetes mellitus, cardiovascular disease and other metabolic-related diseases may have J-type correlation; that is to say, a light to moderate amount of alcohol consumption may bring certain benefits to the above diseases, but excessive alcohol consumption may promote the development of obesity, aggravate liver disease, metabolic abnormalities, and increase the risk of tumors. Screening for metabolic-related disease risk should be considered in addition to the assessment of changing liver lesions when obesity coexists with alcohol consumption. Changing bad living habits, losing weight and abstaining from alcohol are still the basis of treating fatty liver and metabolic disorders. Carefully selecting patients and communicating with them about the risk and benefit of drugs are important indicators of drug therapy. Patients with end-stage liver disease can be considered for liver transplantation and postoperative lifestyle improvement should be emphasized.

Correlation between the level of high-sensitivity C-reactive protein (hs-CRP) and the incidence of intracranial arterial stenosis (ICAS) is unclear. We aim to investigate the relationship between hs-CRP levels and ICAS. A total of 1458 patients aged ≥ 40 years were enrolled in this study. All the participants had a magnetic resonance angiography (MRA) examination for the evaluation of ICAS. Participants were classified into four groups according to stroke and ICAS. Multivariable logistic regression models were used to assess the relationship of hs-CRP levels and ICAS status. A total of 432 (29.63%) subjects had ICAS. The levels of hs-CRP in stroke group were significantly higher than those in non-stroke group (p < 0.001). Patients with ICAS tend to have higher hs-CRP levels (p < 0.001). In multivariate analysis, the fourth hs-CRP quartile had the strongest association with ICAS in both stroke group and non-stroke group (OR 2.512, 95% CI 1.651-3.853, p < 0.001 for stroke group, and OR 2.534, 95% CI 1.435-4.595, p = 0.002 for non-stroke group) among the four quartiles of hs-CRP levels. Our study suggests that elevated serum hs-CRP levels are associated with higher risk of ICAS, in both stroke patients and non-stroke participants.

Higher body mass index (BMI) in late-life has recently been considered as a possible protective factor for Alzheimer's disease (AD), which yet remains conflicting. To test this hypothesis, we have evaluated the cross-sectional and longitudinal associations of BMI categories with CSF biomarkers, brain β-amyloid (Aβ) load, brain structure, and cognition and have assessed the effect of late-life BMI on AD risk in a large sample (n = 1,212) of non-demented elderly from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. At baseline, higher late-life BMI categories were associated with higher levels of CSF Aβ42 (p=0.037), lower levels of CSF total-tau (t-tau, p=0.026) and CSF t-tau/Aβ42 (p=0.008), lower load of Aβ in the right hippocampus (p=0.030), as well as larger volumes of hippocampus (p<0.0001), entorhinal cortex (p=0.009) and middle temporal lobe (p=0.040). But no association was found with CSF phosphorylated-tau (p-tau) or CSF p-tau/Aβ42. Longitudinal studies showed that higher BMI individuals experienced a slower decline in cognitive function. In addition, Kaplan-Meier survival analysis revealed that higher late-life BMI had a reduced risk of progression to AD over time (p = 0.009). Higher BMI in late-life decreased the risk of AD, and this process may be driven by AD-related biomarkers.

Background: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer's disease (AD), which might be explained by a reverse causal relationship., Objective: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment., Methods: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function., Results: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A-/TN-and CDR = 0, p < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p = 0.023, β= -14). Individuals in amyloid positive group exhibited faster weight loss (time×group interaction p = 0.019, β= -0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders., Conclusion: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease.

3,4-Dihydroxyphenylethanol (DOPET) is a potent antioxidant polyphenolic compound. In this study, our objective was to investigate the underlying mechanism of the neuroprotective role of DOPET in attenuating spinal cord injury (SCI). Initially, SCI was induced by performing surgical laminectomy on the rats at T10-T12 level. Then, the neurological function-dependent locomotion was measured using Basso Beattie Bresnahan score, which declined in the SCI-induced group. Increased antioxidant levels such as superoxide dismutase, glutathione peroxidase, and glutathione along with other parameters such as increased lipid peroxidation (LPO) and myeloperoxidase (MPO) activities were all observed in the SCI group. Levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β were upregulated in the serum and spinal cord tissue as observed on the immunoblot. Interestingly, protein levels of apoptotic markers such as Bax, cleaved caspase 3 and RT-PCR analysis-based mRNA level of pro-inflammatory cytokine, nuclear factor- κ activated B cells (NF-κB) were significantly upregulated in the spinal cord tissue. Nonetheless, antiapoptotic factor such as B-cell lymphoma 2 (Bcl-2) protein expression was downregulated in the same group. However, on administering 10 mg/kg of DOPET, the neuronal function was rescued, antioxidants were restored back to the normal levels, LPO and MPO activities were reduced in conjunction with downregulated levels of proinflammatory cytokines and apoptotic markers in the SCI group. These findings show that DOPET could potentially target multiple signalling pathways to combat SCI.

To investigate the relation of higher apolipoprotein B/apolipoprotein AI (apoB/AI) ratio with the risk of suffering intracranial atherosclerotic stenosis (ICAS) in both stroke and non-stroke population, we enrolled 1138 patients with acute ischemic stroke (359 with ICAS, 779 without ICAS) and 1072 non-stroke controls (239 with ICAS, 833 without ICAS) into the study. ICAS was defined as atherosclerotic stenosis >50% or the occlusion of the several main intracranial arteries. ApoB/AI ratio of patients with ICAS was significantly higher than those of individuals without ICAS in both stroke group and non-stroke groups. Increased ratio of apoB/AI was an independent risk factor for ICAS in both stroke group (OR 2.80, 95% CI 1.45-5.42, p =0.002) and non-stroke groups (OR 3.38, 95% CI 1.61-7.12, p <0.001). Compared with the lowest quartile, the third (Stroke OR=1.71, 95%CI, 1.11-2.63, p= 0.014; Non-stroke OR=1.71, 95%CI, 1.04-2.82, p =0.033) and forth quartiles (Stroke OR=2.06, 95%CI, 1.27-3.35, p =0.003; Non-stroke OR=2.00, 95%CI, 1.16-3.49, p =0.012) were independent risk factors for ICAS in both stroke ( p value for trend=0.001)) and non-stroke ( p value for trend=0.006) groups. In summary, increased apoB/AI ratio was a valuable independent risk factor for ICAS in stroke patients as well as in non-stroke controls.

Background: To facilitate differentiation between normal and abnormal values, it is necessary to correct echocardiographic measurements for physiologic variance induced by age, gender, and body size variables., Methods: A total of 34 two-dimensional echocardiographic parameters were measured in 1,224 healthy Chinese adults with body mass index < 25.0 kg/m 2 . An optimized multivariate allometric model and scaling equations were first developed in 858 subjects (group A), and their reliability was then verified in the remaining 366 subjects (group B). The traditional single-variable isometric model in which parameters are linearly corrected by a single body size variable (height, weight, body mass index, or body surface area) was used for comparison. The success of correction was defined as the absence of significant correlations (r > 0.20, P < .05) between the corrected values and age or any body size variables, while maintaining high correlations (r > 0.80) between the corrected and uncorrected values., Results: Before correction, all 34 parameters correlated significantly with one or more of the physiologic variables of age and body size and differed significantly between men and women on 29 parameters (85.3%) in both groups. The success rate of correction with the single-variable isometric model was only 11.0% (15 of 136 corrections due to four variable corrections used for each parameter), while use of the optimized multivariate allometric model successfully corrected all 34 parameters (100%) for physiologic variance induced by age and body size variables and eliminated the gender differences in 32 parameters (94.1%). A new set of reference values for corrected echocardiographic measurements independent of age, gender, and body size variables were established., Conclusions: The novel optimized multivariate allometric model developed in this study is superior to traditional the single-variable isometric model in the correction of echocardiographic parameters for physiologic effects of age, gender, and body size variables and thus should be encouraged in both scientific research and clinical practice., (Copyright © 2019 American Society of Echocardiography. All rights reserved.)

To investigate the association of homocysteine concentration with intracranial atherosclerotic stenosis (ICAS), we assessed 933 acute ischemic stroke patients (346 with ICAS, 587 without ICAS) and 798 non-stroke controls (175 with ICAS, 623 without ICAS) with magnetic resonance angiography (MRA). Homocysteine concentration was found to be significantly higher in participants with ICAS than those without ICAS. In logistic regression analyses, homocysteine concentration was significantly associated with ICAS both in patients (OR: 1.04; 95% CI: 1.01-1.08; P=0.008) and controls (OR: 1.10; 95% CI: 1.06-1.15; P<0.001) for 1 μmol/L increment in homocysteine. Compared with the lowest quartile, the second (OR:1.53; 95% CI: 1.01-2.33), third (OR:1.71; 95% CI: 1.14 -2.60) and fourth (OR:2.48; 95%CI: 1.63-3.81) quartiles were independent predictors of ICAS in patients (P for trend<0.001); the third (OR:1.99; 95% CI: 1.18-3.40) and fourth (OR:2.36; 95%CI: 1.38-4.10) quartiles were independent predictors of ICAS in controls (P for trend<0.001). Hence, elevated homocysteine might be an independent risk for ICAS.

Tau, a microtubule-associated protein, is the main component of the intracellular filamentous inclusions that are involved in neurodegenerative diseases known as tauopathies, including Alzheimer disease (AD), frontotemporal dementia with parkinsonism-17 (FTDP-17), Pick disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Hyperphosphorylated, aggregated tau proteins form the core of neurofibrillary tangles (NFTs), which are shown to be one of the pathological hallmarks of AD. The discovery of mutations in the microtubule-associated protein tau ( MAPT ) gene in patients with FTDP-17 also contributes to a better understanding of the dysfunctional tau as a cause of diseases. Although recent substantial progress has been made in the tau pathology of tauopathies, the mechanisms underlying tau-induced neurodegeneration remain unclear. Here, we present an overview of the biochemical properties of tau protein and the pathogenesis underlying tau-induced neurodegenerative diseases. Meanwhile, we will discuss the tau-related biomarkers and ongoing tau-targeted strategies for therapeutic modulation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease in adults characterized by the deposition of extracellular plaques of β-amyloid protein (Aβ), intracellular neurofibrillary tangles (NFTs), synaptic loss and neuronal apoptosis. AD has a strong and complex genetic component that involving into multiple genes. With recent advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS) technology, UNC5C was identified to have association with AD. Emerging studies on cell and animal models identified that aberrant UNC5C may contribute to AD by activating death-associated protein kinase 1 (DAPK1) which is a new component involved in AD pathogenesis with an extensive involvement in aberrant tau, Aβ and neuronal apoptosis/autophagy. In this review, we briefly summarize the biochemical properties, genetics, epigenetics, and the speculative role of UNC5C in AD. We hope our review would bring comprehensive understandings of AD pathogenesis and provide new therapeutic targets for AD., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Genome-wide association studies (GWAS) have identified one single-nucleotide polymorphism (SNP) rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease (AD) in Caucasians. The effect of rs9271192 on AD needed to be verified in other ethnic cohorts. In order to evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD (LOAD) in the Northern Han Chinese population, we recruited 982 LOAD patients and 1344 sex- and age-matched healthy controls. The results showed that HLA-DRB1 rs9271192 was associated with LOAD (genotype P = 0.015, allele P = 0.04). The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample ( P = 0.004, OR =2.069, 95% CI = 1.262-3.434). When these data were stratified by apolipoprotein E ( APOE ) ε4 status, the observed association was confined to APOE ε4 non-carriers (additive model: P=0.048, OR =1.191, 95% CI =1.001-1.417; recessive model: P < 0.001, OR = 2.601, 95% CI =1.519-4.566). Furthermore, meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD (OR = 1.12, 95% CI = 1.08-1.15). To summarize, the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD., Competing Interests: CONFLICTS OF INTEREST The authors disclose no conflicts of interest.

Alzheimer's disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. Previous association studies gave evidence for the associations of HLA-DRB1/DQB1 alleles with AD. However, how and when the gene variants in HLA-DRB1/DQB1 function in AD pathogenesis has yet to be determined. Here, we firstly investigated the association of gene variants in HLA-DRB1/DQB1 alleles and AD related brain structure on magnetic resonance imaging (MRI) in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We selected hippocampus, subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). Twelve SNPs in HLA-DRB1/DQB1 were identified in the dataset following quality control measures. In the total group hybrid population analysis, our study (rs35445101, rs1130399, and rs28746809) were associated with the smaller baseline volume of the left posterior cingulate and rs2854275 was associated with the larger baseline volume of the left posterior cingulate. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) sub-group analysis, and two risk loci (rs35445101 and rs1130399) were also the smaller baseline volume of the left posterior cingulate in (NC) sub-group analysis. Our study suggested that HLA-DRB1/DQB1 gene variants appeared to modulate the alteration of the left posterior cingulate volume, hence modulating the susceptibility of AD.

There is accumulating evidence that the human leukocyte antigen (HLA) gene variants are associated with Alzheimer's disease (AD). However, how they affect AD occurrence is still unknown. In this study, we firstly investigated the association of gene variants in HLA gene variants and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA on AD pathogenesis. We selected hippocampus, hippocampus CA1 subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). According to the previous association studies of HLA variants and AD, 12 SNPs in HLA were identified in the dataset following quality control measures. In total group analysis, our results showed that TNF-α SNPs at rs2534672 and rs2395488 were significantly positively associated with the volume of the left middle temporal lobe (rs2534672: P = 0.00035, Pc = 0.004; rs2395488: P = 0.0038, Pc = 0.023) at baseline. In the longitudinal study, HFE rs1800562 was remarkably correlated with the lower atrophy rate of right middle temporal lobe (P = 0.0003, Pc = 0.003) and RAGE rs2070600 was associated with the atrophy rate of right hippocampus substructure-CA1 over 2 years (P = 0.003, Pc = 0.035). Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subgroup analysis, as well as the association of rs2534672 with the baseline volume of the left middle temporal lobe in normal cognition (NC) subgroup analysis. Our study provided preliminary evidences that HLA gene variants might participate in the structural alteration of AD associated brain regions, hence modulating the susceptibility of AD.

HLA-A is a locus of the major histocompatibility complex situated on chromosome 6p21.3. HLA-A has been shown to be associated with susceptibility to Alzheimer's disease (AD). In this study, we firstly investigated the association of gene variants in HLA-A and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA-A on AD pathogenesis. We selected the hippocampus, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). In hybrid population analysis, our results showed a marginally significant association between rs9260168 and the atrophy of the left parahippocampus (P = 0.007, Pc = 0.054), rs3823342 and the atrophy of the left parahippocampus (P = 0.014, Pc = 0.054), rs76475517, which only exists in Caucasians with HLA-A23 or HLA-A24 alleles, and the atrophy of the right amygdala (P = 0.010, Pc = 0.085) at baseline. In particular, the haplotype (TGACAAGG), as a surrogate marker of HLA-A2, was founded to be positively associated with the atrophy of the right hippocampus (P = 0.047) at baseline. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subpopulation analysis. Our study provided preliminary evidences supporting HLA-A2 in Caucasians contribute to the risk of AD by modulating the alteration of hippocampal volume and HLA-A gene variants appear to play a role in altering AD-related brain structures on MRI.

The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer's disease (LOAD) based on recent genetic studies. Numerous studies have shown that multiple neuroimaging measures are potent predictors of AD risk and progression, and these measures are also affected by genetic variations in AD. Figuring out the association between CD33 genetic variations and AD-related brain atrophy may shed light on the underlying mechanisms of CD33-related AD pathogenesis. Thus, we investigated the influence of CD33 genotypes on AD-related brain atrophy to clarify the possible means by which CD33 impacts AD. A total of 48 individuals with probable AD, 483 mild cognitive impairment, and 281 cognitively normal controls were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We investigated the influence of CD33 SNPs on hippocampal volume, parahippocampal gyrus volume, posterior cingulate volume, middle temporal volume, hippocampus CA1 subregion volume, and entorhinal cortex thickness. We found that brain regions significantly affected by CD33 genetic variations were restricted to hippocampal and parahippocampal gyrus in hybrid population, which were further validated in subpopulation (MCI and NC) analysis. These findings reaffirm the importance of the hippocampal and parahippocampal gyrus in AD pathogenesis, and present evidences for the CD33 variations influence on the atrophy of specific AD-related brain structures. Our findings raise the possibility that CD33 polymorphisms contribute to the AD risk by altering the neuronal degeneration of hippocampal and parahippocampal gyrus.

Background and Aim: The incidence of nonalcoholic fatty liver disease (NAFLD), ranging from mild steatosis to hepatocellular injury and inflammation, increases with the rise of obesity. However, the implications of transcription factors network in progressive NAFLD remain to be determined., Methods: A co-regulatory network approach by combining gene expression and transcription influence was utilized to dissect transcriptional regulators in different NAFLD stages. In vivo, mice models of NAFLD were used to investigate whether dysregulated expression be undertaken by transcriptional regulators., Results: Through constructing a large-scale co-regulatory network, sample-specific regulator activity was estimated. The combinations of active regulators that drive the progression of NAFLD were identified. Next, top regulators in each stage of NAFLD were determined, and the results were validated using the different experiments and bariatric surgical samples. In particular, Adipocyte enhancer-binding protein 1 (AEBP1) showed increased transcription activity in nonalcoholic steatohepatitis (NASH). Further characterization of the AEBP1 related transcription program defined its co-regulators, targeted genes, and functional organization. The dynamics of AEBP1 and its potential targets were verified in an animal model of NAFLD., Conclusions: This study identifies putative functions for several transcription factors in the pathogenesis of NAFLD and may thus point to potential targets for therapeutic interventions., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Although β-amyloid (Aβ) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aβ degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs)., Objective: To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population., Method: We screened a locus (rs6665) in 3' UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese., Results: The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE ε4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697)., Conclusion: Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Recently, 19 susceptibility loci for Alzheimer's disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and β-amyloid (Aβ) deposition on neuroimaging in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aβ deposition. APOE ε4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE ε4) have been detected to be associated with one or a few established AD-related neuroimaging measures.

Aim: To investigate the key imaging points in distinguishing ossifying inverted papilloma (IP) from polyps., Materials and Methods: The native computed tomography (CT), conventional and enhanced MRI manifestations of 20 ossifying IPs and eight polyps, which were confirmed histopathologically, were retrospectively evaluated by two doctors majoring in head and neck imaging., Results: A significant difference was detected between the two entities for the involved sites (p<0.05). Although two lesions had similar CT findings, the MRI features differed significantly (p<0.05). Twenty ossifying IPs demonstrated heterogeneously isointense with moderate gadolinium enhancement, and a convoluted "cerebriform" configuration. Seven ossifying polyps revealed low T1 and high T2 signal, with marginal enhancement, and one showed isointense with moderate enhancement. The ossification appeared as oval or striped bone-like high attenuation, which consisted of peripheral hyperattenuating cortical bone and central fat-like attenuation of the medullary cavity. The corresponding MRI findings of the ossifying regions were peripherally low signal and centrally high signal on both T1- and T2-weighted images. The occurrence of two key MRI features of cystic appearance and the "cerebriform" sign were significantly different between two entities (p<0.05)., Conclusions: CT can better detect intralesional ossification, but MRI is the optimal imaging technique for discriminating between two disease entities., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Although altered lipid metabolism has been extensively implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cell biological and epidemiological studies, genetic studies linking lipid metabolism and LOAD are still not well understood. MicroRNAs (miRNAs) exert posttranscriptional down-regulation and their target sequence on the 3' untranslated regions (3'UTR) may be altered by single nucleotide polymorphisms (SNPs). We therefore explore whether the six loci in Clusterin gene (CLU) (rs9331949), Lipoprotein lipase gene (LPL) (rs1059507, rs3200218, rs3208305, rs3735964) and Low-density lipoprotein receptor related protein 6 (LRP6) (rs2160525) could modulate LOAD risk through the alteration of miRNA binding sites. We performed a case-control study of 2338 unrelated subjects (984 cases and 1354 age- and gender-matched controls) in the Northern Han Chinese. We found that the minor C allele in rs9331949 significantly increased the risk of LOAD (P<0.001, OR=1.31, 95% CI=1.14-1.51), even after adjusting for multiple testing. Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD, even in Apolipoprotein E (APOE) ε4 allele noncarrier subgroups. However, the other five loci were not significantly associated with LOAD after Bonferroni adjustment. In conclusion, we have identified that the locus (rs9331949) located in the binding site of 3' UTR of CLU has a strong association with LOAD rather than loci in LPL and LRP6. However, additional independent replication is required for further validation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimer's disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accelerated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes.

Alzheimer's disease (AD) has become a considerable public health issue. The mechanisms underlying AD onset and progression remain largely unclear. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a strong functional AD candidate gene because it encodes part of the statin-binding domain of the enzyme, which serves as the rate-limiting step in cholesterol synthesis in all mammalian cells. Here, we evaluated the potential role of HMGCR (rs3846662) in AD-related pathology by assessing neuroimaging biomarkers. We enrolled in 812 subjects from the Alzheimer's disease Neuroimaging Initiative dataset. In general, it is possible that HMGCR (rs3846662) could be involved in preventing the atrophy of right entorhinal (P=0.03385) and left hippocampus (P=0.01839) in the follow-up research of two years. What's more, it lowered the drop rate of glucose metabolism in right temporal. We then further validated them in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. All the results in the MCI groups confirmed the association. The results of our study indicated that HMGCR (rs3846662) plays a vital role in AD pathology mainly by influencing brain structure and glucose metabolism during AD progression.

ABCA7 gene has been identified as a strong genetic locus for Alzheimer's disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

Background: The Plexin-A 4 (PLXNA4) gene has recently been recognized as a functional candidate gene of late-onset Alzheimer's disease (LOAD). The single nucleotide polymorphism (SNP) rs13232207 of PLXNA4 gene has been reported to be associated with Alzheimer's disease (AD) in Japanese cohorts. We sought to clarify whether this novel locus gains the same effect in northern Han Chinese., Methods: To investigate the relationship between SNP rs13232207 and AD sufferers, a case-control study of unrelated individuals was conducted with a total sample size of 2,318 subjects (978 cases and 1,340 age and gender matched healthy controls) in a Northern Han Chinese population. SPSS 22.0 was applied for the statistical process., Results: No significant difference in polymorphic distribution of rs13232207 was observed on LOAD risk independently under dominant (P=0.057), additive (P=0.233) or recessive model (P=0.392). In terms of interaction with apolipoprotein E (APOE), there is also no positive interaction in dominant (P=0.438), additive (P=0.055) or recessive model (P=0.095)., Conclusions: Replication of association between the PLXNA4 rs13232207 and AD in a Han ethnic group indicates that this link is not the result of chance.

Background: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD., Objective: To explore whether these SNPs are associated with AD risk., Methods: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects., Results: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088)., Conclusion: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

What Is Known and Objective: Adefovir dipivoxil (ADV) is recommended for patients infected with lamivudine-refractory hepatitis B virus (HBV). We report a case of low-dose ADV-induced hypophosphatemic osteomalacia that initially presented as diffuse musculoskeletal pain., Case Summary: A 59-year-old Chinese man reported an 18-month history of severe chest wall pain and multiple bone pain during the previous 4 months with no antecedent trauma. There was no clinical evidence of an infectious, inflammatory or malignant process. Medical history showed that the patient had a history of chronic hepatitis B infection, and receiving lamivudine at a daily dose of 100 mg for 70 months. Lamivudine was changed to adefovir (10 mg/day) for the past 42 months. His serum inorganic phosphorus concentration was significantly low (0·4 mmol/l; 0·81-1·5 mmol/L), and the result of a urine routine test was abnormal. Combined with unbearable bone pain, spontaneous fractures, changes in laboratory markers and the result of ECT and other radiographic findings, the diagnosis of Fanconi's syndrome with osteomalacia was established. Dramatic clinical, laboratory and imaging improvement was observed after ADV discontinuation., Whats Is New and Conclusion: This case indicates that Fanconi's syndrome with osteomalacia can be acquired by a chronic hepatitis B patient taking ADV at a conventional dosage of 10 mg/day. Therefore, patients with HBV treated with long-term ADV should be regularly monitored for renal function, serum calcium and serum phosphate. Urine testing for ion concentration should also be undertaken., (© 2015 John Wiley & Sons Ltd.)

Recently, two large genome-wide association studies (GWASs) have identified several variants at 12q14 and 12q24 which are associated with hippocampal volume, one of the most important biological markers of Alzheimer's disease (AD). The strongest association was reported for the rs7294919 polymorphism on chromosome 12q24.22. In order to explore whether rs7294919 polymorphism was also associated with late-onset AD (LOAD) risk, we recruited 1132 LOAD patients and 1159 sex- and age-matched healthy controls in the study. The results showed that rs7294919 polymorphism was significantly associated with LOAD (genotype P<0.01, allele P=0.02). After stratification by APOE, significant difference was only observed in non-APOE ɛ4 carriers (P=0.01). Logistic regression demonstrated that the C allele at rs7294919 was a risk factor for LOAD in dominant and recessive models after adjusting for age, gender and the APOE ɛ4 carrier status. In conclusion, our study demonstrates an association of rs7294919 polymorphism locus on chromosome 12q24.22 with risk for LOAD in Han Chinese., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Complement receptor 1 (CR1) has been considered to play an important role in late-onset Alzheimer's disease (LOAD) pathogenesis. To explore the correlation between the CR1 gene and LOAD, a 2-step design study was conducted in our Northern Han Chinese population. We first sequenced the promoter, exons, the 5' and 3' untranslated regions and exon-intron boundaries of CR1 in a small sample (n = 100). This allowed us to identify a total of 22 variants. In addition, 6 missense variants within the CR1 gene were selected to be genotyped in a total of 2292 individuals. Only 2 SNPs (rs116806486, Thr→Ala; rs6691117, Ile→Val) were significantly associated with an increased risk of LOAD. After stratification by APOE ε4-carrying status, significance was observed in APOE ε4 non-carriers for rs116806486 and in APOE ε4 carriers for rs6691117. Logistic analysis revealed that the rs116806486 polymorphism remained associated with LOAD in a dominant model, whereas the rs6691117 polymorphism was associated with LOAD in additive and recessive models but not in a dominant model after adjusting for sex, age at onset, and APOE ε4 status. Examination of the haplotypes identified the risk of a 3-SNP (rs2274567, rs3737002, and rs6691117) haplotype "ATG" in CR1 was associated with an increased risk for LOAD. These findings provide the evidence that missense variants in the CR1 gene may be involved in LOAD pathologic process in Han Chinese., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72), on chromosome 9p21, has recently been identified as a major cause of familial frontotemporal dementia (FTD). The neuropathology and clinical characteristics associated with C9ORF72 mutations are heterogeneous with the unknown pathomechanism. These cases were reported with a series of neuropathology, including TDP-43 pathology, ubiquilin (UBQLN) pathology, p62 pathology, microglial pathology, RNA-binding protein pathology and pathology associated with dipeptide-repeat (DPR) proteins. TDP-43 positive neuropathology was important in FTD patients with the mutations. Nevertheless, the majority of reports agree with a special pattern of neuropathology with p62 positive, TDP-43-negative inclusions being a consistent feature. Although subjects with the C9ORF72 mutations more frequently present with earlier onset age, earlier death, a shortened survival and a positive family history, most of the subjects present with typical clinical features of FTD. All these findings support that the C9ORF72 mutations become important newly recognized causes of FTD, providing a more detailed characterization of the associated clinical and pathological features. The following review summarizes the pathological development of FTD associated with C9ORF72, the clinical and pathological features of this cohort, some pathological mechanism hypotheses, and describes their phenotypic range and overlap with other neurodegenerative diseases., (© 2013.)

The authors deduced Gaussian function of millimeter wave power distribution, and built up a transient thermal multilayer model for the heating of murine skin by high power millimeter waves with finite volume method (FVM) based on HBHE in the present paper. We analyzed the calculated results and compared them with the results calculated by Pennes' equation and the experimental ones; found that the temperature calculated by HBHE was more reasonable. Especially under high power millimeter wave, the calculated results were basically consistent with the experimental ones, and the superiority of the theoretical model was confirmed.

The real-time myocardial contrast echocardiography (RT MCE) is a new echocardiography technology, which allows clinicians to noninvasively evaluate the perfusion of myocardial capillary of patients, using the quantitative analysis of RT MCE. But the accurate analysis requires tracking the position of region of interest (ROI) within the myocardial area, so as to compensate for the translation or rotation offsets, which are due to such uncontrollable factors as heart motion. We used diamond search method and Brox's coarse-to-fine warping optical flow technique for this ROI tracking problem. We validated our methods by comparing the quantitative analysis results of RT MCE using our methods with those using Lucas & Kanade's optical flow technique, which had been report to be accurate enough for this ROI tracking. We finally present some examples of animal experiment to show the effectiveness and the clinical application value of our ROI tracking methods.

Background: Decreased cardiac contractility has been observed in cirrhosis, suggesting a latent cardiomyopathy in these patients. This study was designed to evaluate left ventricular structure and function in patients with end-stage liver disease by the model for end-stage liver disease (MELD) scoring system., Methods: We recruited 82 patients (72 male, 10 female; mean age 50.3+/-8.9 years) with end-stage liver disease who underwent orthotopic liver transplantation between January 2002 and May 2008. Seventy-eight patients had cirrhosis and 4 had primary liver cancer. Patients were categorized into three groups on the basis of MELD score: ≤ 9 (27 patients, 33%); 10-19 (40, 49%); and ≥ 20 (15, 18%). The relationship between MELD score and cardiac structure and function was determined. Preoperative assessments of blood biochemistry, blood coagulation, serum virology, echocardiography and electrocardiography were performed., Results: MELD score was positively correlated with enlarged left atrial diameter, increased interventricular septum thickness (IVST), increased aortic flow, corrected QT interval (QTc) extension and cardiac output (P=0.033, 0.002, 0.000, 0.000 and 0.009, respectively). International normalized ratio also had a correlation with the above parameters and enlarged left ventricular end-diastolic diameter (P=0.043, 0.010, 0.000, 0.001, 0.016 and 0.008, respectively). Serum creatinine was positively correlated with IVST (r=0.257, P=0.020), but negatively correlated with early maximal ventricular filling velocity/late diastolic or atrial velocity ratio (r=-0.300, P=0.006). A difference of QTc >440 ms among the three groups was statistically significant (X2=9.791, P=0.007)., Conclusions: Abnormalities in cardiac structure and function are common in patients with end-stage liver disease. MELD score is a practically useful approach for the assessment of cardiac function in such patients.

Background: There are few reports of a biological role for glycosyltransferases in the infiltration of osteoarthritic synovitis. The aim of this research was to investigate the expression and cellular location of β-1,4-galactosyltransferase I (β-1,4-GalT-I) in a surgically-induced rat model of knee osteoarthritis (OA), and explore the role of β-1,4-GalT-I in the pathogenesis of OA., Methods: Male Sprague-Dawley rats were randomly divided into three groups: OA group, sham group and normal group. The model of OA was established in the right knees of rats by anterior cruciate ligament transaction (ACLT) with partial medial meniscectomy. Fibroblast-like synoviocytes (FLSs) obtained from normal rat synovial tissue were cultured. The expression of β-1,4-GalT-I mRNA in the synovial tissue, articular cartilage and FLSs treated with tumor necrosis factor-α (TNF-α) were assayed by real-time PCR. Western-blotting and immunohistochemisty were used to observe the expression of β-1,4-GalT-I at the protein level. Double immunofluorescent staining was used to define the location of the β-1,4-GalT-I with macrophage-like synoviocytes, FLSs, neutrophils, and TNF-α in the OA synovium. The alteration of TNF-α in FLSs which were treated with lipopolysaccharide (LPS) and β-1,4-GalT-I-Ab were detected by enzyme-linked immunosorbent assay (ELISA)., Results: The mRNA and protein expression of β-1,4-GalT-I increased in synovial tissue of the OA group compared with the normal and sham groups at two and four weeks after the surgery, however, no significant difference appeared in the articular cartilage. Immunohistochemistry also indicated that the β-1,4-GalT-I expression in OA synovium at four weeks after surgery increased sharply compared with the control group. β-1,4-GalT-I co-localized with macrophage-like synoviocytes, FLSs, neutrophils and TNF-α in rat OA synovitis. Moreover, in vitro β-1,4-GalT-I mRNA in FLSs was affected in a dose- and time-dependent manner in response to TNF-α stimulation. ELISA revealed that the expression of TNF-α was attenuated in FLSs in vitro when treated with anti β-1,4-GalT-I antibody., Conclusion: β-1,4-GalT-I may play an important role in the inflammation process of rat OA synovial tissue which would provide the foundation for further researching into the concrete mechanism of β-1,4-GalT-I in OA synovitis.