High-fat diet caused renal damage in ApoE-/- mice via the activation of RAGE-mediated inflammation.

High-fat diet (HFD) is the primary cause of metabolic syndrome associated chronic kidney disease. This study aimed to investigate the pathogenesis of HFD-induced kidney injury. ApoE-/- mice were fed with HFD and kidney damage was examined. In addition, HK-2 human renal proximal tubular epithelial cells were treated with fructose and receptor of advanced glycation end products (RAGE) siRNA. The results showed that HFD increased body weight, blood glucose and insulin resistance in ApoE-/- mice. The kidney damage was associated with increased oxidative stress and strong staining of RAGE and NF-κB in kidney tissues, as well as high serum levels of TNF-α, IL-1ß and IL-6. Western-blot analysis showed that HFD increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 but decreased the levels of Bcl-2 in kidney tissues. In HK-2 cells, fructose promoted the secretion of TNF-α, IL-1ß and IL-6 and increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9, but decreased the levels of Bcl-2. Moreover, RAGE siRNA could attenuate increased levels of p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 while restore decreased levels of Bcl-2 in fructose-treated HK-2 cells. In conclusion, HFD causes kidney injury by promoting oxidative stress, inflammation and apoptosis possibly through the activation of RAGE/NF-κB pathway.

Association of antinuclear antibodies with the risk of intracranial arterial stenosis.

The prevalence of intracranial arterial stenosis (IAS) as well as antinuclear antibody (ANA) positivity was found to be higher in Asians than that in the Western population. To investigate the relation of ANAs with IAS in patients with acute ischemic cerebrovascular disease, we enrolled 2492 patients with acute ischemic stroke or transient ischemic attack into the study. All the patients were categorized into 3 groups according to the IAS burden. Multinomial logistic regression analyses were used in statistical analysis. The positive rate of ANAs in the IAS ≥ 2 group was higher than that in the single IAS group and the no IAS group (p<0.001). The adjusted odds ratio (OR) for IAS ≥ 2 in ANAs-positive patients was 3.737 (95%CI=2.676-5.220, p<0.001) compared with the ANAs-negative patients. ANAs were associated with multiple IAS rather than single IAS in both male and female subgroups. Besides, ANAs were significantly associated with single and multiple IAS in individuals ≤ 60 years. However, ANAs were only associated with two or more IAS in two age groups (between 61 to 75 years and >75 years old). In summary, ANAs are associated with IAS in patients with acute ischemic cerebrovascular disease.

Effects of Blood Pressure in the Early Phase of Ischemic Stroke and Stroke Subtype on Poststroke Cognitive Impairment.

BACKGROUND AND PURPOSE: Blood pressure (BP) control in the early phase of stroke is controversial to reduce the risk of poststroke cognitive impairment (PSCI). This study was to investigate the impact of BP levels in the early phase of ischemic stroke and stroke subtype on PSCI. METHODS: Seven hundred and ninety-six patients with acute ischemic stroke were included. Cognitive function was assessed after stroke onset using the Montreal Cognitive Assessment. Patients were divided into quintiles according to systolic BP and diastolic BP levels in the early phase. Subtype analyses were according to Trial of ORG 10172 in Acute Stroke Treatment classification (infarct cause) and Oxfordshire Community Stroke Project classification (infarct location). RESULTS: After adjusting for multiple variables, the quintiles with the lowest systolic BP (Q1, 102-127 mm Hg) and with the highest systolic BP (Q5, 171-215 mm Hg) were associated with increased PSCI risk (odds ratio, 1.83; 95% confidence interval, 1.64-2.28; P=0.007 in Q1; odds ratio, 2.32; 95% confidence interval, 1.74-2.90; P<0.001 in Q5) at 3 months as compared with the middle quintile (Q3, 143-158 mm Hg). Similar association was found in diastolic BP quintiles. The analysis of cerebral infarction subtype demonstrated that both large artery atherosclerosis and total anterior circulation infarct were associated with increased risk of PSCI at 3 months after adjusting for multiple variables (large artery atherosclerosis: odds ratio, 1.42; 95% confidence interval, 1.06-1.90; P=0.031; total anterior circulation infarct: odds ratio, 1.68; 95% confidence interval, 1.32-2.15; P=0.001). CONCLUSIONS: Lower or higher BP in the early phase of ischemic stroke was correlated with increased PSCI risk at 3 months. Maintaining systolic/diastolic BP in the levels of 143 to 158/93 to 102 mm Hg might be beneficial to reduce the occurrence of PSCI. Moreover, large artery atherosclerosis subtype and total anterior circulation infarct subtype were correlated with increased PSCI risk at 3 months. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org. Unique identifier: ChiCTR-TRC-14004804.

Blood pressures immediately following ischemic strokes are associated with cerebral perfusion and neurologic function.

The optimal range of blood pressure levels in the early phase of ischemic stroke with hypertension is still controversial. Based on our stroke registry database, we explored the relationship between blood pressure levels and cerebral perfusion in the early phase of ischemic stroke with hypertension and neurofunctional recovery at 3 months after stroke. Total 732 stroke patients with hypertension were finally analyzed. Patients were divided into quintiles according to systolic blood pressure (SBP) and diastolic blood pressure (DBP) to perform multivariable logistic regression to analyze their relation with neurofunctional recovery, respectively. The cerebral perfusion levels displayed a reverse "U" shape curve with the change of blood pressure levels. Sufficient estimated cerebral blood flow (ECBF) in the early phase of ischemic stroke was associated with good neurofunctional recovery at 3 months after stroke. The best neurofunctional recovery was observed in the middle quintiles with SBP at 161 to 177 mm Hg and DBP at 103 to 114 mm Hg, respectively. So maintaining appropriate blood pressure levels in the early phase of ischemic stroke might be beneficial to cerebral perfusion and neurofunctional recovery.

Common Variants in PLXNA4 and Correlation to CSF-related Phenotypes in Alzheimer's Disease.

The Plexin-A 4 (PLXNA4) gene, has recently been identified in genome wide association studies (GWAS), as a novel genetic player associated with Alzheimer's disease (AD). Additionally, PLXNA4 genetic variations were also found to increase AD risk by tau pathology in vitro. However, the potential roles of PLXNA4 variants in the amyloid-ß (Aß) pathology, were not evaluated. Five targeted loci capturing the top common variations in PLXNA4, were extracted using tagger methods. Multiple linear regression models were used to explore whether these variations can affect the cerebrospinal fluid (CSF) (Aß1-42, T-tau, and P-tau) phenotypes in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. We detected that two loci (rs6467431, rs67468325) were significantly associated with CSF Aß1-42 levels in the hybrid population (rs6467431: P = 0.01376, rs67468325: P = 0.006536) and the significance remained after false discovery rate (FDR) correction (rs6467431: Pc = 0.03441, rs67468325: Pc = 0.03268). In the subgroup analysis, we further confirmed the association of rs6467431 in the cognitively normal (CN) subgroup (P = 0.01904, Pc = 0.04761). Furthermore, rs6467431-A carriers and rs67468325-G carriers showed higher CSF Aß1-42 levels than non-carriers. Nevertheless, we did not detect any significant relationships between the levels of T-tau, P-tau and these PLXNA4 loci. Our findings provided preliminary evidence that PLXNA4 variants can confer AD risk through modulating the Aß deposition.

Midterm Blood Pressure Variability Is Associated with Poststroke Cognitive Impairment: A Prospective Cohort Study.

OBJECTIVE: The aim of this study was to investigate the relationship between blood pressure variability (BPV) and poststroke cognitive impairment (PSCI). METHODS: Seven-hundred ninety-six patients with acute ischemic stroke were included in this study. Midterm BPV was evaluated by calculating the SD and coefficient of variation (CV, 100 × SD/mean) of systolic blood pressure (SBP) and diastolic blood pressure during the 7 days after stroke onset. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) at admission and at all follow-up visits. Patients with MoCA scores <26 were considered to have PSCI. RESULTS: The incidence of PSCI reached its peak (72%) 3 months after stroke onset and decreased to 30.3% at 12 months poststroke. After adjusting for covariables, the increase in the prevalence of PSCI at 3 months was independently associated with increases in the CV of blood pressure during the 7 days after stroke [odds ratios and 95% CI for patients in the second to fifth quintiles of SBP CV were 2.28 (1.18, 4.39), 2.33 (1.18, 4.62), 2.69 (1.31, 5.53), and 4.76 (1.95, 11.67), respectively]. Sub-analysis of the MoCA scores revealed that the patients had impairments in visuoperceptual abilities and executive functions, as well as in naming and delayed recall (p < 0.05). CONCLUSION: Midterm BPV during the early phase of acute ischemic stroke is independently associated with PSCI, especially in the visuoperceptual, executive, and delayed recall domains. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn, identifier ChiCTR-TRC-14004804.

Mid-Term Blood Pressure Variability Is Associated With Clinical Outcome After Ischemic Stroke.

BACKGROUND: The aim of this study was to investigate the relation between mid-term blood pressure (BP) variability (BPV) within 7 days of onset and the prognosis in acute stroke patients. METHODS: Total 873 acute ischemic stroke patients were included in this study. Mid-term BPV was evaluated through the calculations of coefficient of variation (CV) of the systolic BP (SBP) and diastolic BP (DBP) within 7 days of onset. Clinical outcomes were assessed using the recovery situations of neurological function at 3 months, the primary outcome (symptomatic recurrent stroke) and the secondary outcomes (recurrent stroke, all-cause mortality, and the composite of cardiovascular events) within 12 months. RESULTS: Among 873 patients with ischemic stroke, 83 died, 125 developed recurrent stroke, and 212 developed cardiovascular events during 12 months' follow-up. At 3 months, systolic or diastolic BPV (within 7 days of onset) was associated with the recovery situations of neurological function in three models (all P < 0.05). Both higher CV of SBP and CV of DBP were significantly correlated with the increased risk of recurrent stroke (hazard ratio [HR] = 2.32, 95% confidence interval [CI]: 1.29-4.18, P = 0.005 for CV of SBP; HR = 2.33, 95% CI: 1.29-4.19, P = 0.005 for CV of DBP) and composite cardiovascular events (HR = 2.22, 95% CI: 1.41-3.48, P = 0.001 for CV of SBP; HR = 2.21, 95% CI: 1.41-3.47, P = 0.001 for CV of DBP) during 12 months' follow-up. CONCLUSIONS: After acute ischemic stroke, high systolic or diastolic BPV within 7 days of onset was associated with the recovery situations of neurological function at 3 months, and recurrent stroke and composite cardiovascular events within 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-TRC-14004804.

Prehospital Identification of Stroke Subtypes in Chinese Rural Areas.

BACKGROUND: Differentiating intracerebral hemorrhage (ICH) from cerebral infarction as early as possible is vital for the timely initiation of different treatments. This study developed an applicable model for the ambulance system to differentiate stroke subtypes. METHODS: From 26,163 patients initially screened over 4 years, this study comprised 1989 consecutive patients with potential first-ever acute stroke with sudden onset of the focal neurological deficit, conscious or not, and given ambulance transport for admission to two county hospitals in Yutian County of Hebei Province. All the patients underwent cranial computed tomography (CT) or magnetic resonance imaging to confirm the final diagnosis based on stroke criteria. Correlation with stroke subtype clinical features was calculated and Bayes' discriminant model was applied to discriminate stroke subtypes. RESULTS: Among the 1989 patients, 797, 689, 109, and 394 received diagnoses of cerebral infarction, ICH, subarachnoid hemorrhage, and other forms of nonstroke, respectively. A history of atrial fibrillation, vomiting, and diabetes mellitus were associated with cerebral infarction, while vomiting, systolic blood pressure ≥180 mmHg, and age <65 years were more typical of ICH. For noncomatose stroke patients, Bayes' discriminant model for stroke subtype yielded a combination of multiple items that provided 72.3% agreement in the test model and 79.3% in the validation model; for comatose patients, corresponding agreement rates were 75.4% and 73.5%. CONCLUSIONS: The model herein presented, with multiple parameters, can predict stroke subtypes with acceptable sensitivity and specificity before CT scanning, either in alert or comatose patients. This may facilitate prehospital management for patients with stroke.

Elevated ZNF703 Protein Expression Is an Independent Unfavorable Prognostic Factor for Survival of the Patients with Head and Neck Squamous Cell Carcinoma.

AIM: Data from The Cancer Genome Atlas (TCGA) show that the ZNF703 gene amplifies and overexpresses in head and neck squamous cell carcinomas (HNSCC). However, the clinical relevance of this observation in HNSCC is unclear. The purpose of this study was to clarify the expression of ZNF703 protein and its prognostic effect on HNSCC. METHODS: Two hundred ten HNSCC patients from Sun Yat-Sen University Cancer Center with complete survival follow-up were included in this study. Tumor samples from primary sites were collected. The expression of the ZNF703 protein was tested by immunohistochemistry (IHC). RESULTS: The high expression of ZNF703 in HNSCC tumor tissues was significantly higher than that of the matched noncancerous tissues (48.6% versus 11.6%, P < 0.001). ZNF703 overexpression was correlated with tumor position (laryngeal carcinoma) and recurrence (all P < 0.05). Multivariate analysis revealed that ZNF703 protein overexpression was an independent prognostic factor (P = 0.022, hazard ratio = 1.635, 95% CI 1.073-2.493) in HNSCC patients. CONCLUSION: ZNF703 overexpression is associated with adverse prognosis in HNSCC, which might be a novel biomarker of HNSCC.

[An analysis of stroke subtypes and influencing factors in different regions of China].

OBJECTIVE: To analyze the stroke subtypes and influencing factors in four largest economic regions of China. METHODS: We analyzed the investigation data of QUEST (Quality Evaluation of Stroke Care and Treatment) study conducted in 2006 which included 62 hospitals in a national scale. According to the concept of four economic regions designed by the Development Research Center of the State Council, we performed the univariate and multivariate analysis for the stroke subtypes and its related risk factors in the different economic regions. RESULTS: There were 3362 (73.5%) ischemic stroke patients and 1214 (26.5%) hemorrhagic stroke patients among the total 4576 first-ever stroke patients. Comparison of stroke subtypes in the four different economic regions was statistically significant (P < 0.001), with a percentage of 80.8% ischemic stroke patients in the northeastern region, 78.9% in the eastern region, 68.3% in the central region and 67.0% in the western region. The comparisons of risk factors such as history of hypertension, diabetes, hyperlipidaemia, coronary artery event, atrial fibrillation, and overweight in the four different economic regions were also statistically significant (P < 0.05). CONCLUSIONS: The subtypes of first-ever stroke vary in the four largest economic regions with a highest proportion of ischemic stroke in the northeastern region and relatively high proportion of hemorrhagic stroke in the central and western economic regions. There are also discrepancies of stroke risk factors in the different economic regions.

Decrease in the production of ß-amyloid by berberine inhibition of the expression of ß-secretase in HEK293 cells.

BACKGROUND: Berberine (BER), the major alkaloidal component of Rhizoma coptidis, has multiple pharmacological effects including inhibition of acetylcholinesterase, reduction of cholesterol and glucose levels, anti-inflammatory, neuroprotective and neurotrophic effects. It has also been demonstrated that BER can reduce the production of beta-amyloid40/42, which plays a critical and primary role in the pathogenesis of Alzheimer's disease. However, the mechanism by which it accomplishes this remains unclear. RESULTS: Here, we report that BER could not only significantly decrease the production of beta-amyloid40/42 and the expression of beta-secretase (BACE), but was also able to activate the extracellular signal-regulated kinase1/2 (ERK1/2) pathway in a dose- and time-dependent manner in HEK293 cells stably transfected with APP695 containing the Swedish mutation. We also find that U0126, an antagonist of the ERK1/2 pathway, could abolish (1) the activation activity of BER on the ERK1/2 pathway and (2) the inhibition activity of BER on the production of beta-amyloid40/42 and the expression of BACE. CONCLUSION: Our data indicate that BER decreases the production of beta-amyloid40/42 by inhibiting the expression of BACE via activation of the ERK1/2 pathway.

Carbonic anhydrase III is insufficient in muscles of myasthenia gravis patients.

Myasthenia gravis (MG) is considered as an autoimmune disease mainly mediated by antibodies against acetylcholine receptor. In recent years, other targets related to MG have been the subject of interest. Our previous research found that protein P25 was lower in muscles of MG patients using two-dimensional electrophoresis. In present study, anti-serum to P25 was prepared, immunohistochemistry and ATPase staining revealed that P25 was a muscle specific cytosolic protein and was mainly distributed in type I muscle fibers. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and precise molecular weight derived from mass spectrometer identified P25 as carbonic anhydrase III (CA III). Some members of CA family are related to autoimmune diseases and CA III is recently reported to be involved in rheumatoid arthritis. The results of immunoblot in this report showed that the level of CA III is specifically insufficient in the skeletal muscle of MG patients. The possible roles that CA III play in MG need further elucidation.

[Incidence and prognosis of intra-and extracranial large-artery stenosis in the rural community of Beijing].

OBJECTIVE: To assess the prevalence rates of intra- and extracranial large-artery stenosis in the rural community population and its related risk to the development of stroke. METHODS: The study subjects included 1337 residents in the rural community of Beijing. Transcranial Doppler was carried our to examine the relation between intra- and extracranial large-artery stenosis and subsequent cerebrovascular events, with a mean follow-up period of 16.7 months. RESULTS: The incidence densities of cerebral infarction and cerebral hemorrhage in persons without cerebral large-artery stenosis were 410.6 and 351.9/100-thousand person-years, respectively. In the group with large-artery stenosis, the incidence density of cerebral infarction was 3303.7/100-thousand person-years. Data from The Fisher's Exact test showed a significant difference in the two groups (P = 0.004). Cerebral large-artery stenosis (OR = 6.593, 95%CI: 1.712 - 25.390) and smoking (OR = 8.437, 95%CI: 2.327 - 30.598) appeared to be independent risk factors to cerebral infarction. CONCLUSION: Cerebral large-artery stenosis and smoking were independent risk factors to cerebral infarction.

[Manipulative reduction for lumbar intervertebral disc herniation: a controlled clinical trial].

OBJECTIVE: To investigate the effects of manipulative reduction on pain and clinical curative effect in patients with lumbar intervertebral disc herniation. METHODS: Eleven thousands one hundred and twenty-eight patients with lumbar intervertebral disc herniation from our hospital were enrolled from November 1986 to June 2007. They were randomly divided into control group and treatment group. Patients of the control group received lumbar traction and various physiotherapies. Patients of the treatment group received manipulative reduction, besides the treatment in the control group. The treatment was performed once a day,ten times as a course. Curative effects were assessed three courses later. Pain was evaluated by visual analogue scale before and after the treatment. RESULTS: No significant difference in the score of visual analogue scale was found before the treatment in the two groups (P > 0.05). As compared with the score before treatment,it was decreased by 4.73 points after treatment in the control group, and decreased by 6.37 points in the treatment group. The decrease was more significant in the treatment group than the control group (P < 0.01). The healing rate was 47.28% and total effective rate was 96.37% in the control group; The healing rate was 73.44% and total effective rate was 98.61% in the treatment group (P < 0.01). CONCLUSION: Manipulative reduction for lumbar intervertebral disc herniation can remarkably relieve lumbar pain and improve clinical curative effect.

Effects of rapamycin in liver transplantation.

BACKGROUND: Rapamycin is a potent new immunosuppressant with a mechanism of action that is distinct from that of calcineurin inhibitors, but few clinical data on rapamycin in liver transplantation are available. Hence it is necessary to evaluate the efficacy and side-effects of rapamycin-based immunosuppression in liver transplant patients. METHODS: We retrospectively analysed 39 liver transplantation patients who took rapamycin as an immunosuppressant. This series consisted of 28 patients with hepatocellular carcinoma, 9 patients with chronic fulminant hepatitis, and 2 patients with end-stage liver cirrhosis. Eight patients used rapamycin for monotherapy, and 31 used rapamycin-based immunosuppression. In the 31 patients, 7 patients used rapamycin instead of mycophenolate mofetil to treat acute rejection. RESULTS: In the 28 patients with hepatocellular carcinoma, the one-year survival rate was 67% without any tumor recurrence. The acute rejection in 7 patients was relieved in 1-2 weeks after the administration of rapamycin. All the 8 patients who received rapamycin monotherapy survived for at least 6 months and liver function tests and biopsy showed nothing abnormal. Jaundice in 8 patients with chronic rejection was reduced sharply after use of rapamycin. CONCLUSIONS: Rapamycin given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies are warranted to evaluate the efficacy and side-effect profile of rapamycin in liver transplant patients.