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Beta amyloid (A beta) accumulation is the earliest pathological marker of Alzheimer's disease (AD), but early AD pathology also affects white matter (WM) integrity. We performed a cross-sectional study including 44 subjects (23 healthy controls and 21 mild cognitive impairment or early AD patients) who underwent simultaneous PET-MR using 18F-Florbetapir, and were categorized into 3 groups based on Ab burden: A beta- [mean mSUVr = 1.17]. Intergroup comparisons of diffusion MRI metrics revealed significant differences across multiple WM tracts. A beta i group displayed more restricted diffusion (higher fractional anisotropy, radial kurtosis, axonal water fraction, and lower radial diffusivity) than both A beta- and A beta+ groups. This nonmonotonic trend was confirmed by significant continuous correlations between mSUVr and diffusion metrics going in opposite direction for 2 cohorts: pooled A beta-/A beta i and pooled A beta i/A beta+. The transient period of increased diffusion restriction may be due to inflammation that accompanies rising A beta burden. In the later stages of A beta accumulation, neurodegeneration is the predominant factor affecting diffusion. (C) 2020 Elsevier Inc. All rights reserved.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

To investigate the ability of a multidisciplinary approach that combines multimodal neuroimaging with video-electroencephalography (v-EEG) to predict post-surgical outcomes in patients with intractable epilepsy, and explore prognostic predictors for these patients.Fifty-eight patients with intractable epilepsy who underwent surgery between March 2016 and October 2019 were reviewed retrospectively. Demographic, clinical, v-EEG, neuroimaging, surgical, and regular follow-up seizure outcome data were collected. Forty-six patients with a follow-up of at least 12 months were graded by Engel scores. Univariate and multivariate analyses were applied to explore prognostic factors that could predict post-surgical seizure outcomes.Of the 58 patients, 28 were males. The median age was 27 years, the median age at first seizure was 11 years, and the median duration of seizures was 10 years. The Kaplan-Meier log-rank test showed that regardless of whether the follow-up duration was considered, epilepsy type, v-EEG, PET/CT, image post-processing methods, and a multidisciplinary approach that combined multimodal imaging with v-EEG were all correlated with seizure outcomes. Multivariate analysis found that the multidisciplinary approach was an independent predictor of post-surgical outcomes in patients with intractable epilepsy (hazard ratio = 11.400, 95% confidence interval = 2.249-57.787, p=0.003).The present study showed that the multidisciplinary approach could provide independent prognostic information for patients with intractable epilepsy undergoing surgery. This approach has strong potential for the easier selection of patients to undergo surgical treatment and accurate prognostication.

MicroRNAs have emerged as crucial regulators of cardiac homeostasis and remodeling in various cardiovascular diseases. We previously demonstrated that miR-221 regulated cardiac hypertrophy in vitro. In the present study, we demonstrated that the cardiac-specific overexpression of miR-221 in mice evoked cardiac dysfunction and heart failure. The lipidated form of microtubule-associated protein 1 light chain 3 was significantly decreased and sequestosome 1 was accumulated in cardiac tissues of transgenic (TG) mice, indicating that autophagy was impaired. Overexpression of miR-221 in vitro reduced autophagic flux through inhibiting autophagic vesicle formation. Furthermore, mammalian target of rapamycin (mTOR) was activated by miR-221, both in vivo and in vitro. The inactivation of mTOR abolished the miR-221-induced inhibition of autophagy and cardiac remodeling. Our previous study has demonstrated that cyclin-dependent kinase (CDK) inhibitor p27 was a direct target of miR-221 in cardiomyocytes. Consistently, the expression of p27 was markedly suppressed in the myocardia of TG mice. Knockdown of p27 by siRNAs was sufficient to mimic the effects of miR-221 overexpression on mTOR activation and autophagy inhibition, whereas overexpression of p27 rescued miR-221-induced autophagic flux impairment. Inhibition of CDK2 restored the impaired autophagic flux and rescued the cardiac remodeling induced by either p27 knockdown or miR-221 overexpression. These findings reveal that miR-221 is an important regulator of autophagy balance and cardiac remodeling by modulating the p27/CDK2/mTOR axis, and implicate miR-221 as a therapeutic target in heart failure.

Galanin and galanin receptors (GalRs) have been reported to be involved in the transmission and modulation of nociceptive information in the central nervous system (CNS). However, the underlying mechanism of the antinociception of GalRs in neuropathic pain remains unclear. This study investigated the antinociception induced by galanin receptor 1 (GalR1) via protein kinase A (PKA) signaling pathway in the nucleus accumbens (NAc) of rats with neuropathic pain. A mononeuropathy model was replicated by ligation of the left sciatic nerve, following which the expression of phospho-PKA (p-PKA) in the NAc were markedly up-regulated at 14th and 28th day after ligation of sciatic nerve, and p-PKA expression was down-regulated by intra-NAc injection of GalR1 agonist M617, but the GalR1 antagonist M35 did not have an effect. We also found that M35 in the NAc blocked the M617-induced increase in the hind paw withdrawal latencies (HWLs) of rats with mononeuropathy, but M35 alone had no effect on HWLs, and PKA inhibitor H-89 attenuated the M617-induced an increase in the HWLs. These results suggested that GalR1 induced an antinociception via inhibiting PKA activation, implying that GalR agonists may be potential and potent therapeutic options to treat chronic neuropathic pain.

Regulator of G-protein signaling 7 (RGS7) is predominately present in the nervous system and is essential for neuronal signaling involving G-proteins. Prior studies in cultured cells showed that RGS7 is regulated via proteasomal degradation, however no protein is known to facilitate proteasomal degradation of RGS7 and it has not been shown whether this regulation affects G-protein signaling in neurons. Here we used a knockout mouse model with conditional deletion of arginyltransferase (Ate1) in the nervous system and found that in retinal ON bipolar cells, where RGS7 modulates a G-protein to signal light increments, deletion of Ate1 raised the level of RGS7. Electroretinographs revealed that lack of Ate1 leads to increased light-evoked response sensitivities of ON-bipolar cells, as well as their downstream neurons. In cultured mouse embryonic fibroblasts (MEF), RGS7 was rapidly degraded via proteasome pathway and this degradation was abolished in Ate1 knockout MEF. Our results indicate that Ate1 regulates RGS7 protein level by facilitating proteasomal degradation of RGS7 and thus affects G-protein signaling in neurons.

Mind wandering is often characterized by attention oriented away from an external task towards our internal, self-generated thoughts. This universal phenomenon has been linked to numerous disruptive functional outcomes, including performance errors and negative affect. Despite its prevalence and impact, studies to date have yet to identify robust behavioral signatures, making unobtrusive, yet reliable detection of mind wandering a difficult but important task for future applications. Here we examined whether electrophysiological measures can be used in machine learning models to accurately predict mind wandering states. We recorded scalp EEG from participants as they performed an auditory target detection task and self-reported whether they were on task or mind wandering. We successfully classified attention states both within (person-dependent) and across (person-independent) individuals using event-related potential (ERP) measures. Non-linear and linear machine learning models detected mind wandering above-chance within subjects: support vector machine (AUC = 0.715) and logistic regression (AUC = 0.635). Importantly, these models also generalized across subjects: support vector machine (AUC = 0.613) and logistic regression (AUC = 0.609), suggesting we can reliably predict a given individual’s attention state based on ERP patterns observed in the group. This study is the first to demonstrate that machine learning models can generalize to “never-seen-before” individuals using electrophysiological measures, highlighting their potential for real-time prediction of covert attention states.

Home-based self-screening and monitoring for obesity is particularly valuable for the prevention and control of chronic diseases. This study aimed to identify an anthropometric index suitable for home-based obesity screening in children and adolescents.The design of this study is a cross-sectional study.A total of 14,042 students (6-17 years) from the Qibao Community, Minhang District, Shanghai, were studied in 2018. The percentage body fat (PBF), height, weight, waist circumference (WC) and hip circumference were measured. Body mass index (BMI), triponderal mass index (TMI), body adiposity index (BAI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. Partial correlation analysis was used to evaluate the relationships between these indices and PBF, and receiver operating characteristic (ROC) curves were used to evaluate their performance for obesity screening.BMI, TMI, WC and WHtR were found to strongly correlate with PBF (r ≥ 0.830, all P 0.001). The optimal index for obesity screening in children (6-11 years) was BMI (area under the ROC curve [AUC] = 0.980 for boys and 0.981 for girls) and in adolescents (12-17 years) was TIM (AUC = 0.976 for boys and 0.945 for girls); however, the optimal cut-off values for BMI and TMI differed among the subgroups. The ROC curve analysis showed that WHtR had similar cut-off values in each subgroup (0.45 for boys of 6-11 years and 0.43 for the other subgroups), excellent performance in children (AUC0.90) and good performance in adolescents (AUC = 0.960 for girls and 0.878 for boys).Owing to its accuracy and stable cut-off value for defining obesity, WHtR should be recommended for home-based obesity screening in children and adolescents.

To assess the expression levels of Fyn in human tissue samples and pancreatic cancer cells and explore the potential mechanisms of Fyn in pancreatic cancer progression.Quantitative PCR and immunohistochemical (IHC) assays were performed to detect the expression of Fyn in 30 cancer tissue samples from pancreatic cancer patients and corresponding adjacent normal tissues. In addition, the potential correlations between Fyn expression levels and clinical pathological features were assessed. We further detected the effects of Fyn on the proliferation, apoptosis, migration, and invasion of the pancreatic cancer cells through colony formation assay, flow cytometry (FCM) assay, wound healing assay, and transwell assay, respectively. The potential effects of Fyn on tumor growth were assessed using an animal model.We demonstrated the possible involvement of Fyn in the progression of pancreatic cancer. We found that Fyn was upregulated in human pancreatic cancer tissues and cells, and we analyzed the correlations between Fyn expression and the clinicopathological features, including metastasis staging (p=0.010*) and tumor size (p=0.025*) of patients with pancreatic cancer. Our data further confirmed that Fyn affects cell proliferation, apoptosis, migration, and invasion of pancreatic cancer cells via the phosphorylation of GluN2b and regulation of AKT signaling pathway. We also demonstrated that Fyn promoted tumor growth of pancreatic cancer cells in vivo.We investigated the potential involvement of Fyn in the progression of pancreatic cancer, and therefore indicated Fyn as a possible therapeutic target for pancreatic cancer.

Objective To investigate the morphological changes in the degeneration and regeneration of neuromuscular junctions （NMJ） during the repair of mouse skeletal muscle contusion and discuss the correlation between the degeneration and regeneration of NMJ and wound age. Methods A total of 50 healthy adult male mice were randomly divided into 10 groups, including 9 experimental groups and 1 control group. Immunofluorescent staining was applied, and neurofilament was marked with neurofilament protein-H （NF-H）, presynaptic membrane was marked with synaptophysin （Syn）, presynaptic membrane was marked with acetylcholine receptor （AChR）. Morphological changes of NMJ regeneration at different time points after mouse skeletal muscle contusion were detected. Results The neurofilament and presynaptic membrane of NMJ at the junction of contusion zones began to degrade after contusion, and completed degradation at about 3 d post-injury. Then they gradually regenerated, roughly completing the regeneration at about 21 d and basically reaching the control group level. The ratio of presynaptic membrane quantity to presynaptic membrane quantity showed a trend of decreasing then rising and finally reaching the control level. Conclusion During the repair of mouse skeletal muscle contusion, the morphological changes and wound age of the NMJ at the junction of contusion zones have a close correlation, which is expected to be one of the biological indicators for forensic skeletal muscle wound age estimation.小鼠骨骼肌挫伤愈合过程中神经肌肉接头降解及再生与损伤时间的关系.目的 研究小鼠骨骼肌挫伤愈合过程中神经肌肉接头（neuromuscular junction，NMJ）降解及再生的形态学变化，探讨NMJ降解及再生与损伤时间的相关性。 方法 将50只健康成年雄性小鼠随机分为10组，其中9组为实验组，1组为对照组。应用免疫荧光染色技术，以高分子量神经丝蛋白（neurofilament protein-H，NF-H）标记神经丝，突触囊泡蛋白（synaptophysin，Syn）标记突触前膜，乙酰胆碱受体（acetylcholine receptor，AChR）标记突触后膜，检测小鼠骨骼肌挫伤后不同时间点NMJ再生的形态学变化。 结果 骨骼肌挫伤后挫伤交界区NMJ突触前膜及神经丝开始降解，3 d左右降解完全，之后逐渐再生，至21 d左右再生大致完成，基本达到对照组水平。突触前膜和后膜数量之比呈现先下降后上升、最终与对照组水平相当的趋势。 结论 小鼠骨骼肌挫伤修复过程中，挫伤交界区NMJ的形态学变化与损伤时间具有相关性，有望成为法医学骨骼肌损伤时间推断的生物学指标之一。.法医病理学；骨骼肌；挫伤；神经肌肉接头；损伤时间推断；小鼠.

Functional MRI (fMRI) can assess language lateralization in brain tumor patients; however, this can be limited if the primary language area—Broca’s area (BA)—is affected by the tumor. We hypothesized that the middle frontal gyrus (MFG) can be used as a clinical indicator of hemispheric dominance for language during presurgical workup. Fifty-two right-handed subjects with solitary left-hemispheric primary brain tumors were retrospectively studied. Subjects performed a verbal fluency task during fMRI. The MFG was compared to BA for fMRI voxel activation, language laterality index (LI), and the effect of tumor grade on the LI. Language fMRI (verbal fluency) activated more voxels in MFG than in BA (MFG = 315, BA = 216, p

This study aimed to evaluate the expression characteristics of lamin A/C proteins in intervertebral disc degeneration (IVD) specimens from patients with different degeneration grades. Lamin A/C proteins have been shown to result in age-related changes in the osteoarticular system. However, the expression characteristics of these nuclear proteins in degenerated human IVD tissues have not been explored previously.Degenerated human IVD tissues were obtained during spinal surgery. Articular cartilage samples after total knee replacement surgery were used as controls. Sections of these tissues were stained with hematoxylin and eosin, Masson, safranin O, and immunostained using lamin A/C antibody. Western blot was performed to evaluate lamin A/C expression in IVD tissues. Lamin A/C expression was analyzed based on different degeneration grades.In patients with IVD degeneration, mild or moderate degenerative discs contained high amounts of lamin A/C proteins. Lamin A/C expression was primarily localized in the nuclear envelope of IVD cells, and associated with apoptosis in cell nuclei, as determined by immunostaining and TUNEL assay.This paper is the first to report that lamin A/C proteins are present in IVD tissues and its expression may be related to disc degeneration.

We investigate the effect of long non-coding RNA H19 in acute myocardial infarction (AMI) and the underlying mechanism.C57BL/6 mice were subjected to AMI and injected with lentivirus pcDNA-H19. After AMI procedures for 3 weeks, cardiac function was detected by echocardiography. The infarct size was stained by triphenyltetrazolium chloride. H19 expression in mice was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Protein expressions of LC3, Beclin-1, and ATG-7 in mice were measured by Western blot.Our results indicated that H19 expression was significantly downregulated in the infarcted myocardium. Overexpression of H19 after injection with pcDNA-H19 in mice could reduce infarct size and improve cardiac function through upregulating the ratio of LC3-II/I and expressions of Beclin-1 and ATG-7.Overexpression of H19 could protect AMI in mice via activating autophagy.

We investigated the correlations of adenosine monophosphate-activated protein kinase (AMPK), Silence information regulator 1 (SIRT1) and energy metabolism with myocardial hypertrophy.Myocardial hypertrophy experimental model was established via transverse aortic constriction (TAC)-induced myocardial hypertrophy and phenylephrine (PE)-induced hypertrophic myocardial cell culture. After activation of AMPK, the messenger ribonucleic acid (mRNA) expressions in myocardial tissue- and myocardial cell hypertrophy-related genes, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), were detected. The production rate of 14C-labeled 14CO2 from palmitic acid was quantitatively determined to detect the fatty acid and glucose oxidation of hypertrophic myocardial tissues or cells, and the glucose uptake of myocardial cells was studied using [14C] glucose. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to detect the changes in SIRT1 mRNA and protein expressions in hypertrophic myocardial tissues. Moreover, SIRT1 small interfering ribonucleic acid (siRNA) was used to interfere in SIRT1 expression to further investigate the role of SIRT1 in the effect of AMPK activation on myocardial hypertrophy.AMPK activation could significantly reduce the mRNA expressions of ANP and β-MHC in vitro and in vivo. AMPK could increase the ejection fraction (EF) and decrease the protein synthesis rate in myocardial cells in mice with myocardial hypertrophy. Besides, AMPK activation could increase the fatty acid oxidation, improve the glucose uptake and reduce the glucose oxidation. After AMPK activation, both SIRT1 mRNA and protein expressions in hypertrophic myocardial tissues and myocardial cells were increased. After SIRT1 siRNA was further used to interfere in SIRT1 expression in myocardial cells, it was found that mRNA expressions and protein synthesis rates of ANP and β-MHC were increased.The activation of AMPK can inhibit the myocardial hypertrophy, which may be realized through regulating the myocardial energy metabolism via SIRT1 signaling pathway.

SUMMARYThe role of the protozoan parasite Toxoplasma gondii in the pathogenesis of liver disease has recently gained much interest. The aim of this study was to determine the prevalence and risk factors associated with T. gondii infection in patients with liver disease from three cities in Shandong and Henan provinces, China. A case–control study was conducted from December 2014 to November 2015 and included 1142 patients with liver disease and 1142 healthy controls. Serum samples were collected from all individuals and were examined with enzyme-linked immunosorbent assay for the presence of anti-T. gondii IgG and IgM antibodies. Information on the demographics, clinical, and lifestyle characteristics of the participants was collected from the medical records and by the use of a questionnaire. The prevalence of anti-T. gondii IgG was 19·7% in patients with liver disease compared with 12·17% in the controls. Only 13 patients had anti-T. gondii IgM antibodies compared with 12 control individuals (1·14% vs. 1·05%, respectively). The highest seroprevalence was detected in patients with liver cancer (22·13%), followed by hepatitis patients (20·86%), liver cirrhosis patients (20·42%), and steatosis patients (20%). Multivariate logistic regression analysis indicated that consumption of raw meat (odds ratio (OR) = 1·32; 95% confidence interval (CI) 1·01–1·71; P = 0·03) and source of drinking water from wells (OR = 1·56; 95% CI 1·08–2·27; P = 0·01) were independent risk factors for T. gondii infection in liver disease patients. These findings indicate that T. gondii infection is more likely to be present in patients with liver disease. Therefore, efforts should be directed toward health education of populations at high risk of T. gondii infection and measures should be taken to protect vulnerable patients with liver disease.

To investigate the effect of dexmedetomidine on the expressions of inflammatory factors, T-lymphocyte subgroups and nuclear factor kappa-B (NF-κB) in peripheral blood monocytes in the perioperative period of radical resection of gastric cancer.We selected 74 patients who were admitted to our hospital for radical resection of gastric cancer between January 2012 and October 2015. All patients were randomly divided into the dexmedetomidine group and the control group. Within 15 min before anesthesia induction, patients in the dexmedetomidine group received the intravenous injection of dexmedetomidine, while the same volume saline in the control group. During the operation, the initial dosage in the dexmedetomidine group was set as 1 μg/kg followed by 0.2 μg/kg•h intravenous injection to the end of operation. Three time points were selected: 15 min before anesthesia induction (T0), 1 h before the end of operation (T1) and 24 h after operation (T2). At these time points, we detected the levels of serum inflammatory factors using enzyme-linked immune sorbent assay (ELISA), immunoturbidimetry, and flow cytometer, respectively.The levels of IL-1β, IL-6, TNF-α, NF-κB and CRP at T1 and T2 were significantly elevated compared with the levels at T0, and the amplitude of elevation in the control group was significantly larger than that in the dexmedetomidine group. The expression levels of T-lymphocyte subgroup in patients in both groups were decreased at T1 (compared with the levels at T0), and the decreasing extent of the ratio of CD4+ to CD8+ in the control group was significantly larger than that in the dexmedetomidine group. Meanwhile, we found that the percentages of CD3+ and CD4+ at T1 and T2 in the control group were significantly lower than those in the dexmedetomidine group.Dexmedetomidine can effectively reduce the release of inflammatory factors in patients that received the radical resection of gastric cancer, and the anti-inflammation effect may be exerted through downregulating the expression of NF-κB. Besides, dexmedetomidine can also alleviate the reduction in subgroups of CD3+ and CD4+, thereby ameliorating the impaired immune functions.

Objectives: We explored the efficacy of minimal invasive surgery including one-stage debridement and intervertebral fusion through extreme lateral channel (XLIF) combined with lateral or percutaneous posterior pedicle screw fixation for the treatment of lumbar spine tuberculosis. Methods: Twenty two patients with lumbar tuberculosis who underwent surgery with XLIF technique and internal fixation were included in the study. Their data about operative time, intraoperative blood loss, bone fusion, kyphosis correction, and clinical recovery were retrospectively collected and analyzed. Results: The mean intraoperative blood loss was 249.8±27.8 ml and the operative time 347.5±20.7 min. At the final follow-up, 11 to 15 months postoperatively, ESR and CRP were normal and pain (VAS) and Oswestry disability index (ODI) were significantly reduced (23.0±-3.1 vs 0.6±-0.7 and 57.2±-1.6 vs 6.4±-1.2 respectively) compared to preoperative values. Progression of the kyphotic deformity was effectively prevented (mean Cobb angle 23.9° +/-1.9° vs 24.5° +/-1.4°, P>0.05). There was one failure of the fixation associated to poor therapy adherence. All the patients showed neurological recovery. Conclusion: Debridement and interbody fusion by extreme lateral channel combined with lateral or percutaneous posterior pedicle screw fixation effectively retained the spine stability and provided clinical and neurologic recovery in selected patients with lumbar spine tuberculosis.

We evaluated the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in treating patients with idiopathic membranous nephropathy (IMN). One hundred seventy-seven biopsy-proven IMN patients were recruited in this retrospective clinical study. Sixty patients received TAC (target blood concentration of 4–8 ng/mL) and 117 patients received daily cyclophosphamide (CYC, 100 mg) combined with prednisone. Remission rates at the end of the first, second and third month in the TAC group were significantly higher than that in the CYC group (1st: 35.0 vs 19.7%, P0.05). No significant difference of relapse rate between the groups was found (16.3 vs 12.0%, P>0.05). Patients were more likely to develop glucose intolerance in the TAC group. The TAC regimen obtained more benefits in treating IMN patients, especially in the first 3 months, than the CYC regimen.

Background: Laparoscopic radical cystectomy (LRC) is increasingly being used for muscle-invasive bladder cancer. However, high levels of clinical evidence comparing laparoscopic vs open radical cystectomy (ORC) are lacking. Methods: A prospective randomised controlled clinical trial comparing LRC vs ORC in patients undergoing radical cystectomy for bladder cancer. Thirty-five patients were eligible for final analysis in each group. Results: The median follow-up was 26 months (range, 4–59 months) for laparoscopic vs 32 months (range, 6–60 months) for ORC. Significant differences were noted in operative time, estimated blood loss (EBL), blood transfusion rate, analgesic requirement, and time to resumption of oral intake. No significant differences were noted in the length of hospital stay, complication rate, lymph node yield (14.1±6.3 for LRC and 15.2±5.9 for ORC), positive surgical margin rate, postoperative pathology, or recurrence rate (7 for LRC and 8 for ORC). The 5-year recurrence-free survival with laparoscopic vs ORC was 78.5% vs 70.9%, respectively (P=0.773). The overall survival with laparoscopic vs ORC was 73.8% vs 67.4%, respectively (P=0.511). Conclusion: Our study demonstrated that LRC is superior to ORC in perioperative outcomes, including EBL, blood transfusion rate, and analgesic requirement. We found no major difference in oncologic outcomes. The number of patients is too small to allow for a final conclusion.

In esophageal squamous cell carcinoma (ESCC), extracapsular extention (ECE) in metastatic lymph nodes portends high rate of recurrence and poor prognosis. To our knowledge, the effectiveness of postoperative chemoradiotherapy (CRT) in these patients has never been investigated. In this retrospective study, we compared the outcomes of surgery with or without postoperative chemoradiotherapy in ESCC patients with ECE. From 2008 to 2009, 90 ECSS patients with ECE were included. Among those patients, 47 only received curative surgery alone, and 43 received additional postoperative concurrent CRT which consisted of radiotherapy (median dose 50 Gy) and chemotherapy (5-fluorouracil 1000 mg/m(2), days 1-4 and 29-32; cisplatinum 25 mg/m(2), days 1-3 and 29-31). Patients treated with postoperative CRT had significantly more T3/4 tumors (p=0.023). Based on log-rank stratified by T stage, postoperative adjuvant CRT significantly improved the overall survival (p=0.017) and progression free survival (p=0.002). In multivariate analysis, adjuvant CRT was identified as an independent prognostic factor (HR=0.494, CI 0.290-0.844, p=0.010). Compared with surgery alone, the CRT group had significantly fewer cases of regional recurrence (P=0.048) and overall recurrence (P=0.024). However, there was no significant difference in distant metastasis between two groups (P=0.755). In conclusion, our data suggest that the postoperative adjuvant CRT might be beneficial in selected subgroups of ESCC patients with ECE. To further verify these results, a prospective trial with a large sample size is needed.

There is no consensus regarding the clinical target volume (CTV) margins which surround the gross tumor volume of metastatic lymph nodes (LN) in radiotherapy of esophageal squamous cell carcinoma (ESCC). This study retrospectively assessed the distance of extracapsular extension (ECE) of metastatic LN in thoracic ESCC and defined nodal CTV margins. Histological sections of metastatic LNs from 217 patients with thoracic ESCC were re-examined. The incidence and maximal distance of ECE of metastatic LNs were assessed. The relationships between ECE and clinicopathologic features were also investigated. The ECE was found in 37.3% of patients (81/217) and 23.1% of metastatic LN (159/689), and the incidences had a significant relationship with N stage and LN size. The median distance of ECE was 1.0 mm (range, 0.2-9.7 mm). The distance of ECE showed a positive correlation with LN size (Spearman's correlation coefficient = 0.419; p

Ticagrelor is a novel direct-acting P2Y12 receptor antagonist used for preventing atherothrombotic events in patients with acute coronary syndromes (ACS). The current recommended dose is 90 mg bid, but a low dose of ticagrelor has not been previously studied in Chinese ACS patients. Therefore, we performed this study to observe the different effects of half- and standard-dose ticagrelor on platelet aggregation in Chinese patients with NSTE-ACS. Sixty-two NSTE-ACS subjects were assigned to half-dose ticagrelor (n = 20), standard-dose ticagrelor (n = 22) and clopidogrel (n = 20) groups. Five days after drug administration, VerifyNow P2Y12 assay was performed to test P2Y12 reaction units (PRU) and inhibition of platelet aggregation (IPA). High-platelet reactivity (HPR) was defined as a PRU > 208. The adverse events, including bleeding events and dyspnoea, were monitored throughout the study. PRU values in the half-dose (44.55 ± 32.88) and standard-dose (39.10 ± 40.02) ticagrelor were dramatically lower than those in the clopidogrel group (189.20 ± 65.22; P < 0.0001). The half-dose (84% ± 10%) and standard-dose (86% ± 13%) ticagrelor both showed greater IPA than clopidogrel (33% ± 20%; P < 0.0001). There were no significant differences in PRU and IPA between the two ticagrelor groups (P = 0.3085 and 0.4028, respectively). HPR rates were significantly lower in the two ticagrelor groups (0% for both) than those in the clopidogrel group (35%). In conclusion, half-dose ticagrelor had a similar inhibitory effect on platelet aggregation as standard-dose ticagrelor in Chinese patients with NSTE-ACS, which was significantly stronger than that of clopidogrel.

The present study aimed to observe the alterations of lipopolysaccharide (LPS) and some other laboratory indexes in children suffering from pulmonary infections, and to investigate the condition of Gram-negative bacterial infection.All the patients received routine blood test, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), Mycoplasma pneumoniae antibody IgM (MP-IgM), LPS, blood culture and chest X-ray examination. The clinical data was collected followed by induction arrangement and statistical analysis.In terms of the rate of abnormity in peripheral white blood cell count and positive rate of blood CRP, no significant difference was found between children with pulmonary infections and the healthy individual in the control group (p0.05). The positive rates of blood MP-IgM were 33.33% and 32.26% in children with different progressive stages of pulmonary infections, which were significantly lower than those in the control group (62.96%) (p0.05). The positive rates of blood LPS in the observation group were higher than those in the control group, especially for those children at progressive stages within one week; and the difference between them was significant (p0.05). With regard to blood bacterial culture, the positive rates were 9.52% and 29.03% for children in progressive stages within one week and over one week in the observation group, respectively; the latter was significantly higher than that in the control group (p0.05). The result of the correlation analysis suggested a weak correlation between the positive rate of increased blood LPS in the observation group and that in blood bacterial culture (χ2 = 6.61, p0.05; Pearson's contingency coefficient C = 0.34). However, there was no significant correlation between the positive rate of increased blood LPS and peripheral blood white cell count, CRP, or MP-IgM (p0.05).Endotoxemia is often accompanied by pulmonary infections, and gram-negative bacterium is a common pathogenic bacterium in children with different progressive stages of pneumonia.

SUMMARYIn recent years, the effect ofToxoplasma gondiiinfection on the cerebrum and neuropsychiatric patients has been increasingly highlighted. However, there is limited information about the epidemiology ofT. gondiiinfection in psychiatric patients in Shandong province, eastern China. Therefore, through a case-control study, 445 patients hospitalized for diacrisis or treatment in Weihai, eastern China, and 445 control subjects from the general population of the same region matched by gender, age, and residence were examined with enzyme-linked immunoassays for the presence of IgG and IgM antibodies toT. gondiiand associated sociodemographic and behavioural characteristics in a population of psychiatric patients. Seroprevalence of IgG antibodies toT. gondiiin psychiatric patients (77/445, 17·30%) was significantly higher than in control subjects (55/445, 12·36%) (P= 0·038). Fourteen (3·15%) psychiatric patients and 10 (2·25%) control subjects had IgM antibodies toT. gondii(P= 0·408). Multivariate analysis using logic regression showed thatT. gondiiinfection was associated with cats at home and consumption of raw/undercooked meat in psychiatric patients. Considering that most psychiatric patients usually have lower cognitive functioning and additional transmission routes related to their inappropriate behaviours that could enhance the risk of infection, psychiatric patients should be considered as a specific group ofT. gondiiinfection.

Background: Neuronal and synaptic function in Alzheimer’s disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). Objective: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. Method: Glucose metabolism was measured using [18F]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score ≧17). PET data were corrected for brain atrophy. Results: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. Conclusion: PET activity measured during audiovisual stimulation was more sensitive to functional alterations inglucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy.

Narrow band imaging (NBI) is a real-time imaging technique. The aim of this meta-analysis was to estimate the sensitivity, specificity, and diagnostic accuracy on the role of NBI in the detection and characterization of specialized intestinal metaplasia (SIM), high-grade dysplasia (HGD) in the Barrett's esophagus. We identified studies by performing a literature search of Medline, EMBASE, and the Cochrane Library databases up to May 2013. We performed data analysis using Meta-DiSc (version 1.4) software. To assess study quality and potential for bias, we used the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). Overall, seven eligible studies including over 3988 lesions of 502 patients were retrieved. The results showed that endoscopic diagnosis of dysplasia performed using NBI has a high diagnostic performance, with an area under the summary receiver operating characteristic (SROC) curve near 0.90 both in HGD lesions and SIM lesions. We also found that NBI has a sensitive and specificity of 0.91 (95% confidence interval [CI] = 0.86-0.94) and 0.85 (95% CI = 0.76-0.92) on a per-patient element, and 0.97 (95% CI = 0.95-0.98) and 0.64 (95% CI = 0.59-0.68) on a per-lesion element for SIM diagnosis, respectively. The pooled per-patient sensitivity and specificity for identifying HGD are 0.91 (95% CI = 0.75-0.98) and 0.95 (95% CI = 0.91-0.97). The pooled per-lesion sensitivity and specificity for identifying HGD are 0.69 (95% CI = 0.63-0.74) and 0.90 (95% CI = 0.88-0.91). In conclusion, we found that endoscopic diagnosis with NBI is an accurate test to diagnosis dysplasia of Barrett's esophagus.

Post-translational processing is essential for the biological activation of many proteins and peptides. After precursor cleavage at specific single residues or pairs of basic residues by the proprotein convertases, the C-terminal basic residues are removed. Carboxypeptidase E was thought to be the only enzyme responsible. Recent studies with carboxypeptidase E-deficient mice, Cpe fat / Cpe fat , indicated the existence of carboxypeptidase E-like carboxypeptidases, such as carboxypeptidase D. In order to define potential redundant functions in vivo , we compared the distributions of both carboxypeptidases in the rat central nervous system and selected endocrine tissues. Carboxypeptidase D messenger RNA was abundantly expressed in glial cells in the gray and white matter, while neurons in several brain regions, such as the piriform cortex, basolateral amygdala and hippocampus, also expressed high levels of carboxypeptidase D messenger RNA. Co-localization of carboxypeptidases E and D messenger RNAs was observed in many brain regions, the spinal cord and endocrine tissues. Immunohistochemistry showed the intracellular distribution of carboxypeptidase D with a perinuclear pattern. The extensive distribution of carboxypeptidase D in both glial and neuronal cells indicates the important role of carboxypeptidase D in peptide processing, possibly working together with furin, a ubiquitously expressed proprotein convertase. The co-localization of carboxypeptidases D and E suggests that carboxypeptidase D may, at least partially, compensate for carboxypeptidase E processing functions in Cpe fat / Cpe fat mice.

Objectives: To examine the relationship between blood lead and blood pressure (BP) and to estimate the possible effects of a decrease in blood lead on BP. Methods: A 2-ml blood sample was collected from a sub-sample of those included in the Health Survey for England 1995, a cross-sectional survey of a nationally representative sample of the adult English population. Blood lead concentration was measured by atomic absorption spectrometry and three BP readings were taken under standardised conditions using the Dinamap 8100 monitor. Analyses were carried out using data on 2563 men and 2763 women aged 16 and over. Results: In stepwise multiple regression analyses adjusting for various confounders—age, body mass index, smoking status, social class, region of residence and alcohol intake—blood lead was found to be significantly and positively associated with diastolic BP, and not systolic BP in men, but not in women. These findings were unaffected by the inclusion or exclusion of those on antihypertensive medication, by whether mean or median BP was used in the regression, or by the adjustment for alcohol consumption. A halving of currently prevalent blood lead levels is estimated to be associated with a decrease of between 0.8 to 1.1 mm Hg diastolic BP in men. Conclusion: These findings in the context of other published data are consistent with a small pressor effect of environmental lead levels on BP. They support recommendations for further efforts to reduce lead in the environment.

To assess the current levels of awareness, treatment and control of hypertension in England and to determine the number and type of drugs prescribed.A cross-sectional household-based survey of English adults.A random sample from the adult English population of 12,116 adults who participated in the 1994 Health Survey for England.Prevalences of treatment hypertension, awareness and control.Using a definition of hypertension as a systolic blood pressureor = 160 mmHg or a diastolic blood pressureor = 95 mmHg, or a patient's being administered antihypertensive treatment, the prevalence of awareness of hypertension was 63%. Among hypertensives, 50% were receiving treatment and 30% had their hypertension controlled (160 mmHg/95 mmHg). Awareness, treatment and control rates are considerably lower than the most recently reported rates from the USA. Diuretics and beta-blockers remain the most common antihypertensive agents used in England.There is considerable scope for improving the treatment and control of hypertension in the English adult population.

To examine the time course of the histopathological effects of bilateral injections of amyloid-beta 25-35 (A beta) and to determine if these effects are associated with a reduction in choline acetyltransferase activity and behavioral impairments, we injected A beta (5.0 nmol) into the amygdala of young male Fischer rats. Control rats received vehicle infusions. For histological analysis, animals were sacrificed at 8, 32, 64, 96, and 128 days postoperatively (n = 21-33 per timepoint). A beta induced neuronal tau-2 staining in the right, but not the left amygdala and hippocampus. A beta also induced reactive astrocytosis and neuronal shrinkage within the right hippocampus and amygdala, respectively. As with tau-2, these same brain regions within the left hemisphere in the A beta-treated rats were significantly less affected. In addition, A beta appeared to induce microglial and neuronal interleukin-1beta staining. The histopathological effects of A beta peaked at 32 days postoperatively but were not associated with a reduction in amygdaloid choline acetyltransferase activity. In a separate experiment, behavioral effects of bilateral intra-amygdaloid injections of A beta were analyzed at 34-52 days postoperatively. In an open field test, the treatment groups differed only in the numbers of rears emitted (p = 0.016). There was no effect of A beta in the Morris water maze or in the acquisition and retention of a one-way conditioned avoidance response. These data suggest a laterality in the histopathological effects of A beta and that the effects of single injections are in part transient. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease, and support the use of this rat model to screen drugs that may alter the initial pathological events associated with Alzheimer's disease, that occur before the manifestations of extensive behavioral impairments become evident.

Objectives To assess the survival benefit of maximum androgen blockade (MAB) using nonsteroidal antiandrogens (NSAAs) through meta-analysis of published randomized controlled trials (RCTs). Methods. All RCTs comparing treatment with NSAA plus either luteinizing hormone-releasing hormone (LHRH) or orchiectomy versus treatment with LHRH or orchiectomy alone were included if the necessary statistical summaries were present in the publication. Estimates and standard errors of log hazard ratio for overall survival and progression-free survival were derived from published studies using two methods: (1) reconstructing an annual life table from graphical presentations of survival distributions and fitting discrete proportional hazard models, and (2) reconstructing the log hazard ratio from reported P values and numbers of deaths. An alternative set of log hazard ratios was derived from figures presented in a summary report by the Prostate Cancer Trialists' Collaborative Group (PCTCG). Comparative meta-analyses were performed using the random effects approach of DerSimonian and Laird. Additionally, published studies were used in a random-effects-based meta-analysis of objective tumor response. Results Nine studies provided enough information to perform a meta-analysis for survival using one of the two methods. Estimates of relative risks (RR) comparing treatment with NSAA plus either LHRH or orchiectomy versus treatment with LHRH or orchiectomy alone with respect to overall survival were 0.78 (95% confidence intervals [Cls]0.67 to 0.90) using method 1, and 0.84 (95% CI 0.76 to 0.93) using method 2. Sensitivity analyses based on PCTCG data showed that a favorable survival result for MAB was associated with NSAAs but not with steroidal antiandrogens and depended on randomization blinding and overall trial quality. Additionally, random-effects-based meta-analysis of published studies showed a significant increase in time-to-progression (RR = 0.74; 95% Cl 0.63 to 0.86) and an increase in objective tumor responses for MAB using NSAAs compared with castration alone (odds ratio = 0.65; 95% Cl 0.51 to 0.81; P = 0.00022). Conclusions Inconsistent results have been published about the benefit of MAB in advanced prostate cancer. This meta-analysis supports a beneficial effect for MAB using NSAAs compared with castration alone, and sensitivity analyses suggest that the design of future trials should carefully address issues of patient characterization, randomization blinding, and other study quality issues.

To determine if amyloid-beta (A beta) induces tau-immunoreactivity (IR) and reactive astrocytosis in vivo, we injected A beta 25-35 (5.0 nmol) into the right amygdala of rats. At 8 days postinjection, the peptide induced tau-2 IR in neuronal cell bodies and processes ipsilaterally in the amygdala, cingulate cortex, and hippocampus. At 32 days postinjection, the intensity of tau-2 IR was greater than at 8 days in the amygdala and hippocampus, but not in the cingulate cortex. Induction of Alz-50 IR also was progressive but the morphology and distribution was different from tau-2 IR. Beaded fibers with occasional neuronal perikarya were visualized with Alz-50, and the IR was primarily observed in the ipsilateral amygdala. In addition, amygdaloid injections of A beta 25-35 induced reactive astrocytosis, particularly in the ipsilateral hippocampus at 32 days postoperatively. To our knowledge, this is the first study to show that in vivo injections of A beta 25-35 induce progressive transsynaptic cytoskeletal and astrogliotic reactions, that gradually spread from the area of injection to brain regions that have prominent efferent connections with that area. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease.

In mice, expression of the transcription factor Oct-3 and the proto-oncogene c-mos is limited to germ cells, suggesting a specific role for these factors in gamete physiology and early embryonic development. We have studied the expression pattern of Oct-3 and c-mos in various reproductive as well as control tissues in the cynomolgus monkey, using reverse transcriptase polymerase chain reaction (RT-PCR) and Northern analysis. Analogously with the data from the mouse model, strong expression of Oct-3 and c-mos could be detected in monkey ovary and oocytes. Unexpectedly, strong expression of c-mos was demonstrable in the pituitary gland and the amount of mRNA expression in the pituitary was roughly equal to that found in the ovary. Of the tissues examined, the testicular expression of c-mos was the most intense. Weak signal for c-mos mRNA was also seen in hypothalamus and brain; however, all other tissue types examined were negative for c-mos expression. In addition to the oocytes, expression of Oct-3 mRNA was detected in the ovarian granulosa cells, fallopian tube, myometrium, cervix, breast, liver, adrenal gland, pituitary, hypothalamus, brain cortex, prostate, and in testis. Thus, in the cynomolgus monkey, Oct-3 is predominantly, but not specifically, expressed in reproductive tissues. In the female monkey reproductive organs, the expression of c-mos seems to be germ cell specific. Therefore, further characterization of c-mos and Oct-3 functions in primate reproductive physiology, especially in gametogenesis and early embryonic development, is highly warranted.

To investigate the effects of electroacupuncture on the episodes of spreading depression (SD) in Wistar rats during focal cerebral ischemia.A model of the middle cerebral artery occlusion (MCAo) in Wistar rats was performed with the intraluminal filament occlusion. The episodes of SD in focal cerebral ischemia within 3 hours and the effects of electroacupuncture on "He gu" point (LI 4) were detected using neuroelectrophysiological method and neuropathological method.Electroacupuncture can reduce the episodes of SD during focal cerebral ischemia.Electroacupuncture can reduce the infarct volume of the focal cerebral ischemia, its mechanism may relate to reducing the episodes of SD during focal cerebral ischemia.