Molecular Insights into the Differential Effects of Acetylation on the Aggregation of Tau Microtubule-Binding Repeats.

Aggregation of tau protein into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The microtubule-binding (MTB) domain of tau, containing either three or four repeats with sequence similarities, plays an important role in determining tau's aggregation. Previous studies have reported that abnormal acetylation of lysine residues displays a distinct effect on the formation of pathological tau aggregates. However, the underlying molecular mechanism remains mostly elusive. In this study, we performed extensive replica exchange molecular dynamics (REMD) simulations of 144 µs in total to systematically investigate the dimerization of four tau MTB repeats and explore the impacts of Lys280 (K280) or Lys321 (K321) acetylation on the conformational ensembles of the R2 or R3 dimer. Our results show that R3 is the most prone to aggregation among the four repeats, followed by R2 and R4, while R1 displays the weakest aggregation propensity with a disordered structure. Acetylation of K280 could promote the aggregation of R2 peptides by increasing the formation of ß-sheet structures and strengthening the interchain interaction. However, K321 acetylation decreases the ß-sheet content of the R3 dimer, reduces the ability of R3 peptides to form long ß-strands, and promotes the stable helix structure formation. The salt bridge and Y310-Y310 π-π stacking interactions of the R3 dimer are greatly weakened by K321 acetylation, resulting in the inhibition of dimerization. This study uncovers the structural ensembles of tau MTB repeats and provides mechanistic insights into the influences of acetylation on tau aggregation, which may deepen the understanding of the pathogenesis of tauopathies.

Mechanistic insight into the disruption of Tau R3-R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study.

The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational therapeutic strategies to combat tauopathy. Previous studies reported that curcumin (Cur, a molecule of a labile natural product) and epinephrine (EP, an important neurotransmitter) could effectively inhibit the formation of Tau fibrillar aggregates and disassociate preformed fibrils. However, the underlying molecular mechanisms remain elusive. In this study, we performed multiple molecular dynamics simulations for 17.5 µs in total to investigate the influence of Cur and EP on the C-shaped Tau protofibril associated with CTE. Our simulations show that the protofibrillar pentamer is the smallest stable Tau R3-R4 protofibril. Taking the pentamer as a protofibril model, we found that both Cur and EP molecules could affect the shape of the Tau pentamer by changing the ß2-ß3 and ß7-ß8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local ß-sheets and the formation of hydrogen bonds, and thus destabilize the global protofibril structure. The contact number analysis shows that Cur has a higher binding affinity with the Tau pentamer than EP, especially in the nucleating segment PHF6. Hydrophobic, π-π and cation-π interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and π-π interactions with Tau than EP, and EP displays a stronger cation-π interaction. Our findings provide molecular insights into the disruptive mechanisms of the Tau R3-R4 protofibrils by curcumin and epinephrine, which may be useful for the design of effective drug candidates for the treatment of CTE.

The effect of whole body vibration on sensorimotor deficits in people with chronic ankle instability: A systematic review and meta-analysis.

OBJECTIVE: To investigate the effects of whole body vibration on chronic ankle instability-associated sensorimotor deficits in balance, strength, joint position sense and muscle activity. DATA SOURCES: Electronic databases including Cochrane Library, PubMed, Embase, Web of Science, EBSCO, China National Knowledge Infrastructure and WanFang were searched from database inception up to 31 March 2022. METHODS: The risk of bias and methodological quality of included studies were assessed using the Cochrane tool and Physiotherapy Evidence Database (PEDro) scale respectively. Standardized mean difference (SMD) and mean differences (MD) with 95% confidence interval (CI) were calculated using the RevMan 5.3 software. Meta-regression was conducted with Stata 16. RESULTS: Eight studies, with 315 subjects were eventually included in this review with an average PEDro score of 6.1/10. Significant effects of whole body vibration on balance (SMD = 0.61, 95% CI: 0.12 to 1.09, P = 0.01), and on the posterolateral direction (MD = 5.52, 95% CI: 1.02 to 10.01, P = 0.02) and medial direction (MD = 3.90, 95% CI: 0.87 to 6.94, P = 0.01) of the star excursion balance test were found. Whole body vibration significantly improved the peak torque (SMD = 0.36, 95% CI: 0.04 to 0.69, P = 0.03), joint position sense (SMD = 0.60, 95% CI: 0.10 to 1.11, P = 0.02), and muscle activity in tibialis anterior (SMD = 0.46, 95% CI: 0.04 to 0.88, P = 0.03) and gastrocnemius (SMD = 0.68, 95% CI: 0.14 to 1.23, P = 0.01). CONCLUSIONS: The current evidence supports the use of whole body vibration to improve sensorimotor deficits involving balance, strength, joint position sense, and muscle activity in people with chronic ankle instability.

Effects of Pre-exercise Acute Vibration Training on Symptoms of Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis.

ABSTRACT: Tan, J, Shi, X, Witchalls, J, Waddington, G, Lun Fu, AC, Wu, S, Tirosh, O, Wu, X, and Han, J. Effects of pre-exercise acute vibration training on symptoms of exercise-induced muscle damage: a systematic review and meta-analysis. J Strength Cond Res 36(8): 2339-2348, 2022-Exercise-induced muscle damage (EIMD) normally occurs after unaccustomed high-intensity eccentric exercises. Symptoms of EIMD include delayed-onset muscle soreness (DOMS), tenderness, stiffness, swelling, reduced strength, and increased creatine kinase (CK) levels in the blood. Vibration training (VT) may be useful as a pre-exercise intervention in attenuating EIMD on the basis of tonic vibration reflex (TVR) through a more efficient distribution of contractile stress over muscle fibers. The objective of this meta-analysis is to examine the effects of acute VT on symptoms of EIMD when performed as the pre-exercise intervention. Randomized controlled trials (RCTs) published in the 8 databases of Cochrane Library, PubMed, Embase, Web of Science, EBSCO, China National Knowledge Infrastructure, Airiti Library and WanFang Data from 1966 (the earliest available time) to January 2019 were searched. A total of 2,324 records were identified and 448 articles were screened with the title and abstract. Two investigators identified eligible studies, extracted data, and assessed the risk of bias independently. Review Manager 5.3 designed by Cochrane was used for the current meta-analysis. Six RCTs involving 180 subjects were included in the analysis. A low-to-moderate methodological quality of the included studies was revealed using the physiotherapy evidence database scale. The results showed that acute VT was superior to the control group for the reduction of DOMS on pain visual analogue scale at 24, 48 hours and pressure pain threshold at 24 hours. In addition, superior effects of acute VT were also found on the indirect markers of muscle damage including CK at 24, 72 hours, and lactate dehydrogenase at 24 hours. The current meta-analysis has collated the evidence to demonstrate that receiving acute VT before unaccustomed high-intensity eccentric exercises may be effective in attenuating markers of muscle damage and the development of DOMS when compared with a control group. The possible mechanisms of this effect could be attributed to an improved synchronization of muscle fiber caused by TVR, which could result in even distribution of exterior loads and eventually attenuate disruptions of muscle fibers. In addition, increased blood flow may also be helpful to prevent accumulation of metabolic substances and attenuate subsequent symptoms of EIMD. Vibration training may be used as a pre-exercise intervention to alleviate symptoms of EIMD caused by unaccustomed high-intensity eccentric exercise. Because of the limited quantity and quality of included studies, more high-quality studies are required to ascertain the effect of VT on symptoms of EIMD.

The ubiquitin ligase RNF43 downregulation increases membrane expression of frizzled receptor in pancreatic ductal adenocarcinoma.

RNF43 is a novel tumor suppressor protein and known to be expressed in a multitude of tissue and dysregulated in cancers of these organs including ovarian and colorectal tissues. RNF43 expression has been shown to be expressed in mutated forms in several pancreatic cell lines. RNF43, by virtue of being an ubiquitin ligase, has the potential to ubiquitinylate membrane receptors like frizzled that subserves sensing Wnt soluble signals at the cell membrane. Thus, normally, RNF43 downregulates Wnt signaling by removing frizzled receptor from the membrane. In the present study, the expression of the tumor suppressor RNF43 was examined in human patient samples of pancreatic ductal adenocarcinoma (PDAC). Reduced levels of expression of RNF43 in PDAC were demonstrated by Western blotting. We incorporated membrane biotinylation assay to examine the expression of frizzled6 receptor in the membrane and demonstrated that it is significantly increased in PDAC tissues. This may be responsible for enhanced Wnt/beta-catenin signaling and provides the first level of evidence of a possible role of this well-known pathway in pancreatic exocrine carcinogenesis. We have utilized appropriate controls to ensure the true positivity of the findings of the present study. The contribution of Wnt/beta-catenin/RNF43 pathway in pancreatic carcinogenesis may provide for utilization of pharmacologic resources for precision-based approaches to treat pancreatic ductal adenocarcinoma.

Impact of roux-en Y gastric bypass surgery on prognostic factors of type 2 diabetes mellitus: meta-analysis and systematic review.

Our aim is to clarify the features of complete type 2 diabetes mellitus (T2DM) remission in patients who undergo Roux-en Y gastric bypass surgery, to better determine factors affecting the outcome of T2DM surgery. A search was conducted for original studies on Medline, PubMed and Elsevier from inception until October 28, 2014. All of the articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: Roux-en Y gastric bypass surgery for T2DM patients in remission or non-remission. The meta-analysis results demonstrated that fasting C-peptide values were significantly associated with increased remission (C-peptide: 95%CI = 0.2-1.0) whereas T2DM duration, patient age, preoperative insulin use, preoperative fasting blood glucose values and preoperative glycosylated haemoglobin values were significantly associated with reduced remission (T2DM duration: 95%CI = -1.2 - -0.7; age: 95%CI = -0.5 - -0.1; percentage of preoperative insulin users: odd ratio = 0.10, 95%CI = 0.07-0.15; preoperative fasting blood glucose: 95%CI = -0.9 - -0.5; preoperative glycosylated haemoglobin: 95%CI = -1.1 - -0.4). However, the results demonstrated that body mass index was not statistically different (body mass index: 95%CI = -0.2-0.6). The results of the systematic review demonstrated that smaller waist circumference; lower total cholesterol, triglycerides and low-density lipoprotein levels, increased higher high-density lipoprotein levels, shorter cardiovascular disease history and less preoperative prevalence of hypertension contribute to the increased postoperative remission rate. Better results are obtained in younger patients with less severe diabetes, a smaller waist circumference, higher preoperative high-density lipoprotein, lower preoperative total cholesterol, triglycerides and low-density lipoprotein levels and fewer other complications of shorter durations.

Endoscopic or laparoscopic approach for hepatolithiasis in the era of endoscopy in China.

BACKGROUND: Many endoscopic procedures have been used to treat hepatolithiasis, including as laparoscopic hepatectomy (LH), laparoscopic intrahepatic duct exploration (LIDE), and endoscopic retrograde cholangiopancreatography (ERCP). However, long-term results of such treatments are rarely reported. The series aimed to evaluate the immediate outcomes and long-term results of these treatments and their optimal indications. METHODS: From January 2002 to April 2010, a total of 124 continuous patients with hepatolithiasis were primarily treated with endoscopic surgery, including LH (LH group, n = 37), LIDE (LIDE group n = 41), and ERCP (ERCP group, n = 46) at our two institutes. These cases were retrospectively reviewed. The patients' demographic variables, operative outcomes, complete clearance rate, and cholangitis recurrence rate were analyzed. RESULTS: Complete stone clearance was achieved in 94.6 % of LH, 78.0 % of LIDE, and 67.4 % of ERCP patients. After a median follow-up period of 5.0 years (rang 2-8 years), we observed stone recurrence in 26.6 % (33/124) of patients and recurrent cholangitis in 24.2 % (30/124) of patients. Stricture, stones in both lobes, and non-hepatectomy treatments were significant risk factors for incomplete stone clearance on multivariate analysis. In addition, recurrent cholangitis was associated with non-hepatectomy therapy, Sphincter of Oddi dysfunction, residual stones, and intrahepatic bile strictures. CONCLUSION: In this study with 2-8 years of follow-up, residual stones, biliary stricture, Sphincter of Oddi dysfunction, and ERCP therapy were associated with recurrent stones and/or cholangitis after treatment, indicating that the modification of Sphincter of Oddi function and maintaining its normal pressure are very important.

Identification of MicroRNAs and target genes involvement in hepatocellular carcinoma with microarray data.

The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT.

Molecular mechanism of activating protein-4 regulated growth of hepatocellular carcinoma.

The molecular regulation of growth of hepatocellular carcinoma (HCC) is yet to be fully clarified. Here we found a significantly higher ratio of phosphorylated ß-catenin (phos-ß-cat) to ß-catenin (ß-cat) as an indicator of an activated Wnt signaling, with significantly higher levels of c-myc and transcription factor activating protein-4 (AP-4) and a significantly lower level of p21 in the resected HCC, compared to the paired adjacent healthy hepatic tissue from the patients. Moreover, strong correlations were detected between phos-ß-cat/ß-cat ratio and c-myc level, between c-myc and AP-4 levels, and between AP-4 and p21 levels. These data support the presence of a Wnt/c-myc/AP-4/p21 regulation cascade in HCC as has been reported in colorectal cancer. To prove it, we overexpressed c-myc in two HCC lines, which significantly increased AP-4 level, inhibited p21 level, and then increased cell growth. Meanwhile, c-myc inhibition in these two HCC lines significantly decreased AP-4 level, increased p21 level, and then decreased cell growth. Moreover, AP-4 inhibition in c-myc-overexpressing HCC lines abolished the inhibitory effect on p21 and abolished the increase in cell growth. In line with these findings, overexpression of AP-4 in these two HCC lines significantly decreased p21 level, and then increased cell growth, while AP-4 inhibition significantly increased p21 level, and then decreased cell growth. Our results on HCC are thus consistent with the model detected in colorectal carcinoma, suggesting that Wnt signaling activated c-myc may increase HCC growth through direct inhibitory effect of AP-4 on p21. Our study thus highlights AP-4 as a novel therapeutic target for HCC.

Prognostic significance of microRNA-141 expression and its tumor suppressor function in human pancreatic ductal adenocarcinoma.

Increasing evidence shows that dysregulation of microRNAs is correlated with tumor development. This study was performed to determine the expression of miR-141 and investigate its clinical significance in pancreatic ductal adenocarcinoma (PDAC). Taqman quantitative RT-PCR was used to detect miR-141 expressions in 94 PDAC tissues and 16 nontumorous pancreatic tissues. Correlations between miR-141 expression and clinicopathologic features and prognosis of patients were statistically analyzed. The effects of miR-141 expression on growth and apoptosis of PDAC cell line (PANC-1) were determined by MTT, colony formation, and flow cytometry assays. Potential target genes were identified by luciferase reporter and Western blot assays. The expression level of miR-141 in PDAC tissues was significantly lower than that in corresponding nontumorous tissues. Downregulation of miR-141 correlated with poorer pT and pN status, advanced clinical stage, and lymphatic invasion. Also, low miR-141 expression in PDAC tissues was significantly correlated with shorter overall survival, and multivariate analysis showed that miR-141 was an independent prognostic factor for PDAC patients. Further, functional researches suggested that miR-141 inhibits growth and colony formation, and enhances caspase-3-dependent apoptosis in PANC-1 cells by targeting Yes-associated protein-1 (YAP1). Therefore, miR-141 is an independent prognostic factor for PDAC patients, and functions as a tumor suppressor gene by targeting YAP1.

Expression of microRNA-218 in human pancreatic ductal adenocarcinoma and its correlation with tumor progression and patient survival.

BACKGROUND: Our aim was to analyze clinicopathologic and prognostic values of microRNA (miR)-218 in pancreatic ductal adenocarcinima (PDAC). METHODS: TaqMan quantitative RT-PCR was used to determine the expression of miR-218 in human PDAC cells and tissue samples. The association of miR-218 expression with clinicopathologic variables was analyzed. Kaplan-Meier survival analysis was performed to analyze the association of miR-218 expression with recurrence-free survival or overall survival of patients. Univariate and multivariate Cox regression analyses were performed. RESULTS: The relative level of miR-218 in PDAC cells was significantly lower than that in normal human pancreatic duct epithelial cell line. Also, the mean level of miR-218 in PDAC tissues was significantly lower than that in normal pancreatic tissues. Statistical analyses indicated that low miR-218 expression was closely associated with poor tumor differentiation, advanced tumor stage, higher incidence of lymph node metastasis, and tumor recurrence. Kaplan-Meier survival analyses showed that patients with low miR-218 expression had lower recurrence-free and overall survival than those with high miR-218 expression. Univariate and multivariate Cox regression analyses showed that miR-218 might be an independent prognostic factor. CONCLUSION: Reduced miR-218 in PDAC tissues was correlated with tumor progression, and might be an independent poor prognostic factor for patients.

Comparison analysis in synchronous and metachronous metastatic colorectal cancer based on microarray expression profile.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis. METHODOLOGY: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted. RESULTS: Total of 36 DEGs including 35 down-regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny. CONCLUSIONS: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment.

Comparison of physical activity and physical fitness in children and adolescents of Chinese Han and Tibet ethnicity.

Background: Physical activity (PA) and physical fitness (PF) are important markers of health status in children and adolescents in different ethnicities. In this study, we aimed to compare the PA and PF indicators between Tibetan and Han children and adolescents. Methods: Children and adolescents of 4-9 grades were recruited in Shigatse (n = 963) and Shanghai (n = 2,525) respectively. The information related to demographic, PA, and PF was collected via a self-reported questionnaire. PA was assessed through the participation of moderate to vigorous PA (MVPA), muscle-strengthening exercise (MSE) and organized sport participation (OSP). PF was estimated using the International Fitness Scale containing components of overall fitness, cardiorespiratory fitness, speed and agility, muscular strength and flexibility. Results: Han (mean age = 13.45 ± 3.3 years; 49.7% girls) and Tibet (mean age = 13.8 ± 2.5 years; 48.3% girls) children and adolescents from Shanghai and Shigatse completed the questionnaire survey. It was revealed that Tibetan students had higher MVPA, MSE and OSP than children and adolescents of Han ethnicity (p < 0.01, small to medium effect size). A relatively higher percentage of student in Shanghai did not participate in any form of PA. On the other hand, less Tibetan students thought their PF indicators including overall fitness, cardiorespiratory fitness, speed and agility, muscular strength and flexibility were poor or very poor than their counterparts of Han ethnicity (p < 0.01, small to medium effect size). Conclusion: Tibetan children and adolescents have higher levels of PA and PF in comparison to their Han counterparts. More children and adolescents of Han ethnicity engage in no PA and think their PF indicators were poor.

Effects of an external static EF on the conformational transition of 5-HT1A receptor: A molecular dynamics simulation study.

The serotonin receptor subtype 1A (5-HT1AR), one of the G-protein-coupled receptor (GPCR) family, has been implicated in several neurological conditions. Understanding the activation and inactivation mechanism of 5-HT1AR at the molecular level is critical for discovering novel therapeutics in many diseases. Recently there has been a growing appreciation for the role of external electric fields (EFs) in influencing the structure and activity of biomolecules. In this study, we used molecular dynamics (MD) simulations to examine conformational features of active states of 5-HT1AR and investigate the effect of an external static EF with 0.02 V/nm applied on the active state of 5-HT1AR. Our results showed that the active state of 5-HT1AR maintained the native structure, while the EF led to structural modifications in 5-HT1AR, particularly inducing the inward movement of transmembrane helix 6 (TM6). Furthermore, it disturbed the conformational switches associated with activation in the CWxP, DRY, PIF, and NPxxY motifs, consequently predisposing an inclination towards the inactive-like conformation. We also found that the EF led to an overall increase in the dipole moment of 5-HT1AR, encompassing TM6 and pivotal amino acids. The analyses of conformational properties of TM6 showed that the changed secondary structure and decreased solvent exposure occurred upon the EF condition. The interaction of 5-HT1AR with the membrane lipid bilayer was also altered under the EF. Our findings reveal the molecular mechanism underlying the transition of 5-HT1AR conformation induced by external EFs, which offer potential novel insights into the prospect of employing structure-based EF applications for GPCRs.

The bibliometric and altmetric analysis of chronic traumatic encephalopathy research: how great is the impact?

Background: The study of chronic traumatic encephalopathy (CTE) has received great attention from academia and the general public. This study aims to analyze the research productivity on CTE and investigate the most discussed articles in academia and the general public by conducting bibliometric and altmetric analyses. Methods: Data of articles were obtained from the Web of Science Core Databases and Altmetric Explore. VOSviewer and CiteSpace software were used to analyze and visualize the articles. The correlation between Altmetric attention scores (AAS) and citation counts were assessed by Spearman correlation coefficient. Results: 788 publications of CTE were eventually gathered and analyzed, and 100 articles with highest citation counts (Top-cited) and 100 articles with highest AASs (Top-AAS) were then identified. The keywords density map showed both the general public and the scientists were particularly interested in the risk factors and pathology of CTE, and scientists were interested in the causes and characteristics of neurodegenerative diseases while the public became increasingly concerned about the detection and prevention of CTE. By examining the shared characteristics of the 44 articles (High-High articles) that overlapped between Top-cited and Top-AAS articles, we identified certain traits that may potentially contribute to their high citation rates and high AASs. Besides, significant positive correlations with varied strength between AAS and citation were observed in the 788 articles, Top-cited, Top-AAS and High-High datasets. Conclusion: This study is the first to link bibliometric and altmetric analyses for CTE publications, which may provide deeper understanding of the attention of the scientists and the general public pay to the study of CTE, and offer some guidance and inspiration for future CTE in the selection of research topics and directions.

Modulation of Heart Rate Variability and Brain Excitability through Acute Whole-Body Vibration: The Role of Frequency.

This cross-over study aimed to explore effects of acute whole-body vibration (WBV) at frequencies of 5-35 Hz on heart rate variability and brain excitability. Thirteen healthy physically active college students randomly completed eight interventions under the following conditions: static upright standing without vibration (CON), static squat exercise (knee flexion 150°) on the vibration platform (SSE), and static squat exercise (knee flexion 150°) combined with WBV at vibration frequency of 5, 9, 13, 20, 25, and 35 Hz. Five bouts × 30 s with a 30-s rest interval were performed for all interventions. The brain's direct current potentials (DCPs), frequency domain variables (FDV) including normalized low frequency power (nLF), normalized high frequency power (nHF) and the ratio of LF to HF (LF/HF), along with the mean heart rate (MHR) were collected and calculated before and after the WBV intervention. Results suggested that WBV frequency at 5 Hz had a substantial effect on decreasing DCPs [-2.13 µV, t(84) = -3.82, p < 0.05, g = -1.03, large] and nLF [-13%, t(84) = -2.31, p = 0.04, g = -0.62, medium]. By contrast, 20-35 Hz of acute WBV intervention considerably improved DCPs [7.58 µV, t(84) = 4.31, p < 0.05, g = 1.16, large], nLF [17%, t(84) = 2.92, p < 0.05, g = 0.79, large] and the LF/HF [0.51, t(84) = 2.86, p < 0.05, g = 0.77, large]. A strong (r = 0.7, p < 0.01) correlation between DCPs and nLF was found at 5 Hz. In summary, acute WBV at 20-35 Hz principally activated the sympathetic nervous system and increased brain excitability, while 5-Hz WBV activated the parasympathetic nervous system and reduced brain excitability. The frequency spectrum of WBV might be manipulated according to the intervention target on heart rate variability and brain excitability.

Precision in liver surgery.

Continuous theoretical and technological progress in the face of increasing expectations for quality health care has transformed the surgical paradigm. The authors systematically review these historical trends and propose the novel paradigm of "precision surgery," featuring certainty-based practice to ensure the best result for each patient with multiobjective optimization of therapeutic effectiveness, surgical safety, and minimal invasiveness. The main characteristics of precision surgery may be summarized as determinacy, predictability, controllability, integration, standardization, and individualization. The strategy of precision in liver surgery is to seek a balance of maximizing the removal of the target lesion, while maximizing the functional liver remnant and minimizing surgical invasiveness. In this article, the authors demonstrate the application of precision approaches in specific settings in complex liver surgery. They propose that the concept of precision surgery should be considered for wider application in liver surgery and other fields as a step toward the ultimate goal of perfect surgery.

High expression of AP-4 predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy.

The aim of this study was to evaluate the association between activating enhancer binding protein 4 (AP-4) tissue expression and patient prognosis in hepatocellular carcinoma (HCC). The levels of AP-4 mRNA and protein in tumor and para-tumor tissue were evaluated in 30 HCC cases by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Additionally, AP-4 protein expression in 112 HCC was analyzed by immunohistochemistry. The correlation of AP-4 expression and patients' clinicopathological parameters was evaluated. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. By RT-PCR and Western blot, the levels of AP-4 mRNA and protein were significantly higher in HCC, compared to that in para-tumor tissue (p < 0.001). Immunohistochemical staining revealed that AP-4 was highly expressed in 53.6 % of the HCC patients. The AP-4 expression level was closely associated with serum alpha fetoprotein elevation, tumor size, histological differentiation, tumor recurrence, tumor metastasis, and tumor stage. Kaplan-Meier survival analysis showed that a high expression level of AP-4 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that AP-4 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that a high expression level of AP-4 serves as a biomarker for poor prognosis for HCC. Thus, we speculate that AP-4 may be a potential target of antiangiogenic therapy for HCC.

Stapleless laparoscopic splenectomy with individual vessel dissection in patients with splenomegaly.

BACKGROUND: Mechanical stapling devices have been established as a mainstay in laparoscopic splenectomy (LS), but limited data are available regarding stapleless LS for splenomegaly with individual vessel dissection (IVD). This study aimed to investigate the feasibility of stapleless LS for splenomegaly and its potential advantage over staple-based LS. METHODS: A total of 51 patients with splenomegaly underwent stapleless LS and were subsequently reviewed. The data collected include the patients' demographics, operative outcomes, and the rates of conversion to open surgery, complications, and mortality. Multiple linear and logistic regression analyses were used to assess the impact of the primary diagnosis, body mass index (BMI), and massive splenomegaly on the perioperative conversion rate. RESULTS: There were no deaths. The mean for various parameters are as follows: spleen length 21.6 cm; spleen weight 1,184 g, operating time 148 min, hospital stay 5.2 days, estimated blood loss 245 ml. The total conversion rate was 9.8 % (including one reoperation for bleeding). The presence of a BMI >30 % and hematologic malignancy-cofactors of portal hypertension (PH)-and a spleen weight >1,000 g were independent predictors of conversion to open surgery. CONCLUSIONS: Stapleless LS for splenomegaly is feasible and safe in selected patients. It has advantages over traditional procedures using staples, at least in patients with benign splenomegaly. Patients with hematologic malignancy, BMI >30 %, coexistence of PH, and spleen weight >1,000 g are susceptible to bleeding during dissection of the splenic hilum, with use of IVD being relatively limited.

Laparoscopic spleen-preserving distal pancreatectomy (LSPDP).

BACKGROUND/AIMS: To study the feasibility and safety of laparoscopic spleen-preserving distal pancreatectomy (LSPDP). METHODOLOGY: Four patients underwent attempted LSPDP from February 2008 to April 2010 in our department and their clinical data and outcome were reviewed retrospectively. RESULTS: A total of 4 laparoscopic distal pancreas resections were attempted for 3 female and 1 male patient. All of these operations were successful with an average operative time of 235 min (range 115-305 min) and average blood loss of 200mL (range 100-450mL). The mean hospital stay time was 12.8 days, ranging from 10 to 21 days. Pancreatic fistula occurred in 1 patient then cured by extending drainage. Postoperative pathological examination showed those 2 cases of serous cystadenoma, 1 case of mucinous cystadenoma and 1 case of insulinoma, respectively. CONCLUSIONS: LSPDP is minimally invasive, safe and feasible for the management of benign pancreatic tail tumors with the advantages of earlier recovery and less morbidity from complications.