Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Disease clearance in ulcerative colitis:A new therapeutic target for the future

Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression.This has fueled the identification of molecular targets,resulting in a rapidly expanding therapeutic armamentarium.Subsequently,management strategies have evolved from symptomatic resolution to well-defined objective endpoints,including clinical remission,endoscopic remission and mucosal healing.While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications,studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures.Current recommendations lack consideration of histological healing.The simultaneous achievement of clinical,endoscopic,and histologic remission has not been fully investigated.This has laid the groundwork for a novel therapeutic outcome termed disease clearance(DC).This article summarizes the concept of DC and its current evidence.

Tip Clearance Flows in Turbine Cascades

This article describes the effects of some factors on the tip clearance flow in axial linear turbine cascades. The measurements of the total pressure loss coefficient are made at the cascade outlets by using a five-hole probe at exit Mach numbers of 0.10, 0.14 and 0.19. At each exit Mach number, experiments are performed at the tip clearance heights of 1.0%, 1.5%, 2.0%, 2.5% and 3.0% of the blade height. The effects of the non-uniform tip clearance height of each blade in the pitchwise direction are also studied. The results show that at a given tip clearance height, generally, total pressure loss rises with exit Mach numbers proportionally. At a fixed exit Mach number, the total pressure loss augments nearly proportionally as the tip clearance height increases. The increased tip clearance heights in the tip regions of two adjacent blades are to be blame for the larger clearance loss of the center blade. Compared to the effects of the tip clearance height, the effects of the exit Mach number and the pitchwise variation of the tip clearance height on the cascade total pressure loss are so less significant to be omitted.

An Error Equivalent Model of Revolute Joints with Clearances for Antenna Pointing Mechanisms

Joint clearances in antenna pointing mechanisms lead to uncertainty in function deviation. Current studies mainly focus on radial clearance of revolute joints, while axial clearance has rarely been taken into consideration. In fact, own?ing to errors from machining and assembly, thermal deformation and so forth, practically, axial clearance is inevitable in the joint. In this study, an error equivalent model(EEM) of revolute joints is proposed with considering both radial and axial clearances. Compared to the planar model of revolute joints only considering radial clearance, the journal motion inside the bearing is more abundant and matches the reality better in the EEM. The model is also extended for analyzing the error distribution of a spatial dual?axis("X–Y" type) antenna pointing mechanism of Spot?beam antennas which especially demand a high pointing accuracy. Three case studies are performed which illustrates the internal relation between radial clearance and axial clearance. It is found that when the axial clearance is big enough, the physical journal can freely realize both translational motion and rotational motion. While if the axial clearance is limited, the motion of the physical journal will be restricted. Analysis results indicate that the consideration of both radial and axial clearances in the revolute joint describes the journal motion inside the bearing more precise. To further validate the proposed model, a model of the EEM is designed and fabricated. Some suggestions on the design of revolute joints are also provided.

Clearance Influence on Dynamic Response of Intermittent Roller Chain Drive

The clearances appear in chain link hinges induced by manufacturing tolerance or wear of components are the most important factor that influences the dynamic performance of the intermittent roller chain drives. Due to the existence of the clearances in chain link hinges, the serious impact vibration phenomenon which influences the stability and the position accuracy of the chain drive system would be caused in the intermittent motion. But, the problem may be that a reasonable modeling on the chain with clearances is difficult due to the large clearance＇s number in chain system and the fact that the clearance＇ size are different. Currently, the studies on the dynamics of the intermittent roller chain considering the multi-clearance＇ joints are rare. Most research works have only focused on the constant moving chains. Taking the intermittent roller chain system as an object, this paper designs and builds the experimental device of this kind of mechanical system. The Longitudinal vibration response of the intermittent chain under the different motion laws was tested. The experimental study shows that the clearances presented in chain link hinges can cause severe impact vibration in the intermittent motion of chain. In subsequent work, the dynamic model of the intermittent roller chain system with the multi-clearance＇ joints was established. By calculating the dynamic response of this kind of mechanical system under the different motion laws, the effect of the clearances on the dynamic response of the intermittent chain drive system was analyzed. The theoretical simulation shows that the serious impact vibration phenomenon of the chain system can be caused by the clearances at the start accelerating period, and the chain drive system is often accompanied by the severe shock and vibration at the moment that the chain moves from the acceleration period to deceleration period. The research conclusions made by the experimental and theoretical studies indicate that the use of motion laws with small and continuous jerk at conversion point can effectively suppress the impact vibration at this point caused by clearances＇ effect. Additionally, the use of nonsymmetrical motion laws with small jerk approaching the end of the indexing period can obtain a smaller residual vibration. The presented motion law can provide an important reference for the improvement of the dynamic performance of the intermittent chain drive systems.

Effects of Semi-floating Ring Bearing Outer Clearance on the Subsynchronous Oscillation of Turbocharger Rotor

Semi-floating ring bearing（SFRB） is developed to control the vibration of turbocharger rotor. The outer clearance of SFRB affects the magnitude and frequency of nonlinear whirl motion, which is significant for the design of turbocharger. In order to explore the effects of outer clearance, a transient finite element analysis program for rotor and oil film bearing is built and validated by a published experimental case. The nonlinear dynamic behaviors ofrotor-SFRB system are simulated. According to the simulation results, two representative subsynchronous oscillations excited by the two hearings respectively are discovered. As the outer clearance of SFRB increases from 24 ~tm to 60 pro, the low-frequency subsynchronous oscillation experiences three steps, including a strong start, a gradual recession and a combination with the other one. At the same time, the high-frequency subsynchronous oscillation starts to appear gradually, then strengthens, and finally combines. If gravity and unbalance are neglected, the combination will start starts from high rotor speed and extents to low rotor speed, just like a ＂zipper＂. It is found from the quantitative analysis that when the outer clearance increases, the vibration amplitude experiences large value firstly, then reduction, and suddenly increasing after combination. A useful design principle of SFRB outer clearance for minimum vibration amplitude is proposed： the outer clearance value should be chosen to keep the frequency of two subsynchronous oscillations clearly separated and their amplitudes close.

Effects of Floating Ring Bearing Manufacturing Tolerance Clearances on the Dynamic Characteristics for Turbocharger

The inner and outer oil film dynamic characteristic coefficients of floating ring bearings（FRBs） change due to the manufacturing tolerance of the floating ring, journal and intermediate, which leads to high-speed turbocharger＇s vibration too large and even causes nonlinear vibration accident. However, the investigation of floating ring bearing manufacturing tolerance clearance on the rotordynamic characteristics is less at present. In order to study the influence law of inner and outer clearance on turbocharger vibration, the rotor dynamic motion equations of turbocharger supported in FRBs are derived by analyzing the size relations between floating ring, journal and intermediate for the inner and outer oil film clearances, the time transient response analysis for combination of FRBs clearance are developed. A realistic turbocharger is taken as a research object, the FE model of the turbocharger with FRBs is modeled. Under the conditions of four kinds of limit state bearing clearances for inner and outer oil film, the nonlinear transient analyses are performed based on the established FE dynamic models of the nonlinear rotor-FRBs system applied incentive combinations of gravity and unbalance force, respectively. From the waterfall, the simulation results show that the speed for the appearance of fractional frequency is not identical and the amplitude magnitude is different under the four kinds of bearing manufacturing tolerance limit clearances, and fractional frequency does not appear in the turbocharger and the amplitude is minimum under the ODMin/IDMax bearing manufacturing tolerance clearances. The turbocharger vibration is reduced by controlling the manufacturing tolerance clearance combinations of FRBs, which is helpful for the dynamic design and production-manufacturing of high-speed turbocharger.

Numerical Analysis of Nozzle Clearance's Effect on Turbine Performance

Variable nozzle turbine （VNT） has become a popular variable geometry turbine （VGT） technology for the diesel engine application. Nozzle clearance, which can＇t be avoided on the hub and shroud side of the VNT turbine due to the pivoting stators, can lead to turbine performance deterioration. However, its mechanism is still not clear. In this paper, numerical investigation, which is validated by experiment, is carried out to study the mechanism of the nozzle clearance＇s effect on the turbine performance. Firstly, performance of the mixed flow turbine with fixed nozzle clearances tested on flow bench. Performance of the tested turbine with the same nozzle clearance is numerically simulated. The numerical result agrees well with the test data, which proves correct of the numerical method. Then the turbine performance with different nozzle clearances is numerically analyzed. The research showed that with nozzle clearance, flow loss in the nozzle increases at first and it reaches the maximum value when the clearance ratio is 5%. Flow at the exit of the nozzle becomes less uniform with nozzle clearance. The negative incidence angle of the rotor also increases with nozzle clearance and leads to more incidence angle loss in the rotor. The low energy fluid formed in the nozzle due to the nozzle clearance migrates from hub to shroud side in the rotor, which is another main reason for the rotor＇s performance degradation. The present research exposed the mechanism of the dramatically decrease of the turbine performance with nozzle clearance： （a） The loss associated with the nozzle leakage increases with the nozzle clearance; （b） The flow loss grows up quickly in the rotor due to the incidence angle loss and migration of the low energy fluid from hub to shroud side.

Indocyanine green clearance test combined with MELD score in predicting the short-term prognosis of patients with acute liver failure

BACKGROUND: Acute liver failure(ALF) is an acute severe deterioration of liver function with high mortality. Early and accurate prognostic assessment of patients with ALF is critically important. Although the model for end-stage liver disease(MELD) scores and King’s College Hospital(KCH) criteria are well-accepted as predictive tools, their accuracy is unsatisfactory.The indocyanine green(ICG) clearance test(ICGR15, ICG retention rate at the 15 minutes) is a sensitive indicator of liver function. In this study, we investigated the efficacy of the ICGR15 for the short-term prognosis in patients with ALF. We compared the predictive value of ICGR15 with the MELD scores and KCH criteria.METHODS: Sixty-nine patients who had been diagnosed with ALF were recruited retrospectively. ICGR15 had been performed by ICG pulse spectrophotometry and relevant clinical and laboratory indices were analyzed within 24 hours of diagnosis.In addition, the MELD scores and KCH criteria were calculated.RESULTS: The three-month mortality of all patients was 47.83%.Age, serum total bilirubin and creatinine concentrations,international normalized ratio for prothrombin time, ICGR15,MELD scores and KCH criteria differed significantly between surviving and deceased patients. A positive correlation was observed between ICGR15 and MELD scores(r=0.328, P=0.006).The ICGR15-MELD model, Logit(P)=0.096×ICGR15+0.174 ×MELD score–9.346, was constructed by logistic regression analysis. The area under the receiver operating characteristic curve was 0.855. When set the cut-off point to-0.4684, the sensitivity was 87.90% and specificity, 72.20%. The area under the receiver operating characteristic curve of the ICGR15-MELD model(0.855) was significantly higher than that of the ICGR15(0.793), MELD scores(0.776) and KCH criteria(0.659).Based on this cut-off value, the patients were divided into two groups. The mortality was 74.36% in the first group(ICGR15-MELD≥-0.4686) and 13.33% in the second group(ICGR15-MELD<-0.4686), with a significant difference between the two groups(χ2=25.307, P=0.000).CONCLUSION: The ICGR15-MELD model is superior to the ICGR15, MELD scores, and KCH criteria in predicting the shortterm prognosis of patients with ALF.

EFFECT OF TIP CLEARANCE ON PERFORMANCE AND FLOW FIELD OF SMALL SIZED HIGH SPEED CENTRIFUGAL FAN

A centrifugal fan with the high speed and compact dimensions is studied numerically and experimentally. The centrifugal fan consists of a shrouded impeller rotating at 34 000 r/min with a small tip clearance 0.7 mm to the fixed outer casing. Computational models with/without the tip clearance are built and the κ-ω shear stress transport （SST） turbulence model and the unstructured mesh are applied to the numerical simulation for unsteady solutions. The overall performance is measured on a standard experimental bench and the major flow feature of each component inside the centrifugal fan is numerically investigated. In the presence of the tip clearance due to the difference of static pressure between leading and trailing edges of the clearance, i. e. , leading and trailing edges of the impeller, a strong return flow exists inside the clearance passage and re-circulates the main stream inside the impeller passage, and produces the strong flow interaction, thus changing the flow field and influencing the overall performance.

Indocyanine green clearance in evaluating the recovery of liver reserve function after superselective transarterial chemoembolization

Transarterial chemoembolization(TACE)may ravage normal liver tissues apart from the neoplastic nodules which offset the anti-tumor effect.This study aimed to evaluate the recovery of liver reserve function(LRF)after TACE by indocyanine green(ICG)clearance test and other routine liver function tests.Forty-six newly diagnosed HCC patients who had undergone TACE as the initial treatment from January 2011 to January 2012 were enrolled in this study.The effects of age,basic ICG clearance rate and interval time between two assessments on the recovery of LRF were analyzed.We found that ICG retention rate at the 15 minutes(ICGR15)was significantly increased after TACE(12.3±8.1%vs 16.8±12.1%,P【0.01)in all the 46 patients.In particular,the ICGR15 value was increased in older patients(age】55 years,20.3±12.5%vs 13.7±7.2%,P【0.01).The interval of ICG test also affected the ICGR15 value(≤47days,17.8±11.4%after vs 12.1±7.1%before TACE,P【0.01).Our data suggested that TACE decreased LRF,especially in older patients.ICG test was more sensitive to evaluate the recovery of LRF after TACE than the Child-Pugh grade and routine liver function tests.

Combined APACH Ⅱ score and arterial blood lactate clearance rate to predict the prognosis of ARDS patients

Objective:To explore the easily applicable indicators of practical value to evaluate the prognosis of acute respiratory distress syndrome（ARDS）.Methods:Blood and biochemical tests and bloodgas analyses were performed upon entry into the ICUs,12 h,24 h,48 h and 72 h after that in 72 ARDS patients（who were admitted to the ICUs of our hospital from January 2000 to December 2009）.Then APACHEⅡscores were achieved by combining relevant physiological parameters and laboratory results.Results:There was a statistical difference between the death group and survival group at different time points upon entering the ICUs in terms of APACHEⅡscore, alveolar-arterial oxygen difference and arterial blood lactate clearance rate.PaO2/FiO2 values were recorded to be statistically different between the death group and survival group 24 h,48 h and 72 h,respectively after entry into the ICUs.In addition,registered linear regression existed between APACHEⅡscore,alveolar-arterial oxygen difference or PaO2/FiO2 value and time. APACHEⅡscore 24 h and 72 h after entering ICUs predicted mortality with an area under the ROC curve（AUC） standing respectively at 0.919 and 0.9SS.Arterial blood lactate clearance rate 12 h, 24 h,48 h and 72 h after entering ICUs predicted mortality with an area under the ROC curve （AUC） at 0.918,0.918,0.909 and 0.991,respectively.Conclusions:APACHEⅡscore applied in combination with arterial blood lactate clearance rate is of clinical significance in assessing the prognosis of ARDS patients.

COMPARISON OF TWO METHODS TO INCREASE TIP CLEARANCE AND ITS EFFECT ON PERFORMANCE OF TURBOCHARGER CENTRIFUGAL COMPRESSOR STAGE

Tip clearance between the blade tip and casing of a centrifugal compressor can be varied through two methods： by changing the blade height （MI） or by changing the casing diameter （M2）. Numerical simulations are carried out to compare these two methods and their effect on the stage and impeller performance. The impeller and diffuser are connected through rotor stator boundary using frozen rotor approach. Overall stage performance and the flow configuration have been investigated for nine tip clearance levels from no gap to 1 mm. Impeller and diffuser performances are also presented separately. It has been found that the overall and impeller performance are comparatively better for MI below tip clearance of 0.5 mm whereas M2 is found advantageous above 0.5 mm of tip clearance. Both MI and M2 show performance degradation with the increase in tip clearance. Two models have been proposed for the stage total pressure ratio and efficiency, which are found to be in agreement with experimental results. The impeller efficiency and the pressure ratio are found to be maximum at tip clearance of 0.1 mm for both the cases however minimum diffuser effectiveness is also observed at the same clearance level. Diffuser effectiveness is found to be maximum at zero gap for both cases. As it is practically impossible to have zero gap for unshrouded impellers so it is concluded that the optimum thickness is 0.5 mm onwards for MI and 0.5 mm for M2 in terms of diffuser effectiveness. Mass averaged flow parameters, entropy, blade loading diagram and relative pressure fields are presented, showing the loss production within the impeller passage with tip clearance.

HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogues therapy

The ideal endpoint of hepatitis B virus(HBV)antiviral therapy is HBsAg loss,a difficult goal to obtain,especially in HBeAg negative patients.Herein,we report the results obtained by the addition of peg-interferonα-2a to a long-lasting nucleos(t)ide analogues therapy in a HBeAg negative,genotype D patient with steadily HBV-DNA negative/HBsAg positive values.In 2002,our Caucasian 44-year-old male patient received lamivudine and,4 years later,added adefovir because of a virological breakthrough.In 2011,considering his young age,liver stiffness(4.3 kPa)and HBsAg levels(3533IU/mL),we added Peg-interferonα-2a for six months(3in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferonα-2a monotherapy).A decrease of HBsAg levels was observed after 1 mo(1.21log)of Peg-interferon and 3 mo(1.88 log)after the discontinuation of all drugs.Later,a complete clearance of HBsAg was obtained with steadily undetectable HBVDNA serum levels(<9 IU/mL).HBsAg clearance by the addition of a short course of Peg-interferonα-2a represents an important result with clinical and pharmacoeconomic implications,considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment.

Topology and Vortex Structures of Turbine Cascade with Different Tip Clearances

This paper uses the topology theory to analyze the surface flowspectrums of straight, positively curved and negatively curvedcascades with relative tip clearances of 0.023 and 0.036, findsapparent differences of topology and vortex structures in the bladetip and the suction side wall corner of single type of cascade withthis two clearances, and studies the mechanism of the differenceformation as well as their effects o the energy loss.

Early lactate clearance as a reliable predictor of initial poor graft function after orthotopic liver transplantation

BACKGROUND:Initial poor graft function (IPGF) following orthotopic liver transplantation is a major determinant of postoperative survival and morbidity.Lactate clearance is a good marker of liver function.In this study,we investigated the clinical utility of early lactate clearance as an early and accurate predictor for IPGF following liver transplantation.METHODS:This was a prospective observational study of 222 patients referred to the surgical intensive care unit (SICU) after orthotopic liver transplantation.The IPGF group consisted of patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1500 IU/L within 72 hours after orthotopic liver transplantation.Early lactate clearance was defined as lactate at SICU presentation (hour 0) minus lactate at hour 6,divided by lactate at SICU presentation.The model for end-stage liver disease (MELD) score,Child-Pugh score and laboratory data including AST,ALT,total bilirubin (TB) and prothrombin time (PT) were recorded at SICU presentation and compared between the non-IPGF and IPGF groups Receiver operating characteristic (ROC) curves were plotted to measure the performance of early lactate clearance,MELD score,Child-Pugh score,TB and PT.RESULTS:IPGF occurred in 45 of the 222 patients (20.3%).The early lactate clearance in the non-IPGF group was markedly higher than that in the IPGF group (43.2±13.8% vs 13.4±13.7% P<0.001).The optimum cut-off value for early lactate clearance predicting IPGF was 24.8% (sensitivity 95.5%,specificity 88.9%).The area under the curve of the ROC was 0.961,which was significantly superior to MELD score,Child-Pugh score TB and PT.Patients with early lactate clearance ≤24.8% had a higher IPGF rate (OR=169) and a higher risk of in-hospital mortality (OR=3.625).CONCLUSIONS:Early lactate clearance can serve as a prompt and accurate bedside predictor of IPGF.Patients with early lactate clearance less than 24.8% are associated with a higher incidence of IPGF.

Comparison and analysis of two Coulomb friction models on the dynamic behavior of slider-crank mechanism with a revolute clearance joint

The objective of this study is to investigate the effects of the Coulomb dry friction model versus the modified Coulomb friction model on the dynamic behavior of the slider-crank mechanism with a revolute clearance joint. The normal and tangential forces acting on the contact points between the journal and the bearing are described by using a Hertzian-based contact force model and the Coulomb friction models, respectively.The dynamic equations of the mechanism are derived based on the Lagrange equations of the first kind and the Baumgarte stabilization method. The frictional force is solved via the linear complementarity problem(LCP) algorithm and the trial-and-error algorithm.Finally, three numerical examples are given to show the influence of the two Coulomb friction models on the dynamic behavior of the mechanism. Numerical results show that due to the stick friction, the slider-crank mechanism may exhibit stick-slip motion and can balance at some special positions, while the mechanism with ideal joints cannot.

DYNAMIC RESPONSE OF ROLLER GEAR INDEXING CAM SYSTEM CONSIDERING CLEARANCE AND MOTOR CHARACTERISTIC

The dynamic responses of roller gear indexing cam mechanism are investigated .With applying Lagarange equation and Gear method,motion equations of this mechanism including clearance,motor characteristic,torsion flexibility are developed and solved.The results show that clearance affects primarily the response on turret,and has little effects on the responses on rotary table.At the same time,the velocity fluctuation of motor shaft is not serious for the existence of inertia of reducer,and the high frequency of velocity fluctuation of camshaft is related with the torsion stiffness of shaft and the clearance between pairs.

Influence of Tip Clearance on the Flow Field and Aerodynamic Performance of the Centrifugal Impeller

This paper studies numerically the influence of the tip clearance on the three dimensional viscous flowfield and performance of the NASA Low Speed Centrifugal Compressor (LSCC) impeller with a vaneless diffuser A three dimensional viscous code developed by the authors is applied with several acceleration methods: local time step, multigrid and residual smoothing The computations were performed under several operating conditions with four different tip clearance sizes(0 0%,50%,100% and 200% design t...

Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer＇s disease.The therapeutic effect of current pharmacotherapies is unsatisfactory,and some treatments cause severe side effects.The meningeal lymphatic vessels might be a new route for amyloid-β clearance.This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain.First,human lymphatic endothelial cells were treated with 100 ng/m L recombinant human vascular endothelial growth factor-C（rh VEGF-C） protein.Light microscopy verified that rh VEGF-C,a specific ligand for vascular endothelial growth factor receptor-3（VEGFR-3）,significantly promoted tube formation of human lymphatic endothelial cells in vitro.In an in vivo study,200 μg/m L rh VEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice,once every 2 days,four times in total.Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer＇s disease mice.One week after rh VEGF-C administration,enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain.The Morris water maze test demonstrated that spatial cognition was restored.These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice,suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer＇s disease.