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Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

World Journal of Gastroenterology 2020年第40期26卷 6111-6140页

作者： Lakmie S Gunarathne Harinda Rajapaksha Nicholas Shackel Peter W Angus chandana b herath Department of Medicine Melbourne Medical SchoolThe University of MelbourneHeidelbergVIC 3084Australia School of Molecular Science College of ScienceHealth and EngineeringLa Trobe UniversityBundooraVIC 3086Australia ANZAC Research Institute ConcordNSW 2139Australia Department of Gastroenterology Austin HealthHeidelbergVIC 3084Australia South Western Sydney Clinical School Faculty of MedicineUniversity of New South WalesIngham Institute for Applied Medical Research1 Campbell StreetLiverpoolNSW 2170Australia

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSbbs). These NSbbs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these *** statins, used alone or in combination with NSbbs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This rev

关键词： Portal hypertension Cirrhosis Intrahepatic vascular resistance Hyperdynamic circulatory state Splanchnic vasodilatation Portal blood flow Non-selective betablockers Alternate renin angiotensin system

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Therapeutic potential of targeting the renin angiotensin system in portal hypertension

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World Journal of Gastrointestinal Pathophysiology 2013年第1期4卷 1-11页

作者： chandana b herath Josephine A Grace Peter W Angus Department of Medicine University of MelbourneAustin HealthHeidelberg Victoria 3084Australia Department of Gastroenterology Austin HealthHeidelbergVictoria 3084Australia

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with *** therapy to reduce portal pressure involves targeting two vascular *** first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle *** second approach is to reduce mesenteric and portal blood ***-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced *** many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of *** there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal *** review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this *** will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

关键词： Angiotensin-(1-7) Portal hypertension Intrahepatic resistance Mesenteric vasodilatation Variceal bleeding Non-selective β-blockers Renin angiotensin system Mas receptor Angiotensin receptor Cirrhosis

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Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2016年第35期22卷 8026-8040页

作者： Christopher Leung chandana b herath Zhiyuan Jia Sof Andrikopoulos bronwyn E brown Michael J Davies Leni R Rivera John b Furness Josephine M Forbes Peter W Angus Department of Medicine the University of MelbourneAustin HealthHeidelbergMelbourne Victoria 3084Australia Department of Gastroenterology and Hepatology Austin HealthAustin HospitalHeidelberg MelbourneVictoria 3084 Australia Heart Research Institute Newtown New South Wales 2042Austrulia University of Melbourne Victoria 3052Australia Metabolic Research Unit School of MedicineDeakin UniversityVictoria 3216Austrialia Glycation and Diabetes Complications Group Mater Medical Research InstituteSouth BrisbaneQueensland 4101Australia

AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57bl6 mice were fed a high fat, high fructose, high cholesterol(HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mR NA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content(a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/-animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.

关键词： Advanced glycation end-products Fructose Steatohepatitis Non-alcoholic fatty liver disease Hepatic fibrosis Oxidative stress

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Current therapies and novel approaches for biliary diseases

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World Journal of Gastrointestinal Pathophysiology 2019年第1期10卷 1-10页

作者： Indu G Rajapaksha Peter W Angus chandana b herath Department of Medicine The University of Melbourne Department of Gastroenterology and Hepatology Austin Health

Chronic liver diseases that inevitably lead to hepatic fibrosis, cirrhosis and/or hepatocellular carcinoma have become a major cause of illness and death worldwide. Among them, cholangiopathies or cholestatic liver diseases comprise a large group of conditions in which injury is primarily focused on the biliary system. These include congenital diseases(such as biliary atresia and cystic fibrosis), acquired diseases(such as primary sclerosing cholangitis and primary biliary cirrhosis), and those that arise from secondary damage to the biliary tree from obstruction, cholangitis or ischaemia. These conditions are associated with a specific pattern of chronic liver injury centered on damaged bile ducts that drive the development of peribiliary fibrosis and, ultimately, biliary cirrhosis and liver failure. For most, there is no established medical therapy and, hence, these diseases remain one of the most important indications for liver *** a result, there is a major need to develop new therapies that can prevent the development of chronic biliary injury and fibrosis. This mini-review briefly discusses the pathophysiology of liver fibrosis and its progression to *** make a special emphasis on biliary fibrosis and current therapeutic options,such as angiotensin converting enzyme-2(known as ACE2) over-expression in the diseased liver as a novel potential therapy to treat this condition.

关键词： Chronic liver disease biliary fibrosis Current therapies for biliary fibrosis Angiotensin converting enzyme-2 Gene therapy

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Development of a Cell-based Model to Derive Direct Runoff Hydrographs for Ungauged Mountainous basins

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Journal of Mountain Science 2007年第4期4卷 309-320页

作者： P. b. Hunukumbura S.b. Weerakoon Srikantha herath Disaster Prevention Research Institute Kyoto University Kyoto Japan Dept. of Civil Engineering University of Peradeniya Sri Lanka Environment and Sustainable Development Programme United Nations University Tokyo Japan

A model to derive direct runoff hydrograph for an ungauged basin using the physical properties of the basin is presented. The basin is divided into grid cells and canal elements. Overland flow is generated from each grid cell of the basin by application of continuous effective rainfall of I mm/hr to the basin, The flow generated is routed through downstream grid cells and the canal elements using the kinematic wave approach. The travel time for direct runoff from each grid cell to the basin outlet is calculated and the S-curve is derived for the basin. The S-curve is used to derive the unit hydrograph of a given duration for the basin. The model, referred as Cell-basin model was applied to the Upper Kotmale basin in Sri Lanka and the model predictions of direct runoff hydrographs for rainfall events agreed with the observations to a reasonable accuracy. Comparison of the unit hydrographs obtained from the model and from the conventional Snyder＇s synthetic unit hydrograph using regionalized parameters assuming the basin as an ungauged basin, with the unit hydrograph derived from the observations showed that the model predicted unit hydrograph was more suitable than that obtained by Snyder＇s method for Sri Lankan up country basins. Thus, the present model is a useful tool to obtain direct runoff hydrograph for ungauged basins.

关键词： Ungauged basin GIS unit hydrograph mountainous basin direct runoff hydrograph model cell-based model cell-basin model

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Cryptocurrency valuation and ethics:a text analytic approach

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Journal of Management Analytics 2020年第3期7卷 367-388页

作者： James R.barth Hemantha S.b.herath Tejaswini C.herath Pei Xu Department of Finance Auburn UniversityAuburnUSA Department of Accounting Brock UniversitySt.CatharinesCanada Department of Finance Operationsand Information SystemsBrock UniversitySt.CatharinesCanada Department of Systems and Technology Auburn UniversityAuburnUSA

A recent and potentially profound innovation is the creation of cryptocurrencies and the underlying technology that is essential for their use in various financial *** the anonymity of a user of a cryptocurrency,such digital currencies may be used for many different types of both lawful and illicit *** main purpose of this paper is to examine the extent to which ethical considerations associated with the use of cryptocurrencies affect the valuations attached to such *** examination is based on a text analytic approach that involves measuring the extent to which ethical and unethical words are used in a discussion related to bitcoin on Twitter to determine if there is a connection between ethics and cryptocurrency *** find the frequency of an unethical discussion about bitcoin is negatively associated with its *** contrast,the frequency of an ethical discussion is positively associated with its price.

关键词： Cryptocurrency bitcoin Ethics Dark Net Crypto-Crime Twitter text analytics market reaction

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Software Defect Prediction based Ensemble Approach

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Computer Systems Science & Engineering 2023年第6期45卷 2313-2331页

作者： J.Harikiran b.Sai chandana b.Srinivasarao b.Raviteja Tatireddy Subba Reddy School of Computer Science and Engineering VIT-AP UniversityAmaravathi522237India Department of Computer Science and Engineering GITAM Deemed to be UniversityTelangana502329India Department of Computer Science and Engineering B.V.Raju Institute of Technology NarsapurMedakTelangana502313India

Software systems have grown significantly and in *** a result of these qualities,preventing software faults is extremely *** defect prediction(SDP)can assist developers in finding potential bugs and reducing maintenance *** it comes to lowering software costs and assuring software quality,SDP plays a critical role in software *** a result,automatically forecasting the number of errors in software modules is important,and it may assist developers in allocating limited resources more *** methods for detecting and addressing such flaws at a low cost have been *** approaches,on the other hand,need to be significantly improved in terms of *** in this paper,two deep learning(DL)models Multilayer preceptor(MLP)and deep neural network(DNN)are *** proposed approaches combine the newly established Whale optimization algorithm(WOA)with the complementary Firefly algorithm(FA)to establish the emphasized metaheuristic search EMWS algorithm,which selects fewer but closely related representative *** find the best-implemented classifier in terms of prediction achievement measurement factor,classifiers were applied to five PROMISE repository *** compared to existing methods,the proposed technique for SDP outperforms,with 0.91%for the JM1 dataset,0.98%accuracy for the KC2 dataset,0.91%accuracy for the PC1 dataset,0.93%accuracy for the MC2 dataset,and 0.92%accuracy for KC3.

关键词： Prediction of a software defect deep learning models enhancedWOA firefly algorithm

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Urinary cystatin C:pediatric reference intervals and comparative assessment as a biomarker of renal injury among children in the regions with high burden of CKDu in Sri Lanka

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World Journal of Pediatrics 2022年第3期18卷 196-205页

作者： Patabandi Maddumage Mihiri Ayesha Sandamini Pallage Mangala Chathura Surendra De Silva Thibbotuwa Deniya Kankanamge Sameera Chathuranga Gunasekara Sakuntha Dewaka Gunarathna Ranawake Arachchige Isini Pinipa Chula herath Sudheera Sammanthi Jayasinghe Ediriweera Patabandi Saman chandana Nishad Jayasundara Department of Zoology Faculty of ScienceUniversity of RuhunaMatara 81000Sri Lanka Department of Nephrology Sri Jayewardenepura General HospitalColombo 10100Sri Lanka Department of Pharmacology Faculty of MedicineUniversity of RuhunaGalle 80000Sri Lanka Department of biosystems Technology Faculty of TechnologyUniversity of RuhunaMatara 81000Sri Lanka The Nicholas School of the Environment Duke UniversityDurhamNC 27708USA

background Cystatin C(Cys-C)is an emerging biomarker of renal diseases and its clinical use,particularly for screening the communities affected by chronic kidney disease of unknown etiology(CKDu),is hindered due to the lack of reference intervals(RIs)for diverse ethnic and age *** present study aimed to define RIs for urinary Cys-C(uCys-C)for a healthy pediatric population in Sri Lanka and in turn compare the renal function of the residential children in CKDu endemic and non-endemic regions in Sri *** A cross-sectional study was conducted with 850 healthy children(10-17 years)from selected locations for reference interval establishment,while a total of 892 children were recruited for the comparative *** samples were collected and analyzed for Cys-C,creatinine(Cr)and ***-adjusted uCys-C levels were partitioned by age,and RIs were determined with quantile regression(2.5th,50th and 97.5th quantiles)at 90%confidence *** The range of median RIs for uCys-C in healthy children was 45.94-64.44 ng/mg Cr for boys and 53.58-69.97 ng/mg Cr for *** median(interquartile range)uCys-C levels of children in the CKDu endemic and non-endemic regions were 58.18(21.8-141.9)and 58.31(23.9-155.3)ng/mg Cr with no significant difference(P=0.781).A significant variation of uCys-C was noted in the children across *** Notably high uCys-C levels were observed in children with elevated ***,uCys-C could be a potential biomarker in identifying communities at high risk of CKDu susceptibility.

关键词： Chronic kidney disease of unknown etiology Cystatin C Pediatric Reference intervals Renal injury Urinary albumin-creatinine ratio

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Evaluation of alternative conceptual models for groundwater modelling

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Geoscience Frontiers 2017年第3期8卷 437-443页

作者： Yangxiao Zhou H.M.P.S.D.herath UNESCO-IHE Institute for Water Education

This study evaluates the alternative conceptual models for groundwater modelling. A true model was created with a synthetic alluvial fan-plain hydrogeological framework. Various alternative conceptual models were evaluated for groundwater flow simulations. The first alternative model is a single aquifer layer model; the second alternative model is a 3-layer aquifer model; and the third model is a b-layer model consisting of 3 aquifers separated by 2 aquitards. All models could fit very well to the observa- tions with optimized values of hydraulic conductivities. However, the single aquifer layer model can only compute water balance components with good accuracy. The 3-layer aquifer model can be used for water balance computation and groundwater head simulation with small errors. The 5-layer model is capable of simulating water budget, groundwater head distribution and travel times with high accuracy. Multi- model analysis found only the 3rd alternative model superior.

关键词： Alternative conceptual modelsMulti-model analysisWater budgetTravel time

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Evaluation of chemopreventive effect of Fumaria indica against N-nitrosodiethylamine and CCl_4-induced hepatocellular carcinoma in Wistar rats

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Asian Pacific Journal of Tropical Medicine 2012年第8期5卷 623-629页

作者： Talib Hussain Hefazat H Siddiqui Sheeba Fareed M Vijayakumar chandana V Rao Department of Pharmacology and Toxicology Faculty of PharmacyIntegral Universitykursi roadLucknow-226026Uttar PradeshIndia Pharmacognosy and Ethnopharmacology Division National Botanical Research Institute(CSIR)Rana Pratap MargP.B.No.436Lucknow 226 001Uttar PradeshIndia

Objective:To investigation the chemopreventive potential of Fumaria indica（***） extract（FIE） on N-nitrosodiethylamine and CCl4-induced hepatocarcinogenesis in Wislar ***:The experimental animals were divided into ... 详细信息

Objective:To investigation the chemopreventive potential of Fumaria indica（***） extract（FIE） on N-nitrosodiethylamine and CClb>4b>-induced hepatocarcinogenesis in Wislar ***:The experimental animals were divided into six groups（n=6）.Hepatocellular carcinoma was induced by single intraperitoneal injection of N-nitrosodiethylamine（NDEA） in normal saline at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CClb>4b>（3 mL/kg/week） for 6 weeks,as the promoter of carcinogenic *** administration of the carcinogen,200 and 400 mg/kg of FIE were administered orally once a day throughout the *** the end of 20 weeks,the body weight,liver weight and relative liver weight were *** percentage of nodule incidence and liver cancer markers such as aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,γ-glutamyl transferase（γ-GT）,total bilirubin level（TbL）,α-feto protein（AFP） and carcinoembryonic antigen were estimated along with histopathological investigation in experimental groups of rats. Results:Obtained results demonstrated that the cotreatment with FIE significantly prevented the decrease of the body weight and also increased in relative liver weight caused by NDEA. The treatment with FIE significantly reduced the nodule incidence and nodule multiplicity in the rats after NDEA *** levels of liver cancer markers such as AST,ALT,ALP,γ-glutamyl transferase,TbL,AFP and carcinoembryonic antigen were substantially increased by NDEA ***,FIE treatment significantly reduced the liver injury and restored the entire liver cancer *** observations of liver tissues too correlated with the biochemical ***:These finding powerfully supports that *** exert chemopreventive effect by suppressing the tumor burden and restoring the activities of hepatic cancer marker enzymes on NDEA and CCl4-induced hepatocarcinogenesis in Wis

关键词： Fumaria indica Hepatocellular carcinoma N-nitrosodiethylamine Alkaline phosphatase α-feto protein

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