Background:Much has been written about the loss to follow-up in the transition between pediatric and adult Congenital Heart Disease(CHD)care centers.Much less is understood about the loss to follow-up(LTF)after a succ...Background:Much has been written about the loss to follow-up in the transition between pediatric and adult Congenital Heart Disease(CHD)care centers.Much less is understood about the loss to follow-up(LTF)after a successful transition.This is critical too,as patients lost to specialised care are more likely to experience mor-bidity and premature mortality.Aims:To understand the prevalence and reasons for loss to follow-up(LTF)at a large Australian Adult Congenital Heart Disease(ACHD)centre.Methods:Patients with moderate or highly complex CHD and gaps in care of>3 years(defined as LTF)were identified from a comprehensive ACHD data-base.Structured telephone interviews examined current care and barriers to clinic attendance.Results:Overall,407(22%)of ACHD patients(n=1842)were LTF.The mean age at LTF was 31(SD 11.5)years and 54%were male;311(76%)were uncontactable.Compared to adults seen regularly,lost patients were younger,with a greater socio-economic disadvantage,and had less complex CHD(p<0.05 for all).We interviewed 59 patients(14%).The top 3 responses for care absences were“feeling well”(61%),losing track of time(36%),and not needing fol-low-up care(25%).Conclusions:A large proportion of the ACHD population becomes lost to specialised cardiac care,even after a successful transition.This Australian study reports younger age,moderate complexity defects,and socio-economic disadvantage as predictive of loss to follow-up.This study highlights the need for novel approaches to patient-centered service delivery even beyond the age of transition and resources to maintain patient engagement within the ACHD service.展开更多
This paper reviews management of obstetric anaemia and the role of intravenous iron for the treatment of obstetric anaemia.Red blood cell transfusions are routinely used for haemoglobin restoration in anaemic women.Th...This paper reviews management of obstetric anaemia and the role of intravenous iron for the treatment of obstetric anaemia.Red blood cell transfusions are routinely used for haemoglobin restoration in anaemic women.The decision for red blood cell transfusion is made on a combination of haemoglobin level and clinical status,and it is suggested that transfusions are not necessary in those who are well compensated or when alternative therapy is available.To reduce the risk,intravenous iron infusion is proposed as a bloodless therapeutic approach.There are a variety of iron preparations.Intravenous iron infusion can reduce the requirement for blood transfusion in hemodynamically stable women with perinatal anaemia,especially in resource-scarce settings.It a cost-effective bloodless approach for the treatment of anaemia than can enhance patient outcomes.According to the literature,when haemoglobin is greater than 90 g/L,blood transfusion is not often required.In perinatal women with anaemia,the decision whether to administer blood or iron is based on patient preferences,haemoglobin levels,clinical symptoms,past and present medical conditions and the clinician’s judgement.Nevertheless,due to the lack of rigid criteria for blood transfusions in the majority of clinical settings,it is considered the default treatment for anaemia in perinatal women.展开更多
Objective:Sudden cardiac death(SCD)and malignant ventricular arrhythmia(VA)are increasingly recognized as important issues for people living with a Fontan circulation,but data are lacking.We sought to characterize the...Objective:Sudden cardiac death(SCD)and malignant ventricular arrhythmia(VA)are increasingly recognized as important issues for people living with a Fontan circulation,but data are lacking.We sought to characterize the cohort who had sudden cardiac death,most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes.Methods:A retrospective cohort study was performed.Inclusion criteria were documented non-sustained ventricular tachycardia,sustained ventricular tachycardia,ventricular fibrillation,resuscitated cardiac arrest or SCD>30 days post-Fontan completion.Results:Of 1611 patients,20(1.2%)had VA;14(1.0%)had VA without SCD and 6(<1%)had SCD(6%of all deaths recorded in Registry;5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated).The median age at first VA was 20.5(14–32)years,10(50%)were females,and the median age at Fontan operation was 8(4–17)years.On univariable analysis,hypoplastic left heart syndrome(p=0.03)and older age Fontan operation(p<0.001)were associated with VA.Earlier Fontan era(p<0.003),atriopulmonary Fontan(p<0.001),pre-Fontan atrioventricular valve repair(p=0.013)pre-or post-Fontan atrial arrhythmia(p=0.010)were associated with SCD.Patients with VA had a 3 times higher risk of death or heart transplant(HR 3.27(1.19,8.98),p=0.02).Conclusions:A proportion of people living with a Fontan circulation have malignant VA.Routine VA screening in this cohort is essential.More data are needed to aid risk stratification.展开更多
Portal hypertension(PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis.Portal pressure can be increased by a rise in portal blood flow,an increase in vascular res...Portal hypertension(PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis.Portal pressure can be increased by a rise in portal blood flow,an increase in vascular resistance,or the combination.In cirrhosis,the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow.Although much of this increase is a mechanical consequence of architectural disturbances,there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis.Many vasoactive substances contribute to the development of PHT.Among these,nitric oxide(NO) is the key mediator that paradoxically regulates the sinusoidal(intra-hepatic) and systemic/splanchnic circulations.NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation.NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation.NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.展开更多
AIM: Prospective evaluation of repeat endoscopic retrograde cholangiopancreatography (ERCP) for failed Schutz grade 1 biliary cannulation in a high-volume center. METHODS: Prospective intention-to-treat analysis of pa...AIM: Prospective evaluation of repeat endoscopic retrograde cholangiopancreatography (ERCP) for failed Schutz grade 1 biliary cannulation in a high-volume center. METHODS: Prospective intention-to-treat analysis of patients referred for biliary cannulation following recent unsuccessful ERCP. RESULTS: Fifty-one patients (35 female; mean age: 62.5 years; age range: 40-87 years) with previous failed biliary cannulation were referred for repeat ERCP. The indication for ERCP was primarily choledocholithiasis (45%) or pancreatic malignancy (18%). Successful biliary can- nulation was 100%. The precut needle knife sphincterotomy (NKS) rate was 27.4%. Complications occurred in 3.9% (post-ERCP pancreatitis). An identif iable reason for initial unsuccessful biliary cannulation was present in 55% of cases. Compared to a cohort of 940 nave pa-pilla patients (female 61%; mean age: 59.9 years; age range: 18-94 years) who required sphincterotomy over the same time period, there was no statistical difference in the cannulation success rate (100% vs 98%) or postERCP pancreatitis (3.1% vs 3.9%). Precut NKS use was more frequent (27.4% vs 12.7%) (P = 0.017). CONCLUSION: Referral to a high-volume center following unsuccessful ERCP is associated with high technical success, with a favorable complication rate, compared to routine ERCP procedures.展开更多
The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are limited.Alternative treatment options are therefore intensively sought...The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are limited.Alternative treatment options are therefore intensively sought after.An interesting candidate is the natural polyphenol resveratrol(RSV) that activates adenosinmonophosphate-activated protein kinase(AMPK) and silent information regulation-2 homolog 1(SIRT1).In addition,RSV has known anti-oxidant and anti-inflammatory effects.Here,we review the current evidence for RSVmediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis(NASH) pathogenesis with respect to free fatty acid(FFA) flux from adipose tissue,hepatic de novo lipogenesis,inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits.We review the in vivo evidence from animal studies and clinical trials.The abundance of animal studies reports a decrease in hepatic triglyceride accumulation,liver weight and a general improvement in histological fatty liver changes,along with a reduction in circulating insulin,glucose and lipid levels.Some studies document AMPK or SIRT1 activation,and modulation of relevant markers of hepatic lipogenesis,inflammation and oxidation status.However,AMPK/SIRT1-independent actions are also likely.Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes.Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.展开更多
Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an ov...Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumourrelated and hepatic function-related considerations. As such, HCC is currently managed largely through nonsurgical means as the criteria, in relation to the above considerations, for surgical management is still largelyrestrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.展开更多
Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disea...Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.展开更多
AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer cells.METHODS:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured a...AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer cells.METHODS:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured at the mRNA and protein level.COX-2 rich cell line SGC-7901 was chosen for subsequent experiments.siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB),Snail,and E-cadherin in gastric cancer cells.Gene expression was determined by Western blot and real-time polymerase chain reaction.To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2(PGE2)on E-cadherin,gastric cancer cells were treated with celecoxib or PGE2,in the presence of NF-κB specific siRNA.RESULTS:Highest expression level of COX-2 was found in SGC-7901 cells,both at mRNA and protein levels.siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail,but an increased expression of E-cadherin in SGC-7901 cells.siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells.However,COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells.Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin.In contrast,treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin.However,siRNAmediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells.CONCLUSION:COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.展开更多
AIM:To evaluate the long-term treatment outcomes of entecavir monotherapy in treatment naive patients in an Australian tertiary care setting. METHODS:A retrospective analysis of treatment naive patients receiving ente...AIM:To evaluate the long-term treatment outcomes of entecavir monotherapy in treatment naive patients in an Australian tertiary care setting. METHODS:A retrospective analysis of treatment naive patients receiving entecavir monotherapy through Westmead Hospital was performed.Patients were excluded if they had received previous treatment with another nucleoside or nucleotide analogue,were pregnant or less than 18 years old. RESULTS:Out of 336 patients,163 patients fulfilled the selection criteria.Range of follow up was 3-46 mo (mean 26 mo).134 patients(82.2%)had pre-treatment biopsies,with 26 patients(16.0%)demonstrating F3-4 fibrosis.In total,153 patients(93.9%)achieved at least Partial Virological Suppression(PVS),with 134 patients (82.2%)achieving complete virological suppression. The cumulative CVS and PVS rates at 36 mo were 82.1%and 96.4%,respectively.3 patients(1.8%)failed to achieve PVS,while 5 patients(3.0%)developed virological rebound.128 patients(78.5%)maintained CVS throughout follow up.Predictors of CVS included lower baseline DNA level(P=0.001),hepatitis B virus e antigen negative status(P=0.001)and increasing age at treatment(log rank 0.001).No significant adverse effects were reported necessitating cessation of entecavir. CONCLUSION:Entecavir monotherapy is efficacious and safe in an Australian tertiary care setting.Resistance and rebound rates are very low.This is similar to data from controlled and uncontrolled trials around the world.展开更多
Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus(HBV) and/or hepatitis C virus(HCV) is a major risk factor in the development of ...Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus(HBV) and/or hepatitis C virus(HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.展开更多
Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1...Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease(NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis(NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation.展开更多
Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers.Every year 1.4 million people die from viral hepa...Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers.Every year 1.4 million people die from viral hepatitisrelated cirrhosis and liver cancer.However,the majority of the infected population are unaware of their condition.This population have significant obstacles to overcome such as lack of awareness,vulnerability,increased migration,disease stigma,discrimination,as well as poor health resources,conflict in policy development and program implementation.Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive.This study aims to present the current global prevalence status and examines potential elimination strategies.The information for this research were obtained through a systematic review,published scientific literatures,the official websites of various government organisations,international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and2018.展开更多
AIM:To clarify the role of activated Notch2 in the invasiveness of gastric cancer.METHODS:To investigate the invasiveness of silencing Notch2 gene expression,we established a Notch2small interfering RNA(siRNA) transfe...AIM:To clarify the role of activated Notch2 in the invasiveness of gastric cancer.METHODS:To investigate the invasiveness of silencing Notch2 gene expression,we established a Notch2small interfering RNA(siRNA) transfected cell line using the MKN-45 gastric cancer cell line.After the successful transfection confirmed by real-time reverse transcription-polymerase chain reaction(RT-PCR) and Western blotting,migration and invasion assays were employed to evaluate the aggressiveness of the gastric cancer.RT-PCR and Western blottings were employed to confirm the down-regulation of Notch2 and to evaluate the expression of epithelial mesenchymal transition-related gene matrix metallopeptidase 9(MMP9),Akt,p-Akt.To confirm the relationship between PI3KAkt and MMP9,the PI3K inhibitor LY294002 was used to treat MKN-45 cells.RESULTS:Notch2 expression was dramatically decreased after Notch2 siRNA transfection(100.00% ± 9.74% vs 11.61% ± 3.85%,P < 0.01 by qRT-PCR).There was also a marked reduction of Notch target gene Hes1(100.00% ± 4.74% vs 61.61% ± 3.58%,P < 0.05) at the mRNA,indicating an inhibition of Notch signaling.Inhibition of Notch signaling was also confirmed by the marked reduction of Notch2 intracellular domain at the protein levels(100.00% ± 9.74% vs 65.61% ± 7.58%,P < 0.05).Down-regulation of Notch2 by siRNA enhanced tumor cell invasion(100.00% ± 21.64% vs 162.22% ± 16.84%,P < 0.05) and expression of MMP9(1.56 fold,P < 0.05),and activated the pro-MMP9 protein to its active form(1.48 fold,P < 0.05).There was no significant difference in the protein levels of Akt between the two groups(100.00% ± 10.87% vs 96.61% ± 7.33%,P > 0.05),while down-regulation of Notch2 elevated p-Akt expression(100.00% ± 9.87% vs 154.61% ± 13.10%,P < 0.05).Furthermore,p-Akt and MMP9 was down-regulated in response to the inhibitor LY294002(p-Akt 100.00% ± 8.87% vs 58.27% ± 5.01%,P < 0.05;MMP9 100.00% ± 9.17% vs 50.03% ± 4.88%,P < 0.05).CONCLUSION:Notch2 may negatively regulate cell invasion by inhibiting the PI3K-Akt signaling展开更多
Rates of non-alcoholic fatty liver disease(NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, nonalcoholic steatohepatitis(NASH) likely to become the most comm...Rates of non-alcoholic fatty liver disease(NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, nonalcoholic steatohepatitis(NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research.展开更多
文摘Background:Much has been written about the loss to follow-up in the transition between pediatric and adult Congenital Heart Disease(CHD)care centers.Much less is understood about the loss to follow-up(LTF)after a successful transition.This is critical too,as patients lost to specialised care are more likely to experience mor-bidity and premature mortality.Aims:To understand the prevalence and reasons for loss to follow-up(LTF)at a large Australian Adult Congenital Heart Disease(ACHD)centre.Methods:Patients with moderate or highly complex CHD and gaps in care of>3 years(defined as LTF)were identified from a comprehensive ACHD data-base.Structured telephone interviews examined current care and barriers to clinic attendance.Results:Overall,407(22%)of ACHD patients(n=1842)were LTF.The mean age at LTF was 31(SD 11.5)years and 54%were male;311(76%)were uncontactable.Compared to adults seen regularly,lost patients were younger,with a greater socio-economic disadvantage,and had less complex CHD(p<0.05 for all).We interviewed 59 patients(14%).The top 3 responses for care absences were“feeling well”(61%),losing track of time(36%),and not needing fol-low-up care(25%).Conclusions:A large proportion of the ACHD population becomes lost to specialised cardiac care,even after a successful transition.This Australian study reports younger age,moderate complexity defects,and socio-economic disadvantage as predictive of loss to follow-up.This study highlights the need for novel approaches to patient-centered service delivery even beyond the age of transition and resources to maintain patient engagement within the ACHD service.
文摘This paper reviews management of obstetric anaemia and the role of intravenous iron for the treatment of obstetric anaemia.Red blood cell transfusions are routinely used for haemoglobin restoration in anaemic women.The decision for red blood cell transfusion is made on a combination of haemoglobin level and clinical status,and it is suggested that transfusions are not necessary in those who are well compensated or when alternative therapy is available.To reduce the risk,intravenous iron infusion is proposed as a bloodless therapeutic approach.There are a variety of iron preparations.Intravenous iron infusion can reduce the requirement for blood transfusion in hemodynamically stable women with perinatal anaemia,especially in resource-scarce settings.It a cost-effective bloodless approach for the treatment of anaemia than can enhance patient outcomes.According to the literature,when haemoglobin is greater than 90 g/L,blood transfusion is not often required.In perinatal women with anaemia,the decision whether to administer blood or iron is based on patient preferences,haemoglobin levels,clinical symptoms,past and present medical conditions and the clinician’s judgement.Nevertheless,due to the lack of rigid criteria for blood transfusions in the majority of clinical settings,it is considered the default treatment for anaemia in perinatal women.
文摘Objective:Sudden cardiac death(SCD)and malignant ventricular arrhythmia(VA)are increasingly recognized as important issues for people living with a Fontan circulation,but data are lacking.We sought to characterize the cohort who had sudden cardiac death,most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes.Methods:A retrospective cohort study was performed.Inclusion criteria were documented non-sustained ventricular tachycardia,sustained ventricular tachycardia,ventricular fibrillation,resuscitated cardiac arrest or SCD>30 days post-Fontan completion.Results:Of 1611 patients,20(1.2%)had VA;14(1.0%)had VA without SCD and 6(<1%)had SCD(6%of all deaths recorded in Registry;5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated).The median age at first VA was 20.5(14–32)years,10(50%)were females,and the median age at Fontan operation was 8(4–17)years.On univariable analysis,hypoplastic left heart syndrome(p=0.03)and older age Fontan operation(p<0.001)were associated with VA.Earlier Fontan era(p<0.003),atriopulmonary Fontan(p<0.001),pre-Fontan atrioventricular valve repair(p=0.013)pre-or post-Fontan atrial arrhythmia(p=0.010)were associated with SCD.Patients with VA had a 3 times higher risk of death or heart transplant(HR 3.27(1.19,8.98),p=0.02).Conclusions:A proportion of people living with a Fontan circulation have malignant VA.Routine VA screening in this cohort is essential.More data are needed to aid risk stratification.
文摘Portal hypertension(PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis.Portal pressure can be increased by a rise in portal blood flow,an increase in vascular resistance,or the combination.In cirrhosis,the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow.Although much of this increase is a mechanical consequence of architectural disturbances,there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis.Many vasoactive substances contribute to the development of PHT.Among these,nitric oxide(NO) is the key mediator that paradoxically regulates the sinusoidal(intra-hepatic) and systemic/splanchnic circulations.NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation.NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation.NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.
文摘AIM: Prospective evaluation of repeat endoscopic retrograde cholangiopancreatography (ERCP) for failed Schutz grade 1 biliary cannulation in a high-volume center. METHODS: Prospective intention-to-treat analysis of patients referred for biliary cannulation following recent unsuccessful ERCP. RESULTS: Fifty-one patients (35 female; mean age: 62.5 years; age range: 40-87 years) with previous failed biliary cannulation were referred for repeat ERCP. The indication for ERCP was primarily choledocholithiasis (45%) or pancreatic malignancy (18%). Successful biliary can- nulation was 100%. The precut needle knife sphincterotomy (NKS) rate was 27.4%. Complications occurred in 3.9% (post-ERCP pancreatitis). An identif iable reason for initial unsuccessful biliary cannulation was present in 55% of cases. Compared to a cohort of 940 nave pa-pilla patients (female 61%; mean age: 59.9 years; age range: 18-94 years) who required sphincterotomy over the same time period, there was no statistical difference in the cannulation success rate (100% vs 98%) or postERCP pancreatitis (3.1% vs 3.9%). Precut NKS use was more frequent (27.4% vs 12.7%) (P = 0.017). CONCLUSION: Referral to a high-volume center following unsuccessful ERCP is associated with high technical success, with a favorable complication rate, compared to routine ERCP procedures.
基金Supported by Aarhus University and the Danish Council for Independent Research,Medical Sciences,No.11-107912The Danish Strategic Research Council has supported the LIRMOI study on RSV effects in NAFLD and metabolic diseases,No.10-093499+5 种基金The NOVO Nordisk Foundation has supported Grnbk H by a research grantsupported by the Robert WStorr Bequest to the Sydney MedicalFoundation,University of Sydneya National Health and Medical Research Council of Australia (NHMRC) Program Grant No.1053206Project grants 632630 and 1049857
文摘The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are limited.Alternative treatment options are therefore intensively sought after.An interesting candidate is the natural polyphenol resveratrol(RSV) that activates adenosinmonophosphate-activated protein kinase(AMPK) and silent information regulation-2 homolog 1(SIRT1).In addition,RSV has known anti-oxidant and anti-inflammatory effects.Here,we review the current evidence for RSVmediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis(NASH) pathogenesis with respect to free fatty acid(FFA) flux from adipose tissue,hepatic de novo lipogenesis,inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits.We review the in vivo evidence from animal studies and clinical trials.The abundance of animal studies reports a decrease in hepatic triglyceride accumulation,liver weight and a general improvement in histological fatty liver changes,along with a reduction in circulating insulin,glucose and lipid levels.Some studies document AMPK or SIRT1 activation,and modulation of relevant markers of hepatic lipogenesis,inflammation and oxidation status.However,AMPK/SIRT1-independent actions are also likely.Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes.Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.
文摘Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumourrelated and hepatic function-related considerations. As such, HCC is currently managed largely through nonsurgical means as the criteria, in relation to the above considerations, for surgical management is still largelyrestrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.
文摘Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
基金Supported by The National Natural Science Funding of China,No.81172366the Fundamental Research Funds for the Central Universities,No.lzujbky-2012-224the Gansu Special Program for High Technology Research and Development,No.0912TCYA027
文摘AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer cells.METHODS:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured at the mRNA and protein level.COX-2 rich cell line SGC-7901 was chosen for subsequent experiments.siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB),Snail,and E-cadherin in gastric cancer cells.Gene expression was determined by Western blot and real-time polymerase chain reaction.To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2(PGE2)on E-cadherin,gastric cancer cells were treated with celecoxib or PGE2,in the presence of NF-κB specific siRNA.RESULTS:Highest expression level of COX-2 was found in SGC-7901 cells,both at mRNA and protein levels.siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail,but an increased expression of E-cadherin in SGC-7901 cells.siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells.However,COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells.Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin.In contrast,treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin.However,siRNAmediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells.CONCLUSION:COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.
文摘AIM:To evaluate the long-term treatment outcomes of entecavir monotherapy in treatment naive patients in an Australian tertiary care setting. METHODS:A retrospective analysis of treatment naive patients receiving entecavir monotherapy through Westmead Hospital was performed.Patients were excluded if they had received previous treatment with another nucleoside or nucleotide analogue,were pregnant or less than 18 years old. RESULTS:Out of 336 patients,163 patients fulfilled the selection criteria.Range of follow up was 3-46 mo (mean 26 mo).134 patients(82.2%)had pre-treatment biopsies,with 26 patients(16.0%)demonstrating F3-4 fibrosis.In total,153 patients(93.9%)achieved at least Partial Virological Suppression(PVS),with 134 patients (82.2%)achieving complete virological suppression. The cumulative CVS and PVS rates at 36 mo were 82.1%and 96.4%,respectively.3 patients(1.8%)failed to achieve PVS,while 5 patients(3.0%)developed virological rebound.128 patients(78.5%)maintained CVS throughout follow up.Predictors of CVS included lower baseline DNA level(P=0.001),hepatitis B virus e antigen negative status(P=0.001)and increasing age at treatment(log rank 0.001).No significant adverse effects were reported necessitating cessation of entecavir. CONCLUSION:Entecavir monotherapy is efficacious and safe in an Australian tertiary care setting.Resistance and rebound rates are very low.This is similar to data from controlled and uncontrolled trials around the world.
文摘Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus(HBV) and/or hepatitis C virus(HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.
基金Supported by The Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney,National Health and Medical Research Council of Australia(NHMRC)Project Grants(No.1047417to Qiao L+5 种基金No.1087297to Hebbard L)Cancer Council NSW Project Grants(No.1070076to Qiao LNo.1069733to Hebbard L)
文摘Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease(NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis(NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation.
文摘Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers.Every year 1.4 million people die from viral hepatitisrelated cirrhosis and liver cancer.However,the majority of the infected population are unaware of their condition.This population have significant obstacles to overcome such as lack of awareness,vulnerability,increased migration,disease stigma,discrimination,as well as poor health resources,conflict in policy development and program implementation.Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive.This study aims to present the current global prevalence status and examines potential elimination strategies.The information for this research were obtained through a systematic review,published scientific literatures,the official websites of various government organisations,international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and2018.
基金Supported by The National Natural Science Foundation of China,No. 30870364Fund for Key Laboratory of Digestive System Tumors,Gansu Province,No. lzujbky-2011-t03
文摘AIM:To clarify the role of activated Notch2 in the invasiveness of gastric cancer.METHODS:To investigate the invasiveness of silencing Notch2 gene expression,we established a Notch2small interfering RNA(siRNA) transfected cell line using the MKN-45 gastric cancer cell line.After the successful transfection confirmed by real-time reverse transcription-polymerase chain reaction(RT-PCR) and Western blotting,migration and invasion assays were employed to evaluate the aggressiveness of the gastric cancer.RT-PCR and Western blottings were employed to confirm the down-regulation of Notch2 and to evaluate the expression of epithelial mesenchymal transition-related gene matrix metallopeptidase 9(MMP9),Akt,p-Akt.To confirm the relationship between PI3KAkt and MMP9,the PI3K inhibitor LY294002 was used to treat MKN-45 cells.RESULTS:Notch2 expression was dramatically decreased after Notch2 siRNA transfection(100.00% ± 9.74% vs 11.61% ± 3.85%,P < 0.01 by qRT-PCR).There was also a marked reduction of Notch target gene Hes1(100.00% ± 4.74% vs 61.61% ± 3.58%,P < 0.05) at the mRNA,indicating an inhibition of Notch signaling.Inhibition of Notch signaling was also confirmed by the marked reduction of Notch2 intracellular domain at the protein levels(100.00% ± 9.74% vs 65.61% ± 7.58%,P < 0.05).Down-regulation of Notch2 by siRNA enhanced tumor cell invasion(100.00% ± 21.64% vs 162.22% ± 16.84%,P < 0.05) and expression of MMP9(1.56 fold,P < 0.05),and activated the pro-MMP9 protein to its active form(1.48 fold,P < 0.05).There was no significant difference in the protein levels of Akt between the two groups(100.00% ± 10.87% vs 96.61% ± 7.33%,P > 0.05),while down-regulation of Notch2 elevated p-Akt expression(100.00% ± 9.87% vs 154.61% ± 13.10%,P < 0.05).Furthermore,p-Akt and MMP9 was down-regulated in response to the inhibitor LY294002(p-Akt 100.00% ± 8.87% vs 58.27% ± 5.01%,P < 0.05;MMP9 100.00% ± 9.17% vs 50.03% ± 4.88%,P < 0.05).CONCLUSION:Notch2 may negatively regulate cell invasion by inhibiting the PI3K-Akt signaling
文摘Rates of non-alcoholic fatty liver disease(NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, nonalcoholic steatohepatitis(NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research.