ACE I/D Gene Polymorphism Can't Predict the Steroid Responsiveness in Asian Children with Idiopathic Nephrotic Syndrome: A Meta-Analysis

The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness. = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable.Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS

TNFα-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release

Although TNFα is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFκB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFα-dependent apoptosis in vitro without inhibiting NFκB or de novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFα cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFα by binding integrins αvβ5, α6β1, and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFα. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFα-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFα. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFα-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFα-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFα cytotoxicity at least in some contexts, these findings may reveal important mediators of TNFα-induced apoptosis in vivo and identify potential therapeutic targets for thwarting TNFα-dependent tissue damage

Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: Diagnosis and management

Nearly one third of the world's population have been infected with hepatitis B and the virus is endemic in many Asian countries. With increasing life expectancy and the expected global increase in cancer, chemotherapy induced reactivation of hepatitis B is likely to become an increasing problem. Patients with significant levels of hepatitis B virus (HBV) DNA in serum prior to chemotherapy and patients receiving intensive chemotherapy for hematological malignancies appear particularly at risk. Most patients who suffer reactivation of hepatitis B are positive for hepatitis B surface antigen (HBsAg) prior to chemotherapy and are therefore easily identifiable by routine screening. In addition, the very large population of patients who have been exposed to the virus and have apparently cleared the virus as assessed by serological testing (HBsAg negative/hepatitis B core antibody [HBcAb] positive) may also be at risk of reactivation. These patients should be monitored and in some cases receive prophylaxis during chemotherapy. Published experience with antiviral prophylaxis has largely been limited to the nucleoside analogue, lamivudine. The commencement of antiviral prophylaxis prior to chemotherapy and its continuation until restitution of normal host immunity is the cornerstone to effective prevention of hepatitis B reactivation. This review summarizes the important issues related to HBV reactivation and suggests an algorithm for managing these patients in the clinical setting

Hepatitis B reactivation in patients receiving cytotoxic chemotherapy: Diagnosis and management

Nearly one third of the world's population have been infected with hepatitis B and the virus is endemic in many Asian countries. With increasing life expectancy and the expected global increase in cancer, chemotherapy induced reactivation of hepatitis B is likely to become an increasing problem. Patients with significant levels of hepatitis B virus (HBV) DNA in serum prior to chemotherapy and patients receiving intensive chemotherapy for hematological malignancies appear particularly at risk. Most patients who suffer reactivation of hepatitis B are positive for hepatitis B surface antigen (HBsAg) prior to chemotherapy and are therefore easily identifiable by routine screening. In addition, the very large population of patients who have been exposed to the virus and have apparently cleared the virus as assessed by serological testing (HBsAg negative/hepatitis B core antibody [HBcAb] positive) may also be at risk of reactivation. These patients should be monitored and in some cases receive prophylaxis during chemotherapy. Published experience with antiviral prophylaxis has largely been limited to the nucleoside analogue, lamivudine. The commencement of antiviral prophylaxis prior to chemotherapy and its continuation until restitution of normal host immunity is the cornerstone to effective prevention of hepatitis B reactivation. This review summarizes the important issues related to HBV reactivation and suggests an algorithm for managing these patients in the clinical setting

Epidemiology and outcomes of marked elevations of alanine aminotransferase >1000 IU/L in an Australian cohort.

Background and Aim: Marked elevations of alanine aminotransferase (ALT) are caused by a limited number of underlying pathologies, including hepatic ischemia, drugs/toxins, viral hepatitis, and-rarely-autoimmune hepatitis. The aim of this study was to determine the relative incidence of pathologies resulting in ALT greater than 1000 IU/L and factors predicting clinical outcomes in an Australian cohort. Methods: A retrospective cohort study of all adult patients with ALT levels greater than 1000 IU/L between January 2013 and December 2015 was conducted at a large teaching hospital network in Australia. Multivariable logistic regression analysis was used to determine predictors of etiology and mortality. Results: There were 287 patients identified with ALT levels greater than 1000 IU/L. The most common causes were ischemia (44%), drugs/toxins (19%), biliary obstruction (16%), and viral hepatitis (7%). Independent predictors of a diagnosis of ischemic hepatitis included (adjusted odds ratio; 95% confidence interval): hypotension (29.2; 8.2-104.7), chronic obstructive pulmonary disease (COPD) (20.2; 2.8-145.3), coronary artery disease (12.9; 1.7-98.9), congestive cardiac failure (7.8; 1.2-49.2), diabetes mellitus (7.4; 1.6-33.9), metabolic acidosis (6.2; 2.0-19.4), gamma-glutamyltransferase < 135 IU/L (5.1; 1.5-17.6), and albumin <34 g/L (3.4; 1.1-11.0). Independent risk factors for all-cause 28-day mortality included: septic shock (14.7; 4.3-50.7), metabolic acidosis (7.3; 2.5-21.3), history of COPD (5.4; 1.6-17.8), cardiogenic shock (4.3; 1.6-11.7), prothrombin time ≥ 20 s (3.7; 1.5-9.2), and age ≥ 65 years (3.0; 1.3-7.2). Conclusions: Ischemic hepatitis was the most common cause of ALT levels greater than 1000 IU/L and was associated with high mortality

Current issues in the prevalence, diagnosis and management of hepatocellular carcinoma in Australia

Hepatocellular carcinoma (HCC) is the commonest primary liver cancer encountered in the community and a leading cause of cancer morbidity and mortality. In Australia, there are several current important issues that need to be addressed in HCC management. There is a dramatically rising incidence of HCC in Australia with comparatively poorer outcomes in remote regions and in socioeconomic disadvantaged groups. Aboriginal people have a greater incidence of HCC on a background of increased liver disease prevalence and face several barriers to delivery of better healthcare outcomes compared to other Australians. The previously adopted use of imaging alone to diagnose HCC is now being challenged with biopsy likely to become increasingly necessary with the increased uptake of personalised medicine management. Managing HCC is complex involving many disciplines with the multidisciplinary team approach being the current accepted standard of care for patients. New immunotherapy combinations promise to offer patients with advanced HCC promising novel management options. However, the Australian inequities in prevalence, diagnosis and service provision, especially in Aboriginal people, need to be redressed concurrently with the adoption of new HCC management options