Acute renal impairment in coronavirus-associated severe acute respiratory syndrome

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.BackgroundSevere acute respiratory syndrome (SARS) is a newly emerged infection from a novel coronavirus (SARS-CoV). Apart from fever and respiratory complications, acute renal impairment has been observed in some patients with SARS. Herein, we describe the clinical, pathologic, and laboratory features of the acute renal impairment complicating this new viral infection.MethodsWe conducted a retrospective analysis of the plasma creatinine concentration and other clinical parameters of the 536 SARS patients with normal plasma creatinine at first clinical presentation, admitted to two regional hospitals following a major outbreak in Hong Kong in March 2003. Kidney tissues from seven other patients with postmortem examinations were studied by light microscopy and electron microscopy.ResultsAmong these 536 patients with SARS, 36 (6.7%) developed acute renal impairment occurring at a median duration of 20 days (range 5–48 days) after the onset of viral infection despite a normal plasma creatinine level at first clinical presentation. The acute renal impairment reflected the different prerenal and renal factors that exerted renal insult occurring in the context of multiorgan failure. Eventually, 33 SARS patients (91.7%) with acute renal impairment died. The mortality rate was significantly higher among patients with SARS and acute renal impairment compared with those with SARS and no renal impairment (91.7% vs. 8.8%) (P < 0.0001). Renal tissues revealed predominantly acute tubular necrosis with no evidence of glomerular pathology. The adjusted relative risk of mortality associated with the development of acute renal impairment was 4.057 (P < 0.001). By multivariate analysis, acute respiratory distress syndrome and age were the most significant independent risk factors predicting the development of acute renal impairment in SARS.ConclusionAcute renal impairment is uncommon in SARS but carries a high mortality. The acute renal impairment is likely to be related to multi-organ failure rather than the kidney tropism of the virus. The development of acute renal impairment is an important negative prognostic indicator for survival with SARS

Engineering the Controlled Assembly of Filamentous Injectisomes in E. coli K-12 for Protein Translocation into Mammalian Cells.

Bacterial pathogens containing type III protein secretion systems (T3SS) assemble large needle-like protein complexes in the bacterial envelope, called injectisomes, for translocation of protein effectors into host cells. The application of these molecular syringes for the injection of proteins into mammalian cells is hindered by their structural and genomic complexity, requiring multiple polypeptides encoded along with effectors in various transcriptional units (TUs) with intricate regulation. In this work, we have rationally designed the controlled expression of the filamentous injectisomes found in enteropathogenic Escherichia coli (EPEC) in the nonpathogenic strain E. coli K-12. All structural components of EPEC injectisomes, encoded in a genomic island called the locus of enterocyte effacement (LEE), were engineered in five TUs (eLEEs) excluding effectors, promoters and transcriptional regulators. These eLEEs were placed under the control of the IPTG-inducible promoter Ptac and integrated into specific chromosomal sites of E. coli K-12 using a marker-less strategy. The resulting strain, named synthetic injector E. coli (SIEC), assembles filamentous injectisomes similar to those in EPEC. SIEC injectisomes form pores in the host plasma membrane and are able to translocate T3-substrate proteins (e.g., translocated intimin receptor, Tir) into the cytoplasm of HeLa cells reproducing the phenotypes of intimate attachment and polymerization of actin-pedestals elicited by EPEC bacteria. Hence, SIEC strain allows the controlled expression of functional filamentous injectisomes for efficient translocation of proteins with T3S-signals into mammalian cells

Reduction of liver stiffness following resolution of acute flares of chronic hepatitis B

Background: Measuring liver stiffness is becoming more popular as a non-invasive tool for assessing liver fibrosis. Aim: To assess the effect of severe hepatitis B flare on liver stiffness and determine factors that correlate with liver stiffness measurements. Methods: Twenty-nine patients with severe hepatitis B flare (ALT > 10 × upper limit of normal) were followed up for 1 year. Serial transient elastography was performed at the time of flare, 3-6, and 12 months after flare. Results: At the time of flare, the median liver stiffness was 16.8 kPa, with no patients having normal liver stiffness (<6 kPa). There was a significant decrease in liver stiffness from baseline to 3-6 months (16.8 vs. 7.9 kPa, respectively, P < 0.001), and a further smaller decline from 3-6 to 12 months (7.9 vs. 6.9 kPa, respectively, P = 0.039). By 12 months, 10 (34%) had normalized their liver stiffness. Baseline parameters which correlated with liver stiffness include bilirubin, ALT, albumin, prothrombin time and platelet levels (all P < 0.05). Conclusion: Liver stiffness was increased in patients with severe hepatitis B flares, with return to near normal levels by 6 months. Transient elastography for proper assessment of liver fibrosis should be performed at least 6 months after flare. © 2010 The Author(s).published_or_final_versionSpringer Open Choice, 31 May 201

Reactivation of Epstein–Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function

EBNA1 is the only Epstein–Barr virus (EBV) latent protein responsible for viral genome maintenance and is expressed in all EBV-infected cells. Zn2+ is essential for oligomerization of the functional EBNA1. We constructed an EBNA1 binding peptide with a Zn2+ chelator to create an EBNA1-specific inhibitor (ZRL5P4). ZRL5P4 by itself is sufficient to reactivate EBV from its latent infection. ZRL5P4 is able to emit unique responsive fluorescent signals once it binds with EBNA1 and a Zn2+ ion. ZRL5P4 can selectively disrupt the EBNA1 oligomerization and cause nasopharyngeal carcinoma (NPC) tumor shrinkage, possibly due to EBV lytic induction. Dicer1 seems essential for this lytic reactivation. As can been seen, EBNA1 is likely to maintain NPC cell survival by suppressing viral reactivation

Telbivudine versus lamivudine in patients with chronic hepatitis B

BACKGROUND: Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B. METHODS: In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log 10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses. RESULTS: At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P = 0.005) or a histologic response (64.7% vs. 56.3%, P = 0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265.) Copyright © 2007 Massachusetts Medical Society.published_or_final_versio

A Large Population Histology Study Showing the Lack of Association between ALT Elevation and Significant Fibrosis in Chronic Hepatitis B

OBJECTIVE: We determined the association between various clinical parameters and significant liver injury in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. METHODS: From 1994 to 2008, liver biopsy was performed on 319 treatment-naive CHB patients. Histologic assessment was based on the Knodell histologic activity index for necroinflammation and the Ishak fibrosis staging for fibrosis. RESULTS: 211 HBeAg-positive and 108 HBeAg-negative patients were recruited, with a median age of 31 and 46 years respectively. 9 out of 40 (22.5%) HBeAg-positive patients with normal ALT had significant histologic abnormalities (necroinflammation grading >/= 7 or fibrosis score >/= 3). There was a significant difference in fibrosis scores among HBeAg-positive patients with an ALT level within the Prati criteria (30 U/L for men, 19 U/L for women) and patients with a normal ALT but exceeding the Prati criteria (p = 0.024). Age, aspartate aminotransferase and platelet count were independent predictors of significant fibrosis in HBeAg-positive patients with an elevated ALT by multivariate analysis (p = 0.007, 0.047 and 0.045 respectively). HBV DNA and platelet count were predictors of significant fibrosis in HBeAg-negative disease (p = 0.020 and 0.015 respectively). An elevated ALT was not predictive of significant fibrosis for HBeAg-positive (p = 0.345) and -negative (p = 0.544) disease. There was no significant difference in fibrosis staging among ALT 1-2 x upper limit of normal (ULN) and > x 2 ULN for both HBeAg-positive (p = 0.098) and -negative (p = 0.838) disease. CONCLUSION: An elevated ALT does not accurately predict significant liver injury. Decisions on commencing antiviral therapy should not be heavily based on a particular ALT threshold.published_or_final_versio

Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review

Retrospective comparison between a regular and a split-dose protocol of 5-fluorouracil, cisplatin, and mitoxantrone for the treatment of far advanced hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>In patients with advanced hepatocellular carcinoma (HCC), combination chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone (FMP) could achieve a response rate > 20%, but the beneficial effect was compromised by formidable adverse events. Chemotherapy given in a split-dose manner was associated with reduced toxicities. In this retrospective study, we compared the efficacies and side effects between a regular and a split-dose FMP protocol approved in our medical center.</p> <p>Methods</p> <p>From 2005 to 2008, the clinical data of 84 patients with far advanced HCC, who had either main portal vein thrombosis and/or extrahepatic metastasis, were reviewed. Of them, 65 were treated by either regular (n = 27) or split-dose (n = 38) FMP and had completed at least one therapeutic course. The remaining 19 patients were untreated. Clinical parameters, therapeutic responses, survivals and adverse events were compared.</p> <p>Results</p> <p>The median overall survival was 6.0, 5.2, and 1.5 months, respectively, in patients receiving regular FMP, split-dose FMP, and no treatment (regular versus split-dose group, P = 0.447; regular or split-dose versus untreated group; P < 0.0001). Patients receiving split-dose treatment had a significantly lower risk of grade 3/4 neutropenia (51.9 versus 10.5%, P = 0.0005). When the two treated groups were combined, the median overall survival was 10.6 and 3.8 months respectively for patients achieving disease control and progressive disease (P < 0.001). Cox proportion hazard model identified Child-Pugh stage B (hazard ratio [HR], 2.216; P = 0.006), presence of extrahepatic metastasis (HR, 0.574; P = 0.048), and achievement of disease control (HR, 0.228; P < 0.001) as independent factors associated with overall survival. Logistic regression analysis revealed that anti-hepatitis C virus antibody (odds ratio [OR], 9.219; P = 0.002) tumor size (OR, 0.816; P = 0.036), and previous anti-cancer therapy (OR, 0.195; P = 0.017) were significantly associated with successful disease control.</p> <p>Conclusions</p> <p>Comparable overall survival was observed between patients receiving regular and split-dose FMP therapies. Patients receiving split-dose therapy had a significantly lower risk of grade 3/4 neutropenia. Positive anti-hepatitis C virus antibody, smaller tumor size, and absence of previous anti-cancer therapy were independent predictors for successful disease control.</p