Ji-Guang Ding

Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model

Summary.  The objective of this study was to determine the predictive value of the model for end‐stage liver disease (MELD) scoring system in patients with acute‐on‐chronic hepatitis B liver failure (ACLF‐HBV), and to establish a new model for predicting the prognosis of ACLF‐HBV. A total of 204 adult patients with ACLF‐HBV were retrospectively recruited between July 1, 2002 and December 31, 2004. The MELD scores were calculated according to the widely accepted formula. The 3‐month mortality was calculated. The validity of the MELD model was determined by means of the concordance (c) statistic. Clinical data and biochemical values were included in the multivariate logistic regression analysis based on which the regression model for predicting prognosis was established. The receiver‐operating characteristic curves were drawn for the MELD scoring system and the new regression model and the areas under the curves (AUC) were compared by the z‐test. The 3‐month mortality rate was 57.8%. The mean MELD score for the patients who died was significantly greater than those who survived beyond 3 months (28.7 vs 22.4, P = 0.003). The concordance (c) statistic (equivalent to the AUC) for the MELD scoring system predicting 3‐month mortality was 0.709 (SE = 0.036, P < 0.001, 95% confidence interval 0.638–0.780). The independent factors predicting prognosis were hepatorenal syndrome (P < 0.001), liver cirrhosis (P = 0.009), HBeAg (P = 0.013), albumin (P = 0.028) and prothrombin activity (P = 0.011) as identified in multivariate logistic regression analysis. The regression model that was constructed by the logistic regression analysis produced a greater prognostic value (c = 0.891) than the MELD scoring system (z = 4.333, P < 0.001). The MELD scoring system is a promising and useful predictor for 3‐month mortality of ACLF‐HBV patients. Hepatorenal syndrome, liver cirrhosis, HBeAg, albumin and prothrombin activity are independent factors affecting the 3‐month mortality. The newly established logistic regression model appears to be superior to the MELD scoring system in predicting 3‐month mortality in patients with ACLF‐HBV.

Retrospective analysis of nosocomial infections in the intensive care unit of a tertiary hospital in China during 2003 and 2007

BackgroundNosocomial infections are a major threat to patients in the intensive care unit (ICU). Limited data exist on the epidemiology of ICU-acquired infections in China. This retrospective study was carried out to determine the current status of nosocomial infection in China.MethodsA retrospective review of nococomial infections in the ICU of a tertiary hospital in East China between 2003 and 2007 was performed. Nosocomial infections were defined according to the definitions of Centers for Disease Control and Prevention. The overall patient nosocomial infection rate, the incidence density rate of nosocomial infections, the excess length of stay, and distribution of nosocomial infection sites were determined. Then, pathogen and antimicrobial susceptibility profiles were further investigated.ResultsAmong 1980 patients admitted over the period of time, the overall patient nosocomial infection rate was 26.8% or 51.0 per 1000 patient days., Lower respiratory tract infections (LRTI) accounted for most of the infections (68.4%), followed by urinary tract infections (UTI, 15.9%), bloodstream (BSI, 5.9%), and gastrointestinal tract (GI, 2.5%) infections. There was no significant change in LRTI, UTI and BSI infection rates during the 5 years. However, GI rate was significantly decreased from 5.5% in 2003 to 0.4% in 2007. In addition, A. baumannii, C. albicans and S. epidermidis were the most frequent pathogens isolated in patients with LRTIs, UTIs and BSIs, respectively. The rates of isolates resistant to commonly used antibiotics ranged from 24.0% to 93.1%.ConclusionThere was a high and relatively stable rate of nosocomial infections in the ICU of a tertiary hospital in China through year 2003–2007, with some differences in the distribution of the infection sites, and pathogen and antibiotic susceptibility profiles from those reported from the Western countries. Guidelines for surveillance and prevention of nosocomial infections must be implemented in order to reduce the rate.

Multifocal skeletal tuberculosis: experience in diagnosis and treatment.

OBJECTIVES Multifocal skeletal tuberculosis (MSTB) is an uncommon presentation of skeletal tuberculosis. In order to provide more clinically meaningful information on the diagnosis and management of MSTB, we present a case of MSTB with multiple tuberculous lesions in multiple locations, along with a review of 13 MSTB cases from different studies. PATIENTS AND METHODS A 29-year-old male patient with a one-year history of back pain was initially diagnosed with ankylosing spondylitis and arthritis deformans, and received treatment with oral glucocorticosteroid and leflunomide for 24 weeks. The back pain worsened with weight loss and fever one month prior to admission to our hospital. The diagnosis, MSTB, with 26 tuberculous lesions in 19 locations, was made by clinical findings, bone scan (computed topography and Tc-99m HDP scintigraphy), and bone marrow smear. RESULT Multiple antituberculous drugs, with supportive and immune-enhancing therapies cured the patient. CONCLUSIONS This case indicates that MSTB may develop in patients on long-term immunosuppressive drugs. In addition, our experience, along with previously reported data, suggest that strong clinical suspicion is required for an early diagnosis of MSTB, and chemotherapy, combined with supportive and immune-based therapies is effective for the treatment of MSTB.

Resveratrol attenuates the progress of liver fibrosis via the Akt/nuclear factor-κB pathways

Liver fibrosis is a wound-healing response to chronic liver injury that results in the accumulation of extracellular matrix proteins. It eventually leads to cirrhosis of the liver and liver failure, and it is a critical threat to the health and lives of patients with chronic liver diseases. No effective treatment is currently available. Resveratrol is a polyphenol with antioxidant, anti‑cancer and anti‑inflammatory properties. It has been reported that resveratrol prevents liver fibrosis, possibly by inhibiting NF‑κB activation. The present study investigated the mechanisms by which resveratrol prevented liver fibrosis, focusing on the possible involvement of the NF‑κB pathway. Mice with carbon tetrachloride (CCl4)‑induced liver fibrosis were treated with various concentrations of resveratrol. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and tumor necrosis factor (TNF)‑α were detected by ELISAs. Expression of α‑smooth muscle actin (α‑SMA), collagen I, inhibitor of NF‑κB (IκB) and NF‑κB were detected by western blot analysis. In addition, the present study examined the effects of resveratrol on the expression of fibrosis markers in LX‑2 cells. Western blot analysis was further used to detect the levels of Akt and phosphorylated Akt, as well as the nuclear levels of IκB, phosphorylated IκB and NF‑κB p65. The expression of α‑SMA in resveratrol‑treated LX‑2 cells was detected by immunofluorescence and flow cytometry, which demonstrated that resveratrol decreased the expression of α‑SMA in LX‑2 cells. Resveratrol also decreased CCl4‑induced upregulation of serum AST, ALT, TNF‑α, α‑SMA and collagen I. Finally, resveratrol prevented the activation of NF‑κB and Akt. The results of the present study therefore indicated that resveratrol attenuates liver fibrosis via the Akt/NF-κB pathways.

Targeting transforming growth factor βRII expression inhibits the activation of hepatic stellate cells and reduces collagen synthesis

Abnormal production of extracellular matrix (ECM) components significantly contributes to the development of liver fibrosis. This study aimed at examining the effects of short-hairpin RNA (shRNA)-mediated transient knockdown of transforming growth factor βRII (TGFβRII) expression on the proliferation and activation of hepatic stellate cells (HSCs) and synthesis of fibrogenic ECM components in HSC cells. Three different shRNA-expressing plasmids were constructed for the expression of shRNA-(a, b, c) targeting to the rat TGFβRII mRNA beginning at nucleotide position 339, 444 and 528 and they were transfected into a rat stellate cell line, HSC-T6 cells, respectively. The levels of TGFβRII, α-smooth muscle actin (α-SMA), and type I and III collagen expressions were characterized by reverse transcription polymerase chain reaction and Western blot assays. The concentrations of hyaluronic acid (HA) and type IV collagen in the supernatants of cultured cells were measured by enzyme-linked immunosorbent assay. Transfection with the TGFβRII-specific shRNAs resulted in varying levels of inhibition in the expression of TGFβRII in HSC-T6 cells, and transfection with the potent shRNA-c inhibited the expression of TGFβRII in a dose-dependent manner. Knockdown of TGFβRII expression significantly reduced the levels of α-SMA, type I, III and IV collagen, and HA expression in HSC-T6 cells (P < 0.01). In conclusion, our data indicated that knockdown of TGFβRII expression inhibited the activation of HSCs and the production of fibrogenic ECM components in HSC-T6 cells. Therefore, our findings support the notion that TGFβRII is an important factor of the pathogenic process of liver fibrosis.

Efficacy and safety of recombinant Mycobacterium tuberculosis ESAT-6 protein for diagnosis of pulmonary tuberculosis: A phase II trial

Background This study aimed to determine the efficacy and safety of recombinant Mycobacterium tuberculosis ESAT-6 protein for diagnosis of pulmonary tuberculosis (TB). Material/Methods A phase II trial was performed in 158 patients with pulmonary TB (145 initially-treated and 13 re-treated) and 133 healthy subjects. Skin testing was carried out by injecting purified protein derivative (PPD) (on left forearm) or recombinant ESAT-6 protein at a dosage of 2, 5, or 10 μg/mL (on the right forearm) in each subject. Reaction activity and adverse events were monitored at 24, 48, and 72 h following the injection. Receiver operating characteristic curves were plotted to determine the areas under the curves (AUCs) and the cut-off induration diameters for the optimal diagnostic performance. Results The reaction activity was significantly increased upon recombinant ESAT-6 injection in pulmonary TB patients compared with healthy subjects. In pulmonary TB patients, the reaction was dose-dependent, and at 48 h, 10 μg/mL recombinant ESAT-6 produced a reaction similar to that produced by PPD. The AUCs for a 10 μg/mL dosage were 0.9823, 0.9552, and 0.9266 for 24 h, 48 h, and 72 h, respectively, and the induration diameters of 4.5–5.5 mm were the optimal trade-off values between true positive rates and false positive rates. No serious adverse events occurred in any subjects. Conclusions Recombinant ESAT-6 protein is efficacious and safe for diagnosing pulmonary TB. Based on the reaction, performance, safety, and practicability, we recommend that 10 μg/mL at 48 h with an induration cut-off value of 5.0 mm be used.

New role and molecular mechanism of Gadd45a in hepatic fibrosis

AIM To investigate the role of Gadd45a in hepatic fibrosis and the transforming growth factor (TGF)-β/Smad signaling pathway. METHODS Wild-type male BALB/c mice were treated with CCl4 to induce a model of chronic liver injury. Hepatic stellate cells (HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs (siRNAs) targeting Gadd45a or the pcDNA3.1-Gadd45a recombinant plasmid. Cellular α-smooth muscle actin (α-SMA), β-actin, type I collagen, phospho-Smad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The mRNA levels of α-SMA, β-actin, and type I collagen were determined by quantitative real-time (qRT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses. RESULTS Significant downregulation of Gadd45a, but not Gadd45b or Gadd45g, accompanied by activation of the TGF-β/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl4 treatment. Overexpression of Gadd45a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient knockdown of Gadd45a with siRNA reversed this process. Gadd45a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA)9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes. CONCLUSION Gadd45a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β/Smad signaling.

Combination lamivudine and adefovir versus entecavir for the treatment of naive chronic hepatitis B patients: a pilot study.

Background The aim of this study was to compare the effect of combination lamivudine (LAM) and adefovir dipivoxil (ADV) versus entecavir (ETV) monotherapy for naïve HBeAg-positive chronic hepatitis B (CHB) patients. Material/Methods Fifty enrolled patients with CHB were evenly divided into 2 groups: a group treated with of lamivudine (LAM) (100 mg/day) plus adefovir (ADV) (10 mg/day) combination, and a group treated with entecavir (ETV) (0.5 mg/day). Serum levels of ALT, AST, creatinine, bilirubin, HBsAg, HBeAg and HBV viral load, and genotypic resistance were analyzed at 0, 12, 24, 52, and 104 weeks. HBV DNA levels were determined by real-time PCR and HBsAg and HBeAg by chemiluminescence. Serum levels of ALT, AST, creatinine, and bilirubin were measured by an automatic biochemical analyzer. Data analysis was performed with SPSS 12.0 software. Results There were no significant differences in the virological response (VR) rates between LAM+ADV and ETV cohorts at 24, 52, and 104 weeks (P>0.05). The HBeAg seroconversion rates were 28% and 20%, and the biochemical response (BR) rates were 88% and 84% at week 104 in the LAM+ADV and ETV groups, respectively. The rates of undetectable HBV DNA, HBeAg seroconversion, and ALT normalization rates were similar in both cohorts. No virological breakthrough or serious adverse effects were noted for any patient during the study period. Conclusions Both LAM + ADV combination therapy and ETV monotherapy were effective and safe in the treatment of naïve HBeAg-positive CHB patients. However, further studies are needed to obtain long-term results.

Antiproliferation effect of the uremic toxin para‑cresol on endothelial progenitor cells is related to its antioxidant activity

Endothelial dysfunction and impaired endothelial regenerative capacity are key contributors to the high incidence of cardiovascular disease in patients with chronic kidney disease (CKD). Uremic toxins are associated with this pathogenesis. Previous studies have revealed that a uremic toxin, para-cresol (p-cresol), exerts an antiproliferation effect on human endothelial progenitor cells (EPCs), but the mechanism remains unclear. In the present study, reactive oxygen species (ROS) were confirmed to function as signaling molecules that regulate growth factor-dependent EPC proliferation. EPCs were treated with p-cresol for 72 h, using a concentration range typically found in CKD patients. ROS production was analyzed by fluorescence microscopy and flow cytometry, and protein expression levels of nicotinamide adenine dinucleotide phosphate oxidase, a major source of ROS, were analyzed by western blot analysis. mRNA expression levels of antioxidant genes were assessed by reverse transcription-quantitative polymerase chain reaction analysis. The results revealed that p-cresol partially inhibits ROS production, and this effect may be associated with a significant reduction in cytochrome b-245 alpha and beta chain expression in EPCs. An increase of glutathione peroxidase 4 mRNA expression was also detected. In conclusion, the present study revealed that the antiproliferation effect of p-cresol on EPCs might act via its antioxidant activity. The results of the present study may facilitate understanding of uremic toxin toxicity on the cardiovascular system.