Predictors of portal vein thrombosis after splenectomy in patients with cirrhosis.

BACKGROUND: Portal vein thrombosis (PVT) is a commonthsn complication after splenectomy in patients with cirrhosis. However, the predictors of postoperative PVT are not known. AIM: To investigate the predictors of PVT after splenectomy in patient with cirrhosis. METHODS: A total of 45 patients with cirrhosis who underwent splenectomy were consecutively enrolled from January 2017 to December 2018. The incidence of PVT at 1 months, 3 months, and 12 months after splenectomy in patients with cirrhosis was observed. The hematological indicators, biochemical and coagulation parameters, and imaging features were recorded at baseline and at each observation point. The univariable, multivariable, receiver operating characteristic curve and time-dependent curve analyses were performed. RESULTS: The cumulative incidence of PVT was 40.0%, 46.6%, and 48.9% at 1 months, 3 months, and 12 months after splenectomy. Multivariable analysis showed that portal vein diameter (PVD) ≥ 14.5 mm and monthsdel end-stage liver disease (MELD) score > 10 were independent predictors of PVT at 1 months, 3 months, and 12 months after splenectomy (P < 0.05). Time-dependent curve showed that the cumulative incidence of PVT was significantly different between patients with MELD score ≤ 10 and > 10 (P < 0.05). In addition, the cumulative incidence of PVT in the PVD ≥ 14.5 mm group was significantly higher than that in the PVD < 14.5 mm group (P < 0.05). CONCLUSION: Wider PVD and MELD score > 10 were independent predictors of PVT at 1 months, 3 months, and 12 months after splenectomy in patient with cirrhosis.

Ferritinophagy: A new idea for liver diseases regulated by ferroptosis.

BACKGROUND: The discovery of regulatory cell death has led to a breakthrough in the therapeutic field. Various forms of cell death, such as necrosis, apoptosis, pyroptosis, autophagy, and ferroptosis, play an important role in the development of liver diseases. In general, more than one form of cell death pathways is responsible for the disease state. Therefore, it is particularly important to study the regulation and interaction of various cell death forms in liver diseases. DATA SOURCES: We performed a PubMed search up to November 2022 with the following keywords: ferritinophagy, ferroptosis, and liver disease. We also used terms such as signal path, inducer, and inhibitor to supplement the query results. RESULTS: This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases. CONCLUSIONS: Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.

Nurses' Burnout, Resilience, and Its Associated Factors in Sichuan, China, During the Peak of Coronavirus Disease 2019 Infection.

AIM: To investigate the level of burnout and resilience, and the associated factors when the coronavirus disease 2019 infection hit a peak in the community in Sichuan, China. METHOD: This was a descriptive cross-sectional design study. Data were collected from 25 to 31 December 2022, at six hospitals in Sichuan province. Using convenience sampling, a total of 717 participants were recruited, using the revised version of the Maslach Burnout InventoryGeneral Survey, and the Resilience Assessment Scale for healthcare workers. RESULTS: More than half of nurses reported a moderate level of emotional exhaustion (66.50%, n = 484), cynicism (68.20%, n = 489), and personal accomplishment (68.76%, n = 493); nearly one-third and one-fourth of nurses experienced a high level of emotional exhaustion (27.48%, n = 197) and cynicism (20.78%, n = 149), respectively. In resilience, the highest scoring dimension was interpersonal connectedness, followed by decisional coping, flexible self-adaptation, and rational thinking. Satisfaction with work income, patient-nurse conflict, frequency of overtime work, age, and marital status were significant factors influencing burnout among nurses (p < .05). CONCLUSION: The findings of the study enlighten nursing administrators on the level of burnout and resilience and associated factors among nurses during the peak of coronavirus disease 2019 infection in China. This would be of immense help in planning a welfare program to support the nurses.

Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice: A case report.

BACKGROUND: The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis (HS), and to broaden the diagnostic thoughts of physicians for patients with jaundice. CASE SUMMARY: A 28-year-old male presented with jaundice, bile duct stone, and splenomegaly, but without anemia. Other causes of jaundice were excluded, and gene sequencing revealed a novel heterozygous variant of c.1801C>T (p.Q601X) in exon 14 of the SPTB (NM_01355436) gene on chromosome 14 (chr14: 65260580) in the patient's blood; the biological parents and child of the patient did not have similar variants. A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery. Thus, a novel gene variant causing HS was identified. This variant may result in the truncation of ß-hemoglobin in the erythrocyte membrane, leading to loss of normal function, jaundice, and hemolytic anemia. The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease, which caused challenges for diagnosis by the clinicians. CONCLUSION: Following a definitive diagnosis, genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.

The disaster resilience trajectory of the first batch front-line nurses at fighting the Novel Coronavirus Disease 2019 in Wuhan: A qualitative study.

Aim: It is widely accepted that resilience is an essential solution to the challenges caused by disasters or crisis. The resilient individual can actively cope with challenges and maintain a good performance in facing of disastrous events. After the outbreak of Novel Coronavirus Disease 2019 (COVID-19) in Wuhan, China, numerous researchers have engaged in studying the experiences of front-line nurses in Wuhan from different perspectives. However, little is known on how the first batch front-line nurses developed their resilience trajectories during the disastrous events. The purpose of the present study is to explore the disaster resilience trajectory of the first batch front-line nurses at the early-stage of COVID-19 outbreak in Wuhan, Hubei province. Method: Qualitative research method was employed using purposive sampling. Nurses from Sichuan who had anti-epidemic experiences in Wuhan were selected to be conducted in-depth phone interviews. The interviews were transcribed verbatim, and data was analysed by adopting Colaizzi phenomenological approach. Results: Three theme categories emerged through the data analysis: (1) Challenges and difficulties; (2) Overcoming difficulties; (3) and Personal growth. Conclusion: Nurses have accumulated relevant experiences in dealing with sudden public health events after the rescue task, which can provide psychological and material supports for coping with similar situation in the future. Additionally, multiple support systems were critical elements for front-line nurses to recover from the disaster. Through uncovering front-line nurses' disaster resilience trajectories, it is significant for health care organizations and managers to establish more comprehensive system in handling with public health emergency events.

Role of annexin A family in tumorigenesis and chemoresistance of gastric cancer.

Gastric cancer (GC) is one of the most common cancer types and the fourth leading cause of cancer-related mortality among all malignant tumors worldwide. Due to insidious onset and lack of reliable early diagnostic markers, most GC patients are at an advanced stage at the time of diagnosis. Annexin is an evolutionally-conserved Ca2+-dependent phospholipid-binding protein superfamily, including five members (A, B, C, D, and E). Annexins in the cells of vertebrates comprised the annexin A family, consisting of 12 members in humans. The biological functions of annexin A are Ca2+-signal transduction, vesicle transport, cell proliferation, cell division, cell apoptosis, signal transduction, anti-inflammatory, proangiogenesis, and anticoagulation, most of which overlap with the basic characteristics of tumors. Accumulating evidence indicated that members of the annexin A family are correlated with tumorigenesis and chemoresistance and can be used as potential tumor prognostic factors and targets for biological therapy. Thus, the current review focused on the role and relative mechanisms of the annexin A family in GC.

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury.

BACKGROUND: Sphingolipids produce pleiotropic signaling pathways, and participate in the pathological mechanism of hepatocyte apoptosis and necrosis during liver injury. However, the role of glucosylceramide synthase (GCS)-key enzyme that catalyzes the first glycosylation step, in liver injury is still vague. METHODS: All experiments were conducted using 7-9-week-old pathogen-free male C57BL/6 mice. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected in murine models of liver disease, in addition to histological characterization of liver injuries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of the GCS, matrix metallopeptidase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes. The GCS was observed through a fluorescence microscope, and the flow cytometry was used to detect hepatocyte apoptosis. The concentrations of serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immune-sorbent assay (ELISA) kit. MMP-1 and TIMP-1 protein expression was measured via western blot (WB) analysis. RESULTS: Con A is often used as a mitogen to activate T lymphocytes and promote mitosis. A single dose of Con A injected intravenously will cause a rapid increase of ALT and AST, which is accompanied by the release of cytokines that cause injury and necrosis of hepatocytes. In this study, we successfully induced acute immune hepatitis in mice by Con A. Con A administration resulted in GCS upregulation in liver tissues. Moreover, the mice in the Con A group had significantly higher levels of ALT, AST, IL-4, IL-6, IL-10 and increased hepatocyte apoptosis than the control group. In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 (i.e., a glucosylceramide synthase inhibitor) to inhibit the GCS gene. Additionally, the histopathological changes observed herein were consistent with our ALT, AST, IL-4, IL-6, and IL-10 expression results. However, unlike this, hepatocyte apoptosis has been further increased on the basis of the Con A group. Moreover, our qRT-PCR and WB results indicated that the expression of MMP-1 in the Con A group was significantly lower than that in the control group, whereas TIMP-1 exhibited the opposite trend. Conversely, MMP-1 expression in the GCS siRNA and Genz-123346 groups was higher than that in the Con A group, whereas TIMP-1 expression was lower. CONCLUSIONS: GCS inhibition reduces Con A-induced immune-mediated liver injury in mice, which may be due to the involvement of GCS in the hepatocyte repair process after injury.

Invariant natural killer T cells: Not to be ignored in liver disease.

The liver is an important immune organ. Hepatocellular injury can be caused by many factors, which further leads to chronic liver diseases by activating the immune system. Multiple immune cells, such as T lymphocytes, B lymphocytes, natural killer cells (NKs), natural killer T cells (NKTs), and γδT cells, accumulate and participate in the immune regulation of the liver. NKTs are an indispensable component of immune cells in the liver, and invariant natural killer T cells (iNKTs) are the main subpopulation of NKTs. iNKTs activated by glycolipid antigen presented on CD1d secrete a series of cytokines and also act on other immune cells through cell-to-cell contact. Studies on the relationship between iNKTs and liver immunity have provided clues to uncover the pathogenesis of liver diseases and develop a promising strategy for the diagnosis and treatment of liver diseases.

The role of glucosylceramide and glucosylceramide synthase in liver disease: from bench to bedside - Review.

The cell membrane, which is lipid-rich, is not only a simple mechanical barrier but also an important and complex component of the cell. It also communicates with the external environment. Sphingomyelin is an important class of phospholipids in the membrane that performs many functions. Interest in sphingomyelin-based liposomes, which are a critical component of cell membranes, have become the focus of intense study in recent years. Through additional research, the function of sphingomyelin and its derivatives in diseases can be gradually elucidated. Sphingomyelin consists of ceramide and its derivatives including ceramide-1-phosphate glucosylceramide and sphingosine-1-phosphate. The metabolism of glucosylceramide is regulated by glucosylceramide synthase (EC: 2.4.1.80) which is the key enzyme in the glycosylation of ceramide. The activity of glucosylceramide synthase directly affects the level of glucosylceramide in cells which in turn affects the function of cells and may eventually lead to diseases. Recently, the relationship between glucosylceramide and its metabolic enzymes, with diseases has become a relatively new area of study. The purpose of this paper is to address the relationship between glucosylceramide, glucosylceramide synthase, and their possible association with liver diseases at the theoretical level.

Total bile acid-to-cholesterol ratio as a novel noninvasive marker for significant liver fibrosis and cirrhosis in patients with non-cholestatic chronic hepatitis B virus infection.

Although serum bile acids and total cholesterol (TC) are closely related to liver cirrhosis, the potential diagnostic value of total bile acid-to-cholesterol ratio (TBA/TC) for liver fibrosis is unclear. The present study aimed to evaluate the value of TBA/TC in the diagnosis of cirrhosis and the relationship between TBA/TC and significant liver fibrosis in chronic hepatitis B virus (HBV) infected patients without cholestasis.667 patients with alkaline phosphatase (ALP) ≤ 1.5 upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≤ 3 ULN were rigorously included in this cross-sectional study. Liver biopsy was performed in 32 patients and METAVIR scoring system was used to evaluate liver fibrosis stage. Liver ultrasound elastography was performed in 138 patients, significant fibrosis was defined as fibrosis ≥ F2. Multiple logistic regression as well as receiver operating characteristic (ROC) curves analyses were performed.Compared to patients with non-cirrhosis, TBA and TBA/TC were significantly higher in cirrhosis while TC was significantly lower (all P < .001). In multivariate analysis, TBA/TC was also independently associated with cirrhosis [odds ratio (OR) = 1.102, 95% confidence interval (CI): 1.085-1.166]. The area under the curve (AUC) of TBA/TC (0.87) was almost equivalent to the aspartate aminotransferase to platelet ratio index (APRI, AUC = 0.84) and fibrosis 4 score (FIB-4, AUC = 0.80), and the optimal cut-off value for TBA/TC to diagnose cirrhosis was 2.70. Among the patients performed liver biopsy, TBA/TC were significantly higher both in significant fibrosis and cirrhosis as well as significantly correlated with fibrosis stage (all P < .001). Furthermore, In patients performed liver ultrasound elastography, TBA/TC was also independently associated with significant fibrosis (OR = 1.040, 95% CI: 1.001-1.078).Assessment of TBA/TC could serve as an additional marker of significant liver fibrosis and cirrhosis in non-cholestatic chronic HBV infection.

Whole-Liver Apparent Diffusion Coefficient Histogram Analysis for the Diagnosis and Staging of Liver Fibrosis.

BACKGROUND: Conventional diffusion-weighted imaging is limited in the quantitative evaluation of liver fibrosis, and whole-liver apparent diffusion coefficient (ADC) histogram analysis might contribute to the diagnosis and staging of liver fibrosis. PURPOSE: To explore the value of whole-liver ADC histogram parameters in the diagnosis and staging of liver fibrosis. STUDY TYPE: Retrospective. POPULATION: Twenty individuals with no liver disease and 86 patients with liver fibrosis, including 30 with chronic viral hepatitis, 29 with autoimmune hepatitis, and 27 with unexplained liver fibrosis patients. FIELD STRENGTH/SEQUENCE: 3.0T/T1 -weighted, T2 -weighted, and diffusion-weighted images. ASSESSMENT: A region of interest (ROI) was drawn in each slice of the diffusion-weighted images. Whole-liver histogram parameters were obtained with dedicated software by accumulating all ROIs. The effectiveness of the parameters in differentiating stage 1 or greater (≥F1), stage 2 or greater (≥F2), and stage 3 or greater (≥F3) liver fibrosis was assessed. STATISTICAL TESTS: Mann-Whitney U-test and receiver operating characteristic curve analysis. RESULTS: Kurtosis, entropy, skewness, mode, and 90th and 75th percentiles exhibited significant differences among the pathological fibrosis stages (P < 0.05). Kurtosis was found to be the most meaningful parameter in differentiating fibrosis stages of the viral hepatitis, autoimmune hepatitis, and unexplained liver fibrosis group (area under the curve) (AUC = 0.793, 0.771, 0.798, respectively). In the combined liver fibrosis group, kurtosis achieved the highest AUC (0.801; 95% confidence interval [CI]: 0.702-0.900; sensitivity: 0.750; specificity: 0.850; positive likelihood ratio: 4.953; negative likelihood ratio: 0.302; positive predictive value: 0.946; negative predictive value: 0.486), with a cutoff value of 1.817, in differentiating fibrosis stage ≥F1. DATA CONCLUSION: Kurtosis, entropy, skewness, mode, and 90th and 75th percentiles may contribute to the diagnosis and staging of liver fibrosis, especially kurtosis. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1745-1754.

Human umbilical cord mesenchymal stem cells inhibit proliferation of hepatic stellate cells in vitro.

The effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on the proliferation of hepatic stellate cells (HSCs) is largely unknown. The purpose of this study was to explore the mechanism of action of hUC­MSCs on the proliferation of HSCs in vitro. The upper and lower double-cell co-culture system was established between hUC­MSCs and HSCs in the experimental group. HSCs were cultured alone as a negative control group. Cell proliferation and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Cell supernatants were harvested to determine the concentration of transforming growth factor-ß1 (TGF-ß1) by ELISA. mRNA and protein of TGF-ß1, Smad3 and Smad7 in HSCs were determined by reverse transcription-polymerase chain reaction and western blotting, respectively. In the co-culture group, the proliferation of HSCs was significantly inhibited compared with the negative control group at 24 and 48 h (p<0.05). Apoptosis of HSCs in the co-culture group increased compared with that in the negative control group, which was more obvious at 48 h (p<0.05). The concentration of TGF-ß1 in the co-culture group was significantly lower than in the HSCs cultured alone (p<0.05). After HSCs were co-cultured with hUC­MSCs for 48 h, expression of TGF-ß1 and Smad3 mRNA and protein was reduced and expression of Smad7 mRNA and protein was increased compared with the negative control group (p<0.05). hUC­MSCs inhibited proliferation of HSCs, possibly through inhibiting TGF-ß1 and Smad3 expression and increasing Smad7 protein expression.

[Distribution of HCV genotypes in Chinese Han population with chronic hepatitis C].

OBJECTIVE: To investigate the distribution of HCV genotypes in Chinese Han population with chronic hepatitis C (CHC). METHODS: This randomized multicenter study included 1 014 CHC patients from 28 hospitals in different regions of China. SPSS 20.0 was applied to analyze the relationship among region, HCV genotype, gender and the replication level of HCV-RNA. RESULTS: HCV 1 genotype (56.80%) was the most common genotype. The majority of CHC patients were of genotype 1, 2, 3, 6 in the order of frequency, except those in southwestern, southern and central China. HCV 1, 2, 3, 6 genotypes were most common among male patients in southern China; among female patients in northern China; among male patients in northern and northwestern China and among male patients in northwestern China, respectively (all P <0.05). There was no statistical significance between different genders in other regions. The high viral load was more common than the low viral load among HCV 1, 2, 3, 6 genotype-infected patients. CONCLUSION: There are different distributions of HCV genotypes among the different regions. In addition, HCV genotypes are correlated with gender and HCV-RNA load.

Bone marrow-derived mesenchymal stem cells inhibit the proliferation of hepatic stellate cells by inhibiting the transforming growth factor ß pathway.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered to be a potential therapy for end-stage liver disease. However, the therapeutic mechanism of BM-MSCs remains unclear. The aim of the current study was to investigate the role of paracrine signaling in BM­MSCs in liver cirrhosis in vitro. Human BM­MSCs and hepatic stellate cells (HSCs) were cultured using a vertical double cell co­culture system. Groups were divided into HSCs alone (control group) and the co­culture system of BM­MSCs with HSCs (experimental group). HSC morphology was observed by inverted phase contrast microscopy. The proliferative capacity of HSCs was measured with the MTT assay and flow cytometry. Hoechst staining was performed to examine the apoptosis of HSCs. Transforming growth factor (TGF)­ß1 and Smad7 mRNA expression were detected by reverse transcription­quantitative polymerase chain reaction and western blotting. BM­MSCs did not inhibit the proliferation of HSCs at 24 h, however significantly inhibited the proliferation of HSCs at 48 and 72 h. BM­MSCs additionally induced the apoptosis of HSCs at 48 h. The concentration of TGF­ß1 in the supernatant at 24 h and 48 h in the co­cultured system was observed to be significantly lower than in the control group (P<0.05). The level of TGF­ß1 mRNA in the experimental group at 48 h was significantly lower than the control group, however Smad7 mRNA levels were significantly greater than in the control group. Additionally, TGF­ß1 protein levels were significantly lower than in the control group, however levels of Smad7 were greater than the control group. It was concluded that BM­MSCs are able to inhibit the proliferation and promote the apoptosis of HSCs. In addition, the mechanism may be associated with inhibition of the TGF-ß1/Smad pathway in HSCs.

Possible factors affecting thyroid dysfunction in hepatitis C virus-infected untreated patients.

The present study investigated the association of thyroid dysfunction (TD) with the distribution of chronic hepatitis C virus (HCV) infection in untreated patients. A total of 1,012 cases of HCV-infected patients were collected from different regions, of which 209 patients demonstrated a type of TD (chronic thyroiditis complicated with hyperthyroidism, chronic thyroiditis complicated with hypothyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, hyperthyroidism, hypothyroidism or chronic thyroiditis). The results showed the existence of geographical differences in the types of TD present with HCV infection. The female patients had a higher incidence of autoimmune-related TD than the male patients. High levels of HCV RNA expression were most common in all HCV-infected patients, regardless of the presence of TD. High and medium expression levels of HCV RNA were more prevalent in the patients with autoimmune-related TD. Relative analysis of the HCV RNA levels showed that the pathogenesis of TD was not correlated with the HCV RNA expression levels; however, it may have been associated with autoimmunity. The HCV-infected patients with TD were most commonly middle-aged, whereas young adults were the largest group of patients with HCV and normal thyroid function. Among all HCV genotypes, type 1b was the most common HCV genotype and type 2 was the second most common. Types 3 and 6 were scarce in this study population. No associations were identified between HCV genotypes and thyroid disease. The data of liver function showed that HCV-infected patients with TD had a higher liver dysfunction rate compared with that of the patients with normal thyroid function. Therefore, liver dysfunction may be associated with thyroid disease. This study supports the potential of individualized treatment for HCV-infected patients.

Correlation between the genetic variations in interleukin 28B and chronic hepatitis C virus genotypes in the Chinese population.

Genetic variations at the interleukin 28B (IL-28B) locus and chronic hepatitis C virus (HCV) genotypes are significant factors in predicting the therapeutic outcome for HCV infection. The present study aimed to determine the geographical distribution of HCV genotypes and single nucleotide polymorphisms (SNPs) associated with IL-28B in Chinese patients infected with HCV. The gene frequencies of 13 types of IL-28B SNPs and HCV genotypes were investigated in 1,014 patients infected with HCV, who were recruited from varying regions of China. The correlation between the SNPs of IL-28B, the HCV genotypes and age, gender and geographical location were investigated. The data revealed geographical differences in age, gender and HCV genotypes in the Chinese HCV patients. HCV genotype 1 was distributed extensively and had a higher incidence compared with other HCV genotypes in all regions, with the exception of South (38%) and Northwest China (45.6%). A gender differences also existed (P<0.01). The distribution of genotype 6 was lower compared with other HCV genotypes in the majority of the regions (P<0.01). In middle­aged patients, the number of male patients was higher than the number of female patients in North and South China, which was the opposite of the results found in the other regions. There were no geographical differences in IL-28B SNPs in Chinese HCV­infected populations. Notably, there were significant differences between HCV genotype 1 and 2 in the genotype percentages of the majority of SNPs (P<0.01). In conclusion, a geographical distribution in HCV genotypes and a correlation between HCV genotypes and IL-28B SNPs have been identified, and indicate that these variants may be associated with spontaneous and treatment-induced HCV clearance.

[Clinical efficacy of various antiviral-based strategies to treat chronic hepatitis patients with positivity for hepatitis B e antigen and rtN236T mutation].

OBJECTIVE: To compare the efficacy and safety of the common antivirals, including adefovir dipivoxil (ADV), pegylated-interferon alpha-2a (peg-IFN) and lamivudine (LAM), used as combination therapies to treat chronic hepatitis B (CHB) patients with positivity for the hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) harboring the ADV-resistance mutation, rtN236T, and to explore the factors associated with curative outcome. METHODS: Sixty-five adult CHB patients (age range: 20-60 years) who were unresponsive to ADV therapy (HBeAg-positive; HBV DNA >or= 10(5) copies/ml), LAM-naive, and tested positive for the rtN236T HBV mutation were enrolled in the study and randomly divided into two treatment groups: Group A (n = 33), who were administered ADV (10 mg/day, orally) plus peg-IFN (180 microg/week, subcutaneous injection) for 48 weeks; and Group B (n = 32 patients), who received the ADV plus LAM (100 mg/day, orally) for 48 weeks followed by continued LAM treatment for an additional 24 weeks. Pre- (baseline), during and post-treatment measurements of HBV viral loads and hepatitis B markers were made by quantitative PCR and electrochemiluminescence assays, respectively. All patients underwent liver biopsies to determine the histological activity index (HAI) and treatment response regarding inflammation and fibrosis stage. The rates of virological response (VR), HBeAg-negativity, HBeAg seroconversion, and alanine aminotransferase (ALT) normalization were calculated, and the significance of differences between groups were assessed by Student's t-test and Chi2 test. RESULTS: There were no significant differences between the two groups in regards to sex, age, or baseline levels of HBV DNA, ALT, and total bilirubin (P > 0.05). At weeks 24 and 48 of treatment and 24 after treatment end, group A showed significantly higher (vs. group B, P < 0.05) rates of reduced HBV DNA viral loads (81.8%, 90.9%, and 75.8% vs. 53.1%, 56.2%, and 59.4%), VR (48.5%, 60.6%, and 42.4% vs. 31.3%, 34.4%, and 31.3%), HBeAg-negativity (39.4%, 60.6%, and 54.5% vs. 12.5%, 37.5%, and 37.5%), HBeAg seroconversion (27.3%, 54.5%, and 48.5% vs. 6.3%, 15.6%, and 18.8%), and ALT normalization (72.7%, 84.8%, and 78.8% vs. 46.9%, 56.3%, and 46.9%). After 48 weeks of treatment, group A showed significantly improved HAI (vs. group B, P < 0.05). With the exception of treatment-related increased creatinine (P < 0.05), group A showed significantly higher rates of adverse reactions; although, none was serious enough to threaten patient safety or necessitate early termination of the treatment regimen. Twenty-four weeks after treatment completion, five patients had HBV viral loads of >or= 2log10 copies/ml and four had < or= 500 copies/ml, and ALT was normalized in 28 patients. The four patients in group A with HBV DNA < or= 500 copies/ml and elevated ALT during treatment did not show HBeAg seroconversion. CONCLUSION: Peg-IFN plus ADV combination therapy produced better outcomes than the ADV plus LAM combination therapy in regards to HBV viral loads, VR rate, HBeAg-negative rate, HBeAg seroconversion rate, ALT normalization rate, and HAI, but was associated with a higher rate of adverse reactions (none of which were severe). Lack of HBeAg seroconversion was associated with higher virus load and ALT levels.

[Inhibition effect of small interfering RNA targeting connective tissue growth factor on liver fibrosis in rats].

OBJECTIVE: To design and synthesize small interfering RNA (siRNA) targeting connective tissue growth factor (CTGF) and to investigate its effect on liver fibrosis. METHODS: The interference sequence of CTGF was designed and synthesized. Rat hepatic fibrosis model was induced by intraperitoneal injection of 40 % CCl4(3 ml/kg). Thirty male rats were randomly divided into 5 groups: in normal control and model groups rats received tail vein injection of normal saline every 3 days for 8 consecutive weeks; in preventive group rats received tail vein injection of CTGF siRNA (0.1 mg/kg) every 3 days for 8 weeks; in 2-w treatment group CTGF siRNA was given for 6 weeks starting from two weeks after CCl4 injection; in 4-w treatment group CTGF siRNA was given for 4 weeks starting 4 weeks after CCl4 injection. The serum and hepatic tissue samples were harvested 3 days after the last CCl4 injection. Hepatic fibrosis indices were measured. Expression of CTGF mRNA and protein in the liver was evaluated by RT-PCR and Western blot, respectively. Fibrosis in rat liver was analyzed by Masson staining. RESULTS: Compared with model group (0.544 0.019), the expression of CTGF mRNA and protein in liver of both preventive(0.105 ± 0.003) and 2-w treatment groups (0.190 ± 0.006) were markedly down-regulated (P<0.05). Inflammation, necrosis and fibrosis in hepatic tissue were significantly attenuated. In addition, the serum ration of liver fibrosis indices was greatly reduced(P<0.05). Compared with preventive and 2-w treatment groups, the expression of CTGF mRNA and protein in liver in 4 weeks of treatment group were up-regulated (P<0.05); inflammation, necrosis and fibrosis in hepatic tissue were relative increased; and the serum concentrations of liver fibrosis indices were relatively higher (P<0.05). CONCLUSION: The highly effective CTGF siRNA has been successfully synthesized, which can inhibit CTGF expression in liver, prevent hepatic fibrosis and its progress in rats.