Differences in clinical characteristics among 726 patients with Chinese herbal medicine- or Western medicine-induced liver injury.

The differences between Chinese herbal medicine (CHM)- and Western medicine (WM)-induced liver injury have rarely been reported. Our aim was to investigate the clinical features of patients with drug-induced liver injury (DILI) caused by CHM or WM. The medical records of 726 DILI patients were retrospectively collected at Peking University First Hospital from January 1995 through August 2019. The number of inpatients with DILI in our hospital showed an increasing trend over time. The incidence of DILI caused by CHM exhibited a linear trend toward an increase with time (P = .0012). Of the 726 DILI patients, females accounted for 65.8%. There were 353 cases (48.6%) caused by CHM and 225 cases (40.0%) caused by WM. The 3 most common causative CHMs were Polygonum multiflorum (38 cases), Fructus Psoraleae (35 cases), and Epimedium (26 cases). The proportions of female patients, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, total bilirubin (TBIL) levels and antinuclear antibody (ANA) positivity rates among cases caused by CHM were higher than those of cases caused by WM (P < .05). There were more patients with severe cases caused by CHM than with severe cases caused by WM (P < .05). The clinical characteristics of DILI caused by CHM differ from those caused by WM. The incidence of DILI caused by CHM is increasing yearly. The medication time of DILI caused by CHM is longer than that of DILI caused by WM, and the severity is greater. Therefore, it is necessary to scientifically and rationally use traditional CHM and monitor liver function. For DILI caused by CHM, the CHM prescription should be recorded in detail to provide detailed clinical data for scientific research on the liver toxicity of CHM.

Shifting demographics and comorbidity burden in adult Chinese urban patients with chronic hepatitis B, 2013 and 2016.

Chronic hepatitis B demographics and comorbidity data are limited in China. Materials & methods: The China Health Insurance Association claims database from 2013 and 2016 was used to augment the existing data: the proportion of patients aged >45 years increased significantly from 40.3% in 2013 to 49% in 2016 (p < 0.001). Results: Significant increases in multiple comorbidities were observed, including hypertension (9.4-14.5%), hyperlipidemia (4.7-7.0%) and cardiovascular disease (5.7-10%; p < 0.001 for all comparisons). Increases were observed in renal impairment (8.8-10.0%; p < 0.001) and osteoporosis and/or pathologic nontraumatic bone fracture (3.8-7.3%; p < 0.001). Conclusion: Careful selection of treatment options and comorbidity monitoring should be considered when managing adult Chinese patients with chronic hepatitis B.

A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients.

BACKGROUND: Few models to predict antiviral response of peginterferon were used in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients and the prediction efficacy was unsatisfied. Quantitative antibody to hepatitis B core antigen (anti-HBc) is a new predictor of treatment response. We aimed to develop a new model to identify HBeAg-positive Chinese patients who were more likely to respond to peginterferon. METHODS: Data from 140 peginterferon recipients with HBeAg-positive were applied with generalized additive models and multiple logistic regression analysis to develop a baseline scoring system to predict serological response (SR: HBeAg loss and HBeAg seroconversion 24 weeks post-treatment) and combined response (CR: SR plus serum HBV DNA levels <2000 IU/mL 24 weeks post-treatment). RESULTS: Anti-HBc levels, alanine aminotransferase ratio, and HBeAg were retained in the final model. The new model scored from 0 to 3. Among patients with scores of 0, 1, or ≥2, SR was achieved in 6.45% (2/31), 13.21% (7/51), and 55.36% (31/56), respectively, and CR in 3.23% (1/31), 9.43% (5/53), and 25.00% (14/56), respectively. Our model has a higher AUROC for SR comparing to Chan's (Z = 2.77 > 1.96, p < 0.05) and Lampertico's (Z = 2.06 > 1.96, p < 0.05) model. The negative predictive value for SR and CR were both 100% in patients with score 0 and hepatitis B surface antigen ≥20,000 IU/mL at week 12. CONCLUSIONS: Patients with higher scores at baseline were more likely to respond to peginterferon. This new model may predict the treatment response.

Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population.

BACKGROUND: Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI. AIM: To identify SNPs that indicate susceptibility to PM-DILI. METHODS: We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant. RESULTS: The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database. CONCLUSION: rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Deficiency of canonical Wnt/ß-catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease manifested with the aberrant activation of hepatic dendritic cells (HDCs) and the subsequent breakdown of immune homeostasis. As an important player, HDC maintains immunological balance between tolerance to self-antigens versus destruction against pathogens in liver. However, the intracellular signalling networks that program HDC remain unclear. We have now found the role of canonical Wnt/ß-catenin signalling in HDCs. METHODS: Liver sections from AIH patients and healthy subjects were stained for the markers of Wnt/ß-catenin signalling. Concanavalin A (ConA) and HDC/Hepa1-6 vaccine-induced AIH mouse models were examined for liver injury, inflammation and immune cell functions by serum biochemistry, histology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry analysis. Wnt/ß-catenin signalling expression was measured using immunoblot and qRT-PCR. RESULTS: Canonical Wnt/ß-catenin signalling in HDC is deficient in AIH patients and a mouse model, which coincides with the immunogenic function of HDCs. Furthermore, Wnt ligand engagement reactivates Wnt/ß-catenin signalling and recovers the immunoregulatory phenotype of HDCs, in turn alleviating the severity of AIH. Likewise, pharmacologic activation of Wnt/ß-catenin signalling attenuates AIH progression. CONCLUSIONS: We report here that the constitutively active canonical Wnt/ß-catenin signalling confers HDCs tolerogenicity under steady-state conditions. Deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH. It may act as a new pathogenesis and treatment target for AIH.

A human ciliopathy with polycystic ovarian syndrome and multiple subcutaneous cysts: A rare case report.

RATIONALE: Ciliopathies is a group of clinically and genetically overlapping disorders due to cilia abnormalities and multiple organ systems are involved in. PATIENT CONCERNS: We present a young female patient who showed renal function impairment, Caroli syndrome (CS), liver cirrhosis, polycystic ovarian syndrome, and multiple subcutaneous cysts. DIAGNOSES: The patient was diagnosed with ciliopathy according to the clinical manifestations and whole-genome sequencing. INTERVENTIONS: She received treatment of intravenous albumin, polyene phosphatidyl choline, furosemide, and antisterone. OUTCOMES: The patient showed clinical improvement in her edema and liver tests, and ultrasonography revealed that the ascites had disappeared. Unfortunately, the edema relapsed a year later. The patient received the same treatment as before, and there was clinical improvement of the edema. Since the family cannot afford liver and kidney transplantation, the patient only accepted symptomatic treatment. LESSONS: Polycystic ovarian syndrome and multiple subcutaneous cysts have never before been reported to be associated with ciliopathy. This finding could remind doctors to consider the possibility of ciliopathy disease for patients suffering from similar conditions. In addition, the phenotype of the patient differs from those of patients reported with the same mutations, which also reminds doctors that the clinical manifestation of a given mutation may show patient-specific differences. This case report extends the phenotypic spectrum of ciliopathy, and these findings might represent a new ciliopathy syndrome, which could facilitate the diagnosis of ciliopathies.

Gilbert syndrome combined with prolonged jaundice caused by contrast agent: Case report.

This case highlights a patient with Gilbert syndrome who underwent endoscopic retrograde cholangiopancreatography (ERCP) with removal of bile duct stones, who then experienced an unexplained increase in bilirubin, with total bilirubin (TBIL) levels increasing from 159.5 µmol/L to 396.2 µmol/L and to a maximum of 502.8 µmol/L after 9 d. Following the decrease in the TBIL level, enhanced magnetic resonance cholangiopancreatography (MRCP) was performed to exclude any possible remaining choledocholithiasis. Nevertheless, the serum bilirubin level increased again, with TBIL levels rising from 455.7 µmol/L to 594.8 µmol/L and a maximum level of 660.3 µmol/L with no remaining bile duct stones. A liver biopsy showed severe bile duct cholestasis with no inflammation. Based on the exclusion of other potential causes of hyperbilirubinemia and the fact that both instances of increased bilirubin occurred after ERCP and MRCP, the contrast agents iopromide and gadoterate meglumine were suspected to be the causes of the hyperbilirubinemia. As of the writing of this report, the patient's bilirubin levels have spontaneously returned to baseline levels. In summary, ERCP and MRCP utilizing the contrast agents iopromide and gadoterate meglumine may possibly induce prolonged hyperbilirubinemia.

Features and outcomes from a retrospective study of 570 hospitalized Chinese patients with drug-induced liver injury.

AIMS: To investigate the clinical features and outcomes of hospitalized patients with drug-induced liver injury (DILI). METHODS: The medical records of hospitalized patients with DILI from January 1997 through July 2016 were reviewed. RESULTS: Five hundred seventy cases were reviewed, of which 381 (66.8%) were female. Four hundred fifty-eight cases (80.4%) presented with hepatocellular injury, 53 (9.3%) with cholestatic injury and 59 (10.4%) with mixed injury. Chronicity was more common in cholestatic and mixed injury cases than in hepatocellular cases (P<0.001). In the hepatocellular injury group, patients in the severity score≥3 group were younger than the patients in the severity score≤2 group (P=0.040). In the entire cohort, 487/570 (85.4%) patients resolved, 57/570 (10.0%) developed chronic liver injury, and 11/570 (1.9%) died. Thirty-two acute DILI patients with severity scores of 3 received steroid therapy, but no improvement was observed in the recovery time or resolution rate of these patients compared with that of the non-steroid group. Chinese herbal medicines were the most commonly used drugs, followed by antimicrobials, cardiovascular agents, endocrine agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: Hepatocellular injury was the most common DILI pattern, and 10.0% of patients developed chronic DILI. Steroid therapy was not associated with an improved recovery time or survival in acute severe DILI patients.

The Molecular Mechanisms of Ciprofloxacin Resistance in Clinical Campylobacter jejuni and Their Genotyping Characteristics in Beijing, China.

We assessed the susceptibility of 182 Campylobacter jejuni isolates from patients with diarrhea to eight antibiotics and analyzed the molecular mechanisms of ciprofloxacin resistance as well as the genetic characteristics based on multilocus sequence typing (MLST). The C257T mutation was found on the quinolone resistance-determining region (QRDR) of the gyrA gene in all ciprofloxacin-resistant strains. Mutations on the QRDR of the gyrB gene were silent. A total of 74 strains had 7 inverted repeat (IR) (a 16-bp IR on the intergenic region between cmeR and cmeABC) mutation polymorphisms. Compared with strains without the IR mutations, strains with the IR mutations had higher resistance rates to ciprofloxacin (94.6% vs. 83.3%), nalidixic acid (94.6% vs. 83.3%), tetracycline (98.6% vs. 85.2%), doxycycline (91.9% vs. 71.3%), florfenicol (59.5% vs. 17.6%), chloramphenicol (25.7% vs. 4.6%), gentamicin (16.2% vs. 3.7%), and multidrug resistance than those without IR mutations (all p < 0.05). With C257T mutation alone, 89.9% strains with minimum inhibitory concentration (MIC) values focused on 16, 32, and 64 µg/mL, whereas strains with C257T mutation in combination with the IR mutations had a higher ciprofloxacin resistance level with 88.6% MIC values focused on 64, 128, and 512 µg/mL (p < 0.0001). The strains in this study showed a high genetic variability based on MLST with 117 sequence types (STs), 37 of which were novel. CC-21 was the most common clonal complex (CC) followed by CC-353 and CC-45. No association was found between STs and ciprofloxacin resistance. In conclusion, the C257T mutation on gyrA was the major mechanism for ciprofloxacin resistance, and the C257T mutation in combination with the IR mutations might result in more severe ciprofloxacin resistance to C. jejuni.

A seventeen-year observation of the antimicrobial susceptibility of clinical Campylobacter jejuni and the molecular mechanisms of erythromycin-resistant isolates in Beijing, China.

OBJECTIVES: To investigate the dynamic development of the antimicrobial resistance of Campylobacter jejuni isolated from human diarrhea in Beijing, China, between 1994 and 2010, and to further analyze the molecular mechanisms of erythromycin-resistant strains. METHODS: Susceptibility tests were performed on 203 non-duplicate clinical C. jejuni strains against eight common antibiotics using the standard agar dilution method. The molecular determinants were further studied in the erythromycin (ERY) non-susceptible strains. The analysis focused on the 23S rRNA gene, the rplD and rplV ribosomal genes, the ermB gene, and the regulatory region of the CmeABC efflux pump. RESULTS: The rates of resistance of C. jejuni to ciprofloxacin (CIP), nalidixic acid (NAL), doxycycline (DOX), tetracycline (TET), florfenicol (FFC), and chloramphenicol (CHL) increased significantly over the period studied (all p<0.05). Similarly, the proportions of resistant patterns (CIP-NAL-DOX-TET, CIP-NAL-DOX-TET-FFC, and CIP-NAL-DOX-TET-CHL) increased remarkably. In this study, 4.4% (9/203) of C. jejuni strains were ERY non-susceptible. The A2075G mutation in the 23S rRNA was found in all of the resistant strains except cj8091, which harbored the ermB gene. Interestingly, the ermB gene was also detected in intermediately resistant isolates, and the earliest ermB-positive strain cj94473 was derived in 1994. Moreover, none of the ribosomal rplD or rplV genes harbored mutations that have been described to confer resistance to macrolides. Different mutations affecting the regulatory region of the CmeABC efflux pump were also found. CONCLUSIONS: This is the first comprehensive study on the recent trend in antimicrobial resistance and the molecular mechanisms of macrolide resistance in clinical C. jejuni strains isolated in China. More stringent monitoring and regulation of human and animal antimicrobial use are warranted.

Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon.

A recent study revealed that quantitative hepatitis B core antibody (qAnti-HBc) level could serve as a novel marker for predicting treatment response. In the present study, we further investigated the predictive value of qAnti-HBc level in HBeAg-positive patients undergoing PEG-IFN therapy. A total of 140 HBeAg-positive patients who underwent PEG-IFN therapy for 48 weeks and follow-up for 24 weeks were enrolled in this study. Serum samples were taken every 12 weeks post-treatment. The predictive value of the baseline qAnti-HBc level for treatment response was evaluated. Patients were further divided into 2 groups according to the baseline qAnti-HBc level, and the response rate was compared. Additionally, the kinetics of the virological and biochemical parameters were analyzed. Patients who achieved response had a significantly higher baseline qAnti-HBc level (serological response [SR], 4.52±0.36 vs. 4.19±0.58, p=0.001; virological response [VR], 4.53±0.35 vs. 4.22±0.57, p=0.005; combined response [CR], 4.50±0.36 vs. 4.22±0.58, p=0.009)). Baseline qAnti-HBc was the only parameter that was independently correlated with SR (p=0.008), VR (p=0.010) and CR(p=0.019). Patients with baseline qAnti-HBc levels ≥30,000 IU/mL had significantly higher response rates, more HBV DNA suppression, and better hepatitis control in PEG-IFN treatment. In conclusion, qAnti-HBc level may be a novel biomarker for predicting treatment response in HBeAg-positive patients receiving PEG-IFN therapy.

Kinetics and prediction of HBsAg loss during long-term therapy with nucleos(t)ide analogues of different potency in patients with chronic hepatitis B.

BACKGROUND & AIMS: About 350-400 million people are infected with hepatitis B virus (HBV) chronically and 1 million people die of hepatitis B virus (HBV)-related liver diseases. Nucleos(t)ide analogues (NAs) have been used for the treatment against HBV. However, few studies have investigated the long-term effects of different nucleos(t)ide analogues on levels of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB). The aims of this study were to measure the magnitude of HBsAg reduction by long-term monotherapy with adefovir dipivoxil (ADV) and entecavir (ETV), to compare HBsAg reduction between the two drugs of different potency and to predict the expected time needed to achieve HBsAg loss. METHODS: We retrospectively evaluated the kinetics of HBsAg in 67 patients with CHB who all exhibited persistent viral suppression. These patients were treated with ADV or ETV for at least 6 years. HBV genotype was determined at baseline. Liver biochemistry, HBV serological markers, serum HBV DNA and HBsAg titers were determined at baseline, half year and yearly from year 1 to 6. RESULTS: Serum HBsAg titers after treatment with ADV or ETV were significantly lower than the baseline titers (P<0.05). HBsAg reduction rate of patients treated with ETV (0.11 log10 IU/mL/ year) was higher than that treated with ADV (0.10 log10 IU/mL/year), and the calculated expected time to HBsAg loss for patients treated with ETV (approximate 24.99 years) was shorter than that with ADV (approximate 30.33 years), but there was no statistically significant difference between two groups (P>0.05). CONCLUSION: Serum HBsAg titers gradually decreased during long-term treatment with either ADV or ETV. It appears that the potency of ADV on HBsAg reduction is close to that of ETV, as long as patients have achieved persistent viral suppression.

Kinetics of serum HBsAg in Chinese patients with chronic HBV infection with long-term adefovir dipivoxil treatment.

BACKGROUND: Knowledge on Hepatitis B surface antigen (HBsAg) kinetics in chronic hepatitis B (CHB) patients with long-term adefovir dipivoxil (ADV) treatment is limited. The aims of this study were to investigate HBsAg kinetics in patients with chronic hepatitis B virus (HBV) infection treated with long-term ADV and to evaluate different characteristics between patients with and without HBsAg loss. METHODS: We retrospectively evaluated HBsAg kinetics in 24 Chinese patients with chronic HBV infection who achieved continuous virologic suppression during ADV therapy. HBV genotype was determined at baseline. Liver biochemistry, hepatitis B e antigen status, serum HBV DNA, and HBsAg levels were measured at baseline, 6 months, and once every year thereafter. RESULTS: Of these 24 patients, 3, 1, and 20 patients were followed up for 3, 5, and 6 years, respectively. Baseline serum HBsAg level had a moderate correlation with baseline HBV DNA level (r = 0.52, P = 0.01). The median rate of HBsAg reduction during the therapy period was 0.08 lg IU × ml(-1) × y(-1). Baseline serum HBsAg level was significantly higher than other time points (P ranges from 0.046 to 0.002). The HBsAg reduction rate during the first year was similar to that in other years (P > 0.05). The HBsAg reduction rate during the first year in patients with eventual HBsAg loss was significantly faster than that in patients without HBsAg loss (P = 0.005). CONCLUSIONS: Serum HBsAg levels in Chinese CHB patients receiving long-term ADV demonstrated a gradual reduction. Patients with eventual HBsAg loss had a significantly faster HBsAg reduction rate during the first year than those without HBsAg loss.

Management of acute diarrhea in adults in China: a cross-sectional survey.

BACKGROUND: The aim of this study was to evaluate the management of acute adult diarrhea in China and assess adherence of clinical practice to national guidelines and 2012 World Gastroenterology Organization guidelines. METHODS: A cross-sectional survey was carried out among physicians in 20 hospitals in two different areas of China (Beijing, 10; Shaanxi province, 10). Summary statistics were calculated for the overall study group and for each region. Between-region differences were assessed with χ(2) or t-tests. RESULTS: Data were collected for 800 patients (≥18 years; mean ± SD age 37.0 ± 16.3 years; 56.4% female). The mean ± SD time between diarrhea onset and visiting a diarrhea clinic was 2.4 ± 1.6 days; this interval was significantly shorter in Beijing than Shaanxi (2.0 ± 1.4 vs 2.8 ± 1.8 days, respectively; p < 0.001). Overall, 31.4% of patients self-medicated before visiting the clinic, most commonly with antibiotics. Routine stool examinations were ordered for 70.6% of patients, vibrio cholera stool culture for 57.5%, but non-vibrio bacteria stool culture for only 11.4%. Only 61.6% of patients received fluid and electrolyte therapy: 28.3% oral rehydration solution (ORS) and 33.4% intravenous fluids (even though only 13.8% needed). Antibiotics were the most common drugs (60.8%) and the most common antibiotics were fluoroquinolones, followed by aminoglycosides. Totally 51.3% of patients received irrational antibiotic treatment (unnecessary for 47.9%; indicated but not prescribed for 3.4%). After antibiotics, the most commonly prescribed drugs were dioctahedral smectite (59.3%); For Shaanxi compared with Beijing, less individuals received ORS (7.8% vs 48.5%,respectively; p < 0.001) and more received intravenous fluids (46.3% vs 20.5%, respectively; p < 0.001). Significantly more of the patients in Shaanxi province were administered antibiotics (64.5% vs 57%, respectively; p = 0.03), and more received intravenous antibiotics than Beijing (49.0% vs 27.0%, respectively; p < 0.001). CONCLUSIONS: Adherence to both national guidelines and 2012 World Gastroenterology Organization guidelines for the management of acute diarrhea in adult was limited among tertiary hospital physicians. The findings suggest nationwide education and effective health policies are needed to improve medical practice and reduce the unnecessary burden on the healthcare system.

An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.

Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.

Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes.

We investigated clinical features, therapy, and outcomes of patients hospitalized for drug-induced liver injury (DILI). DILI resolution was defined as liver biochemistry values back to normal or lower than CIOMS laboratory criteria; Chronicity was defined as persistent biochemical abnormality for >6 months after drugs' withdrawal. Three-hundred cases were reviewed retrospectively; mean age 51 (13-86) years, and 204 (68 %) were females. It included 267 (89 %) hepatocellular injury, 16 (5.3 %) cholestatic injury, and 17 (5.7 %) mixed injury cases. In hepatocellular injury group, 197 (73.8 %) patients with TBIL < 10× ULN included 142 (72.1 %) females and 70 (26.2 %) patients with TBIL ≥ 10× ULN included 39 (55.7 %) females (P = 0.012). Of 70 patients (TBIL ≥ 10× ULN), 20 were treated with steroid step-down therapy (79 ± 26 days) and others with non-steroid therapy. The steroid therapy group showed higher DILI resolution rate (P = 0.029) and shorter recovery time (P = 0.012). Notably, 274/300 (91.3 %) patients resolved, 18/300 (6 %) developed chronic liver injury, 7/300 (2.3 %) died, and one patient received liver transplantation. In death group, TBIL, ALB, PT, and PTA revealed more severe abnormality than in recovery group. In 121/300 (40.3 %) patients, use of herbal medicines was the leading cause of liver injury, followed by antibiotics, cardiovascular drugs, and endocrine drugs. We concluded that step-down steroid therapy for DILI improved curative effect, shortened disease course, and was safe.

Clinical manifestations of Campylobacter jejuni infection in adolescents and adults, and change in antibiotic resistance of the pathogen over the past 16 years.

BACKGROUND: Campylobacter jejuni infection, traditionally a paediatric illness, is now seen more frequently in adolescents and adults in northern China. Published surveillance reports on C. jejuni infection in these patients are rare. We aimed to characterize (1) the clinical manifestations of this infection in adolescents and adults, and (2) changes in antibiotic resistance of the pathogen. METHODS: We retrospectively examined 492 cases of C. jejuni infection in patients aged ≥ 14 y treated at the Peking University First Hospital, Beijing, China, for the period January 1994 to December 2010. RESULTS: The disease was more common in patients aged 14-24 y and in men (57.9%; p < 0.0001 vs women). The peak incidence was seen between May and October. The infection manifested with acute diarrhoea (< 10 bowel movements per day, loose or mucous stool), fever (mostly low grade), and abdominal cramps and pain. Faecal leukocytes and erythrocytes were demonstrated in, respectively, 90.9% and 79.3% of stool specimens, while leukocytes > 10 per high-power field were detected in 70.3%. In 1994-1998, 44.5% of C. jejuni strains were resistant to fluoroquinolone, 0% to gentamicin, and 0% to cefuroxime; in 2005-2010, resistance increased significantly to 97.9%, 16.7%, and 93.0%, respectively (p < 0.0001). The resistance to erythromycin did not change significantly (3% vs 6.4%, p = 0.4). CONCLUSIONS: Manifestations of C. jejuni infection in adolescent and adult patients are similar to those in children. Over the 16-y study period, resistance of C. jejuni to fluoroquinolones, gentamicin, and cefuroxime significantly increased.

Pegylated interferon α-2b up-regulates specific CD8+ T cells in patients with chronic hepatitis B.

AIM: to investigate the effect of pegylated interferon (IFN) α-2b on specific CD8+ T lymphocytes in patients with chronic hepatitis B (CHB). METHODS: twenty-one patients with CHB were treated with pegylated IFN α-2b. Periphery blood mononuclear cells were isolated from fresh heparinized blood by Ficoll-Hypaque density gradient centrifugation (density: 1.077 g/L, Pharmingen) at weeks 0, 4, 8, 12, and 24, respectively. Frequency of circulating hepatitis B virus (HBV) epitope-specific CD8 T cells was detected by flow cytometry. Cytokines were detected by cytometric bead assay. RESULTS: the frequency of circulating HBV core or env-specific CD8 T cells was higher (P < 0.05), the number of HBV core specific CD8 T cells was greater at week 24 (P < 0.05), the level of Th1-type cytokines [interleukin (IL)-12, tumor necrosis factor-α, and IFN-γ] was higher, while that of Th2-type cytokines (IL-4, IL-6, and IL-10) was lower in responders than in non-responders (P < 0.05) after pegylated IFN α-2b treatment. The IL-6 level was correlated with HBV DNA (r = 0.597, P = 0.04), while the inducible protein-10 (IP-10) level was correlated with serum alanine aminotransferase (ALT) (r = 0.545, P = 0.005). The IP-10 level at week 8 after pegylated IFN α-2b treatment could predict the normalization of ALT in CHB patients (positive predict value = 56%, negative predict value = 92%). CONCLUSION: pegylated IFN α-2b can enhance the immune response of CHB patients by increasing the frequency of HBV specific CD8+ T cells and regulating the Th1/Th2 cytokines.

The clinical and histological characteristics and outcomes of drug induced chronic liver injury after removing causative drugs.

BACKGROUND/AIMS: To investigate characteristics and outcomes of drug induced chronic liver injury after removing causative drugs. METHODOLOGY: Between Apr 2001 and Mar 2010, patients diagnosed as drug induced liver injury and with chronic courses, were observed. Chronic liver injury was defined as persistent biochemical abnormality for more than 6 months after drugs withdrawal. RESULTS: Forty patients were observed with mean age 41 years and female 28 (70%). Of the 40 patients, 32 (80%) cases showed hepatocellular injury at the onset of liver damage, 4 (10%) cases showed cholestatic injury, and 4 (10%) cases showed mixed injury. Of 32 patients with hepatocellular injury, 24 (75%) cases resemble acute icteric hepatitis at the onset of liver damage. Of 27 patients with hepatocellular injury who underwent liver biopsy, 14 (51.9%) cases showed chronic hepatitis with a mean follow up of 17 months. Of total 40 patients, 15 (37.5%) patients resolved; 18 (45%) cases remained persistent liver injury, 4 (10%) cases developed cirrhosis, 3 (7.5%) cases died. Herbs (45.5%) are the commonest drugs implicated in chronic liver injury. CONCLUSIONS: Most cases with drug induced chronic liver injury after removing causative drugs resemble acute icteric hepatitis at the onset of liver damage. Some patients can resolve, some may progress to cirrhosis. Herbs are important drugs for drug induced chronic liver injury.