Developmental Consequences of Prenatal Telbivudine Exposure during the Third Trimester.

Hepatitis B virus (HBV) infection is a global health issue. Mother-to-child transmission (MTCT) is the most prominent route for chronic HBV infection in Asian countries.1 Although standard immunoprophylaxis has been effective in preventing MTCT, a significantly higher rate of MTCT has been observed among mothers with high levels of viremia.2 Tenofovir disoproxil, telbivudine (LdT), and lamivudine, used in third trimester, have been shown to significantly reduce MTCT of HBV for highly viremic mothers.3 Although the efficacy and short-term safety of LdT in preventing MTCT have been demonstrated in several large cohort studies in recent years, fewer data exist on the safety assessment of infants' neurocognitive development after fetal exposure to LdT.4-6 Therefore, we conducted a prospective cohort study to investigate the effect of LdT on infants' neurocognitive development.

Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens.

BACKGROUND & AIMS: Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. METHODS: Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. RESULTS: 420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P > .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. CONCLUSION: NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

Predictors of sustained functional cure in hepatitis B envelope antigen-negative patients achieving hepatitis B surface antigen seroclearance with interferon-alpha-based therapy.

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)-negative CHB patients. In this prospective study, 176 HBeAg-negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3-6 months during the 48-week follow-up. The sustained functional cure was evaluated. After the 48-week follow-up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135-127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824-37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.

Relationship between Phenotypic Changes of Dendritic Cell Subsets and the Onset of Plateau Phase during Intermittent Interferon Therapy in Patients with CHB.

Objective: This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40, CD80, CD83, and CD86. Method: This was a cross-sectional study in which patients were divided into a natural history group (namely NH group), a long-term oral nucleoside analogs treatment group (namely NA group), and a plateau-arriving group (namely P group). The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. Results: In total, 143 patients were enrolled (NH group, n = 49; NA group, n = 47; P group, n = 47). The results demonstrated that CD141/CD1c double negative myeloid dendritic cell (DNmDC)/lymphocytes and monocytes (%) in P group (0.041 [0.024, 0.069]) was significantly lower than that in NH group (0.270 [0.135, 0.407]) and NA group (0.273 [0.150, 0.443]), and CD86 mean fluorescence intensity of DNmDCs in P group (1832.0 [1484.0, 2793.0]) was significantly lower than that in NH group (4316.0 [2958.0, 5169.0]) and NA group (3299.0 [2534.0, 4371.0]), Adjusted P all < 0.001. Conclusion: Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury.

Objective: To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury (DILI) caused by different drugs and their correlation with clinical indicators. Method: The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests (RUCAM) scoring criteria and clinically diagnosed with DILI. Based on Chinese herbal medicine, cardiovascular drugs, non-steroidal anti-inflammatory drugs (NSAIDs), anti-infective drugs, and other drugs, patients were divided into five groups. Cytokines were measured by Luminex technology. Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results: 73 patients were enrolled. Age among five groups was statistically different ( P = 0.032). Alanine aminotransferase (ALT) ( P = 0.033) and aspartate aminotransferase (AST) ( P = 0.007) in NSAIDs group were higher than those in chinese herbal medicine group. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with Chinese herbal medicine (IL-6: P < 0.001; TNF-α: P < 0.001) and cardiovascular medicine (IL-6: P = 0.020; TNF-α: P = 0.001) were lower than those in NSAIDs group. There was a positive correlation between ALT ( r = 0.697, P = 0.025), AST ( r = 0.721, P = 0.019), and IL-6 in NSAIDs group. Conclusion: Older age may be more prone to DILI. Patients with NSAIDs have more severe liver damage in early stages of DILI, TNF-α and IL-6 may partake the inflammatory process of DILI.

[Association study for gene polymorphism of folic acid/homocysteine metabolic pathway and nonsyndromic cleft lip with or without cleft palate in Chinese populations].

OBJECTIVE: To explore the association between 18 candidate genes encoding enzymes on the folate/homocysteine metabolism pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese populations. METHODS: A total of 806 NSCL/P trios were drawn by an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate genes affecting risks to NSCL/P. The transmission disequilibrium test (TDT) was used for deviation from Mendelian expectations for 257 SNPs in 18 folate/homocysteine metabolism-related genes. The interactions between markers in these gene and environmental risk factors were also tested using conditional Logistic regressions. RESULTS: Although four SNPs (rs6428977, rs12060264, rs7730643 and rs4920037) showed nominal significant association with NSCL/P in the TDT on 806 NSCL/P trios (P<0.05), no significant evidence of linkage and association remained in all the SNPs after Bonferroni correction. Similar tests for interactions between genes and maternal smoking, environmental tobacco smoke, alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons. CONCLUSION: Folate/homocysteine metabolism-related genes could not influence the risk of NSCL/P.

[A comparative study on blood pressure, obesity, smoking and alcohol drinking behavior in Chinese twins reared apart and together].

OBJECTIVE: To test the potential feasibility for studies conducted in twins reared apart and together from the Chinese National Twin Registry (CNTR) and to answer the question whether the rearing environment affects chronic disease risk factors. METHODS: The samples were composed of twins from two sub-registries, which included 503 twin pairs in Lishui and 505 twin pairs in Qingdao. RESULTS: There was a big difference in the rates of twins reared apart in different areas (from 0.6% in Qingdao to 5.4% in Lishui). Only nine pairs of dizygotic twins reared apart in Lishui were recruited. The intraclass correlation coefficients for many indices were not significant. Rearing environment might affect diastolic blood pressure and smoking behavior, but it was hard to interpret its impacts in systolic blood pressure, body mass index, waist-hip ratio and drinking behavior. CONCLUSION: The design of twins reared apart is a valuable study and can be conducted in the CNTR, but the current sample size is still a big issue which requires the registry to recruit more twins to support it.

Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius.

Neurons in the ventrolateral medulla (VLM) and in the nucleus tractus solitarius (NTS) play important roles in the regulation of cardiovascular and other autonomic functions. In the present study, we demonstrate an inhibition of brown adipose tissue (BAT) thermogenesis evoked by activation of neurons in the VLM, as well as by neurons in the intermediate NTS, of chloralose/urethane-anesthetized, artificially ventilated rats. Activation of neurons in either rostral VLM or caudal VLM with N-methyl-d-aspartate (12 nmol) reversed the cold-evoked increase in BAT sympathetic nerve activity (SNA), BAT temperature, and end-expired CO(2). Disinhibition of neurons in either VLM or NTS with the GABA(A) receptor antagonist, bicuculline (30 pmol), reversed the increases in BAT SNA, BAT temperature, and end-expired CO(2) that were elicited 1) by cold defense; 2) during the febrile model of nanoinjection of prostaglandin E(2) into the medial preoptic area; 3) by activation of neurons in the dorsomedial hypothalamus or in the rostral raphe pallidus (rRPa); or 4) by the micro-opioid receptor agonist fentanyl. Combined, but not separate, inhibitions of neurons in the VLM and in the NTS, with the GABA(A) receptor agonist, muscimol (120 pmol/site), produced increases in BAT SNA, BAT temperature, and expired CO(2), which were reversed by nanoinjection of glycine (30 nmol) into the rRPa. These findings suggest that VLM and NTS contain neurons whose activation inhibits BAT thermogenesis, that these neurons receive GABAergic inputs that are active under these experimental conditions, and that neurons in both sites contribute to the tonic inhibition of sympathetic premotor neuronal activity in the rRPa that maintains a low level of BAT thermogenesis in normothermic conditions.

[Study of twin-birth on genetic or environmental determinants of male Chinese smoking initiation].

OBJECTIVE: To determine the role of genetic and environmental factors in the onset of smoking in Chinese male twins. METHODS: Retrospective data on initiation and age at onset of smoking, reported by 1,006 adult twin pairs [aged 18 year-old or more, 638 pairs of monozygotic (MZ) twins and 368 pairs of dizygotic (DZ) twins] were analyzed to calculate the heritability of smoking behavior and smoking initiation. RESULTS: Different from western culture, 66.8% of males in this Chinese sample are smokers or have the experience of smoking, but only 0.2% of females do so. In the MZ twins, 88.7% (566/638 pairs) of them are both smokers or have smoking experience or both non-smokers, while the number is 63.6% (234/368 pairs) in the DZ twins. The heritability of smoking in this Chinese twin sample is 69.0%+/-4.1%. The smokers usually started their smoking at the age of 20.4+/-5.3 years old. The correlation coefficient for age at onset of smoking in male MZ twin smokers is 0.393, compared to correlation coefficient 0.860 in male DZ twin smokers. CONCLUSION: The moderate level of heritability shows that genetic factors have influence on smoking choice; when the smokers start their smoking, however, this depends more on individual environmental variation in our Chinese twin sample.

[Correlation of angiotensin-converting enzyme 2 gene polymorphism with antihypertensive effects of benazepril].

OBJECTIVE: To explore the correlation of rs2106809 from angiotensin-converting enzyme 2 gene with antihypertensive effects of benazepril, as well as its interactions with polymorphisms of angiotensinogen(AGT) and angiotensin II type 1 receptor(AGTR1) gene. METHODS: Correlation between rs2106809 and blood pressure reduction was estimated based on a field trail with 1 831 hypertensive patients using benazepril for 2 weeks. Generalized multifactor dimensionality reduction (GMDR) was used to explore the interactions of rs2106809 and 8 single nucleotide polymorphisms (SNPs) of AGTR1 gene and 3 SNPs of AGT gene. RESULTS: rs2106809 was found to be associated with reduction in systolic blood pressure and pulse pressure in women, as well as pulse pressure reduction in men. T allele carriers presented more blood pressure reduction (1.4, 1.3 and 0.9 mmHg/T allele respectively). Gene-gene interactions involving rs2106809 were found in systolic blood pressure reduction of men, and the response to benazepril of non-sensitive genotypes carriers was 8.2 (95% confidence interval: 6.6-9.7) mmHg, lower than that of sensitive genotypes carriers. CONCLUSION: rs2106809 might act as an independent influencing factor or component of gene-gene interaction in blood pressure reducing effects of benazepril.

[Cost-effectiveness of female sex worker interventions by using SEX 2.0 Tool in Dehong prefecture, Yunnan province].

OBJECTIVE: To perform cost-effectiveness analysis of interventions in female sex workers in Dehong prefecture in China, with an aim of providing evidence for rational resource allocation in female sex worker interventions in the future. METHODS: The data of expenses for female sex worker interventions in Dehong from 2005 - 2007 were obtained through questionnaire survey. Meanwhile, the data from baseline survey in 2004, from surveillance of female sex workers from 2005 through 2007 as well as from the special survey on sexual transmission in 2007 were collected. Intervention effectiveness was estimated by using SEX 2.0 Tool recommended by UNAIDS. The cost-effectiveness ratio is calculated as the total cost divided by the number of estimated non-HIV patients due to these interventions. RESULTS: The total cost for female sex worker interventions is 916 400 RMB from 2005 through 2007, and a total of 3297 female sex workers were effectively intervened in these three years. Thus, the actual intervention cost for each female sex worker (unit cost) is 277.9 RMB. If all the intervention work is performed as required, the predicted unit cost for female sex worker intervention would be 500.5 RMB. During the period of 2005 through 2007, 69 female sex workers had been successfully prevented from HIV infection; therefore, the cost-effectiveness ratio is 13 282 RMB. CONCLUSION: Intervention among female sex workers is highly cost-effective.

[Screening of different metabolites in teenage football players after exercise fatigue].

Objective: To investigate the changes of metabolites of teenage football players after exercise-induced fatigue. Methods: Twelve male teenage football players (14～16 yrs) were selected as experimental subjects in this study. And an exercise model including aerobic and anaerobic exercise as one group exercise was established by using power bicycle: completion 6 min 150 W load, 60～65 r/min of riding exercise and 30 s of riding exercise which load was the maximum speed set by the tester's weight. The rest took 1 min in the middle of one group exercise, and repeat 3 times of one group exercise, then rest for 3 min after one group exercise. The maximum oxygen uptake (VO2 max) and average anaerobic power were measured after each group exercise. Their urine samples were collected before and after the whole exercise model, and gas chromatograph-mass spectrometer (GC-MS) was used to detect the differential metabolites. Results: The teenage football players had a significant decrease in anaerobic capacity after fatigue. Compared with pre-exercise, a total of 25 differential metabolites were screened out, of which 3 metabolites were significantly higher and 22 metabolites were markedly lower. The related metabolic pathways of above differential metabolites were classified as glycine-serine-threonine metabolism, tricarboxylic acid cycle, tyrosine metabolism, nitrogen metabolism and glycerophospholipid metabolism, respectively. Conclusion: After exercise-induced fatigue occurs in teenage football players, the body's metabolites: sarcosine, L-allothreonine, creatine, serine, succinic acid, citric acid, 4-hydroxyphenylacetic acid, hydroxylamine, and ethanolamine produce significant changes. The above-mentioned differential metabolites can be used as indicators for teenage football players' exercise-induced fatigue evaluation.

Expression and prognostic significance of THBS1, Cyr61 and CTGF in esophageal squamous cell carcinoma.

BACKGROUND: Thrombospondin1 (THBS1), cystene-rich protein 61 (Cyr61) and connective tissue growth factor (CTGF) are all involved in the transforming growth factor-beta (TGF-beta) signal pathway, which plays an important role in the tumorigenesis. The purpose of this study is to explore the expression and prognostic significance of these proteins in esophageal squamous cell carcinoma (ESCC). METHODS: We used immunohistochemistry and western blotting to examine the expression status of THBS1, Cyr61 and CTGF in ESCC. Correlations of THBS1, Cyr61 and CTGF over-expressions with various clinicopathologic factors were also determined by using the Chi-square test or Fisher's exact probability test. Survival analysis was assessed by the Kaplan-Meier analysis and the log-rank test. Relative risk was evaluated by the multivariate Cox proportional hazards model. RESULTS: THBS1, Cyr61 and CTGF were all over-expressed in ESCC. THBS1 over-expression was significantly associated with TNM stage (P = 0.029) and regional lymph node involvement (P = 0.026). Kaplan-Meier survival analysis showed that over-expression of THBS1, Cyr61 or CTGF was related to poor survival of ESCC patients (P = 0.042, P = 0.020, P = 0.018, respectively). Multivariate Cox analysis demonstrated that Cyr61 and CTGF were independent factors in prognosis of ESCC. CONCLUSION: Cyr61, CTGF and THBS1 were all over-expressed in ESCC and might be new molecular markers to predict the prognosis of ESCC patients.

A genetic epidemiologic study of social support in a Chinese sample.

Accumulated evidence suggests that social support is influenced by genetic and environmental factors. However, there are little data that examine this issue from Asian samples. We reported results from a preliminary study that examined familial effects on social support in a Chinese adult twin sample. We administered a 10-item social support instrument that measures three dimensions of social support (i.e., objective support, subjective support, and utilization of support) developed for the Chinese population. Two hundred forty-two same-sex twin pairs, where both members of the pair completed the personal interview, were included in the final analysis. Structural equation modeling was used to estimate additive genetic (A), shared environmental (C), and nonshared environmental (E) effects on each dimension of social support. Familial factors (A+C) explained 56.63% [95% CI = 45.48-65.72%] and 42.42% [95% CI = 29.93-53.25%] of the total phenotypic variances of subjective support and utilization of support, respectively. For the objective support, genetic effects did not exist, but common environmental effect explained 37.56% [95% CI = 26.17-48.28%] of the total phenotypic variances. Neither gender nor age effects were seen on any dimension of social support. Except for objective support, genetic factors probably influence variation in subjective support and utilization of support. Shared environmental factors may influence all dimensions of social support.

[Current situation and influential factors concerning the sexual transmission of HIV in Dehong prefecture, Yunnan province].

OBJECTIVE: To investigate the current situation of the sexual transmission of HIV in Dehong prefecture, analyze the influential factors, and provide support for drafting pertinent preventive interventions in the future. METHODS: We had analyzed the data of case report from 2005 to 2007, and the prostitutes surveillance data from 2003 to 2007. A special survey was conducted from October 26 to November 7, 2007. Totally 685 people including prostitutes, the clients of prostitutes, people who were HIV positive and their partners, key insiders were interviewed in order to better understand the influential factors related to sexual transmission of HIV. RESULTS: Among 1636 cases reported from January 1 to September 20, 2007, 52% were infected through sexual transmission. Among 586 cases infected through sexual transmission, 40.6% had commercial sexual behavior and 28.6% had unmarried sexual behavior. And the average rate of condom use was below 30%. The prostitutes' surveillance data from 2003 to 2007 showed that the HIV positive rate in prostitutes was 3.3% - 5.5%. The rate of condom use in the last month was 29.4% - 84.4% during commercial sexual activity, but it was 9.5% - 34.8% with fixed sexual partners. Although the rate of HIV and AIDS-related knowledge among prostitutes was 95.0%, there were still many misunderstanding regarding certain aspects of HIV and AIDS awareness. CONCLUSION: Sexual transmission has become one of the main transmission routes of HIV in Dehong prefecture. The main factors involved in the sexual transmission of HIV in Dehong prefecture might include the wide spreading of sexual services, cohabitation among unmarried couples, having multiple partners, casual sexual behavior, and the low rate of condom use.

Association of Cytokines with Alanine Aminotransferase, Hepatitis B Virus Surface Antigen and Hepatitis B Envelope Antigen Levels in Chronic Hepatitis B.

BACKGROUND: Cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to investigate the changes of cytokines concentration and its correlation to alanine aminotransferase (ALT), HBV deoxyribonucleic acid (HBV-DNA), hepatitis B envelope antigen (HBeAg), and HBV surface antigen (HBsAg) in the development of chronic hepatitis B (CHB). METHODS: Thirteen healthy individuals (HI), 30 chronic HBV-infected patients in immune tolerant (IT) phase, and 55 CHB patients were enrolled between August 2015 and May 2017. The peripheral blood samples were collected from all individuals. The levels of interferon (IFN)-α2, interleukin (IL)-10, transforming growth factor (TGF)-ß1, HBV-DNA, HBsAg, and HBeAg and liver function were measured. The quantitative determinations of cytokines levels, including IFN-α2, IL-10, and TGF-ß1 were performed using Luminex multiplex technology. The correlation of cytokines to ALT, HBV-DNA, HBsAg, and HBeAg was analyzed by linear regression analysis. RESULTS: IFN-α2 levels were similar between HI and IT groups (15.35 [5.70, 67.65] pg/ml vs. 15.24 [4.07, 30.73] pg/ml, Z = -0.610, P = 0.542), while it elevated significantly in CHB group (35.29 [15.94, 70.15] pg/ml vs. 15.24 [4.07, 30.73] pg/ml; Z = -2.522, P = 0.012). Compared with HI group (3.73 [2.98, 11.92] pg/ml), IL-10 concentrations in IT group (5.02 [2.98, 10.11] pg/ml), and CHB group (7.48 [3.10, 18.00] pg/ml) slightly increased (χ2 = 2.015, P = 0.365), and there was no significant difference between IT and CHB group (Z = -1.419, P = 0.156). The TGF-ß1 levels among HI (3.59 ± 0.20 pg/ml), IT (3.62 ± 0.55 pg/ml), and CHB groups (3.64 ± 0.30 pg/ml) were similar (χ2 = 2.739, P = 0.254). In all chronic HBV-infected patients (including patients in IT and CHB groups), the elevation of IFN-α2 level was significantly associated with ALT level (ß= 0.389, t = 2.423, P = 0.018), and was also negatively correlated to HBV-DNA load (ß = -0.358, t = -2.308, P = 0.024), HBsAg (ß = -0.359, t = -2.288, P = 0.025), and HBeAg contents (ß = -0.355, t = -2.258, P = 0.027). However, when both ALT level and cytokines were included as independent variable, HBV-DNA load, HBsAg, and HBeAg contents were only correlated to ALT level (ß = -0.459, t = -4.225, P = 0.000; ß = -0.616, t = -6.334, P = 0.000; and ß = -0.290, t = -2.433, P = 0.018; respectively). CONCLUSIONS: IFN-α2 elevation was associated with ALT level in patients with chronic HBV infection. However, in CHB patients, only ALT level was correlated to HBV-DNA, HBsAg and HBeAg contents.

Plasmacytoid Dendritic Cell Function and Cytokine Network Profiles in Patients with Acute or Chronic Hepatitis B Virus Infection.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) and cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to explore the frequency and function of pDC and serum cytokine network profiles in patients with acute or chronic HBV infection. METHODS: The healthy individuals (HI group), hepatitis B envelope antigen (HBeAg)-positive chronic HBV patients in immune tolerance (IT) phase (IT group), HBeAg-positive chronic HBV patients (CHB group), and acute HBV patients (AHB group) were enrolled in this study. The frequency of cluster of differentiation antigen 86 (CD86) + pDC and the counts of CD86 molecular expressed on surface of pDC were tested by flow cytometer. The quantitative determinations of cytokines, including Fms-like tyrosine kinase 3 ligand (Flt-3L), interferon (IFN)-α2, IFN-γ, interleukin (IL)-17A, IL-6, IL-10, transforming growth factor (TGF)-ß1 and TGF-ß2, were performed using Luminex multiplex technology. RESULTS: In this study, there were 13 patients in HI group, 30 in IT group, 50 in CHB group, and 32 in AHB group. Compared with HI group, HBV infected group (including all patients in IT, CHB and AHB groups) had significantly higher counts of CD86 molecular expressed on the surface of pDC (4596.5 ± 896.5 vs. 7097.7 ± 3124.6; P < 0.001). The counts of CD86 molecular expressed on the surface of pDC in CHB group (7739.2 ± 4125.4) was significantly higher than that of IT group (6393.4 ± 1653.6, P = 0.043). Compared with IT group, the profile of cytokines of Flt-3L, IFN-γ, and IL-17A was decreased, IFN-α2 was significantly increased (P = 0.012) in CHB group. The contents of IL-10, TGF-ß1, and TGF-ß2 in AHB group were significantly increased compared with IT and CHB groups (all P < 0.05). CONCLUSIONS: This study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-α2 might involve triggering the immune response from IT to hepatitis active phase in HBV infection. Acute patients mainly presented as down-regulation of the immune response by enhanced IL-10 and TGF-ß.

Quantitation of Plasmacytoid Dendritic Cells in Chronic Hepatitis B Patients with HBeAg Positivity During PEG-IFN and Entecavir Therapy.

Plasmacytoid dendritic cells (pDCs) are crucial for control of chronic hepatitis B (CHB) virus infection. In this study, we evaluated the frequencies of pDCs and expression of functional molecules on pDCs in patients treated with PEG-IFN-α-2a or entecavir (ETV) and investigated changes during treatment. The mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDCs and frequencies of pDCs and CD86+ pDCs in peripheral blood were measured. Compared with baseline, CD86+ pDC% and CD86MFI increased obviously after PEG-IFN-α-2a treatment for 12 and 24 weeks. For patients treated with ETV, only pDC% increased observably after treatment weeks 12 and 24 (P < 0.001) compared with baseline. Hepatitis B surface antigen (HBsAg) decline was significantly associated with elevated CD86+ pDC% (r = 0.348, P = 0.015) during PEG-IFN-α-2a treatment. In the HBsAg response group, CD86+ pDC% and CD86MFI (P < 0.001) increased observably after PEG-IFN-α-2a therapy, whereas only CD86MFI had a statistically significant difference after therapy compared with baseline (12 weeks versus 0 weeks, P = 0.022; 24 weeks versus 0 weeks, P = 0.015) in the HBsAg nonresponse group. CD86+ pDC% between the 2 groups had statistically significant differences at baseline (P = 0.001) and at the treatment time points of 12 and 24 weeks (P < 0.001), respectively. For patients receiving ETV therapy, pDC% increased observably, but CD86+ pDC% decreased significantly (P < 0.001) in the HBV DNA nonresponse group during early treatment with ETV. In CHB patients, HBsAg response in PEG-IFN-α-2a therapy correlated with the increase of CD86+ pDC% and HBV DNA nonresponse in ETV treatment correlated with the decrease of CD86+ pDC%.

Thermogenesis activated by central melanocortin signaling is dependent on neurons in the rostral raphe pallidus (rRPa) area.

The central melanocortin system plays a critical role in regulation of energy balance, including thermogenesis in brown adipose tissue (BAT). Activation of the hypothalamic melanocortin signaling stimulates sympathetically-mediated interscapular BAT (IBAT) thermogenesis. The rostral raphe pallidus (rRPa) and adjacent area have been proposed as the location of sympathetic premotor neurons for the central nervous system (CNS) control of IBAT thermogenesis. To determine if neuronal activity in rRPa area is required for the central melanocortin-induced thermogenesis, we studied the effects of inhibition of the activity of neurons in the rRPa area on the sympathetic nerve activity (SNA) to IBAT evoked by lateral ventricular injection of the melanocortin 3/4 receptor (MC3/4R) agonist, MTII, in urethane-chloralose-anesthetized rats and the effects on O(2) consumption induced by third or fourth ventricular injection of MTII in conscious freely moving mice. Icv injection of MTII (1 nmol) significantly increased rat IBAT SNA (+741% of control). Both third and fourth ventricular injections of MTII (1 nmol) significantly increased O(2) consumption in conscious C57BL/6J mice (45% higher than that of saline control for third ventricular injection and 44% higher than that of saline control for fourth ventricular injection). The increases in IBAT SNA and in O(2) consumption were reversed by inhibition of neurons in the rRPa and adjacent area with microinjections of glycine or muscimol into rRPa. These results suggest that the neurons in the RPa and its immediate vicinity play an essential role in mediating the increase in IBAT thermogenesis induced by activation of central melanocortin signaling.

Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naïve Patients with Chronic Hepatitis B Virus Infection.

BACKGROUND: Estimating the grades of liver inflammation is critical in the determination of antiviral therapy in patients chronically infected with hepatitis B virus (HBV). The aim of this study was to investigate the correlation of serum levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) with the liver inflammation grades in treatment-naïve patients with chronic HBV infection. METHODS: We retrospectively enrolled 584 treatment-naïve HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used for statistical analysis of all relevant data. RESULTS: The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively (Χ2 = 26.00, P < 0.001). The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff, respectively; both antigens tended to decrease as the grade of inflammation increased (Χ2 = 99.68 and Χ2 = 99.23, respectively; both P < 0.001). The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 log S/CO, respectively, l to distinguish minimal grade and other grades of treatment-naïve HBeAg-positive patients with chronic HBV infection. CONCLUSIONS: Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values might help us to distinguish minimal grades and other grades and detect those who do not need antiviral therapy in treatment-naïve HBeAg-positive patients with chronic HBV infection.