Enhanced Activation of Memory,but Not Na?ve,B Cells in Chronic Hepatitis C Virus-Infected Patients with Cryoglobulinemia and Advanced Liver Fibrosis

Mixed cryoglobulinemia is the most common extrahepatic disease manifestation of chronic hepatitis C virus (HCV) infection, where immunoglobulins precipitate at low temperatures and cause symptoms such as vasculitis, glomerulonephritis and arthralgia. HCV-associated cryoglobulinemia is also strongly linked with the development of B cell non-Hodgkin lymphoma. Abnormal B cell function in HCV infections can lead to the formation of HCV cryoglobulin complexes that usually comprise monoclonal rheumatoid factor and HCV-specific immune complexes. The aim of this study was to characterize the activation phenotype of B cells from patients with chronic HCV infection in comparison to healthy controls using flow cytometry. In addition, we determined how the activation status varies depending on the presence of cryoglobulinemia and advanced liver fibrosis. We found that only memory B cells, not naïve cells, were significantly activated in chronic HCV infection when compared with healthy controls. We also identified markers of memory B cell activation that were specific for HCV patients with cryoglobulinemia (CD86, CD71, HLA-DR) and advanced liver disease (CD86). Our results demonstrate that HCV infection has differential effects on B cells depending on the severity of hepatic and extrahepatic disease.     

Is Hepatitis B Immunoglobulin Necessary in Prophylaxis of Hepatitis B Recurrence after Liver Transplantation? A Meta-Analysis

Background & Aims

Application of nucleoside analogues and hepatitis B immunoglobulin (HBIG) has reduced hepatitis B virus (HBV) recurrence rate after liver transplantation (LT) dramatically. Recent data suggests therapy without HBIG is also effective. We sought to evaluate the necessity of HBIG in prophylaxis of HBV recurrence after LT.

Methods

A meta-analysis was performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literatures. The major end points were recurrence rate, patient survival, and YMDD mutant. Risk difference (RD) or risk ratio (RR) was calculated to synthesize the results.

Results

Nineteen studies with a total of 1484 patients were included in this analysis. Application of HBIG was helpful to reduce HBV recurrence [P<0.001; RD = 0.16; 95% confidence interval (CI)(0.12, 0.20)] and virus mutants [P<0.001; RR = 3.13; 95%CI (1.86–5.26)], it also improved patients'' 1-year [P = 0.03; RD = 0.08; 95%CI (0.01, 0.15)] and 3-year survival rates [P = 0.005; RD = 0.17; 95%CI(0.05, 0.28)]. No significant difference was found for patients'' 5-year survival [P = 0.46; RD = −0.06; 95%CI (−0.21, 0.10)]. Sub-group analysis showed that in patients with positive pre-operative HBV DNA status, HBIG was necessary to reduce HBV recurrence rate (P<0.001; RD = 0.42; 95%CI (0.32, 0.52)). In patients with negative HBV DNA, combined therapy gained no significant advantages (P = 0.18; RD = 0.06; 95%CI (−0.03, 0.14)). Non-Lamivudine (non-LAM) antiviral drugs performed as well as combination therapy in prophylaxis of HBV recurrence after LT (P = 0.37; RD = 0.06; 95%CI (−0.02, 0.14)).

Conclusions

HBIG with nucleoside analogues is helpful to reduce HBV recurrence and virus mutants. The necessity of HBIG in prophylaxis of HBV recurrence after LT when using new potent nucleoside analogues, especially for patients with negative pre-transplant HBV DNA status remains to be evaluated.     

Serum γ-glutamyl Transferase Levels,Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

Background and Aims

Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.

Methods

843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT.

Results

By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB).

Conclusions

In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.     

Large Variations in Risk of Hepatocellular Carcinoma and Mortality in Treatment Na?ve Hepatitis B Patients: Systematic Review with Meta-Analyses

Background

The complications to chronic hepatitis B (HBV) include incidence of hepatocellular carcinoma (HCC) and mortality. The risk of these complications may vary in different patient groups.

Aim

To estimate the incidence and predictors of HCC and in untreated HBV patients.

Methods

Systematic review with random effects meta-analyses of randomized controlled trials and observational studies. Results are expressed as annual incidence (events per 100 person-years) with 95% confidence intervals. Subgroup and sensitivity analyses of patient and study characteristics were performed to identify common risk factors.

Results

We included 68 trials and studies with a total of 27,584 patients (264,919 person-years). In total, 1,285 of 26,687 (5%) patients developed HCC and 730 of 12,511 (6%) patients died. The annual incidence was 0.88 (95% CI, 0.76–0.99) for HCC and 1.26 (95% CI, 1.01–1.51) for mortality. Patients with cirrhosis had a higher risk of HCC (incidence 3.16; 95% CI, 2.58–3.74) than patients without cirrhosis (0.10; 95% CI, 0.02–0.18). The risk of dying was also higher for patients with than patients without cirrhosis (4.89; 95% CI, 3.16–6.63; and 0.11; 95% CI, 0.09–0.14). The risk of developing HCC increased with HCV coinfection, older age and inflammatory activity. The country of origin did not clearly predict HCC or mortality estimates.

Conclusions

Cirrhosis was the strongest predictor of HCC incidence and mortality. Patients with HBV cirrhosis have a 31-fold increased risk of HCC and a 44-fold increased mortality compared to non-cirrhotic patients. The low incidence rates should be taken into account when considering HCC screening in non-cirrhotic patients.

Trial Registration

Prospero CRD42013004764     

Assessing Relations between PTSD’s Dysphoria and Reexperiencing Factors and Dimensions of Rumination

The purpose of the present study was to investigate the relations between posttraumatic stress disorder’s (PTSD) dysphoria and reexperiencing factors and underlying dimensions of rumination. 304 trauma-exposed primary care patients were administered the Stressful Life Events Screening Questionnaire, PTSD Symptom Scale based on their worst traumatic event, and Ruminative Thought Style Questionnaire (RTSQ). Confirmatory factor analyses (CFAs) were conducted to determine the dysphoria and reexperiencing factors’ relationships with the four factors of rumination. Results revealed that both the dysphoria and reexperiencing factors related more to problem-focused thinking and anticipatory thoughts than counterfactual thinking. Additionally, the reexperiencing factor related more to anticipatory thinking than repetitive thinking. Clinical and theoretical implications are discussed.     

Emergence of Coxiella burnetii in Ruminants on Reunion Island? Prevalence and Risk Factors

Q fever is a widespread zoonosis that is caused by Coxiella burnetii (C. burnetii), and ruminants are identified as the main sources of human infections. Some human cases have been described, but very limited information was available about Q fever in ruminants on Reunion Island, a tropical island in the Indian Ocean. A cross-sectional study was undertaken from March 2011 to August 2012 to assess the Q fever prevalence and to identify the major risk factors of C. burnetii infection in ruminants. A total of 516 ruminants (245 cattle, 137 sheep and 134 goats) belonging to 71 farms and localized in different ecosystems of the island were randomly selected. Samples of blood, vaginal mucus and milk were concomitantly collected from females, and a questionnaire was submitted to the farmers. Ticks from positively detected farms were also collected. The overall seropositivity was 11.8% in cattle, 1.4% in sheep and 13.4% in goats. C. burnetii DNA was detected by PCR in 0.81%, 4.4% and 20.1% in cow, sheep and goat vaginal swabs, respectively. C. burnetii shedding in milk was observed in 1% of cows, 0% in sheep and 4.7% in goats. None of the ticks were detected to be positive for C. burnetii. C. burnetii infection increased when the farm was exposed to prevailing winds and when there were no specific precautions for a visitor before entering the farm, and they decreased when a proper quarantine was set up for any introduction of a new ruminant and when the animals returned to the farm at night. MLVA genotyping confirmed the role of these risk factors in infection.     

Prevalence and Risk Factors of Chronic Otitis Media: The Korean National Health and Nutrition Examination Survey 2010–2012

BackgroundThe performance of nationwide studies of chronic otitis media (COM) in adults has been insufficient in Korea. We evaluated the prevalence and risk factors of COM in Korea.MethodsThis study was conducted using data from the fifth Korean National Health and Nutrition Examination Survey (n = 23,621). After excluding the subjects under 20 year old and suffered from cancers, 16,063 patients were evaluated for COM. Participants underwent a medical interview, physical examination, endoscopic examination, and blood and urine test. COM was diagnosed by trained residents in the Department of Otorhinolaryngology using an ear, nose, and throat questionnaire and otoendoscopy findings. Data on the presence and absence of COM were collected. Multivariate logistic regression analyses were performed to identify its risk factors.ResultsOf the 16,063 participants aged above 20 year old, the weighted prevalence of COM was 3.8%. In the multivariate analyses, the following factors showed high odds ratios (ORs) for COM: pulmonary tuberculosis (adjusted OR, 1.78; 95% confidence interval [CI], 1.06-3.01), chronic rhinosinusitis (adjusted OR, 1.87; 95% CI, 1.17-2.98), mild hearing impairment (adjusted OR, 1.95; 95% CI, 1.34-2.85), moderate hearing impairment (adjusted OR, 4.00; 95% CI, 2.21-7.22), tinnitus (adjusted OR, 1.82; 95% CI, 1.34-2.49), increased hearing thresholds in pure tone audiometry in the right ear (adjusted OR, 1.02; 95% CI, 1.01-1.03), and left ear (adjusted OR, 1.03; 95% CI, 1.02-1.04). The following factors showed low odds ratios for COM: hepatitis B (adjusted OR, 0.28; 95% CI, 0.08-0.94) and rhinitis (adjusted OR, 0.60; 95% CI, 0.42-0.88). In addition, high levels of vitamin D, lead, and cadmium, EQ-5D index; and low red blood cell counts were associated with development of COM (Student’s t-test, P < 0.01).ConclusionsOur population-based study showed that COM is not rare in Korea, and its development may be associated with various host and environmental factors. Further research on its relationships and the pathogenesis are needed.     

Incidence and Risk Factors of Homicide–Suicide in Swiss Households: National Cohort Study

Background

Homicide–suicides are rare but catastrophic events. This study examined the epidemiology of homicide-suicide in Switzerland.

Methods

The study identified homicide–suicide events 1991–2008 in persons from the same household in the Swiss National Cohort, which links census and mortality records. The analysis examined the association of the risk of dying in a homicide–suicide event with socio-demographic variables, measured at the individual-level, household composition variables and area-level variables. Proportional hazards regression models were calculated for male perpetrators and female victims. Results are presented as age-adjusted hazard ratios (HR) with 95% confidence intervals (95%CI).

Results

The study identified 158 deaths from homicide–suicide events, including 85 murder victims (62 women, 4 men, 19 children and adolescents) and 68 male and 5 female perpetrators. The incidence was 3 events per million households and year. Firearms were the most prominent method for both homicides and suicides. The risk of perpetrating homicide-suicide was higher in divorced than in married men (HR 3.64; 95%CI 1.56–8.49), in foreigners without permanent residency compared to Swiss citizens (HR 3.95; 1.52–10.2), higher in men without religious affiliations than in Catholics (HR 2.23; 1.14–4.36) and higher in crowded households (HR 4.85; 1.72–13.6 comparing ≥2 with <1 persons/room). There was no association with education, occupation or nationality, the number of children, the language region or degree of urbanicity. Associations were similar for female victims.

Conclusions

This national longitudinal study shows that living conditions associated with psychological stress and lower levels of social support are associated with homicide-suicide events in Switzerland.     

No Association between Low Birth Weight and Cardiovascular Risk Factors in Early Adulthood: Evidence from S?o Paulo,Brazil

Background

A growing literature suggests that low birth weight increases the risk of poor health outcomes in adulthood. We tested this hypothesis among young adults living in São Paulo State, Brazil.

Methods and Findings

To identify the effects of low birth weight on young adulthood outcomes, a medical assessment of 297 individuals born between 1977 and 1989 was conducted at a primary care unit in São Paulo State, Brazil. We analyzed body mass index (BMI), waist-hip ratio, blood pressure, fasting glucose and total cholesterol levels using linear and logistic regressions. Low birth was negatively associated with BMI (β = −2.0, 95% CI: −3.69, −0.27, p = 0.02), fasting glucose levels (β = −1.9, 95% CI: −3.9, −0.07, p = 0.05), waist-hip ratio (β = −0.03, 95% CI: −0.07, −0.01, p = 0.10), systolic blood pressure (β = −3.32, 95% CI: −7.60, 0.96, p = 0.12), and total cholesterol levels (β = −3.19, 95% CI: −16.43, 10.05, p = 0.636). Low birth weight was also associated with lower odds of young adults being overweight and obese, but neither association was statistically significant. Weight gain in the first 12 months of life was associated with higher adult BMI (β = 0.79, 95% CI: −0.0455, 1.623, p = 0.064) and blood pressure (β = 2.79, 95% CI: 0.22, 5.35, p = 0.034). No associations were found between low birth weight and early life (catch-up) growth.

Conclusions

Low birth weight was not associated with poor health outcomes among young adults in Brazil. These results appear inconsistent with the original Barker hypothesis, but will need to be corroborated in larger samples with longer follow-ups to allow a more general evaluation of the validity of the hypothesis in low and middle income countries.     

Targeting cIAPs,a New Option for Functional Cure of Chronic Hepatitis B Infection?

正Hepatitis B virus (HBV) infection causes a wide spectrum of liver diseases in more than 240 million people world-wide (Ott et al. 2012). Patients with chronic hepatitis B(CHB) may progress to HBV-related end-stage liver diseases, such as hepatic failure, cirrhosis or hepatocellular     

Prevalence of and Risk Factors for Asymptomatic In?ammatory (NIH-IV) Prostatitis in Chinese Men

Background

While many investigators have studied symptomatic prostatitis, little research has been done with regard to asymptomatic (NIH-IV) prostatitis.

Purpose

To describe the prevalence of and risk factors for NIH-IV prostatitis among a large male population.

Methods

The study population was comprised of 1,868 men at the second phase recruitment of a population-based cohort in China. Asymptomatic and symptomatic men were defined by the National Institutes of Health Chronic Prostatitis (CP) Symptom Index. Meanwhile, EPS specimens and their leukocyte count were collected. Lifestyle and demographic characteristics were obtained through a questionnaire.

Results

Prevalence of NIH-IV prostatitis was 21.1% among 1,868 asymptomatic men aged 19–78 years and increased with age. After adjusteing for potential confounding variables (age, smoking habits, alcohol drinking habits, education, physical activity, hypertension, dyslipidemia, obesity and diabetes), age remained a significant factor for NIH-IV prostatitis (OR = 1.35; 95% CI = 1.06–1.71; P = 0.01) and the risk of NIH-IV prostatitis was significantly higher in smokers≧15 pack/years than non-smokers (OR = 1.33; 95% CI = 1.01–1.75; P = 0.03). In addition, compared with non-drinkers, the OR of NIH-IV prostatitis in drinkers ≧1 drinks/week was 1.35 (95% CI = 1.03, 1.77, p = 0.02) after adjusting for the other variables above. In addition, having less than a college education may be a risk factor for NIH-IV prostatitis, although a statistically significant difference did not exist in our data (OR = 1.22; 95% CI = 0.97–1.52; P = 0.08).

Conclusions

Our findings suggest that NIH-IV prostatitis is prevalent in China. Age, smoking, drinking and lower education levels were associated with an increased risk of NIH-IV prostatitis. The prevalence of NIH-IV prostatitis should be taken into account when estimating the total prevalence of CP in future studies.     

Reactivation of Snail Genes in Renal Fibrosis and Carcinomas: A Process of Reversed Embryogenesis?

While the activity of Snail genes is required during embryonic development for the formation of different tissues and organs, they must be repressed in the adult in order to maintain epithelial integrity and homeostasis. Indeed, pathological activation of Snail in epithelial tumors induces malignancy and the recurrence of tumors. Here we show that in dedifferentiated areas of human renal carcinomas, Snail undergoes a process of reactivation. In addition to tumor progression, renal fibrosis is also linked to the activity of Snail genes and indeed, reactivation of Snail in the adult kidney is sufficient to induce fibrosis. Thus, Snail genes illustrate a paradigm whereby reactivation of crucial embryonic genes in adult tissues provokes the onset of devastating diseases.     

Differential Relevance of NF-κB and JNK in the Pathophysiology of Hemorrhage/Resususcitation-Induced Liver Injury after Chronic Ethanol Feeding

Background

Chronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.

Methods

Male mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.

Results

H/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.

Conclusions

These results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.     

Are Consanguineous Marriage and Swaddling the Risk Factors of Developmental Dysplasia of the Hip?

The purpose of this study was to investigate prospectively the effects of swaddling and consanguineous marriage on developmental dysplasia of the hip and associated risk factors. We screened by ultrasound 265 infants using the Graf method. The Pediatrics Department referred all newborn infants with suspected instability or a recognized risk factor to the orthopedic clinic. Risk factors of developmental dysplasia of the hip were searched and noted in these patients. Swaddling and consanguineous marriage were also determined and noted. We observed 164 of 265 infants (61.9 %) who had been swaddled and that 64 of 265 infants’ parents were in a consanguineous marriage (24.2 %). In the statistical analysis that was conducted for swaddling and consanguineous marriage, highly significant differences were found. Our study showed that the rate of developmental dysplasia of the hip is very high, 11.7 %, in our region, eastern Turkey. Also, we commonly see improper swaddling and consanguineous marriage in our region, which affects many infants.     

Depressive Symptoms and the Risk of Ischemic Stroke in the Elderly—Influence of Age and Sex

Although a relationship between depression and cardiovascular events has been suggested, past study results regarding the risk of stroke in relation to depression by subgroups are ambiguous. The aim of this study was to investigate the influence of depressive symptoms on risk of incident ischemic stroke in elderly according to age and sex. This prospective cohort study followed up 3852 subjects older than 55 years. Baseline depressive symptoms were defined by a score ≥5 on the Geriatric Depression Scale or antidepressant intake. The outcome measure was incident ischemic stroke within 6 years of follow-up. Multivariate Cox-proportional hazard models as well as cumulative survival analyses were computed. A total of 156 ischemic strokes occurred during the study period (24 strokes in the age-group<65 years and 132 strokes in the age-group≥65 years). The distribution of strokes in sex-subgroups was 4.5% in men and 3.7% in women. The multivariate analysis showed an elevated stroke risk (Hazard Ratio (HR): 2.84, 95% CI 1.11–7.29, p = 0.030) in subjects from 55 to 64 years with depressive symptoms at baseline but not in subjects older than 65 years. In the multivariate analysis according to sex the risk was increased in women (HR: 1.62, 95% CI 1.02–2.57, P = 0.043) but not in men. The Cox-regression model for interaction showed a significant interaction between age and sex (HR: 3.24, 95% CI 1.21–8.69, P = 0.020). This study corroborates that depressive symptoms pose an important risk for ischemic stroke, which is particularly remarkable in women and patients younger than 65 years.