Inactive Status Research Articles

BKI1 Regulates Plant Architecture through Coordinated Inhibition of the Brassinosteroid and ERECTA Signaling Pathways in Arabidopsis

Hundreds of leucine-rich repeat receptor-like kinases (LRR-RLKs) play indispensable roles in a wide range of plant developmental and physiological processes. The mechanisms controlling LRR-RLKs at a basal and inactive status are essential but rarely studied. BKI1 is the only reported inhibitor of receptor kinases in Arabidopsis, which negatively regulates BRI1 in the brassinosteroid pathway. In this study, we found that BKI1 can also interact with another important LRR-RLK, ERECTA (ER). Phenotypic analysis showed that BKI1 and ER together regulate plant architecture, including pedicel orientation, which is a newly reported phenotype in the BR- and ER-mediated developmental processes. Gene expression analysis revealed that BKI1 regulates a subset of ER-responsive genes. Kinase assays demonstrated that BKI1 inhibits ER kinase activity. In addition, the release of BKI1 inhibition on ER signaling relies largely on BRI1 activation. Our data provide significant insights into the regulation and activation of RLKs and suggest that BKI1 functions as a common suppressor of the BRI1 and ER signaling pathways.

The Role of Sphingomyelin (SM) in Tissue Factor (TF) Encryption: ATP-Induced Activation of Acid Sphingomyelinase in Macrophages Decrypts Tissue Factor By Hydrolysis of SM in the Outer Leaflet

While tissue factor (TF)-mediated blood coagulation is essential for maintaining hemostasis, the aberrant activation of TF-mediated coagulation is a major determinant of thrombotic occlusions, the precipitating event in acute myocardial infarction, unstable angina, and ischemic stroke. Typically, TF on cell surfaces exists in inactive coagulant status (cryptic TF). Cell injury leads conversion of cryptic TF to coagulant active/prothrombotic TF. Molecular differences between cryptic and procoagulant TF and the mechanisms that are responsible for the conversion from one to the other form are poorly understood and often controversial. A majority of the evidence in the literature suggest that level of anionic phospholipids, such as phosphatidylserine (PS), in the outer leaflet of the plasma membrane plays a critical role in regulating TF procoagulant activity at the cell surface. However, other pathways, such as the thioredoxin system or thiol-disulfide exchange pathways involving protein-disulfide isomerase (PDI), were also shown to contribute to TF activation by inducing structural changes in TF. It is unknown at present whether TF on cell surfaces of naïve cells exists primarily in the cryptic state because of the limited availability of anionic phospholipids at the outer leaflet or phospholipids present in the outer leaflet play an active role in maintaining TF in the cryptic state. In the outer leaflet of mammalian plasma membrane, sphingomyelin (SM) constitutes up to 50% of the total phospholipids present on the cell surface. It is possible that a high SM content in the outer leaflet may be responsible for maintaining TF in its cryptic state at the cell surface in naïve cells, and the hydrolysis of SM on the outer leaflet mediated by factors released in cell injury contributes to TF activation. The present study was carried out to investigate this possibility.First, we tested the potential effect of SM on TF activity in a reconstituted system in which full-length TF was reconstituted into phospholipid vesicles composed of varying molar concentrations of SM with the remainder of the vesicle consisting of phosphatidylcholine (PC). SM, at 35 mol % or higher concentration in the proteoliposome, inhibited TF coagulant activity significantly as measured in factor X activation assay. Ceramide, having a similar sphingosine backbone as of SM, had no inhibitory effect on TF-FVIIa activation of FX. Measurement of FVIIa-TF amidolytic activity showed that SM does not inhibit the amidolytic activity of FVIIa-TF, indicating that SM neither affects FVIIa binding to TF nor TF-FVIIa cleavage of the small substrate peptide. SM also inhibited significantly TF activity of TF reconstituted in PC/PS (94%:6% mol/mol) vesicles. Next, human monocyte-derived macrophages (MDMs) were treated with varying concentrations of bacterial sphingomyelinase (b-SMase) to hydrolyze SM in the outer leaflet. b-SMase treatment increased cell surface TF activity in a dose-dependent manner. SMase treatment also enhanced the release of TF-bearing microparticles (MPs). SMase treatment had no significant effect on cell surface prothrombinase activity or annexin V binding to MDMs, indicating that b-SMase treatment did not increase PS availability at the cell surface under our experimental conditions. Similar to that observed in bone marrow-derived mouse macrophages, ATP (200 µM) stimulation of MDMs increased cell surface TF activity by about 3-fold and triggered the release of TF+ MPs. Immunofluorescence confocal microscopy revealed that ATP stimulation induced in the translocation of acid(a)-SMase from intracellular compartments to the outer leaflet of the plasma membrane. Treatment of MDMs with sphingomyelinase inhibitors, desipramine and imipramine (1 and 5 µM), or silencing a-SMase with siRNA markedly reduced the ATP-induced increased TF activity at the cell surface and TF+ MPs release. Finally, ATP stimulation was shown to increase the hydrolysis of SM in the outer leaflet of MDMs markedly. a-SMase inhibitors or silencing of a-SMase attenuated the ATP-induced SM hydrolysis. In summary, our data indicate that SM plays a critical role in maintaining TF in the cryptic state in resting cells. Activation/translocation of a-SMase to the outer leaflet following the activation of ATP receptor P2X7 leads to hydrolysis of SM and thus relieves the inhibitory effect of SM on TF, leading to TF decryption and the release of TF+ MPs. DisclosuresNo relevant conflicts of interest to declare.

Time Trend in Psychotropic Medication Use in Spain: A Nationwide Population-Based Study.

Background: We performed an epidemiologic study to analyze nationwide time trends in adult psychotropic drug use over a period from 2006 to 2012, and to identify those factors associated with the likelihood of consumption of these drugs during the study period; Methods: Cross-sectional study on psychotropic medication in the Spanish adult population. We used secondary individualized data drawn from the 2006 and 2012 Spanish National Health Surveys (SNHS). The dependent variable was the use of psychotropic drugs in the previous two weeks. Independent variables included socio-demographic characteristics, comorbidity, lifestyles and healthcare resource utilization. Using logistic multivariate regression models, we analyzed the temporal evolution of psychotropic medication consumption between 2006 and 2012 in both sexes; Results: The prevalence of psychotropic drug use was significantly greater in women (18.14% vs. 8.08% in 2012 (p < 0.05). In Spanish women, the variables associated with a greater probability of psychotropic use were, age, unemployment (adjusted odds ratio (AOR), 1.60; 95% CI, 1.24–2.07), negative perception of health or taking non-psychotropic drugs. Among men, psychotropic use is associated with presence of chronic disease, negative perception of health (AOR, 3.27; 95% CI, 2.62–4.07 in 2012) or inactive status; Conclusions: Between 2006 and 2012, the probability of having taken psychotropic drugs increased by 16% among women. Unemployed women aged ≥45 years with a negative perception of their health constitute a clear risk profile in terms of psychotropic drug use. Inactive men who have a negative perception of their health are the group most likely to consume psychotropic drugs.

Facilitating access to the renal transplant waiting list does not increase the number of transplantations: comparative study of two French regions.

BackgroundIn France, there are important regional disparities of access to the renal transplant waiting list and transplantation. Our objectives were to compare the characteristics of patients with end-stage renal disease (ESRD) of two French regions (Ile-de-France and Bretagne) and to identify determinants of access to the waiting list and subsequent transplantation, with a focus on temporary inactive status (TIS) periods.MethodsAll 18–80-year-old incident patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 were included (n = 6160). Associations between patients' characteristics and placement on the waiting list or transplantation were assessed using a Fine and Gray model to take into account the competing risk of death and living donor transplantation.ResultsAt the end of the follow-up (31 December 2013), more patients had undergone transplantation in Bretagne than in Ile-de-France (30 versus 27%), although the percentage of waitlisted patients was higher in Ile-de-France than in Bretagne (47 versus 33%). More patients were on TIS and with a longer median TIS duration in Ile-de-France. Independent of age and clinical characteristics, patients in Bretagne were less likely to be waitlisted than those in Ile-de-France [subdistribution hazard ratio 0.77 (95% confidence interval 0.7–0.9)]. After waitlisting, patients in Bretagne were four times more likely to be transplanted.ConclusionsOur study highlights clinical practice differences in Bretagne and Ile-de-France and shows that facilitating access to the waiting list is not sufficient to improve access to renal transplantation, which also depends on organ availability.

Delays in Prior Living Kidney Donors Receiving Priority on the Transplant Waiting List.

Prior living donors (PLDs) receive very high priority on the Organ Procurement and Transplantation Network (OPTN) kidney waiting list. Program delays in adding PLDs to the waiting list, setting their status to active, and submitting requests for PLD priority can affect timely access to transplantation. We used the OPTN and the Centers for Medicare and Medicaid Services data to examine timing of (1) listing relative to start of dialysis, (2) activation on the waiting list, and (3) requests for PLD priority relative to listing date. There were 210 PLDs (221 registrations) added to the OPTN kidney waiting list between January 1, 2010 and July 31, 2015. As of September 4, 2015, 167 of the 210 PLDs received deceased donor transplants, six received living donor transplants, two died, five were too sick to transplant, and 29 were still waiting. Median waiting time to deceased donor transplant for PLDs was 98 days. Only 40.7% of 221 PLD registrations (n=90) were listed before they began dialysis; 68.3% were in inactive status for <90 days, 17.6% were in inactive status for 90-365 days, 8.6% were in inactive status for 1-2 years, and 5.4% were in inactive status for >2 years. Median time of PLDs waiting in active status before receiving PLD priority was 2 days (range =0-1450); 67.4% of PLDs received PLD priority within 7 days after activation, but 15.4% waited 8-30 days, 8.1% waited 1-3 months, 4.1% waited 3-12 months, and 5.0% waited >1 year in active status for PLD priority. After receiving priority, most were transplanted quickly. Median time in active status with PLD priority before deceased donor transplant was 23 days. Fewer than one half of listed PLDs were listed before starting dialysis. Most listed PLDs are immediately set to active status and receive PLD priority quickly, but a substantial number spends time in active status without PLD priority or a large amount of time in inactive status, which affects access to timely transplants.

Establishment of X chromosome inactivation and epigenomic features of the inactive X depend on cellular contexts.

X chromosome inactivation (XCI) is an essential epigenetic process that ensures X-linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a uniform mechanism in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi.

The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study.

Hepatitis B eantigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers. Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period. At the baseline, the mean age was 57.5±13.1years and 42% of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035±252days). Loss of inactive carrier status was seen in 75 patients (19.3%). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95% confidence interval 1.07-1.19, p<0.001), HBV DNA (hazard ratio 2.70, 95% confidence interval 1.63-4.49, p<0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95% confidence interval 1.00-1.02, p=0.003) at the baseline. Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear; therefore, careful follow-up of inactive carriers is needed.

Biogenesis of sperm acrosome is regulated by pre-mRNA alternative splicing of Acrbp in the mouse

Proper biogenesis of a sperm-specific organelle, the acrosome, is essential for gamete interaction. An acrosomal matrix protein, ACRBP, is known as a proacrosin-binding protein. In mice, two forms of ACRBP, wild-type ACRBP-W and variant ACRBP-V5, are generated by pre-mRNA alternative splicing of Acrbp Here, we demonstrate the functional roles of these two ACRBP proteins. ACRBP-null male mice lacking both proteins showed a severely reduced fertility, because of malformation of the acrosome. Notably, ACRBP-null spermatids failed to form a large acrosomal granule, leading to the fragmented structure of the acrosome. The acrosome malformation was rescued by transgenic expression of ACRBP-V5 in ACRBP-null spermatids. Moreover, exogenously expressed ACRBP-W blocked autoactivation of proacrosin in the acrosome. Thus, ACRBP-V5 functions in the formation and configuration of the acrosomal granule during early spermiogenesis. The major function of ACRBP-W is to retain the inactive status of proacrosin in the acrosome until acrosomal exocytosis.

A Mixed Methods Study of Telepathic Interspecies Communication with Therapeutic Riding Horses and Their Recovering Wounded Veteran Partners

Telepathic parapsychology research is a subject of much debate. This small pilot study explored the proposition that telepathic communication between humans and therapy equines may be possible with a human utilizing contemplative/meditative techniques to shift consciousness. The human participants were 7 military veterans in retired or inactive status diagnosed with combat-related posttraumatic stress disorder (PTSD). Each veteran was assigned to one therapy horse. The 12 equine participants all had the same guardians. The veterans signed an online consent to participate and submitted questions for their horses on the consent form. Both veterans and guardians were blind as to which of 2 telepathic animal communicators would be randomly assigned to the session by the principal researcher. Both animal communicators were physically located in another town from the horses when the sessions were conducted. The answers to the veteran’s questions, allegedly received telepathically from the horses, were documented and emailed to the principal researcher. The summary document from each session was shared with the veteran for their horse by the guardians, and all summaries were shared with the guardians. During an in-person or telephone interview with the principal researcher, the veterans offered qualitative comments and used Likert scales to rate the usefulness of the information received from 1 (not at all useful) to 6 (extremely useful). The average overall usefulness rating as judged by the veterans was 4.9. The guardians also submitted Likert ratings and qualitative comments on the usefulness of the information received; the guardian ratings average was 5.75. These findings contribute to the body of equine therapy studies as well as the wealth of literature that supports the human-animal bond. Further research is needed to explore additional nuances of this category of consciousness and healing research.

Serum Levels of Hepatitis B Surface Antigen and DNA Can Predict Inactive Carriers With Low Risk of Disease Progression.

Serum levels of hepatitis B virus (HBV) DNA (≤2000 IU/mL) and hepatitis B surface antigen (HBsAg) (<1000 IU/mL) have been shown to distinguish inactive carriers with high accuracy. The goal of this study was to validate the predictability of one-time measurement of quantitative HBsAg and HBV DNA levels for inactive carrier status and chronic hepatitis B (CHB) progression in a community-based cohort. This study included 1529 participants chronically infected with HBV genotype B or C from the REVEAL-HBV cohort. They were ascertained as inactive or active CHB after 18 months of follow-up. Validity of the one-time measurement was assessed by sensitivity, specificity, and receiver operating characteristic curves, while associations with clinical outcomes were calculated with Cox proportional hazards regressions. The one-time baseline measurement of HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL distinguished inactive carriers from active CHB with a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 71%, 85%, 83%, 74%, and 78%, respectively. Those identified as inactive carriers using the one-time baseline measurement had multivariate adjusted hazard ratios of 0.36 (95% confidence interval [CI], 0.20-0.63) and 0.36 (0.23-0.56) for hepatocellular carcinoma and liver cirrhosis, respectively, and an adjusted rate ratio of 6.97 (95% CI, 5.21-9.33) for HBsAg seroclearance. Areas under the receiver operating characteristic curve of predicting these outcomes using the one-time definition were similar to those obtained when using long-term follow-up defined carrier status for prediction. This study confirms the predictability of a one-time combined HBsAg and HBV DNA measurement for future inactive carriers. This single-point strategy provides new and complementary information useful for management of patients with chronic hepatitis B infection. (Hepatology 2016;64:381-389).

Oxidative stress and related factors in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine and sacroiliac joints of unknown etiology. Recent studies have reported increased oxidative stress, which is implicated in the pathogenesis of a number of diseases, in AS. The purpose of this study was to investigate oxidative stress and related factors in AS. Eighty-five patients with AS [36 (16-64) years; 65 male/20 female] and 56 healthy subjects [36 (21-63) years; 39 male/17 female] with no known cardiovascular risk factors were enrolled. Serum total oxidant status (TOS) and total anti-oxidant status (TAS) were studied. The Bath ankylosing spondylitis functional index (BASFI), Bath ankylosing spondylitis disease activity index (BASDAI), and Bath ankylosing spondylitis metrology index (BASMI) were calculated. A logistic regression model was used to identify the independent risk factors for TOS. No differences were observed in terms of demographic characteristics, laboratory findings, or TAS concentrations between the patient and control groups. However, the serum TOS levels were significantly higher in the AS group than in the controls (p=0.003). The comparison of cases of active (BASDAI ≥4) and inactive AS revealed significantly higher TOS levels in the active disease group. The TOS and TAS concentrations did not differ between patients treated with biological agents and those treated with conventional agents. Correlation analysis yielded significant correlations between TOS and TAS, BASMI, BASFI, BASDAI, erythrocyte sedimentation rate (ESR), and high-sensitive C-reactive protein (hs-CRP) (p<0.05; r values ranged from 0.291 to 0.452) and a positive correlation between TAS and BASMI (p<0.05; r=0.344). Based on regression analysis, BASDAI, BASMI, and hs-CRP independently predicted the TOS levels [p<0.05, R2: 0.262, and standard error of the estimate (SEE): 10.96]. Oxidative stress levels were higher in patients with AS than in healthy subjects. Patients with active disease status had significantly higher oxidative stress than patients with inactive disease status and healthy controls. Treatment status has no effect on TOS, and BASMI, BASDAI, and hs-CRP are independent variables associated with TOS. The TAS levels were found to be associated with only BASMI.

Lung Transplantation for Lymphangioleiomyomatosis in Japan.

BackgroundLung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported.MethodsIn this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network.ResultsTransplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053).ConclusionsLung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.

Correlation between disease activity of pediatric-onset systemic lupus erythematosus and level of vitamin D in Taiwan: A case-cohort study.

Vitamin D deficiency has been associated with systemic lupus erythematosus (SLE), but there is no consensus on the role of serum vitamin D in evaluating or predicting disease activity. This study aimed to demonstrate the direct correlation between vitamin D level and pediatric-onset SLE disease activity by a retrospective cohort study design. Thirty-five patients with pediatric-onset SLE and paired sera at the active and inactive disease states were enrolled. Disease activity was defined by Systemic Lupus Erythematosus Disease Activity Index 2000, and active lupus nephritis (LN) was defined as active urine sediment, and proteinuria >2+on stick or >500mg/day. All data were reviewed and calculated from previous medical records. The levels of both vitamin D2 and vitamin D3 were checked by electrochemiluminescence immunoassay. Serum 25-hydroxyvitamin D (25-OH D) levels in the active status were significantly lower compared to that in inactive disease status (12.0±7.2ng/mL vs. 15.4±7.4ng/mL, p=0.005). A subgroup analysis revealed that at active disease status, patients with LN had lower 25-OH D levels than patients without LN (16.3±8.2ng/mL vs. 9.8±5.6ng/mL, p=0.023). Moreover, there is a significant inverse correlation between serum 25-OH D levels and Systemic Lupus Erythematosus Disease Activity Index 2000 at both inactive (r=-0.335, p=0.003) and active (r=-0.373, p=0.016) disease status. Serum vitamin D levels are inversely correlated with SLE disease activity at both active and inactive disease status, and also with the presence of LN at active disease stage.

Underwater Sound Levels at a Wave Energy Device Testing Facility in Falmouth Bay, UK.

Passive acoustic monitoring devices were deployed at FaBTest in Falmouth Bay, UK, a marine renewable energy device testing facility during trials of a wave energy device. The area supports considerable commercial shipping and recreational boating along with diverse marine fauna. Noise monitoring occurred during (1) a baseline period, (2) installation activity, (3) the device in situ with inactive power status, and (4) the device in situ with active power status. This paper discusses the preliminary findings of the sound recording at FabTest during these different activity periods of a wave energy device trial.

Características socioeconómicas y rendimiento académico. El caso de una universidad argentina

The aim of our research is to assess the relationships between socioeconomic characteristics of students in undergraduate courses of Northeastern University (UNNE, Argentina) and their academic results using statistical regression, and to compare the findings with the ones obtained in similar studies in other national universities. There is strong evidence that variables of Socioeconomic Status (SES) are significant in explaining the differences in academic achievement between students of the several schools. The variables used as indicators of high SES presented a positive correlation, and variables that were used as indicators of lower SES have presented a negative correlation. The variables female sex, age, married marital status and inactive employment status are associated with better academic performance, while the variables number of children of the student, busy employment status, employment status, medical coverage, and beneficiary of social plans are related to lower academic performance. Regarding gender, the most important finding is that female students with children have lower performance than male students with children.

Quantification of serum HBV RNA allows differentiation of disease stages of hepatitis B virus (HBV) infections

Introduction: Inactive carriers of HBV infections are distinguished from individuals with active HBV infections by serum levels of HBV DNA. HBV RNA is another surrogate marker of HBV replication which can be quantified from serum. The aim of this study was to explore whether HBV RNA levels permits a better differentiation between the various stages of HBV infection. Methods: Serum samples from 12 patients with acute and 96 with chronic HBV infection (34 inactive HBsAg carrier with HBV DNA < 4 log10 copies/ml and ALT within normal ranges, 34 HBeAg negative and 28 HBeAg positive patients with chronic active hepatitis B (mean age 45.4 ± 15.6 (17 – 77) years, m/w = 73/35, mean ALT 8.7 ± 19.2 (0.22 – 100)µkat/ml, mean HBsAg 4.3 ± 0.9 (0.7 – 6.0) log10 ng/ml) were retrospectively analyzed. HBV DNA was measured by real-time PCR (limit of detection 2.6 log10 copies/ml). HBV-RNA levels were quantified based on a sensitive One-Step-RACE-PCR-Assay which was developed and validated (limit of detection 2.9 log10 copies/ml). Results: HBV RNA could be detected in 9 of 12 patients with acute HBV infection with a mean of 3.4 ± 1.6 (2.0 – 5.9) log10 copies/ml. HBV RNA was detectable in 29 out of 34 HBeAg negative patients and in all 28 patients with HBeAg positive chronic active HBV infection and showed a high correlation with HBV DNA levels (r = 0.93). Mean HBV DNA levels were significantly lower in HBeAg negative as compared to HBeAg positive patients (6.8 ± 1.3 (4.2 – 8.9) vs. 8.2 ± 1.4 (4.5 – 10.5) log10 copies/ml, p < 0.001), and so were mean HBV RNA levels (4.4 ± 1.5 (2.0 – 7.0) vs. 6.8 ± 1.2 (4.3 – 9.1) log10 copies/ml, p < 0.001). In contrast, HBV RNA was detectable in only in 2 out of 34 inactive HBsAg carriers (2.0 ± 0.2 (2.0 – 2.7) log10 copies/ml), while in 28 of those patients HBV DNA was still detectable with a mean of 3.1 ± 0.7 (2.0 – 4.6) log10 copies/ml. Conclusion: Serum levels of HBV RNA show a high correlation with HBV DNA levels in patients with active chronic HBV infection. However, in patients with inactive HBV infections, HBV RNA is less frequently detected than HBV DNA. It needs to be studied whether HBV RNA serum levels can identify patient inactive carrier status that have disease progression. Corresponding author: Krauel, Alexander E-Mail:Alexander.Krauel@medizin.uni-leipzig.de

Update Chronic Viral Hepatitis B and C

Chronic hepatitis B has a complex natural history. The age at infection, comorbidities, coinfections, and other, yet to be identified factors, determine the probability of developing a chronic infection. The HBV virus can never be completely eliminated and remains in the hepatocytes for life. However, to reach an inactive carrier status is a realistic goal of the therapy. For HBV treatment, pegylated interferon and direct antivirals are available. To screen persons at risk and to vaccinate all of the population are important prophylactic measures. Chronic hepatitis C infection leads, in 30% of cases, to liver cirrhosis. Treatment is recommended from fibrosis stage Metavir 2. New DAA allows short treatment, with a high response rate and very few adverse effects.

Long‐Term Safety, Efficacy, and Quality of Life in Patients With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept for Up to Seven Years

ObjectiveThe efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease‐modifying antirheumatic drugs were previously established in a phase III study that included a 4‐month open‐label lead‐in period, a 6‐month double‐blind withdrawal period, and a long‐term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient‐reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup.MethodsPatients enrolled in the phase III trial could enter the open‐label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double‐blind period.ResultsOne hundred fifty‐three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient‐years) of adverse events decreased during the LTE phase (433.61 events during the short‐term phase [combined lead‐in and double‐blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time.ConclusionLong‐term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality‐of‐life benefits in patients with JIA.

Pre-Transplant Weight Loss and Survival after Kidney Transplantation

Background/Aims: We examined post-transplant survival among obese kidney candidates who were temporarily designated waitlist inactive (status 7) due to their weight. Methods: Using OPTN/United Network for Organ Sharing data, patient and graft survival of adult status 7 recipients with a registration body mass index (BMI) ≥30 kg/m² (n = 328) were compared to all others (controls; n = 74,066). Status 7 recipients were then matched to controls to assess whether pre-transplant weight loss was associated with a survival benefit. Results: Median BMI at registration (38 vs. 27 kg/m², p < 0.001) and transplant (36 vs. 27 kg/m², p < 0.001) and reduction in BMI while waitlisted (-5.0 vs. 0.0%, p < 0.001) were higher among status 7 than controls. Patient (status 7: 87.3%; control: 89.3%; p = 0.90) and graft survival (status 7: 82.9%; control: 81.6%; p = 0.75) were similar over 4 years. There was no association between status 7 and mortality (HR 0.96, 95% CI 0.59-1.57) or graft loss (HR 0.95, 95% CI 0.66-1.38) in the overall population nor between matched status 7 recipients and controls (patient survival: 86.0 vs. 87.5%, p = 0.20; graft survival: 82.6 vs. 77.2%, p = 0.61). Conclusion: Among obese status 7 kidney candidates previously considered too obese for transplant, patient and graft survival were comparable to the general transplant population. No difference in survival was observed with pre-transplant weight loss.

Deregulation of NR2E3, an orphan nuclear receptor, by benzo(a)pyrene-induced oxidative stress is associated with histone modification status change of the estrogen receptor gene promoter

We previously reported that NR2E3, an orphan nuclear receptor, plays an important role in maintaining the basal expression of estrogen receptor α (ER) and that the NR2E3 level is highly correlated with the relapse-free survival of breast cancer patients. Here, we investigated the role of NR2E3 in benzo(a)pyrene (BaP)-mediated cell injury. BaP treatment reduced NR2E3 homo-dimer formation and expression and subsequently decreased ER expression. The chromatin immunoprecipitation assay results showed that the treatment of MCF-7 breast cancer cells and the mouse liver with BaP released NR2E3 from the ER promoter to transform the transcriptionally active histone modification status into a repressive state. NR2E3 depletion in MCF-7 cells also induced a similar inactive epigenetic status in the ER promoter region, indicating that NR2E3 is an essential epigenetic player that maintains basal ER expression. Interestingly, these negative effects of BaP on the expression levels of NR2E3 and ER were rescued by antioxidant treatment. Collectively, our study provides novel evidence to show that BaP-induced oxidative stress decreases ER expression, in part by regulating NR2E3 function, which modulates the epigenetic status of the ER promoter. NR2E3 is likely an essential epigenetic player that maintains basal ER expression to protect cells from BaP-induced oxidative injury.