Journals

Quantification of HBsAg in nucleos(t)ide-naïve patients treated for chronic hepatitis B with entecavir with or without tenofovir in the BE-LOW study.

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Quantification of HBsAg in nucleos(t)ide-naïve patients treated for chronic hepatitis B with entecavir with or without tenofovir in the BE-LOW study.

J Hepatol. 2014 Aug 28;

Authors: Zoulim F, Carosi G, Greenbloom S, Mazur W, Nguyen T, Jeffers L, Brunetto M, Yu S, Llamoso C

Abstract

BACKGROUND AND AIMS: Serum hepatitis B surface antigen (HBsAg) levels may predict treatment response in chronic hepatitis B (CHB). We examined the association between changes in HBsAg levels and response to treatment in the BE-LOW study.

METHODS: In this open-label, multicenter study, 379 nucleos(t)ide-naïve patients with hepatitis B e antigen (HBeAg)-positive or -negative CHB were randomized and treated with daily entecavir 0.5 mg, alone (n = 182) or combined with tenofovir 300 mg (n = 197) for 100 weeks. HBsAg levels were quantified (Abbott Architect assay) at baseline and Weeks 12, 48 and 96.

RESULTS: Mean baseline HBsAg levels were comparable across subgroups by baseline alanine aminotransferase (ALT), genotype, age, and treatment type, but were higher in HBeAg-positive than in HBeAg-negative patients. Mean HBsAg changes from baseline at Weeks 12, 48, and 96 were more pronounced in HBeAg-positive than in HBeAg-negative patients, in patients with genotype A than in those with genotypes C or D, and in patients with elevated baseline ALT, but were similar between treatment groups and between patients of different age categories. Mean HBsAg changes over 96 weeks were also comparable in patients with or without HBV DNA <50 IU/mL at Week 96, but among patients HBeAg-positive at baseline, changes were greater for those with Week 96 HBeAg loss than for those without.

CONCLUSIONS: In this population of HBeAg-positive and HBeAg-negative, nucleos(t)ide-naïve patients, a greater HBsAg decline through 96 treatment weeks was observed in HBeAg-positive patients, especially in those who achieved subsequent HBeAg loss.

PMID: 25176615 [PubMed - as supplied by publisher]

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism.

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Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism.

Neuropsychopharmacology. 2014 Sep 1;

Authors: Sullivan EM, Timi P, Elliot Hong L, O’Donnell P

Abstract

Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either picrotoxin or MK-801 did not affect frequency-specific oscillatory activity when tested 24 hr after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting skull EEG may be a powerful tool for further translational studies.Neuropsychopharmacology accepted article preview online, 01 September 2014. doi:10.1038/npp.2014.228.

PMID: 25176166 [PubMed - as supplied by publisher]

Testing the Predictive Value of Peripheral Gene Expression for Non-Remission Following Citalopram Treatment for Major Depression.

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Testing the Predictive Value of Peripheral Gene Expression for Non-Remission Following Citalopram Treatment for Major Depression.

Neuropsychopharmacology. 2014 Sep 1;

Authors: Guilloux JP, Bassi S, Ding Y, Walsh C, Turecki G, Tseng G, Cyranowski JM, Sibille E

Abstract

Major depressive disorder (MDD) in general, and anxious depression in particular, are characterized by poor rates of remission with first-line treatments, contributing to the chronic illness burden suffered by many patients. Prospective research is needed to identify biomarkers predicting non-remission prior to treatment initiation. We collected blood samples from a discovery cohort of 34 adult MDD patients with co-occurring anxiety and 33 matched, non-depressed controls at baseline and after 12 weeks (of citalopram plus psychotherapy treatment for the depressed cohort). Samples were processed on gene arrays and group differences in gene expression were investigated. Exploratory analyses suggest that at pre-treatment baseline, non-remitting patients differ from controls, with gene function and transcription factor analyses potentially related to elevated inflammation and immune activation. In a second phase, we applied an unbiased machine learning prediction model and corrected for model selection bias. Results show that baseline gene expression predicted non-remission with 79.4% corrected accuracy with a 13 gene model. The same gene-only model predicted non-remission after 8 weeks of citalopram treatment with 76% corrected accuracy in an independent validation cohort of 63 MDD patients treated with citalopram at another institution. Together, these results demonstrate the potential, but also the limitations, of baseline peripheral blood-based gene expression to predict non-remission after citalopram treatment. These results support their use in future prediction tools, but also suggest that increased accuracy may be obtained with the inclusion of additional predictors (eg, genetics, clinical scales).Neuropsychopharmacology accepted article preview online, 01 September 2014. doi:10.1038/npp.2014.226.

PMID: 25176167 [PubMed - as supplied by publisher]

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention.

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Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention.

Neuropsychopharmacology. 2014 Sep 1;

Authors: Bowers ME, Ressler KJ

Abstract

Posttraumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnr1) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition, we hypothesize that a functional interaction between Cnr1 and CCKBR is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BL/6J mice after consolidation of auditory fear conditioning. Knockout of the CCKB receptor (CCKBR), however, had no effect on fear- or anxiety-like behaviors. Nonetheless, administration of a Cnr1 antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. Additionally, we found that Cnr1-positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnr1 contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnr1-CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.Neuropsychopharmacology accepted article preview online, 01 September 2014. doi:10.1038/npp.2014.225.

PMID: 25176168 [PubMed - as supplied by publisher]

Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†

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Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†

Eur Heart J. 2014 Aug 31;

Authors: Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD, for the CONFIRM-HF Investigators

Abstract

AIM: The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF).

METHODS AND RESULTS: CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%). Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n = 152) or placebo (saline, n = 152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance from baseline to Week 24. Secondary end-points included changes in New York Heart Association (NYHA) class, Patient Global Assessment (PGA), 6MWT distance, health-related quality of life (QoL), Fatigue Score at Weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. Treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 ± 11 m, P < 0.001). Throughout the study, an improvement in NYHA class, PGA, QoL, and Fatigue Score in patients treated with FCM was detected with statistical significance observed from Week 24 onwards. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio (95% confidence interval): 0.39 (0.19-0.82), P = 0.009]. The number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of adverse events were comparable between both groups.

CONCLUSION: Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF (ClinicalTrials.gov number NCT01453608).

PMID: 25176939 [PubMed - as supplied by publisher]

Prognosis and treatment of atrial fibrillation patients by European cardiologists: One Year Follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot registry).

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Prognosis and treatment of atrial fibrillation patients by European cardiologists: One Year Follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot registry).

Eur Heart J. 2014 Aug 31;

Authors: Lip GY, Laroche C, Ioachim PM, Rasmussen LH, Vitali-Serdoz L, Petrescu L, Darabantiu D, Crijns HJ, Kirchhof P, Vardas P, Tavazzi L, Maggioni AP, Boriani G

Abstract

BACKGROUND: The EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot) provides systematic collection of contemporary data regarding the management and treatment of 3119 subjects with AF from 9 member European Society of Cardiology (ESC) countries. In this analysis, we report the development of symptoms, use of antithrombotic therapy and rate vs. rhythm strategies, as well as determinants of mortality and/or stroke/transient ischaemic attack (TIA)/peripheral embolism during 1-year follow-up in this contemporary European registry of AF patients.

METHODS: The registry population comprised consecutive in- and out-patients with AF presenting to cardiologists in participating ESC countries. Consecutive patients with AF documented by ECG were enrolled. Follow-up was performed by the local investigator, initially at 1 year, as part of a long-term cohort study.

RESULTS: At the follow-up, patients were frequently asymptomatic (76.8%), but symptoms are nevertheless common among paroxysmal and persistent AF patients, especially palpitations, fatigue, and shortness of breath. Oral anticoagulant (OAC) use remains high, ∼78% overall at follow-up, and of those on vitamin K antagonist (VKA), 84% remained on VKA during the follow-up, while of those on non-VKA oral anticoagulant (NOAC) at baseline, 86% remained on NOAC, and 11.8% had changed to a VKA and 1.1% to antiplatelet therapy. Digitalis was commonly used in paroxysmal AF patients. Of rhythm control interventions, electrical cardioversion was performed in 9.7%, pharmacological cardioversion in 5.1%, and catheter ablation in 4.4%. Despite good adherence to anticoagulation, 1-year mortality was high (5.7%), with most deaths were cardiovascular (70%). Hospital readmissions were common, especially for atrial tachyarrhythmias and heart failure. On multivariate analysis, independent baseline predictors for mortality and/or stroke/TIA/peripheral embolism were age, AF as primary presentation, previous TIA, chronic kidney disease, chronic heart failure, malignancy, and minor bleeding. Independent predictors of mortality were age, chronic kidney disease, AF as primary presentation, prior TIA, chronic obstructive pulmonary disease, malignancy, minor bleeding, and diuretic use. Statin use was predictive of lower mortality.

CONCLUSION: In this 1-year follow-up analysis of the EORP-AF pilot general registry, we provide data on the first contemporary registry focused on management practices among European cardiologists, conducted since the publication of the new ESC guidelines. Overall OAC use remains high, although persistence with therapy may be problematic. Nonetheless, continued OAC use was more common than in prior reports. Despite the high prescription of OAC, 1-year mortality and morbidity remain high in AF patients, particularly from heart failure and hospitalizations.

PMID: 25176940 [PubMed - as supplied by publisher]

Vagal nerve stimulation in heart failure.

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Vagal nerve stimulation in heart failure.

Eur Heart J. 2014 Aug 31;

Authors: Camm AJ, Savelieva I

PMID: 25176941 [PubMed - as supplied by publisher]

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the neural cardiac therapy for heart failure (NECTAR-HF) randomized controlled trial.

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Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the neural cardiac therapy for heart failure (NECTAR-HF) randomized controlled trial.

Eur Heart J. 2014 Aug 31;

Authors: Zannad F, De Ferrari GM, Tuinenburg AE, Wright D, Brugada J, Butter C, Klein H, Stolen C, Meyer S, Stein KM, Ramuzat A, Schubert B, Daum D, Neuzil P, Botman C, Caste MA, D’Onofrio A, Solomon SD, Wold N, Ruble SB

Abstract

AIM: The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy.

METHODS: Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers.

RESULTS: Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group.

CONCLUSION: Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

PMID: 25176942 [PubMed - as supplied by publisher]

Towards novel theranostic approaches in cardiac transplantation medicine.

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Towards novel theranostic approaches in cardiac transplantation medicine.

Eur Heart J. 2014 Aug 31;

Authors: Batkai S, Thum T

PMID: 25176943 [PubMed - as supplied by publisher]

MicroRNAs as non-invasive biomarkers of heart transplant rejection.

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MicroRNAs as non-invasive biomarkers of heart transplant rejection.

Eur Heart J. 2014 Aug 31;

Authors: Duong Van Huyen JP, Tible M, Gay A, Guillemain R, Aubert O, Varnous S, Iserin F, Rouvier P, François A, Vernerey D, Loyer X, Leprince P, Empana JP, Bruneval P, Loupy A, Jouven X

Abstract

AIM: Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.

METHODS: We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.

RESULTS: We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.

CONCLUSION: This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.

PMID: 25176944 [PubMed - as supplied by publisher]