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Cancer therapeutics-related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations. [ABSTRACT FROM AUTHOR]

Background and Purpose Axillary web syndrome (AWS) and seroma are common and function-limiting side effects following treatments for breast cancer. Studies of AWS and seroma are rare, and there are no guidelines for physical therapy in these cases. Case Description After left breast lumpectomy due to invasive ductal carcinoma, a 65-year-old female patient underwent intraoperative radiation therapy and whole breast radiation. Seven months later, during treatment for breast swelling, AWS and breast seroma were identified by a physical therapist certified in lymphedema treatment. Treatment goals were to reduce breast swelling and pain and to improve shoulder movements. Interventions included manual lymph drainage, left arm stretching, and instruction about self–lymphatic-drainage and stretching exercise. Also, a compression bra was ordered, and continued daily activities and physical activity were recommended. Outcomes Improvement in shoulder movement, breast swelling, and pain. Discussion Because evidence for treatment guidelines following treatments for breast cancer is lacking, close follow-up for treatment-related complications is recommended. Management should be chosen according to signs and symptoms. Realistic expectations can reduce patient frustration and improve coping strategies and compliance with self-treatment demands. Clinical studies to support these conclusions are required. [ABSTRACT FROM AUTHOR]

OBJECTIVES Transapical off-pump mitral valve intervention with neochordae implantation is a novel, minimally invasive procedure for treatment of degenerative mitral valve regurgitation. The aim of this study was to apply control charts (CUSUM curves) to monitor the performance of NeoChord repair during the initial phase of its adoption. METHODS The first 112 consecutive patients who underwent NeoChord repair at our institution between November 2013 and March 2016 were included in the analysis. Mitral Valve Academic Research Consortium criteria for 1-year patient success was utilized to determine failed procedures. Control charts had predetermined acceptable and unacceptable failure rates of 5% and 15%, respectively. RESULTS The actual incidence of 1-year-patient failure was 11% (12 of 112 cases), with a cluster of failures within the first 20 cases. The CUSUM analysis demonstrated an initial learning curve; however, the upper boundary (alarm line) was never crossed. The reassurance line was first crossed after 40 procedures and performance remained stable after 49 procedures. CONCLUSIONS NeoChord repair is a safe procedure, and the results are maintained through the 1-year follow-up. A relative high number of implants were required to overcome the learning curve at our institution due to the concurrent development of patient selection criteria and the technical refinement of the procedure. Future studies are needed to assess the evolution of the learning curve after the wide adoption of the procedure across European and North American centres. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) transport has not been described in morbidly obese patients, a population that can pose significant challenges in obtaining vascular access, indexed flows and transport logistics. We sought to study the feasibility and safety of transporting obese and morbidly obese patients during extracorporeal support. METHODS: We conducted a retrospective review of all patients transported to our institution while receiving ECMO from September 2008 to September 2016. Survival to decannulation and survival to discharge were the primary outcomes. Obesity and morbid obesity were defined as a body mass index of greater than 30 kg/m2 and greater than 40 kg/m2, respectively. RESULTS: From 2008 to 2016, 222 patients were transported to our institution while receiving ECMO. Among these included patients, 131 were non-obese (interquartile range 22-27 kg/m2), 63 were obese (interquartile range 31-35 kg/m2) and 28 were morbidly obese (interquartile range 41-49 kg/m2), with 6 patients having a body mass index greater than 50 kg/m2 (range 52.3-79 kg/m2). Pre-ECMO arterial blood gases, disease severity indices, cannulation strategies and transport distances were similar between these 3 groups. There was no mortality of patients during transport, and survival to discharge was 66% (n = 87) in non-obese patients, 56% (n = 35) in obese patients and 82% (n = 23) in morbidly obese patients (P = 0.042). On multivariable logistic regression analysis, body mass index was not a predictor of in-hospital mortality (odds ratio 0.99, 95% confidence interval 0.95-1.03; P = 0.517). CONCLUSIONS: Transport of morbidly obese patients receiving ECMO may be performed safely and with excellent results in the setting of a dedicated ECMO transport programme with well-established management protocols. [ABSTRACT FROM AUTHOR]

Background. Electrical stimulation is often used to treat weakness in people with spinal cord injury (SCI); however its efficacy for increasing strength and trophism is weak, and the mechanisms underlying the therapeutic benefits are unknown. Objective. The purpose of this study was to analyze the effects of neuromuscular electrical stimulation (NMES) on muscle function, trophism, and the Akt pathway signaling involved in muscular plasticity after incomplete SCI in rats. Design. This was an experimental study. Methods. Twenty-one adult female Wistar rats were divided into sham, SCI, and SCI plus NMES groups. In injured animals, SCI hemisection was induced by a surgical procedure at the C5-C7 level. The 5-week NMES protocol consisted of biceps brachii muscle stimulation 5 times per week, initiated 48 h after injury. Forepaw function and strength, biceps muscle trophism, and the expression of phosphorylated Akt, p70S6K, and GSK-3β cellular anabolic pathway markers in stimulated muscle tissue were assessed. Results. There was an increase in bicep muscle strength in the NMES group compared with the untreated SCI group, from postoperative day 21 until the end of the evaluation period. Also, there was an increase in muscle trophism in the NMES group compared with the SCI group. Forelimb function gradually recovered in both the SCI group and the NMES group, with no differences between them. Regarding muscle protein expression, the NMES group had higher values for phospho-Akt, phospho-p70S6K, and phospho-GSK-3β than did the SCI group. Limitations. The experimental findings were limited to an animal model of incomplete SCI and may not be fully generalizable to humans. Conclusions. Early cyclical NMES therapy was shown to increase muscle strength and induce hypertrophy after incomplete SCI in a rat model, probably by increasing phospho-Akt, phospho-p70S6K, and phospho-GSK-3β signaling protein synthesis. [ABSTRACT FROM AUTHOR]

Background. The objective was to investigate the long-term development of pain and hyperalgesia after patella fractures. The secondary objective was to report the association between tibiofemoral and patellofemoral osteoarthritis, pain and hyperalgesia. Methods. The study used a cohort design. Patients who were treated for patella fractures between January 2006 and December 2009 were identified. Patients age 20 to 78 years were included. The main outcome was the pain pressure threshold (PPT). Moreover, visual analog scale (VAS) for pain, radiological outcomes of patellofemoral and tibiofemoral osteoarthritis and the pain subscale of the WOMAC and EQ-5D questionnaires were used. Results. Forty-nine patients were included, with a mean age of 53.9 years and a mean follow-up time of 8.5 years. The injured knee region showed significantly decreased PPT levels (P< 0.046), but decreases in PPT were not found for the forearm region (P50.24). The VAS score for the worst pain during the last 24 hours was reported, with a mean of 2.9 6 2.4 cm. The EQ-5D-5L-pain scale was reported, with a mean score of 2.4 (95% confidence interval [CI] 5 2.0-2.7). The WOMAC Pain score was reported, with a mean score of 3.9 (95% CI52.8- 4.9). Moderate correlations were found between the VAS scores and PPT levels (R50.428, P50.002). Weak correlations were found between VAS scores and PPT levels for site 7 (forearm; R50.313, P50.03). Conclusions. The present study suggests that longlasting local hyperalgesia following a patella fracture is common. No side-to-side difference at the forearms were observed, indicating that the observed local hyperalgesia was not part of a generalized sensitization. [ABSTRACT FROM AUTHOR]

Auxin is essential for various aspects of plant development, and modulation of auxin pathways has great potential for crop improvement. Although the current understanding of auxin biology including auxin biosynthesis, transport, and signaling mainly originated from studies in Arabidopsis, several key auxin genes were first discovered in rice, indicating that it is useful to employ several plant systems for auxin research. In this review, we summarize the recent advances in auxin biology in rice, highlight the main contributions of rice research to auxin biology, and discuss the potential for crop improvement through modulating auxin pathways. [ABSTRACT FROM AUTHOR]

Exercise is associated with unequivocal health benefits and results in many structural and functional changes of the myocardium that enhance performance and prevent heart failure. However, intense exercise also presents a significant hemodynamic challenge in which the right-sided heart chambers are exposed to a disproportionate increase in afterload and wall stress that can manifest as myocardial fatigue or even damage if intense exercise is sustained for prolonged periods. This review focuses on the physiological factors that result in a disproportionate load on the right ventricle during exercise and the long-term consequences. The changes in cardiac structure and function that define 'athlete's heart' disproportionately affect the right-sided heart chambers and this can raise important diagnostic overlap with some cardiac pathologies, particularly some inherited cardiomyopathies. The interaction between exercise and arrhythmogenic right ventricular cardiomyopathy (ARVC) will be highlighted as an important example of how hemodynamic stressors can combine with deficiencies in cardiac structural elements to cause cardiac dysfunction predisposing to arrhythmias. The extent to which extreme exercise can cause adverse remodelling in the absence of a genetic predisposition remains controversial. In the athlete with profound changes in heart structure, it can be extremely challenging to determine whether common symptoms such as palpitations may be a marker of more sinister arrhythmias. This review discusses some of the techniques that have recently been proposed to identify pathology in these circumstances. Finally, we will discuss recent evidence defining the role of exercise restriction as a therapeutic intervention in individuals predisposed to arrhythmogenic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) dysfunction is a strong predictor of outcome in heart failure and is a key determinant of exercise capacity. Despite these crucial findings, the RV remains understudied in the clinical, experimental, and computer modelling literature. This review outlines how recent advances in using computer modelling and cardiac imaging synergistically help to understand RV function in health and disease. We begin by highlighting the complexity of interactions that make modelling the RV both challenging and necessary, and then summarize the multiscale modelling approaches used to date to simulate RV pump function in the context of these interactions. We go on to demonstrate how these modelling approaches in combination with cardiac imaging have improved understanding of RV pump function in pulmonary arterial hypertension, arrhythmogenic right ventricular cardiomyopathy, dyssynchronous heart failure and cardiac resynchronization therapy, hypoplastic left heart syndrome, and repaired tetralogy of Fallot. We conclude with a perspective on key issues to be addressed by computational models of the RV in the near future. [ABSTRACT FROM AUTHOR]

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin–angiotensin–aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-b. Endothelin-1, TGF-bs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling. [ABSTRACT FROM AUTHOR]

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the risk of atrioventricular valve failure (valve intervention or moderate or greater regurgitation) during the lifetime of patients with single ventricle physiology and common atrioventricular valve. METHODS: Patients' data were extracted from an existing bi-national, population based registry. A retrospective review of their medical records was undertaken to determine the incidence of atrioventricular valve repair/replacement or moderate or greater regurgitation. RESULTS: From a registry of 1468 Fontan survivors, 136 patients with common atrioventricular valve were identified. Complete echocardiographic follow-up was available for 114 patients. Median length of follow-up was 10.2 years (interquartile range 5-15 years). Twentyfive year survival and freedom from Fontan failure were 94% [95% confidence interval (CI), 88-100%] and 74% (95% CI, 64-87%), respectively. Twenty-eight patients underwent 24 initial repairs and 4 replacements. The 24 patients undergoing repair subsequently needed 6 rerepairs, 2 replacements and 8 had moderate or greater regurgitation at last follow-up. Four-year freedom from atrioventricular valve repair failure was 50% (95% CI, 34-75%). An additional 30 patients developed moderate or greater atrioventricular valve regurgitation (6 New York Heart Association >3, 10 Fontan failures, 0 deaths). Cumulative incidence of the composite endpoint of atrioventricular valve failure at 28 years was 62% (95% CI, 49-74%). CONCLUSIONS: Patients with single ventricle physiology and common atrioventricular valve experience a continuous decline in valve function. The majority of patients experience valve failure in the first 30 years of life. [ABSTRACT FROM AUTHOR]

The effect of experimentally increasing the postpartum protein supply on plasma protein synthesis, rumen tissue proliferation, and immune homeostasis was studied using 8 periparturient Holstein cows in a complete randomized design. At calving, cows were assigned to abomasal infusion of water (CTRL) or casein (CAS) in addition to a lactation diet. Casein infusion was gradually decreased from 696 ± 1 g/d at +2 d relative to calving (DRTC) to 212 ± 10 g/d at +29 DRTC to avoid excessive supply. Synthesis rate of plasma proteins was measured at -14, +4, +15, and +29 DRTC by measuring [13C]Phe isotopic enrichment in arterial plasma free Phe, total plasma proteins, and albumin after 3, 5, and 7 h of jugular ring[13C]Phe infusion. Plasma volume was determined at +4 and +29 DRTC by dilution of a [125I]BSA dose. Synthesis rate of tissue protein in biopsied rumen papillae was determined by measuring [13C]Phe isotopic enrichment, and mRNA expression of selected genes was measured by real-time qPCR. Total and differential leukocyte counts were performed and immune responsiveness of monocytes was evaluated by tumor necrosis factor α (TNFα) concentration on ex vivo whole blood stimulation with Escherichia coli lipopolysaccharide (LPS) and responsiveness of T-lymphocytes by interferon β (IFNβ) concentration on stimulation with Staphylococcus aureus enterotoxin ß (SEB). Further, ELISA plasma concentrations of IgM, IgA, and IgG were determined. The DRTC affected the majority of investigated parameters as expected. The CAS treatment increased milk protein yield (P = 0.04), and tended to lower TNFα (P = 0.06), and lowered IFNβ (P = 0.03) responsiveness per monocyte and lymphocyte, respectively, compared with CTRL. Further, fractional synthesis rate of albumin was greater at +4 DRTC for CAS compared with CTRL but did not differ by +29 DRTC (interaction: P = 0.01). In rumen papillae, synthesis rate of tissue protein was greater for CAS compared with CTRL (P < 0.01) and mRNA expression of genes for cell proliferation tended to be or were greater for CAS compared with CTRL (P ≤ 0.07). In conclusion, increased postpartum protein supply seem to enhance vital body functions as interpreted from increased liver synthesis of albumin, increased rumen papillae proliferation, and stabilized the ex vivo inflammatory responsiveness of leukocytes. Further studies are needed to enlighten the importance of increased postpartum protein supply in periparturient cows. [ABSTRACT FROM AUTHOR]

We performed 2 experiments to study the effects of supplementing sow diets with Saccharomyces cerevisiae refermented sorghum dried distiller's grains with solubles (SSDDGS) from late gestation to weaning on the performance of sows and their progeny. In Exp. 1, 24 sows at 85 d of gestation were allocated to the following 3 dietary treatments: 1) sows fed a basal diet from late gestation to weaning (n = 8), 2) sows fed a diet with 2% SSDDGS (n = 8), and 3) sows fed a diet with 4% SSDDGS (n = 8). The 4% SSDDGS treatment significantly improved the sows' ADFI, the litter weaning alive rate, and the individual piglet weaning weights and significantly reduced the litter stillbirth rate and the levels of urea N and somatic cell counts (SCC) in the milk. However, the 2% SSDDGS treatment did not alter the performance of the sows or progeny. Therefore, we considered the volume of 4% SSDDGS to be more efficient than 2% SSDDGS. To verify the results of Exp. 1, we performed Exp. 2, in which 60 sows at 85 d of gestation were allocated into the following 2 dietary treatments: 1) sows fed a basal gestation diet from 85 d of gestation to weaning (n = 30) and 2) sows fed a basal diet with 4% SSDDGS from 85 d of gestation to weaning (n = 30). The 4% SSDDGS supplementation tended to increase the sows' ADFI, litter weaning size, litter weight gain during lactation, and individual piglet weaning weight and weight gain during lactation, and it also increased the milk yield and the fat and DM contents of the milk. This treatment also decreased the levels of urea N and SCC in the milk. Therefore, the present study indicates that supplementing sow diets with 4% SSDDGS from late gestation to weaning has the potential to 1) increase sow ADFI, 2) promote progeny growth performance, 3) increase sow milk production and quality, and 4) improve the maternal health status as indicated by improved protein utilization and reduced potential inflammatory response. [ABSTRACT FROM AUTHOR]

Study Question: What is the clinical association of maternal thyroid function with placental hemodynamic function?Summary Answer: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance.What Is Known Already: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion.Study Design, Size, Duration: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy.Participants/materials, Setting, Method: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women.Main Results and the Role Of Chance: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively.Limitations, Reasons For Caution: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes.Wider Implications Of the Findings: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction.Study Funding/competing Interest(s): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Animal studies and case reports have suggested that methylphenidate exerts adverse effects on gonadal hormones. This study aimed to determine whether methylphenidate alters testosterone levels in children with attentiondeficit/ hyperactivity disorder through comparison of those with or without methylphenidate treatment. Methods: This 4-week, nonrandomized, prospective study conducted in Taiwan included 203 attention-deficit/hyperactivity disorder patients with a mean age of 8.7 years (boys: 75.8%). After the initial recruitment, 137 received daily methylphenidate treatment (medicated group) and 66 were assessed through naturalistic observation (nonmedicated group). The saliva samples of attention-deficit/hyperactivity disorder patients were used to quantify testosterone levels at baseline and the endpoint by using the chemiluminescence immunoassay. At the 4th week, 86 patients in the medicated group and 46 patients in the nonmedicated group were eligible for statistical analyses. Results: During the study period, salivary testosterone levels did not significantly change in the medicated group (P = .389) or in the nonmedicated group (P = .488). After correction for the potential confounding effects of age and sex, salivary testosterone levels still remained unchanged in the medicated and nonmedicated groups during the 4-week follow-up. In the medicated group, changes in salivary testosterone levels over 4 weeks were not significantly correlated with the methylphenidate daily dose (mean daily dose: 18.1 mg). Conclusions: Findings suggest that short-term treatment with methylphenidate at usual doses does not significantly alter salivary testosterone levels in attention-deficit/hyperactivity disorder patients. Future studies should clarify whether long-term methylphenidate treatment disrupts testosterone production as well as the function of the reproductive system. [ABSTRACT FROM AUTHOR]

Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaineinduced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine's reinforcing and psychomotor effects. [ABSTRACT FROM AUTHOR]

Background. Parkinson disease (PD) impairs control of well-learned movements. Movement control improvements are found when individuals complete tasks while focusing attention externally on manipulating an object, which is argued to occur due to automatic processing associated with well-learned movements. Focusing attention internally (on movements of one's limbs) is believed to involve conscious control networks and hinders movement performance. Previous work has shown that an external focus of attention (EFA) improved postural stability in individuals with PD (compared with an internal focus of attention [IFA]), but this improvement occurred when patients were taking dopamine medication, which modulates basal ganglia functioning responsible for well-learned movements. Objective. The purpose of this study was to determine whether an EFA or IFA is beneficial for postural stability in individuals with PD in the absence of dopamine replacement. Design. A within-participant design was utilized. Methods. Nineteen individuals with PD stood on a firm, unstable platform in 3 attentional conditions: (1) EFA, (2) IFA, and (3) control (participant asked to stand still). Displacement and variability of anterior-posterior and medial-lateral postural sway were measured with a balance system for fall risk assessment. The protocol was completed both "on" and "off" (mininum 12-hour withdrawal of) dopaminergic medications. Results. While off medications, anterior-posterior sway variability was significantly lower during an IFA compared with the EFA and control. Anterior-posterior sway displacement and variability were significantly lower during the IFA, when off medications were compared with IFA and EFA while on medications. Limitations. There was no comparison with a healthy age-matched control group, and a safety harness was used due to task difficulty. Conclusions. An EFA may recruit automatic processes that involve degenerated basal ganglia in PD, and absence of dopamine exacerbates dysfunction. Training with an EFA may improve upon these automatic processes in individuals with PD. [ABSTRACT FROM AUTHOR]

Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation. [ABSTRACT FROM AUTHOR]

Objective. The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-termmultimodal treatment are lacking. Methods. We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n519). Treatment response at follow-up was defined as pain relief >30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation. Results. At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n517, P< 0.05), whereas there was no improvement in nonresponders (n57). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r50.49, P< 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression. Conclusion. Thus, the persistence of blunt hyperalgesia seems to be associated with impaired pairedpulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup. [ABSTRACT FROM AUTHOR]

Immune senescence as well as disturbed CD8+ T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers ( n = 10), viral non-controllers ( n = 16) and patients on ART ( n = 20), were analysed and compared to uninfected controls ( n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer+ CD8+ T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57+CD8+ T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127+CD8+ cells increased in Tcm and TemRO. We observed a reduction of CD127- T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8+ TemRO cells predominantly displayed a CD127-CD57+ phenotype in untreated HIV-patients, whereas the CD127+CD57- phenotype was under-represented in these patients. The frequency of the CD127+CD57-CD8+ T cell subpopulation correlated strongly with absolute CD4+ counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8+ memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Aortic valve replacement (AVR) via minimally invasive surgery (MIS) may provide clinical benefits in patients with aortic valve disease. A new class of bioprosthetic valves that enable rapid deployment AVR (RDAVR) may facilitate MIS. We here report the 1-year results of a randomized, multicentre trial comparing the outcomes for MIS-RDAVR with those for conventional AVR via full sternotomy (FS) with a commercially available stented aortic bioprosthesis. METHODS: A total of 100 patients with aortic stenosis were enrolled in a prospective, multicentre, randomized comparison trial (CADENCEMIS). Key exclusion criteria included AVR requiring concomitant procedures, ejection fraction of <25% and recent myocardial infarction or stroke. Patients were randomized to undergo MIS-RDAVR via upper hemisternotomy (EDWARDS INTUITY) or AVR via FS with a commercially available stented valve. Procedural, early and late clinical outcomes were assessed for both groups. Haemodynamic performance was evaluated by an echocardiography CoreLaboratory. RESULTS: Technical success was achieved in 94% of MIS-RDAVR patients. MIS-RDAVR was associated with significantly reduced cross-clamp times compared with FS (41.3 ± 20.3 vs 54.0 ± 20.3 min, P < 0.001). Clinical and functional outcomes were similar at 30 days and 1 year postoperatively for both groups. While both groups received a similarly sized implanted valve (22.9 ± 2.1 mm MIS-RDAVR vs 23.0 ± 2.1 mm FSAVR; P = 0.91), MIS-RDAVR patients had significantly lower peak gradients 1 year postoperatively (16.9 ± 5.3 vs 21.9 ± 8.6 mmHg; P = 0.033) and a trend towards lower mean gradients (9.1 ± 2.9 vs 11.5 ± 4.3 mmHg; P = 0.082). In addition, MIS-RDAVR patients had a significantly larger effective orifice area 1 year postoperatively (1.9 ± 0.5 vs 1.7 ± 0.4 cm2; P = 0.047). Paravalvular leaks, however, were significantly more common in the MIS-RDAVR group (P = 0.027). CONCLUSIONS: MIS-RDAVR is associated with a significantly reduced cross-clamp time and better valvular haemodynamic function than FS-AVR. However, paravalvular leak rates are higher with MIS-RDAVR. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The optimal surgical treatment strategy for transposition of the great arteries (TGA) associated with ventricular septal defect (VSD) and left ventricular outflow tract obstruction (LVOTO) leading to the best long-term outcome has not been established yet. The wide range of anatomical variability has led to the development of different surgical treatment options. In a retrospective single-centre review, we aimed to report the long-term outcome in patients who underwent biventricular repair. METHODS: Between 1992 and 2015, 49 patients underwent biventricular repair for TGA with VSD and LVOTO. On the basis of anatomical substrate, the type of repair was chosen. According to the type of repair, the patients were divided into two groups. Group A (n = 30 patients) includes all patients who underwent intraventricular rerouting (Rastelli, n = 22; réparation à l'étage ventriculaire, n = 8); Group B patients (n = 14) had repair on an arterial level (arterial switch operation + VSD closure + LVOTO resection, n = 10; Bex-Nikaidoh, n = 4). RESULTS: The follow-up was completed in 90% with a median follow-up of 12.3 years (17.1-17.7 years). There was no difference in survival (Group A: 97% at 5, 10 and 15 years; Group B: 92% at 5, 10 and 15 years) and functional outcome between the groups. All patients were in New York Heart Association class I, having sinus rhythm and normal left ventricular (LV) function. Neurological and educational development was adequate for age in all but one who suffered from attention-deficit hyperactivity disorder. Group A exhibited significantly less freedom from right ventricular outflow tract (RVOT) reoperations/reintervention (79, 48 and 21% at 5, 10 and 15 years) (P = 0.008) due to RVOT dysfunction and endocarditis. Event-free LVOTO survival in Group A at 5, 10 and 15 years amounted to 96, 91 and 91% and was similar to Group B with event-free LVOTO survival at 5, 10 and 15 years of 100, 88 and 88%, respectively. CONCLUSIONS: LV function is well preserved irrespective of the type of procedure. Patients who had undergone intraventricular rerouting (Group A) suffered from recurrent RVOT interventions due to RVOT dysfunction and endocarditis. The neurological outcome and the educational level were adequate for age in both groups. Executing the appropriate type of surgery for the individual patient's anatomy provides excellent functional and event-free outcome. [ABSTRACT FROM AUTHOR]

Background: The striatal dopamine system undergoes vast ontogenetic changes during adolescence, making the brain vulnerable to drug treatments that target this class of neurotransmitters. Atypical antipsychotic drugs are often prescribed to children and adolescents for off-label treatment of neuropsychiatric disorders, yet the long-term impact this treatment has on brain development remains largely unknown. Methods: Adolescent male rats were treated with olanzapine or vehicle for 3 weeks (during postnatal day 28-49) using a dosing condition designed to approximate closely D2 receptor occupancies in the human therapeutic range. We assessed D2 receptor modulation of corticostriatal inputs onto medium spiny neurons in the adult ventral striatum using in vitro wholecell current clamp recordings. Results: The D2/D3 agonist quinpirole (5 μM) enhanced cortically driven medium spiny neuron synaptic responses in slices taken from adult rats treated with vehicle during adolescence, as in untreated adult rats. However, in slices from mature rats treated with olanzapine during adolescence, quinpirole reduced medium spiny neuron activation. The magnitude of decrease was similar to previous observations in untreated, prepubertal rats. These changes may reflect alterations in local inhibitory circuitry, as the GABA-A antagonist picrotoxin (100 μM) reversed the effects of quinpirole in vehicle-treated slices but had no impact on cortically evoked responses in olanzapine-treated slices. Conclusions: These data suggest that adolescent atypical antipsychotic drug treatment leads to enduring changes in dopamine modulation of corticostriatal synaptic function. [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling. [ABSTRACT FROM AUTHOR]

Objective: Better Nights/Better Days, a distance intervention for insomnia in school-aged children (with and without attention-deficit/hyperactivity disorder [ADHD]), was evaluated to determine its effectiveness on children's sleep and psychosocial functioning.Methods: A single center, parallel group design randomized controlled trial (stratified on ADHD diagnosis) was conducted. Parents were randomized to intervention (n = 31) or waitlist control (n = 30), and completed questionnaires administered over the phone at baseline, postintervention (2 months), and follow-up (6 months). Actigraphy was also collected. The intervention consisted of a five-session manual and weekly telephone coach support.Results: The intervention group demonstrated a significant reduction in sleep problems and improved psychosocial functioning at postintervention and follow-up. Actigraphy results indicated improved sleep onset, but not sleep duration. Children with and without ADHD responded in a similar manner to this intervention. Parents provided high satisfaction ratings.Conclusions: This intervention holds promise as an accessible, sustainable, and effective program to address insomnia in school-aged children. [ABSTRACT FROM AUTHOR]

Unlabelled: OBJECTIVE : To determine how between- and within-person variability in perceived sleep quality were associated with adolescent diabetes management.Methods: A total of 236 older adolescents with type 1 diabetes reported daily for 2 weeks on sleep quality, self-regulatory failures, frequency of blood glucose (BG) checks, and BG values. Average, inconsistent, and daily deviations in sleep quality were examined.  RESULTS : Hierarchical linear models indicated that poorer average and worse daily perceived sleep quality (compared with one's average) was each associated with more self-regulatory failures. Sleep quality was not associated with frequency of BG checking. Poorer average sleep quality was related to greater risk of high BG. Furthermore, inconsistent and daily deviations in sleep quality interacted to predict higher BG, with more consistent sleepers benefitting more from a night of high-quality sleep.  CONCLUSIONS : Good, consistent sleep quality during late adolescence may benefit diabetes management by reducing self-regulatory failures and risk of high BG. [ABSTRACT FROM AUTHOR]

Objectives: To examine subjective fatigue and sleepiness as predictors of functional outcomes in long-term pediatric hematopoietic stem cell transplant (HSCT) survivors.Methods: Participants included 76 survivors assessed 5-14 years post-HSCT. Self-report and parent-proxy (i.e., N = 38) measures of fatigue, excessive daytime sleepiness (EDS), emotional and behavioral functioning, executive functioning, and quality of life (QOL) were completed. Health-related correlates were obtained from medical records.Results: Survivors exhibited significant fatigue for self (M = 69.21 ± 20.14) and parent-proxy (M = 72.15 ± 20.79) report. EDS was endorsed for 20-33% of survivors, depending on the respondent. EDS was not significant for parent-proxy outcomes, but was associated with poorer self-reported QOL and internalizing problems (p < .0016). Fatigue was associated with poorer functioning across all domains (p's < .0016).Conclusions: A substantial number of pediatric HSCT survivors exhibit sleepiness and fatigue. Fatigue is associated with statistically and clinically greater functional difficulties, highlighting the importance of examining sleep and fatigue and considering interventions to improve alertness. [ABSTRACT FROM AUTHOR]

Background. Low-intensity ultrasound (LUIS) can reduce pain and improve function in arthritic joints. Neutrophils are first-line actors in host defense that recruit macrophages. Dead neutrophils are removed during resolution of inflammation. Delayed neutrophil clearance can lead to extended inflammation or even chronic autoimmune disease. Although neutrophil extracellular traps (NETs) in arthritic tissue are involved in the pathogenesis of arthritis, their functional role has not been clarified. Objectives. This study aimed to investigate the effect of LUIS on synovial inflammation and its resolution via neutrophil clearance. Methods. Synovitis was induced by intra-articular injection of complete Freund's adjuvant (CFA) into the left knee joint of 58 adult male Sprague-Dawley rats. Low-intensity ultrasound (1 MHz, 200 mW/cm") was applied for 10 minutes daily. Neutrophil clearance was assessed with the expression of myeloperoxidase (MPO). In addition, terminal deoxynucleotidyl trans-ferase dUTP nick end labeling (TUNEL) staining and NET formation in the synovium were observed. In neutrophil and macrophage cultures from peripheral blood, the effect of NET clearance by LUIS was investigated. Results. In CFA-induced synovitis, MPO-positive neutrophils peaked after 2 to 3 days, filling the inflammatory core. Monocytes and macrophages in the periphery later infiltrated the core and were reduced thereafter. Low-intensity ultrasound reduced synovial hyperplasia and induced earlier MPO clearance. Neutrophils in the core of the inflamed synovium exhibited NET formation, which LIUS increased. Low-intensity also induced NETs in peripheral poly-morphonuclear cells in an intensity-dependent manner and potentiated phorbol myristate acetate (PMA)-induced NETosis. The PMA-induced NETs were cleared by macrophages; clearance was enhanced by LIUS. Limitations. The effect of LIUS on CFA-induced inflammation was observed only during the acute phase. Although the effect of LIUS on NETosis in the in vitro neutrophil culture system was clear, the in vivo NETosis cannot be quantified. Conclusions. Neutrophil extracellular traps act in inflammatory synovitis, and LIUS enhanced the NETs and resulted in neutrophil clearance by enhancing the phagocytosis of macrophages, which might be a factor underlying the therapeutic effect of LIUS in arthritic synovium. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation has shown promise to improve recovery in patients with post-stroke aphasia, but previous studies have only assessed stimulation effects on impairment parameters, and evidence for long-term maintenance of transcranial direct current stimulation effects from randomized, controlled trials is lacking. Moreover, due to the variability of lesions and functional language network reorganization after stroke, recent studies have used advanced functional imaging or current modelling to determine optimal stimulation sites in individual patients. However, such approaches are expensive, time consuming and may not be feasible outside of specialized research centres, which complicates incorporation of transcranial direct current stimulation in day-to-day clinical practice. Stimulation of an ancillary system that is functionally connected to the residual language network, namely the primary motor system, would be more easily applicable, but effectiveness of such an approach has not been explored systematically. We conducted a randomized, parallel group, sham-controlled, double-blind clinical trial and 26 patients with chronic aphasia received a highly intensive naming therapy over 2 weeks (8 days, 2 × 1.5 h/day). Concurrently, anodal-transcranial direct current stimulation was administered to the left primary motor cortex twice daily at the beginning of each training session. Naming ability for trained items (n = 60 pictures that could not be named during repeated baseline assessments), transfer to untrained items (n = 284 pictures) and generalization to everyday communication were assessed immediately post-intervention and 6 months later. Naming ability for trained items was significantly improved immediately after the end of the intervention in both the anodal (Cohen's d = 3.67) and sham-transcranial direct current stimulation groups (d = 2.10), with a trend for larger gains in the anodal-transcranial direct current stimulation group (d = 0.71). Treatment effects for trained items were significantly better maintained in the anodal-transcranial direct current stimulation group 6 months later (d = 1.19). Transfer to untrained items was significantly larger in the anodal-transcranial direct current stimulation group after the training (d = 1.49) and during the 6 month follow-up assessment (d = 3.12). Transfer effects were only maintained in the anodal-transcranial direct current stimulation group. Functional communication was significantly more improved in the anodal-transcranial direct current stimulation group at both time points compared to patients treated with sham-transcranial direct current stimulation (d = 0.75-0.99). Our results provide the first evidence from a randomized, controlled trial that transcranial direct current stimulation can improve both function and activity-related outcomes in chronic aphasia, with medium to large effect sizes, and that these effects are maintained over extended periods of time. These effects were achieved with an easy-to-implement and thus clinically feasible motor-cortex montage that may represent a promising 'backdoor' approach to improve language recovery after stroke. [ABSTRACT FROM AUTHOR]

Aims: Data on longer right to left ventricular activation delay (RV-LV AD) predicting clinical outcome after cardiac resynchronization therapy (CRT) by left bundle branch block (LBBB) are limited. We aimed to evaluate the impact of RV-LV AD on N-terminal pro-B-type natriuretic peptide (NT-proBNP), ejection fraction (EF), and clinical outcome in patients implanted with CRT, stratified by LBBB at baseline.Methods and Results: Heart failure (HF) patients undergoing CRT implantation with EF ≤ 35% and QRS ≥ 120 ms were evaluated based on their RV-LV AD at implantation. Baseline and 6-month clinical parameters, EF, and NT-proBNP values were assessed. The primary endpoint was HF or death, the secondary endpoint was all-cause mortality. A total of 125 patients with CRT were studied, 62% had LBBB. During the median follow-up of 2.2 years, 44 (35%) patients had HF/death, 36 (29%) patients died. Patients with RV-LV AD ≥ 86 ms (lower quartile) had significantly lower risk of HF/death [hazard ratio (HR): 0.44; 95% confidence interval (95% CI): 0.23-0.82; P = 0.001] and all-cause mortality (HR: 0.48; 95% CI: 0.23-1.00; P = 0.05), compared with those with RV-LV AD < 86 ms. Patients with RV-LV AD ≥ 86 ms and LBBB showed the greatest improvement in EF (28-36%; P<0.001), NT-proBNP (2771-1216 ng/mL; P < 0.001), and they had better HF-free survival (HR: 0.23, 95% CI: 0.11-0.49, P < 0.001) and overall survival (HR: 0.35, 95% CI: 0.16-0.75; P = 0.007). There was no difference in outcome by RV-LV AD in non-LBBB patients.Conclusion: Left bundle branch block patients with longer RV-LV activation delay at CRT implantation had greater improvement in NT-proBNP, EF, and significantly better clinical outcome. [ABSTRACT FROM AUTHOR]

Duloxetine is a second-generation selective serotonin and norepinephrine reuptake inhibitor used primarily for the treatment of depression. Relatively few fatalities have been reported in association with its use. Similarly, there are no known reports that provide a comprehensive analysis of blood, fluid and tissue samples in an overdose setting. Herein we present a fatal case of duloxetine toxicity with both the highest reported post-mortem blood concentration and a comprehensive toxicological analysis of duloxetine in femoral blood, vitreous humor, liver tissue, urine and gastric contents. In doing so, we hope to provide data that can assist both toxicologists and forensic pathologists with assessing duloxetine toxicity in the future. [ABSTRACT FROM AUTHOR]

Aims: Right ventricular pacing adversely affects left atrial (LA) structure and function that may trigger atrial fibrillation (AF). This study compares the occurrence of persistent/permanent AF during long-term Hisian area (HA), right ventricular septal (RVS), and right ventricular apex (RVA) pacing in patients with complete/advanced atrioventricular block (AVB).Methods and Results: We collected retrospective data from 477 consecutive patients who underwent pacemaker implantation for complete/advanced AVB. Ventricular pacing leads were located in the HA, RVS, and RVA in 148, 140, and 189 patients, respectively. The occurrence of persistent/permanent AF was observed in 114 (23.9%) patients (follow-up 58.5 ± 26.5 months). Hisian area groups presented a lower rate of AF occurrence (16.9%) compared with RVS and RVA groups (25.7 and 28.0%, respectively), P = 0.049. Cox's proportional hazard model was used to estimate HR. The risk of persistent/permanent AF was significantly lower in the patients paced from HA compared with those paced from RVA, HR = 0.28 (95% CI 0.16-0.48, P = 0.0001). The RVS and RVA pacing groups showed a similar AF risk: HR 1.04 (95% CI 0.66-1.64, P = 0.856). Other independent predictors of persistent/permanent AF occurrence included previous (before device implantation) paroxysmal AF (HR = 4.08; 95% CI 3.15-7.31, P = 0.0001), LA diameter, and age, whereas baseline bundle-branch block was associated with a lower risk of AF occurrence (HR = 0.56; 95% CI 0.35-0.81, P = 0.003).Conclusions: HA pacing compared with RVA or RVS pacing seems to be associated with a lower risk of persistent/permanent AF occurrence. The risk of persistent/permanent AF was similar in the RVA vs. RVS groups. [ABSTRACT FROM AUTHOR]

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. [ABSTRACT FROM AUTHOR]

Aims: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts.Method and Results: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference.Conclusion: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening. [ABSTRACT FROM AUTHOR]

The present study evaluates antigenotoxic and antimutagenic properties of diphenyl ditelluride (DPDT) against several known mutagens in Chinese hamster lung fibroblasts (V79 cells). DPDT was not cytotoxic and genotoxic at concentrations ranging from 0.01 to 0.1 µM. The pre-treatment for 2 h with this organotellurium compound at non-cytotoxic dose range (0.01, 0.05 and 0.1 µM) increased cell survival after challenge with hydrogen peroxide (H2O2), t-butyl hydroperoxide (t-BOOH), methylmethanesulphonate (MMS) or ultraviolet (UV)C radiation. In addition, the pre- treatment with DPDT decreased the DNA damage and Formamidopyrimidine DNA-glycosylase (Fpg)- and Endonuclease III (Endo III) sensitive sites induction by the studied genotoxic agents, as verified by comet assay and modified comet assay, respectively. The pre-treatment also reduced micronucleus frequency, revealing the protector effect of DPDT against MMS and UVC-induced mutagenesis. Our results demonstrate that DPDT -treated cells at concentration range of 0.01-0.1 µM do not change thiobarbituric acid reactive species (TBARS) levels and ROS generation. Moreover, DPDT pre-treatment at this concentration range decreases the ROS induction by H2O2 and t-BOOH treatment indicating antioxidant potential. On the other hand, concentrations higher than 0.1 µM increase TBARS formation and inhibited superoxide dismutase (SOD) activity, suggesting pro-oxidative effect of this compound at high concentrations. Our results suggest that DPDT presents antigenotoxic and antimutagenic properties at concentration range of 0.01-0.1 µM. The protection effect could be attributed to antioxidant capacity of DPDT at this concentration range in V79 cells. [ABSTRACT FROM AUTHOR]

Aims Right ventricular (RV) as well as left ventricular (LV) function has been recognized as an important prognostic factor for heart failure patients. Our objective was thus to investigate the prognostic significance of combined assessment of bi-ventricular functional reserve for patients with dilated cardiomyopathy (DCM). Methods and results We studied 104DCMpatients with ejection fractions (EF) of 32±9%, and speckle-tracking echocardiography was used to assess both RV and LV contractile reserve under dobutamine stress (20 µg/kg/min). RV contractile function was measured as peak global longitudinal strain (GLS) from the RV free wall (RV-free), and LV function as global circumferential strain (GCS) and GLS, respectively. Event-free survival was then tracked for 17 months. Twenty-one patients (20%) developed cardiovascular events. A multivariate Cox proportional-hazards analysis revealed that the baseline EF, E/A, and the relative change in EF (ΔEF), in GCS (ΔGCS), and in RV-free (ΔRV-free) during dobutamine stress were the independent predictors of cardiovascular events (P <0.001, <0.05, <0.01, <0.05, and <0.01, respectively). A Cox model based on baseline clinical and echocardiographic variables (χ² = 23.6) was improved by the addition of LV contractile reserve parameters (plus DGCS and DEF) (χ² = 49.1; P < 0.001) and further improved by adding RV contractile reserve (plus ΔRV-free) (χ² = 60.3, P < 0.001). Conclusion Assessment of RV contractile reserve during dobutamine stress offers a significantly better prognostic value for patients with DCM. Bi-ventricular contractile reserve may be required for a favourable outcome, so that estimation of RV contractile reserve should be considered part of a comprehensive functional assessment of these patients. [ABSTRACT FROM AUTHOR]

Chronic wounds are a growing medical problem that cause high rates of morbidity and mortality, costing the healthcare industry in the United States millions of dollars annually. Chronic wound healing is hampered by the presence of bacterial infections that form biofilms, in which the bacteria are encased in exopolysaccharide (EPS) and are less metabolically active than their free-living counterparts. Bacterial biofilms make chronic wounds more refractory to treatment and slow tissue repair by stimulating chronic inflammation at the wound site. Bacterial species communicate through a mechanism known as quorum sensing (QS) to regulate and coordinate the gene expression that is important for virulence-factor production, including biofilm formation. This review focuses on the relationships between chronic wounds, biofilms, and QS in the virulence of chronic-wound pathogens. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive dysfunction is reported in women with breast cancer even prior to receipt of adjuvant therapy; however, there is little understanding of underlying mechanisms. We tested the hypothesis that pretreatment neurocognitive dysfunction in newly diagnosed patients is related to immunological activation, as indexed by proinflammatory cytokines. Methods: One hundred seventy-four postmenopausal patients with newly diagnosed breast cancer underwent a comprehensive neuropsychological evaluation (assessment of cognitive function, mood, and fatigue) and measurement of key cytokine levels prior to surgery. Age-matched control participants without cancer were evaluated concurrently. Multivariable regression analyses examined the contribution of circulating Interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and soluble TNF receptor type two (sTNF-RII) in predicting neurocognitive performance in patients after controlling for key factors thought to impact functioning. All tests of statistical significance were two-sided. Results: Memory performance was statistically significantly reduced, in patients compared with controls (P = .02). Of the three cytokines measured, only IL-1ra was statistically significantly elevated in cancer patients when compared with control participants (mean ± SD, 375 ± 239 pg/mL vs 291 ± 169 pg/mL, P = .007). After controlling for age, education, race, mood, fatigue, body mass index, and comorbidity, cytokines independently explained 6.0% of the total variance in memory performance (P = .01) in cancer patients but not control participants, with higher sTNF-RII associated with worse functioning. Exploratory analyses found that comorbidity statistically significantly explained variance in processing speed and executive functioning (P = .03 and P = .03, respectively). Conclusion: An association of TNF with memory, previously reported in patients after exposure to chemotherapy, was found prior to initiation of any treatment, including surgery. This association requires further investigation as sTNF-RII was not higher in cancer patients relative to control participants. [ABSTRACT FROM AUTHOR]

Background: Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort. Methods: Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided. Results: Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from $183 in the fourth quarter of 2009 to $15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study. Conclusions: The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage. [ABSTRACT FROM AUTHOR]

Aims Since myocardial dysfunction in diabetic patients without coronary artery disease (CAD) is subtle at rest, the assessment during dobutamine stress echocardiography (DSE) may be more sensitive for detection of myocardial involvement. We assessed systolic function of the left ventricle during all stages of DSE in 3diabetic patients free of significant CAD using state-of-the-art speckle-tracking quantification. Methods and results We performed DSE in 250 patients with angina recording views during baseline (0), peak (1), and recovery phase (2). All patients had coronary anatomy verified with ≥50% stenosis in left main and ≥70% in other arteries considered as significant. In this analysis, we included 25 subjects with diabetes mellitus (DM) but without CAD (mean age 62 ± 8) and compared them with an age- and sex-matched group of 85 controls without DM and CAD (mean age 60 ± 9). Global peak systolic longitudinal strain (PSLS) of the left ventricle was obtained by automated function imaging (AFI) at rest, peak, and recovery phase of DSE. The global PSLS was similar in both groups at baseline (-17.3 ± 4.0% in diabetics vs. -18.7 ± 3.3% in controls, P = ns)andatpeakstageofDSE (-16.4 ± 4.5% in diabetics vs. -17.9 ± 4.2% in controls, P = ns),whereas at recovery absolute valuewaslower in patientswith DM (-15.3 ± 3.2% vs. -17.2 ± 3.3%, P = 0.01). Conclusion Peak systolic longitudinal strain measured by AFI during recovery of DSE was impaired in diabetic patients. It may reflect longer time needed for full restoration of myocardial systolic function in this group of subjects. [ABSTRACT FROM AUTHOR]

SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including general constitutional symptoms and extraglandular features. A multidisciplinary approach focused on both local and systemic medical therapies is needed as the disease has a wide clinical spectrum. The current treatment for SS is mainly symptomatic. However, there is evidence that systemic drugs are effective in controlling extraglandular manifestations of the disease. Overall evidence for the role of conventional immunosuppressive therapy is limited. A number of attempts to use biologic therapies have led to variable results. Biologic agents targeting B cells, such as rituximab, epratuzumab and belimumab, have shown promising results, but further studies are needed to validate the findings. Early-phase studies with abatacept and alefacept proved that T cell stimulation inhibition is another potentially effective target for SS treatment. Modulation or inhibition of other targets such as IFN, IL-6 and Toll-like receptor are also currently being investigated. We have summarized the available evidence regarding the efficacy of biologic treatments and discuss other potential therapies targeting pathways or molecules recognized as being involved in the pathogenesis of SS. [ABSTRACT FROM PUBLISHER]

Objectives. The aim of the study was to examine the effect of bosentan on blood flow in the hand in a subset of patients who had reduced blood flow relative to healthy subjects. Additionally, the relationship between blood flow in the hands of SSc patients and the presence of digital ulcers (DUs) was assessed.Methods. SSc patients with a recent history of DUs and healthy subjects were included. Patients were classified into four subgroups: no current DUs or pitting scars, pitting scars only, new DUs or persistent DUs. The hand was categorized into three regions of interest (ROIs) and blood flow was measured by laser Doppler perfusion imaging at baseline, 4 and 12 weeks. Patients who had a reduction in blood flow of >50% relative to healthy control subjects in ROI 1 on baseline were treated with bosentan for 12 weeks.Results. Fifty-two SSc patients and 51 healthy subjects were included in the analysis. There was no significant difference in blood flow in the hand across the patient subgroups at baseline. Sixteen SSc patients had a reduction of blood flow of ≥50% vs healthy subjects and received bosentan. Bosentan significantly (P < 0.05) increased blood flow in the whole hand after 12 weeks compared with baseline.Conclusion. No relationship was found between blood flow in the hands and the presence of DUs. After 12 weeks of bosentan treatment, blood flow had increased in the SSc patients but had not normalized to that of healthy subjects.Trial registration: https://www.clinicaltrialsregister.eu/ (EudraCT number 2010-023908-27). [ABSTRACT FROM PUBLISHER]

Objective. The aim of this study was to investigate the effect of umbilical cord mesenchymal stem cells (UC-MSCs) on circulating T follicular helper (cTfh) cells in primary SS (pSS) patients.Methods. The percentage of CXCR5+PD-1+CD4+ T cells in peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry. PBMCs were co-cultured with UC-MSCs by cell-to-cell contact or in a trans-well system. Naive CD4+ T cells were isolated from PBMCs and then co-cultured with UC-MSCs under Tfh cell-polarizing conditions. The percentage of CXCR5+PD-1+CD4+ T cells, carboxyfluorescein succinimidyl ester (CFSE) fluorescence intensity and annexin V were determined by flow cytometric analysis. Real-time PCR and Luminex cytokine assay were performed to detect mRNA expression and supernatant protein levels. The activity of indoleamine 2,3-dioxygenase (IDO) was measured by HPLC.Results. Increased frequency of cTfh cells was found in pSS patients and was positively correlated with serum anti-La/SSB levels and the European League Against Rheumatism SS Disease Activity Index score. In vitro, UC-MSCs suppressed the differentiation and proliferation of cTfh cells. Real-time PCR analysis showed significantly higher IDO mRNA expression on UC-MSCs when co-cultured with naive CD4+ T cells under Tfh cell-polarizing conditions in pSS patients. However, IDO mRNA expression on UC-MSCs was only a little higher when UC-MSCs were co-cultured with naive CD4+ T cells in a trans-well system. In addition, HPLC showed increased IDO enzymic activity in the supernatant of UC-MSCs co-cultured with naive CD4+ T cells under Tfh cell-polarizing conditions in pSS. The addition of the IDO inhibitor 1-MT partly reversed the suppressive effect of UC-MSCs on the differentiation of cTfh cells.Conclusion. These results suggest an inhibitory effect of UC-MSCs on the differentiation of cTfh cells via the secretion of IDO, and soluble factors secreted by activated CD4+ T cells might contribute to IDO secretion by UC-MSCs. [ABSTRACT FROM PUBLISHER]

The issue of inter-hemispheric connectivity is an emerging new area in understanding the pathophysiology of depression. This study was designed to analyse the pattern of inter-hemispheric connectivity in patients with major depressive disorder (MDD). The resting-state functional magnetic resonance imaging (RFMRI) was acquired in all enrolled patients and controls. We used a method of voxel-mirrored homotopic connectivity (VMHC) to estimate the significant differences in inter-hemispheric connectivity between 44 patients with first-episode medication-naïve MDD and 27 normal controls. The patients and controls were matched for age and gender. The patients with first-episode medication-naïve MDD showed lower VMHC than normal controls in bilateral medial frontal cortex, anterior cingulate and cerebellar posterior lobe. The strength of inter-hemispheric connectivity VMHC value was negatively correlated with clinical severity of MDD. From the results, we suggested that decreased inter-hemispheric connectivity in the anterior sub-network of the default mode network and the cerebellar posterior lobe might represent an emerging finding in the pathophysiology for MDD. [ABSTRACT FROM AUTHOR]

Aims During activation of cardiac myocytes, less than 1% of cytosolic Ca is free; the rest is bound to buffers, largely SERCA, and troponin C. Signalling by phosphorylation, as occurs during β-adrenergic stimulation, changes the Ca-binding affinity of these proteins and may affect the systolic Ca transient. Our aim was to determine the effects of β-adrenergic stimulation on Ca buffering and to differentiate between the roles of SERCA and troponin. Methods and results Ca buffering was studied in cardiac myocytes from mice: wild-type (WT), phospholamban-knockout (PLN-KO), and mice expressing slow skeletal troponin I (ssTnI) that is not protein kinase A phosphorylatable. WT cells showed no change in Ca buffering in response to the β-adrenoceptor agonist isoproterenol (ISO). However, ISO decreased Ca buffering in PLN-KO myocytes, presumably unmasking the role of troponin. This effect was confirmed in WT cells in which SERCA activity was blocked with the application of thapsigargin. In contrast, ISO increased Ca buffering in ssTnI cells, presumably revealing the effect of an increase in Ca binding to SERCA. Conclusions These data indicate the individual roles played by SERCA and troponin in Ca buffering during β-adrenergic stimulation and that these two buffers effectively counterbalance each other so that Ca buffering remains constant during β-adrenergic stimulation, a factor which may be physiologically important. This study also emphasizes the importance of taking into account Ca buffering, particularly in disease states where Ca binding to myofilaments or SERCA may be altered. [ABSTRACT FROM AUTHOR]

Background Manual therapies for chronic neck pain are imprecise, inconsistent, and brief due to therapist fatigue. A previous study showed that computerized mobilization of the cervical spine in the sagittal plane is a safe and potentially effective treatment of chronic neck pain. Objective To investigate the safety and efficacy of computerized mobilization of the cervical spine in a three-dimensional space for the treatment of chronic neck pain. Design Pilot, open trial. Setting Physical therapy outpatient department. Participants Nine patients with chronic neck pain. Interventions A computerized cradle capable of three-dimensional neck mobilizations was used. Treatment sessions lasted 20 minutes, biweekly, for six weeks. Main Outcome Measures Visual analog scale ( VAS) for pain, cervical range of motion ( CROM), neck disability index ( NDI), joint position error ( JPE), and muscle algometry. Results Comparing baseline at week one with week six (end of treatment), the VAS scores dropped by 2.9 points ( P < 0.01). The six directions of movement studied by the CROM showed a combined increase of 11% ( P = 0.01). The NDI decreased significantly from 16 to 10 ( P = 0.03), and the JPE decreased significantly from 3.7° to 1.9° ( P = 0.047). There was no change in the pressure pain threshold in any muscle tested. There were no significant adverse effects. Conclusions These preliminary results demonstrate that this novel, computerized, three-dimensional cervical mobilization device is probably safe. The data also suggest that this method is effective in alleviating neck pain and associated headache, and in increasing the CROM, although the sample size was small in this open trial. [ABSTRACT FROM AUTHOR]

Objective. We previously reported the coexistence, within cultured mesenchymal stem cells (MSCs) from human synovial membrane, of single-cell-derived clonal cell populations with distinct differentiation potency. The aim of this study was to investigate marker sets for prospective purification of functionally distinct MSC subsets.Methods. Cells were enzymatically released from human synovium and culture expanded. Phenotype analysis was performed by flow cytometry using combinations of MSC markers. Sorting was carried out using the FACS DiVA cell sorter. Sorted cell populations were assessed for clonogenicity, kinetics of growth, cell senescence and chondro-osteogenic potency.Results. During culture expansion, the co-localization of CD39 within the CD73+ cell population identified a small cell subset that was maintained from passage 1 (P1) up to at least P12 in all donors tested. The CD73+CD39+ cell subset displayed higher expression levels of Sox9 and Runx2 and a significantly greater chondro-osteogenic potency than the CD73+CD39− cell subset. In contrast, it was less clonogenic and proliferative. There was no difference in cell senescence between the sorted MSC subsets and the parental MSCs. Notably, there were no detectable differences in chondro-osteogenic potency between the CD73+CD39− and CD73+CD39+ cell subsets purified from fresh synovial cell populations.Conclusion. Our findings indicate that the combination of CD73 and CD39 allows the prospective purification from culture-expanded heterogeneous synovial MSC populations of a distinct MSC subset with greater chondro-osteogenic potency. We anticipate that such an approach will enhance the consistency of cell-based therapeutic protocols for the repair of osteochondral defects. [ABSTRACT FROM AUTHOR]

Objective. In OA, there is enhanced expression of pro-inflammatory cytokines such as IL-1β in the affected joint. Delphinidin, an anthocyanidin found in pigmented fruits and vegetables, has been shown to possess anti-inflammatory and antioxidant properties. In the present study we determined whether delphinidin would inhibit the IL-1β-induced activation of NF-κB in human chondrocytes and determined the mechanism of its action. Methods. PGE2 levels and activation of NF-κB p65 in human OA chondrocytes were determined by ELISA-based assays. Protein expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of kinases was determined by western immunoblotting. Expression level of mRNAs was determined by TaqMan assays. Results. Delphinidin inhibited IL-1β-induced expression of COX-2 and production of PGE2 in human chondrocytes. Delphinidin also inhibited IL-1β-mediated phosphorylation of IL-1 receptor-associated kinase-1Ser376, phosphorylation of IKKα/β, expression of IKKβ, degradation of IκBα, and activation and nuclear translocation of NF-κB/p65. Phosphorylation of TGF-β-activated kinase 1 was not observed but NF-κB-inducing kinase (NIK) was phosphorylated and phosphorylation of NIK was blocked by delphinidin in IL-1β-treated human chondrocytes.Conclusion. These data identify delphinidin as a novel inhibitor of IL-1β-induced production of cartilage-degrading molecule PGE2 via inhibition of COX-2 expression and provide new insight into the mechanism of its action. Our results also identify inhibition of IRAK1Ser376 phosphorylation by delphinidin in IL-1β-induced activation of NF-κB in human chondrocytes. Given the important role played by IL-1β-induced NF-κB activation, COX-2 expression and PGE2 production in OA, our results may have important implications for the development of novel therapeutic strategies for the prevention/treatment of OA. [ABSTRACT FROM AUTHOR]

Objective. To assess the relative efficacy of subsequent biologic therapies in patients with RA who have had an inadequate response to prior therapy with a TNF-α inhibitor.Methods. A systematic review was conducted using the MEDLINE, Embase and Cochrane Library databases and abstract lists from the European League Against Rheumatism, American College of Rheumatology and British Society of Rheumatology congresses. Searches covered the period from May 2009 (August 2009 for MEDLINE) to January 2011. Therapies considered were abatacept, adalimumab, etanercept, infliximab and rituximab, used at European licensed standard dose regimens.Results. Four full publications and 41 congress abstracts met the criteria for inclusion. Significant improvements in RA signs and symptoms were reported for TNF inhibitors (individual agents or groups of agents, depending on the study) and for abatacept and rituximab. Rituximab was also associated with significantly improved radiographic outcomes. No head-to-head randomized controlled trials directly comparing different agents were published during the search period. Comparative data from registries and other observational studies suggest that rituximab is at least as effective as an alternative TNF inhibitor, and in some studies significantly more effective, in TNF inadequate responders.Conclusions. RA patients with an inadequate response to one or more TNF inhibitors derive significant clinical benefit from subsequent therapy with an alternative TNF inhibitor or with rituximab or abatacept. Prospective randomized controlled trials are needed to help physicians in the best choice of further therapy for their patients. [ABSTRACT FROM PUBLISHER]