Search

Few studies have examined brief transdiagnostic groups. The Take Control Course (TCC) was developed for patients with mild to moderate common mental health problems. We examined whether TCC is non-inferior to individual low-intensity cognitive behaviour therapy (CBT) in a single-blind individually randomised parallel non-inferiority trial. The primary outcomes were depression (PHQ9) and anxiety (GAD7) at 6-month follow-up (primary outcome point) and 12-month follow-up. The non-inferiority margin that we set, based on previous trials, corresponds to approximately 3 points on the PHQ9 and approximately 2.5 points on the GAD7. Intention-to-treat (ITT) and per-protocol (PP) analyses of 6-month data of 156 randomised patients indicated that TCC was non-inferior to individual low-intensity CBT on anxiety (ITT Coefficient = 0.24; 95% CI: -1.45 to 1.92; d  = 0.04; p  = .79), and depression (ITT Coefficient = 0.82; 95% CI: -1.06 to 2.69; d  = 0.14; p  = .39) outcomes, and functioning (ITT Coefficient = 0.69; 95% CI: -2.56 to 3.94; d  = 0.08; p  = .68). The findings at 12 months were inconclusive and require further testing. This randomised trial provides preliminary support that TCC is not less effective than short-term individual CBT within Improving Access to Psychological Therapies (IAPT) services.

Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response assessment, follow-up, and treatment decision-making, and to provide interim guidance by our expert consensus. We used a three-stage consensus process. First, we systematically reviewed and appraised the quality of existing evidence. Second, we generated a list of 153 statements based on the literature review to be agreed or disagreed with, with an additional statement added after the first round. Third, the 154 statements were scored by a panel of 26 experts purposively sampled from authors of published research on haematological tumours on a 1 (strongly disagree) to 9 (strongly agree) Likert scale in a two-round electronic Delphi review. The RAND and University of California Los Angeles appropriateness method was used for analysis. Between one and 14 systematic reviews were identified on each topic. All were rated as low to moderate quality. After two rounds of voting, there was consensus on 139 (90%) of 154 of the statements. There was consensus on most statements concerning the use of PET in non-Hodgkin and Hodgkin lymphoma. In multiple myeloma, more studies are required to define the optimal sequence for treatment assessment. Furthermore, nuclear medicine physicians and haematologists are awaiting consistent literature to introduce volumetric parameters, artificial intelligence, machine learning, and radiomics into routine practice., Competing Interests: Declaration of interests IB has received research grants from Dosisoft, GE Healthcare, and Siemens Healthineers, and is a member of the Society of Nuclear Medicine and Molecular Imaging Artificial Intelligence Task Force. BC has received research support from GWT and Technical University of Dresden, and won a 2021 Gilead Oncology Award to support his research; has received consulting fees from and is on the data safety monitoring board for Roche, BMS, Regeneron, and ADC; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, BMS, and Astra Zeneca; has received support for travel from Gilead; has submitted patents for molecular subclassification of DLBCL; and declares that he is a speaker of the Aggressive Lymphoma working group and is a steering board member of the German Lymphoma Alliance. UD has received institutional funding from Celgene and has served as a member of the Data Safety Monitoring Board for Amgen and Avencell Europe. EL has received grants from AIRC and the Italian Ministry of Health, royalties from Springer, and honoraria for lectures at the European Society of Molecular Imaging, Therapy and Molecular Imaging, and Therapy congresses. MN has received a research grant from Takeda. PR-O has received honoraria from Amgen, Bristol-Myers Squibb, Glaxo SmithKline, Janssen, Regeneron, and Sanofi, and has served as a member of the data safety monitoring board for Bristol-Myers Squibb, Glaxo SmithKline, Janssen, Oncopeptides, Pfizer, Sanofi, and Takeda. EZ has received honoraria from Amgen, Bristol Myers Squibb, Janssen, and Takeda. PLZ has received honoraria from and has participated on advisory boards or data safety monitoring boards for AstraZeneca, Beigene, Bristol Myers Squibb, Eusapharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, Mundipharma, Novartis, Roche, Sanofi, and Takeda. KH reports personal fees from Adacap, Ktis Oncology, Amgen, Bayer, Curium, Endocyte, Ipsen, GE Healthcare, Novartis, Pharma15, Siemens Healthineers, SIRTEX, Theragnostics, and ymabs; personal fees and other from Sofie Biosciences; grants and personal fees from BTG; and non-financial support from ABX outside the submitted work. JK has received consulting fees from Telix and has served as a member of the data safety monitoring board for Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 ( PKP2 ). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways., Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes., Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in I CaL , I NaL , and Ca 2+ spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca 2+ handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion., Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.

This paper draws on the work of Michel Foucault and Friedrich Hayek to understand threats to personal and enterprise freedom, arising from public health governance. Whereas public choice theory examines the incentives these institutions provide to agents, the analysis here understands those incentives as framed by discursive social constructions that affect the identity, power, and positionality of different actors. It shows how overlapping discourses of scientific rationalism may generate a 'road to serfdom' narrowing freedom of action and expression across an expanding terrain. As such, the paper contributes to the growing literature emphasising the importance of narratives, stories and metaphors as shaping political economic action in ways feeding through to outcomes and institutions., (© The Author(s) 2021.)

In New Zealand, many concerns have been raised over the presence of methamphetamine contamination in households, especially when its provenance is unknown. Previous research found that contamination levels on household surfaces were higher after the premises had been used as a clandestine laboratory. It is believed that the levels of contamination produced from smoking methamphetamine are much less than those produced through manufacture. This study's aim was to determine the amount of methamphetamine contamination produced, after simulated smoking, on a range of common, smooth surface types. Accumulation over time was also investigated. The experiment, comprising four simulated smoking events (referred to as 'smokes') of 0.2 g followed by a fifth simulated smoking event of 1.2 g (a cumulative total of 2 g) of methamphetamine hydrochloride, was carried out in a shipping container. Subsequent swabs were taken from squares of 100 cm 2 , following the NIOSH 9111 method. Results were quantified using LC-MS/MS. The methamphetamine concentrations measured gave a range from an overall mean of 0.91 µg/100 cm 2 after the first smoke and 15.9 µg/100 cm 2 after the final smoke. A rate of accumulation for each surface type was established, as well as an order of surfaces showing the most to least observed contamination. A significant reduction in the level of contamination was observed over a short period of time, although a clear rate was not established. Finally, a relationship between the recovered amounts of methamphetamine and amphetamine produced through the pyrolysis (smoking) process was also determined., (Copyright © 2022. Published by Elsevier B.V.)

The teeth and their supporting tissues provide an easily accessible source of oral stem cells. These different stem cell populations have been extensively studied for their properties, such as high plasticity and clonogenicity, expressing stem cell markers and potency for multilineage differentiation in vitro. Such cells with stem cell properties have been derived and characterised from the dental pulp tissue, the apical papilla region of roots in development, as well as the supporting tissue of periodontal ligament that anchors the tooth within the alveolar socket and the soft gingival tissue. Studying the dental pulp stem cell populations in a continuously growing mouse incisor model, as a traceable in vivo model, enables the researchers to study the properties, origin and behaviour of mesenchymal stem cells. On the other side, the oral mucosa with its remarkable scarless wound healing phenotype, offers a model to study a well-coordinated system of healing because of coordinated actions between epithelial, mesenchymal and immune cells populations. Although described as homogeneous cell populations following their in vitro expansion, the increasing application of approaches that allow tracing of individual cells over time, along with single-cell RNA-sequencing, reveal that different oral stem cells are indeed diverse populations and there is a highly organised map of cell populations according to their location in resident tissues, elucidating diverse stem cell niches within the oral tissues. This review covers the current knowledge of diverse oral stem cells, focusing on the new approaches in studying these cells. These approaches "decode" and "map" the resident cells populations of diverse oral tissues and contribute to a better understanding of the "stem cells niche architecture and interactions. Considering the high accessibility and simplicity in obtaining these diverse stem cells, the new findings offer potential in development of translational tissue engineering approaches and innovative therapeutic solutions., Competing Interests: Conflicts of interest statement: All authors declare no conflict of interest.

The COVID-19 pandemic is a global challenge, demanding researchers address different approaches in relation to prevention, diagnostics and therapeutics. Amongst the many tactics of tackling these therapeutic challenges, small extracellular vesicles (sEVs) or exosomes are emerging as a new frontier in the field of ameliorating viral infections. Exosomes are part of extracellular vesicles (EVs)-spherical biological structures with a lipid bilayer of a diameter of up to 5000 nm, which are released into the intercellular space by most types of eukaryotic cells, both in physiological and pathological states. EVs share structural similarities to viruses, such as small size, common mechanisms of biogenesis and mechanisms for cell entry. The role of EVs in promoting the viral spread by evading the immune response of the host, which is exhibited by retroviruses, indicates the potential for further investigation and possible manipulation of these processes when tackling the spread and treatment of COVID-19. The following paper introduces the topic of the use of exosomes in the treatment of viral infections, and presents the future prospects for the use of these EVs.

[Figure: see text].

In this work, the authors attempt to interpret the visible, infrared and Raman spectra of ferrate(VI) by means of theoretical physical-inorganic chemistry and historical highlights in this field of interest. In addition, the sacrificial decomposition of ferrate(VI) during water treatment will also be discussed together with a brief mention of how Rayleigh scattering caused by the decomposition of Fe VI O 4 may render absorbance readings erroneous. This work is not a compendium of all the instrumental methods of analysis which have been deployed to identify ferrate(VI) or to study its plethora of reactions, but mention will be made of the relevant techniques (e.g., Mössbauer Spectroscopy amongst others) which support and advance this overall discourse at appropriate junctures, without undue elaboration on the foundational physics of these techniques.2- may render absorbance readings erroneous. This work is not a compendium of all the instrumental methods of analysis which have been deployed to identify ferrate(VI) or to study its plethora of reactions, but mention will be made of the relevant techniques (e.g., Mössbauer Spectroscopy amongst others) which support and advance this overall discourse at appropriate junctures, without undue elaboration on the foundational physics of these techniques.

The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation forthe variance in this heterogeneous condition. Peripheral blood measures of cytokines and chemokines constitute the bulk of evidence, with consistent meta-analytic data implicating raised proinflammatory cytokines such as IL6, IL1β and TNF. Among the potential mechanisms linking immunobiological changes to affective neurobiology is the accelerated biological ageing seen in MDD, particularly via the senescence associated secretory phenotype (SASP). However, the cellular source of immunobiological markers remains unclear. Pre-clinical evidence suggests a role for peripheral blood mononuclear cells (PBMC), thus here we aimed to explore the transcriptomic profile using RNA sequencing in PBMCs in a clinical sample of people with various levels of depression and treatment response comparing it with that in healthy controls (HCs). There were three groups with major depressive disorder (MDD): treatment-resistant (n = 94), treatment-responsive (n = 47) and untreated (n = 46). Healthy controls numbered 44. Using PBMCs gene expression analysis was conducted using RNAseq to a depth of 54.5 million reads. Differential gene expression analysis was performed using DESeq2. The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC. Biological ageing was evident in these data as a transcriptional signature of 888 age-associated genes (adjusted p < 0.05, absolute log2fold > 0.6) that also correlated strongly with chronological age (spearman correlation coefficient of 0.72). Future work should expand clinical sample sizes and reduce clinical heterogeneity. Exploration of RNA-seq signatures in other leukocyte populations and single cell RNA sequencing may help uncover more subtle differences. However, currently the subtlety of any PBMC signature mitigates against its convincing use as a diagnostic or predictive biomarker., (© 2021. The Author(s).)

Transcriptional analysis and live-cell imaging are a powerful tool to investigate the dynamics of complex biological systems. In vitro expanded porcine oral mucosal cells, consisting of populations of epithelial and connective lineages, are interesting and complex systems for study via microarray transcriptomic assays to analyze gene expression profile. The transcriptomic analysis included 56 ontological groups with particular focus on 7 gene ontology groups that are related to the processes of differentiation and development. Most analyzed genes were upregulated after 7 days and downregulated after 15 and 30 days of in vitro culture. The performed transcriptomic analysis was then extended to include automated analysis of differential interference contrast microscopy (DIC) images obtained during in vitro culture. The analysis of DIC imaging allowed to identify the different populations of keratinocytes and fibroblasts during seven days of in vitro culture, and it was possible to evaluate the proportion of these two populations of cells. Porcine mucosa may be a suitable model for reference research on human tissues. In addition, it can provide a reference point for research on the use of cells, scaffolds, or tissues derived from transgenic animals for applications in human tissues reconstruction.

The mechanisms of wound healing and vascularization are crucial steps of the complex morphological process of tissue reconstruction. In addition to epithelial cells, fibroblasts play an important role in this process. They are characterized by dynamic proliferation and they form the stroma for epithelial cells. In this study, we have used primary cultures of oral fibroblasts, obtained from porcine buccal mucosa. Cells were maintained long-term in in vitro conditions, in order to investigate the expression profile of the molecular markers involved in wound healing and vascularization. Based on the Affymetrix assays, we have observed three ontological groups of markers as wound healing group , response to wounding group and vascularization group , represented by different genes characterized by their expression profile during long-term primary in vitro culture (IVC) of porcine oral fibroblasts. Following the analysis of gene expression in three previously identified groups of genes, we have identified that transforming growth factor beta 1 ( TGFB1 ), ITGB3 , PDPN , and ETS1 are involved in all three processes, suggesting that these genes could be recognized as markers of repair specific for oral fibroblasts within the porcine mucosal tissue.

Myostatin inhibition is thought to improve whole body insulin sensitivity and mitigate the development of insulin resistance in models of obesity. However, although myostatin is known to be a major regulator of skeletal muscle mass, the direct effects of myostatin inhibition in muscle on glucose uptake and the mechanisms that may underlie this are still unclear. We investigated the effect of local myostatin inhibition by adeno-associated virus-mediated overexpression of the myostatin propeptide on insulin-stimulated skeletal muscle glucose disposal in chow-fed or high fat diet-fed mice and evaluated the molecular pathways that might mediate this. We found that myostatin inhibition improved glucose disposal in obese high fat diet-fed mice alongside the induction of muscle hypertrophy but did not have an impact in chow-fed mice. This improvement was not associated with greater glucose transporter or peroxisome proliferator-activated receptor-γ coactivator-1α expression or 5' AMP-activated protein kinase activation as previously suggested. Instead, transcriptomic analysis suggested that the improvement in glucose disposal was associated with significant enrichment in genes involved in fatty acid metabolism and translation of mitochondrial genes. Thus, myostatin inhibition improves muscle insulin-stimulated glucose disposal in obese high fat diet-fed mice independent of muscle hypertrophy, potentially involving previously unidentified pathways.

Exosomes are a heterogenous subpopulation of extracellular vesicles 30-150 nm in range and of endosome-derived origin. We explored the exosome formation through different systems, including the endosomal sorting complex required for transport (ESCRT) and ESCRT-independent system, looking at the mechanisms of release. Different isolation techniques and specificities of exosomes from different tissues and cells are also discussed. Despite more than 30 years of research that followed their definition and indicated their important role in cellular physiology, the exosome biology is still in its infancy with rapidly growing interest. The reasons for the rapid increase in interest with respect to exosome biology is because they provide means of intercellular communication and transmission of macromolecules between cells, with a potential role in the development of diseases. Moreover, they have been investigated as prognostic biomarkers, with a potential for further development as diagnostic tools for neurodegenerative diseases and cancer. The interest grows further with the fact that exosomes were reported as useful vectors for drugs.

Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

Fields such as, diagnostic testing, biotherapeutics, drug development, and toxicology among others, center on the premise of searching through many specimens for a rare event. Scientists in the business of "searching for a needle in a haystack" may greatly benefit from the use of group screening design strategies. Group screening, where specimens are composited into pools with each pool being tested for the presence of the event, can be much more cost-efficient than testing each individual specimen. A number of group screening designs have been proposed in the literature. Incomplete block screening designs are described here and compared with other group screening designs. It is shown under certain conditions, that incomplete block screening designs can provide nearly a 90% cost saving compared to other group screening designs such as when prevalence is 0.001 and screening 3876 specimens with an ICB-sequential design vs. a Dorfman design. In other cases, previous group screening designs are shown to be most efficient. Overall, when prevalence is small (≤0.05) group screening designs are shown to be quite cost effective at screening a large number of specimens and in general there is no one design that is best in all situations. © 2018 American Institute of Chemical Engineers Biotechnol Progress, 35: e2770, 2019., (© 2018 American Institute of Chemical Engineers.)

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Aims: Post-operative atrial fibrillation (POAF) is a predictor of morbidity and mortality after cardiac surgery. Latent predisposing factors may reside in the epicardial adipose tissue (EAT) due to its anatomical position and high protein production rate. In order to explore a possible mechanistic link, we characterized proteins secreted by the EAT preceding the onset of POAF., Methods and Results: Epicardial adipose tissue samples were collected from 76 consecutive patients with no history of AF undergoing coronary artery bypass surgery, 50 samples for proteomic analysis and 26 for gene expression studies, further divided according to development of POAF. Ten vs. 10 matched samples representing EAT secretome were analysed by two-dimensional difference in-gel electrophoresis (2D-DIGE) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify differentially expressed proteins (P < 0.05, expression change >1.2 fold). Findings were validated by Western blotting on EAT protein extracts and by gene expression studies via quantitative polymerase chain reaction (qPCR). Proteomics returned 35 differentially expressed proteins. Amongst those, gelsolin was down regulated in POAF. Western blot analysis confirmed a significant reduction in gelsolin in the AF group. Gene expression for gelsolin was significantly reduced in the AF group confirming the proteomics findings., Conclusion: For the first time we describe EAT secretome as a possible substrate for POAF. It contains various proteins differentially expressed in patients who later develop POAF. Amongst those gelsolin, involved in inflammation and ion channel regulation, was associated with maintenance of sinus rhythm. Understanding the role of EAT may offer novel insights into prevention and treatment of AF.

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies., (© 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

As heart failure with preserved ejection fraction (HFpEF) rises to epidemic proportions, major steps in patient management and therapeutic development are badly needed. With the current position paper we seek to update our view on HFpEF as a highly complex systemic syndrome, from risk factors and mechanisms to long-term clinical manifestations. We will revise recent advances in animal model development, experimental set-ups and basic and translational science approaches to HFpEF research, highlighting their drawbacks and advantages. Directions are provided for proper model selection as well as for integrative functional evaluation from the in vivo setting to in vitro cell function testing. Additionally, we address new research challenges that require integration of higher-order inter-organ and inter-cell communication to achieve a full systems biology perspective of HFpEF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

This review summarizes the current knowledge about DBA/2 mice and genetically epilepsy-prone rats (GEPRs) and discusses the contribution of such animal models on the investigation of possible new therapeutic targets and new anticonvulsant compounds for the treatment of epilepsy. Also, possible chemical or physical agents acting as proconvulsant agents are described. Abnormal activities of enzymes involved in catecholamine and serotonin synthesis and metabolism were reported in these models, and as a result of all these abnormalities, seizure susceptibility in both animals is greatly affected by pharmacological manipulations of the brain levels of monoamines and, prevalently, serotonin. In addition, both genetic epileptic models permit the evaluation of pharmacodynamic and pharmacokinetic interactions among several drugs measuring plasma and/or brain level of each compound. Audiogenic models of epilepsy have been used not only for reflex epilepsy studies, but also as animal models of epileptogenesis. The seizure predisposition (epileptiform response to sound stimulation) and substantial characterization of behavioral, cellular, and molecular alterations in both acute and chronic (kindling) protocols potentiate the usefulness of these models in elucidating ictogenesis, epileptogenesis, and their mechanisms. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Integration/differentiation of mental processes is major mechanism of development. Developmental theories ascribe intellectual development to it. In psychometric theory, Spearman's law of diminishing returns postulates that increasing g allows increasing differentiation of cognitive abilities, because increased mental power allows variable investment in domain-specific learning. Empirical evidence has been inconsistent so far, with some studies supporting and others contradicting this mechanism. This state of affairs is due to a developmental phenomenon: Both differentiation and strengthening of relations between specific processes and g may happen but these changes are phase-specific and ability-specific, depending upon the developmental priorities in the formation of g in each phase. We present eight studies covering the age span from 4 to 85 years in support of this phenomenon. Using new powerful modeling methods we showed that differentiation and binding of mental processes in g occurs in cycles. Specific processes intertwine with g at the beginning of cycles when they are integrated into it; when well established, these processes may vary with increasing g, reflecting its higher flexibility. Representational knowledge, inductive inference and awareness of it, and grasp of logical constraints framing inference are the major markers of g, first intertwining with in their respective cycles and differentiating later during the periods of 2-6, 7-11, and 11-20 years, respectively. The implications of these findings for an overarching cognitive developmental/differential theory of human mind are discussed.

Previous research has shown that both anxiety and depression are associated with strength of lateralisation for the processing of emotive faces, although these clinical measures have always been considered in separate studies. In the present study, we measure depression and anxiety, within the same non-clinical sample, and consider whether these variables can predict strength of lateralisation, measured using the chimeric faces test. There are two key findings from this study. First, for females only, anxiety is negatively associated with right hemispheric superiority for processing of negative emotional expressions. Second, there was only one finding for depression, showing a relationship with strength of lateralisation for the processing of fearful faces that differed according to sex.

Background: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy., Methods: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images., Results: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy., Conclusions: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.

The Global Polio Eradication Initiative (GPEI) has significantly reduced the worldwide incidence of poliomyelitis. However, polio remains endemic in Pakistan which poses a threat to the success of the GPEI. Issues faced by Pakistan relate to politics, terrorism, war, natural disasters, funding constraints, misconceptions and inadequate infrastructure. These contribute in hampering the aims of the GPEI and allow the deadly poliovirus to maintain its reservoir in Pakistan. Until polio is completely eradicated, all countries remain at risk of its re-emergence and this is of grave concern as potentially it could reverse the polio-free certified status of a whole World Health Organisation (WHO) region. With the increase in global travel and international migration, even the smallest potential risk should not be taken lightly. Recommendations are made to help to improve the state of polio in Pakistan to make full use of the GPEI investment and move towards a polio-free world.

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome., Competing Interests: HEB is a shareholder of CellAegis Inc.

During the 1990s, Brazil and Russia diverged in their policy response to AIDS. This is puzzling considering that both nations were globally integrated emerging economies transitioning to democracy. This article examines to what extent international pressures and partnerships with multilateral donors motivated these governments to increase and sustain federal spending and policy reforms. Contrary to this literature, the cases of Brazil and Russia suggest that these external factors were not important in achieving these outcomes. Furthermore, it is argued that Brazil's policy response was eventually stronger than Russia's and that it had more to do with domestic political and social factors: specifically, AIDS officials' efforts to cultivate a strong partnership with NGOs, the absence of officials' moral discriminatory outlook towards the AIDS community, and the government's interest in using policy reform as a means to bolster its international reputation in health.

Background and Aims: Familial hypercholesterolaemia (FH) profoundly increases the risk of coronary artery disease (CAD). We investigated whether diet and a bile-acid sequestrant decrease coronary atherosclerosis in patients with FH., Methods: We identified 26 men with FH and CAD, participating in the St Thomas' Atherosclerosis Regression Study, who had been randomized to receive a fat-modified diet plus cholestyramine (8 g twice daily) (DC, n = 12) or usual care (UC, n = 14), and investigated the relative effects of these treatments on the angiographic progression of coronary atherosclerosis over 39 months. FH was defined as probable/definite according to Dutch Lipid Clinic Network criteria; mean FH score was 8.7 (range 6-15) and mean baseline low-density lipoprotein cholesterol (LDL-Ch) concentration was 5.4 (SD 1.4) mmol/L. Coronary atherosclerosis was assessed by serial quantitative angiography as the global changes in mean and minimum absolute width of segments (MAWS and MinAWS, respectively)., Results: Mean plasma LDL-Ch concentration fell by 35% with DC and remained significantly (p < 0.001) lower during the trial at 3.78 (SD 0.98) mmol/L compared with UC at 4.89 (1.04). MAWS decreased by 0.252 (SEM 0.072) mm in the UC group and by 0.001 (0.065) mm in the DC group (p = 0.007), with corresponding reductions in MinAWS of 0.290 (0.087) mm and 0.013 (0.058) mm (p = 0.009); these changes were significant after adjusting for baseline variables, including coronary luminal dimensions and lipoprotein(a). Progression was observed in 7 patients (50%) on UC and 3 (25%) on DC (p = 0.19), with regression in no patients (0%) and 3 patients (25%) (p < 0.05), respectively., Conclusions: This investigation, carried out in the pre-statin era, demonstrates that a prudent diet and cholestyramine could improve the course of coronary atherosclerosis in men with phenotypic FH through sustained reductions in LDL-Ch., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: IL6 promotes tumor growth and signal transduction via both its membrane-bound (CD126) and soluble receptors (sCD126). We aimed to study whether the levels of CD126 expression in chronic lymphocytic leukemic (CLL) cells can predict in vitro and in vivo treatment response., Experimental Design: The levels of membrane-bound CD126 expression were determined on freshly isolated CLL B cells (n = 58) using flow cytometry. These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6-mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated., Results: CD126 surface expression was found in all cases and positively correlated with the levels of in vivo constitutive STAT3 activity. The levels of CD126 expression were significantly and positively correlated with the resistance of CLL cells to in vitro treatment with chlorambucil or fludarabine and poor in vivo treatment response of CLL patients. Blocking IL6 signaling with the anti-CD126 antibody, tocilizumab, had profound effects on STAT3-mediated survival and growth signals: decreased Mcl-1 and Bcl-xL, favoring an apoptotic profile; and decreased p27 with increased cyclin E and CDK2 expression, leading to cell-cycle shift from G0-G1 These tocilizumab-mediated changes induced chemosensitization in resistant CLL cells, with the greatest effect seen in cells with higher CD126 expression (P < 0.001)., Conclusions: CLL cells with higher CD126 expression are more resistant to treatment in vivo and in vitro via IL6-CD126-STAT3 axis. Blocking CD126 using tocilizumab sensitizes CLL cells to chemotherapy. Clin Cancer Res; 22(10); 2462-9. ©2015 AACR., (©2015 American Association for Cancer Research.)

Chronic inflammation is often accompanied by angiogenesis, the development of new blood vessels from existing ones. This vascular response is a response to chronic hypoxia and/or ischemia, but is also contributory to the progression of disorders including atherosclerosis, arthritis, and tumor growth. Proinflammatory and proangiogenic mediators and signaling pathways form a complex and interrelated network in these conditions, and many factors exert multiple effects. Inflammation drives angiogenesis by direct and indirect mechanisms, promoting endothelial proliferation, migration, and vessel sprouting, but also by mediating extracellular matrix remodeling and release of sequestered growth factors, and recruitment of proangiogenic leukocyte subsets. The role of inflammation in promoting angiogenesis is well documented, but by facilitating greater infiltration of leukocytes and plasma proteins into inflamed tissues, angiogenesis can also propagate chronic inflammation. This review examines the mutually supportive relationship between angiogenesis and inflammation, and considers how these interactions might be exploited to promote resolution of chronic inflammatory or angiogenic disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Trauma exposure and intrusive thoughts are commonly reported in both schizophrenia and posttraumatic stress disorder (PTSD). Information processing accounts suggest that intrusions occur in the two conditions as a result of insufficient state and/or trait contextual processing in long-term memory. Most research has focused on intrusions about past events, while growing evidence suggests that intrusions about prospective imagined events warrants further investigation. Prospective intrusive imagery has yet to be examined in psychotic disorders but could provide crucial information regarding the aetiology and maintenance of psychotic symptoms. The current study examines the role of prospective intrusive imagery, posttraumatic intrusions and anxiety in schizophrenia. Fifty-seven participants (30 patients and 27 healthy controls) completed measures of trauma, PTSD, anxiety, general non-affective use of imagery, and intrusive prospective imagery. Patients reported significantly more intrusive prospective imagery relative to control participants but, importantly, not greater use of general non-affective imagery. Intrusive prospective imagery was associated with posttraumatic intrusions and anxiety in schizophrenia. The findings are consistent with information processing models of intrusions and psychosis, and provide novel insights for theoretical accounts, clinical formulation and therapeutic targets for psychotic symptoms in schizophrenia., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Antibiotic-associated diarrhea (AAD) is a well-recognized adverse reaction to oral penicillins. This review analyzed the literature to determine the incidence of AAD following amoxicillin, amoxicillin/clavulanate, and penicillin V oral therapy in pediatric clinical trials., Methods: An advanced search was conducted in MEDLINE and Embase databases for articles in any language reporting the incidence of AAD following oral penicillin therapy for any indicated infection in children (0-17 years). The search was limited to clinical trials. Articles were excluded if treatment was related to chronic conditions, involved concomitant antimicrobials, or if the dose or number of patients was not specified., Results: Four hundred thirty-five articles relating to clinical trials were identified (307 from Embase; 128 from MEDLINE). Thirty-five articles reporting on 42 studies were included for analysis. The indications included acute otitis media, sinusitis, pharyngitis, and pneumonia. Thirty-three trials reported on amoxicillin/clavulanate, 6 on amoxicillin, and 3 on penicillin V. In total, the 42 trials included 7729 children who were treated with an oral penicillin. On average, 17.2% had AAD. Data were pooled for each penicillin. The AAD incidence was 19.8% for amoxicillin/clavulanate, 8.1% for amoxicillin, and 1.2% for penicillin V. The amoxicillin/clavulanate data were analyzed according to formulation: pooled-average. The incidence of ADD was 24.6% for the 4:1 formulation, 12.8% for the 7:1 formulation, 19.0% for the 8:1 formulation, and 20.2% for the 14:1 formulation., Conclusions: These results demonstrate substantially increased incidence of AAD following use of amoxicillin/clavulanate, compared to use of amoxicillin and penicillin V, as well as varying AAD rates with diffierent amoxicillin/clavulanate formulations. These findings warrant consideration when prescribing. The underlying mechanisms of AAD in children remain unclear.

Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatography-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in observed metabolite relative concentrations between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust analysis of these data. Overall, this is a large scale and non-targeted chromatographic MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or reference dataset for understanding the 'normal' relative concentrations and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).