In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.

Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation.

Pressure overload ventricular hypertrophy is accompanied by dysfunctional beta-adrenergic receptor signaling due to increased levels of the beta-adrenergic receptor kinase-1, which phosphorylates and desensitizes beta-adrenergic receptors. In this study, we examined whether increased beta-adrenergic receptor kinase 1 expression is associated with myocardial hypertrophy induced by adrenergic stimulation. With use of implanted mini-osmotic pumps, we treated mice with isoproterenol, phenylephrine, or vehicle to distinguish between alpha1- and beta-adrenergic stimulation. Both treatments resulted in cardiac hypertrophy, but only isoproterenol induced significant increases in beta-adrenergic receptor kinase-1 protein levels and activity. Similarly, in isolated adult rat cardiac myocytes, 24 hours of isoproterenol stimulation resulted in a significant 2.8-fold increase in beta-adrenergic receptor kinase-1 protein levels, whereas 24 hours of phenylephrine treatment did not alter beta-adrenergic receptor kinase-1 expression. Our results indicate that increased beta-adrenergic receptor kinase-1 is not invariably associated with myocardial hypertrophy but apparently is controlled by the state of beta-adrenergic receptor activation.

Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function.

The short arms of the ten acrocentric human chromosomes share several repetitive DNAs, including ribosomal RNA genes (rDNA). The rDNA arrays correspond to nucleolar organizing regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by expressing a mutant version of telomere binding protein TRF2 (dnTRF2) causes non-random acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible for acrocentric chromosome sensitivity to dysfunctional telomeres are unclear. In this study, we show that TRF2 normally associates with the nucleolus and rDNA. However, when telomeres are crippled by dnTRF2 or RNAi knockdown of TRF2, gross nucleolar and chromosomal changes occur. We used the controllable dnTRF2 system to precisely dissect the timing and progression of nucleolar and chromosomal instability induced by telomere dysfunction, demonstrating that nucleolar changes precede the DNA damage and morphological changes that occur at acrocentric short arms. The rDNA repeat arrays on the short arms decondense, and are coated by RNA polymerase I transcription binding factor UBF, physically linking acrocentrics to one another as they become fusogenic. These results highlight the importance of telomere function in nucleolar stability and structural integrity of acrocentric chromosomes, particularly the rDNA arrays. Telomeric stress is widely accepted to cause DNA damage at chromosome ends, but our findings suggest that it also disrupts chromosome structure beyond the telomere region, specifically within the rDNA arrays located on acrocentric chromosomes. These results have relevance for Robertsonian translocation formation in humans and mechanisms by which acrocentric-acrocentric fusions are promoted by DNA damage and repair.

Splintered memories or vivid landmarks? Qualities and organization of traumatic memories with and without PTSD

One hundred and eighty-one students answered a standardized questionnaire on Post-Traumatic Stress Disorder (PTSD): 25 reported trauma(s) and indicated a pattern of after-effects that matched a PTSD symptom profile, whereas 88 indicated trauma(s) but no PTSD symptom profile. Both groups answered a questionnaire addressing the recollective quality, integration and coherence of the traumatic memory that currently affected them most. Participants with a PTSD symptom profile reported more vivid recollection of emotion and sensory impressions. They reported more observer perspective in the memory (seeing themselves 'from the outside'), but no more fragmentation. They also agreed more with the statement that the trauma had become part of their identity, and perceived more thematic connections between the trauma and current events in their lives. The two groups showed different patterns of correlations which indicated different coping styles. Overall, the findings suggest that traumas form dysfunctional reference points for the organization of other personal memories in people with PTSD symptoms, leading to fluctuations between vivid intrusions and avoidance. Copyright © 2003 John Wiley & Sons, Ltd.

A case study of pre-midlife crisis: an extraordinary transformational episode in an ordinary life

This case study explored a single in-depth narrative of an episode of crisis. The participant, an English Jewish man in his late thirties (Guy), was selected using a ‘random purposeful’ design from a sample who had previously participated in a study on the experience of crisis in pre-midlife adulthood. From a subgroup of participants chosen for giving full accounts of both inner and outer dimensions of crisis, the individual was selected randomly. Data collection comprised two interviews followed by an email discussion. The crisis occurred in Guy’s late thirties, just before the midlife transition, and so can be considered a ‘pre-midlife’ crisis. It subsumed the period surrounding leaving a high-profile banking career and a dysfunctional marriage, and the ensuing attempts to rebuild life after this difficult and emotional period. Qualitative analysis found four trajectories of personal transformation over the course of the episode: Firstly there was a shift away from the use of a conventional persona to a more spontaneous and ‘authentic’ expression of self; secondly there was a move away from materialistic values toward relational values; thirdly a developing capacity to reflect on himself and his actions; fourthly an emerging feminine component of his personality. The case study portrays an extraordinary event in the life of an ordinary man approaching middle age. It illustrates the transformative nature of crisis in ordinary lives, the dramatic nature of narrative surrounding crisis, and also illustrates existing theory about the nature of adult crises.

Amplifying applied game development and uptake

The established (digital) leisure game industry is historically one dominated by large international hardware vendors (e.g. Sony, Microsoft and Nintendo), major publishers and supported by a complex network of development studios, distributors and retailers. New modes of digital distribution and development practice are challenging this business model and the leisure games industry landscape is one experiencing rapid change. The established (digital) leisure games industry, at least anecdotally, appears reluctant to participate actively in the applied games sector (Stewart et al., 2013). There are a number of potential explanations as to why this may indeed be the case including ; A concentration on large-scale consolidation of their (proprietary) platforms, content, entertainment brand and credibility which arguably could be weakened by association with the conflicting notion of purposefulness (in applied games) in market niches without clear business models or quantifiable returns on investment. In contrast, the applied games industry exhibits the characteristics of an emerging, immature industry namely: weak interconnectedness, limited knowledge exchange, an absence of harmonising standards, limited specialisations, limited division of labour and arguably insufficient evidence of the products efficacies (Stewart et al., 2013; Garcia Sanchez, 2013) and could, arguably, be characterised as a dysfunctional market. To test these assertions the Realising an Applied Gaming Ecosystem (RAGE) project will develop a number of self contained gaming assets to be actively employed in the creation of a number of applied games to be implemented and evaluated as regional pilots across a variety of European educational, training and vocational contexts. RAGE is a European Commission Horizon 2020 project with twenty (pan European) partners from industry, research and education with the aim of developing, transforming and enriching advanced technologies from the leisure games industry into self-contained gaming assets (i.e. solutions showing economic value potential) that could support a variety of stakeholders including teachers, students, and, significantly, game studios interested in developing applied games. RAGE will provide these assets together with a large quantity of high-quality knowledge resources through a self-sustainable Ecosystem, a social space that connects research, the gaming industries, intermediaries, education providers, policy makers and end-users in order to stimulate the development and application of applied games in educational, training and vocational contexts. The authors identify barriers (real and perceived) and opportunities facing stakeholders in engaging, exploring new emergent business models ,developing, establishing and sustaining an applied gaming eco system in Europe.

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder.

BACKGROUND:Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder.METHOD: Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale.RESULTS:Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups.CONCLUSIONS: In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

'Robes on Tight Ropes: The Judicialisation of Politics in Nigeria'

This account of judicialised politics in the Nigerian transition experience examines the regulation of the judiciary of the political space, through the resolution of intergovernmental contestations in a dysfunctional federation. It analyses the judicialisation of elite power disputes which have resonance for due process and the rule of law in particular and governance in general. A study of the role of the judiciary in stabilising the country, itself a pivot in the West Africa region in particular and Africa in general, is important. This is especially in view of its classification as a ‘weak state,’ despite its enormous human and natural resources. The analyses here suggest the Supreme Court has taken a strategic position in the task of democratic institutional building and the reinstitution of the rule of law in the country. This strategic measure has received the acclaim of the public. However, the account also discloses that the judiciary, in the course of its numerous interventions, has been drawn into overly political disputes that overreach its jurisprudential preferences. Of even more significance, it demonstrates that the judiciary is itself still challenged by institutional dysfunctions constituting part of the legacies of the authoritarian era. The situation leads back to the need for closer scrutiny of the judicial function in transitional societies.

Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.

The ‘Public Interest’ Agency of International Organizations? The case of the OECD Principles of Corporate Governance

This article seeks to outline and explore some of the conditions necessary for International Organizations (IOs) to perform in a public interest fashion through a case study of the Principles of corporate governance formulated by the OECD. Rather than the more commonly documented pathological and dysfunctional behavioural forms of IOs, the case of the Principles, both in their formulation by the OECD, and in their assessment by the World Bank through the ROSC process, represent an episode of IO agency protecting and promoting a wider public interest. In exercising their agency, IO staff, have made the Principles more agreeable to a wider range of interested parties, giving them a general interest orientation, in accordance with a proceduralist definition of public interest. This case should therefore encourage IPE scholars to consider carefully and systematically the sets of circumstances and conditions, which might be required for IO agency to take more socially useful forms. In the final section, three indicators are identified which might be evaluated in future research into the positive public interest agency of IOs across a range of cases.

Nasal potential difference to detect Na+ channel dysfunction in acute lung injury

Pulmonary fluid clearance is regulated by the active transport of Na+ and Cl- through respiratory epithelial ion channels. Ion channel dysfunction contributes to the pathogenesis of various pulmonary fluid disorders including high-altitude pulmonary edema (HAPE) and neonatal respiratory distress syndrome (RDS). Nasal potential difference (NPD) measurement allows an in vivo investigation of the functionality of these channels. This technique has been used for the diagnosis of cystic fibrosis, the archetypal respiratory ion channel disorder, for over a quarter of a century. NPD measurements in HAPE and RDS suggest constitutive and acquired dysfunction of respiratory epithelial Na+ channels. Acute lung injury (ALI) is characterized by pulmonary edema due to alveolar epithelial-interstitial-endothelial injury. NPD measurement may enable identification of critically ill ALI patients with a susceptible phenotype of dysfunctional respiratory Na+ channels and allow targeted therapy toward Na+ channel function. text of link

Parenting stress and children with cerebral palsy: A European cross-sectional survey

Aim
The aim of this study was to describe stress in the parents of children with cerebral palsy and investigate associations with very high stress.

Method
A cross-sectional survey was conducted of parents of 818 children aged 8 to 12 years from nine regions in Europe. Families were eligible to participate if they were living in one of the specified geographic areas. Parental stress was captured using the Parenting Stress Index Short Form, which has 36 items and takes 10 minutes to complete. Parents rate items on a 5-point Likert scale, with higher scores indicating higher stress. The Short Form yields scores on three subscales and a Total Stress score. A trained research associate administered the questionnaire in the child’s home and visits lasted 90 to 120 minutes. All data collected were reported by parents unless otherwise stated.

Results
The Total Stress score on the Parenting Stress Index was dichotomized into scores of less than 99 or 99 or more, the latter indicating ‘very high’ stress. Most respondents were mothers (94%), and 26% reported very high stress levels. The parents of children with communication impairment had higher odds for very high stress (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.2–3.0) than those whose child had no such impairment; the parents of children with moderate or severe pain had higher odds for very high stress (OR 1.7 [95% CI 1.1–2.4] and 2.5 [95% CI 1.5–4.3] respectively) than those whose child had no pain; and the parents of children with an intellectual impairment had higher odds for very high stress (OR 1.8; 95% CI 1.2–2.9) than those whose child had none. There was no association between very high stress and motor impairment. The subscales ‘parent–child dysfunctional interaction’ and ‘difficult child’ contributed most to the Total Stress score.

Interpretation
Parents of children with communication difficulties, intellectual impairment, or pain are at very high risk of stress. The final model explained 12% of the observed variation in very high stress.

Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury

Introduction Changes in the distribution of interstitial cells (IC) are reportedly associated with dysfunctional bladder. The present study investigated whether spinal cord injury (SCI) resulted in changes to IC subpopulations (vimentin-positive with the ultrastructural profile of IC), smooth muscle and nerves within the bladder wall and correlated cellular remodelling with functional properties. Methods Bladders from SCI (T8/9 transection) and sham-operated rats five-weeks post-injury were used for ex vivo pressure-volume experiments or processed for morphological analysis with transmission electron microscopy (TEM) and light/confocal microscopy. Results Pressure-volume relationships revealed low-pressure, hypercompliance in SCI bladders indicative of decompensation. Extensive networks of vimentin-positive IC were typical in sham lamina propria and detrusor but were markedly reduced post-SCI; semi-quantitative analysis showed significant reduction. Nerves labelled with anti-neurofilament and anti-vAChT were notably decreased post-SCI. TEM revealed lamina propria IC and detrusor IC which formed close synaptic-like contacts with vesicle-containing nerve varicosities in shams. Lamina propria and detrusor IC were ultrastructurally damaged post-SCI with retracted/lost cell processes and were adjacent to areas of cellular debris and neuronal degradation. Smooth muscle hypertrophy was common to SCI tissues. Conclusions IC populations in bladder wall were decreased five weeks post-SCI, accompanied with reduced innervation, smooth muscle hypertrophy and increased compliance. These novel findings indicate that bladder wall remodelling post-SCI affects the integrity of interactions between smooth muscle, nerves and IC, with compromised IC populations. Correlation between IC reduction and a hypercompliant phenotype suggests that disruption to bladder IC contribute to pathophysiological processes underpinning the dysfunctional SCI bladder.

Behavioural and cognitive behavioural training interventions for assisting foster carers in the management of difficult behaviour.

Background The provision of training for foster carers is now seen as an important factor contributing to the successful outcome of foster care placements. Since the late 1960s, foster carer training programs have proliferated, and few of the many published and unpublished training curricula have been systematically evaluated. The advent of cognitive-behavioural therapy (CBT) and the research evidence demonstrating its effectiveness as a psychotherapeutic treatment of choice for a range of emotional and behavioural problems, has prompted the development of CBT-based training programmes. CBT approaches to foster care training derive from a ’skill-based’ training format that also seeks to identify and correct problematic thinking patterns that are associated with dysfunctional behaviour by changing and/or challenging maladaptive thoughts and beliefs. Objectives To assess the effectiveness of cognitive-behavioural training interventions in improving a) looked-after children’s behavioural/relationship problems, b) foster carers’ psychological well-being and functioning, c) foster family functioning, d) foster agency outcomes. Search methods We searched databases including: CENTRAL (Cochrane Library Issue 3, 2006), MEDLINE (January 1966 to September 2006), EMBASE (January 1980 to September 2006), CINAHL (January 1982 to September 2006), PsycINFO (January 1872 to September 2006), ASSIA (January 1987 to September 2006), LILACS (up to September 2006), ERIC (January 1965 to September 2006), Sociological Abstracts (January 1963 to September 2006), and the National Research Register 2006 (Issue 3).We contacted experts in the field concerning current research. Selection criteria Random or quasi randomised studies comparing behavioural or cognitive-behavioural-base Data collection and analysis Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Main results Six trials involving 463 foster carers were included. Behavioural and cognitive-behavioural training interventions evaluated to date appear to have very little effect on outcomes relating to looked-after children, assessed in relation to psychological functioning, extent of behavioural problems and interpersonal functioning. Results relating to foster carer(s) outcomes also show no evidence of effectiveness in measures of behavioural management skills, attitudes and psychological functioning. Analysis pertaining to fostering agency outcomes did not show any significant results. However, caution is needed in interpreting these findings as their confidence intervals are wide. Authors’ conclusions There is currently little evidence about the efficacy of behavioural or cognitive-behavioural training intervention for foster carers. The need for further research in this area is highlighted.

eNOS overexpression exacerbates vascular closure in the obliterative phase of OIR and increases angiogenic drive in the subsequent proliferative stage

Purpose: In ischemic retinopathies, the misdirection of reparative angiogenesis away from the hypoxic retina leads to pathologic neovascularization. Thus, therapeutic strategies that reverse this trend would be extremely beneficial. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important mediator of vascular endothelial growth factor (VEGF) function facilitating vascular growth and maturation. However, in addition to NO, eNOS can also produce superoxide (O), exacerbating pathology. Here, our aim was to investigate the effect of eNOS overexpression on vascular closure and subsequent recovery of the ischemic retina.

Methods: Mice overexpressing eNOS-GFP were subjected to oxygen-induced retinopathy (OIR) and changes in retinal vascularization quantified. Background angiogenic drive was assessed during vascular development and in aortic rings. NOS activity was measured by Griess assay or conversion of radiolabeled arginine to citrulline, nitrotyrosine (NT), and superoxide by immunolabeling and dihydroethidium fluorescence and VEGF by ELISA.

Results: In response to hyperoxia, enhanced eNOS expression led to increased NOS-derived superoxide and dysfunctional NO production, NT accumulation, and exacerbated vessel closure associated with tetrahydrobiopterin (BH) insufficiency. Despite worse vaso-obliteration, eNOS overexpression resulted in elevated hypoxia-induced angiogenic drive, independent of VEGF production. This correlated with increased vascular branching similar to that observed in isolated aortas and during development. Enhanced recovery was also associated with neovascular tuft formation, which showed defective NO production and increased eNOS-derived superoxide and NT levels.

Conclusions: In hyperoxia, reduced BH bioavailability causes overexpressed eNOS to become dysfunctional, exacerbating vaso-obliteration. In the proliferative phase, however, eNOS has important prorepair functions enhancing angiogenic growth potential and recovery in ischemia. © 2012 The Association for Research in Vision and Ophthalmology, Inc.