Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity

Copyright © 2011 Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

The interpretation of low mood and worry by high users of secondary care with medically unexplained symptoms

DA - 20111021 IS - 1471-2296 (Electronic) IS - 1471-2296 (Linking) LA - eng PT - Journal Article SB - IMPeer reviewedPublisher PD

Development and validation of the Self-Regulation of Eating Behaviour Questionnaire for adults

Background Eating self-regulatory capacity can help individuals to cope with the obesogenic environment and achieve, as well as maintain, a healthy weight and diet. At present, there is no comprehensive, reliable and valid questionnaire for assessing this capacity and measuring change in response to self-regulation interventions in adults. This paper reports the development of the Self-regulation of Eating Behaviour Questionnaire (SREBQ) for use in UK adults, and presents evidence for its reliability and construct validity. The development of the SREBQ involved generation of an item pool, followed by two pilot studies (Samples 1 and 2) and a test of the questionnaire’s underlying factor structure (Sample 3). The final version of the SREBQ was then assessed for reliability and construct validity (Sample 4). Results Development of the SREBQ resulted in a 5-item questionnaire. The face validity was satisfactory, as assessed by the pilot studies. The factor structure analysis (Sample 3) suggested that it has a single underlying factor, which was confirmed in a second sample (Sample 4). The SREBQ had strong construct validity, showing a positive correlation with general measures of self-regulation. It was also positively correlated with motivation and behavioural automaticity, and negatively correlated with food responsiveness and emotional over-eating (p < 0.001). It showed good discriminant validity, as it was only weakly associated with satiety responsiveness, food fussiness and slowness in eating. Conclusions The SREBQ is a reliable and valid measure for assessment of eating self-regulatory capacity in the general UK adult population

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity

Purpose of Review: There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Recent Findings: Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Summary: Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment

Activation of p38MAPK Contributes to Expanded Polyglutamine-Induced Cytotoxicity

The signaling pathways that may modulate the pathogenesis of diseases induced by expanded polyglutamine proteins are not well understood.Herein we demonstrate that expanded polyglutamine protein cytotoxicity is mediated primarily through activation of p38MAPK and that the atypical PKC iota (PKCiota) enzyme antagonizes polyglutamine-induced cell death through induction of the ERK signaling pathway. We show that pharmacological blockade of p38MAPK rescues cells from polyglutamine-induced cell death whereas inhibition of ERK recapitulates the sensitivity observed in cells depleted of PKCiota by RNA interference. We provide evidence that two unrelated proteins with expanded polyglutamine repeats induce p38MAPK in cultured cells, and demonstrate induction of p38MAPK in an in vivo model of neurodegeneration (spinocerebellar ataxia 1, or SCA-1).Taken together, our data implicate activated p38MAPK in disease progression and suggest that its inhibition may represent a rational strategy for therapeutic intervention in the polyglutamine disorders

JNK Isoforms Differentially Regulate Neurite Growth and Regeneration in Dopaminergic Neurons In Vitro

Parkinson’s disease is characterized by selective and progressive loss of midbrain DAergic neurons (MDN) in the substantia nigra and degeneration of its nigrostriatal projections. Whereas the cellular pathophysiology has been closely linked to an activation of c-Jun N-terminal kinases (JNKs) and c-Jun, the involvement of JNKs in regenerative processes of the nigrostriatal pathway is controversially discussed. In our study, we utilized a mechanical scratch lesion paradigm of midbrain DAergic neurons in vitro and studied regenerative neuritic outgrowth. After a siRNA-mediated knockdown of each of the three JNK isoforms, we found that JNKs differentially regulate neurite regeneration. Knockdown of JNK3 resulted in the most prominent neurite outgrowth impairment. This effect was attenuated again by plasmid overexpression of JNK3. We also evaluated cell survival of the affected neurons at the scratch border. JNK3 was found to be also relevant for survival of MDN which were lesioned by the scratch. Our data suggest that JNK isoforms are involved in differential regulation of cell death and regeneration in MDN depending on their neurite integrity. JNK3 appears to be required for regeneration and survival in the case of an environment permissive for regeneration. Future therapeutic approaches for the DAergic system may thus require isoform specific targeting of these kinases

Loss of ATF2 Function Leads to Cranial Motoneuron Degeneration during Embryonic Mouse Development

The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS

Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity

The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GR(Cx30CreERT2) mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GR(Cx30CreERT2) mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-alpha and Il-1 beta as well as TNF-alpha protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+. The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTP-injected GR(Cx30CreERT2) mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of postmortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology

Effectiveness and cost-effectiveness of an exposure-based return-to-work programme for patients on sick leave due to common mental disorders: design of a cluster-randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>To reduce the duration of sick leave and loss of productivity due to common mental disorders (CMDs), we developed a return-to-work programme to be provided by occupational physicians (OPs) based on the principles of exposure in vivo (RTW-E programme). This study evaluates this programme's effectiveness and cost-effectiveness by comparing it with care as usual (CAU). The three research questions we have are: 1) Is an RTW-E programme more effective in reducing the sick leave of employees with common mental disorders, compared with care as usual? 2) Is an RTW-E programme more effective in reducing sick leave for employees with anxiety disorders compared with employees with other common mental disorders? 3) From a societal perspective, is an RTW-E programme cost-effective compared with care as usual?</p> <p>Methods/design</p> <p>This study was designed as a pragmatic cluster-randomized controlled trial with a one-year follow-up and randomization on the level of OPs. We aimed for 60 OPs in order to include 200 patients. Patients in the intervention group received the RTW-E programme. Patients in the control group received care as usual. Eligible patients had been on sick leave due to common mental disorders for at least two weeks and no longer than eight weeks. As primary outcome measures, we calculated the time until full return to work and the duration of sick leave. Secondary outcome measures were time until partial return to work, prevalence rate of sick leave at 3, 6, 9, and 12 months' follow-up, and scores of symptoms of distress, anxiety, depression, somatization, and fatigue; work capacity; perceived working conditions; self-efficacy for return to work; coping behaviour; avoidance behaviour; patient satisfaction; and work adaptations. As process measures, we used indices of compliance with the intervention in the intervention group and employee-supervisor communication in both groups. Economic costs were calculated from a societal perspective. The total costs consisted of the costs of consuming health care, costs of production loss due to sick leave and reduced productivity, and out-of-pocket costs of patients for travelling to their OP.</p> <p>Discussion</p> <p>The results will be published in 2009. The strengths and weaknesses of the study protocol are discussed.</p> <p>Trial registration</p> <p>ISRCTN72643128</p

Activation of c-Jun N-Terminal Kinase (JNK) during Mitosis in Retinal Progenitor Cells

Most studies of c-Jun N-terminal Kinase (JNK) activation in retinal tissue were done in the context of neurodegeneration. In this study, we investigated the behavior of JNK during mitosis of progenitor cells in the retina of newborn rats. Retinal explants from newborn rats were kept in vitro for 3 hours and under distinct treatments. Sections of retinal explants or freshly fixed retinal tissue were used to detect JNK phosphorylation by immunohistochemistry, and were examined through both fluorescence and confocal microscopy. Mitotic cells were identified by chromatin morphology, histone-H3 phosphorylation, and location in the retinal tissue. The subcellular localization of proteins was analyzed by double staining with both a DNA marker and an antibody to each protein. Phosphorylation of JNK was also examined by western blot. The results showed that in the retina of newborn rats (P1), JNK is phosphorylated during mitosis of progenitor cells, mainly during the early stages of mitosis. JNK1 and/or JNK2 were preferentially phosphorylated in mitotic cells. Inhibition of JNK induced cell cycle arrest, specifically in mitosis. Treatment with the JNK inhibitor decreased the number of cells in anaphase, but did not alter the number of cells in either prophase/prometaphase or metaphase. Moreover, cells with aberrant chromatin morphology were found after treatment with the JNK inhibitor. The data show, for the first time, that JNK is activated in mitotic progenitor cells of developing retinal tissue, suggesting a new role of JNK in the control of progenitor cell proliferation in the retina