Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation

Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory, effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100-300 nM, 15 min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18 h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300 nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (-)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes

Flavonoids are plant-derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti-oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE-luc) assay showed that the dietary flavan-3-ol (-)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF-E2-related factor-2 (Nrf2), a key transcription factor in ARE-mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert-butylhydroquinone (100 mu M) and (-)epicatechin (100 nM). (-)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3-kinase-dependent pathway. Finally, (-)epicatechin increased glutathione levels in astrocytes consistent with an up-regulation of ARE-mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti-oxidant gene expression.

Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle

As an obligatory parasite of humans, the body louse (Pediculus humanus humanus) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.

Geographic distribution of plant pathogens in response to climate change

Geographic distributions of pathogens are the outcome of dynamic processes involving host availability, susceptibility and abundance, suitability of climate conditions, and historical contingency including evolutionary change. Distributions have changed fast and are changing fast in response to many factors, including climatic change. The response time of arable agriculture is intrinsically fast, but perennial crops and especially forests are unlikely to adapt easily. Predictions of many of the variables needed to predict changes in pathogen range are still rather uncertain, and their effects will be profoundly modified by changes elsewhere in the agricultural system, including both economic changes affecting growing systems and hosts and evolutionary changes in pathogens and hosts. Tools to predict changes based on environmental correlations depend on good primary data, which is often absent, and need to be checked against the historical record, which remains very poor for almost all pathogens. We argue that at present the uncertainty in predictions of change is so great that the important adaptive response is to monitor changes and to retain the capacity to innovate, both by access to economic capital with reasonably long-term rates of return and by retaining wide scientific expertise, including currently less fashionable specialisms.

Are the NICE guidelines for Obsessive Compulsive Disorder being used in primary care?

This study aims to: 1) assess the proportion of General Practioners (GPs) who are aware of or who have read the National Institute for Health and Clinical Excellence (NICE; 2005a) guidelines for Obsessive Compulsive Disorder (OCD), 2) compare this with the proportion of other mental health disorders found by previous research and 3) establish the prevalence of OCD in primary care. Questionnaires were sent to all GPs (n = 795) and practice managers (n = 157) in Berkshire and Buckinghamshire, South East England. These contained 19 questions and took 5 min to complete. After the first set of responses, larger practices were visited and telephoned to encourage further responses. The response rates were 10.1% from GPs and 19.1% from practice managers. In all, 48.7% of the GPs were aware of the NICE guidelines for OCD and 30.3% reported that they had read them – higher than for Post-Traumatic Stress Disorder, but lower than for depression. Of registered patients, 0.2% were diagnosed with OCD, lower than the 1.1% found in epidemiological studies.

Neurotrophic gene polymorphisms and response to psychological therapy

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR=0.60 (0.42–0.85), P=0.005). These effects remained even when other clinically relevant covariates were accounted for (OR=0.62 (0.41–0.92), P=0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions.

Cognitive behaviour therapy for low self-esteem: A preliminary randomized controlled trial in a primary care setting

Background and Objectives Low self-esteem (LSE) is associated with psychiatric disorder, and is distressing and debilitating in its own right. Hence, it is frequent target for treatment in cognitive behavioural interventions, yet it has rarely been the primary focus for intervention. This paper reports on a preliminary randomized controlled trial of cognitive behaviour therapy (CBT) for LSE using Fennell’s (1997) cognitive conceptualisation and transdiagnostic treatment approach ( [Fennell, 1997] and [Fennell, 1999]). Methods Twenty-two participants were randomly allocated to either immediate treatment (IT) (n = 11) or to a waitlist condition (WL) (n = 11). Treatment consisted of 10 sessions of individual CBT accompanied by workbooks. Participants allocated to the WL condition received the CBT intervention once the waitlist period was completed and all participants were followed up 11 weeks after completing CBT. Results The IT group showed significantly better functioning than the WL group on measures of LSE, overall functioning and depression and had fewer psychiatric diagnoses at the end of treatment. The WL group showed the same pattern of response to CBT as the group who had received CBT immediately. All treatment gains were maintained at follow-up assessment. Limitations The sample size is small and consists mainly of women with a high level of educational attainment and the follow-up period was relatively short. Conclusions These preliminary findings suggest that a focused, brief CBT intervention can be effective in treating LSE and associated symptoms and diagnoses in a clinically representative group of individuals with a range of different and co-morbid disorders.

The contribution of primary and secondary somatosensory cortices to the representation of body parts and body sides: an fMRI adaptation study

Although the somatosensory homunculus is a classically used description of the way somatosensory inputs are processed in the brain, the actual contributions of primary (SI) and secondary (SII) somatosensory cortices to the spatial coding of touch remain poorly understood. We studied adaptation of the fMRI BOLD response in the somatosensory cortex by delivering pairs of vibrotactile stimuli to the finger tips of the index and middle fingers. The first stimulus (adaptor) was delivered either to the index or to the middle finger of the right or left hand, whereas the second stimulus (test) was always administered to the left index finger. The overall BOLD response evoked by the stimulation was primarily contralateral in SI and was more bilateral in SII. However, our fMRI adaptation approach also revealed that both somatosensory cortices were sensitive to ipsilateral as well as to contralateral inputs. SI and SII adapted more after subsequent stimulation of homologous as compared with nonhomologous fingers, showing a distinction between different fingers. Most importantly, for both somatosensory cortices, this finger-specific adaptation occurred irrespective of whether the tactile stimulus was delivered to the same or to different hands. This result implies integration of contralateral and ipsilateral somatosensory inputs in SI as well as in SII. Our findings suggest that SI is more than a simple relay for sensory information and that both SI and SII contribute to the spatial coding of touch by discriminating between body parts (fingers) and by integrating the somatosensory input from the two sides of the body (hands).

The role of sky conditions on gross primary production in a mixed deciduous forest

The role of different sky conditions on diffuse PAR fraction (ϕ), air temperature (Ta), vapor pressure deficit (vpd) and GPP in a deciduous forest is investigated using eddy covariance observations of CO2 fluxes and radiometer and ceilometer observations of sky and PAR conditions on hourly and growing season timescales. Maximum GPP response occurred under moderate to high PAR and ϕ and low vpd. Light response models using a rectangular hyperbola showed a positive linear relation between ϕ and effective quantum efficiency (α = 0.023ϕ + 0.012, r2 = 0.994). Since PAR and ϕ are negatively correlated, there is a tradeoff between the greater use efficiency of diffuse light and lower vpd and the associated decrease in total PAR available for photosynthesis. To a lesser extent, light response was also modified by vpd and Ta. The net effect of these and their relation with sky conditions helped enhance light response under sky conditions that produced higher ϕ. Six sky conditions were classified from cloud frequency and ϕ data: optically thick clouds, optically thin clouds, mixed sky (partial clouds within hour), high, medium and low optical aerosol. The frequency and light responses of each sky condition for the growing season were used to predict the role of changing sky conditions on annual GPP. The net effect of increasing frequency of thick clouds is to decrease GPP, changing low aerosol conditions has negligible effect. Increases in the other sky conditions all lead to gains in GPP. Sky conditions that enhance intermediate levels of ϕ, such as thin or scattered clouds or higher aerosol concentrations from volcanic eruptions or anthropogenic emissions, will have a positive outcome on annual GPP, while an increase in cloud cover will have a negative impact. Due to the ϕ/PAR tradeoff and since GPP response to changes in individual sky conditions differ in sign and magnitude, the net response of ecosystem GPP to future sky conditions is non-linear and tends toward moderation of change.

Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

LRRK2 is one of the most important genetic contributors to Parkinson’s disease (PD). Point mutations in this gene cause an autosomal dominant form of PD, but to date no cellular phenotype has been consis- tently linked with mutations in each of the functional domains (ROC, COR and Kinase) of the protein product of this gene. In this study, primary fibroblasts from individuals carrying pathogenic mutations in the three central domains of LRRK2 were assessed for alterations in the autophagy/lysosomal pathway using a combination of biochemical and cellular approaches. Mutations in all three domains resulted in alterations in markers for autophagy/lysosomal function compared to wild type cells. These data high- light the autophagy and lysosomal pathways as read outs for pathogenic LRRK2 function and as a marker for disease, and provide insight into the mechanisms linking LRRK2 function and mutations.

Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders

Background We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome. Aims To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829). Method Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed. Results There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes. Conclusions The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples.

Simulation of tree-ring widths with a model for primary production, carbon allocation, and growth

We present a simple, generic model of annual tree growth, called "T". This model accepts input from a first-principles light-use efficiency model (the "P" model). The P model provides values for gross primary production (GPP) per unit of absorbed photosynthetically active radiation (PAR). Absorbed PAR is estimated from the current leaf area. GPP is allocated to foliage, transport tissue, and fine-root production and respiration in such a way as to satisfy well-understood dimensional and functional relationships. Our approach thereby integrates two modelling approaches separately developed in the global carbon-cycle and forest-science literature. The T model can represent both ontogenetic effects (the impact of ageing) and the effects of environmental variations and trends (climate and CO2) on growth. Driven by local climate records, the model was applied to simulate ring widths during the period 1958–2006 for multiple trees of Pinus koraiensis from the Changbai Mountains in northeastern China. Each tree was initialised at its actual diameter at the time when local climate records started. The model produces realistic simulations of the interannual variability in ring width for different age cohorts (young, mature, and old). Both the simulations and observations show a significant positive response of tree-ring width to growing-season total photosynthetically active radiation (PAR0) and the ratio of actual to potential evapotranspiration (α), and a significant negative response to mean annual temperature (MAT). The slopes of the simulated and observed relationships with PAR0 and α are similar; the negative response to MAT is underestimated by the model. Comparison of simulations with fixed and changing atmospheric CO2 concentration shows that CO2 fertilisation over the past 50 years is too small to be distinguished in the ring-width data, given ontogenetic trends and interannual variability in climate.

Clinical predictors of response to cognitive-behavioural therapy in pediatric anxiety disorders: the Genes for Treatment (GXT) Study

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.

The experience of the hidden curriculum for autistic girls at mainstream primary schools

This article presents the findings of ethnographic case studies of three girls on the autistic spectrum attending mainstream primary schools and illustrates the difficulties they experience and the ways in which these are often unrecognised. The observations of the girls and subsequent individual interviews with their mothers, class teachers, SENCO’s and ultimately themselves, reveal the personal adjustments the girls make in response to the hidden curriculum and the ways in which these go unnoticed, effectively masking their need for support, and contributing to their underachievement in school. The research also identifies a misunderstanding of autism in girls by some teachers that contributes to a lack of support for their needs, despite their diagnosis. Teachers need to understand how autistic girls present, and how they learn, if they are to recognise the need to illuminate the hidden curriculum. The implications of these findings are that without this awareness autistic girls in mainstream settings are also at risk of limited access to the known curriculum and of social isolation.