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Childhood abuse is a risk factor for poorer illness course in bipolar disorder, but the reasons why are unclear. Trait-like features such as affective instability and impulsivity could be part of the explanation. We aimed to examine whether childhood abuse was associated with clinical features of bipolar disorder, and whether associations were mediated by affective instability or impulsivity.
We analysed data from 923 people with bipolar I disorder recruited by the Bipolar Disorder Research Network. Adjusted associations between childhood abuse, affective instability and impulsivity and eight clinical variables were analysed. A path analysis examined the direct and indirect links between childhood abuse and clinical features with affective instability and impulsivity as mediators.
Affective instability significantly mediated the association between childhood abuse and earlier age of onset [effect estimate (θ)/standard error (SE): 2.49], number of depressive (θ/SE: 2.08) and manic episodes/illness year (θ/SE: 1.32), anxiety disorders (θ/SE: 1.98) and rapid cycling (θ/SE: 2.25). Impulsivity significantly mediated the association between childhood abuse and manic episodes/illness year (θ/SE: 1.79), anxiety disorders (θ/SE: 1.59), rapid cycling (θ/SE: 1.809), suicidal behaviour (θ/SE: 2.12) and substance misuse (θ/SE: 3.09). Measures of path analysis fit indicated an excellent fit to the data.
Affective instability and impulsivity are likely part of the mechanism of why childhood abuse increases risk of poorer clinical course in bipolar disorder, with each showing some selectivity in pathways. They are potential novel targets for intervention to improve outcome in bipolar disorder.
Farrowing crates are widely used in commercial practice but restrict sow movement. Pens have therefore been developed which allow the sow greater freedom of movement but this may result in piglets being exposed to events likely to cause injury or death due to crushing. This is particularly the case immediately after farrowing. The behaviour of sows during lying and piglet aggregation behaviour may be factors contributing to these problems. We therefore wished to compare these behaviours and production performance in crates and oval pens.
The subjects were 18 Large White x Landrace sows; 10 farrowed in crates and 8 in oval pens (balanced for parity and time of year; c. half farrowed Aug. - Nov. 1996 and half April - July 1997). Sows entered the accommodation five days before the farrowing date. Feeding was manual, daily at 08.00h and 15.00h. Crates and oval pens were cleaned and shavings (crate) or straw (pen) were added daily. There was a piglet drinker in each accommodation and creep feed was available 14 days post-partum. Piglets were teeth-clipped and iron-injected within 48h post-partum.
Competition resulting in high social status and maintenance of that status within farmed pigs may have both welfare and economic consequences. Aggressive behaviours, associated with the establishment and maintenance of a dominance hierarchy, may cause poor welfare and skin damage reducing the value of pigs at slaughter. In order to investigate the impact of social status on welfare we first need to establish the status of individuals relative to their peers. In this paper we compare two alternative indicators of pig rank, namely: (i) aggressive interactions between individuals - the occurrence of aggressive behaviour from pig A to pig B is often assumed to imply social dominance of pig A over pig B; and (ii) the order in which pigs stand at the feeder - an advantage of attaining high social status in many populations is priority of access to food. Social rank of individuals based on observed aggressive behaviour can only be assigned once evidence for a linear or quasi-linear hierarchy has been established (Langbein and Puppe, 2004). In a population with a purely hierarchical structure we expect all triads of individuals to be transitive, that is A→B, B→C implies A→C. For observational studies it is unlikely that interactions between all individuals will be observed. Here we present a novel methodology by which we can assess the linearity of the dominance structure that is not affected by missing or null interactions between individuals. By conducting a census of all types of triad in a social network we can assess whether the subset of interactions observed provide evidence of a linear or quasi-linear hierarchy. Transitive triads provide evidence of linear hierarchy whilst intransitive triads, such as A→B, B→C, C→A, contradict the presence of a linear hierarchy.
A wide range of measures have been employed in an attempt to determine social structure in groups of animals and different analyses of social behaviour may result in the construction of different hierarchies (Tomback et al. 1989). In order to investigate social aspects of welfare in group-housed sows it is important to establish a meaningful measure of group dynamics. We therefore wished to establish whether different measures of social status resulted in the construction of similar hierarchies in dry-sows housed in indoor or outdoor group-housing systems.
There has been considerable concern over the welfare of sows housed in farrowing crates due to the severe restriction of movement this imposes upon them. A number of alternative systems have therefore been developed which allow sows greater freedom of movement. The aim of this study was to compare the behaviour and performance of sows housed in conventional crates with sows housed in a group-house Thorstensson system.
A total of 18 Large White x Landrace sows were farrowed in crates or a group-housing Thorstensson system (balanced for parity and time of year). Two batches of seven were farrowed through the Thorstensson system of which five in each batch were selected for the current analysis (based on ease of observation). Thus a total of ten sows were analysed from the group-system (mean parity: 1.90 ± 0.40; 6 gilts). In addition eight sows were analysed from crates (mean parity 1.62 ± 0.26; 4 gilts).
Avilamycin (antibiotic growth promoter) and zinc oxide are both included in the diets of newly weaned piglets to enhance growth performance and reduce the incidence of diarrhoea (MLC, 2000). It is thought that both compounds positively influence the bacterial populations residing in the gastrointestinal tract. However, growing concerns regarding antibiotic resistance and environmental pollution are likely to result in the banning of these dietary additives within the EU. This experiment, therefore, aimed to investigate what effect removing both avilamycin and zinc oxide from the post-weaning diet would have on the growth performance of weaned piglets.
Although often described as “welfare-friendly”, the greater freedom of movement and choice of environments offered by communal farrowing systems does have potential welfare risks, primarily for the piglets. The maternal qualities of the sow will have a greater influence on the survival and growth of piglets in this communal farrowing system, than in a conventional farrowing crate and may be influenced by genotype. The objectives of this study were to compare the welfare of sows and piglets housed in farrowing crates and a communal farrowing system and to investigate whether sow genotype influences the quantity and quality of maternal behaviour and subsequent litter performance.
The impending EU-wide ban on the use of antibiotic growth promoters (AGP), and potential legislation over the use of zinc oxide (ZnO), necessitates the need to find credible alternatives. Zinc oxide has proven to be effective at promoting post-weaning growth and reducing the incidence of diarrhoea, although its mode of action remains unclear. The use of probiotics is often proposed as an alternative, but their efficacy remains unpredictable and unproven. Probiotics do, however, have the potential to modulate the gastrointestinal microbiota and immune response (Perdigon et al., 1995). This experiment aimed to investigate whether dietary supplementation with ZnO and a recognised and characterised probiotic strain would enhance post-weaning piglet performance in the absence of AGP.
Mood instability is common, and an important feature of several psychiatric
disorders. We discuss the definition and measurement of mood instability,
and review its prevalence, characteristics, neurobiological correlates and
clinical implications. We suggest that mood instability has underappreciated
transdiagnostic potential as an investigational and therapeutic target.
The majority of species are under predatory risk in their natural habitat and targeted by
predators as part of the food web. During the evolution of ecosystems, manifold mechanisms
have emerged to avoid predation. So called secondary defences, which are used after a
predator has initiated prey-catching behaviour, commonly involve the expression of toxins
or deterrent substances which are not observable by the predator. Hence, the possession of
such secondary defence in many prey species comes with a specific signal of that defence
(aposematism). This paper builds on the ideas of existing models of such signalling
behaviour, using a model of co-evolution and generalisation of aversive information and
introduces a new methodology of numerical analysis for finite populations. This new
methodology significantly improves the accessibility of previous models.
In finite populations, investigating the co-evolution of defence and signalling requires
an understanding of natural selection as well as an assessment of the effects of drift as
an additional force acting on stability. The new methodology is able to reproduce the
predicted solutions of preceding models and finds additional solutions involving negative
correlation between signal strength and the extent of secondary defence. In addition,
genetic drift extends the range of stable aposematic solutions through the introduction of
a new pseudo-stability and gives new insights into the diversification of aposematic
We introduce a game theoretical model of stealing interactions. We model the situation as
an extensive form game when one individual may attempt to steal a valuable item from
another who may in turn defend it. The population is not homogeneous, but rather each
individual has a different Resource Holding Potential (RHP). We assume that RHP not only
influences the outcome of the potential aggressive contest (the individual with the larger
RHP is more likely to win), but that it also influences how an individual values a
particular resource. We investigate several valuation scenarios and study the prevalence
of aggressive behaviour. We conclude that the relationship between RHP and resource value
is crucial, where some cases lead to fights predominantly between pairs of strong
individuals, and some between pairs of weak individuals. Other cases lead to no fights
with one individual conceding, and the order of strategy selection is crucial, where the
individual which picks its strategy first often has an advantage.
The majority of people at ultra high risk (UHR) of psychosis also present with co-morbid affective disorders such as depression or anxiety. The neuroanatomical and clinical impact of UHR co-morbidity is unknown.
We investigated group differences in grey matter volume using baseline magnetic resonance images from 121 participants in four groups: UHR with depressive or anxiety co-morbidity; UHR alone; major depressive disorder; and healthy controls. The impact of grey matter volume on baseline and longitudinal clinical/functional data was assessed with regression analyses.
The UHR-co-morbidity group had lower grey matter volume in the anterior cingulate cortex than the UHR-alone group, with an intermediate effect between controls and patients with major depressive disorder. In the UHR-co-morbidity group, baseline anterior cingulate volume was negatively correlated with baseline suicidality/self-harm and obsessive–compulsive disorder symptoms.
Co-morbid depression and anxiety disorders contributed distinctive grey matter volume reductions of the anterior cingulate cortex in people at UHR of psychosis. These volumetric deficits were correlated with baseline measures of depression and anxiety, suggesting that co-morbid depressive and anxiety diagnoses should be carefully considered in future clinical and imaging studies of the psychosis high-risk state.
Affective instability (AI) is poorly defined but considered clinically important. The aim of this study was to examine definitions and measures of AI employed in clinical populations.
This study was a systematic review using the PRISMA guidelines. MEDLINE, Embase, PsycINFO, PsycArticles and Web of Science databases were searched. Also five journals were hand searched. Primary empirical studies involving randomized controlled trials (RCTs), non-RCTs, controlled before and after, and observational investigations were included. Studies were selected, data extracted and quality appraised. A narrative synthesis was completed.
A total of 11 443 abstracts were screened and 37 studies selected for final analysis on the basis that they provided a definition and measure of AI. Numbers of definitions for each of the terms employed in included studies were: AI (n = 7), affective lability (n = 6), affective dysregulation (n = 1), emotional dysregulation (n = 4), emotion regulation (n = 2), emotional lability (n = 1), mood instability (n = 2), mood lability (n = 1) and mood swings (n = 1); however, these concepts showed considerable overlap in features. A total of 24 distinct measures were identified that could be categorized as primarily measuring one of four facets of AI (oscillation, intensity, ability to regulate and affect change triggered by environment) or as measuring general emotional regulation.
A clearer definition of AI is required. We propose AI be defined as ‘rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences’. No single measure comprehensively assesses AI and a combination of current measures is required for assessment. A new short measure of AI that is reliable and validated against external criteria is needed.
Previous work has shown that hunger and food intake are lower in individuals on high-protein (HP) diets when combined with low carbohydrate (LC) intakes rather than with moderate carbohydrate (MC) intakes and where a more ketogenic state occurs. The aim of the present study was to investigate whether the difference between HPLC and HPMC diets was associated with changes in glucose and ketone body metabolism, particularly within key areas of the brain involved in appetite control. A total of twelve men, mean BMI 34·9 kg/m2, took part in a randomised cross-over trial, with two 4-week periods when isoenergetic fixed-intake diets (8·3 MJ/d) were given, with 30 % of the energy being given as protein and either (1) a very LC (22 g/d; HPLC) or (2) a MC (182 g/d; HPMC) intake. An 18fluoro-deoxyglucose positron emission tomography scan of the brain was conducted at the end of each dietary intervention period, following an overnight fast (n 4) or 4 h after consumption of a test meal (n 8). On the next day, whole-body ketone and glucose metabolism was quantified using [1,2,3,4-13C]acetoacetate, [2,4-13C]3-hydroxybutyrate and [6,6-2H2]glucose. The composite hunger score was 14 % lower (P= 0·013) for the HPLC dietary intervention than for the HPMC diet. Whole-body ketone flux was approximately 4-fold greater for the HPLC dietary intervention than for the HPMC diet (P< 0·001). The 9-fold difference in carbohydrate intakes between the HPLC and HPMC dietary interventions led to a 5 % lower supply of glucose to the brain. Despite this, the uptake of glucose by the fifty-four regions of the brain analysed remained similar for the two dietary interventions. In conclusion, differences in the composite hunger score observed for the two dietary interventions are not associated with the use of alternative fuels by the brain.
Cancers are fundamentally caused by genomic changes in the cancer cells that lead to their uncontrolled growth (Balmain et al., 2003; Stratton et al., 2009). Understanding these changes, which include DNA copy number alterations, is an intense focus of current research into the causes of, and potential therapies for, every type of cancer. Major research projects, such as the Cancer Genome Atlas (TCGA) project (The Cancer Genome Atlas Research Network, 2008), aim to comprehensively catalog all genomic changes in cancer. This chapter discusses the problem of interpreting copy number data, specifically in the context of cancer research.
To measure copy number, whole-genome genotyping array assays hybridize sample DNA to oligonucleotides deposited on the array. Modern designs use synthetic oligonucleotides to measure copy number at frequent intervals along the genome, especially in regions of known copy number variation. Modern arrays also include many probes that target both alleles of a large number of common single-nucleotide polymorphisms (SNPs). These platforms are therefore widely used in genotyping studies. Array-based assays available for measuring genome-wide copy number include arrays from Illumina, Sentrix, Agilent, and Affymetrix. Data from next-generation sequencing of DNA can also be used to detect copy number alterations and is rapidly becoming cost competitive with array-based platforms.
Molecular inversion probe (MIP) arrays (Wang et al., 2007, 2009; Ji and Welch, 2009) are another platform that can be used for large-scale copy number analysis and genotyping. MIP technology uses less DNA, can handle lower quality DNA, has a greater dynamic range, has higher quality markers, and better separates allelic information than other array-based approaches.
The Cancer Genome Atlas (TCGA) is an ambitious undertaking of the National Institutes of Health (NIH), jointly led by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), to identify all key genomic changes in the major types and subtypes of cancer. In the following section, we briefly review the history and goals of the TCGA project. Section 2.3 describes how samples are collected and analyzed by the TCGA. Section 2.4 details how data are processed, stored, and made available to qualified researchers. Section 2.5 briefly surveys several widely available tools that can be used to analyze TCGA data. Section 2.6 summarizes the chapter.
History and Goals of the TCGA Project
At the turn of the century, it was clear (Balmain et al., 2003) that genomic alterations played a key role in cancer development and progression and that understanding these changes would be enormously important for devising improved methods for diagnosing clinically relevant cancer subtypes and for developing novel molecular therapies aimed at a specific cancer subtype. Several successful treatments for targeting cancer cells with specific genomic changes had been developed – for instance, Gleevec for chronic myeloid leukemia and Herceptin for breast cancer. Early experiments to determine the genomic basis of specific cancers had made it clear that the scope of the genomic changes concerned was enormously complex: an individual cancer could involve hundreds or thousands of genomic alterations, and these changes were for the most part specific to the cancer concerned.
A 2 × 2 factorial experiment was conducted to determine the effects of rearing environment (indoor (In) v. outdoor (Out)) and dietary zinc oxide (ZnO) supplementation (0 (−Zn) v. 3100 (+Zn) mg/kg feed) on the response of weaned pigs to a challenge infection with enterotoxigenic Escherichia coli (ETEC). Pigs from the two rearing environments were weaned onto trial diets at 4 weeks of age, moved into conventional accommodation and infected 3 days later with 109 CFU ETEC per os. Faecal ETEC shedding was determined before and after challenge. After 7 days of ETEC infection, all pigs were euthanized for gut lactic acid bacteria (LAB)-to-coliform ratio, pH and small intestine morphological measurements. Both ZnO and outdoor rearing reduced ETEC excretion, and these effects were additive. Outdoor rearing increased small intestine and colon tissue weight. ZnO increased villus height and goblet cell number in the upper small intestine, LAB-to-coliform ratio (through reduced coliforms) in the lower small intestine and proximal colon, and improved growth performance. There were interactive effects of rearing environment and ZnO supplementation on upper small intestine villus height and daily gain, as outdoor rearing conferred advantages on these variables only with ZnO dietary supplementation. Daily gains were 233, 174, 277 and 347 (s.e.m. 27.2) g/day for the In − Zn, Out − Zn, In + Zn and Out + Zn, respectively. These results suggest different, but complementary mechanisms of intestinal health and performance in outdoor-reared pigs and those offered ZnO supplemented diets. The results indicate that the benefits of ZnO to the weaned pig extend beyond suppression of ETEC and appear mediated through altered development of the small intestine mucosa.
The optical properties and their modification by crystal defects of wurtzite GaN are investigated using spatially resolved electron energy-loss spectroscopy (EELS) in a dedicated ultra-high vacuum field emission gun scanning transmission electron microscope. The calculated density of states of the bulk crystal reproduces well the features of the measured spectra. The profound effect of a prismatic stacking fault on the local electronic structure is shown by the spatial variation of the optical properties derived from low-loss spectra. It is found that a defect state at the fault appears to bind 1.5 electrons per atom.
Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia.
fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load.
In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS.
Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.