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A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Major depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range.
Planning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40–80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis.
Higher anxiety ratings were associated with lower planning performance (β = −0.20; p < 0.0001) independent of age (β = 0.03; p = 0.47). When directly comparing the predictive value of depression and anxiety on cognition, only anxiety attained significance (β = −0.19; p = 0.0047), whereas depression did not (β = −0.01; p = 0.71).
Subclinical levels of anxiety but not of depression showed negative associations with cognitive functioning independent of age. Our results demonstrate that associations observed in clinical groups might differ from those in population-based samples, also with regard to the trajectory across the life span. Further studies are needed to uncover causal interrelations of anxiety and cognition, which have been proposed in the literature, in order to develop interventions aimed at reducing this negative affective state and to improve executive functioning.
We present results from a multiwavelength study of the blazar PKS 1954–388 at radio, UV, X-ray, and gamma-ray energies. A RadioAstron observation at 1.66 GHz in June 2012 resulted in the detection of interferometric fringes on baselines of 6.2 Earth-diameters. This suggests a source frame brightness temperature of greater than 2 × 1012 K, well in excess of both equipartition and inverse Compton limits and implying the existence of Doppler boosting in the core. An 8.4-GHz TANAMI VLBI image, made less than a month after the RadioAstron observations, is consistent with a previously reported superluminal motion for a jet component. Flux density monitoring with the Australia Telescope Compact Array confirms previous evidence for long-term variability that increases with observing frequency. A search for more rapid variability revealed no evidence for significant day-scale flux density variation. The ATCA light-curve reveals a strong radio flare beginning in late 2013, which peaks higher, and earlier, at higher frequencies. Comparison with the Fermi gamma-ray light-curve indicates this followed ~ 9 months after the start of a prolonged gamma-ray high-state—a radio lag comparable to that seen in other blazars. The multiwavelength data are combined to derive a Spectral Energy Distribution, which is fitted by a one-zone synchrotron-self-Compton (SSC) model with the addition of external Compton (EC) emission.
A number of laser facilities coming online all over the world promise the capability of high-power laser experiments with shot repetition rates between 1 and 10 Hz. Target availability and technical issues related to the interaction environment could become a bottleneck for the exploitation of such facilities. In this paper, we report on target needs for three different classes of experiments: dynamic compression physics, electron transport and isochoric heating, and laser-driven particle and radiation sources. We also review some of the most challenging issues in target fabrication and high repetition rate operation. Finally, we discuss current target supply strategies and future perspectives to establish a sustainable target provision infrastructure for advanced laser facilities.
Prenatal and early-life environmental exposures play a key role in the development of atopy and allergic disease. The Family Atherosclerosis Monitoring In earLY life Study is a general, population-based Canadian birth cohort that prospectively evaluated prenatal and early-life traits and their association with atopy and/or allergic disease. The study population included 901 babies, 857 mothers and 530 fathers. Prenatal and postnatal risk factors were evaluated through questionnaires collected during the antenatal period and at 1 year. The end points of atopy and allergic diseases in infants were evaluated through questionnaires and skin prick testing. Key outcomes included atopy (24.5%), food allergy (17.5%), cow’s milk allergy (4.8%), wheezing (18.6%) and eczema (16%). The association between infant antibiotic exposure [odds ratio (OR): 2.04, 95% confidence interval (CI): 1.45–2.88] and increased atopy was noted in the multivariate analysis, whereas prenatal maternal exposure to dogs (OR: 0.60, 95% CI: 0.42–0.84) and acetaminophen (OR: 0.68, 95% CI: 0.51–0.92) was associated with decreased atopy. This population-based birth cohort in Canada demonstrated high rates of atopy, food allergy, wheezing and eczema. Several previously reported and some novel prenatal and postnatal exposures were associated with atopy and allergic diseases at 1 year of age.
In Germany tularemia is a re-emerging zoonotic disease. Therefore, we investigated wild animals and environmental water samples for the presence and phylogenetic diversity of Francisella tularensis in the poorly studied Berlin/Brandenburg region. The phylogenomic analysis of three isolates from wild animals revealed three new subclades within the phylogenetic tree of F. tularensis [B.71 from a raccoon dog (Nyctereutes procyonoides); B.74 from a red fox (Vulpes vulpes), and B.75 from a Eurasian beaver (Castor fiber albicus)]. The results from histological, PCR, and genomic investigations on the dead beaver showed that the animal suffered from a systemic infection. Indications were found that the bacteria were released from the beaver carcass into the surrounding environment. We demonstrated unexpectedly high and novel phylogenetic diversity of F. tularensis in Germany and the fact that the bacteria persist in the environment for at least one climatic season. These findings support a broader host species diversity than previously known regarding Germany. Our data further support the assumption derived from previous serological studies of an underestimated frequency of occurrence of the pathogen in the environment and in wild animals. F. tularensis was isolated from animal species not previously reported as natural hosts in Germany.
Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder.
To quantify the shared genetic variability between bipolar disorder and cognitive measures.
Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder.
Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|–|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|–|1.00|), which remained significant after covarying for affective symptoms.
Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.
Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered.
The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates.
Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis.
Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.
Bipolar disorder is a highly heritable polygenic disorder. Recent
enrichment analyses suggest that there may be true risk variants for
bipolar disorder in the expression quantitative trait loci (eQTL) in the
We sought to assess the impact of eQTL variants on bipolar disorder risk
by combining data from both bipolar disorder genome-wide association
studies (GWAS) and brain eQTL.
To detect single nucleotide polymorphisms (SNPs) that influence
expression levels of genes associated with bipolar disorder, we jointly
analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls)
and a genome-wide brain (cortical) eQTL (193 healthy controls) using a
Bayesian statistical method, with independent follow-up replications. The
identified risk SNP was then further tested for association with
hippocampal volume (n = 5775) and cognitive performance
(n = 342) among healthy individuals.
Integrative analysis revealed a significant association between a brain
eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes
factor = 5.48; bipolar disorder P =
5.85×10–5). Follow-up studies across multiple independent
samples confirmed the association of the risk SNP (rs6088662) with gene
expression and bipolar disorder susceptibility (P =
3.54×10–8). Further exploratory analysis revealed that
rs6088662 is also associated with hippocampal volume and cognitive
performance in healthy individuals.
Our findings suggest that 20q11.22 is likely a risk region for bipolar
disorder; they also highlight the informative value of integrating
functional annotation of genetic variants for gene expression in
advancing our understanding of the biological basis underlying complex
disorders, such as bipolar disorder.
Innate-like B1a lymphocytes arise from long-lived progenitors produced exclusively by fetal stem cells. Any insults coinciding with this early lymphopoietic wave could have a permanent impact on the B1a population and its unique protein products, the natural antibodies (NAb). We investigated early life nutritional influences on NAb concentrations of pre-adolescent children (n=290) in rural Nepal for whom we had extensive information on exposures from pregnancy and early infancy. Infant size and growth were strongly associated with NAb concentrations at 9–13 years of age among males (e.g., for neonatal weight: βBOYS=0.43; P<0.001), but not females (e.g., for neonatal weight: βGIRLS=−0.16; P=0.26). In females, season of birth was associated with NAb concentrations, with marked reductions among girls born during the pre-monsoon (March–May; βGIRLS=−0.39; P=0.01) and pre-harvest (September–November; βGIRLS=−0.35; P=0.03) seasons. Our findings suggest that nutritional or other environmental influences on immune development may vary by sex, with potential consequences for immune function during infancy and long-term risk of immune-mediated disease.
The physical structure value of conserved grass/clover forages of spring harvest was evaluated by assessing effects of harvest time, conservation method, iNDF/NDF ratio and NDF intake (NDFI) per kg BW on chewing activity and fecal particle size in dairy heifers. A mixed sward consisting of ryegrass (Lolium perenne), red clover (Trifolium pratense) and white clover (Trifolium repens) was harvested in 2009 on May 9 (early) and 25 (late), and both cuts were conserved as silage and hay. The early silage, early hay, late silage and late hay contained dry matter (DM) of 454, 842, 250 and 828 g/kg, and NDF of 315, 436, 414 and 503 g/kg DM, respectively. Forages were fed as sole feed to four Jersey heifers of 435±30 kg BW in a 4×4 Latin square experiment. Feeding level was 90% of individual ad libitum intake, divided equally across two daily meals offered at 0800 and 1530 h. Chewing activity was estimated from recorded jaw movements (JM) oscillations continuously logged for 96 h and summarized per 24 h as mean effective rumination time and eating time. Eating behavior was further observed during four 20-min test meals. Weight proportion of large feces particles (>1.0 mm) and geometric mean fecal particle size (GPS) were calculated. Potentially indigestible NDF (iNDF) was estimated by incubation for 288 h in situ. The daily DM intake (DMI) decreased with progressing maturity at harvest (P<0.001) while daily NDFI was unaffected by harvest time (P>0.05). Earlier harvest led to less rumination per kg NDFI (P<0.01), similar eating time per kg NDFI (P>0.05) and similar proportion of large particles (P>0.01) compared with later harvest. Rumination time per kg NDFI decreased with higher NDFI per kg BW (P<0.001) and with lower iNDF/NDF ratio (P<0.01). Content and potential digestibility of NDF was greater in hay than in silage from the same harvest probably due to field loss and therefore confounded effects of conservation method. This study of high digestibility grass/clover silage and hay showed that NDF content and NDFI per kg BW affect fecal particle size and rumination time per kg NDF, and suggests implementation of NDFI per kg BW in systems evaluating physical structure in diets.
The objective of this study was to assess effects of feed intake and NDF content of highly digestible grass-clover silage on chewing behavior, fecal particle size distribution and apparent digestibility in restrictively fed heifers. Four grass-clover silages (Lolium perenne, Trifolium pratense and Trifolium repens) were harvested in 2009 at different regrowth stages, resulting in silages with NDF contents of 312, 360, 371 and 446 g/kg dry matter (DM), respectively. Four rumen-fistulated Jersey heifers (343±32 kg BW) were fed silage at 90% of ad libitum levels in a 4×4 Latin square design, replicated with further restricted feeding levels (50%, 60%, 70% or 80% of ad libitum) in a balanced 4×4×4 Greco-Latin square design. Eating activity was estimated from test meal observations, while rumination activity was estimated from jaw movements logged by a jaw recorder system. Total tract digestibility was estimated from chromic oxide marker and fecal spot sampling, and fecal particle size distribution in washed and freeze-dried particulate DM was determined by dry sieving (2.36, 1.0, 0.5, 0.212 and 0.106 mm, and bottom bowl). Higher NDF content of silage stimulated longer eating time per kg DM intake (P<0.001), while reduced feeding level caused a reduction in eating time per kg DM intake (P<0.001) and NDF (P<0.001). Rumination time per kg DM intake (P<0.01) increased with reduced feeding level, with less effect of feeding level at lower NDF contents (P<0.01) and more rumination with greater NDF content (P<0.01). Relative to NDF intake, rumination time increased with greater NDF content (P<0.01), at a higher rate with reduced feeding level (P<0.05). Digestibility of potentially digestible NDF (DNDF) decreased with greater NDF content (P<0.001) and increased with reduced feeding level (P<0.05). Increasing NDF content resulted in more particulate DM in feces (g/kg DM; P<0.05) and larger mean particle size (P<0.001). In conclusion, feeding heifers with grass-clover silages of decreasing NDF content increased chewing time relative to NDF intake, reduced mean fecal particle size, and increased DNDF digestibility. Restricting feeding level made heifers eat for a shorter time period while rumination and total chewing was increased, causing the ratio between eating and rumination time to decrease with lower intake of forage fiber. Particle size reduction and digestibility depended mostly on changes in NDF content, especially the indigestible NDF content.
Welfare concerns for intensive beef production have often been raised, but on-farm welfare assessment studies are rare. The aim of this study was to apply the Welfare Quality® (WQ) welfare assessment system for fattening cattle on beef bull farms to evaluate the state of welfare at the level of WQ measures and of aggregated scores, as well as overall classification. In addition, the purpose was to evaluate two ways of providing feedback information to the farmers with regard to possible welfare improvements on the farms. The study was conducted in Austria, Germany and Italy on a total of 63 beef bull farms with deep litter or cubicle-housing systems. Assessments were carried out 3 times (1 month and 7 months apart from the initial visit). In every country, farmers were assigned to two treatment groups (feedback from initial visit as written report, F, written feedback plus oral advice, FA) and a control group (C), which did not receive any feedback. At the criterion level, the highest average welfare scores were obtained from ‘Absence of prolonged hunger’ (94/100 points) followed by ‘Absence of pain induced by management procedures’ (88/100) and ‘Comfort around resting’ (77/100). Most welfare concerns related to the criteria ‘Absence of disease’ (40/100), ‘Expression of social behaviour’ (44/100) and ‘Positive emotional state’ (48/100), thus indicating room for improvements. Two-thirds of the farms achieved the ‘Enhanced’ level, about one-third was judged ‘Acceptable’ and only one farm ‘Excellent’. After 6 months of monitoring period, there was no significant welfare improvement in both the treatment groups as compared with the control group. Reasons for the lack of effect may mainly be seen in the short monitoring period and a lack of external incentives. In conclusion, the WQ assessment system revealed areas for improvement, but longer term studies and investigations on alternative ways of transferring outcomes from on-farm welfare assessments to farmers should be carried out in future.
Consistency over time of (on-farm) animal welfare assessment systems forms part of reliability, meaning that results of the assessment should be representative of the longer-term welfare state of the farm as long as the housing and management conditions have not changed considerably. This is especially important if assessments are to be used for certification purposes. It was the aim of the present study to investigate consistency over time of the Welfare Quality® (WQ®) assessment system for fattening cattle at single measure level, aggregated criterion and principle scores, and overall classification across short-term (1 month) and longer-term periods (6 months). We hypothesized that consistency over time of aggregated criterion and principle scores is higher than that of single measures. Consistency was also expected to be lower with longer intervals between assessments. Data were obtained using the WQ® protocol for fattening cattle during three visits (months 0, 1 and 7) on 63 beef farms in Austria, Germany and Italy. Only data from farms where no major changes in housing and management had taken place were considered for analysis. At the single measure level, Spearman rank correlations between visits were >0.7 and variance was lower within farms than between farms for six and two of 19 measures after 1 month and 6 months, respectively. After aggregation of single measures into criterion and principle scores, five and two of 10 criteria and three and one of four principles were found reliable after 1 and 6 months, respectively. At the WQ® principle level, this was the case for three and one of four principles. Seventy-nine per cent and 75% of the farms were allocated to the same overall welfare category after 1 month and 6 months. Possible reasons for a lack of consistency are seasonal effects or short-term fluctuations that occur under normal farm conditions, low prevalence of clinical measures and probably insufficient sample size, whereas poor inter-observer agreement leading to inflation of correlation can be ruled out. At the criterion and principle level, aggregation of information into scores appears to partly smoothen undirected variation at the single measure level without losing sensitivity in terms of welfare evaluation. Reliable on-farm animal welfare assessments should therefore be based on repeated assessments. Further long-term studies are recommended to better understand the factors influencing consistency over time.
The meeting was attended by 5 members of the WG (E. Bowell, G. Consolmagno, R. Courtain, R. Lopez, R. Schulz) one Task Group member (J. Watanabe), and several guests from the CSBN and CBAT. It was decided at the beginning of the meeting that the attending members of the WGPSN would discuss matters, provide their opinion or vote, and then ask the other 8 formal members to do the same via email. As a consequence the following discussed items have been agreed by majority vote of the WG members.
Individuals with a history of bipolar disorder demonstrate abnormalities of executive function, even during euthymia. The neural architecture underlying this and its relationship with genetic susceptibility for illness remain unclear.
We assessed 18 remitted individuals with bipolar disorder, 19 of their unaffected first degree relatives and 19 healthy controls using functional magnetic resonance imaging (fMRI) and a paced verbal fluency task with two levels of difficulty.
Bipolar patients made significantly more errors in the easy level of the verbal fluency task than their relatives or controls. Analysis of variance of fMRI data demonstrated a significant main effect of group in a large cluster including retrosplenial cortex and adjacent precuneate cortex (x=7, y=−56, x=15). All three groups showed deactivation in these areas during task performance relative to a neutral or rest condition. Group differences comprised a lesser amount of deactivation in unaffected relatives compared with controls in the easy condition [F(2, 55)=3.42, p=0.04] and in unaffected relatives compared with bipolar patients in the hard condition [F(2, 55)=4.34, p=0.018]. Comparison with the control group indicated that both bipolar patients and their relatives showed similar deficits of deactivation in retrosplenial cortex and reduced activation of left prefrontal cortex.
Bipolar disorder may be associated with an inherited abnormality of a neural network incorporating left prefrontal cortex and bilateral retrosplenial cortex.