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Acute stress affects interoception, but it remains unclear if this is due to activation of the sympatho-adreno-medullary (SAM) or hypothalamic–pituitary–adrenocortical axis. This study aimed to investigate the effect of SAM axis activation on interoceptive accuracy (IAcc). Central alpha2-adrenergic receptors represent a negative feedback mechanism of the SAM axis. Major depressive disorder and adverse childhood experiences (ACE) are associated with alterations in the biological stress systems, including central alpha2-adrenergic receptors. Here, healthy individuals with and without ACE as well as depressive patients with and without ACE (n = 114; all without antidepressant medication) were tested after yohimbine (alpha2-adrenergic antagonist) and placebo. We assessed IAcc and sensibility in a heartbeat counting task. Increases in systolic and diastolic blood pressure after yohimbine confirmed successful SAM axis activation. IAcc decreased after yohimbine only in the healthy group with ACE, but remained unchanged in all other groups (Group × Drug interaction). This effect may be due to selective upregulation of alpha2-adrenergic receptors after childhood trauma, which reduces capacity for attention focus on heartbeats. The sympathetic neural pathway including alpha2-adrenergic circuitries may be essential for mediating interoceptive signal transmission. Suppressed processing of physical sensations in stressful situations may represent an adaptive response in healthy individuals who experienced ACE.
We here present a comparison of methods for the pretreatment of a batch of tree rings for high-precision measurement of radiocarbon at the Aarhus AMS Centre (AARAMS), Aarhus University, Denmark. The aim was to develop an efficient and high-throughput method able to pretreat ca. 50 samples at a time. We tested two methods for extracting α-cellulose from wood to find the most optimal for our use. One method used acetic acid, the other used HCl acid for the delignification. The testing was conducted on background 14C samples, in order to assess the effect of the different pretreatment methods on low-activity samples. Furthermore, the extracted wood and cellulose fractions were analyzed using Fourier transform infrared (FTIR) spectroscopy, which showed a successful extraction of α-cellulose from the samples. Cellulose samples were pretreated at AARAMS, and the graphitization and radiocarbon analysis of these samples were done at both AARAMS and the radiocarbon dating laboratory at Lund University to compare the graphitization and AMS machine performance. No significant offset was found between the two sets of measurements. Based on these tests, the pretreatment of tree rings for high-precision radiocarbon analysis at AARAMS will henceforth use HCI for the delignification.
Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing.
We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8–18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task.
Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression.
Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.
We sought to explore whether obstetric complications (OCs) are more likely to occur in the presence of familial/genetic susceptibility for schizophrenia or whether they themselves represent an independent environmental risk factor for schizophrenia.
The presence of OCs was assessed through maternal interview on 216 subjects, comprising 36 patients with schizophrenia from multiply affected families, 38 of their unaffected siblings, 31 schizophrenic patients with no family history of psychosis, 51 of their unaffected siblings and 60 normal comparison subjects. We examined the familiality of OCs and whether OCs were commoner in the patient and sibling groups than in the control group.
OCs tended to cluster within families, especially in multiply affected families. Patients with schizophrenia, especially those from multiply affected families, had a significantly higher rate of OCs compared to normal comparison subjects, but there was no evidence for an elevated rate of OCs in unaffected siblings.
Our data provides little evidence for a link between OCs and genetic susceptibility to schizophrenia. If high rates of OCs are related to schizophrenia genes, this relationship is weak and will only be detected by very large sample sizes.
The consequences of Childhood trauma (CT) become increasingly apparent. The available data suggest that (1) CT is related to persisting alterations of HPA activity, (2) CT is related to psychopathology in patients with substance use disorders (SUD), and (3) alterations of HPA activity are related to craving and psychopathology. However, none of the existing studies have tried to integrate these different perspectives.
We assessed anxiety (STAI), depression (BDI) and craving (OCDS-D) in a consecutive sample of 42 patients with alcohol dependence (37% female, 63% male) on day 1 (t1) and day 14 (t2) after their admission to a detoxification unit. Morning plasma levels of cortisol and ACTH were assessed and a standard dexamethasone test (DST) was performed (t2). Finally, the Childhood Trauma Questionnaire was administered.
At t1, cortisol levels correlated significantly with anxiety (r=.34*) and sexual abuse (r=.38*). An inverse relationship was found between ACTH levels and both, emotional abuse and emotional neglect (t1: r=-.33*, r=-.39*; t2: r=-.32*, r=-.51**). This relationship persisted when controlling for depression. Craving was related to anxiety and depression (t1: r=.53**, r=.60**; t2: r=.39*, r=.35*), but not to cortisol or ACTH levels. No relationships existed between CT and the DST outcome.
Our results give first evidence that CT is related to changes of the HPA activity in SUD patients, but they could not be further clarified by the DST. Psychopathology was related to both, early trauma and craving. Future studies should try to further examine these complex relationships.
This study addresses the questions if and for which patients expressed emotion (EE) has a predictive validity in an 8 year follow-up study and if this is dependent on the residential form, especially on patients and relatives living together. Eight years after a baseline examination (Camberwell Family Interviews [CFI], global assessment scale [GAS], symptom score) 69 of 99 patients were reexamined. The number and duration of rehospitalizations as well as the symptom and GAS scores were recorded. These was no difference between outcome of high and low EE patients with a duration of illness of less than 4.5 years and for those living with partners. Patients from high EE parents with a longer duration of illness (> 4.5 years) at the outset of the study were significantly more often and longer in hospital. They had significantly higher symptom and GAS scores at the outset of the study and after 8 years. The EE effect was equal in the first and second 4 years of the follow-up and was independent from patients and parents living together. The results emphasize the significance of the EE index as a long-term predictor for the course of schizophrenic illness. The independence of the prediction from living together is an argument against a simple causal interpretation of the connection between EE and the course of schizophrenia.
Neurocognitive and functional neuroimaging studies point to frontal lobe abnormalities in schizophrenia. Molecular and behavioural genetic studies suggest that the frontal lobe is under significant genetic influence. We carried out structural magnetic resonance imaging (MRI) of the frontal lobe in monozygotic (MZ) twins concordant or discordant for schizophrenia and healthy MZ control twins.
The sample comprised 21 concordant pairs, 17 discordant affected and 18 discordant unaffected twins from 19 discordant pairs, and 27 control pairs. Groups were matched on sociodemographic variables. Patient groups (concordant, discordant affected) did not differ on clinical variables. Volumes of superior, middle, inferior and orbital frontal gyri were calculated using the Cavalieri principle on the basis of manual tracing of anatomic boundaries. Group differences were investigated covarying for whole-brain volume, gender and age.
Results for superior frontal gyrus showed that twins with schizophrenia (i.e. concordant twins and discordant affected twins) had reduced volume compared to twins without schizophrenia (i.e. discordant unaffected and control twins), indicating an effect of illness. For middle and orbital frontal gyrus, concordant (but not discordant affected) twins differed from non-schizophrenic twins. There were no group differences in inferior frontal gyrus volume.
These findings suggest that volume reductions in the superior frontal gyrus are associated with a diagnosis of schizophrenia (in the presence or absence of a co-twin with schizophrenia). On the other hand, volume reductions in middle and orbital frontal gyri are seen only in concordant pairs, perhaps reflecting the increased genetic vulnerability in this group.
Affective symptomatology has repeatedly been suggested to confer susceptibility to tardive dyskinesia (TD). In our sample of 174 schizophrenic patients a history of depressive symptoms was not associated with the occurrence of TD, whereas manic symptomatology was significantly associated with the absence of TD. Thus, our data suggest that affective symptomatology cannot unambiguously be considered to predispose to TD.
Single-year measurements of radiocarbon (14C) in tree rings have led to the discovery of rapid cosmic-ray events as well as longer lasting anomalies, which have given new insights into the Sun’s behavior in the past. Here, we present two new single-year 14C records based on Danish oak that span the periods AD 692–790 and 966–1057, respectively, and consequently include the two rapid cosmic-ray events in AD 775 and 994. The new data are presented along with relevant information on the dendrochronological dating of the wood pieces, implying that these new measurements may contribute towards generating the next international calibration curve. The new data covering the AD 966–1057 period suggest that the increase in atmospheric 14C associated with the cosmic-ray event in AD 994 actually occurred in AD 993, i.e. one year earlier than the year reported in Fogtmann-Schulz et al. (2017) based on oak from southern Denmark. Careful reanalysis of the dendrochronology that underpins the new 14C records based on oak material from southern Denmark reveals that the cosmic-ray event reported in Fogtmann-Schulz et al. (2017) actually took place in AD 993.
N-methyl-D-aspartate receptor (NMDA) encephalitis is a recently described autoimmune disease that typically presents with prodromal symptoms including upper respiratory tract infection, headache, fever, nausea, vomiting and diarrhea. Psychiatric symptoms follow within weeks, including anxiety, insomnia, mania, paranoia and grandiose delusions. The diagnosis is confirmed by the detection of NMDA antibodies in the serum or cerebrospinal fluid (CSF).1 Tumours, especially teratomas, are frequently associated with NMDA encephalitis; however, only 5% of male patients older than 18 years have been found to have an underlying tumour. Optic neuropathy associated with NMDA encephalitis is being increasingly recognised in the literature2–6 and was reviewed most recently by Mugavin et al.2 in 2017. In this report, we present a case of bilateral optic neuropathy in a young man diagnosed with NMDA receptor encephalitis.
The thymus undergoes a critical period of growth and development early in gestation and, by mid-gestation, immature thymocytes are subject to positive and negative selection. Exposure to undernutrition during these periods may permanently affect phenotype. We measured thymulin concentrations, as a proxy for thymic size and function, in children (n = 290; aged 9–13 years) born to participants in a cluster-randomized trial of maternal vitamin A or β-carotene supplementation in rural Nepal (1994–1997). The geometric mean (95% confidence interval) thymulin concentration was 1.37 ng/ml (1.27, 1.47). A multivariate model of early-life exposures revealed a positive association with gestational age at delivery (β = 0.02; P = 0.05) and higher concentrations among children born to β-carotene-supplemented mothers (β = 0.19; P < 0.05). At ∼9–12 years of age, thymulin was positively associated with all anthropometric measures, with height retained in our multivariate model (β = 0.02; P < 0.001). There was significant seasonal variation: concentrations tended to be lower pre-monsoon (β = −0.13; P = 0.15), during the monsoon (β = −0.22; P = 0.04), and pre-harvest (β = −0.34; P = 0.01), relative to the post-harvest season. All early-life associations, except supplementation, were mediated in part by nutritional status at follow-up. Our findings underscore the known sensitivity of the thymus to nutrition, including potentially lasting effects of early nutritional exposures. The relevance of these findings to later disease risk remains to be explored, particularly given the role of thymulin in the neuroendocrine regulation of inflammation.
Maternal systemic inflammation during pregnancy may restrict embryo−fetal growth, but the extent of this effect remains poorly established in undernourished populations. In a cohort of 653 maternal−newborn dyads participating in a multi-armed, micronutrient supplementation trial in southern Nepal, we investigated associations between maternal inflammation, assessed by serum α1-acid glycoprotein and C-reactive protein, in the first and third trimesters of pregnancy, and newborn weight, length and head and chest circumferences. Median (IQR) maternal concentrations in α1-acid glycoprotein and C-reactive protein in the first and third trimesters were 0.65 (0.53–0.76) and 0.40 (0.33–0.50) g/l, and 0.56 (0.25–1.54) and 1.07 (0.43–2.32) mg/l, respectively. α1-acid glycoprotein was inversely associated with birth size: weight, length, head circumference and chest circumference were lower by 116 g (P = 2.3 × 10−6), and 0.45 (P = 3.1 × 10−5), 0.18 (P = 0.0191) and 0.48 (P = 1.7 × 10−7) cm, respectively, per 50% increase in α1-acid glycoprotein averaged across both trimesters. Adjustment for maternal age, parity, gestational age, nutritional and socio-economic status and daily micronutrient supplementation failed to alter any association. Serum C-reactive protein concentration was largely unassociated with newborn size. In rural Nepal, birth size was inversely associated with low-grade, chronic inflammation during pregnancy as indicated by serum α1-acid glycoprotein.
The electrical reliability of multilayer high density interconnection printed circuit boards (HDI-PCBs) is mainly affected by the thermo-mechanical stability of stacked micro via interconnections. Here, a critical failure mode is the stress related crack between the electrolytically filled via and the target pad, commonly known as target pad separation. The junction includes two Cu-Cu-interfaces, one between the target Cu pad and the thin electroless Cu layer and the second between electroless Cu and electrolytic Cu. In this paper we will show that state-of-the-art electroless Cu plating processes are able to provide solid, completely recrystallized and highly reliable stacked via junctions. Defect free interfaces were achieved by using ionic Pd-activators and electroless Cu baths with a cyanide based stabilizer system. Cyanide free electroless Cu baths tend more to the formation of nanometer sized defects, discovered via Transmission Electron Microscopy (TEM). In this case a precise adjustment of single stabilizer components is mandatory to achieve defect free layers. The defects are hollow and were identified as “nano voids”. A critical density of these nano voids weakens the interface, predefines the crack path and reduces the overall reliability of the junction. A precise localization of the nano voids within the junction was enabled by detecting the Ni-containing electroless Cu layer via TEM-Ni mapping. Slower volume exchange of the electroless Cu solution within the blind micro via (BMV) substantially increases the nano void density. The ability of nano voids to migrate and coalesce at elevated temperatures was investigated as well.
Substantial amounts of annual radiocarbon (14C) data have recently been produced with the purpose of increasing the time resolution of 14C records used for constructing the calibration curve and for studying the occurrence of abrupt cosmic-ray events. In this study, we investigate if it is possible to resolve sub-annual scale changes in the atmospheric 14C content by measuring radiocarbon in early-wood and late-wood fractions from Danish oak. The tree-ring samples span the period 1954–1970 CE, hereby covering the peak of the bomb pulse. A least squares test comparing the atmospheric 14C content and the new sub-annual 14C record from Danish tree rings reveals that by measuring early-wood and late-wood fractions, it may be possible to resolve sub-annual variations in past atmospheric 14C levels.
Each year our Clinical and Translational Science Award pilot projects program awards approximately $500,000 in translational pilot funding to advance health in South Texas. We identified needs to improve the timeliness, transparency, and efficiency of the review process by surveying applicants. Lean six sigma methodologies, following a “Define, Measure, Analyze, Improve, Control” approach, were used to streamline the pilot project application and review by identifying and removing bottlenecks from process flows. We evaluated the impact of our reorganized review process by surveying applicants and reviewers. Process mapping identified pilot project review as the main source of delay, leading to the implementation of a study section-style review mechanism. After one cycle, 90.3% of pilot applicants and 100% of reviewers were highly satisfied with the new processes and time to award notice was reduced by 2 months. All reviewers familiar with both review processes preferred the study section. We demonstrated how lean six sigma, a methodology not commonly applied in research administration, can be used to evaluate processes in translational science in academic health centers. Through our efforts, we were able to improve timeliness, transparency, and efficiency of the review process.
Environmental enteric dysfunction (EED) and systemic inflammation (SI) are common in developing countries and may cause stunting. In Bangladesh, >40 % of preschool children are stunted, but EED and SI contributions are unknown. We aimed to determine the impact of EED and SI (assessed with multiple indicators) on growth in children (n 539) enrolled in a community-based randomised food supplementation trial in rural Bangladesh. EED was defined with faecal myeloperoxidase, α-1 antitrypsin and neopterin and serum endotoxin core antibody and glucagon-like peptide-2, consolidated into gut inflammation (GI) and permeability (GP) scores, and urinary lactulose:mannitol α-1 acid glycoprotein (AGP) characterised SI. Biomarker associations with anthropometry (15-, 18- and 24-month length-for-age (LAZ), weight-for-length (WLZ) and weight-for-age (WAZ) z scores) were examined in pairwise correlations and adjusted mixed-effects regressions. Stunting, wasting and underweight prevalence at 18 months were 45, 15 and 37 %, respectively, with elevated EED and SI markers common. EED and SI were not associated with 15–24-month length trajectory. Elevated (worse) GI and GP scores predicted reduced 18–24-month WLZ change (β −0·01 (se 0·00) z score/month for both). Elevated GP was also associated with reduced 15–18-month WLZ change (β −0·03 (se 0·01) z score/month) and greater 15-month WLZ (β 0·16 (se 0·05)). Higher AGP was associated with reduced prior and increased subsequent WLZ change (β −0·04 (se 0·01) and β 0·02 (se 0·00) z score/month for 15–18 and 18–24 months). The hypothesised link from EED to stunting was not observed in this sample of Bangladeshi 18-month-olds, but the effects of EED on constrained weight gain may have consequences for later linear growth or for other health and development outcomes.
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.