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RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.
RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.
RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.
In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.
After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.
Frowning expresses negative emotions like anger, fear, and sadness. According to the facial feedback hypothesis, suppression of frowning will also diminish the corresponding negative emotions. Hence, mood improvement has been observed in patients who underwent treatment of glabellar frown lines with botulinum neurotoxin. This observation suggests the possibility that the intervention may be employed for the management of psychiatric disorders associated with negative emotions. Preliminary data from an open case series indicate that the intervention might improve the symptoms of depression.
Aims & objectives
To test whether an onabotulinumtoxinA injection into the glabellar region is benefical as an adjunctive treatment of major depression within a clinical trial.
We used a randomized, double-blinded, placebo-controlled study design (n = 30; ClinicalTrials.gov, number, NCT00934687).
We show that a single onabotulinumtoxinA treatment shortly leads to a strong and sustained improvement in partly chronic major depression that did not respond sufficiently to previous treatment. As for the primary end-point, Hamilton Depression Rating Scale (HAM-D17) six weeks after treatment compared to baseline, scores of onabotulinumtoxinA recipients showed 37.9% (8.34 points) more improvement than those of placebo-treated participants (F = 12.30, p = 0.002, η2 = 0.31, d = 1.28).
Our findings support the concept that the facial musculature not only expresses, but also regulates, mood states. As it stands, treatment of glabellar frown lines with botulinum neurotoxin can be considered for depressed patients with the objective of inducing mood-lifting effects.
Thromboxane (TX) A2 and the activation of its receptor have been shown to modulate vasoconstriction, platelet aggregation, but also dopaminergic and serotonergic signaling.
As dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and as these systems are main targets of antipsychotics, we hypothesized that antipsychotics might also influence TXA2 production.
We measured levels of TXB2, the metabolite of the very unstable molecule TXA2, in the stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin-1 (TSST-1) and the monoclonal antibody against the surface antigen CD3 combined with the protein CD40 (OKT3/CD40) as stimulants. Blood was either supplemented with antipsychotics (chlorpromazine, clozapine, and its metabolite N-desmethylclozapine with four different concentrations each) or not.
Under TSST-1 as well as OKT3/CD40 stimulation, mean TXB2 concentrations were significantly (p < 0.05) decreased by clozapine over all of the applied concentrations. N-desmethylclozapine led to a decrease in TXB2 levels under TSST-1 stimulation only. Chlorpromazine did not show any significant influence on TXB2 production.
Clozapine might, complementary to serotonin and dopamine receptor binding, act on the dopaminergic and serotonergic system via a modulation of TXA2 production. Additionally, side effects of clozapine such as orthostatic hypotension may be a result of the reported TXA2 changes.
Mental trauma may precede persistent changes in a person's mental health in the form of psychosis and dissociation. Presently, there are no subtypes to the diagnosis of PTSD. A psychotic subtype of PTSD has been proposed, and studies show that these patients differ as well in symptoms as biologically from patients with non-psychotic PTSD. Dissociation and psychosis are generally viewed as different phenomena. Where dissociation is understood as a disintegration of the mind, psychosis is viewed as a neurodegenerative disorder on a mainly biological/genetic basis. The delineation of psychotic and dissociative symptoms is not clear however.
Our objective is to clarify, whether psychologists and psychiatrists describe trauma-related changes of consciousness (TCC) differently as dissociative or psychotic. Furthermore, we wish to compare scientific journals, and look for differences in how psychiatrists’ and psychologists’ make use of the terms dissociation and psychosis in relation to TCC.
We aim to investigate whether TCC are interpreted differently among psychiatrists and psychologists.
This study is a systematic critical review of the literature. The databases PubMed, Embase and PsychInfo will be used. Articles involving PTSD with TCC will be included. Studies will be classified as viewing TCC's as either psychotic or dissociative, based on the terms the authors use to describe the observed phenomena.
The results will be presented at the EPA in March 2016 in Madrid.
The study will reveal differences in how psychiatrists and psychologists classify TCC's in PTSD.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Music performance anxiety (MPA) is one of the most common disorders among professional musicians, nevertheless, little is known about the disease. With this systematic review, prevalence, risk factors and treatment procedures for MPA were assessed, and for the first time, quality assessments were carried out for all studies using standardized assessment tools. A systematic literature search was conducted via search algorithms in the databases MEDLINE, EMBASE, CINAHL, PsycArticles, PsycInfo and ERIC. Included were case reports, case–control, cohort, cross-sectional and intervention studies examining professional musicians with MPA. For quality assessment, adapted tools of the National Heart, Lung, and Blood Institute were used. A total of 43 studies were included (10 case reports, 21 intervention, 11 cross-sectional, one cohort study). Quality ratings ranged from −11 to 6 out of a maximum of 15/16 points for cross-sectional/cohort studies and −4 to 11 out of 18 points for intervention studies. The prevalence of MPA was between 16.5% and 60%. More women than men were affected and musicians older than 45–50 years reported less MPA than younger musicians. Regarding treatment cognitive behavioural therapy (CBT) and β-blockers were most often researched with beneficial results for CBT. However, studies with adequate control groups for CBT interventions are needed to clarify its efficacy. Studies showed methodological weaknesses, especially in the selection of participants, recording of influencing factors, blinding of interventions, randomization of participants and analysis of comorbidity. Recommendations for further research are made.
The Wisconsin Twin Project comprises multiple longitudinal studies that span infancy to early adulthood. We summarize recent papers that show how twin designs with deep phenotyping, including biological measures, can inform questions about phenotypic structure, etiology, comorbidity, heterogeneity, and gene–environment interplay of temperamental constructs and mental and physical health conditions of children and adolescents. The general framework for investigations begins with rich characterization of early temperament and follows with study of experiences and exposures across childhood and adolescence. Many studies incorporate neuroimaging and hormone assays.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.
In Central America, population and food demands are rising rapidly, while yields of staple crops, maize and beans, remain low. To identify the main factors limiting production, field trials were established in six maize- and bean-producing regions in Guatemala, Honduras and El Salvador, representing about three-quarters of the maize-producing area. Potential yield-limiting factors were evaluated in 2017 and included: water stress, nutrient deficiency, pest and disease pressure, and/or inter-plant competition. When considering all sites, improved fertilization and pest and disease control significantly improved yields in maize by 11 and 16%, respectively but did not have a significant effect in beans. Irrigation had no effect due to good rainfall distribution over the growing season. Optimized planting arrangement resulted in an average 18% increase in maize yield, making it the most promising factor evaluated. The treatment and site combinations that increased both crop productivity and net profit included management changes that improved resource use efficiency. However, the contribution of each limiting factor to yield gaps varied across sites and no treatment was effective at increasing yield consistently across sites. Production constraints are highly dependent on local management practices and agroecological location. Therefore, public and private development efforts that seek to increase production should conduct multi-year, participatory experiments to identify limitations pertinent to the area in question. The next step is then to evaluate sustainable and profitable practices, to address those limitations and provide sound recommendations to farmers while decreasing the environmental and economic costs.
Laser-based compact MeV X-ray sources are useful for a variety of applications such as radiography and active interrogation of nuclear materials. MeV X rays are typically generated by impinging the intense laser onto ~mm-thick high-Z foil. Here, we have characterized such a MeV X-ray source from 120 TW (80 J, 650 fs) laser interaction with a 1 mm-thick tantalum foil. Our measurements show X-ray temperature of 2.5 MeV, flux of 3 × 1012 photons/sr/shot, beam divergence of ~0.1 sr, conversion efficiency of ~1%, that is, ~1 J of MeV X rays out of 80 J incident laser, and source size of 80 m. Our measurement also shows that MeV X-ray yield and temperature is largely insensitive to nanosecond laser contrasts up to 10−5. Also, preliminary measurements of similar MeV X-ray source using a double-foil scheme, where the laser-driven hot electrons from a thin foil undergoing relativistic transparency impinging onto a second high-Z converter foil separated by 50–400 m, show MeV X-ray yield more than an order of magnitude lower compared with the single-foil results.
Although sorghum [Sorghum bicolor (L.) Moench ssp. bicolor] is the fifth most important grain crop in terms of global production, no commercial hybrids carry genetically engineered (GE) traits for resistance to insect pests or herbicides due to regulatory concerns about gene flow to weedy relatives. However, non-GE herbicide resistance currently is being developed in grain sorghum and will likely transfer to related weeds. Monitoring the impact of this new nuclear technology on the evolution and invasiveness of related weeds requires a baseline understanding of the population biology of grain sorghum genes once they transfer to in situ weed populations. We previously characterized the rate of gene flow from grain sorghum to shattercane [Sorghum bicolor (L.) Moench nothosubsp. drummondii (Steud.) de Wet ex. Davidse], a conspecific weed relatively common in North America; as well as the ecological fitness of an F1 population when S. bicolor nothosubsp. drummondii was the maternal parent. Here we report the ecological fitness of a S. bicolor nothosubsp. drummondii × S. bicolor ssp. bicolor F2 population relative to its crop and weed parents. Parental and F2 populations were grown in two Nebraska environments in 2012 and 2013. Traits evaluated included overwinter survival, field emergence, biomass production and partitioning at anthesis, total seed production, and 100-seed weight. Results indicated that F2 traits were generally intermediate between the parents, but more similar to S. bicolor nothosubsp. drummondii than to grain sorghum. The one exception was overwinter survival, which was nearly 0% for both the F2 and the grain sorghum parent in these northern environments. Thus, the frequency of crop alleles stably introgressed into S. bicolor nothosubsp. drummondii populations appears to primarily depend on overwinter survival of the F2 and which selective pressures are imposed upon it by the cropping system. These data provide needed baseline information about the environmental fate of nuclear genetic technologies deployed in this important global crop.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
We sought to comprehensively assess the prevalence and outcomes of complications associated with Staphylococcus aureus bacteremia (SAB) in children. Secondarily, prevalence of methicillin resistance and outcomes of complications from methicillin-resistant S. aureus (MRSA) vs. methicillin-susceptible S. aureus SAB were assessed. This is a single-center cross-sectional study of 376 patients ⩽18 years old with SAB in 1990–2014. Overall, 197 (52%) patients experienced complications, the most common being osteomyelitis (33%), skin and soft tissue infection (31%), and pneumonia (25%). Patients with complications were older (median 3 vs. 0·7 years, P = 0·05) and more had community-associated SAB (66% vs. 34%, P = 0·001). Fewer patients with complications had a SAB-related emergency department or hospital readmission (10% vs. 19%, P = 0·014). Prevalence of methicillin resistance increased from 1990–1999 to 2000–2009, but decreased in 2010–2014. Complicated MRSA bacteremia resulted in more intensive care unit admissions (66% vs. 47%, P = 0·03) and led to increased likelihood of having ⩾2 foci (58% vs. 26%, P < 0·001). From multivariate analysis, community-associated SAB increased risk and concurrent infections decreased risk of complications (odds ratio (OR) 1·82 (1·1–3·02), P = 0·021) and (OR 0·58 (0·34–0·97), P = 0·038), respectively. In conclusion, children with SAB should be carefully evaluated for complications. Methicillin resistance remains associated with poor outcomes but have decreased in overall prevalence.
There is a lack of evidence pointing to the efficacy of any specific psychotherapy for adults with anorexia nervosa (AN). The aim of this study was to compare three psychological treatments for AN: Specialist Supportive Clinical Management, Maudsley Model Anorexia Nervosa Treatment for Adults and Enhanced Cognitive Behavioural Therapy.
A multi-centre randomised controlled trial was conducted with outcomes assessed at pre-, mid- and post-treatment, and 6- and 12-month follow-up by researchers blind to treatment allocation. All analyses were intention-to-treat. One hundred and twenty individuals meeting diagnostic criteria for AN were recruited from outpatient treatment settings in three Australian cities and offered 25–40 sessions over a 10-month period. Primary outcomes were body mass index (BMI) and eating disorder psychopathology. Secondary outcomes included depression, anxiety, stress and psychosocial impairment.
Treatment was completed by 60% of participants and 52.5% of the total sample completed 12-month follow-up. Completion rates did not differ between treatments. There were no significant differences between treatments on continuous outcomes; all resulted in clinically significant improvements in BMI, eating disorder psychopathology, general psychopathology and psychosocial impairment that were maintained over follow-up. There were no significant differences between treatments with regard to the achievement of a healthy weight (mean = 50%) or remission (mean = 28.3%) at 12-month follow-up.
The findings add to the evidence base for these three psychological treatments for adults with AN, but the results underscore the need for continued efforts to improve outpatient treatments for this disorder.
Hairworms (Nematomorpha) are a little-known group of parasites, and despite having been represented in the taxonomic literature for over a century, the implementation of molecular genetics in studies of hairworm ecology and evolution lags behind that of other parasitic taxa. In this study, we characterize the genetic diversity of the New Zealand nematomorph fauna and test for genetic structure within the most widespread species found. We provide new mitochondrial and nuclear ribosomal sequence data for three previously described species from New Zealand: Gordius paranensis, Parachordodes diblastus and Euchordodes nigromaculatus. We also present genetic data on a previously reported but undescribed Gordius sp., as well as data from specimens of a new Gordionus sp., a genus new for New Zealand. Phylogenetic analyses of CO1 and nuclear rDNA regions correspond with morphological classification based on scanning electron microscopy, and demonstrate paraphyly of the genus Gordionus and the potential for cryptic species within G. paranensis. Population-level analyses of E. nigromaculatus showed no genetic differentiation among sampling locations across the study area, in contrast to previously observed patterns in known and likely definitive hosts. Taken together, this raises the possibility that factors such as definitive host specificity, intermediate host movement, and passive dispersal of eggs and larvae may influence host–parasite population co-structure in hairworms.
Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset.
Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA.
Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) < 0.01]. The structure of EPDS responses significantly differed between Europe and the USA (∆*CFI > 0.01), but not between European countries (∆*CFI < 0.01).
Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.
A new generation of solar instruments provides improved spectral, spatial, and temporal resolution, thus facilitating a better understanding of dynamic processes on the Sun. High-resolution observations often reveal multiple-component spectral line profiles, e.g., in the near-infrared He i 10830 Å triplet, which provides information about the chromospheric velocity and magnetic fine structure. We observed an emerging flux region, including two small pores and an arch filament system, on 2015 April 17 with the ‘very fast spectroscopic mode’ of the GREGOR Infrared Spectrograph (GRIS) situated at the 1.5-meter GREGOR solar telescope at Observatorio del Teide, Tenerife, Spain. We discuss this method of obtaining fast (one per minute) spectral scans of the solar surface and its potential to follow dynamic processes on the Sun. We demonstrate the performance of the ‘very fast spectroscopic mode’ by tracking chromospheric high-velocity features in the arch filament system.
Preterm birth and exposure to childhood sexual abuse (CSA) are early physiological and psychological adversities that have been linked to reduced social functioning across the lifespan. However, the joint effects of being born preterm and being exposed to CSA on adult social outcomes remains unclear. We sought to determine the impact of exposure to both preterm birth and CSA on adult social functioning in a group of 179 extremely low birth weight (ELBW; <1000 g) survivors and 145 matched normal birth weight (>2500 g) participants in the fourth decade of life. Social outcome data from a prospective, longitudinal, population-based Canadian birth cohort initiated between the years of 1977 and 1982 were examined. At age 29–36 years, ELBW survivors who experienced CSA reported poorer relationships with their partner, worse family functioning, greater loneliness, lower self-esteem and had higher rates of avoidant personality problems than those who had not experienced CSA. Birth weight status was also found to moderate associations between CSA and self-esteem (P=0.032), loneliness (P=0.021) and family functioning (P=0.060), such that the adverse effects of CSA were amplified in ELBW survivors. Exposure to CSA appears to augment the adult social risks associated with perinatal adversity. Individuals born preterm and exposed to CSA appear to be a group at particularly high risk for adverse social outcomes in adulthood.