Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics

Background Pharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown. Discussion The majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders. Summary Despite the complexities, examinations of post-mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics

Genetic and epigenetic regulation in Lingo-1 : Effects on cognitive function and white matter microstructure in a case-control study for schizophrenia

Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3′-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016–1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology

No measure for culture? Value in the new economy

This paper explores articulations of the value of investment in culture and the arts through a critical discourse analysis of policy documents, reports and academic commentary since 1997. It argues that in this period, discourses around the value of culture have moved from a focus on the direct economic contributions of the culture industries to their indirect economic benefits. These indirect benefits are discussed here under three main headings: creativity and innovation, employability, and social inclusion. These are in turn analysed in terms of three forms of capital: human, social and cultural. The paper concludes with an analysis of this discursive shift through the lens of autonomist Marxist concerns with the labour of social reproduction. It is our argument that, in contemporary policy discourses on culture and the arts, the government in the UK is increasingly concerned with the use of culture to form the social in the image of capital. As such, we must turn our attention beyond the walls of the factory in order to understand the contemporary capitalist production of value and resistance to it. </jats:p

Emulating Natural Disturbances for Declining Late- Successional Species: A Case Study of the Consequences for Cerulean Warblers (Setophaga cerulea)

Forest cover in the eastern United States has increased over the past century and while some late-successional species have benefited from this process as expected, others have experienced population declines. These declines may be in part related to contemporary reductions in small-scale forest interior disturbances such as fire, windthrow, and treefalls. To mitigate the negative impacts of disturbance alteration and suppression on some late-successional species, strategies that emulate natural disturbance regimes are often advocated, but large-scale evaluations of these practices are rare. Here, we assessed the consequences of experimental disturbance (using partial timber harvest) on a severely declining late-successional species, the cerulean warbler (Setophaga cerulea), across the core of its breeding range in the Appalachian Mountains. We measured numerical (density), physiological (body condition), and demographic (age structure and reproduction) responses to three levels of disturbance and explored the potential impacts of disturbance on source-sink dynamics. Breeding densities of warblers increased one to four years after all canopy disturbances (vs. controls) and males occupying territories on treatment plots were in better condition than those on control plots. However, these beneficial effects of disturbance did not correspond to improvements in reproduction; nest success was lower on all treatment plots than on control plots in the southern region and marginally lower on light disturbance plots in the northern region. Our data suggest that only habitats in the southern region acted as sources, and interior disturbances in this region have the potential to create ecological traps at a local scale, but sources when viewed at broader scales. Thus, cerulean warblers would likely benefit from management that strikes a landscape-level balance between emulating natural disturbances in order to attract individuals into areas where current structure is inappropriate, and limiting anthropogenic disturbance in forests that already possess appropriate structural attributes in order to maintain maximum productivity

Emulating Natural Disturbances for Declining Late-Successional Species: A Case Study of the Consequences for Cerulean Warblers (Setophaga cerulea)

Forest cover in the eastern United States has increased over the past century and while some late-successional species have benefited from this process as expected, others have experienced population declines. These declines may be in part related to contemporary reductions in small-scale forest interior disturbances such as fire, windthrow, and treefalls. To mitigate the negative impacts of disturbance alteration and suppression on some late-successional species, strategies that emulate natural disturbance regimes are often advocated, but large-scale evaluations of these practices are rare. Here, we assessed the consequences of experimental disturbance (using partial timber harvest) on a severely declining latesuccessional species, the cerulean warbler (Setophaga cerulea), across the core of its breeding range in the Appalachian Mountains. We measured numerical (density), physiological (body condition), and demographic (age structure and reproduction) responses to three levels of disturbance and explored the potential impacts of disturbance on source-sink dynamics. Breeding densities of warblers increased one to four years after all canopy disturbances (vs. controls) and males occupying territories on treatment plots were in better condition than those on control plots. However, these beneficial effects of disturbance did not correspond to improvements in reproduction; nest success was lower on all treatment plots than on control plots in the southern region and marginally lower on light disturbance plots in the northern region. Our data suggest that only habitats in the southern region acted as sources, and interior disturbances in this region have the potential to create ecological traps at a local scale, but sources when viewed at broader scales. Thus, cerulean warblers would likely benefit from management that strikes a landscape-level balance between emulating natural disturbances in order to attract individuals into areas where current structure is inappropriate, and limiting anthropogenic disturbance in forests that already possess appropriate structural attributes in order to maintain maximum productivity

A multilevel analytical framework for studying cultural evolution in prehistoric hunter-gatherer societies

Over the past decade, a major debate has taken place on the underpinnings of cultural changes in human societies. A growing array of evidence in behavioural and evolutionary biology has revealed that social connectivity among populations and within them affects, and is affected by, culture. Yet the interplay between prehistoric hunter-gatherer social structure and cultural transmission has typically been overlooked. Interestingly, the archaeological record contains large data sets, allowing us to track cultural changes over thousands of years: they thus offer a unique opportunity to shed light on long‐term cultural transmission processes

Complex structural rearrangements are present in high-grade dysplastic Barrett\u27s oesophagus samples

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett’s oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC

The Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in Dutch advanced cancer patients

Item does not contain fulltextPURPOSE: Depression is highly prevalent in advanced cancer patients, but the diagnosis of depressive disorder in patients with advanced cancer is difficult. Screening instruments could facilitate diagnosing depressive disorder in patients with advanced cancer. The aim of this study was to determine the validity of the Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in advanced cancer patients. METHODS: Patients with advanced metastatic disease, visiting the outpatient palliative care department, were asked to fill out a self-questionnaire containing the Beck Depression Inventory (BDI-II) and a single screening question "Are you feeling depressed?" The mood section of the PRIME-MD was used as a gold standard. RESULTS: Sixty-one patients with advanced metastatic disease were eligible to be included in the study. Complete data were obtained from 46 patients. The area under the curve of the receiver operating characteristics analysis of the BDI-II was 0.82. The optimal cut-off point of the BDI-II was 16 with a sensitivity of 90% and a specificity of 69%. The single screening question showed a sensitivity of 50% and a specificity of 94%. CONCLUSIONS: The BDI-II seems an adequate screening tool for a depressive disorder in advanced cancer patients. The sensitivity of a single screening question is poor.1 februari 201

A prospective longitudinal study of Pasireotide in Nelson's syndrome

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients. CONCLUSIONS: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume. TRIAL REGISTRATION: Clinical Trials.gov ID, NCT01617733