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Objective: In the study of bipolar affective disorder and schizophrenia, there is some evidence suggesting a phenotypic and genetic overlap between the two disorders. A possible link between bipolar affective disorder and schizophrenia remains arguable, however. The authors hypothesized that dysbindin, which is a probable susceptibility gene for schizophrenia, was associated with bipolar affective disorder and tested this hypothesis using a case-control design study.Method: Participants included 213 patients with bipolar I disorder and 197 comparison subjects. In each subject, 10 polymorphisms in the dysbindin gene were genotyped and assessed.Results: Two polymorphisms showed individual genotypic association with bipolar I disorder. Multiple marker haplotypes were more strongly associated, with the rarer of the two common haplotypes being overrepresented in the patients with bipolar affective disorder. A similar finding was reported in patients with schizophrenia in a previous study.Conclusions: Findings suggest that the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder, which underscores a potentially important area of etiological overlap with schizophrenia. The existence of shared genetic risk factors will, in time, lead to changes in the current nosology of major psychoses. [ABSTRACT FROM AUTHOR]

In conservation, trust and justice are increasingly recognized as both intrinsically valuable and critical for successful socio-ecological outcomes. However, the interdependence between these concepts has not been explored. In reviewing the conservation trust scholarship, we find efforts to build trust between conservation and local actors, yet this is often conceived to incentivize local cooperation within dominant paradigms. We argue that trust-building which does not actively plan to address power asymmetries in conservation practice may inadvertently re-embed inequities, and therefore offer a justice-trust model to provide a critical analysis of conservation partnerships. We draw on environmental justice theory to better calibrate trust literature for the historical-political settings of conservation, especially in the Global South. We demonstrate that justice and trust share strong theoretical links with important practical implications for understanding relationships. We apply our justice-trust framework to multiple case-studies, exploring i) how perceptions of (in)justice can shape willingness to trust, and ii) the ways in which nature-dependent communities and marginalized conservation workers are trusted, or the conditions they give trust under, can lead to partnerships being perceived as (un)just. We argue that focusing on trust in tandem with justice can help identify power dynamics so they can be more readily addressed. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

In patients with renal cancer, brain metastasis is associated with poor survival and high morbidity. Poor life expectancy is often associated with widespread extracranial metastases. In such patients, a multidisciplinary approach is paramount. Brain metastases-specific therapies may include surgery, radiosurgery, conventional radiation and targeted therapies (TT) or a combination of these treatments. Some factors are important prognostically when choosing the best strategy: performance status, the number, size and location of brain metastases, the extension of systemic metastases and a well-controlled primary tumour. Failure of chemical therapy has always been attributed to an intact blood-brain barrier and acquired drug resistance by renal cancer cells. Recent studies have demonstrated objective responses with TT in a variety of cancer types, including renal cancer. In most cases, these agents have been used in combination and in conjunction with whole-brain radiation therapy and radiosurgery. Local control appears to be better with the combined method if the patient has a good performance status and may improve overall survival. This review summarizes current literature data on multidisciplinary approach in the management of renal brain metastasis with radiation, surgery and TT with an emphasis on potential better outcomes with a combination of current treatment methods., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Effective screening of mentally-ill defendants in the criminal court system requires cooperation between legal professionals in the criminal justice system (CJS), and health and social care workers in the mental-health service (MHS). This interagency working, though, can be problematic, as recognized in the Bradley inquiry that recommended joint training for MHS and CJS professionals. The aim of this study was to examine the experiences and attitudes of workers in the CJS and MHS to inform the development of relevant training. The method was a survey of mental-health workers and legal professionals in the court. The results showed that both agencies were uncertain of their ability to work with the other and there is little training that supports them in this. Both recognized the importance of mentally-ill defendants being dealt with appropriately in court proceedings but acknowledged this is not achieved. There is a shared willingness to sympathize with defendants and a common lack of willingness to give a definite, unqualified response on the relationship between culpability, mental-illness and punishment. Views differ around defendants' threat to security.Findings suggest there is scope to develop interprofessional training programs between the CJS and MHS to improve interagency working and eventually impact on the quality of defendants' lives. Recommendations are made on the type of joint training that could be provided.

Minocycline possesses anti-inflammatory properties independently of its antibiotic activity although the underlying molecular mechanisms are unclear. Lipopolysaccharide (LPS)-induced cytokines and pro-inflammatory protein expression are reduced by minocycline in cultured macrophages. Here, we tested a range of clinically important tetracycline compounds (oxytetracycline, doxycycline, minocycline and tigecycline) and showed that they all inhibited LPS-induced nitric oxide production. We made the novel finding that tigecycline inhibited LPS-induced nitric oxide production to a greater extent than the other tetracycline compounds tested. To identify potential targets for minocycline, we assessed alterations in the macrophage proteome induced by LPS in the presence or absence of a minocycline pre-treatment using 2-DE and nanoLC-MS. We found a number of proteins, mainly involved in cellular metabolism (ATP synthase β-subunit and aldose reductase) or stress response (heat shock proteins), which were altered in expression in response to LPS, some of which were restored, at least in part, by minocycline. This is the first study to document proteomic changes induced by minocycline. The observation that minocycline inhibits some, but not all, of the LPS-induced proteomic changes shows that minocycline specifically affects some signalling pathways and does not completely inhibit macrophage activation., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: Court liaison services aim to reduce mental illness in prison through early treatment and/or diversion into care of defendants negotiating their court proceedings. However, liaison services may inadvertently contribute to gender inequalities in mental health in the prison system because women often do not access liaison services. This is attributed to services failing to recognize that women have different needs from men. To address this, it is essential that the needs of women in contact with the criminal justice system (CJS) are clearly articulated. However, there is a dearth of research that considers women's needs at this stage of their journey through the CJS. This paper aims to identify these needs before women enter prison. It does so through an analysis of a pilot Women's Support Service based at a magistrates' court, a response to concerns that women were not accessing the local liaison service., Methods: Proformas were completed by a women's specialist worker for 86 women defendants assessed over four months. Information was collected on characteristics including education, domestic violence, accommodation, physical and mental health. This specialist worker recorded the range of needs identified by defendants at assessment and the services to which women were referred., Results: Access to the Women's Support Service is high, with only 11.3% of women refusing to use the service. Women attending have high levels of physical and mental health issues. Their mental health issues have not being addressed prior to accessing the service. Women often come from single households and environments high in domestic abuse. Women have multiple needs related to benefits, finance, housing, domestic abuse, education and career guidance. These are more frequent than those that explicitly link to mental health. The women's worker providing the service referred women to 68 services from a wide variety of statutory and voluntary organizations., Conclusions: The Women's Support Service is accessed by a higher number of women, many more than access the local liaison service. It is suggested that this is due to their multiple and gender-specific needs being adequately addressed by the former service and the organizations to which they are referred. Mental health needs may also be secondary to other more basic needs, which makes the generic service provided by the Women's Support Service more appropriate than a liaison service that deals with mental health support alone.

Provision of mental health reports for defendants in contact with the criminal justice system is problematic. This paper explores factors that facilitate the flow of information on a defendant between the courts and the mental health services. It identifies key challenges to this information transfer from a court worker's perspective. It also explores potential mismatches in the expectations held by the criminal justice system and the mental health services of the timeframes in which reports should be delivered and examines the perceived usefulness of reports. In Part 1, questionnaires were distributed to a population of 2107 court workers. In Part 2, monitoring forms were completed by court and health professionals on each report request made over a seven month period. Three key challenges to information transfer were identified: delays in report production, perceived inadequacies in the report content and report funding. Perceived timelines within which respondents believed reports should be delivered varied and there is a mismatch between the expectations of the two services. Perceptions on the usefulness of court reports also varied. Poor inter-agency communications are caused by lack of a clear, shared protocol outlining agreed timelines, report content and lines of responsibility relating to resource provision. Clear service level agreements are required between services to achieve clarity.

G-protein coupled receptors (GPCRs) typically have a functionally important C-terminus which, in the largest subfamily (family A), includes a membrane-parallel eighth helix. Mutations of this region are associated with several diseases. There are few C-terminal studies on the family B GPCRs and no data supporting the existence of a similar eighth helix in this second major subfamily, which has little or no sequence homology to family A GPCRs. Here we show that the C-terminus of a family B GPCR (CLR) has a disparate region from N400 to C436 required for CGRP-mediated internalization, and a proximal region of twelve residues (from G388 to W399), in a similar position to the family A eighth helix, required for receptor localization at the cell surface. A combination of circular and linear dichroism, fluorescence and modified waterLOGSY NMR spectroscopy (SALMON) demonstrated that a peptide mimetic of this domain readily forms a membrane-parallel helix anchored to the liposome by an interfacial tryptophan residue. The study reveals two key functions held within the C-terminus of a family B GPCR and presents support for an eighth helical region with striking topological similarity to the nonhomologous family A receptor. This helix structure appears to be found in most other family B GPCRs.

Background: Controlling vertebrate predators is one of the most widespread forms of wildlife management and it continues to cause conflict between stakeholders worldwide. It is important for managers and policy-makers to make decisions on this issue that are based on the best available scientific evidence. Therefore, it is first important to understand if there is indeed an impact of vertebrate predators on prey, and then to quantify this impact., Methodology/principal Findings: Using the UK as a case study, we use a meta-analytical approach to review the available evidence to assess the effect of vertebrate predation on animal prey abundance. We find a significant effect of predators on prey abundance across our studies. On average, there is a 1.6 fold increase in prey abundance in the absence of predation. However, we show significant heterogeneity in effect sizes, and discuss how the method of predator control, whether the predator is native or non-native, and aspects of study design, may be potential causes., Conclusions/significance: Our results allow some cautious policy recommendations to be made regarding the management of predator and prey populations. Meta-analysis is an important tool for understanding general patterns in the effect of predators on prey abundance across studies. Such an approach is especially valuable where management decisions need to be made in the absence of site-specific information.

The objective of this study was to examine whether the functional genetic polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene influences cognitive deterioration in a sample of patients with psychosis under treatment with atypical antipsychotics. Eighty-seven patients with psychosis were genotyped for this polymorphism and were assessed with three Wechsler Adult Intelligence Scale (WAIS)-III subtests (Vocabulary, Information, and Digit Symbol-Coding). Performance on these three subtests was used to compute a 'cognitive deterioration index', and the effect of COMT genotype on this cognitive deterioration index was examined. A linear relationship between the number of Val alleles and the score on the cognitive deterioration index (i.e. the more Val alleles, the more cognitive deterioration) was observed. These results confirm the role of COMT genotype in the cognition of patients under treatment for psychosis, suggesting that it influences the extent of their cognitive deterioration.

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, -205-G/A, -7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the -205-A/G polymorphisms and disease, an excess of allele -7685-C was observed in patients (p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium (p<0.0001) and strongly associated with disease (p<1x 10(-5)). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.

Pharmacogenetic research has identified response-related mutant variants in metabolic enzymes and drug-targeted receptors. Allelic variants of dopaminergic and serotonergic receptors have been associated with clinical outcome and adverse events such as movement disorders. Deficient metabolic enzymes have been related to drug accumulation and toxic events. This information will help to design safer and more efficient drugs. However, the field is moving rapidly towards a new goal: the application of pharmacogenetics as a clinical tool for the prediction of treatment outcome. The first studies in this direction have proved the feasibility of using genetic information for the prediction of response to antipsychotic drugs and to treatment of Alzheimer's disease. New strategies investigating genes related to specific symptoms and side-effects have produced encouraging results that can contribute to the improvement of the levels and accuracy of the predictions. This review tries to summarise recent advances and provides an overview of future clinical applications.

Past laboratory and field studies show that the effort necessary to obtain food acts as a determinant of food selection and consumption. Two studies examined the impact of increasing the effort needed to obtain candy or potato chips on selection in a normal lunch setting. In the first study, food selection, acceptance and intake were obtained during the first week baseline and under the effort manipulation during the second week. With increased effort, candy selection dropped dramatically in week 2. Subjects substituted items from the desert, fruit and accessory food groups. In the second study, food selection and acceptance were measured during a 2-week baseline, a 3-week effort period, and a 3-week recovery period. With increased effort, potato chip selection dropped dramatically and only partially recovered in the last phase. Subjects substituted items from the starch food group. These results demonstrate that changes in the effort needed to obtain food can have a nutritional impact in an actual eating situation and could be an important part of a healthy eating strategy.

Activation of the Ki-ras oncogene by specific point mutations at codon 12 occurs at a remarkably high frequency in pancreatic ductal adenocarcinoma and is likely to be an important event in the pathogenesis of this cancer. To determine whether ras activation also occurs in noninvasive proliferative lesions of the pancreas, a series of cases of ductal papillary hyperplasia, intraductal papillary neoplasia, and intraduct extensions of ductal adenocarcinoma were examined for activating mutations of Ki-ras at codons 12, 13, and 61 using polymerase chain reaction amplification. Specific mutations at Ki-ras codon 12 were found in 5 of 6 cases (83%) of intraduct extensions of carcinomas and in 12 of 16 (75%) invasive carcinomas. In cases with both intraductal and invasive components, the same mutation was identified in each. No mutations were found in 5 intraductal papillary neoplasms and 9 cases of ductal papillary hyperplasia. The authors conclude that Ki-ras activation at codon 12 is important in the tumorigenesis of ductal adenocarcinoma of the pancreas but is not required in the pathogenesis of ductal papillary hyperplasia or intraductal papillary neoplasm.

The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.

The expression of the EGF receptor, c-erbB-2 and PDGF receptor proteins has been studied in a series of human brain tumour biopsies and cell lines. Western blotting was used to determine the amount of protein present and their intrinsic and ligand promoted enzyme activities were studied by immunoprecipitation followed by autophosphorylation. EGF receptors were found to be expressed at very high levels in 40% of primary tumour biopsies, but at uniformly low levels in tumour derived cell lines. The c-erbB-2 protein was not detected in tumour biopsies, but was present at variable, but low levels in extracts of tumour cell lines. PDGF receptors were also found at moderate to low levels in both primary tumours and cell lines. The EGF receptor gene was amplified in four out of 14 primary tumours and this generally correlated with high levels of protein expression. The c-erbB-2 gene was not amplified. Employing the polymerase chain reaction and sequence specific oligonucleotides as probes there was no evidence of mutations in the c-erbB-2 gene transmembrane region. These results suggest that alterations of expression of the EGF receptor may play a role in human brain tumours. There was however no evidence for aberrant expression of the c-erbB-2 protein. Additional experiments are required to assess the influence of PDGF receptor expression in brain tumour cells.

The gene for the alpha polypeptide chain (alpha s) of the heterotrimeric G protein Gs can be activated to the putative oncogene gsp by specific point mutations at codons 201 and 227. Such mutations have been reported in 40% of human growth hormone-secreting pituitary adenomas and in a single autonomously functioning thyroid adenoma. We examined an archival series of 45 differentiated human thyroid tumors by polymerase chain reaction amplification and oligonucleotide hybridization to identify point mutations at each of the affected codons. Successful amplification was achieved in 38 cases, and activating mutations were identified in 5 of 13 (38%) autonomously functioning adenomas, but in none of 16 nonfunctioning adenomas, six papillary carcinomas, or three follicular carcinomas. Our results confirm that the gsp oncogene is involved in the pathogenesis of autonomously functioning tumors but do not support a role in other thyroid tumors.

We have previously shown that activation of ras oncogenes by mutation is a frequent early event in human thyroid neoplasia. Using amphotropic retroviral vectors to achieve gene transfer, we demonstrate here that human primary thyroid epithelial cells can be partially transformed by an activated cellular or viral Ha-ras oncogene, in the absence of a cooperating oncogene. The transformation event induced by ras involves temporary rescue from senescence for up to 20 rounds of cell division together with morphological alteration, growth factor independence and anchorage independence. It has therefore been possible to reconstruct in vitro a key early event in the genesis of human epithelial neoplasia.

The c-erb B-2 oncogene encodes a 190 kD transmembrane growth factor receptor which is closely related to the EGF receptor and has been found to be amplified and overexpressed in a number of human adenocarcinomas, particularly of the breast. We have analysed, by immunocytochemistry using the 21N antibody, expression of c-erb B-2 in a retrospective series of pancreatic adenocarcinoma, chronic pancreatitis, and examples of histologically normal pancreas. In three cases (21 per cent) of chronic pancreatitis, there were focal areas of cytoplasmic immunoreactivity in regenerating epithelium. In 15 cases (17 per cent) of pancreatic adenocarcinoma, cytoplasmic immunoreactivity was seen, while in two cases (2 per cent) strong membrane staining of tumour cells was seen which could be blocked by peptide controls. c-erb B-2 immunoreactivity was also demonstrated using a second antibody, 20N, which recognizes another peptide sequence of the c-erb B-2 protein. There was no relationship between immunoreactivity and histological subtype or grade, but there was absolute concordance between staining in primary and metastatic deposits. Since the rat homologue (neu) of the c-erb B-2 oncogene may be activated by a specific point mutation in its transmembrane region, we have analysed 23 cases from this series for mutations by polymerase chain reaction amplification and sequence-specific oligonucleotide hybridization. We were unable to identify activity mutations in this series. These data suggest that there is abnormal expression of c-erb B-2 oncogene in nearly 20 per cent of cases although mutational activation of this gene is not seen in human pancreatic adenocarcinoma.

The rat neu proto-oncogene, which is a putative growth factor receptor closely related to the epidermal growth factor receptor, can be activated in vivo by a single point mutation in the sequence encoding its transmembrane region. The human homologue of neu, c-erbB-2, can be activated in vitro to an oncogenic form by point mutations in the same relative position in the gene. We have sought the presence of such activating mutations in a series of 100 cases of human breast cancer by polymerase chain reaction amplification and sequence-specific oligonucleotide hybridization, and also by a designed restriction fragment length polymorphism strategy in cases with Southern blot evidence of c-erbB-2 amplification. No evidence of activating point mutations in the c-erbB-2 protooncogene was found in any of these cases.

The c-erbB-1 and c-erbB-2 proto-oncogenes are frequently activated by gene amplification and overexpression in a variety of human cancers. In an analysis of a large series of benign and malignant thyroid tumours, no abnormalities of structure or expression of either of c-erbB-1 or c-erbB-2 were found. Activation of these oncogenes is not a necessary event in neoplasia of this epithelial system.