Cleft Palate Is Caused by CNS Dysfunction in Gad1 and Viaat Knockout Mice

BACKGROUND: Previous studies have shown that disruption of GABA signaling in mice via mutations in the Gad1, Gabrb3 or Viaat genes leads to the development of non-neural developmental defects such as cleft palate. Studies of the Gabrb3 and Gad1 mutant mice have suggested that GABA function could be required either in the central nervous system or in the palate itself for normal palatogenesis. METHODOLOGY/PRINCIPAL FINDINGS: To further examine the role of GABA signaling in palatogenesis we used three independent experimental approaches to test whether Gad1 or Viaat function is required in the fetal CNS for normal palate development. We used oral explant cultures to demonstrate that the Gad1 and Viaat mutant palates were able to undergo palatogenesis in culture, suggesting that there is no defect in the palate tissue itself in these mice. In a second series of experiments we found that the GABA(A) receptor agonist muscimol could rescue the cleft palate phenotype in Gad1 and Viaat mutant embryos. This suggested that normal multimeric GABA(A) receptors in the CNS were necessary for normal palatogenesis. In addition, we showed that CNS-specific inactivation of Gad1 was sufficient to disrupt palate development. CONCLUSIONS/SIGNIFICANCE: Our results are consistent with a role for Gad1 and Viaat in the central nervous system for normal development of the palate. We suggest that the alterations in GABA signaling lead to non-neural defects such as cleft palate as a secondary effect due to alterations in or elimination of fetal movements

Unexpected Novel Relational Links Uncovered by Extensive Developmental Profiling of Nuclear Receptor Expression

Nuclear receptors (NRs) are transcription factors that are implicated in several biological processes such as embryonic development, homeostasis, and metabolic diseases. To study the role of NRs in development, it is critically important to know when and where individual genes are expressed. Although systematic expression studies using reverse transcriptase PCR and/or DNA microarrays have been performed in classical model systems such as Drosophila and mouse, no systematic atlas describing NR involvement during embryonic development on a global scale has been assembled. Adopting a systems biology approach, we conducted a systematic analysis of the dynamic spatiotemporal expression of all NR genes as well as their main transcriptional coregulators during zebrafish development (101 genes) using whole-mount in situ hybridization. This extensive dataset establishes overlapping expression patterns among NRs and coregulators, indicating hierarchical transcriptional networks. This complete developmental profiling provides an unprecedented examination of expression of NRs during embryogenesis, uncovering their potential function during central nervous system and retina formation. Moreover, our study reveals that tissue specificity of hormone action is conferred more by the receptors than by their coregulators. Finally, further evolutionary analyses of this global resource led us to propose that neofunctionalization of duplicated genes occurs at the levels of both protein sequence and RNA expression patterns. Altogether, this expression database of NRs provides novel routes for leading investigation into the biological function of each individual NR as well as for the study of their combinatorial regulatory circuitry within the superfamily

Reconstructing ‘the Alcoholic’: Recovering from Alcohol Addiction and the Stigma this Entails

Public perception of alcohol addiction is frequently negative, whilst an important part of recovery is the construction of a positive sense of self. In order to explore how this might be achieved, we investigated how those who self-identify as in recovery from alcohol problems view themselves and their difficulties with alcohol and how they make sense of others’ responses to their addiction. Semi-structured interviews with six individuals who had been in recovery between 5 and 35 years and in contact with Alcoholics Anonymous were analysed using Interpretative Phenomenological Analysis. The participants were acutely aware of stigmatising images of ‘alcoholics’ and described having struggled with a considerable dilemma in accepting this identity themselves. However, to some extent they were able to resist stigma by conceiving of an ‘aware alcoholic self’ which was divorced from their previously unaware self and formed the basis for a new more knowing and valued identity

Pedomorphosis revisited: thyroid hormone receptors are functional in Necturus maculosus

Heterochrony, a difference in developmental timing, is a central concept in modern evolutionary biology. An example is pedomorphosis, retention of juvenile characteristics in sexually mature adults, a phenomenon largely represented in salamanders. The mudpuppy ( Necturus maculosus ) is an obligate pedomorphic amphibian, never undergoing metamorphosis. Thyroid hormone induces tissue transformation in metamorphosing species and this action is mediated by nuclear thyroid hormone (TH) receptors (TRs). The absence of metamorphosis in Necturus has been attributed to a resistance to TH action as treatment with exogenous TH fails to induce transformation. The failure to metamorphose could be due to the lack of TR expression in target tissues, or to a loss of TR function. Toward understanding the molecular basis for the failure of Necturus tissues to respond to TH, and the ultimate cause for the expression of the obligate pedomorphic life history, we characterized the structure, function, and expression of TR genes in Necturus . Strikingly, we found that Necturus TRΑ and TRΒ genes encode fully functional TR proteins. These TRs bind both DNA and TH and can transactivate target genes in response to TH. Both TRΑ and TRΒ are expressed in various tissues. TH treatment in vivo induced expression in the gill of some but not all genes known to be activated by TH in anuran larvae, caused whole organism metabolic effects, but induced no external morphological changes in adults or larvae. Thus, Necturus possesses fully functional TRs and its tissues are not generally resistant to the actions of TH. Rather, the absence of metamorphosis may be due to the loss of TH-dependent control of key genes required for tissue transformation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75694/1/j.1525-142X.2006.00099.x.pd

Measuring capital in active addiction and recovery: the development of the strengths and barriers recovery scale (SABRS).

BACKGROUND: The international Life In Recovery (LiR) surveys have provided an important message to the public and policy makers about the reality of change from addiction to recovery, consistently demonstrating both that there are marked gains across a range of life domains and that the longer the person is in recovery the better their recovery strengths and achievements. However, to date, no attempt has been made to quantify the Life In Recovery scales and to assess what levels of change in removing barriers and building strengths is achieved at which point in the recovery journey. METHODS: The current study undertakes a preliminary analysis of strengths and barriers from the Life in Recovery measure, using data from a European survey on drug users in recovery (n = 480), and suggests that the instrument can be edited into a Strengths And Barriers Recovery Scale (SABRS). The new scale provides a single score for both current recovery strengths and barriers to recovery. RESULTS: The resulting data analysis shows that there are stepwise incremental changes in recovery strengths at different recovery stages, but these occur with only very limited reductions in barriers to recovery, with even those in stable recovery typically having at least two barriers to their quality of life and wellbeing. Greater strengths in active addiction are associated with greater strengths and resources in recovery. CONCLUSION: As well as demonstrating population changes in each of the domains assessed, the current study has shown the potential of the Life In Recovery Scale as a measure of recovery capital that can be used to support recovery interventions and pathways

Attitudes towards 12-step groups and referral practices in a 12-step naive treatment culture; a survey of addiction professionals in Norway

<p>Abstract</p> <p>Background</p> <p>Addressing substance use disorders effectively requires a long-term approach. Substance abuse treatment is typically of short duration; referring patients to Twelve Step based self-help groups (TSGs) – e.g. Narcotics Anonymous, represents a promising complementary recovery resource. Clinicians' attitudes and referral practices towards the TSGs have mainly been studied in countries with high integration of the 12-step philosophy in their substance abuse services and where the TSGs are widely available, such as the US. In Norway, there are currently 294 weekly TSG meetings (6 per 100,000 inhabitants). This study describes clinicians' attitudes and referral practices to TSGs in Norway where health authorities seek to promote self-help participation, but where the treatment culture is unfamiliar with 12-step fellowships.</p> <p>Methods</p> <p>Data collected by a self-administered questionnaire, adapted from established US and UK instruments. Information covered the attitudes, knowledge and referral practices towards TSGs among addiction treatment professionals in Norway in mid 2008.</p> <p>Results</p> <p>The return rate was 79.7% (n = 291). Participants had moderately positive attitude scores towards TSGs, but referral to these groups among Norwegian addiction professionals was low, as was the level of knowledge about TSGs. More than six out of ten did not refer any patients to TSGs in the previous week. Local variation with more referrals to TSGs in the county with the one established 12-step treatment facility was observed. Respondents' integration of the 12-steps in their own treatment work, higher self-efficacy for making a successful referral, and greater TSG knowledge were associated with referring patients.</p> <p>Conclusion</p> <p>Low referral rates to TSGs point to the need for education and training to raise the awareness and knowledge about it among addiction professionals unfamiliar with these 12-step fellowships. Training should focus on the usefulness of these groups for all types of treatment models regardless of therapeutic orientation. Increased knowledge is expected to lead to higher referral rates, which in turn would maximize the likelihood of positive long-term patient outcomes.</p

The courage to change: Patient perceptions of 12-Step fellowships

<p>Abstract</p> <p>Background</p> <p>From a health services perspective, peer-based resources merit special attention. Participation in self-help fellowships, like the Twelve Step Groups (TSGs), have been shown to improve outcomes of patients with substance use disorder (SUD) and they represent a valuable adjunct to the SUD treatment system. This study investigated the relationship between patient perceptions of TSGs and the intent to participate in TSGs after receiving detoxification treatment.</p> <p>Methods</p> <p>We included 139 patients that entered a detoxification unit (detox) in Kristiansand, Norway. We analyzed factors associated with the intention to participate in TSGs post-discharge with contingency tables and ordinal regression analysis.</p> <p>Results</p> <p>Forty-eight percent of patients had participated in TSGs before entering detox. Respondents saw more advantages than disadvantages in TSG participation, but only 40% of patients showed high intentions of participating in TSGs post-discharge. A high intention to participate in TSGs was most strongly correlated with the notion that participation in TSGs could instill the courage to change. In a multivariate analysis, the perception that TSGs were beneficial was the strongest factor related to a high intention of TSG participation after treatment.</p> <p>Conclusions</p> <p>Our findings increased the understanding of factors most likely to influence decisions to attend TSGs in SUD treatment contexts with uncommon TSG participation. Our results suggested that the majority of patients may be sufficiently influenced by highlighting the potential gains of TSG participation. Treatment programs that do not focus on self-help group attendance during and after treatment should consider implementing facilitative measures to enhance utilization of these fellowships.</p

IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data

The IUPHAR database is an established online reference resource for several important classes of human drug targets and related proteins. As well as providing recommended nomenclature, the database integrates information on the chemical, genetic, functional and pathophysiological properties of receptors and ion channels, curated and peer-reviewed from the biomedical literature by a network of experts. The database now includes information on 616 gene products from four superfamilies in human and rodent model organisms: G protein-coupled receptors, voltage- and ligand-gated ion channels and, in a recent update, 49 nuclear hormone receptors (NHRs). New data types for NHRs include details on co-regulators, DNA binding motifs, target genes and 3D structures. Other recent developments include curation of the chemical structures of approximately 2000 ligand molecules, providing electronic descriptors, identifiers, link-outs and calculated molecular properties, all available via enhanced ligand pages. The interface now provides intelligent tools for the visualization and exploration of ligand structure-activity relationships and the structural diversity of compounds active at each target. The database is freely available at http://www.iuphar-db.org