Age-related hearing loss and provider-patient communication across primary and secondary care settings: a cross-sectional study.

BACKGROUND: The prevalence of age-related hearing loss (ARHL) increases with age. Older adults are amongst the most dependent users of healthcare and most vulnerable to medical error. This study examined health professionals' strategies, as well as level of formal training completed, for communication with older adults with ARHL, and their views on the contribution of ARHL to suboptimal quality of patient care. METHODS: A 17-item questionnaire was distributed to a sample of Irish primary care physicians, as well as hospital-based clinicians providing inpatient palliative care and geriatric services. RESULTS: A total of 172 primary care physicians and 100 secondary care providers completed the questionnaire. A total of 154 (90%) primary and 97 (97%) secondary care providers agreed that ARHL had a negative impact on quality of care. Across both settings, 10% of respondents reported that communication issues contributed to multiple medication error events each year. Although only 3.5% of secondary care providers and 13% of primary care physicians attended formal training on communication with hearing-impaired patients, 66.5% of respondents were confident in their capacity to communicate with these patients. Primary care physicians reported that they either never used assistive hearing technology (44%) or were unfamiliar with this technology (49%). CONCLUSIONS: Primary and secondary care health providers reported that ARHL reduces patient care quality and may initiate errors leading to patient harm. Formal training addressing the communication needs of ARHL patients appears to be underdeveloped, and there is a limited familiarity with assistive hearing technology. This is both an error in health professional training and healthcare services.

Burnout syndrome among non-consultant hospital doctors in Ireland: relationship with self-reported patient care.

OBJECTIVE: Intensive workload and limited training opportunities for Irish non-consultant hospital doctors (NCHDs) has a negative effect on their health and well-being, and can result in burnout. Burnout affects physician performance and can lead to medical errors. This study examined the prevalence of burnout syndrome among Irish NCHDs and its association with self-reported medical error and poor quality of patient care. METHODS: A cross-sectional quantitative survey-based design. SETTING: All teaching hospitals affiliated with University College Cork. PARTICIPANTS: NCHDs of all grades and specialties. INTERVENTION(S): The following instruments were completed by all participants: Maslach Burnout Inventory-Human Service Survey (MBI-HSS), assessing three categories of burnout syndrome: Emotional exhaustion (EE), Personal Achievement (PA) and Depersonalization (DP); questions related to self-reported medical errors/poor patient care quality and socio-demographic information. MAIN OUTCOME MEASURE(S): Self-reported measures of burnout and poor quality of patient care. RESULTS: Prevalence of burnout among physicians (n = 265) was 26.4%. There was a significant gender difference for EE and DP, but none for PA. A positive weak correlation was observed between EE and DP with medical error or poor patient care. A negative association was reported between PA and medical error and reduced quality of patient care. CONCLUSIONS: Burnout is prevalent among NCHDs in Ireland. Burnout syndrome is associated with self-reported medical error and quality of care in this sample population. Measures need to be taken to address this issue, with a view to protecting health of NCHDs and maintaining quality of patient care.

Attitudes towards professionalism in graduate and non-graduate entrants to medical school.

BACKGROUND: The number of places available in Ireland and the United Kingdom (UK) for graduate entry to medical school has increased in the past decade. Research has primarily focused on academic and career outcomes in this cohort, but attitudes towards professionalism in medicine have not been systematically assessed. The purpose of this study was to compare the importance of items related to professional behaviour among graduate entrants and their 'school-leaver' counterparts. METHODS: This was a quantitative cross-sectional study, conducted in University College Cork (UCC), Ireland. A validated questionnaire was distributed to undergraduate-entry (UG) and graduate-entry (GE) students with items addressing the following areas: Demographic and academic characteristics and attitudes towards several classes of professional behaviours in medicine. RESULTS: GE students ascribed greater importance, relative to UG students, to various aspects of professionalism across the personal characteristics, interaction with patients and social responsibility categories. Additionally, in UG students, a significant decrease in perceived importance of the following professionalism items was evident across the course of the degree programme: Respect for patients as individuals, treating the underprivileged and reporting dishonesty of others. Among both groups of students, individual mentoring was rated the most important method for teaching professionalism in medicine. DISCUSSION: This study is the first comparison of attitudes to professionalism in UG and GE students. This study highlighted important group differences between GE and UG students in attitudes towards professional behaviours, together with different perspectives regarding how professionalism might be incorporated within the curriculum.

Genetic models of schizophrenia and related psychotic disorders: progress and pitfalls across the methodological "minefield".

The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia. In the present review, we explore those conceptual and practical issues that relate specifically to the genetic modelling of schizophrenia and related disorders in rodents. Practical issues that impact on the robustness of endophenotypic findings and their translational relevance are discussed with reference to evidence from selective genetic models of candidate risk genes and copy number variants implicated in schizophrenia.

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes.

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Mutant mouse models in evaluating novel approaches to antipsychotic treatment.

In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more "real-world" paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs.

Selection of student-selected component [SSCs] modules across the medical undergraduate curriculum: relationship with motivational factors.

Student-selected components (SSCs) encourage the following within the undergraduate medical curriculum: greater exploration of core curriculum topics; exploration of non-core subjects/experiences; research and self-directed learning; and personal and professional development opportunities. This study examined the motivational factors which influence SSC choice to assess (a) SSC selection patterns across each year of the curriculum (direct and graduate entry) and (b) motivation underlying SSC selection across the curriculum. During SSC registration at University College Cork, all medical undergraduates (years 1-3, graduate-entry medicine) were required to select an SSC and provide a written justification for their selection. Five primary motivational factors were identified: correction of perceived deficits; genuine interest in subject and wish to study in more depth; career strategy; exam strategy; and taking a chance. A complex pattern of relationships emerged in relation to matching of motivational factors with SSC categories, e.g. selection of research skills SSCs was strongly associated with the 'career strategy' motivation. Significant differences were observed across curriculum years, as well as between direct-entry versus graduate-entry undergraduates, with respect to SSC selections and underlying motivation. This study provides insight into changing patterns of SSC selection in medicine, as well as accompanying motivational factors, across the undergraduate years.

Medical student empathy and breaking bad news communication in a simulated consultation.

OBJECTIVES: This study examined the relationship between self-reported empathy and breaking bad news (BBN) communication skills performance in a sample of undergraduate medical students (n = 100) in the clinical years of their program. METHODS: Correlational and regression analysis examined the relationship between Jefferson Scale of Physician Empathy (JSPE-S) and Empathy Quotient (EQ) scores, and communication skills performance based on students' application of the SPIKES protocol to a BBN scenario in a simulated encounter. RESULTS: Higher BBN communication skills performance was positively correlated with scores on the "Social Skills" EQ sub-scale (r (99) = 0.31, p = 0.002), which measures spontaneous and context-independent use of social skills. Multiple regression confirmed that "Social Skills" sub-scale variation predicted BBN score variation (B = 2.17, 95% CI = 0.65-3.69, p < 0.01). A weak positive association was also observed between BBN score and the "Standing in Patient's Shoes" JSPE sub-scale (r (99) = 0.22, p = 0.03). CONCLUSIONS: Findings suggest that specific aspects of dispositional empathy may moderate BBN communications skills competence in medical students. PRACTICE IMPLICATIONS: A better understanding of the moderating role of personality may lead to more tailored BBN communications skills training interventions and improved transfer of skills to workplace settings.

Cannabis Use, Schizotypy and Kamin Blocking Performance.

Cannabis use has been associated with increased risk for a first episode of psychosis and inappropriate assignment of salience to extraneous stimuli has been proposed as a mechanism underlying this association. Psychosis-prone (especially schizotypal) personality traits are associated with deficits in associative learning tasks that measure salience allocation. The aim of this study was to examine the relationship between history of cannabis use and Kamin blocking (KB), a form of selective associative learning, in a non-clinical sample. Additionally, KB was examined in relation to self-reported schizotypy and aberrant salience scale profiles. A cross-sectional study was conducted in 307 healthy participants with no previous psychiatric or neurological history. Participants were recruited and tested using the Testable Minds behavioural testing platform. KB was calculated using Oades' "mouse in the house task", performance of which is disrupted in schizophrenia patients. Schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), and the Aberrant Salience Inventory (ASI) was used to assess self-reported unusual or inappropriate salience. The modified Cannabis Experience Questionnaire (CEQm) was used to collect detailed history of use of cannabis and other recreational drugs. Regression models and Bayesian t-tests or ANOVA (or non-parametric equivalents) examined differences in KB based on lifetime or current cannabis use (frequent use during previous year), as well as frequency of use among those who had previously used cannabis. Neither lifetime nor current cannabis use was associated with any significant change in total or trial-specific KB scores. Current cannabis use was associated with higher Disorganised SPQ dimension scores and higher total and sub-scale values for the ASI. A modest positive association was observed between total KB score and Disorganised SPQ dimension scores, but no relationships were found between KB and other SPQ measures. Higher scores on "Senses Sharpening" ASI sub-scale predicted decreased KB score only in participants who have not engaged in recent cannabis use. These results are discussed in the context of our understanding of the effects of long-term cannabis exposure on salience attribution, as well as inconsistencies in the literature with respect to both the relationship between KB and schizotypy and the measurement of KB associative learning phenomena.

Bridging the divide between medical school and clinical practice: identification of six key learning outcomes for an undergraduate preparatory course in radiology.

BACKGROUND: There exists a significant divide between what is learnt in medical school and subsequently what is required to practice medicine effectively. Despite multiple strategies to remedy this discordance, the problem persists. Here, we describe the identification of a comprehensive set of learning outcomes for a preparation for practice course in radiology. METHODS: Assessment of interns' readiness to interact with the radiology department was conducted using a national survey of both interns and radiologists. In parallel, group concept mapping (GCM) which involves a combination of qualitative and quantitative techniques was used to identify the shared understanding of participants from a diverse range of medical specialties regarding what topics should be included in an intern preparatory course for interacting with the radiology department. RESULTS: The survey demonstrated that most interns and radiologists felt that undergraduate medical training did not prepare interns to interact with the radiology department. GCM identified six learning outcomes that should be targeted when designing a preparatory module: requesting investigations; clinical decision support; radiology department IT and communication; adverse reactions and risks; interpretation of radiology results and urgent imaging. The thematic clusters from the group concept mapping corroborated the deficiencies identified in the national survey. CONCLUSION: We have identified six key learning outcomes that should be included in a preparation for practice module in radiology. Future courses targeting these thematic clusters may facilitate a smoother transition from theory to practice for newly graduated doctors.

Impact of hearing loss on clinical interactions between older adults and health professionals: a systematic review.

PURPOSE: Age-related hearing loss increases significantly in people aged 60 years and older. An ageing population with impaired hearing presents an additional burden to the multiple comorbidities found among older patients, who are high users of medical services. We sought to quantify the extent to which hearing loss is cited and/or accounted for in studies of older adult interactions with health professionals. METHOD: We conducted a systematic review focusing on clinical communication with older adults, based on a literature search within two databases, PubMed and SCOPUS. Thematic analysis was used to classify studies based on type of health communication. RESULTS: The following health communication categories were identified: quality of clinical communication; enhancement of patient-centred care; information exchange between patient and health professionals; informed consent and shared decision-making. The health profession category 'Physician'/'Doctor' contributed most of the articles (N = 81), and the remaining articles (N = 28) belonged to the other health professions. Twenty-eight papers of 109 (25.7%) mentioned hearing loss; 18 only referred to hearing loss within the context of the text, five referred to hearing loss as an exclusion criterion, three were associational findings, and only two studies included an intervention. CONCLUSIONS: Despite the high prevalence of age-related hearing loss, we demonstrate that across the health professions, very few studies on health professional-older patient communication have incorporated hearing loss as a variable in their study design or analyses. Additionally, there is a lack of research focusing specifically on interventions designed to mitigate the effects of hearing loss on clinical communication.

Does cannabis use predict psychometric schizotypy via aberrant salience?

Cannabis can induce acute psychotic symptoms in healthy individuals and exacerbate pre-existing psychotic symptoms in patients with schizophrenia. Inappropriate salience allocation is hypothesised to be central to the association between dopamine dysregulation and psychotic symptoms. This study examined whether cannabis use is associated with self-reported salience dysfunction and schizotypal symptoms in a non-clinical population. 910 University students completed the following questionnaire battery: the cannabis experience questionnaire modified version (CEQmv); schizotypal personality questionnaire (SPQ); community assessment of psychic experience (CAPE); aberrant salience inventory (ASI). Mediation analysis was used to test whether aberrant salience mediated the relationship between cannabis use and schizotypal traits. Both frequent cannabis consumption during the previous year and ASI score predicted variation across selected positive and disorganised SPQ subscales. However, for the SPQ subscales 'ideas of reference' and 'odd beliefs', mediation analysis revealed that with the addition of ASI score as a mediating variable, current cannabis use no longer predicted scores on these subscales. Similarly, cannabis use frequency predicted higher total SPQ as well as specific Positive and Disorganised subscale scores, but ASI score as a mediating variable removed the significant predictive relationship between frequent cannabis use and 'odd beliefs', 'ideas of reference', 'unusual perceptual experiences', 'odd speech', and total SPQ scores. In summary, cannabis use was associated with increased psychometric schizotypy and aberrant salience. Using self-report measures in a non-clinical population, the cannabis-related increase in selected positive and disorganised SPQ subscale scores was shown to be, at least in part, mediated by disturbance in salience processing mechanisms.

Ethologically based behavioural and neurochemical characterisation of mice with isoform-specific loss of dysbindin-1A in the context of schizophrenia.

Dysbindin-1 is implicated in several aspects of schizophrenia, including cognition and both glutamatergic and dopaminergic neurotransmission. Targeted knockout of dysbindin-1A (Dys-1A KO), the most abundant and widely expressed isoform in the brain, is associated with deficits in delay/interference-dependent working memory. Using an ethologically based approach, the following behavioural phenotypes were examined in Dys-1A KO mice: exploratory activity, social interaction, anxiety and problem-solving ability. Levels of monoamines and their metabolites were measured in striatum, hippocampus and prefrontal cortex using high-performance liquid chromatography with electrochemical detection. The ethogram of initial exploration in Dys-1A KO mice was characterised by increased rearing from a seated position; over subsequent habituation, stillness was decreased relative to wildtype. In a test of dyadic social interaction with an unfamiliar conspecific in a novel environment, female KO mice showed an increase in investigative social behaviours. Marble burying behaviour was unchanged. Using the puzzle-box test to measure general problem-solving performance, no effect of genotype was observed across nine trials of increasing complexity. Dys-1A KO demonstrated lower levels of 5-HT in ratio to its metabolite 5-HIAA in the prefrontal cortex. These studies elaborate the behavioural and neurochemical phenotype of Dys-1A KO mice, revealing subtle genotype-related differences in non-social and social exploratory behaviours and habituation of exploration in a novel environment, as well as changes in 5-HT activity in brain areas related to schizophrenia.

Mutant models for genes associated with schizophrenia.

Schizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene-gene and gene-environment interactions in relation to schizophrenia.

Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action.

Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond.

Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a "hub," dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These studies, and other recent work that has extended this approach to other developmental regulators, may facilitate identification of novel molecular pathways leading to improved antipsychotic treatments.

Medical students' empathy and attitudes towards professionalism: Relationship with personality, specialty preference and medical programme.

BACKGROUND: Existing research has suggested that self-reported empathy in medical students is moderated by personality traits and diverse demographic and educational factors including age, gender, nationality, career aspirations, as well as year of curriculum. It is unclear how empathy, personality, and background factors might impact on students' attitudes towards professionalism in medicine. METHODS: A cross-sectional questionnaire-based study was conducted in first and final year medical students at an Irish medical school. The following instruments were administered: (a) Jefferson Scale of Empathy; (b) NEO Five-Factor Inventory (NEO-FFI-3); (c) Attitudes towards Professionalism Scale. Demographic and educational variables were also measured. Descriptive and correlational analysis was conducted to examine the association between empathy, personality, professionalism-related attitudes and additional measures. Regression analysis was used to examine determinants of attitudes towards professional behaviour. RESULTS: Both selected NEO-FFI personality traits and empathy were independently associated with distinct categories of professional behaviour. Specifically, Openness to Experience was associated with higher empathy scores, and higher 'Social responsibility'. Extraversion was linked with higher scores on the "Personal characteristics" and "Interactions with team" categories, while Conscientiousness was also positively associated with "Personal characteristics". In agreement with previous studies, the personality traits most associated empathy were Agreeableness and Openness to Experience. Empathy did not vary according to programme year or career specialty preference. CONCLUSIONS: This study is the first to show that empathy and personality factors may act as determinants of students' attitudes towards medical professionalism in a manner which is dependent upon category of professional behaviour.

Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous 'knockout' of the schizophrenia risk gene neuregulin-1.

Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous 'knockout' of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light-dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype.

Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour.

A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques.

Translational Genetic Modelling of 3D Craniofacial Dysmorphology: Elaborating the Facial Phenotype of Neurodevelopmental Disorders Through the "Prism" of Schizophrenia.

PURPOSE OF REVIEW: In the context of human developmental conditions, we review the conceptualisation of schizophrenia as a neurodevelopmental disorder, the status of craniofacial dysmorphology as a clinically accessible index of brain dysmorphogenesis, the ability of genetically modified mouse models of craniofacial dysmorphology to inform on the underlying dysmorphogenic process and how geometric morphometric techniques in mutant mice can extend quantitative analysis. RECENT FINDINGS: Mutant mice with disruption of neuregulin-1, a gene associated meta-analytically with risk for schizophrenia, constitute proof-of-concept studies of murine facial dysmorphology in a manner analogous to clinical studies in schizophrenia. Geometric morphometric techniques informed on the topography of facial dysmorphology and identified asymmetry therein. SUMMARY: Targeted disruption in mice of genes involved in individual components of developmental processes and analysis of resultant facial dysmorphology using geometric morphometrics can inform on mechanisms of dysmorphogenesis at levels of incisiveness not possible in human subjects.