Survey of Irish general practitioners' preferences for continuing professional development.

BACKGROUND: Doctors' continuing professional development (CPD) training needs are known to be strongly influenced by national and local contextual characteristics. Given the changing national demographic profile and government-mandated changes to primary care health care provision, this study aimed to investigate Irish General Practitioners' (GPs) perceptions of, and preferences for, current and future CPD programmes. METHODS: A cross-sectional questionnaire, using closed- and open-ended questions, was administered to Irish GPs, focusing on training needs analysis; CPD course content; preferred format and the learning environment. RESULTS: The response rate was 719/1000 (71.9%). GPs identified doctor-patient communication as the most important and best-performed GP skill. Discrepancies between perceived importance (high) and current performance (low) emerged for time/workload management, practice finance and business skills. GPs identified clinically-relevant primary care topics and non-clinical topics (stress management, business skills, practice management) as preferences for future CPD. Flexible methods for CPD delivery were important. Gender and practice location (urban or rural) significantly influenced CPD participation and future course preference. CONCLUSION: The increasing diversity of services offered in the Irish primary care setting, in both clinical and non-clinical areas, should be tailored based to include GP practice location and structure.

Doctors' attitudes towards the introduction and clinical operation of do not resuscitate orders (DNRs) in Ireland.

BACKGROUND: Do not resuscitate orders (DNRs) are documents which state that should a patient suffer from cardiopulmonary failure, resuscitation should not be attempted. Internationally, DNRs are often misunderstood and used inappropriately in a clinical setting. AIMS: The aim of this paper was to determine the current understanding of DNRs and their clinical operation among hospital doctors in Ireland. METHODS: A cross-sectional, questionnaire-based study was conducted involving doctors from the Cork teaching hospitals. The questionnaire sought information regarding understanding of DNRs and their clinical operation, as well as attitudes regarding the current absence of relevant Irish guidelines. The questionnaire also collected information regarding demographics, clinical specialty, and level of experience. RESULTS: 45.9% (47/103) of all doctors stated that their clinical knowledge was sufficient to draft a DNR, but 48.7% of this group (n = 23) chose the incorrect definition for a DNR when provided with three separate options. Thirty-five percent (n = 36) of all doctors surveyed demonstrated an incorrect understanding of a DNR. Neither specialty nor experience level had any effect on level of understanding of DNRs (p > 0.05). 93.2% (n = 96) agreed that there is a need for introduction of domestic guidelines regarding DNRs. 57.6% (n = 59) would draft more DNRs in the event that such domestic guidelines were in place. CONCLUSIONS: A substantial proportion of hospital doctors surveyed demonstrated an incomplete understanding of DNRs and their clinical operation. However, the overwhelming majority of the present sample believe that domestic guidelines are needed on the matter.

Disrupted in schizophrenia 1 (DISC1) L100P mutants have impaired activity-dependent plasticity in vivo and in vitro.

Major neuropsychiatric disorders are genetically complex but share overlapping etiology. Mice mutant for rare, highly penetrant risk variants can be useful in dissecting the molecular mechanisms involved. The gene disrupted in schizophrenia 1 (DISC1) has been associated with increased risk for neuropsychiatric conditions. Mice mutant for Disc1 display morphological, functional and behavioral deficits that are consistent with impairments observed across these disorders. Here we report that Disc1 L100P mutants are less able to reorganize cortical circuitry in response to stimulation in vivo. Molecular analysis reveals that the mutants have a reduced expression of PSD95 and pCREB in visual cortex and fail to adjust expression of such markers in response to altered stimulation. In vitro analysis shows that mutants have impaired functional reorganization of cortical neurons in response to selected forms of neuronal stimulation, but there is no altered basal expression of synaptic markers. These findings suggest that DISC1 has a critical role in the reorganization of cortical plasticity and that this phenotype becomes evident only under challenge, even at early postnatal stages. This result may represent an important etiological mechanism in the emergence of neuropsychiatric disorders.

Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1.

Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development.

Enhanced research assessment performance in graduate vs. undergraduate-entry medical students: implications for recruitment into academic medicine.

BACKGROUND: Studies investigating variance between the academic performance of direct-entry (DEM) versus graduate-entry (GEM) medical students have yielded conflicting results, but their performance in undergraduate research-based assessments has not been compared to-date. AIM: We aimed to compare the results of DEM and GEM students with respect to their senior research dissertation module. METHODS: This retrospective study examined the final year results between 2011-2012 in DEM, (n = 219) and GEM (n = 84) students. Between-group comparisons of dissertation module marks were conducted using independent t-tests. Correlations between marks in dissertation module and in other disciplines assessed during the final year were attained using Pearson's correlation. Multiple regression analysis was employed to adjust for potential confounding factors such as student age and gender. RESULTS: No apparent difference was apparent between the DEM and GEM students with respect to results achieved across the clinical disciplines examined. However, GEM students performed significantly better than DEMs in their senior research dissertation assessment (Mean = 66.81% vs. 65.00%, fully adjusted p = 0.048). The variable which remained influential in regression analysis was nationality, where North American and Asian students were demonstrated to score lower than their Irish counterparts in the dissertation module (B coefficient = -1.90, SE = 0.94, P = 0.045 and B coefficient = -4.88, SE = 1.00, P < 0.001 respectively). CONCLUSIONS: Performance in the research-based module was significantly better in GEM relative to their DEM colleagues. This finding may have implications for future recruitment into academic medicine, as aptitude and interest in research at undergraduate level has been shown to be associated with increased likelihood of an academic career in medicine.

D-amphetamine and antipsychotic drug effects on latent inhibition in mice lacking dopamine D2 receptors.

Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (Drd2-/-), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes.

Disruption of exploratory and habituation behavior in mice with mutation of DISC1: an ethologically based analysis.

Disrupted-in-schizophrenia-1 (DISC1) is a gene that has been functionally linked with neurodevelopmental processes and structural plasticity in the brain. Clinical genetic investigations have implicated DISC1 as a genetic risk factor for schizophrenia and related psychoses. Studies using mutant mouse models of DISC1 gene function have demonstrated schizophrenia-related anatomical and behavioral endophenotypes. In the present study, ethologically based assessment of exploratory and habituation behavior in the open field was conducted in DISC1 (L100P), wild-type (WT), heterozygous (HET), and homozygous (HOM) mutant mice of both sexes. Ethological assessment was conducted in an open-field environment to explore specific topographies of murine exploratory behavior across the extended course of interaction from initial exploration through subsequent habituation (the ethogram). During initial exploration, HET and HOM DISC1 mutants evidenced increased levels of locomotion and rearing to wall compared with WT. A HOM-specific increase in total rearing and a HET-specific increase in sifting behavior and reduction in rearing seated were also observed. Over subsequent habituation, locomotion, sniffing, total rearing, rearing to wall, rearing free, and rearing seated were increased in HET and HOM mutants vs. WT. Overall, grooming was increased in HOM relative to other genotypes. HET mice displayed a selective decrease in habituation of sifting behavior. These data demonstrate impairment in both initial exploratory and habituation of exploration in a novel environment in mice with mutation of DISC1. This is discussed in the context of the functional role of the gene vis à vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping.

Disruption of thermal nociceptive behaviour in mice mutant for the schizophrenia-associated genes NRG1, COMT and DISC1.

Abnormalities in pain perception, especially altered warmth and heat pain sensitivity, have been reported in schizophrenia. Therefore, genes associated with schizophrenia, including neuregulin-1 (NRG1), catechol-O-methyltranferase (COMT) and disrupted-in-schizophrenia-1 (DISC1), may play a role in modulating the physiological and psychological effects of pain stimuli in such patients. Thermal pain sensitivity was assessed in NRG1, COMT and DISC1 mutant mice, and the anti-nociceptive effects of acute Delta(9)-tetrahydrocannabinol (THC) were compared in NRG1 and COMT mutants. At baseline, deletion of NRG1 and DISC1 each reduced thermal pain sensitivity, while deletion of COMT increased pain sensitivity. Neither NRG1 nor COMT deletion altered the anti-nociceptive effects of acute systemic THC (8.0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis-à-vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase.

Catechol-O-methyltransferase is an important enzyme in the metabolism of dopamine and an important regulator of aspects of dopamine-dependent working memory in prefrontal cortex that are disturbed in schizophrenia. This study investigated the phenotype of mice with heterozygous deletion vs. homozygous knockout of the catechol-O-methyltransferase gene across paradigms that access processes relevant for psychotic illness. Homozygotes evidenced improved performance in spontaneous alternation, an index of immediate spatial working memory; this effect appeared more substantive in males and was reflected in performance in aspects of the Barnes maze, an index of spatial learning/memory. Heterozygotes evidenced impaired performance in object recognition, an index of recognition memory; this effect was evident for both sexes at a retention interval of 5 min but appeared more enduring in males. There were no material effects for either genotype in relation to sociability or social novelty preference. While homozygous catechol-O-methyltransferase deletion results in improvement in spatial learning/working memory with little effect on social behavior, heterozygous deletion results in impairment of recognition memory. We have reported recently, using similar methods, that mice with deletion of the schizophrenia risk gene neuregulin-1 evidence disruption to social behavior, with little effect on spatial learning/working memory. The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome.

Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1.

Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.

The effect of amphetamine on Kamin blocking and overshadowing.

Schizophrenic patients show deficits on stimulus salience tasks such as latent inhibition and blocking, which measure the ability to disregard irrelevant stimuli. Amphetamine-treated animals show similar deficits in analogous tasks, thereby providing a model of the stimulus-selection deficits observed in schizophrenia. In two experiments, the effect of the indirect dopamine (DA) agonist D-amphetamine sulphate (1.0 mg/kg, i.p.) on Kamin blocking and overshadowing were examined and compared, in the rat, using the conditioned lick suppression procedure. The aim was to provide some insight into the behavioural and pharmacological mechanisms underlying amphetamine effects in both paradigms. In experiment 1, it was shown that amphetamine selectively disrupted Kamin blocking, when given either at stage 2 alone, or at both stages of the task. In experiment 2, amphetamine treatment significantly abolished Kamin blocking and overshadowing, when administered prior to compound conditioning in both tasks. These data suggest that dopamine may play a critical role in mediating performance in tasks measuring stimulus salience processes. The results are discussed in the framework of the role of DA in stimulus-selection performance.

Evidence for dopamine D(1) receptor involvement in the stimulus selection task: overshadowing in the rat.

RATIONALE: A number of lines of evidence suggest that dopamine might play a role in stimulus selection, the process whereby specific cues are selected to guide action. OBJECTIVES: In order further to define the potential role for dopamine in stimulus selection, the present series of studies examined whether dopaminergic drugs modulate overshadowing, a paradigm that involves stimulus selection in rats. Overshadowing is where preferential learning occurs to one (usually the more salient) element of a stimulus compound. METHODS: Overshadowing was measured in rats using a thirst motivated conditioned emotional response paradigm (CER). Two simultaneously presented stimuli (light and tone) were paired with an aversive unconditioned stimulus (mild footshock); overshadowing is observed when learning to the less salient stimulus is weaker than learning to the same stimulus when it is conditioned alone. RESULTS: d-Amphetamine sulphate (1 mg/kg, IP) was found selectively to disrupt overshadowing, without affecting the CER in control animals. The dopamine (DA) D(2) receptor antagonists, haloperidol (0.2 mg/kg, IP) or raclopride (0.5 mg/kg, IP), failed to reverse amphetamine-induced disruption of overshadowing. In contrast, the selective DA D(1) antagonist SCH 23390 (0.05 mg/kg, IP) reversed amphetamine-induced disruption of overshadowing. The partial DA D(1) agonist SKF 38393 (5 mg/kg, IP) was found to abolish overshadowing when given alone. CONCLUSION: These data indicate a modulatory role for the DA D(1) receptor in the expression of stimulus selection and suggest that the DA D(1) receptor might play a role in salience allocation aspects of learning.