Is non-completion of treatment related to security need?

BACKGROUND: Treatment completion difficulties are common in forensic mental health settings and may have a profound impact on recidivism rates. AIMS: To test for associations between measures of risk and of security needs on the one hand and treatment non-completion on the other among male offender-patients in one medium security hospital. METHODS: We conducted a retrospective file study in a Flemish medium security hospital. A random sample of 25 treatment non-completers was compared to a random same-size sample of completers, each rated, blind to outcome, on the DUNDRUM-1 security needs scale from data recorded at the time of admission to the unit. 'Non-completion' was defined as any failure to complete treatment, whether staff-terminated or self-terminated; in Flanders, failure to comply with the judicial conditions of placement can result in re-imprisonment. We used binary logistic regression to test relationships between treatment completion/non-completion and security need, measured with the DUNDRUM-1, together with a range of possible confounding variables. RESULTS: Most patients had psychosis and/or personality disorder and often substance use disorders also. Treatment non-completion was invariably staff ordered because of security breaches. DUNDRUM-1 and PCL-R Facet 4 scores at the time of admission and HCR-20 scores during admission were significantly higher among non-completers than completers, but after binary logistic regression, only the DUNDRUM-1 rating was independently associated with non-completion. CONCLUSIONS: Our study showed that an admission DUNDRUM-1 rating, indicating levels of security need, co-varies only to a small extent with the historical items of the HCR-20, so may be regarded as measuring complementary domains. While conditions in Flanders at the time of the study complicated it in that medium security hospital units offered the highest level of hospital security available, the finding that non-completion of treatment was particularly likely when the DUNDRUM-1 indicated a higher security need than facilities could provide may have implications for all secure hospital services.

PCL-R field validity in prison and hospital settings.

Recent field studies have questioned the interrater reliability (IRR) and predictive validity regarding (violent) recidivism of the Psychopathy Checklist-Revised (PCL-R). Using a forensic psychiatric sample, the current study investigated discrepancies in scoring between hospital and prison settings, as well as differences in predictive validity across these two settings. PCL-R information was collected from prison and hospital files, resulting in 224 PCL-R total scores and 74 double scores. When examining repeated measurements, large individual differences were found together with an intraclass correlation coefficient (ICCA,1) of .42 for the total score. Discrepant results were found for Factor 2, with repeated scores within the same setting having an ICCA,1 of .28 versus an ICCA,1 of .57 for repeated scores between settings. However, areas under the curve (AUCs) from receiver operating characteristic (ROC) analyses for total, factor and facet scores did not differ between settings. For the whole sample, Factor 2 scores marginally predicted violent and general recidivism after 2 years (AUC = .62 and .63), whereas Factor 1 did not predict (violent) recidivism. Consistent with recent studies from other countries, these results suggest inadequate field reliability and validity in prison and hospital settings in Flanders (Belgium). (PsycINFO Database Record

Intelligence is in the eye of the beholder: investigating repeated IQ measurements in forensic psychiatry.

BACKGROUND: A stable assessment of cognition is of paramount importance for forensic psychiatric patients (FPP). The purpose of this study was to compare repeated measures of IQ scores in FPPs with and without intellectual disability. METHODS: Repeated measurements of IQ scores in FPPs (n = 176) were collected. Differences between tests were computed, and each IQ score was categorized. Additionally, t-tests and regression analyses were performed. RESULTS: Differences of 10 points or more were found in 66% of the cases comparing WAIS-III with RAVEN scores. Fisher's exact test revealed differences between two WAIS-III scores and the WAIS categories. The WAIS-III did not predict other IQs (WAIS or RAVEN) in participants with intellectual disability. DISCUSSION: This study showed that stability or interchangeability of scores is lacking, especially in individuals with intellectual disability. Caution in interpreting IQ scores is therefore recommended, and the use of the unitary concept of IQ should be discouraged.

Excellence in forensic psychiatry services: international survey of qualities and correlates.

BACKGROUND: Excellence is that quality that drives continuously improving outcomes for patients. Excellence must be measurable. We set out to measure excellence in forensic mental health services according to four levels of organisation and complexity (basic, standard, progressive and excellent) across seven domains: values and rights; clinical organisation; consistency; timescale; specialisation; routine outcome measures; research and development. AIMS: To validate the psychometric properties of a measurement scale to test which objective features of forensic services might relate to excellence: for example, university linkages, service size and integrated patient pathways across levels of therapeutic security. METHOD: A survey instrument was devised by a modified Delphi process. Forensic leads, either clinical or academic, in 48 forensic services across 5 jurisdictions completed the questionnaire. RESULTS: Regression analysis found that the number of security levels, linked patient pathways, number of in-patient teams and joint university appointments predicted total excellence score. CONCLUSIONS: Larger services organised according to stratified therapeutic security and with strong university and research links scored higher on this measure of excellence. A weakness is that these were self-ratings. Reliability could be improved with peer review and with objective measures such as quality and quantity of research output. For the future, studies are needed of the determinants of other objective measures of better outcomes for patients, including shorter lengths of stay, reduced recidivism and readmission, and improved physical and mental health and quality of life.

Distinct regulation of developmental and heart disease-induced atrial natriuretic factor expression by two separate distal sequences.

Nppa, encoding atrial natriuretic factor, is expressed in fetal atrial and ventricular myocardium and is downregulated in the ventricles after birth. During hypertrophy and heart failure, Nppa expression is reactivated in the ventricles and serves as a highly conserved marker of heart disease. The Nppa promoter has become a frequently used model to study mechanisms of cardiac gene regulation. Nevertheless, the regulatory sequences that provide the correct developmental pattern and ventricular reactivation during cardiac disease remain to be defined. We found that proximal Nppa fragments ranging from 250 bp to 16 kbp provide robust reporter gene activity in the atria and correct repression in the atrioventricular canal and the nodes of the conduction system in vivo. However, depending on fragment size and site of integration into the genome of mice, the fetal ventricular activity was either absent or present in an incorrect pattern. Furthermore, these fragments did not provide ventricular reactivation in heart disease models. These results indicate that the proximal promoter does not provide a physiologically relevant model for ventricular gene activity. In contrast, 2 modified bacterial artificial chromosome clones with partially overlapping genomic Nppa sequences provided appropriate reactivation of the green fluorescent protein reporter during pressure overload-induced hypertrophy and heart failure in vivo. However, only 1 of these bacterial artificial chromosomes provided correct fetal ventricular green fluorescent protein activity. These results show that distinct distal regulatory sequences and divergent regulatory pathways control fetal ventricular activity and reactivation of Nppa during cardiac disease, respectively.

Structured versus unstructured judgment: DUNDRUM-1 compared to court decisions.

BACKGROUND: Criteria to determine in which level of security forensic patients should receive treatment are currently non-existent in Belgium. Courts largely rely on the evaluations of the prison psychiatrists and psychologists to form their decision. None of the few available instruments - e.g., the DUNDRUM-1 - is currently used to provide structured clinical judgment when determining security level. METHOD: DUNDRUM-1 scores were collected for 150 forensic patients. Security levels according to DUNDRUM-1 assessment were compared to security levels as decided by the court. RESULTS: There was little agreement between DUNDRUM-1 scores and proposals for secure care made by the court. The DUNDRUM-1 predicted eventual admission to a high security setting, but not a medium security setting. CONCLUSION: The DUNDRUM-1 is an instrument that can help clinicians and judges to make more reliable and transparent decisions regarding secure care. However, further research with regard to practical applicability is needed.

Suppression of intrusive thoughts and working memory capacity in repressive coping.

Previous research using a thought suppression paradigm found that repressors are more skilled in suppressing anxious autobiographical thoughts than low anxious, high anxious, and defensive high anxious people. Another line of research showed that individual differences in working memory capacity are related to the ability to intentionally suppress intrusive thoughts. This study aimed at combining these findings and sought to investigate whether repressors' superior ability to suppress intrusive thoughts is related to a larger working memory capacity. Results indicate that in a thought suppression paradigm, repressors report fewer intrusive thoughts for their most anxious experiences than participants in the 3 other subgroups. Furthermore, the superior ability of repressors to avoid intrusive thoughts can be explained largely by their higher working memory capacity.

No Evidence of Association between Childhood Urban Environment and Cortical Thinning in Psychotic Disorder.

BACKGROUND: The alterations in cortical morphology, such as cortical thinning, observed in psychotic disorder, may be the outcome of interacting genetic and environmental effects. It has been suggested that urban upbringing may represent a proxy environmental effect impacting cortical thickness (CT). Therefore, the current study examined whether the association between group as a proxy genetic variable (patients with psychotic disorder [high genetic risk], healthy siblings of patients [intermediate risk] and healthy control subjects [average risk]) and CT was conditional on different levels of the childhood urban environment and whether this was sex-dependent. METHODS: T1-weighted MRI scans were acquired from 89 patients with a psychotic disorder, 95 non-psychotic siblings of patients with psychotic disorder and 87 healthy control subjects. Freesurfer software was used to measure CT. Developmental urban exposure was classified as low, medium, and high, reflecting the population density and the number of moves between birth and the 15th birthday, using data from the Dutch Central Bureau of Statistics and the equivalent database in Belgium. Multilevel regression analyses were used to examine the association between group, sex, and urban upbringing (as well as their interactions) and cortical CT as the dependent variable. RESULTS: CT was significantly smaller in the patient group compared to the controls (B = -0.043, p <0.001), but not in the siblings compared to the controls (B = -0.013, p = 0.31). There was no main effect of developmental urbanicity on CT (B = 0.001, p = 0.91). Neither the three-way group × urbanicity × sex interaction (χ2 = 3.73, p = 0.16), nor the two-way group × urbanicity interaction was significant (χ2 = 0.51, p = 0.77). CONCLUSION: The negative association between (familial risk for) psychotic disorder and CT was not moderated by developmental urbanicity, suggesting that reduced CT is not the outcome of familial sensitivity to the proxy environmental factor 'urban upbringing'.

Reconviction and revocation rates in Flanders after medium security treatment.

AIM: To examine the criminal outcome of Flemish forensic psychiatric patients ('internees') after medium security treatment. Also, the effect of conditional release on recidivism of two subgroups (internees under conditional release and internees who received unconditional release) was examined. METHOD: Reconviction rates and revocation rates were collected for all participants. Kaplan-Meier survival analyses were used to investigate recidivism rates while controlling for time at risk. RESULTS: During the 10-year period, 502 offenders were discharged from medium security treatment. Over a follow-up period averaging 3.6years, 7.4% of discharged patients were reconvicted or received a new 'not guilty by reason of insanity' (NGRI) verdict for a violent offence. One-quarter of the population had their conditional release revoked. Part of the study population was granted unconditional release. Reconviction rates were higher after unconditional release in comparison to conditional release. CONCLUSIONS: The results of this study suggest that the court supervision of NGRI patients in Flanders is effective in protecting the community from further offending.

How reliable is the visual appraisal of a surgeon for diagnosing orbital fractures?

PURPOSE: The aim of this study was to evaluate the usefulness of intra-operative visualisation, endoscopic assistance, and CT measurements for estimating the orbital fracture size and complexity. METHODS: Ten human cadaver heads were subjected to thin-slice computed tomography (CT). Standardised fractures were created using piezoelectric surgery in accordance with the Jaquiéry classification system. Four surgeons and one anatomist used six different observation methods to visualise and describe the orbital defects. RESULTS: The intraclass correlation coefficients (ICCs) for the fracture length measurements were relatively low for all observation methods (range, 0.666-0.883). CT measurements of width showed high consistency (ICC, 0.910). The surface area of the defect was highly overestimated by all methods (range, 121-184%). None of the observers was able to accurately estimate the length or width of 95% of the defects within an error range of ±0.75 cm. CONCLUSION: CT measurements are the most consistent and accurate tool for estimating the critical size of orbital factures. In daily practice, a measurement tool in a DICOM viewer could be used, although software packages that allow manual adjustments are advisable. Direct intraoperative visualisation and surgeon experience are of limited value in the estimation of fracture size and complexity, and endoscopy provides no additional advantages.

Regulatory modules in the developing heart.

Fragments of regulatory DNA of cardiac genes drive reporter gene expression in sometimes unexpected subdomains of the heart. These patterns have revealed that the regulatory DNA of genes consists of distinct subfragments (regulatory modules) that are active in different regions of the developing heart. In this review we give an overview of the activity of regulatory modules in vivo. Furthermore, we investigated the relationship between the activity domains of the regulatory modules, the building blocks of the heart and the developmental patterning of the myocardium. Most of the regulatory modules show a domain of activity broader than the morphological boundary of a cardiac compartment and seem to respond to a patterning program along the antero-posterior axis.

Semi-metric analysis of the functional brain network: Relationship with familial risk for psychotic disorder.

BACKGROUND: Dysconnectivity in schizophrenia can be understood in terms of dysfunctional integration of a distributed network of brain regions. Here we propose a new methodology to analyze complex networks based on semi-metric behavior, whereby higher levels of semi-metricity may represent a higher level of redundancy and dispersed communication. It was hypothesized that individuals with (increased risk for) psychotic disorder would have more semi-metric paths compared to controls and that this would be associated with symptoms. METHODS: Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings and 72 controls. Semi-metric percentages (SMP) at the whole brain, hemispheric and lobar level were the dependent variables in a multilevel random regression analysis to investigate group differences. SMP was further examined in relation to symptomatology (i.e., psychotic/cognitive symptoms). RESULTS: At the whole brain and hemispheric level, patients had a significantly higher SMP compared to siblings and controls, with no difference between the latter. In the combined sibling and control group, individuals with high schizotypy had intermediate SMP values in the left hemisphere with respect to patients and individuals with low schizotypy. Exploratory analyses in patients revealed higher SMP in 12 out of 42 lobar divisions compared to controls, of which some were associated with worse PANSS symptomatology (i.e., positive symptoms, excitement and emotional distress) and worse cognitive performance on attention and emotion processing tasks. In the combined group of patients and controls, working memory, attention and social cognition were associated with higher SMP. DISCUSSION: The results are suggestive of more dispersed network communication in patients with psychotic disorder, with some evidence for trait-based network alterations in high-schizotypy individuals. Dispersed communication may contribute to the clinical phenotype in psychotic disorder. In addition, higher SMP may contribute to neuro- and social cognition, independent of psychosis risk.

Default mode network connectivity as a function of familial and environmental risk for psychotic disorder.

BACKGROUND: Research suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder. METHODS: Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group × environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology. RESULTS: There was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity. DISCUSSION: Increased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait-related network alterations. The within-network "connectivity at rest" intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure.

Anti-citrullinated protein antibodies contribute to platelet activation in rheumatoid arthritis.

INTRODUCTION: Although the role of platelets in rheumatoid arthritis (RA) is relatively unexplored, recent studies point towards a contribution of platelets in arthritis. We set out to determine platelet phenotype in RA and studied whether this could be influenced by the presence of anti-citrullinated protein antibodies (ACPA). METHODS: Platelets from healthy controls were incubated in the presence of plasma of patients with RA or age- and sex-matched healthy controls and plasma from ACPA(neg) or ACPA(pos) patients or in the presence of plate-bound ACPA. Characteristics of platelets isolated from patients with RA were correlated to disease activity. RESULTS: Platelets isolated from healthy controls displayed markers of platelet activation in the presence of plasma derived from RA patients, as determined by P-selectin expression, formation of aggregates and secretion of soluble CD40 ligand (sCD40L). Furthermore, levels of P-selectin expression and sCD40L release correlated with high ACPA titres. In accordance with these findings, enhanced platelet activation was observed after incubation with ACPA(pos) plasma versus ACPA(neg) plasma. Pre-incubation of platelets with blocking antibodies directed against low-affinity immunoglobulin G receptor (FcγRIIa) completely inhibited the ACPA-mediated activation. In addition, expression of P-selectin measured as number of platelets correlated with Disease Activity Score in 44 joints, C-reactive protein level, ACPA status and ACPA level. CONCLUSIONS: We show for the first time that ACPA can mediate an FcγRIIa-dependent activation of platelets. As ACPA can be detected several years before RA disease onset and activated platelets contribute to vascular permeability, these data implicate a possible role for ACPA-mediated activation of platelets in arthritis onset.

Brain-derived neurotrophic factor/FK506-binding protein 5 genotype by childhood trauma interactions do not impact on hippocampal volume and cognitive performance.

In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered.

Microstructural white matter alterations in psychotic disorder: a family-based diffusion tensor imaging study.

BACKGROUND: There is evidence for microstructural white matter alterations in patients with psychotic disorder, suggesting altered interregional connectivity. Less is known about the presence and role of white matter alterations in well individuals at higher than average genetic risk for psychotic disorder. METHODS: 85 patients with psychotic disorder, 93 non-psychotic siblings of patients with psychotic disorder and 80 healthy controls underwent a diffusion tensor imaging (DTI) scanning protocol. In a whole brain voxel-based analysis using Tract Based Spatial Statistics (TBSS), fractional anisotropy (FA) values were compared between the three groups. Effects of antipsychotic medication and drug use were examined. RESULTS: The patients displayed significantly lower mean FA than the controls in the following regions: corpus callosum (genu, body, splenium), forceps major and minor, external capsule bilaterally, corona radiata (anterior, posterior) bilaterally, left superior corona radiata and posterior thalamic radiation bilaterally. Similar FA differences existed between the patients and siblings; the siblings did not differ from the controls. CONCLUSION: Profound microstructural white matter alterations were found in the corpus callosum and other tracti and fasciculi in the patients with psychotic disorder, but not in siblings and the controls. These alterations may reflect brain pathology associated with the illness, illness-related environmental risk factors, or its treatment, rather than genetic risk.

The effects of FreeSurfer version, workstation type, and Macintosh operating system version on anatomical volume and cortical thickness measurements.

FreeSurfer is a popular software package to measure cortical thickness and volume of neuroanatomical structures. However, little if any is known about measurement reliability across various data processing conditions. Using a set of 30 anatomical T1-weighted 3T MRI scans, we investigated the effects of data processing variables such as FreeSurfer version (v4.3.1, v4.5.0, and v5.0.0), workstation (Macintosh and Hewlett-Packard), and Macintosh operating system version (OSX 10.5 and OSX 10.6). Significant differences were revealed between FreeSurfer version v5.0.0 and the two earlier versions. These differences were on average 8.8 ± 6.6% (range 1.3-64.0%) (volume) and 2.8 ± 1.3% (1.1-7.7%) (cortical thickness). About a factor two smaller differences were detected between Macintosh and Hewlett-Packard workstations and between OSX 10.5 and OSX 10.6. The observed differences are similar in magnitude as effect sizes reported in accuracy evaluations and neurodegenerative studies.The main conclusion is that in the context of an ongoing study, users are discouraged to update to a new major release of either FreeSurfer or operating system or to switch to a different type of workstation without repeating the analysis; results thus give a quantitative support to successive recommendations stated by FreeSurfer developers over the years. Moreover, in view of the large and significant cross-version differences, it is concluded that formal assessment of the accuracy of FreeSurfer is desirable.

Reduced cortical thickness as an outcome of differential sensitivity to environmental risks in schizophrenia.

BACKGROUND: The etiology of schizophrenia is thought to involve differential-likely genetically mediated-sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. METHODS: T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. RESULTS: A significant group × developmental trauma interaction (χ(2) = 9.65, p = .01), as well as a significant group × cannabis interaction (χ(2) = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling-control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. CONCLUSIONS: The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene-environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives.

Species-specific differences of myosin content in the developing cardiac chambers of fish, birds, and mammals.

Key morphogenetic events during heart ontogenesis are similar in different vertebrate species. We report that in primitive vertebrates, i.e., cartilaginous fishes, both the embryonic and the adult heart show a segmental subdivision similar to that of the embryonic mammalian heart. Early morphogenetic events during cardiac development in the dogfish are long-lasting, providing a suitable model to study changes in pattern of gene expression during these stages. We performed a comparative study among dogfish, chicken, rat, and mouse to assess whether species-specific qualitative and/or quantitative differences in myosin heavy chain (MyHC) distribution arise during development, indicative of functional differences between species. MyHC RNA content was investigated by means of in situ hybridisation using an MyHC probe specific for a highly conserved domain, and MyHC protein content was assessed by immunohistochemistry. MyHC transcripts were found to be homogeneously distributed in the myocardium of the tubular and embryonic heart of dogfish and rodents. A difference between atrial and ventricular MyHC content (mRNA and protein) was observed in the adult stage. Interestingly, differences in the MyHC content were observed at the tubular heart stage in chicken. These differences in MyHC content illustrate the distinct developmental profiles of avian and mammalian species, which might be ascribed to distinct functional requirements of the myocardial segments during ontogenesis. The atrial myocardium showed the highest MyHC content in the adult heart of all species analysed (dogfish (S. canicula), mouse (M. musculus), rat (R. norvegicus), and chicken (G. gallus)). These observations indicate that in the adult heart of vertebrates the atrial myocardium contains more myosin than the ventricular myocardium.

Cardiac expression of Gal4 causes cardiomyopathy in a dose-dependent manner.

Cardiac expression of a transgene is a common approach for determining the role of gene products in the processes underlying cardiomyopathy and heart failure (HF). We have generated transgenic mice that express the 'harmless' yeast transcription factor Gal4 in the heart under control of the alpha-myosin heavy chain promoter and found that expression of this gene causes cardiomyopathy and HF, the severity of which correlated with the number of copies of the transgene integrated into the genome and with the expression level. A line with a single copy of the transgene targeted to the hprt locus correctly expressed the transgene but did not develop cardiomyopathy. Our results indicate that expression of a transgene in the heart may non-specifically cause HF in a dose-dependent manner.