Public Figure Fixation: Cautionary Findings for Mental Health Practitioners.

Research in western nations has found that pathologically fixated individuals pose a risk of serious harm to public figures, and that many of these fixated persons are mentally ill and require treatment. Over the past decade, integrated fixated threat assessment agencies have been established in western Europe and Australia to specifically assess and manage this group. The current study examines 400 consecutive referrals to a fixated threat assessment center in Queensland, Australia, with a particular focus on the mental health and risk profile of those who engage in inappropriate contact with public office holders. It considers the high proportion of delusional disorders in this cohort, and their identification and management by psychiatric services. The authors conclude with a discussion of the mental health response to this group and impediments to mitigating the risks posed by fixated persons. Copyright © 2016 John Wiley & Sons, Ltd.

A model for managing the mentally ill fixated person at major events.

OBJECTIVE: The main risk of serious harm at major public figure gatherings comes not from terrorists or criminal activity but from fixated persons, many of whom have a serious mental illness. This paper reviews a collaborative mental health-police diversionary model for assessing and managing mentally ill individuals who attend major events because of their fixation on a dignitary or some idiosyncratic cause. METHOD: We examine the role of a multidisciplinary fixated threat assessment service during the pre-operational, operational and post-operational phases of major events in Queensland in 2014, including the G20 World Leaders' Summit. The benefits and challenges of this unique approach are reviewed. RESULTS: The royal visit and G20 Finance Ministers' Meeting presented opportunities for the Queensland Fixated Threat Assessment Centre to develop and refine its approach to assessing and managing the threat posed by fixated persons at such events. Based on this experience, we also developed a typology to assist in the assessment of mentally ill people who present at public figure gatherings. In the week prior to the G20 Summit, six fixated people required hospitalisation for acute psychosis. A further 18 cases were identified during the event, one of whom was an involuntary patient whose leave from hospital was revoked as a consequence of his concerning behaviour at one of the G20 venues. There were no other admissions to hospital during the event, but in the remaining cases, where indicated, follow-up was arranged through the treating mental health service or general practitioner. There were no disruptive incidents involving fixated individuals during the G20. CONCLUSION: This novel diversionary model for assessing and intervening with concerning, fixated persons at major events proved effective in mitigating the risk posed by these individuals. It also highlighted the need for police, security and mental health services to consider the fixated in major event planning, for the safety of the event, the public and vulnerable mentally ill, fixated persons.

The pathway ontology - updates and applications.

BACKGROUND: The Pathway Ontology (PW) developed at the Rat Genome Database (RGD), covers all types of biological pathways, including altered and disease pathways and captures the relationships between them within the hierarchical structure of a directed acyclic graph. The ontology allows for the standardized annotation of rat, and of human and mouse genes to pathway terms. It also constitutes a vehicle for easy navigation between gene and ontology report pages, between reports and interactive pathway diagrams, between pathways directly connected within a diagram and between those that are globally related in pathway suites and suite networks. Surveys of the literature and the development of the Pathway and Disease Portals are important sources for the ongoing development of the ontology. User requests and mapping of pathways in other databases to terms in the ontology further contribute to increasing its content. Recently built automated pipelines use the mapped terms to make available the annotations generated by other groups. RESULTS: The two released pipelines - the Pathway Interaction Database (PID) Annotation Import Pipeline and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Annotation Import Pipeline, make available over 7,400 and 31,000 pathway gene annotations, respectively. Building the PID pipeline lead to the addition of new terms within the signaling node, also augmented by the release of the RGD "Immune and Inflammatory Disease Portal" at that time. Building the KEGG pipeline lead to a substantial increase in the number of disease pathway terms, such as those within the 'infectious disease pathway' parent term category. The 'drug pathway' node has also seen increases in the number of terms as well as a restructuring of the node. Literature surveys, disease portal deployments and user requests have contributed and continue to contribute additional new terms across the ontology. Since first presented, the content of PW has increased by over 75%. CONCLUSIONS: Ongoing development of the Pathway Ontology and the implementation of pipelines promote an enriched provision of pathway data. The ontology is freely available for download and use from the RGD ftp site at ftp://rgd.mcw.edu/pub/ontology/pathway/ or from the National Center for Biomedical Ontology (NCBO) BioPortal website at http://bioportal.bioontology.org/ontologies/PW.

The clinical measurement, measurement method and experimental condition ontologies: expansion, improvements and new applications.

BACKGROUND: The Clinical Measurement Ontology (CMO), Measurement Method Ontology (MMO), and Experimental Condition Ontology (XCO) were originally developed at the Rat Genome Database (RGD) to standardize quantitative rat phenotype data in order to integrate results from multiple studies into the PhenoMiner database and data mining tool. These ontologies provide the framework for presenting what was measured, how it was measured, and under what conditions it was measured. RESULTS: There has been a continuing expansion of subdomains in each ontology with a parallel 2-3 fold increase in the total number of terms, substantially increasing the size and improving the scope of the ontologies. The proportion of terms with textual definitions has increased from ~60% to over 80% with greater synchronization of format and content throughout the three ontologies. Representation of definition source Uniform Resource Identifiers (URI) has been standardized, including the removal of all non-URI characters, and systematic versioning of all ontology files has been implemented. The continued expansion and success of these ontologies has facilitated the integration of more than 60,000 records into the RGD PhenoMiner database. In addition, new applications of these ontologies, such as annotation of Quantitative Trait Loci (QTL), have been added at the sites actively using them, including RGD and the Animal QTL Database. CONCLUSIONS: The improvements to these three ontologies have been substantial, and development is ongoing. New terms and expansions to the ontologies continue to be added as a result of active curation efforts at RGD and the Animal QTL database. Use of these vocabularies to standardize data representation for quantitative phenotypes and quantitative trait loci across databases for multiple species has demonstrated their utility for integrating diverse data types from multiple sources. These ontologies are freely available for download and use from the NCBO BioPortal website at http://bioportal.bioontology.org/ontologies/1583 (CMO), http://bioportal.bioontology.org/ontologies/1584 (MMO), and http://bioportal.bioontology.org/ontologies/1585 (XCO), or from the RGD ftp site at ftp://rgd.mcw.edu/pub/ontology/.

Rat Genome Database: a unique resource for rat, human, and mouse quantitative trait locus data.

The rat has been widely used as a disease model in a laboratory setting, resulting in an abundance of genetic and phenotype data from a wide variety of studies. These data can be found at the Rat Genome Database (RGD, http://rgd.mcw.edu/), which provides a platform for researchers interested in linking genomic variations to phenotypes. Quantitative trait loci (QTLs) form one of the earliest and core datasets, allowing researchers to identify loci harboring genes associated with disease. These QTLs are not only important for those using the rat to identify genes and regions associated with disease, but also for cross-organism analyses of syntenic regions on the mouse and the human genomes to identify potential regions for study in these organisms. Currently, RGD has data on >1,900 rat QTLs that include details about the methods and animals used to determine the respective QTL along with the genomic positions and markers that define the region. RGD also curates human QTLs (>1,900) and houses>4,000 mouse QTLs (imported from Mouse Genome Informatics). Multiple ontologies are used to standardize traits, phenotypes, diseases, and experimental methods to facilitate queries, analyses, and cross-organism comparisons. QTLs are visualized in tools such as GBrowse and GViewer, with additional tools for analysis of gene sets within QTL regions. The QTL data at RGD provide valuable information for the study of mapped phenotypes and identification of candidate genes for disease associations.

Analysis of disease-associated objects at the Rat Genome Database.

The Rat Genome Database (RGD) is the premier resource for genetic, genomic and phenotype data for the laboratory rat, Rattus norvegicus. In addition to organizing biological data from rats, the RGD team focuses on manual curation of gene-disease associations for rat, human and mouse. In this work, we have analyzed disease-associated strains, quantitative trait loci (QTL) and genes from rats. These disease objects form the basis for seven disease portals. Among disease portals, the cardiovascular disease and obesity/metabolic syndrome portals have the highest number of rat strains and QTL. These two portals share 398 rat QTL, and these shared QTL are highly concentrated on rat chromosomes 1 and 2. For disease-associated genes, we performed gene ontology (GO) enrichment analysis across portals using RatMine enrichment widgets. Fifteen GO terms, five from each GO aspect, were selected to profile enrichment patterns of each portal. Of the selected biological process (BP) terms, 'regulation of programmed cell death' was the top enriched term across all disease portals except in the obesity/metabolic syndrome portal where 'lipid metabolic process' was the most enriched term. 'Cytosol' and 'nucleus' were common cellular component (CC) annotations for disease genes, but only the cancer portal genes were highly enriched with 'nucleus' annotations. Similar enrichment patterns were observed in a parallel analysis using the DAVID functional annotation tool. The relationship between the preselected 15 GO terms and disease terms was examined reciprocally by retrieving rat genes annotated with these preselected terms. The individual GO term-annotated gene list showed enrichment in physiologically related diseases. For example, the 'regulation of blood pressure' genes were enriched with cardiovascular disease annotations, and the 'lipid metabolic process' genes with obesity annotations. Furthermore, we were able to enhance enrichment of neurological diseases by combining 'G-protein coupled receptor binding' annotated genes with 'protein kinase binding' annotated genes. Database URL: http://rgd.mcw.edu

PhenoMiner: quantitative phenotype curation at the rat genome database.

The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses >40 000 rat gene records as well as human and mouse orthologs, >2000 rat and 1900 human quantitative trait loci (QTLs) records and >2900 rat strain records. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. Recently, a project was initiated at RGD to incorporate quantitative phenotype data for rat strains, in addition to the currently existing qualitative phenotype data for rat strains, QTLs and genes. A specialized curation tool was designed to generate manual annotations with up to six different ontologies/vocabularies used simultaneously to describe a single experimental value from the literature. Concurrently, three of those ontologies needed extensive addition of new terms to move the curation forward. The curation interface development, as well as ontology development, was an ongoing process during the early stages of the PhenoMiner curation project. Database URL: http://rgd.mcw.edu.

The Rat Genome Database 2013--data, tools and users.

The Rat Genome Database (RGD) was started >10 years ago to provide a core genomic resource for rat researchers. Currently, RGD combines genetic, genomic, pathway, phenotype and strain information with a focus on disease. RGD users are provided with access to structured and curated data from the molecular level through the organismal level. Those users access RGD from all over the world. End users are not only rat researchers but also researchers working with mouse and human data. Translational research is supported by RGD's comparative genetics/genomics data in disease portals, in GBrowse, in VCMap and on gene report pages. The impact of RGD also goes beyond the traditional biomedical researcher, as the influence of RGD reaches bioinformaticians, tool developers and curators. Import of RGD data into other publicly available databases expands the influence of RGD to a larger set of end users than those who avail themselves of the RGD website. The value of RGD continues to grow as more types of data and more tools are added, while reaching more types of end users.

Exploring genetic, genomic, and phenotypic data at the rat genome database.

The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have relevance to human physiology and disease. The Rat Genome Database (RGD, http://rgd.mcw.edu) is a model organism database that provides access to a wide variety of curated rat data including disease associations, phenotypes, pathways, molecular functions, biological processes, and cellular components for genes, quantitative trait loci, and strains. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat.

Ontology searching and browsing at the Rat Genome Database.

The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40 000 rat gene records, as well as human and mouse orthologs, 1857 rat and 1912 human quantitative trait loci (QTLs) and 2347 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. RGD uses more than a dozen different ontologies to standardize annotation information for genes, QTLs and strains. That means a lot of time can be spent searching and browsing ontologies for the appropriate terms needed both for curating and mining the data. RGD has upgraded its ontology term search to make it more versatile and more robust. A term search result is connected to a term browser so the user can fine-tune the search by viewing parent and children terms. Most publicly available term browsers display a hierarchical organization of terms in an expandable tree format. RGD has replaced its old tree browser format with a 'driller' type of browser that allows quicker drilling up and down through the term branches, which has been confirmed by testing. The RGD ontology report pages have also been upgraded. Expanded functionality allows more choice in how annotations are displayed and what subsets of annotations are displayed. The new ontology search, browser and report features have been designed to enhance both manual data curation and manual data extraction. DATABASE URL: http://rgd.mcw.edu/rgdweb/ontology/search.html.

The Rat Genome Database curation tool suite: a set of optimized software tools enabling efficient acquisition, organization, and presentation of biological data.

The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40,000 rat gene records as well as human and mouse orthologs, 1771 rat and 1911 human quantitative trait loci (QTLs) and 2209 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. A suite of tools has been developed to aid curators in acquiring and validating data objects, assigning nomenclature, attaching biological information to objects and making connections among data types. The software used to assign nomenclature, to create and edit objects and to make annotations to the data objects has been specifically designed to make the curation process as fast and efficient as possible. The user interfaces have been adapted to the work routines of the curators, creating a suite of tools that is intuitive and powerful. Database URL: http://rgd.mcw.edu.

Mechanisms underlying increased reactivity of pulmonary arteries contralateral to a localized high-flow anastomosis.

OBJECTIVES: Our model of a systemic-pulmonary shunt exhibits enhanced reactivity of pulmonary arteries contralateral to a localized shunt between the left lower lobe pulmonary artery and aorta relative to those of ipsilateral or control pulmonary arteries 48 hours after anastomosis. We examined the contribution of nitric oxide, cyclooxygenase, lipoxygenase, or cytochrome P450 production to mediating this enhanced reactivity. METHODS: We created a surgical end-to-side anastomosis of the left lower lobe pulmonary artery to the aorta. Forty-eight hours later, we tested tension of pulmonary artery rings from the right and left lower lobes for contraction to the thromboxane mimetic U46619 in the presence of vehicle or inhibitors of nitric oxide synthase, cyclooxygenase, cytochrome P450, or lipoxygenase. Western blots of pulmonary artery homogenates were probed for endothelial nitric oxide synthase or isoforms metabolizing arachidonic acid. Eicosanoid products from intact pulmonary artery rings were detected using labeled arachidonic acid and high-performance liquid chromatography separation. RESULTS: Enhanced reactivity of unshunted right pulmonary arteries over that of left pulmonary arteries from high-flow hosts was not eliminated by inhibitors of nitric oxide synthase, cyclooxygenase, cytochrome P450. Treatment with 2 different lipoxygenase inhibitors, nordihydroguaiaretic acid and cinnamyl-3,4-dihydroxy-α-cyanocinnamate, closed the difference in contractility of shunted and unshunted pulmonary arteries. Pulmonary arteries contralateral to shunts metabolized arachidonic acid to 12-hydroxyeicosatetraenoic acid in greater quantities than analogous pulmonary arteries from the experimental left or control pulmonary arteries. CONCLUSIONS: Forty-eight hours after anastomosis, enhanced reactivity of contralateral pulmonary arteries is attributable in part to increased lipoxygenase products as opposed to nitric oxide or other eicosanoid products.

Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period.

Previously, we reported that the hypoxic ventilatory response (HVR) in rats was weakest at postnatal day (P) P13, concomitant with neurochemical changes in respiratory nuclei. A major determinant of minute ventilation (Ve) is reportedly the metabolic rate [O(2) consumption (Vo(2)) and CO(2) production (Vco(2))]. The present study aimed at testing our hypothesis that daily metabolic rates changed in parallel with ventilation during development and that a weak HVR at P13 was attributable mainly to an inadequate metabolic rate in hypoxia. Ventilation and metabolic rates were monitored daily in P0-P21 rats. We found that 1) ventilation and metabolic rates were not always correlated, and Ve/Vo(2) and Ve/Vco(2) ratios were not constant during development; 2) metabolic rate and Ve/Vo(2) and Ve/Vco(2) ratios at P0-P1 were significantly different from the remaining first postnatal week in normoxia and hypoxia; 3) at P13, metabolic rates and Ve/Vo(2) and Ve/Vco(2) ratios abruptly increased in normoxia and were compromised in acute hypoxia, unlike more stable trends during the remaining second and third postnatal weeks; and 4) the respiratory quotient (Vco(2)/Vo(2)) was quite stable in normoxia and fluctuated slightly in hypoxia from P0 to P21. Thus our data revealed heretofore unsuspected metabolic adjustments at P0-P1 and P13. At P0-P1, ventilation and metabolic rates were uncorrelated, whereas at P13, they were closely correlated under normoxia and hypoxia. The findings further strengthened the existence of a critical period of respiratory development around P13, when multiple physiological and neurochemical adjustments occur simultaneously.

The Rat Genome Database 2009: variation, ontologies and pathways.

The Rat Genome Database (RGD, http://rgd.mcw.edu) was developed to provide a core resource for rat researchers combining genetic, genomic, pathway, phenotype and strain information with a focus on disease. RGD users are provided with access to structured and curated data from the molecular level through to the level of the whole organism, including the variations associated with disease phenotypes. To fully support use of the rat as a translational model for biological systems and human disease, RGD continues to curate these datasets while enhancing and developing tools to allow efficient and effective access to the data in a variety of formats including linear genome viewers, pathway diagrams and biological ontologies. To support pathophysiological analysis of data, RGD Disease Portals provide an entryway to integrated gene, QTL and strain data specific to a particular disease. In addition to tool and content development and maintenance, RGD promotes rat research and provides user education by creating and disseminating tutorials on the curated datasets, submission processes, and tools available at RGD. By curating, storing, integrating, visualizing and promoting rat data, RGD ensures that the investment made into rat genomics and genetics can be leveraged by all interested investigators.

Structural and functional alterations in the rat lung following whole thoracic irradiation with moderate doses: injury and recovery.

PURPOSE: To characterize structural and functional injuries following a single dose of whole-thorax irradiation that might be survivable after a nuclear attack/accident. METHODS: Rats were exposed to 5 or 10 Gy of X-rays to the whole thorax with other organs shielded. Non-invasive measurements of breathing rate and arterial oxygen saturation, and invasive evaluations of bronchoalveolar lavage fluid, (for total protein, Clara cell secretory protein), vascular reactivity and histology were conducted for at least 6 time points up to 52 weeks after irradiation. RESULTS: Irradiation with 10 Gy resulted in increased breathing rate, a reduction in oxygen saturation, an increase in bronchoalveolar lavage fluid protein and attenuation of vascular reactivity between 4-12 weeks after irradiation. These changes were not observed with the lower dose of 5 Gy. Histological examination revealed perivascular edema at 4-8 weeks after exposure to both doses, and mild fibrosis beyond 20 weeks after 10 Gy. CONCLUSIONS: Single-dose exposure of rat thorax to 10 but not 5 Gy X-irradiation resulted in a decrease in oxygen uptake and vasoreactivity and an increase in respiratory rate, which paralleled early pulmonary vascular pathology. Vascular edema resolved and was replaced by mild fibrosis beyond 20 weeks after exposure, while lung function recovered.

Health-related quality of life in chronic fatigue syndrome: predictors of physical functioning and psychological distress.

This study investigated health-related quality of life (HRQoL; physical functioning and psychological distress) in an Australian chronic fatigue syndrome (CFS) population. The aims of the study were to compare HRQoL in those with CFS to the normal population, and to investigate the extent to which sociodemographic (age, gender, partner status, education), illness-related (illness duration, symptom frequency), and fatigue severity (physical, mental) variables predicted HRQoL. A total of 139 people meeting CFS criteria completed questionnaires. HRQoL was assessed using standardised measures of distress and physical functioning. Compared with norms, those with CFS obtained significantly lower scores on all physical functioning areas, whereas 63% of participants reported clinically significant psychological distress. Hierarchical regression analyses indicated that physical fatigue severity and symptom frequency were the strongest predictors of deficits in physical domain HRQoL. Physical HRQoL outcomes were also predicted by mental fatigue severity, older age, and female gender. All predictors were unrelated to psychological distress apart from weak positive associations with physical fatigue and symptom frequency. Results identify a potent set of predictors of HRQoL and show that CFS has a pervasive negative impact on quality of life, particularly physical and psychological functioning.

Postnatal changes in ventilation during normoxia and acute hypoxia in the rat: implication for a sensitive period.

Previously, we found heightened expression of inhibitory neurochemicals and depressed expression of excitatory neurochemicals with a sudden drop in metabolic activity around postnatal day (P) 12 in rat brainstem respiratory nuclei, suggesting that this period is a critical window during which respiratory control or regulation may be distinctly different. To test this hypothesis, the hypoxic ventilatory responses (HVR) to 10% oxygen were tested in rats every day from P0 to P21. Our data indicate that (1) during normoxia (N), breathing frequency (f) increased with age, peaking at P13, followed by a gradual decline, whereas both tidal volume (V(T)) and minute ventilation (.V(E) ) significantly increased in the second postnatal week, followed by a progressive increase in V(T) and a relative plateau in .V(E); (2) during 5 min of hypoxia (H), .V(E) exhibited a biphasic response from P3 onward. Significantly, the ratio of .V(E)(H) to .V(E)(N) was generally > 1 during development, except for P13-16, when it was < 1 after the first 1-2 min, with the lowest value at P13; (3) the H : N ratio for f, V(T) and .V(E) during the first 30 s and the last minute of hypoxia all showed a distinct dip at P13, after which the V(T) and .V(E) values rose again, while the f values declined through P21; and (4) the H : N ratios for f, V(T) and .V(E) averaged over 5 min of hypoxia all exhibited a sudden fall at P13. The f ratio remained low thereafter, while those for V(T) and .V(E) increased again with age until P21. Thus, hypoxic ventilatory response is influenced by both f and V(T) before P13, but predominantly by V(T) after P13. The striking changes in normoxic ventilation as well as HVR at or around P13, together with our previous neurochemical and metabolic data, strongly suggests that the end of the second postnatal week is a critical period of development for brainstem respiratory nuclei in the rat.

Apnea and bradycardia due to anaphylaxis to tobacco glycoprotein in the infant rabbit.

Prenatal and postnatal exposure to cigarette smoke is associated with an increased incidence of the sudden infant death syndrome, although the cause(s) for this is unknown. Tobacco glycoprotein (TGP), a group of proteins purified from cured tobacco leaves and present in cigarette smoke, have been shown to cause anaphylaxis in excised hearts and lungs of adult rabbits that were neonatally sensitized to TGP and later rechallenged. We sought to determine whether anaphylaxis occurred in live infant rabbits who were neonatally sensitized to TGP. At the age of 1 day, 12 animals were sensitized to TGP (0.1mg in 0.25 cc alum) via intraperitoneal injection (i.p.i.) followed by a booster ipi at the age of 30 days (TGP-S). Seven animals received i.p.i. of antigen-free alum only (controls). All animals underwent an intravenous TGP challenge at age 42+/-2 days. Heart rate (HR) and respiratory rate (RR) were recorded for 2 min prior to and 5 min after the challenge. Baseline HR (approximately 260) and RR (approximately 120) were similar in all animals. Seven TGP-S animals developed apnea (1.9-4.7s) within 60s of the challenge while none of the controls did. The TGP-S also became bradycardic (the lowest HR over 50 consecutive beats), with the HR decreasing from 260 to 220 vs the controls, whose HR remained constant (approximately 250). We conclude that some rabbits neonatally sensitized to TGP develop apnea and bradycardia upon further intravenous TGP challenge. These studies suggest that cigarette smoke exposure may be associated with a higher rate of SIDS via an anaphylactic mechanism.