Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Contemporary specificities of labour in the health care sector: introductory notes for discussion

BACKGROUND: This paper combines the literature on public health, on economics of health and on economics of technological innovation to discuss the peculiarities of labour in the health care sector. METHOD AND FRAMEWORK: The starting point is the investigation of the economic peculiarities of medical care. RESULTS AND DISCUSSIONS: This investigation leads to the identification of the prevalence of non-market forms of medical care in the countries of the Organisation for Economic Co-operation and Development (OECD). Furthermore, the health care system has a distinctive characteristic from other economic sectors: it is the intersection between social welfare and innovation systems. The relationship between technological innovation and cost in the health care sector is surveyed. Finally, the Brazilian case is discussed as an example of a developing country. CONCLUSION: The peculiarities of labour in the health care sector suggest the need to recognize the worth of sectoral labour and to cease to treat it separately. This process should take into account the rapid development of the health innovation system and one important consequence: the obsolescence of the acquired knowledge. One way to dignify labour is to implement continued education and training of health professions personnel

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets

Serotonergic, brain volume and attentional correlates of trait anxiety in primates.

Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low- and high-anxious animals were identified by behavioral responses to a human intruder (HI) that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a HI and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders.This research was supported by a Medical Research Programme Grant (G0901884) from the Medical Research Council UK (MRC) to Angela Roberts, and a PhD studentship from MRC and final-term funding from Trinity College, Cambridge, UK to Yevheniia Mikheenko.This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/npp/journal/v40/n6/full/npp2014324a.htm

Transporte intra-hospitalar de pacientes sob ventilação invasiva: repercussões cardiorrespiratórias e eventos adversos Intrahospital transport of patients on invasive ventilation: cardiorespiratory repercussions and adverse events

OBJETIVO: Verificar a ocorrência de alterações cardiorrespiratórias e identificar eventos adversos durante o transporte intra-hospitalar de pacientes sob ventilação invasiva. MÉTODOS: Estudo observacional prospectivo não-randomizado, conduzido em dois hospitais terciários, entre abril de 2005 e dezembro de 2006. Foram incluídos pacientes sob ventilação invasiva que necessitaram de transporte intra-hospitalar durante o período do estudo. Os critérios de exclusão foram: estar sob suspeita de morte encefálica; ter sido submetido a períodos de ventilação mecânica e de nebulização em tubo T; e ter sido transportado para o centro cirúrgico. Antes e após o transporte, os seguintes parâmetros foram avaliados: gasometria arterial, sinais vitais, uso de medicamentos através de uma bomba de infusão contínua, parâmetros do ventilador mecânico, duração do transporte, distância percorrida e número de profissionais envolvidos. RESULTADOS: Foram incluídos 48 pacientes, num total de 58 transportes. Observou-se alteração cardiorrespiratória importante em 39 transportes, totalizando 86 episódios, assim como 16 eventos adversos relacionados à falha de equipamento e falha da equipe, dentre eles problemas com baterias e falhas de comunicação. CONCLUSÕES: Durante o transporte intra-hospitalar de pacientes submetidos à ventilação invasiva, alterações cardiorrespiratórias foram frequentes (67,2%), e eventos adversos ocorreram em 75,7% dos transportes realizados.<br>OBJECTIVE: To determine the occurrence of cardiorespiratory alterations and to identify adverse events during the intrahospital transport of patients on invasive ventilation. METHODS: A prospective observational non-randomized study was conducted at two tertiary hospitals between April of 2005 and December of 2006. We included patients on invasive ventilation who required intrahospital transport during the study period. Exclusion criteria were as follows: being under suspicion of brain death; being submitted to alternate periods of mechanical ventilation/nebulization via a T-piece; and being transported to the operating room. Prior to and after transport, we evaluated blood gas analysis results, vital signs, use of medications by means of a continuous infusion pump, parameters regarding the mechanical ventilator, duration of transport, transport distance and number of professionals involved. RESULTS: We included 48 patients in a total of 58 intrahospital transports. Relevant cardiorespiratory alterations were identified in 39 transports, totaling 86 episodes, as well as 16 adverse events related to equipment or personnel failure, such as problems related to batteries and to miscommunication. CONCLUSIONS: During the intrahospital transport of patients on invasive ventilation, cardiorespiratory alterations were common (67.2%), and adverse events occurred in 75.7% of the transports

Going above and beyond for implementation: the development and validity testing of the Implementation Citizenship Behavior Scale (ICBS)

BACKGROUND: In line with recent research on the role of the inner context of organizations in implementation effectiveness, this study extends research on organizational citizenship behavior (OCB) to the domain of evidence-based practice (EBP) implementation. OCB encompasses those behaviors that go beyond what is required for a given job that contribute to greater organizational effectiveness. The goal of this study was to develop and test a measure of implementation citizenship behavior (ICB) or those behaviors that employees perform that go above and beyond what is required in order to support EBP implementation. METHODS: The primary participants were 68 supervisors from ten mental health agencies throughout California. Items measuring ICB were developed based on past research on OCB and in consultation with experts on EBP implementation in mental health settings. Supervisors rated 357 of their subordinates on ICB and implementation success. In addition, 292 of the subordinates provided data on self-rated performance, attitudes towards EBPs, work experience, and full-time status. The supervisor sample was randomly split, with half used for exploratory factor analyses and the other half for confirmatory factor analyses. The entire sample of supervisors and subordinates was utilized for analyses assessing the reliability and construct validity of the measure. RESULTS: Exploratory factor analyses supported the proposed two-factor structure of the Implementation Citizenship Behavior Scale (ICBS): (1) Helping Others and (2) Keeping Informed. Confirmatory factor analyses with the other half of the sample supported the factor structure. Additional analyses supported the reliability and construct validity for the ICBS. CONCLUSIONS: The ICBS is a pragmatic brief measure (six items) that captures critical behaviors employees perform to go above and beyond the call of duty to support EBP implementation, including helping their fellow employees on implementation-related activities and keeping informed about issues related to EBP and implementation efforts. The ICBS can be used by researchers to better understand the outcomes of improved organizational support for implementation (i.e., implementation climate) and the proximal predictors of implementation effectiveness. The ICBS can also provide insight for organizations, practitioners, and managers by focusing on key employee behaviors that should increase the probability of implementation success. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13012-015-0255-8) contains supplementary material, which is available to authorized users