Out-of-Hospital Pediatric Video Laryngoscopy With an Adult Device: A Case Series Presented With a Contemporary Group Intubated With Direct Laryngoscopy.

OBJECTIVES: After introducing an adult video laryngoscope (VL) in our physician-paramedic prehospital and retrieval medical service, our quality assurance process identified this blade being used during pediatric intubations. We present a case series of pediatric intubations using this oversized adult VL alongside a contemporaneous group of direct laryngoscopy (DL) intubations. METHODS: We performed a retrospective review of intubated patients 15 years or younger in our electronic quality assurance registry from January 1, 2017, to December 31, 2020. Data collected were demographic details, intubation equipment, drug doses, the number of intubation attempts, and complications. Results are presented according to those intubated with C-MAC4 VL (Karl Storz) alongside age-appropriate DL sizes. RESULTS: Ninety-nine pediatric patients were intubated, 67 (67%) by CMAC4 and 32 (33%) by DL. Video laryngoscopy had a first-attempt success rate of 96% and DL 91%. A Cormach and Lehane view 1 or 2 was found in 66 VL (99%) and 29 DL patients (91%). Desaturation was reported in two VL and 1 DL patient. CONCLUSIONS: Adult VL became the most common method of intubation in patients older than 1 year during the study period. An adult C-MAC4 VL could be considered for clinicians who prefer VL when a pediatric VL is unavailable or as a second-line device if a pediatric VL is not present when intubating children older than 1 year.

“It’s as if I’m the one suffering”: Narratives of parents of children with disability in the Philippines

@#<p style="text-align: justify;"><strong>Background.</strong> Children comprise a significant proportion of persons with disabilities (PWDs) in the Philippines, and represent a major public health challenge. One under-explored topic is the "lived experiences" of their parents and guardians as well as the roles they play in caring for their children. This qualitative study responds to this research gap by eliciting and foregrounding their experiences and narratives.</p><p style="text-align: justify;"><strong>Methods.</strong> Six focus group discussions (FGDs) were conducted among parents of children with disabilities (CWDs) in Davao City and Tagum City. These were complemented by 12 key informant interviews among healthcare providers in both cities.</p><p style="text-align: justify;"><strong>Results.</strong> For many parents, coming to terms with a disability is a difficult and lengthy process, but one that ends with a measure of relief and eventual adaptation. Living with disability, meanwhile, is fraught with medical, financial, educational, and social challenges. A positive religious outlook allows them to make sense of disability, helping them to overcome these challenges. Support groups and the health care system are likewise crucial factors towards family resilience.</p><p style="text-align: justify;"><strong>Conclusion.</strong> Our findings show that the experience of disability is shared among family members, particularly, the parents of CWDs; thus, underscoring the need for a family-centered approach in policies, clinical care, and communications efforts involving children with disability in the Philippines.</p>

NMDAR activation regulates the daily rhythms of sleep and mood.

STUDY OBJECTIVES: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. METHODS: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day-night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings. RESULTS: NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1-4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm. DISCUSSION: These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.

Implementation of national action plans on noncommunicable diseases, Bhutan, Cambodia, Indonesia, Philippines, Sri Lanka, Thailand and Viet Nam.

By 2016, Member States of the World Health Organization (WHO) had developed and implemented national action plans on noncommunicable diseases in line with the Global action plan for the prevention and control of noncommunicable diseases (2013-2020). In 2018, we assessed the implementation status of the recommended best-buy noncommunicable diseases interventions in seven Asian countries: Bhutan, Cambodia, Indonesia, Philippines, Sri Lanka, Thailand and Viet Nam. We gathered data from a range of published reports and directly from health ministries. We included interventions that addressed the use of tobacco and alcohol, inadequate physical activity and high salt intake, as well as health-systems responses, and we identified gaps and proposed solutions. In 2018, progress was uneven across countries. Implementation gaps were largely due to inadequate funding; limited institutional capacity (despite designated noncommunicable diseases units); inadequate action across different sectors within and outside the health system; and a lack of standardized monitoring and evaluation mechanisms to inform policies. To address implementation gaps, governments need to invest more in effective interventions such as the WHO-recommended best-buy interventions, improve action across different sectors, and enhance capacity in monitoring and evaluation and in research. Learning from the Framework Convention on Tobacco Control, the WHO and international partners should develop a standardized, comprehensive monitoring tool on alcohol, salt and unhealthy food consumption, physical activity and health-systems response.

En 2016, les États membres de l'Organisation mondiale de la Santé (OMS) avaient élaboré et mis en œuvre des plans d'action nationaux sur les maladies non transmissibles conformément au Plan d'action mondial pour la lutte contre les maladies non transmissibles (2013­2020). En 2018, nous avons évalué l'état de l'application des interventions les plus avantageuses recommandées en matière de maladies non transmissibles dans sept pays asiatiques: le Bhoutan, le Cambodge, l'Indonésie, les Philippines, le Sri Lanka, la Thaïlande et le Viet Nam. Nous avons recueilli des données à partir de toute une série de rapports publiés et directement auprès des ministères de la Santé. Nous avons inclus les interventions qui concernaient la consommation de tabac et d'alcool, une activité physique inadéquate et une consommation de sel élevée, ainsi que les réponses des systèmes de santé, et nous avons identifié les lacunes et proposé des solutions. En 2018, les progrès étaient variables selon les pays. Les lacunes étaient largement dues à un financement inadéquat; des capacités institutionnelles limitées (malgré des unités dédiées aux maladies non transmissibles); une action inadéquate dans les différents secteurs au sein et en dehors du système de santé; et l'absence de mécanismes de suivi et d'évaluation standardisés pour orienter les politiques. Afin de combler ces lacunes, les gouvernements doivent investir davantage dans des interventions efficaces telles que les interventions les plus avantageuses recommandées par l'OMS, améliorer l'action dans les différents secteurs, et renforcer les capacités en matière de suivi et d'évaluation, mais aussi de recherche. En s'inspirant de la Convention-cadre pour la lutte antitabac, l'OMS et ses partenaires internationaux devraient élaborer un outil de suivi complet et standardisé sur la consommation d'alcool, de sel et d'aliments malsains, l'activité physique et la réponse des systèmes de santé.

Para 2016, los Estados miembros de la Organización Mundial de la Salud (OMS) habían elaborado y aplicado planes de acción nacionales sobre las enfermedades no contagiosas de acuerdo con el Plan de acción mundial para la prevención y el control de las enfermedades no transmisibles (2013-2020). En 2018, se evaluó el estado de implementación de las intervenciones recomendadas en siete países asiáticos en materia de enfermedades no contagiosas: Bhután, Camboya, Filipinas, Indonesia, Sri Lanka, Tailandia y Vietnam. Se recopilaron datos de una serie de informes publicados y directamente de los ministerios de salud. Se incluyeron intervenciones que abordaron el uso del tabaco y el alcohol, la actividad física inadecuada y la ingesta elevada de sal, así como las respuestas de los sistemas de salud, se identificaron las deficiencias y se propusieron soluciones. En 2018, el progreso fue desigual entre los países. Las deficiencias en la aplicación se debieron en gran medida a la falta de financiación, a la limitada capacidad institucional (a pesar de las dependencias designadas para las enfermedades no contagiosas), a la inadecuación de las medidas adoptadas en los diferentes sectores dentro y fuera del sistema de salud y a la falta de mecanismos normalizados de supervisión y evaluación que sirvieran de base a las políticas. Para subsanar las deficiencias en materia de aplicación, los gobiernos deben invertir más en intervenciones eficaces, como las recomendadas por la OMS, mejorar las medidas adoptadas en los distintos sectores y aumentar la capacidad de seguimiento y evaluación y de investigación. A partir de las enseñanzas del Convenio Marco para el Control del Tabaco, la OMS y los asociados internacionales deberían elaborar un instrumento de seguimiento normalizado y completo para el consumo de alcohol, sal y alimentos no saludables, la actividad física y la respuesta de los sistemas de salud.

Screening for Adult ADHD in Patients with Fibromyalgia Syndrome.

Objective: Fibromyalgia syndrome (FMS) is a common chronic pain disorder associated with altered activity of neurotransmitters involved in pain sensitivity such as dopamine, serotonin, and noradrenaline. FMS may significantly impact an individual's functioning due to the presence of chronic pain, fatigue, and cognitive impairment. Dyscognition may be more disabling than the chronic pain but is mostly under-recognized. This study aimed to assess the potential co-occurrence of FMS and adult attention deficit hyperactivity disorder (ADHD), a chronic neurodevelopmental disorder also associated with impaired cognition and dopaminergic function. Methods: In a cross-sectional observational study, 123 previously confirmed FMS patients were screened for adult ADHD using the World Health Organization Adult ADHD Self Report scale v1.1. The Revised Fibromyalgia Impact Questionnaire (FIQ-R) was used to assess the impact of FMS. Cognitive assessment was based on self-report in accordance with the 2011 modified American College of Rheumatology criteria and the FIQ-R, respectively. Results: Of the 123 participants, 44.72% (N = 55) screened positive for adult ADHD. Participants with both FMS and a positive adult ADHD screening test scored higher on the FIQ-R score (64.74, SD = 17.66, vs 54.10, SD = 17.10). Self-reported cognitive impairment was rated higher in the combined group (odds ratio = 10.61, 95% confidence interval; 3.77-29.86, P < 0.01). Conclusions: These results indicate that the co-occurrence of adult ADHD in FMS may be highly prevalent and may also significantly impact the morbidity of FMS. Patients with FMS should be assessed for the presence of adult ADHD.

Entre a "Velha" e a "Nova" Ciência Política: Continuidade e Renovação Acadêmica na Primeira Década da Revista DADOS (1966-1976) / Between the "Old" and the "New" Political Science: Continuity and Academic Renovation in the First Decade of DADOS Journal's Publication (1966-1976) / Entre la "Vielle" et la "Nouvelle" Science Politique: Continuité et Rénovation Académique lors de la Première Décennie de la Revue DADOS (1966-1976) / Entre la "Vieja" y la "Nueva" Ciencia Política: Continuidad y Renovación Académica en la Primera Década de la Revista DADOS (1966-1976)

RESUMO O presente artigo apresenta um mapeamento contextualizado dos debates acadêmicos travado ao longo da primeira década de existência da Revista DADOS (1966-1976). Do ponto de vista histórico, trata-se do processo de endurecimento do regime militar; do ponto de vista temático e teórico, cuida-se da passagem da antiga ideologia nacional-desenvolvimentista para uma sociologia do conhecimento que, ao final do período estudado, divide-se entre uma sociologia histórica e uma ciência política, preocupadas ambas com o estudo do autoritarismo em geral e do brasileiro em particular. Quanto aos autores, vê-se a passagem de bastão da velha Ciência Política brasileira, ensaísta e nacionalista, para uma nova, comprometida com uma reflexão rigorosa baseado em critérios profissionais, mas também com os valores democráticos.

ABSTRACT The following article provides a contextualized mapping of the academic debates characterizing the first decade of DADOS journal's publication (1966-1976). Historically speaking, this reflects a tightening of the military dictatorship, while from a thematic and theoretical point of view, it concerns the shift from the former national-developmental ideology to a sociology of knowledge that, at the end of the period under study, splits into a form of historic sociology and a form of political science, with both concerned with the study of authoritarianism in general and the study of this in Brazil in particular. In terms of authors, the shift is one from the old essayist and nationalist Brazilian political science to a new strand committed to rigorous reflection based on professional criteria, as well as democratic values.

RÉSUMÉ Le présent article propose une cartographie contextualisée des débats universitaires menés au long de la première décennie d'existence de la Revue DADOS (1966-1976). Du point de vue historique, il s'agit d'une période de durcissement du régime militaire, tandis que l'on a assisté, au niveau thématique, au passage de l'ancienne idéologie national-développementiste à une sociologie de la connaissance, qui, à la fin de la période en question, s'est divisée entre sociologie historique et science politique, néanmoins toutes deux impliquées dans l'étude de l'autoritarisme en général et de la situation brésilienne à cet égard. Pour ce qui est des auteurs, on constate un passage de relais entre les anciennes sciences politiques brésiliennes pamphlétaires et nationalistes et les nouvelles, engagées dans une réflexion rigoureuse se basant sur des critères professionnels, mais également sur des valeurs démocratiques.

RESUMEN Este artículo presenta un estudio contextualizado de los debates académicos llevados a cabo en el transcurso de la primera década de existencia de la revista DADOS (1966-1976). Desde el punto de vista histórico, se trata del proceso de endurecimiento del régimen militar; desde el punto de vista temático y teórico, se refiere al paso de la antigua ideología nacional-desarrollista a una sociología del conocimiento que, al final del periodo estudiado, se divide entre una sociología histórica y una ciencia política, ambas preocupadas por el estudio del autoritarismo en general y del brasileño en particular. En cuanto a los autores, se ve el paso del testigo de la vieja ciencia política brasileña, ensayista y nacionalista, a una nueva, comprometida con una reflexión rigurosa basada en criterios profesionales y también con los valores democráticos.

EEG-ß/γ spectral power elevation in rat: a translatable biomarker elicited by GABA(Aα2/3)-positive allosteric modulators at nonsedating anxiolytic doses.

Benzodiazepine drugs, through interaction with GABA(Aα1), GABA(Aα2,3), and GABA(Aα5) subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABA(Aα2,3)-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABA(Aα2,3)-mediated vs. GABA(Aα1) or GABA(Aα5) currents in voltage clamped oocytes transfected with those GABA(A) subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [(3)H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the ß- and and γ-bands. Finally, the dose range that increased γ-power coincided with that eliciting punished over unpunished responding in a behavioral conflict model of anxiety, indicative of anxiolysis without sedation. EEG γ-band power increases showed a significant positive correlation to in vitro GABA(Aα2,3) modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABA(Aα2,3) signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABA(Aα2,3)-subtype-selective drugs for anxiety and potentially other indications.

"A multidão é louca, a multidão é mulher": a demofobia oligárquico-federativa da Primeira República e o tema da mudança da capital / "The crowd is crazy, the crowd is a woman": the oligarchical-federal demophobia of the First Republic and the issue of transferring the capital

Examina as expressões de demofobia da classe política da Primeira República, em faces das manifestações do povo carioca, relacionando-as à necessidade de mudar para o interior a sede do governo federal. A literatura demófoba produzida pelos liberais europeus contrários à democratização em seus países impregnou a orientação da classe política brasileira do período. Empenhados em construir uma federação oligárquica, viam a população do Rio de Janeiro como uma ameaça. Contra um subversivo povo-multidão de uma capital cosmopolita, artificial e estrangeirada, o federalismo oligárquico valorizava um ‘autêntico' povo brasileiro que remetia ao imaginário de uma população interiorana e ordeira.

This study examines the expressions of demophobia of the political class of the First Republic, faced with demonstrations against the government in Rio de Janeiro, and relates them to the need to move to the seat of the federal government inland. The demophobic literature produced by liberal Europeans against democratization in their countries pervaded the orientation of the Brazilian political class during the period. Committed to building an oligarchic federation, they saw the population of Rio de Janeiro as a threat. Compared to a subversive crowd of people in a huge, artificial capital suffering from foreign influence, oligarchic federalism valued the ‘authentic' Brazilian people, referred to the image of a provincial, orderly population.

"The crowd is crazy, the crowd is a woman": the oligarchical-federal demophobia of the First Republic and the issue of transferring the capital.

This study examines the expressions of demophobia of the political class of the First Republic, faced with demonstrations against the government in Rio de Janeiro, and relates them to the need to move to the seat of the federal government inland. The demophobic literature produced by liberal Europeans against democratization in their countries pervaded the orientation of the Brazilian political class during the period. Committed to building an oligarchic federation, they saw the population of Rio de Janeiro as a threat. Compared to a subversive crowd of people in a huge, artificial capital suffering from foreign influence, oligarchic federalism valued the 'authentic' Brazilian people, referred to the image of a provincial, orderly population.

Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials.

BACKGROUND: Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4ß4/α4ß2 nicotine receptor antagonist dihydro-beta-erythroidine (DHßE), and the α4ß2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHßE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4ß2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHßE blocks the effects of nicotine through a non-α4ß2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHßE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHßE but not MLA blocked the effect of nicotine on event-related gamma. CONCLUSIONS/SIGNIFICANCE: These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHßE sensitive mechanism, but suggests that this does not occur through activation of α4ß2 receptors. Event-related gamma is strongly influenced by activation of α4ß2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.

Development and SAR of functionally selective allosteric modulators of GABAA receptors.

Positive modulators at the benzodiazepine site of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA(A) receptors and that show no functional activity at α1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA(A) receptors, while simultaneously neutral antagonists at α1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.

Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors.

BACKGROUND: Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates. METHODS: Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 µg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout. RESULTS: Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg. CONCLUSIONS: These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend.

Stimulus-specific adaptation in auditory cortex is an NMDA-independent process distinct from the sensory novelty encoded by the mismatch negativity.

The significance of the mismatch negativity (MMN), an event-related potential measured in humans which indexes novelty in the auditory environment, has motivated a search for a cellular correlate of this process. A leading candidate is stimulus-specific adaptation (SSA) in auditory cortex units, which shares several characteristics with the MMN. Whether auditory cortex responses encode sensory novelty, a defining property of the MMN, however, has not been resolved. To evaluate this key issue, we used several variations of the auditory oddball paradigm from the human literature and examined psychophysical and pharmacological properties of multiunit activity in the auditory cortex of awake rodents. We found converging evidence dissociating SSA from sensory novelty and the MMN. First, during an oddball paradigm with frequency deviants, neuronal responses showed clear SSA but failed to encode novelty in a manner analogous to the human MMN. Second, oddball paradigms using intensity or duration deviants revealed a pattern of unit responses that showed sensory adaptation, but again without any measurable novelty correlates aligning to the human MMN. Finally NMDA antagonists, which are known to disrupt the MMN, suppressed the magnitude of multiunit responses in a nonspecific manner, leaving the process of SSA intact. Together, our results suggest that auditory novelty detection as indexed by the MMN is dissociable from SSA at the level of activity encoded by auditory cortex neurons. Further, the NMDA sensitivity reported for the MMN, which models the disruption of MMN observed in schizophrenia, may occur at a mechanistic locus outside of SSA.

Performance on the portable rod and frame test predicts variation in learning the kayak roll.

Expert performers in sports that include a high proportion of closed skills have often been found to score relatively high in field independence tests; a field-independent cognitive style may be advantageous for learning and performance of closed skills. The relationship between field dependence-independence (measured on a Portable Rod and Frame Test) and the acquisition of a kayak skill was examined. Undergraduates (6 men, 11 women; M age=21.6 yr., SD=3.2) who had no previous kayaking experience participated. Participants completed a structured teaching session (2 hr.) designed to develop three key subskills necessary for the kayak roll. Number of trials taken to consistently perform the underwater orientation and paddle movement subskills and duration of practice taken to develop the upper/lower body separation subskill as well as participants' ability to complete the roll were assessed. Field independence was associated with better performance of subskills and skill acquisition tests. Learners with greater field independence may have an advantage when acquiring sport skills that require cognitive restructuring and a strong reliance on kinesthetic and proprioceptive feedback.

Reversal of ketamine-induced working memory impairments by the GABAAalpha2/3 agonist TPA023.

BACKGROUND: Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms. METHODS: Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection. RESULTS: Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms. CONCLUSIONS: Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.

Entre o Leviatã e o Beemote: soberania, constituição e excepcionalidade no debate político dos séculos XVII e XVIII / Between the Leviathan and the Behemoth: sovereignty, constitution, and exceptionality in 17th and 18th centuries political debate / Entre le Léviathan et le Behemoth: souveraineté, constitution et exceptionnalité dans le débat public aux XVIIe et XVIIIe siècles

The article seeks to retrace the theoretical approaches to the problem of exceptionality of power, i.e., the manifestation of sovereign power within a limited government with shared power - as in the tradition of mixed Constitution (longstanding in political thinking) - in the 17th and 18th centuries. Already present in authors like Machiavelli, Harrington, and Locke, the debate bifurcated between England and France in the early 18th century. The specificities of English politics led it to consecrate a tradition of mixed Constitutionalism in which the discretionary element lost relevance in the political system as a whole. In France, on the other hand, the unpopularity of the nobility and the centrality of sovereignty as a concept disaccredited formulas that compromised with the discretionary nature of power. This bifurcation contributed to the formation of two distinct patterns of Constitutional government: the Anglo-Saxon and the French/Continental.

Dans cet article, le propos est de montrer les voies théoriques empruntées par la question de l'exceptionnalité du pouvoir, c'est-à-dire la manifestation du pouvoir souverain à l'intérieur d'un gouvernement limité et au pouvoir partagé - cas de la constitution mixte, vieille tradition de la pensée politique européenne aux XVIIe -XVIIIe siècles. Débat qu'on retrouve déjà chez des auteurs tels que Machiavel, Harrington et Locke, et qui se dédouble au début du XVIIIe siècle entre l'Angleterre et la France. D'un côté, si les spécificités de la politique anglaise l'ont amenée à consacrer une tradition de constitution mixte où l'élément discrétionnaire voyait son importance amoindrie au sein du système politique, de l'autre , en France, l'impopularité de la noblesse et la centralité du concept de souveraineté ont discrédité les formules s'accommodant du caractère discrétionnaire du pouvoir. Cette bifurcation aurait favorisé la formation de deux modèles différents de gouvernement constitutionnel: l'anglo-saxon et le franco-occidental.

A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning.

M(1) muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M(1) receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M(1) receptor affinity for acetylcholine. We found that activation of the M(1) receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M(1) receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M(1) receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M(1) receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M(1) mAChR subtype may ameliorate impairments in cognitive function.

Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes.

AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of alpha7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective alpha7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178-1.78 mg/kg) and the compound effect was found to be absent in homozygous alpha7 KO animals. Together, these data indicate that selective interaction with alpha7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective alpha7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.