Cost of severe asthma in Brazil-systematic review.

INTRODUCTION: Severe asthma is characterized by frequent exacerbations, symptoms limiting daily activities and nocturnal symptoms. It requires the continuous use of medications, at high doses, and, sometimes, continuous use of oral corticosteroids, representing a significant burden to health system and society. This systematic review sought to address economic data related to severe asthma in Brazil. METHOD: In June 2014, electronic searches were conducted to identify relevant publications. Quality criteria were developed and applied to each selected study. In order to compare results across the selected studies, costs were refined to an annual basis, grouped according to the study perspective, inflated and converted to 2014 USD. RESULTS: Cost analyses from the Brazilian public health system perspective were derived from two studies and showed an average annual hospital cost per patient of 135 USD and 733 USD, respectively. From the family perspective, average annual direct costs per patient varied from 764 USD to 929 USD. CONCLUSION: Hospitalizations and medications seem to be the most important resources funded by the Brazilian public health system and by patients and their families. Although further studies are necessary, as information on cost of this disease is scarce in Brazil, these findings suggest that there is a potential room for improving severe asthma care among Brazilian patients.

GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity.

The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.

Avaliação econômica da adição de omalizumabe ao tratamento de pacientes com asma alérgica grave não controlada sob a perspectiva do Sistema Único de Saúde do Brasil / Economic evaluation of omalizumab add-on therapy in patients with uncontrolled severe allergic asthma from the perspective of Unified Health System in Brazil

Determinar a relação de custo-efetividade da adição de omalizumabe à terapia padrão (TP) comparada à TP isolada em pacientes com asma alérgica grave não controlada sob a perspectiva do Sistema Único de Saúde. Método: Um modelo de Markov baseado no estudo INNOVATE foi utilizado para comparar custos e desfechos ao longo da vida. No modelo os pacientes transitaram entre os estados de sintomas diários (asma controlada), exacerbações não grave clinicamente significantes (CS) e exacerbações graves CS. Os estados de morte foram separados em morte por todas as causas e morte devido à exacerbação grave da asma. Os desfechos foram exacerbações clinicamente significantes (ECS), eventos não graves e graves, e exacerbações graves clinicamente significantes (EGCS) evitadas. Os custos e ECS/EGCS evitadas foram utilizados para calcular RCEI (razão de custo-efetividade incremental) de omalizumabe. Análises de sensibilidade univariada e probabilística foram realizadas. Resultados: Os resultados mostraram que a adição de omalizumabe, quando comparada à TP isolada, representou um custo incremental de R$ 78.351/ECS evitada e R$ 103.170/EGCS evitada. As análises de sensibilidade confirmaram a robustez do modelo. Conclusão: Conforme demonstrado nas análises de sensibilidade, para que a razão de custo-efetividade da adição de omalizumabe passe a ser atrativa (probabilidade de pelo menos 70% de a RCEI ser menor que três PIB, produto interno bruto, per capita do Brasil, 2013), uma redução de 35% sobre o custo de aquisição do medicamento deve ser atribuída, em relação ao caso base...

Aversion in the elevated plus-maze: role of visual and tactile cues.

Thigmotaxis, a tendency to be close to vertical surfaces, leads rats to avoid open arms in the elevated plus-maze. Evidences support a role in thigmotaxis for the vibrissal sense as well as for vision. In this study, sensory inputs for both senses were manipulated in order to identify which of them mainly contributes to thigmotaxis. This was achieved by manipulating the length of rats' mystacial vibrissae, the presence of walls in the "open" arms and their transparency. As expected, rats avoided arms which lacked walls. On the other hand, rats did not avoid "open" arms surrounded by transparent walls as one could expect if they were using mainly vision while exploring the maze. Furthermore, these "open" arms were explored similarly to arms surrounded by opaque walls. Acute vibrissotomy resulted in minor effects in rats tested in a conventional elevated plus-maze. These findings suggest that vibrissotomized rats seemed to be able to compensate the absence of mystacial vibrissae by means of other sensory pathways (tactile or non-tactile) and by adjusting some exploratory aspects. Thus, the current results indicate that rats rely more on other sensory cues than on vision in avoiding open arms in the elevated plus-maze.

Sex differences in synaptic plasticity in stress-responsive brain regions following chronic variable stress.

Increased stress responsiveness is implicated in the etiology of mood and anxiety disorders, including depression and post-traumatic stress disorder. Additionally, stress-related affective disorders have a higher incidence in women than men. Chronic stress in rodents produces numerous neuromorphological changes in a variety of limbic brain regions. Here, we examined the sex-dependent differences in presynaptic innervation of the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), bed nucleus of the stria terminalis (BST), and amygdala in response to chronic variable stress (CVS). Following 14 days of CVS, the presynaptic protein synaptophysin was assessed in male and female rats. Our results demonstrate that synaptophysin staining density was higher in females than males in all brain areas evaluated, indicating sex differences in the organization of presynaptic innervation. After CVS, the PVN, principal nucleus of the BST (BSTpr), and basolateral nucleus of the amygdala (BLA) displayed significantly reduced synaptophysin density in females but not males. Furthermore, males showed an increase in synaptophysin in the PVN after CVS, suggesting a sex difference in the modulation of presynaptic inputs to the PVN following chronic stress. Overall, these data suggest marked sex differences in PVN, BSTpr, and BLA presynaptic innervation as a consequence of chronic stress, which may be associated with differential stress responsivity and perhaps susceptibility to pathologies in males and females.

Role of nitric oxide in the periaqueductal gray in defensive behavior in mice: influence of prior local N-methyl-D-aspartate receptor activation and aversive condition

Glutamate N-methyl-D-aspartate (NMDA) receptor activation within the dorsal column of the periaqueductal gray (dPAG) leads to antinociceptive, autonomic, and behavioral responses characterized as the fear reaction. Activation of NMDA receptors in the brain increases nitric oxide (NO) synthesis, and NO has been proposed to be a mediator of the aversive action of glutamate. This paper reviews a series of studies investigating the effects of neuronal NO synthase (nNOS) inhibition in the dPAG of mice in different aversive conditions. nNOS inhibition by infusion of Nù-propyl-L-arginine (NPLA) prevents fear-like reactions (e.g., jumping, running, freezing) induced by NMDA receptor stimulation within the dPAG and produces anti-aversive effects when injected into the same midbrain site in mice confronted with a predator. Interestingly, nNOS inhibition within the dPAG does not change anxiety-like behavior in mice exposed to the elevated plus maze (EPM), but it reverses the effect of an anxiogenic dose of NMDA injected into the same site in animals subjected to the EPM. Altogether, the results support a role for glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice. However, dPAG nitrergic modulation of anxiety-like behavior appears to depend on the magnitude of the aversive stimulus.(AU)

Role of nitric oxide in the periaqueductal gray in defensive behavior in mice: influence of prior local N-methyl-D-aspartate receptor activation and aversive condition

Glutamate N-methyl-D-aspartate (NMDA) receptor activation within the dorsal column of the periaqueductal gray (dPAG) leads to antinociceptive, autonomic, and behavioral responses characterized as the fear reaction. Activation of NMDA receptors in the brain increases nitric oxide (NO) synthesis, and NO has been proposed to be a mediator of the aversive action of glutamate. This paper reviews a series of studies investigating the effects of neuronal NO synthase (nNOS) inhibition in the dPAG of mice in different aversive conditions. nNOS inhibition by infusion of Nω-propyl-L-arginine (NPLA) prevents fear-like reactions (e.g., jumping, running, freezing) induced by NMDA receptor stimulation within the dPAG and produces anti-aversive effects when injected into the same midbrain site in mice confronted with a predator. Interestingly, nNOS inhibition within the dPAG does not change anxiety-like behavior in mice exposed to the elevated plus maze (EPM), but it reverses the effect of an anxiogenic dose of NMDA injected into the same site in animals subjected to the EPM. Altogether, the results support a role for glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice. However, dPAG nitrergic modulation of anxiety-like behavior appears to depend on the magnitude of the aversive stimulus.

Evidence for the thalamic targets of the medial hypothalamic defensive system mediating emotional memory to predatory threats.

Previous studies from our laboratory have documented that the medial hypothalamic defensive system is critically involved in processing actual and contextual predatory threats, and that the dorsal premammillary nucleus (PMd) represents the hypothalamic site most responsive to predatory threats. Anatomical findings suggest that the PMd is in a position to modulate memory processing through a projecting branch to specific thalamic nuclei, i.e., the nucleus reuniens (RE) and the ventral part of the anteromedial nucleus (AMv). In the present study, we investigated the role of these thalamic targets in both unconditioned (i.e., fear responses to predatory threat) and conditioned (i.e., contextual responses to predator-related cues) defensive behaviors. During cat exposure, all experimental groups exhibited intense defensive responses with the animals spending most of the time in the home cage displaying freezing behavior. However, during exposure to the environment previously associated with a cat, the animals with combined RE+AMv lesions, and to a lesser degree, animals with single AMv unilateral lesions, but not animals with single RE lesions, presented a reduction of contextual conditioned defensive responses. Overall, the present results provide clear evidence suggesting that the PMd's main thalamic targets (i.e., the nucleus reuniens and the AMv) seem to be critically involved in the emotional memory processing related to predator cues.

Role of glutamate NMDA receptors and nitric oxide located within the periaqueductal gray on defensive behaviors in mice confronted by predator.

RATIONALE: The midbrain periaqueductal gray (PAG) is part of the brain system involved in active defense reactions to threatening stimuli. Glutamate N-methyl-D: -aspartate (NMDA) receptor activation within the dorsal column of the PAG (dPAG) leads to autonomic and behavioral responses characterized as the fear reaction. Nitric oxide (NO) has been proposed to be a mediator of the aversive action of glutamate, since the activation of NMDA receptors in the brain increases NO synthesis. OBJECTIVES: We investigated the effects of intra-dPAG infusions of NMDA on defensive behaviors in mice pretreated with a neuronal nitric oxide synthase (nNOS) inhibitor [Nomega-propyl-L: -arginine (NPLA)], in the same midbrain site, during a confrontation with a predator in the rat exposure test (RET). MATERIALS AND METHODS: Male Swiss mice received intra-dPAG injections of NPLA (0.1 or 0.4 nmol/0.1 microl), and 10 min later, they were infused with NMDA (0.04 nmol/0.1 microl) into the dPAG. After 10 min, each mouse was placed in the RET. RESULTS: NMDA treatment enhanced avoidance behavior from the predator and markedly increased freezing behavior. These proaversive effects of NMDA were prevented by prior injection of NPLA. Furthermore, defensive behaviors (e.g., avoidance, risk assessment, freezing) were consistently reduced by the highest dose of NPLA alone, suggesting an intrinsic effect of nitric oxide on defensive behavior in mice exposed to the RET. CONCLUSIONS: These findings suggest a potential role of glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice during a confrontation with a predator in the RET.

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze.

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal-acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine, respectively, this does not seem to be a useful measure of escape from a proximal threat in this species.

Investigation of the hypothalamic defensive system in the mouse.

The hypothalamus plays especially important roles in various endocrine, autonomic, and behavioral responses that guarantee the survival of both the individual and the species. In the rat, a distinct hypothalamic defensive circuit has been defined as critical for integrating predatory threats, raising an important question as to whether this concept could be applied to other prey species. To start addressing this matter, in the present study, we investigated, in another prey species (the mouse), the pattern of hypothalamic Fos immunoreactivity in response to exposure to a predator (a rat, using the Rat Exposure Test). During rat exposure, mice remained concealed in the home chamber for a longer period of time and increased freezing and risk assessment activity. We were able to show that the mouse and the rat present a similar pattern of hypothalamic activation in response to a predator. Of particular note, similar to what has been described for the rat, we observed in the mouse that predator exposure induces a striking activation in the elements of the medial hypothalamic defensive system, namely, the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus. Moreover, as described for the rat, predator-exposed mice also presented increased Fos levels in the autonomic and parvicellular parts of the paraventricular hypothalamic nucleus, lateral preoptic area and subfornical region of the lateral hypothalamic area. In conclusion, the present data give further support to the concept that a specific hypothalamic defensive circuit should be preserved across different prey species.

Effects of intra-PAG infusion of ovine CRF on defensive behaviors in Swiss-Webster mice.

The midbrain dorsal periaqueductal gray (DPAG) is part of the brain defensive system involved in active defense reactions to threatening stimuli. Corticotrophin releasing factor (CRF) is a peptidergic neurotransmitter that has been strongly implicated in the control of both behavioral and endocrine responses to threat and stress. We investigated the effect of the nonspecific CRF receptor agonist, ovine CRF (oCRF), injected into the DPAG of mice, in two predator-stress situations, the mouse defense test battery (MDTB), and the rat exposure test (RET). In the MDTB, oCRF weakly modified defensive behaviors in mice confronted by the predator (rat); e.g. it increased avoidance distance when the rat was approached and escape attempts (jump escapes) in forced contact. In the RET, drug infusion enhanced duration in the chamber while reduced tunnel and surface time, and reduced contact with the screen which divides the subject and the predator. oCRF also reduced both frequency and duration of risk assessment (stretch attend posture: SAP) in the tunnel and tended to increase freezing. These findings suggest that patterns of defensiveness in response to low intensity threat (RET) are more sensitive to intra-DPAG oCRF than those triggered by high intensity threats (MDTB). Our data indicate that CRF systems may be functionally involved in unconditioned defenses to a predator, consonant with a role for DPAG CRF systems in the regulation of emotionality.