Inhibition of the NMDA receptor/Nitric Oxide pathway in the dorsolateral periaqueductal gray causes anxiolytic-like effects in rats submitted to the Vogel conflict test

Abstract Background Several studies had demonstrated the involvement of the dorsolateral portion of periaqueductal grey matter (dlPAG) in defensive responses. This region contains a significant number of neurons containing the enzyme nitric oxide synthase (NOS) and previous studies showed that non-selective NOS inhibition or glutamate NMDA-receptor antagonism in the dlPAG caused anxiolytic-like effects in the elevated plus maze. Methods In the present study we verified if the NMDA/NO pathway in the dlPAG would also involve in the behavioral suppression observed in rats submitted to the Vogel conflict test. In addition, the involvement of this pathway was investigated by using a selective nNOS inhibitor, Nω-propyl-L-arginine (N-Propyl, 0.08 nmol/200 nL), a NO scavenger, carboxy-PTIO (c-PTIO, 2 nmol/200 nL) and a specific NMDA receptor antagonist, LY235959 (4 nmol/200 nL). Results Intra-dlPAG microinjection of these drugs increased the number of punished licks without changing the number of unpunished licks or nociceptive threshold, as measure by the tail flick test. Conclusion The results indicate that activation of NMDA receptors and increased production of NO in the dlPAG are involved in the anxiety behavior displayed by rats in the VCT.

Proinflammatory profile of in vitro monocytes in the ageing is affected by lymphocytes presence

Background: Aging is associated with complex and constant remodeling of the immune function, resulting in an increasing susceptibility to infection and others diseases. The infections caused by Gram-negative microorganisms, present in nursing homes and hospitals, constitute one of the most common infections in the elderly, and are mainly combated by innate immune cells. Although the functions of innate immunity seem more preserved during aging than of adaptive immune mechanisms, two systems operate in an integrated way in the body, so that injury in one part of the immune system inevitably affects the other as they are part of a defensive network. The aim of this study was to investigate the in vitro production of proinflammatory (TNF-α, IL-6, IL-1α, CXCL-8 and MCP-1) and antiinflammatory (TGF-α and IL-10) cytokines by monocytes, stimulated or not (basal) with lipopolysaccharide, from healthy young and elderly subjects. By means of PBMCs, we also studied if cytokine profile is altered in these different patient groups, in the presence of lymphocytes, under the same experimental conditions. Results: The monocytes from elderly presented higher basal production of TNF-α, MCP-1 and lower of TGF-α than young monocytes. PBMC showed similar cytokines production, irrespective age or stimulation presence. In the presence of lymphocytes, the spontaneous production of IL-10 was higher and of TGF-α was lower than monocytes, regardless of age. After LPS-stimulation, the presence of lymphocytes resulted in increased IL-6, IL-1α, MCP-1 and IL-10 and decreased CXCL-8 and TGF-α in comparison to pure culture of monocytes from young patients. With age, the same differences were observed, except for CXCL-8 and TGF-α which production was the same between monocytes and PBMC stimulated with LPS.

Cause-specific mortality and income inequality in São Paulo, Brazil

OBJECTIVE: To analyze cause-specific mortality rates according to the relative income hypothesis. METHODS: All 96 administrative areas of the city of São Paulo, southeastern Brazil, were divided into two groups based on the Gini coefficient of income inequality: high (>0.25) and low (<0.25). The propensity score matching method was applied to control for confounders associated with socioeconomic differences among areas. RESULTS: The difference between high and low income inequality areas was statistically significant for homicide (8.57 per 10,000; 95%CI: 2.60;14.53); ischemic heart disease (5.47 per 10,000 [95%CI 0.76;10.17]); HIV/AIDS (3.58 per 10,000 [95%CI 0.58;6.57]); and respiratory diseases (3.56 per 10,000 [95%CI 0.18;6.94]). The ten most common causes of death accounted for 72.30% of the mortality difference. Infant mortality also had significantly higher age-adjusted rates in high inequality areas (2.80 per 10,000 [95%CI 0.86;4.74]), as well as among males (27.37 per 10,000 [95%CI 6.19;48.55]) and females (15.07 per 10,000 [95%CI 3.65;26.48]). CONCLUSIONS: The study results support the relative income hypothesis. After propensity score matching cause-specific mortality rates was higher in more unequal areas. Studies on income inequality in smaller areas should take proper accounting of heterogeneity of social and demographic characteristics.

New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray

Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction.

Evolução dos homicídios e indicadores de segurança pública no Município de São Paulo entre 1996 a 2008: um estudo ecológico de séries temporais

OBJETIVO: analisar a associação entre homicídios e indicadores de segurança pública no MSP entre 1996 e 2008, após controle para taxa de desemprego e proporção de jovens na população. METODOLOGIA: estudo ecológico de série temporal, tendo como unidade de análise o Município de São Paulo (MSP), entre 1996 e 2008. Variável dependente: óbitos por homicídio; variáveis independentes principais: taxa de aprisionamento-encarceramento (TAE), o acesso a armas de fogo (AAF), e a atividade policial (ATP). A análise dos dados foi realizada com o software Stata.IC 10.0. Modelos de regressão binomial negativa simples e multivariados foram construídos. RESULTADOS: A análise univariada demonstrou associação entre óbitos por homicídio e TAE e entre óbitos e ATP. O AAF não se mostrou associado à redução no número de óbitos por homicídios (p > 0,05). Após ajuste houve perda da significância na associação com ambos indicadores de Segurança Pública. CONCLUSÕES: No MSP o papel das ações de segurança pública perdem importância como fatores explicativos para a redução nos níveis de homicídios após controle para taxa de desemprego e redução na proporção de jovens. Os resultados reforçam a importância dos fatores socioeconômicos e demográficos para a mudança no cenário da segurança em São Paulo.

Orfandade por aids ou por homicídio apresenta efeitos sobre o estado nutricional das crianças?

O artigo tem como objetivos avaliar o estado nutricional de órfãos por aids ou homicídios residentes em São Paulo e estimar a associação de índices nutricionais com variáveis relacionadas à orfandade. Trata-se de estudo transversal de base domiciliar que utilizou amostra representativa de 484 indivíduos de 5 a 14 anos que perderam um ou ambos os pais durante os anos de 2000 e 2004 devido à aids ou a homicídio no município de São Paulo. A avaliação nutricional foi feita com o índice de massa corporal-para-idade (IMC) e da altura-para-idade (altura). A associação entre os índices nutricionais e as variáveis relacionadas à orfandade foi estimada em análise hierárquica, com uso de modelo de regressão linear múltiplo. Órfãos por aids ou homicídios diferiram quanto às características da orfandade e à idade média. As condições econômicas, domiciliares, o estado de saúde e o estado nutricional foram semelhantes entre os grupos. O déficit de IMC ocorreu em 1,3% das crianças abaixo de 10 anos e em 2,1% dos adolescentes. O déficit de altura ocorreu em 0,7% das crianças e em 4,0% dos adolescentes. O excesso de peso ocorreu em 19% e 20% das crianças e adolescentes, respectivamente. A análise hierárquica indicou ausência de efeito das variáveis relacionadas à orfandade sobre o IMC ou a altura; o principal determinante do estado nutricional foi de natureza econômica. Os órfãos por aids ou homicídio de São Paulo apresentaram estado nutricional semelhante e majoritariamente influenciado pela situação econômica. O perfil nutricional identificado no grupo, caracterizado pelo excesso de peso, sugere que os órfãos de São Paulo não apresentam riscos adicionais decorrentes da orfandade.

Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury

The activation of heme oxygenase-1 (HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection. In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload (with signs of a chronic hepatitis) and iron deficiency anemia (with paradoxical increased levels of ferritin). Hypoxia induces HO-1 expression in multiple rodent, bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types (endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.