Phosphoinositide-3 Kinase gamma Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

Rationale Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase gamma (PI3K gamma) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. Objectives: This study aimed to determine the specific role of the kinase activity of PI3K gamma in the pathogenesis of sepsis and multiorgan damage. Methods. PI3K gamma wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3K gamma inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. Measurements and Main Results: Both genetic and pharmaceutical PI3K gamma kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3K gamma pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. Conclusions: This study establishes PI3K gamma as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

Risk of Potential Drug-Drug Interactions among Brazilian Elderly A Population-Based, Cross-Sectional Study

Background: Drug-drug interactions (DDIs) are one of the main causes of adverse reactions related to medications, being responsible for up to 23% of hospital admissions. However, only a few studies have evaluated this problem in elderly Brazilians. Objectives: To determine the prevalence of potential DDIs (PDDIs) in community-dwelling elderly people in Brazil, analyse these interactions with regard to severity and clinical implications, and identify associated factors. Methods: A population-based cross-sectional study was carried out involving 2143 elderly (aged 60 years) residents of the metropolitan area of Sao Paulo, Brazil. Data were obtained from the SABE (Saude, Bem estar e Envelhecimento [Health, Well-Being, and Aging]) survey, which is a multicentre study carried out in seven countries of Latin America and the Caribbean, coordinated by the Pan-American Health Organization. PDDIs were analysed using a computerized program and categorized according to level of severity, onset, mechanism and documentation in the literature. The STATA software statistical package was used for data analysis, and logistic regression was conducted to determine whether variables were associated with PDDIs. Results: Analysis revealed that 568 (26.5%) of the elderly population included in the study were taking medications that could lead to a DDI. Almost two-thirds (64.4%) of the elderly population exposed to PDDIs were women, 50.7% were aged >= 75 years, 71.7% reported having fair or poor health and 65.8% took 2-5 medications. A total of 125 different PDDIs were identified; the treatment combination of an ACE inhibitor with a thiazide or loop diuretic (associated with hypotension) was the most frequent cause of PDDIs (n=322 patients; 56.7% of individuals with PDDIs). Analysis of the PDDIs revealed that 70.4% were of moderate severity, 64.8% were supported by good quality evidence and 56.8% were considered of delayed onset. The multivariate analysis showed that the risk of a PDDI was significantly increased among elderly individuals using six or more medications (odds ratio [OR] 3.37) and in patients with hypertension (OR 2.56), diabetes mellitus (OR 1.73) or heart problems (OR 3.36). Conclusions: Approximately one-quarter of the elderly population living in Sao Paulo could be taking two or more potentially interacting medicines. Polypharmacy predisposes elderly individuals to PDDIs. More than half of these drug combinations (57.6%, n = 72) were part of commonly employed treatment regimens and may be responsible for adverse reactions that compromise the safety of elderly individuals, especially at home. Educational initiatives are needed to avoid unnecessary risks.

Clinical and Immunological Insights on Severe, Adverse Neurotropic and Viscerotropic Disease following 17D Yellow Fever Vaccination

Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-gamma R in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3(+) CD16(+/-) CD56(+/-)/CD3(+) ratio), activated T cells (CD4(+) and CD8(+) cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-gamma(+)], tumor necrosis factor alpha positive [TNF-alpha(+)], and IL-4 positive [IL-4(+)]), CD8(+) T cells (IL-4(+) and IL-5(+)), and B lymphocytes (TNF-alpha(+), IL-4(+), and IL-10(+)). The analysis of CD4(+) T cells revealed a complex profile that consisted of an increased frequency of IL-12(+) and IFN-gamma(+) cells and a decreased percentage of TNF-alpha(+), IL-4(+), and IL-5+ cells. Depressed cytokine synthesis was observed in monocytes (TNF-alpha(+)) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

Tagging Giant Otters (Pteronura brasiliensis) (Carnivora, Mustelidae) for radio-telemetry studies

Memphis Zoo, U.S. Forest Service, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico CNPq, Earthwatch Institute

Survey of Ticks (Acari: Ixodidae) and Their Rickettsia in an Atlantic Rain Forest Reserve in the State of Sao Paulo, Brazil

The current study investigated the occurrence of ticks and their rickettsiae in the Serra do Mar State Park, which encompasses one of the largest Atlantic rain forest reserves of Brazil. From July 2008 to June 2009, a total of 2,439 ticks (2,196 free living and 243 collected on hosts) was collected, encompassing the following 13 species: Amblyomma aureolatum (Pallas), Amblyomma brasiliense Aragao, Amblyomma dubitatum Neumann, Amblyomma fuscum Neumann, Amblyomma incisum Neumann, Amblyomma longirostre (Koch), Amblyomma naponense (Packard), Amblyomma nodosum Neumann, Amblyomma ovale Koch, Haemaphysalis juxtakochi Cooley, Ixodes aragaoi Fonseca, Lodes loricatus Neumann, and Rhipicephalus sanguineus (Latreille). Ticks were submitted to polymerase chain reaction assays targeting portions of the rickettsial genes gltA and ompA. Polymerase chain reaction products were DNA sequenced and compared with corresponding sequences available in GenBank. Rickettsia bellii, a rickettsia of unknown pathogenicity, was detected in one A. aureolatum, one A. ovate, and three A. incisum specimens. At least 8.8% (3/34) of the free-living A. ovale ticks, 13.6% (8/59) of the A. ovale ticks collected from dogs, and 1.9% (1/54) of the R. sanguineus (Latreille) ticks were found to be infected by Rickettsia sp strain Atlantic rain forest, a novel strain that has been shown to cause an eschar-associated spotted fever in the state of Sao Paulo. Our results suggest that A. ovale is the vector of Rickettsia sp strain Atlantic rain forest in the state of Sao Paulo.

Pharmacological Manipulation of Immune-Induced Food Aversion in Rats

Background: Mice allergic to ovalbumin (OVA) avoid drinking a solution containing this antigen. This was interpreted as related to IgE-dependent mast cell degranulation and sensory C fiber activation. Methods: We employed pharmacological manipulation to further investigate the mediators involved in immune-induced food aversion. Results: While nonimmunized rats preferred a sweetened OVA solution, immunized rats avoided it. We also employed a paradigm in which rats are conditioned to drink water for two 10-min sessions a day. Tolerant rats presented lower IgE titers, and this manipulation abrogated food aversion. Dexamethasone (1.0 mg/kg) prevented the aversion of OVA-immunized rats to the antigen-containing solution. Combined blockade of H(1) and 5-hydroxytryptamine (5-HT)(2) receptors by promethazine (3.0 mg/kg) plus methysergide (5.0 mg/kg) was unable to alter food aversion. Blockade of 5-HT(3) receptors by ondansetron (1.0 mg/kg) caused a twofold increase in the ingestion of the sweetened OVA solution by immunized rats, suggesting the involvement of 5-HT(3) receptors in food aversion. Finally, we showed that dexamethasone or promethazine plus methysergide, but not ondansetron, effectively prevented the IgE-dependent mast-cell-degranulation-induced increase in vascular permeability in rats. Conclusion: We suggest that regardless of whether or not they cause edema, IgE-mediated mast cell degranulation and consequent 5-HT(3) signaling are involved in the process that triggers avoidance to the source of the allergen in allergic rats. Copyright (C) 2008 S. Karger AG, Basel

Effect of diabetes on orthodontic tooth movement in a mouse model

Orthodontic tooth movement is achieved by the remodeling of alveolar bone in response to mechanical loading. Type 1 diabetes results in bone remodeling, suggesting that this disease might affect orthodontic tooth movement. The present study investigated the effects of the diabetic state on orthodontic tooth movement. An orthodontic appliance was placed in normoglycemic (NG), streptozotocin-induced diabetes (DB), and insulin-treated DB (IT) C57BL6/J mice. Histomorphometric analysis and quantitative PCR of periodontium were performed. The DB mice exhibited greater orthodontic tooth movement and had a higher number of tartrate-resistant acid phosphate (TRAP) -positive osteoclasts than NG mice. This was associated with increased expression of factors involved in osteoclast activity and recruitment (Rankl, Csf1, Ccl2, Ccl5, and Tnfa) in DB mice. The expression of osteoblastic markers (Runx2, Ocn, Col1, and Alp) was decreased in DB mice. Reversal of the diabetic state by insulin treatment resulted in morphological findings similar to those of NG mice. These results suggest that the diabetic state up-regulates osteoclast migration and activity and down-regulates osteoblast differentiation, resulting in greater orthodontic tooth movement.

CCR5 Down-regulates Osteoclast Function in Orthodontic Tooth Movement

During orthodontic tooth movement, there is local production of chemokines and an influx of leukocytes into the periodontium. CCL5 plays an important role in osteoclast recruitment and activation. This study aimed to investigate whether the CCR5-receptor influences these events and, consequently, orthodontic tooth movement. An orthodontic appliance was placed in wild-type mice (WT) and CCR5-deficient mice (CCR5(-/-)). The expression of mediators involved in bone remodeling was evaluated in periodontal tissues by Real-time PCR. The number of TRAP-positive osteoclasts and the expression of cathepsin K, RANKL, and MMP13 were significantly higher in CCR5(-/-). Meanwhile, the expression of two osteoblastic differentiation markers, RUNX2 and osteocalcin, and that of bone resorption regulators, IL-10 and OPG, were lower in CCR5(-/-). Analysis of the data also showed that CCR5(-/-) exhibited a greater amount of tooth movement after 7 days of mechanical loading. The results suggested that CCR5 might be a down-regulator of alveolar bone resorption during orthodontic movement.

A trag??dia da regi??o serrana do Rio de Janeiro em 2011: procurando respostas

O estudo de caso trata do desastre natural ocorrido na regi??o serrana do Rio de Janeiro nos dias 11 e 12 de janeiro de 2011, considerado a maior cat??strofe clim??tica e geot??cnica do pa??s, causado por fortes chuvas que provocaram enchentes e deslizamentos em sete munic??pios. O caso tem por finalidade despertar a discuss??o sobre as vari??veis e atores que influenciaram o processo de gest??o da crise, contextualizando o desastre no cen??rio da regi??o e reconstituindo, especialmente, o processo de resposta imediata dada ?? trag??dia pelos ??rg??os envolvidos. O estudo pode ser utilizado em cursos que abordem, entre outros, os seguintes t??picos: gest??o de crise e gest??o de riscos, negocia????o, comunica????o e planejamento estrat??gico

Sistema de coleta on-line do Censo Escolar da Educa????o B??sica (Educacenso)

O Educacenso ?? um sistema eletr??nico de coleta de informa????es educacionais composto por um aplicativo web, que permite a coleta, migra????o e altera????o de dados educacionais das escolas em todo o territ??rio nacional, e por um banco de dados relacional, que armazena de forma sistem??tica todas estas informa????es. O Educacenso representa uma inova????o, pois se trata de um banco de dados ??nico, de base nacional, alimentado por dados e informa????es que v??m diretamente das escolas, por meio da internet. Constitui-se no mais completo cadastro de escolas, alunos e docentes do pa??s. A constru????o de um banco de dados com informa????es individualizadas amplia as possibilidades de comunica????o com outras bases de dados do governo federal. O novo desenho metodol??gico e a utiliza????o de recursos de tecnologia da informa????o permitiram ampliar a precis??o e a fidedignidade dos dados do Censo Escolar, o que possibilita realiza????o de ajustes na pol??tica educacional e maior efetividade do gasto p??blico com a educa????o b??sica

??ndice de desenvolvimento da educa????o b??sica (Ideb)

O ??ndice de Desenvolvimento da Educa????o B??sica (Ideb) ?? um indicador que combina informa????es de fluxo e de desempenho dos alunos, criado para promover um sistema de accountability visando a melhoria da qualidade da educa????o no pa??s. Ao elaborar metas detalhadas para cada rede e escola ??? com as quais governadores e prefeitos se comprometeram por meio do Compromisso Todos Pela Educa????o ??? ao calcular e divulgar amplamente os resultados do Ideb, o Instituto Nacional de Estudos e Pesquisas Educacionais An??sio Teixeira (Inep) possibilitou que os atores educacionais pudessem ser responsabilizados pelos resultados de sua unidade e que o Minist??rio da Educa????o (MEC) identificasse e premiasse as escolas que atingem as metas, mas tamb??m oferecesse assist??ncia t??cnica e financeira para as redes com piores resultados. Entre os principais resultados j?? alcan??ados, pode-se destacar que o Ideb do pa??s para os anos iniciais do ensino fundamental cresceu de 3,8, em 2005, para 4,2, em 2007

Como elaborar programa de aten????o ?? sa??de da mulher que enfrente assimetrias de cor, ra??a ou etnia?

O caso aborda o processo de estrutura????o de pol??tica p??blica voltada para o combate aos preconceitos de g??nero e ra??a no Sistema ??nico de Sa??de. Por meio da experi??ncia de Ana Cl??udia, enfermeira e pesquisadora da sa??de da mulher, s??o relatados epis??dios comuns no cotidiano de mulheres negras em per??odo de pr??-natal, parto e puerp??rio. Al??m disso, ao longo da narrativa, s??o apresentadas informa????es sobre pol??ticas, planos e projetos do setor p??blico, al??m de dados de pesquisas, sobre a tem??tica da sa??de da popula????o negra e da mulher. Apesar de seu foco na estrutura????o de um programa de combate ?? discrimina????o na sa??de p??blica, o caso suscita quest??es para debate nas ??reas de diversidade racial e de g??nero, al??m de t??picos relacionados ?? gest??o de pol??ticas p??blicas. O relato pode ser aplicado em cursos sobre pol??ticas p??blicas e desenho e gest??o de programas e projetos

O sistema de avalia????o e monitoramento das pol??ticas e programas do MDS

A experi??ncia diz respeito ?? cria????o de um sistema de avalia????o e monitoramento dos programas e pol??ticas do Minist??rio de Desenvolvimento Social e Combate ?? Fome, MDS, formulado e implementado pela Secretaria de Avalia????o e Gest??o da Informa????o, SAGI. A cria????o e o conjunto de a????es dessa secretaria constituem uma inova????o na gest??o governamental brasileira, pois at?? ent??o n??o existia, em nenhum minist??rio, uma secretaria com essa finalidade exclusiva. O relato descreve, sucintamente, as a????es necess??rias para a implementa????o do sistema, apresentando-se um quadro dos recursos humanos e financeiros contratados, al??m dos resultados produzidos. Foram constru??dos e calculados 60 indicadores relativos aos programas, bem como duas ferramentas para o tratamento da informa????o: Dicion??rio de Vari??veis e Indicadores de Programas, DICI-VIP e a Matriz de Informa????es Sociais, MI Social. Na ??rea de avalia????o, existem, finalizadas, em andamento ou a contratar, 62 pesquisas, divulgadas por diferentes tipos de publica????o

Programa Bolsa Fam??lia: financiando fam??lias para o desenvolvimento

O estudo de caso trata da implementa????o do Bolsa Fam??lia, um programa de transfer??ncia de renda para fam??lias pobres, condicionada ao atendimento de exig??ncias espec??ficas por parte dos benefici??rios (comumente conhecida como ???transfer??ncia condicionada de renda???). Ap??s a descri????o dos antecedentes, apontando experi??ncias em n??vel local que inspiraram a pol??tica nacional, o autor apresenta as fases de implementa????o do programa, identificando dificuldades, cr??ticas recebidas e solu????es encontradas pelo governo federal. Em seguida, documenta impactos na redu????o da pobreza e da desigualdade social, e analisa a expans??o do espa??o p??blico originada da experi??ncia do Bolsa Fam??lia. O caso ilustra situa????o que suscita reflex??o e an??lise dos alunos com rela????o ao desenho e desenvolvimento de programa complexo de pol??tica social, podendo se desdobrar em novas pesquisas sobre o Bolsa Fam??lia, seus fatores cr??ticos e de sucesso

Mudan??a organizacional em busca da excel??ncia

Este trabalho apresenta a experi??ncia do programa de mudan??as em busca da excel??ncia do Instituto de Engenharia Nuclear (IEN), unidade da Comiss??o Nacional de Energia Nuclear, implementado por meio de uma abordagem baseada na teoria dos sistemas complexos. Foi desenvolvido um sistema adaptativo de gest??o para organiza????es que lidam com tecnologia perigosa, como a nuclear, baseado no Modelo de Excel??ncia do Pr??mio Nacional da Qualidade e na cultura de seguran??a, sendo a seguran??a tratada como dimens??o estrat??gica para a excel??ncia. A implementa????o pr??tica do sistema foi conduzida por meio de uma interven????o do tipo mudan??a facilitada, que proporcionou certo grau de governan??a ao programa. Foi obtida uma evolu????o de 119% no n??vel de excel??ncia da gest??o do IEN no per??odo entre 2000 e 2003, assim como aprimoramentos na cultura de seguran??a do instituto