Human peripheral blood V alpha 24(+) V beta 11(+) NKT cells expand following administration of alpha-galactosylceramide-pulsed dendritic cells

Background and Objectives We have undertaken the first clinical trial involving the administration of alpha-GalactosylCeramine (alpha-GalCer)-pulsed dendritic cells (DCs) to human subjects, to determine safety, optimal dose, optimal administration route and immunological effects. Materials and Methods Subjects (n = 4) with metastatic malignancy received two infusions of alpha-GalCer-pulsed DCs intravenously, and two infusions intradermally. The percentages of Valpha24 Vbeta11 NKT cells in peripheral blood (PB) were determined by three-colour flow cytometry and the PB NKT cell numbers were calculated using the total number of PB lymphocytes/ml determined by automated full-blood counts. Results No serious treatment related adverse events were observed during the study period. Administration of alpha-GalCer-pulsed DCs in vivo can significantly (P < 0.03) increase PB Valpha24(+) Vbeta11(+) NKT cell numbers above pretreatment baseline levels after the transient fall in the NKT numbers within 48 h. Conclusions Administration of alpha-GalCer-pulsed DCs is well tolerated, modulates PB Valpha24(+) Vbeta11(+) NKT cells and may have a role in the therapy of malignancies sensitive to activities of Valpha24(+) Vbeta11(+) NKT cells, or for autoimmune diseases.

Adapting immunity with subunit vaccines: case studies with group A Streptococcus and malaria

Although vaccines have widely been regarded as the most cost-effective way to improve public health, for some organisms new technological advances in vaccine design and delivery, incurring additional developmental costs, will be essential. These organisms are typically those for which natural immunity is either slow to develop or does not develop at all. Clearly, such organisms have evolved strategies to evade immune responses and innovative approaches will be required to induce a type of immune response which is both different to that which develops naturally and is effective. This article describes some approaches to develop vaccines for two such organisms (malaria parasites and Streptococcus pyogenes (group A Streptococcus)) that are associated with widespread mortality and morbidity, mostly in the poorest countries of the world. At this stage, the challenges are primarily scientific, but if these hurdles are surmounted then the challenges will become financial ones - developing much needed vaccines for people least able to afford them. (C) 2002 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved.

Systemic administration of interleukin-1 beta activates select populations of central amygdala afferents

The central nucleus of the amygdala (CeA) is activated robustly by an immune challenge such as the systemic administration of the proinflammatory cytokine interleukin-1beta (IL-1beta). Because IL-1beta is not believed to cross the blood-brain barrier in any significant amount, it is likely that IL-1beta elicits CeA cell recruitment by means of activation of afferents to the CeA. However, although many studies have investigated the origins of afferent inputs to the CeA, we do not know which of these also respond to IL-1beta. Therefore, to identify candidate neurons responsible for the recruitment of CeA cells by an immune challenge, we iontophoretically deposited a retrograde tracer, cholera toxin b-subunit (CTb), into the CeA of rats 7 days before systemic delivery of IL-1beta (1 mug/kg, i.a.). By using combined immunohistochemistry, we then quantified the number of Fos-positive CTb cells in six major regions known to innervate the CeA. These included the medial prefrontal cortex, paraventricular thalamus (PVT), ventral tegmental area, parabrachial nucleus (PB), nucleus tractus solitarius, and ventrolateral medulla. Our results show that after deposit of CTb into the CeA, the majority of double-labeled cells were located in the PB and the PVT, suggesting that CeA cell activation by systemic IL-1beta is likely to arise predominantly from cell bodies located in these regions. These findings may have significant implications in determining the central pathways involved in generating acute central responses to a systemic immune challenge. J. Comp. Neurol. 452:288-296, 2002. (C) 2002 Wiley-Liss, Inc.

Chapter 16: Prophylactic Human Papillomavirus Vaccines

Candidate prophylactic vaccines based on papillomavirus L1 virus-like particles (VLPs) are currently in human clinical trials. The main long-term goal of the vaccine is to reduce the incidence of cervical cancer and its precursors. In animal papillomavirus models, systemic immunization with L1 VLPs can induce high titers of neutralizing antibodies that confer protection against high-dose experimental papillomavirus challenge. In humans, systemic vaccination with L1 VLPs has been well tolerated and induced high serum antibody titers (at least 40 times higher than titers seen following natural infection). A recent proof of principle HPV16 L1 VLP efficacy trial has shown excellent protection against persistent HPV16 infection and associated cytological abnormalities. Large scale efficacy trials of L1 VLPs from HPV16 and 18 (the HPV types found most frequently in cervical cancer), with or without HPV6 and 11 (the HPV types responsible for most genital warts), are planned. If the results of these large trials support the encouraging results of the early trials, they should lead to a commercial prophylactic HPV vaccine. Implementation issues may include how to make the vaccine available in the developing world, where the majority of cervical cancer cases occur, the appropriate age of vaccination, and the role of male vaccination. Because a VLP vaccine is likely to provide type-specific protection, increasing the number of cancer-associated HPV types in the vaccine is a likely approach to broadening the protection to additional types. There will probably also be efforts to develop alternative vaccine formulations better suited to implementation in developing countries as well as attempts to develop vaccines with a therapeutic activity against established HPV infection because a combined prophylactic/therapeutic vaccine may be expected to have an even greater impact than a purely prophylactic vaccine on HPV induced disease.

The medicine and epidemiology of bovine respiratory disease in feedlots

Bovine Respiratory Disease (BRD) results from a complex, multifactorial interaction of stressors, animal susceptibility, and respiratory pathogens. The infectious agents associated with BRD are ubiquitous among cattle populations. Typically, one or a combination of stressors are necessary to initiate BRD. Prevention of BRD should, therefore, address management procedures to minimise stressors. Administration of vaccines against BRD agents may help reduce the incidence of BRD but is unlikely to eliminate the condition. The effectiveness of antimicrobials in the treatment of BIRD depends primarily on early recognition and treatment. The use of antioxidant vitamins, minerals or other agents in the prevention and treatment of BRD warrants further research.

??cole Nationale d'Administration Publique: d??velopper les comp??tences des fonctionnaires pour augmenter la capacit?? de L'Etat dans la gestion des politiques publiques

Plus d???une vingtaine d???ann??es d???existence d??di??es ?? la mission de d??velopper les comp??tences des fonctionnaires pour augmenter la capacit?? de l?????tat dans la gestion des politiques publiques fait de l???ENAP un mod??le dans le domaine de la formation. Rattach??e au Minist??re du Plan, du Budget et de la Gestion, l?????cole, d??s sa cr??ation en 1986, a re??ue 245 mille fonctionnaires de tout le pays. En 2007, 26 mille fonctionnaires de l???administration f??d??rale ont attendu un de nos 60 stages offerts.

Brazilian National School of Public Administration

The Brazilian National School of Public Administration (Escola Nacional de Administra????o P??blica ??? ENAP) is a public foundation linked to the Ministry of Planning, Budget and Management. Founded in 1986, its core mission is ???to develop competencies of civil servants in order to enhance government capacity for managing public policies???. To fulfill its mission, a wide program of learning and continued education is offered to public policy managers as well as e-learning and customized courses, in accordance to governmental and institutional strategic objectives. ENAP???s courses are framed according to governmental strategic demands for social inclusion, poverty reduction as well as economic development in order to strengthen the leading South American democracy. The range and diversity of its programs mirrors the challenges of deep changes in the jobs market and the work environment, faced by the current 550,000 federal civil servants and the over 7,000,000 state and municipal civil servants in Brazil, as last counted in 2006.

Preval��ncia e fatores associados �� infec����o pelo M. tuberculosis entre agentes comunit��rios de sa��de

Introdu����o: A tuberculose �� uma doen��a milenar e que, ainda hoje, constitui grave problema de sa��de p��blica em todo o mundo. Objetivo: Estimar a preval��ncia e os fatores associados �� infec����o latente pelo MTB entre Agentes Comunit��rios de Sa��de atuantes na rede b��sica de sa��de de Munic��pios priorit��rios para o controle de TB ��� Cuiab��/MT, Manaus/AM, Salvador/BA e Vit��ria/ES. M��todos: Estudo de corte transversal no qual os dados foram coletados atrav��s de question��rio, composto de quest��es abertas e fechadas sobre caracter��sticas pessoais; informa����es a respeito da tuberculose; utiliza����o de medidas preventivas, etc. Aplicou-se prova tubercul��nica, com leitura ap��s 48-72h por enfermeiros treinados, considerando como ponte de corte positivo 5 e 10 mm de endura����o. A an��lise m��ltipla foi feita por meio de regress��o log��stica hierarquica. Foram inclu��das no modelo as vari��veis que mostraram associa����o com desfecho com p<0,1. Permaneceram no modelo as vari��veis independentes que mantiveram associa����o com desfecho ap��s ajuste (p<0,05). Este estudo obteve aprova����o do Comit�� de ��tica em Pesquisa com seres humanos do Centro de Ci��ncias da Sa��de da Universidade Federal do Esp��rito Santo, n�� de registro CEP-07/2010 e das Secretarias Municipais de Sa��de, por meio de uma Carta de Apresenta����o. Resultados: 322 Agentes Comunit��rios de Sa��de (ACS) aceitaram participar voluntariamente do estudo por meio da assinatura do Termo de Consentimento Livre e Esclarecido. Destes, 10 n��o compareceram para leitura, sendo estes considerados como perdas, al��m do que um indiv��duo foi exclu��do pelo fato do teste r��pido para HIV ter resultado positivo, perfazendo uma amostra final de 311 participantes. Ainda em rela����o aos ACS triados, a positividade a Prova Tubercul��nica, levando-se em considera����o o ponto de corte ao teste de 10 mm e de 5 mm de endura����o, foi de 37,30% (IC95%: 0,31-0,42) e de 57,88% (IC95%: 0,52-0,63), respectivamente.Conclus��es: Faz-se necess��rio um programa de realiza����o de Prova Tubercul��nica, de rotina, combinado com interven����es para reduzir o risco de transmiss��o nosocomial, bem como a realiza����o de outros estudos para avaliar a efic��cia de novos testes para detec����o de tuberculose latente.

Desenvolvimento e padroniza����o de um m��todo para determina����o da sensibilidade do mycobacterium tuberculosis a f��rmacos contra tuberculose

A resist��ncia a f��rmacos antituberculose tem constitu��do uma grande amea��a ao controle da tuberculose em ��mbito mundial. A sua detec����o precoce permite ao m��dico instituir um esquema de tratamento mais adequado ao paciente e consequentemente quebrar a cadeia de transmiss��o dos bacilos. Os testes de sensibilidade a antimicrobianos atuais, embora eficientes, s��o caros e/ou demorados e/ou trabalhosos. Com base nesta premissa, nos propusemos a desenvolver e padronizar um m��todo fenot��pico direto para determina����o da sensibilidade do Mycobacterium tuberculosis a antimicrobianos de primeira linha do tratamento da tuberculose. Para o desenvolvimento deste novo teste, utilizaram-se os princ��pios do m��todo das propor����es e do exame de cultura pelo m��todo de Ogawa���Kudoh. O estudo foi dividido em duas fases. A primeira, caracterizada pelo desenvolvimento e padroniza����o do m��todo proposto e a segunda, pela an��lise da concord��ncia entre o m��todo desenvolvido e o m��todo do MGIT (padr��o-ouro). Na primeira fase, foram realizados diversos ensaios para definir: os volumes de absor����o e de libera����o de l��quidos de diferentes tipos de swab, o meio de cultura, as concentra����es dos antimicrobianos e o tempo de leitura/interpreta����o das culturas. Al��m disso, foi verificado se a amostra deveria ou n��o ser dilu��da. Com base nos resultados destes ensaios, padronizou-se o m��todo com: swab comercial, em meio de cultura Ogawa- Kudoh contendo separadamente 0,2 ��g/mL de isoniazida, 40,0 ��g/mL de rifampicina, 10,0 ��g/mL de estreptomicina e 500,0 ��g/mL de ��cido para-nitrobenz��ico. Padronizou-se ainda a inocula����o da amostra de escarro de forma direta, ou seja, sem diluir e a leitura/interpreta����o do resultado do teste no per��odo entre 21 e 28 dias. A an��lise comparativa entre este m��todo e o teste de sensibilidade a antimicrobianos no sistema MGIT realizada na segunda fase do projeto indicou um ��ndice kappa igual a 1,000, ou seja, uma concord��ncia muito boa em rela����o ao padr��o-ouro. Diante desses resultados promissores, acreditamos que o m��todo desenvolvido apresente um grande potencial para ser utilizado em laborat��rios com pouca infra-estrutura, por ser de baixo custo, f��cil execu����o e relativamente r��pido.

Avalia����o do teste Quantiferon TB Gold in tube no diagn��stico de infec����o latente pelo Mycobacterium tuberculosis em profissionais de sa��de da aten����o b��sica

Introdu����o: Os ensaios de libera����o do interferon- �� (ELIG) surgiram como uma alternativa para o diagn��stico de infec����o latente pelo Mycobacterium tuberculosis (ILTB). Neste estudo, n��s comparamos o desempenho de um dos ELIG, teste Quantiferon TB Gold in tube ��� QFT, com a prova tubercul��nica (PT) em dois pontos de corte (��� 5 mm e ��� 10 mm), em profissionais de sa��de da aten����o b��sica �� sa��de (ABS). M��todos: Estudo transversal realizado em profissionais de sa��de da ABS de quatro capitais nacionais com alta incid��ncia de TB. O resultado do teste QFT foi comparado com o resultado da PT nos pontos de corte ��� 5mm e ��� 10 mm. Resultados: Foram inclu��dos 632 profissionais de sa��de. Ao considerar o ponto de corte ��� 10 mm para a PT, a concord��ncia entre QFT e a PT foi de 69% (k = 0,31) e para o ponto de corte ��� 5 mm, a concord��ncia entre os testes foi de 57% (k = 0,22). Devido a baixa concord��ncia entre a PT e o QFT, n��s avaliamos os poss��veis fatores associados com a discord��ncia entre eles. Ao comparar o grupo PT- / QFT- com o grupo PT+ / QFT-, no ponto de corte ��� 5 mm, a idade entre 41-45 [OR = 2,70, IC 95%: 1,32-5,51] e 46-64 [OR = 2,04, IC 95%: 1,05-3,93], presen��a de cicatriz vacinal do BCG [OR = 2,72, IC 95%: 1,40-5,25] e trabalhar apenas na ABS [OR = 2,30, IC 95 %: 1,09-4,86] apresentaram associa����o estat��stica significativa. Para o ponto de corte ��� 10 mm, a presen��a de cicatriz vacinal do BCG [OR = 2,26, IC 95%: 1,03-4,91], ter tido contato domiciliar com paciente portador de tuberculose ativa [OR = 1,72, IC 95%: 1,01-2,92] e ter feito a PT anteriormente [OR = 1,66, IC 95%: 1,05-2,62] revelaram associa����o estat��stica significativa. Curiosamente, a discord��ncia observada no grupo PT- / QFT + n��o apresentou associa����o estatistica com nenhuma das vari��veis consideradas, independentemente do ponto de corte da PT. Conclus��es: Apesar de termos identificado que a vacina BCG contribuiu para a discord��ncia entre os testes, as recomenda����es brasileiras para o in��cio do tratamento da ILTB n��o devem ser alteradas devido as limita����es do QFT.

Participa����o da apolipoprote��na-E na atividade microbicida ���in vitro��� contra o Mycobacterium tuberculosis

A parede celular de Mycobacterium tuberculosis (Mtb) �� constitu��da por 60% de lip��dios, impedindo a passagem de uma grande quantidade de subst��ncias, al��m de desempenhar um importante papel na imunopatog��nese. A apresenta����o desses ant��genos aos linf��citos se d�� por meio de mol��culas do tipo CD1.Por sua vez a Apolipoprote��na-E (ApoE), glicoprote��na amplamente distribu��da nos tecidos, pode facilitar a apresenta����o de lip��dios pelo CD1. A ApoE possui tr��s principais alelos ApoE- ���2, 3 e 4, que codificam tr��s isoformas de prote��nas, tipos 2, 3 e 4, que possuem diferentes estruturas e fun����es. A presen��a de determinadas isoformas da ApoE est�� associada a doen��as infecciosas, como herpes labial, dano hep��tico severo causado pelo v��rus da hepatite C, diarr��ia infantil e tuberculose pulmonar. Neste contexto, avaliamos a participa����o da ApoE na atividade microbicida in vitro frente ao Mtb. Para tanto, foram arrolados 13 indiv��duos PPD-, 17 indiv��duos PPD+ e 4 indiv��duos com tuberculose pulmonar ativa. O uso de plasma humano depletado de ApoE nos experimentos de atividade microbicida in vitro mostraram um aumento significante (p=0,02) no n��mero de micobact��rias (431.5 �� 81.92 UFC) quando comparado ao grupo controle (313.0 �� 74.61 UFC). Esses resultados foram confirmados por um modelo experimental utilizando esplen��citos de camundongos de camundongos C57BL/6 (815.9 �� 76.32 UFC) e animais APOE nocaute (1133 �� 86.85 UFC) (p = 0.021). Quanto �� produ����o de IL-10, no grupo PPD+, observamos que o grupo com deple����o de ApoE (866.7 �� 447.8) apresentou uma produ����o menor desta citocina com rela����o ao controle infectado (1089 �� 481.3) (p=0,023). J�� em rela����o ao IFN-���, em ambos os grupos observou-se, ap��s 72 horas, uma tend��ncia �� diminui����o da produ����o dessa citocina no grupo com deple����o, com rela����o ao grupo controle. Esses dados sugerem que a ApoE tem papel distinto na ativa����o da resposta imune e sua aus��ncia pode prejudicar a resposta imune frente �� tuberculose

Security issues during Lula's administration: from the reactive to the assertive approach

Brazil's security agenda during Lula's administration was not homogeneous through the two mandates: the first tenure (2002-2006) revealed a reactive approach towards security topics, while the second one (2006-2010) was more assertive. More specifically, the shift occurred in terms of both its geographical scope - once it incorporated global issues in a more systematic way -, and instruments through which the security agenda was exercised, given the multilateral initiative of Unasur's CDS

Brazilian foreign policy towards South America during the Lula administration: caught between South America and Mercosur

The aim of this article is to analyze Brazil's foreign policy towards the South American region during President Lula's administration. As such, the article intends to highlight two specific dimensions: the extent to which foreign policy during this period has differed from previous periods and the relative importance granted by Brazilian diplomacy to recent cooperation and integration efforts, more specifically the Unasur and Mercosur. The article argues that the Lula administration has behaved differently from its predecessors by prioritizing the building up of Brazilian leadership in South America on several different fronts, especially by strengthening multilateral institutions in the region

Mapping the Obama administration's response to the Arab Spring

When the Arab Spring broke out, the United States was in a quandary over how to handle the crisis in its attempt to balance its moral obligations and ideals without undercutting its strategic interests and those of its close allies. Flaws in US diplomatic approach have contributed to one of the most serious foreign policy crisis for a US administration to date with consequential upheaval and erosion of the US-built balance of power. The reactions and policy responses of the Obama administration highlight the difficulties in grasping with the new reality in the Middle East and in enunciating a policy platform that could combine American interests and values.