Detection of a novel microsporidium with intranuclear localization in farmed Penaeus vannamei from Latin America.

Microsporidia are emerging intracellular parasites of most known animal phyla in all ecological niches. In shrimp aquaculture, the microsporidium Enterocytozoon hepatopenaei (EHP) is a major cause of concern inflicting tremendous losses to shrimp producers in southeast Asia. During a histopathological examination of Penaeus vannamei samples originating in a country from Latin America presenting slow growth, we observed abnormal nuclei in the epithelial cells of the hepatopancreas. A PCR screening of the samples using DNA isolated from paraffin embedded tissues for the SSU rRNA gene of EHP provided a 149 bp amplicon. In situ hybridization using the SSU rRNA gene probe provided a positive signal in the nuclei instead of the cytoplasm. Sequence analysis of the SSU rRNA gene product revealed a 91.3 %, 89.2 % and 85.4 % sequence identity to Enterocytozoon bieneusi, E. hepatopenaei and Enterospora canceri respectively. Furthermore, phylogenetic analysis revealed the newly discovered microsporidium clustered with E. bieneusi. Considering the intranuclear location of the novel microsporidium and the differences in the sequence of the SSU rRNA, we tentatively consider this parasite a new member of the genus Enterospora sp. The pathogenicity and distribution of the shrimp Enterospora sp. are currently unknown. Our future efforts are focused on the characterization and development of diagnostic tools for this parasite to understand if it acts as an emergent pathogen that might require surveillance to prevent its spread.

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción / Expansion of family medicine in Latin America: challenges and lines of action / Expansão da medicina familiar na América Latina: desafios e linhas de ação

Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.(AU)

This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.(AU)

Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.(AU)

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción

[RESUMEN]. Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.

[ABSTRACT]. This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

[RESUMO]. Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Medicina de Família e Comunidade, Atenção Primaria e Violência: Formação e ação em Iberoamerica / Family Medicine, Primary Care and Violence: Training and action in Iberoamerica / Medicina de Família e Comunidade, Atenção Primaria e Violência: Formação e ação em Iberoamerica

Objetivo: Identificar la percepción de médicos de familia y comunidad, así como de otros profesionales de Atención Primaria, en los 20 países que conforman la Confederación Iberoamericana de Medicina de Familia (CIMF), sobre las formas de violencia más prevalentes en su país y en las comunidades que asisten. Además, identificar la percepción sobre sus propias capacitación y motivación, además aquellas de los médicos de familia en sus países, para abordar la violencia y contribuir a la cultura de la paz. Métodos: Estudio exploratorio, corte-transversal, de carácter descriptivo y enfoque cuantitativo, realizado en los 20 países miembros de CIMF, entre los meses de septiembre de 2017 a marzo de 2018. Se construyó un instrumento tipo encuesta, a partir de revisión bibliográfica del fenómeno de estudio, discusión y validación con diferentes profesionales de la medicina familiar considerados expertos en el tema. Se divulgó con el apoyo de las diferentes sociedades científicas de Medicina Familiar que componen los 20 países de CIMF, alcanzando 242 respuestas. Resultados: Más del 92% de profesionales consideran carecer de formación suficiente para abordar la violencia en su cotidianidad laboral y solo 24% considera haber recibido formación suficiente en la Cultura de Paz. Por otro lado, es alarmante en la región la percepción de prevalencia de los diversos tipos de violencia desde el punto de vista personal, familiar y comunitario. Conclusiones: Es necesario integrar en la formación de los médicos familiares y profesionales de la Atención Primaria, asimismo en los currículos de pregrado de Medicina, contenidos relacionados con el abordaje de la violencia y la contribución a la cultura de paz para superar la violencia. Es visible la brecha de conocimiento en estos temas por parte de los médicos de familia y demás profesionales que actúan en la Atención Primaria. Por otro lado, es notable el potencial beneficio de tener esos profesionales actuando en esto grave problema de salud por su elevada prevalencia y especialmente considerando su contacto frecuente y longitudinal con las personas, familias y comunidades quienes han sido víctimas de violencia.

Objective: To identify the perception of family and community doctors - as well as other professionals in 20 countries that make up the Ibero-American Confederation of Family Medicine (CIMF) - on the most prevalent forms of violence in their country and in the communities they attend. Also, to identify the perception about their own motivation and ability, as well as that of family physicians from their countries, to address violence and contribute to the culture of peace. Methods: Cross-sectional, exploratory study, descriptive and quantitative approach, carried out in the 20 member countries of CIMF, between the months of September 2017 to March 2018. A survey was designed based on a literature review of the study phenomenon, discussion and validation with different family medicine professionals considered to be experts in the subject. It was disseminated with the support of the different scientific societies of Family Medicine that make up the 20 countries of the CIMF, reaching 242 responses. Results: More than 92% of professionals consider that they lack sufficient training to deal with violence in their daily work and only 24% consider that they have received sufficient training in the Culture of Peace. On the other hand, the perception of prevalence of the different types of violence from the personal, family and community point of view in the region is alarming. Conclusions: It is necessary to integrate in the training of family doctors and primary care professionals, as well as in the undergraduate curricula of Medicine, contents related to the approach to violence and the contribution to the culture of peace to overcome violence. The knowledge gap on these issues is visible by family doctors and other professionals who work in Primary Care. On the other hand, the potential benefit of having these professionals acting in this serious and prevalent health problem is remarkable, especially considering their frequent and longitudinal contact with people, families and communities who have been victims of violence.

Objetivo: Identificar a percepção de médicos de família e comunidade, bem como outros profissionais, em 20 países que compõem a Confederação Ibero-americana de Medicina de Família (CIMF), sobre as formas mais prevalentes de violência em seu país e nas comunidades que atendem. Além disso, identificar a percepção sobre suas próprias motivação e capacitação, além daquelas dos médicos de família de seus países para abordar a violência e contribuir para a cultura da paz. Métodos: Estudo corte-transversal, exploratório, de abordagem descritiva e quantitativa, realizado nos 20 países membros da CIMF entre os meses de setembro 2017 a março de 2018. A pesquisa foi projetada com base em uma revisão da literatura sobre o fenômeno de estudo. Um questionário foi elaborado e validado com diferentes profissionais de medicina de família considerados especialistas no assunto e posteriormente disseminado com o apoio das diferentes sociedades científicas de Medicina de Família que compõem os 20 países do CIMF, alcançando 242 respostas. Resultados: Mais de 92% dos profissionais consideram que não possuem treinamento suficiente para lidar com a violência em seu cotidiano de trabalho e apenas 24% consideram que receberam treinamento suficiente na Cultura de Paz. Por outro lado, a percepção da prevalência, na região, dos diferentes tipos de violência, do ponto de vista pessoal, familiar e comunitário é alarmante. Conclusões: É necessário integrar na formação de médicos de família e os profissionais de cuidados primários, bem como nos currículos de graduação de Medicina, conteúdos relacionados com a abordagem à violência e a contribuição para a cultura da paz para a superação da mesma. A lacuna de conhecimento sobre essas questões é visível pelos médicos de família e outros profissionais que trabalham na Atenção Primára. Por outro lado, é notável, o benefício potencial de ter esses profissionais atuando nesse grave e prevalente problema de saúde, especialmente considerando seu contato frequente e longitudinal com pessoas, famílias e comunidades vítimas de violência.

[Expansion of family medicine in Latin America: challenges and lines of actionExpansão da medicina familiar na América Latina: desafios e linhas de ação]. / Expansión de la medicina familiar en América Latina: desafíos y líneas de acción.

This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción / Expansion of family medicine in Latin America: challenges and lines of action / Expansão da medicina familiar na América Latina: desafios e linhas de ação

RESUMEN Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.

ABSTRACT This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

RESUMO Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Influence of simultaneous liver and peritoneal resection on postoperative morbi-mortality and survival in patients with colon cancer treated with surgical cytoreduction and intraperitoneal hyperthermic chemotherapy. / Influencia de la resección hepática y peritoneal simultánea, en la morbimortalidad y supervivencia de los pacientes con cáncer de colon intervenidos mediante cirugía citorreductora con quimioterapia intraperitoneal hipertérmica.

INTRODUCTION: Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (HIPEC) has recently been established as the treatment of choice for selected patients with peritoneal carcinomatosis of colonic origin. Until recently, the simultaneous presence of peritoneal and hepatic dissemination has been considered a contraindication for surgery. The aim of this paper is to analyze the morbidity, mortality and survival of patients with simultaneous peritoneal and hepatic resection with HIPEC for peritoneal carcinomatosis secondary to colon cancer. METHODS: Between January 2010 and January 2015, 61 patients were operated on, 16 had simultaneous peritoneal and hepatic dissemination (group RH+), and 45 presented only peritoneal dissemination (group RH-). RESULTS: There were no differences between the groups in terms of demographic data, length of surgery and extension of peritoneal disease. Postoperative grade III-V complications were significantly higher in the RH+ group (56.3 vs. 26.6%; P=.032). For the whole group, mortality rate was 3.2% (two patients in group RH-, and none in group RH+). Patients with liver resection had a longer postoperative stay (14.4 vs. 23.1 days) (P=.027). Median overall survival was 33 months for RH-, and 36 for RH+ group. Median disease-free survival was 16 months for RH-, and 24 months for RH+ group. CONCLUSIONS: Simultaneous peritoneal cytoreduction and hepatic resection resulted in a significantly higher Clavien grade III-V morbidity and a longer hospital stay, although the results are similar to other major abdominal interventions. The application of multimodal oncological and surgical treatment may obtain similar long-term survival results in both groups.

Influencia de la resección hepática y peritoneal simultánea, en la morbimortalidad y supervivencia de los pacientes con cáncer de colon intervenidos mediante cirugía citorreductora con quimioterapia intraperitoneal hipertérmica / Influence of simultaneous liver and peritoneal resection on postoperative morbi-mortality and survival in patients with colon cancer treated with surgical cytoreduction and intraperitoneal hyperthermic chemotherapy

INTRODUCCIÓN: La citorreducción con quimioterapia intraperitoneal hipertérmica (HIPEC) se ha postulado como tratamiento de elección en pacientes seleccionados con carcinomatosis peritoneal por cáncer de colon. La presencia simultánea de diseminación peritoneal y hepática ha sido considerada una contraindicación para esta cirugía. El objetivo del presente estudio es analizar la morbimortalidad y supervivencia de los pacientes con carcinomatosis peritoneal por cáncer de colon, intervenidos mediante una citorreducción peritoneal y resección hepática simultánea con HIPEC. MÉTODOS: Entre enero de 2010 y enero de 2015 se intervinieron 61 pacientes, 45 pacientes con carcinomatosis peritoneal (grupo RH−) y 16 con carcinomatosis peritoneal y metástasis hepáticas (grupo RH+). RESULTADOS: No hubo diferencias significativas entre los 2grupos en los datos demográficos, ASA, duración de la intervención, ni extensión de la enfermedad peritoneal. Las complicaciones postoperatorias Clavien III-V fueron significativamente superiores en el grupo RH+ (56,3 vs. 26,6%; p = 0,03). La mortalidad global de la serie fue del 3,2% (2 pacientes en el grupo RH− y ninguno en el grupo RH+). Los pacientes con resección hepática presentaron una estancia hospitalaria significativamente más larga (14,4 vs. 23,1 días; p = 0,027). La mediana estimada de supervivencia global fue de 33 meses para RH− y de 36 meses para RH+, y la de supervivencia libre de enfermedad fue de 16 meses para RH− y de 24 para RH+. CONCLUSIONES: La citorreducción peritoneal con resección hepática simultánea presenta una morbilidad postoperatoria y una estancia hospitalaria significativamente mayores, aunque las cifras son similares a las de otras cirugías abdominales mayores. La aplicación de un tratamiento oncológico y quirúrgico multimodal permite obtener resultados de supervivencia similares en ambos grupos

INTRODUCTION: Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (HIPEC) has recently been established as the treatment of choice for selected patients with peritoneal carcinomatosis of colonic origin. Until recently, the simultaneous presence of peritoneal and hepatic dissemination has been considered a contraindication for surgery. The aim of this paper is to analyze the morbidity, mortality and survival of patients with simultaneous peritoneal and hepatic resection with HIPEC for peritoneal carcinomatosis secondary to colon cancer. METHODS: Between January 2010 and January 2015, 61 patients were operated on, 16 had simultaneous peritoneal and hepatic dissemination (group RH+), and 45 presented only peritoneal dissemination (group RH−). RESULTS: There were no differences between the groups in terms of demographic data, length of surgery and extension of peritoneal disease. Postoperative grade III-V complications were significantly higher in the RH+ group (56.3 vs. 26.6%; P=.032). For the whole group, mortality rate was 3.2% (two patients in group RH−, and none in group RH+). Patients with liver resection had a longer postoperative stay (14.4 vs. 23.1 days) (P=.027). Median overall survival was 33 months for RH−, and 36 for RH+ group. Median disease-free survival was 16 months for RH−, and 24 months for RH+ group. CONCLUSIONS: Simultaneous peritoneal cytoreduction and hepatic resection resulted in a significantly higher Clavien grade III-V morbidity and a longer hospital stay, although the results are similar to other major abdominal interventions. The application of multimodal oncological and surgical treatment may obtain similar long-term survival results in both groups

Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses.

Marginal zone (MZ) and B1 B cells have the capacity to respond to foreign Ags more rapidly than conventional B cells, providing early immune responses to blood-borne pathogens. Ly9 (CD229, SLAMF3), a member of the signaling lymphocytic activation molecule family receptors, has been implicated in the development and function of innate T lymphocytes. In this article, we provide evidence that in Ly9-deficient mice splenic transitional 1, MZ, and B1a B cells are markedly expanded, whereas development of B lymphocytes in bone marrow is unaltered. Consistent with an increased number of these B cell subsets, we detected elevated levels of IgG3 natural Abs and a striking increase of T-independent type II Abs after immunization with 2,4,6-trinitrophenyl-Ficoll in the serum of Ly9-deficient mice. The notion that Ly9 could be a negative regulator of innate-like B cell responses was supported by the observation that administering an mAb directed against Ly9 to wild-type mice selectively eliminated splenic MZ B cells and significantly reduced the numbers of B1 and transitional 1 B cells. In addition, Ly9 mAb dramatically diminished in vivo humoral responses and caused a selective downregulation of the CD19/CD21/CD81 complex on B cells and concomitantly an impaired B cell survival and activation in an Fc-independent manner. We conclude that altered signaling caused by the absence of Ly9 or induced by anti-Ly9 may negatively regulate development and function of innate-like B cells by modulating B cell activation thresholds. The results suggest that Ly9 could serve as a novel target for the treatment of B cell-related diseases.

Resultados de la rehabilitación multimodal en la duodenopancreatectomía cefálica / Outcomes of an enhanced recovery after surgery programme for pancreaticoduodenectomy

INTRODUCCIÓN: La rehabilitación multimodal precoz (RMP) ha demostrado en la cirugía colorrectal una reducción de la morbilidad y de la hospitalización sin comprometer la seguridad de los pacientes. La experiencia de la RMP en la duodenopancreatectomía cefálica (DPC) es más limitada. Los objetivos de este estudio fueron analizar la aplicabilidad de un programa RMP en los pacientes intervenidos mediante una DPC en nuestro medio y evaluar los resultados postoperatorios. MÉTODOS: Estudio retrospectivo utilizando una base de datos prospectiva de 41 pacientes a los que se realizó DPC y fueron incluidos en un programa de RMP. Se evaluaron 3 elementos clave: retirada precoz de sondas y drenajes, ingesta oral y movilización precoz. Las variables analizadas fueron la mortalidad, morbilidad, datos perioperatorios, estancia hospitalaria, reintervenciones y reingresos. Este grupo de pacientes fue comparado con un grupo control de 44 pacientes consecutivos, en los que se realizó una DPC con manejo postoperatorio estándar. RESULTADOS: Se estudió a 85 pacientes intervenidos con DPC (41 pacientes en el grupo RMP y 44 pacientes en el grupo control). La mortalidad global fue del 2,4%: 2 pacientes pertenecientes al grupo control. No encontramos diferencias significativas en la mortalidad, ingreso en Reanimación, reintervenciones ni reingresos. El grupo RMP presentó una morbilidad menor que el grupo control (32 vs. 48%; p = 0,072), y una estancia hospitalaria menor (14,2 vs. 18,7 días; p = 0,014). Todos los elementos clave propuestos fueron conseguidos. CONCLUSIONES: La RMP en la DPC puede implantarse con seguridad en nuestro medio. Permite unificar los cuidados perioperatorios, disminuir la variabilidad clínica y la estancia media y como consecuencia, el coste hospitalario

BACKGROUND: Enhanced recovery after surgery (ERAS) has demonstrated in colorectal surgery a reduction in morbidity and length of stay without compromising security. Experience with ERAS programs in pancreatoduodenectomy (PD) is still limited. The aims of this study were first to evaluate the applicability of an ERAS program for PD patients in our hospital, and second to analyze the postoperative results. METHODS: A retrospective study using a prospectively maintained database identified 41 consecutive PD included in an ERAS program. Key elements studied were early removal of tubes and drainages, early oral feeding and early mobilization. Variables studied were mortality, morbidity, perioperative data, length of stay, re-interventions and inpatient readmission. This group of patients was compared with an historic control group of 44 PD patients with a standard postoperative management. RESULTS: A total of 85 pancreatoduodenectomies were analyzed (41 patients in the ERAS group, and 44 patients in the control group. General mortality was 2.4% (2 patients) belonging to the control group. There were no statistical differences in mortality, length of stay in intensive care, reoperationss, and readmissions. ERAS group had a lower morbidity rate than the control group (32 vs. 48%; P=.072), as well as a lower length of stay (14.2 vs. 18.7 days). All the key ERAS proposed elements were achieved. CONCLUSIONS: ERAS programs may be implemented safely in pancreaticoduodenectomy. They may reduce the length of stay, unifying perioperative care and diminishing clinical variability and hospital costs

Outcomes of an enhanced recovery after surgery programme for pancreaticoduodenectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) has demonstrated in colorectal surgery a reduction in morbidity and length of stay without compromising security. Experience with ERAS programs in pancreatoduodenectomy (PD) is still limited. The aims of this study were first to evaluate the applicability of an ERAS program for PD patients in our hospital, and second to analyze the postoperative results. METHODS: A retrospective study using a prospectively maintained database identified 41 consecutive PD included in an ERAS program. Key elements studied were early removal of tubes and drainages, early oral feeding and early mobilization. Variables studied were mortality, morbidity, perioperative data, length of stay, re-interventions and inpatient readmission. This group of patients was compared with an historic control group of 44 PD patients with a standard postoperative management. RESULTS: A total of 85 pancreatoduodenectomies were analyzed (41 patients in the ERAS group, and 44 patients in the control group. General mortality was 2.4% (2 patients) belonging to the control group. There were no statistical differences in mortality, length of stay in intensive care, reoperationss, and readmissions. ERAS group had a lower morbidity rate than the control group (32 vs. 48%; P=.072), as well as a lower length of stay (14.2 vs. 18.7 days). All the key ERAS proposed elements were achieved. CONCLUSIONS: ERAS programs may be implemented safely in pancreaticoduodenectomy. They may reduce the length of stay, unifying perioperative care and diminishing clinical variability and hospital costs.

Role of SLAM family receptors and specific adapter SAP in innate-like lymphocytes.

Innate-like lymphocytes, which comprise an integral part of the immune system, possess unique developmental and functional capabilities that set them apart from conventional T and B lymphocytes. Strategically located to act as a first line of defense against pathogens, they behave as innate cells. To efficiently perform their innate functions, these populations are endowed with common phenotypic characteristics that include the expression of semi-invariant TCR or BCR and activation/memory cell markers. Moreover, they have the capacity to rapidly respond to pathogenic threats and the ability to ignite adaptive immune response in synchrony with myeloid cells. Indeed, all of these common features mirror a shared molecular program, in which Signaling Lymphocytic Activation Molecule Family (SLAMF) receptors and their cytoplasmic binding partner, the adapter signaling lymphocytic activation-associated protein (SAP), play a crucial role. Despite the extensive characterization of SLAMF molecules as a group of cell-surface receptors that regulate and interconnect both innate and adaptive immune cells, their relevance in innate-like lymphocyte ontogeny and physiology has recently taken center stage. Here, we review the current understanding of the roles SLAMF receptors and SAP adaptor molecules play in the biology of innate-like lymphocytes.

Determination of soluble tumor necrosis factor receptor 2 produced by alternative splicing.

Soluble cytokine receptors have proven to be very useful biomarkers in a large variety of diseases, including cancer, infections, and chronic inflammatory diseases. These soluble receptors are produced by proteolytic cleavage or alternative splicing. Several cytokine receptors including tumor necrosis factor receptor 2 (TNFR2) can be generated by both mechanisms. However, the conventional ELISA systems do not differentiate between these two types of soluble receptors. We describe a sandwich ELISA to specifically quantify soluble TNFR2 protein generated by alternative splicing. This method requires the use of a capturing monoclonal antibody (mAb) specific of an epitope present in the soluble TNFR2 generated by alternatively splicing but absent in the proteolytically generated isoform. Here we present a detailed protocol for the production and validation of such a mAb. This method has the potential to be applied for measuring other soluble cell surface molecules generated by alternative splicing.

Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens.

The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9 (-/-) mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4(+) T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses.

Cutting edge: Ly9 (CD229), a SLAM family receptor, negatively regulates the development of thymic innate memory-like CD8+ T and invariant NKT cells.

Signaling lymphocytic activation molecule family receptors and the specific adapter signaling lymphocytic activation molecule-associated protein modulate the development of innate-like lymphocytes. In this study, we show that the thymus of Ly9-deficient mice contains an expanded population of CD8 single-positive cells with the characteristic phenotype of innate memory-like CD8(+) T cells. Moreover, the proportion of these innate CD8(+) T cells increased dramatically postinfection with mouse CMV. Gene expression profiling of Ly9-deficient mice thymi showed a significant upregulation of IL-4 and promyelocytic leukemia zinc finger. Analyses of Ly9(-/-)IL4ra(-/-) double-deficient mice revealed that IL-4 was needed to generate the thymic innate CD8(+) T cell subset. Furthermore, increased numbers of invariant NKT cells were detected in Ly9-deficient thymi. In wild-type mice, IL-4 levels induced by α-galactosylceramide injection could be inhibited by a mAb against Ly9. Thus, Ly9 plays a unique role as an inhibitory cell surface receptor regulating the size of the thymic innate CD8(+) T cell pool and the development of invariant NKT cells.

Signaling lymphocyte activation molecule regulates development of colitis in mice.

BACKGROUND & AIMS: Signaling lymphocyte activation molecule (Slamf)1 is a co-stimulatory receptor on T cells and regulates cytokine production by macrophages and dendritic cells. Slamf1 regulates microbicidal mechanisms in macrophages, therefore we investigated whether the receptor affects development of colitis in mice. METHODS: We transferred CD45RB(hi) CD4(+) T cells into Rag(-/-) or Slamf1(-/-)Rag(-/-) mice to induce colitis. We also induced colitis by injecting mice with an antibody that activates CD40. We determined the severity of enterocolitis based on disease activity index, histology scores, and levels of cytokine production, and assessed the effects of antibodies against Slamf1 on colitis induction. We quantified migration of monocytes and macrophage to inflamed tissues upon induction of colitis or thioglycollate-induced peritonitis and in response to tumor necrosis factor-α in an air-pouch model of leukocyte migration. RESULTS: Colitis was reduced in Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after transfer of CD45RB(hi) CD4(+) T cells or administration of the CD40 agonist. The numbers of monocytes and macrophages were reduced in inflamed tissues of Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after induction of colitis and other inflammatory disorders. An antibody that inhibited Slamf1 reduced the level of enterocolitis in Rag(-/-) mice. CONCLUSIONS: Slamf1 contributes to the development of colitis in mice. It appears to indirectly regulate the appearance of monocytes and macrophages in inflamed intestinal tissues. Antibodies that inhibit Slamf1 reduce colitis in mice, so human SLAMF1 might be a therapeutic target for inflammatory bowel disease.

Cutting edge: Slamf8 is a negative regulator of Nox2 activity in macrophages.

Slamf8 (CD353) is a cell surface receptor that is expressed upon activation of macrophages (MΦs) by IFN-γ or bacteria. In this article, we report that a very high NADPH oxidase (Nox2) enzyme activity was found in Slamf8(-/-) MΦs in response to Escherichia coli or Staphylococcus aureus, as well as to PMA. The elevated Nox2 activity in Slamf8(-/-) MΦs was also demonstrated in E. coli or S. aureus phagosomes by using a pH indicator system and was further confirmed by a reduction in the enzyme activity after transfection of the receptor into Slamf8-deficient primary MΦs or RAW 264.7 cells. Upon exposure to bacteria or PMA, protein kinase C activity in Slamf8(-/-) MΦs is increased. This results in an enhanced phosphorylation of p40phox, one key component of the Nox2 enzyme complex, which, in turn, leads to greater Nox2 activity. Taken together, the data show that, in response to inflammation-associated stimuli, the inducible receptor Slamf8 negatively regulates inflammatory responses.

A novel isoform of the Ly108 gene ameliorates murine lupus.

Studies of human systemic lupus erythematosus patients and of murine congenic mouse strains associate genes in a DNA segment on chromosome 1 with a genetic predisposition for this disease. The systematic analysis of lupus-prone congenic mouse strains suggests a role for two isoforms of the Ly108 receptor in the pathogenesis of the disease. In this study, we demonstrate that Ly108 is involved in the pathogenesis of lupus-related autoimmunity in mice. More importantly, we identified a third protein isoform, Ly108-H1, which is absent in two lupus-prone congenic animals. Introduction of an Ly108-H1-expressing transgene markedly diminishes T cell-dependent autoimmunity in congenic B6.Sle1b mice. Thus, an immune response-suppressing isoform of Ly108 can regulate the pathogenesis of lupus.

SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages.

Phagocytosis is a pivotal process by which macrophages eliminate microorganisms after recognition by pathogen sensors. Here we unexpectedly found that the self ligand and cell surface receptor SLAM functioned not only as a costimulatory molecule but also as a microbial sensor that controlled the killing of gram-negative bacteria by macrophages. SLAM regulated activity of the NADPH oxidase NOX2 complex and phagolysosomal maturation after entering the phagosome, following interaction with the bacterial outer membrane proteins OmpC and OmpF. SLAM recruited a complex containing the intracellular class III phosphatidylinositol kinase Vps34, its regulatory protein kinase Vps15 and the autophagy-associated molecule beclin-1 to the phagosome, which was responsible for inducing the accumulation of phosphatidylinositol-3-phosphate, a regulator of both NOX2 function and phagosomal or endosomal fusion. Thus, SLAM connects the gram-negative bacterial phagosome to ubiquitous cellular machinery responsible for the control of bacterial killing.

Mouse CD84 is a pan-leukocyte cell-surface molecule that modulates LPS-induced cytokine secretion by macrophages.

CD84 is 1 of the 9 SLAM family cell-surface receptors involved in leukocyte activation. The CD84 ectodomain is highly glycosylated, and its cytoplasmic tail contains 2 copies of an ITSM, which can be phosphorylated. Here, we report that although mouse CD84 was present on all BM HSCs, its expression declined in developing thymic and BM lymphocytes. However, CD84 expression levels did increase significantly during the later maturation stages and were expressed abundantly on mature B and T cells. Among lymphocyte subsets, the highest expression was found on innate-like lymphocytes; specifically, on NKT and marginal zone B cells. Splenic CD4+ T(FH) cells exhibited higher levels of CD84 compared with the other CD4+ T cell subsets. CD84 was expressed abundantly on monocytes, macrophages, granulocytes, and DCs. Moreover, as the function of CD84 in myeloid cells remains unknown, we focused on the role this receptor plays in mouse macrophage activation. Transfection of CD84 in RAW-264.7 macrophages led to an increase in MAPK phosphorylation and NF-κB activation upon LPS stimulation. Concomitantly, the presence of CD84 increased the LPS-induced secretion of TNF-α and MCP-1 but lowered IL-10 and IL-6 production significantly. This modulatory effect was mediated by Y(300) within the second ITSM of CD84. Additionally, CD84 knock-down decreased TNF-α and IL-6 production in LPS-activated BMDMs. Taken together, these results show that mouse CD84 is a pan-leukocyte receptor, able to modulate signaling pathways downstream of TLR4, and regulates macrophage cell-fate decisions and effector functions.