Sobre el aprendizaje en salud y para la salud / About learning on and for health

Los sistemas de salud en todo el mundo están sufriendo transformaciones como consecuencia de situaciones que ejercen presiones de índole diversa que hacen no solo pertinente sino necesaria una reflexión acerca de los procesos formativos tanto de los profesionales de la salud como de las comunidades y personas del común, para que unos y otros sean partícipes de la construcción de condiciones adecuadas y sostenibles de salud y bienestar, en especial para todas y todos los colombianos. Sin embargo, tales acciones educativas requieren una articulación eficiente con un sistema de ciencia, tecnología e innovación en salud que permita la producción y apropiación de conocimiento en la frontera científica, así como la apropiación social por todos los actores sociales, de manera que se promuevan procesos de innovación tecnológica y social para responder a las necesidades y desafíos más urgentes de la salud individual y colectiva. En particular, se reflexiona sobre la necesidad de asumir lineamientos mundiales como los Objetivos de Desarrollo Sostenible y las propuestas de la Organización Mundial de la Salud. Adicionalmente, se propone tener en cuenta las ocho propuestas generales del foco de ciencias de la vida y de la salud de la Misión de Sabios 2019, así como las reflexiones particulares sobre educación para la salud: educación para una vida con bienestar, educación en salud: formación académica y profesional y educación para aportar a las acciones del sistema de salud.

Health systems around the world are undergoing transformations because of situations that exert pressures of a diverse type that make it not only pertinent, but also necessary, to analyze and modify the training processes of both health professionals and people of communities, so that both can take part in the construction of adequate and sustainable conditions of health and well-being, especially for all Colombians. However, such educational actions require an efficient articulation with a science, technology and innovation health system that allows the production and appropriation of knowledge in the scientific frontier, as well as the social appropriation by all social actors, so that they can develop processes of technological and social innovation to respond to the most urgent needs and challenges of individual and collective health. This paper reflects on the need to assume global guidelines such as the sustainable development goals and the proposals of the World Health Organization. Additionally, it considers the eight general proposals of the focus on life and health sciences of the Mission of Experts 2019, as well as the particular reflections on Health Education: education for a life with well-being, Health Education: academic and professional training, and Education to contribute to the actions of the health system.

Ciencia, tecnología e innovación en salud para pos COVID-19 / Science, technology and innovation in health for post-COVID-19

Las presiones sociales, económicas y sobre el sistema de salud que ha producido la pandemia de la COVID-19 desencadenaron situaciones de diversa índole que pusieron en evidencia las capacidades y limitaciones de los sistemas de CTI y de salud en todo el mundo. La mayor parte de los países tuvieron una respuesta errática que se concentró en la aplicación de medidas de aislamiento, distanciamiento social y uso de dispositivos de protección individual y solo fue hasta la aparición de las vacunas y su aplicación masiva que se cambiaron de forma radical las condiciones. El principal aprendizaje puede ser que para responder a los efectos globales de una enfermedad infecciosa se requiere conocimiento científico y desarrollo experimental que permitan crear e implementar iniciativas que ofrezcan las mejores alternativas para abordar los desafíos que se producirán como consecuencia de epidemias futuras. Colombia tiene la oportunidad de consolidar un sistema de CTI en salud que, además de ayudar a resolver muchas de las dificultades que se evidenciaron en el contexto de la COVID-19, podría robustecer el aparato científico para generar procesos de innovación que preparen a la sociedad para situaciones que afecten la salud de manera significativa.

The social, economic and health effects produced by the COVID-19 pandemic triggered several situations that revealed the capacities and limitations of the STI and health systems around the world. Most of the countries had an erratic response that focused on the application of isolation measures, social distancing, and the use of individual protection devices, and it was only until the appearance of vaccines and their massive application that conditions were radically changed. The main lesson may be that responding to the global effects of an infectious disease requires scientific knowledge and experimental development to create and implement initiatives that offer the best alternatives to address the challenges of future epidemics. Colombia can consolidate a STI system in health that, in addition to helping to solve many of the difficulties that became evident in the context of COVID-19, could strengthen the scientific apparatus to generate innovation processes to prepare society for those situations that significantly affect health.

Antibody Responses in COVID-19: A Review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide as a severe pandemic. Although its seroprevalence is highly variable among territories, it has been reported at around 10%, but higher in health workers. Evidence regarding cross-neutralizing response between SARS-CoV and SARS-CoV-2 is still controversial. However, other previous coronaviruses may interfere with SARS-CoV-2 infection, since they are phylogenetically related and share the same target receptor. Further, the seroconversion of IgM and IgG occurs at around 12 days post onset of symptoms and most patients have neutralizing titers on days 14-20, with great titer variability. Neutralizing antibodies correlate positively with age, male sex, and severity of the disease. Moreover, the use of convalescent plasma has shown controversial results in terms of safety and efficacy, and due to the variable immune response among individuals, measuring antibody titers before transfusion is mostly required. Similarly, cellular immunity seems to be crucial in the resolution of the infection, as SARS-CoV-2-specific CD4+ and CD8+ T cells circulate to some extent in recovered patients. Of note, the duration of the antibody response has not been well established yet.

Aerobic physical training does not condition against strenuous exercise-induced changes in immune function but modulates T cell proliferative responses.

BACKGROUND: Exercise-induced stress induces considerable changes in the immune system. To better understand the mechanisms related to these immune changes during acute and chronic physical stress, we studied the effects of aerobic physical training (APT) on several parameters of the immune system. METHODS: Previously untrained males (18-25 years of age) were divided into a group that was subjected to 6 months of APT (N.=10) and a sedentary control group (N.=7). The subjects performed a cardiopulmonary exercise test (CET) at 0, 3, and 6 months of the APT program. B cell (CD19+), T cell (CD4+ and CD8+), and natural killer cell (CD56+) levels, and mitogen-induced T cell proliferation and cytokine production (interleukin-1, interleukin-4, interleukin-12, and interferon-γ) were evaluated before and at 30 seconds and 24 hours after the CET. RESULTS: There was a significant increase in CD4+ T cells and natural killer cells and a significant reduction in T cell proliferation in both groups 30 seconds after the CET at 0, 3 and 6 months of the APT program. Of note, the trained group showed significantly lower resting T cell proliferation (before and 24 hour after the CET) than the sedentary control groups at 0, 3 and 6 months of the APT program. There were no significant differences in cytokine production after the CET between both groups at any time point of the APT program. CONCLUSIONS: These data show that APT does not condition against strenuous exercise-induced immune changes but significantly modulates T cell proliferative responses.

Characterization of nCD64 expression in neutrophils and levels of s-TREM-1 and HMGB-1 in patients with suspected infection admitted in an emergency department / Caracterización de la expresión de nCD64 en neutrófilos y de los niveles de s-TREM-1 y HMGB-1 en pacientes con sospecha de infección admitidos en el departamento de emergencias

Introduction: The nCD64 receptor, the soluble triggering receptor expressed in myeloid cells (s-TREM-1), and the high mobility group-box 1 protein (HMGB-1) have been proposed as significant mediators in sepsis. Objective: To evaluate the prognostic value of these markers in patients with suspected infection recently admitted in an emergency department (ED). Materials and methods: All patients who presented to the ED with suspected infection were eligible for enrollment in this study. Baseline clinical data, Sequential Organ Failure Assessment score (SOFA) score, APACHE II score, HMGB-1 levels, s-TREM-1 levels, and nCD64 levels were analyzed. The HMGB-1 and sTREM-1 serum concentrations were determined using commercially available ELISA kits, and CD64 on the surface of neutrophils was measured by flow cytometry. Results:. A total of 579 patients with suspected infection as their admission diagnosis were enrolled in this study. The median patient age was 50 years (IQR = 35-68). Morbidity during the 28-day followup period was 11.1% (n=64). The most frequent diagnosis at the time of admission was communityacquired pneumonia (CAP) in 23% (n=133) patients, followed by soft tissue infection in 16.6% (n=96), and urinary tract infection in 15% (n=87). After multivariable analysis, no significant association was identified between any biomarker and 28-day mortality. Conclusion: In the context of a tertiary care hospital emergency department in a Latin-American city, the nCD64 receptor, s-TREM-1, and HMGB-1 biomarkers do not demonstrate prognostic utility in the management of patients with infection. The search continues for more reliable prognostic markers in the early stages of infection.

Introducción. El receptor CD64, receptor soluble ´desencadenador´ expresado en células mieloides (sTREM-1) y la proteína del grupo Box-1 de alta movilidad (HMGB-1), se han propuesto como mediadores en la sepsis. Objetivo. Evaluar el valor pronóstico de estos marcadores en pacientes con sospecha de infección, recientemente admitidos en un departamento de emergencias. Materiales y métodos. Se incluyeron en el estudio pacientes que consultaron al hospital con sospecha de infección. Se analizó la base de datos clínica, el puntaje SOFA, el puntaje APACHE II, los niveles de HMGB-1, los niveles de sTREM-1 y los niveles de nCD64. Se determinaron las concentraciones en suero de HMGB-1 y sTREM-1, usando kits de ELISA disponibles comercialmente, y la de CD64 se midió por citometría de flujo. Resultados. Se analizaron 579 pacientes con sospecha de infección al ingreso. La edad media fue de 50 años (rango intercuartílico=35-68), y 11,1 % (n=64) murieron durante el seguimiento de 28 días. El diagnóstico más frecuente en el momento del ingreso fue neumonía adquirida en la comunidad, en 23 % (n=133) de los pacientes, seguida de infección de tejidos blandos, en 16,6 % (n=96), e infección urinaria, en 15 % (n=87). Después de un análisis multivariado, no hubo asociación significativa entre ningún biomarcador y la mortalidad a los 28 días. Conclusión. Los resultados sugieren que en el contexto de un departamento de emergencias de tercer nivel de una ciudad latinoamericana típica, los tres marcadores evaluados no ofrecieron ninguna ventaja en el pronóstico de infección. La búsqueda de marcadores pronósticos más confiables en estadios tempranos de la infección aún continúa abierta.

Characterization of nCD64 expression in neutrophils and levels of s-TREM-1 and HMGB-1 in patients with suspected infection admitted in an emergency department.

INTRODUCTION: The nCD64 receptor, the soluble triggering receptor expressed in myeloid cells (s-TREM-1), and the high mobility group-box 1 protein (HMGB-1) have been proposed as significant mediators in sepsis. OBJECTIVE: To evaluate the prognostic value of these markers in patients with suspected infection recently admitted in an emergency department (ED). MATERIALS AND METHODS: All patients who presented to the ED with suspected infection were eligible for enrollment in this study. Baseline clinical data, Sequential Organ Failure Assessment score (SOFA) score, APACHE II score, HMGB-1 levels, s-TREM-1 levels, and nCD64 levels were analyzed. The HMGB-1 and sTREM-1 serum concentrations were determined using commercially available ELISA kits, and CD64 on the surface of neutrophils was measured by flow cytometry. RESULTS: . A total of 579 patients with suspected infection as their admission diagnosis were enrolled in this study. The median patient age was 50 years (IQR = 35-68). Morbidity during the 28-day followup period was 11.1% (n=64). The most frequent diagnosis at the time of admission was communityacquired pneumonia (CAP) in 23% (n=133) patients, followed by soft tissue infection in 16.6% (n=96), and urinary tract infection in 15% (n=87). After multivariable analysis, no significant association was identified between any biomarker and 28-day mortality. CONCLUSION: In the context of a tertiary care hospital emergency department in a Latin-American city, the nCD64 receptor, s-TREM-1, and HMGB-1 biomarkers do not demonstrate prognostic utility in the management of patients with infection. The search continues for more reliable prognostic markers in the early stages of infection.

Diagnostic accuracy of HMGB-1, sTREM-1, and CD64 as markers of sepsis in patients recently admitted to the emergency department.

OBJECTIVES: The objectives were to evaluate the diagnostic accuracy for sepsis in an emergency department (ED) population of the cluster of differentiation-64 (CD64) glycoprotein expression on the surface of neutrophils (nCD64), serum levels of soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1), and high-mobility group box-1 protein (HMGB-1). METHODS: Patients with any of the following as admission diagnosis were enrolled: 1) suspected infection, 2) fever, 3) delirium, or 4) acute hypotension of unexplained origin within 24 hours of ED presentation. Levels of nCD64, HMGB-1, and s-TREM-1 were measured within the first 24 hours of the first ED evaluation. Baseline clinical data, Sepsis-related Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, daily clinical and microbiologic information, and 28-day mortality rate were collected. Because there is not a definitive criterion standard for sepsis, the authors used expert consensus based on clinical, microbiologic, laboratory, and radiologic data collected for each patient during the first 7 days of hospitalization. This expert consensus defined the primary outcome of sepsis, and the primary data analysis was based in the comparison of sepsis versus nonsepsis patients. The cut points to define sensitivity and specificity values, as well as positive and negative likelihood ratios (LRs) for the markers related to sepsis diagnosis, were determined using receiver operative characteristics (ROC) curves. The patients in this study were a prespecified nested subsample population of a larger study. RESULTS: Of 631 patients included in the study, 66% (95% confidence interval [CI] = 62% to 67%, n = 416) had sepsis according with the expert consensus diagnosis. Among these sepsis patients, SOFA score defined 67% (95% CI = 62% to 71%, n = 277) in severe sepsis and 1% (95% CI = 0.3% to 3%, n = 6) in septic shock. The sensitivities for sepsis diagnosis were CD64, 65.8% (95% CI = 61.1% to 70.3%); HMGB-1, 57.5% (95% CI = 52.7% to 62.3%); and s-TREM-1, 60% (95% CI = 55.2% to 64.7%). The specificities were CD64, 64.6% (95% CI = 57.8% to 70.8%), HMGB-1, 57.8% (95% CI = 51.1% to 64.3%), and s-TREM-1, 59.2% (95% CI = 52.5% to 65.6%). The positive LR (LR+) for CD64 was 1.85 (95% CI = 1.52 to 2.26) and the negative LR (LR-) was 0.52 (95% CI = 0.44 to 0.62]; for HMGB-1 the LR+ was 1.36 (95% CI = 1.14 to 1.63) and LR- was 0.73 (95% CI = 0.62 to 0.86); and for s-TREM-1 the LR+ was 1.47 (95% CI = 1.22 to 1.76) and the LR- was 0.67 (95% CI = 0.57 to 0.79). CONCLUSIONS: In this cohort of patients suspected of having any infection in the ED, the accuracy of nCD64, s-TREM-1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis.

New promising Euphorbiaceae extracts with activity in human lymphocytes from primary cell cultures.

CONTEXT: Euphorbiaceae plants exhibit anti-inflammatory and immunomodulatory properties. METHODS: We evaluated the activity of 14 extracts from seven Euphorbiaceae plants on primary immune cell cultures from healthy individuals. Peripheral blood mononuclear cells (PBMC) were exposed to the extracts w/o phytohaemagglutinin A or cycloheximide as agents that induce proliferation or apoptosis in PBMC, respectively. RESULTS: We found that five up to 14 Euphorbiaceae's extracts had the ability to modulate at least one of the immune parameters evaluated in this study. However, only the latex extracts of Euphorbia cotinifolia and Euphorbia tirucalli strongly induced both proliferation and apoptosis in PBMC. These extracts were further subfractioned by silica gel column chromatography. Two subfractions with enhanced activity in comparison to the crude extracts were obtained. Although these subfractions induced proliferation on both CD3(+) and CD3(-) cells, the most prominent effects were observed in the former subpopulation. Interestingly, the subfraction from E. tirucalli induced lymphocyte proliferation without the need of accessory cells; this ability was not inhibited by the carbohydrates d-galactose and α-Methyl-D-Mannopyranoside. CONCLUSIONS: Altogether, these results reveal the presence of novel candidates within the Euphorbia plants to induce proliferation and apoptosis in human lymphocytes, mainly in CD3(+) T cells.

Broad histopathologic patterns of non-glabrous skin and glabrous skin from patients with a new variant of endemic pemphigus foliaceus-part 1.

A prospective, controlled epidemiologic survey performed in El Bagre, Colombia revealed a new variant of endemic pemphigus disease, occurring in a gold mining region. The disease resembled Senear-Usher syndrome, and occurred in an endemic fashion. The aim of this study is to describe the most frequent histopathologic patterns in non-glabrous skin and in glabrous skin observed in these patients, and their clinical correlation. The study was performed on non-glabrous skin biopsies of 30 patients from the dominantly clinical affected areas (either on the chest, arms or face). Simultaneously, biopsies from the palms were obtained in 10 randomly chosen patients of the 30 total patients. The specimens were examined following hematoxylin and eosin (H&E) staining. The most common blisters observed were subcorneal, although in some cases intraspinous and subepidermal blisters were visualized. Our results showed a very heterogeneous pattern of histopathologic patterns in non-glabrous skin, which seemed to correlate with the clinical features. The most common pattern was typical pemphigus foliaceus-like, with some lupus erythematosus-like features. A non-specific, chronic dermatitis pattern prevailed in the clinically controlled patients taking daily corticosteroids. In the patients who have had the most severe and relapsing pemphigus, early sclerodermatous changes and scleredermoid alterations prevailed in their reticular dermis. In addition to the scleredermoid alterations, the reticular dermis showed a paucity of appendageal structures. On the contrary, in the palms, a similar pattern was seen in all cases, including thickening of the stratum corneum, hypergranulosis, edema in the papillary and reticular dermis and a dermal perivascular lymphocytic infiltrate. The direct immunofluorescence of the glabrous vs. the non-glabrous skin also showed some differences. We conclude that the histopathologic features of this new variant of endemic pemphigus are complex, therefore, classical histopathologic features previously described for superficial, endemic pemphigus cannot be used alone to diagnose this disease.

Ejercicio y sistema inmune / Exercise and the immune system

Se ha demostrado que el ejercicio hecho a diferentes intensidades cumple una función moduladora sobre diversos sistemas, y que su acción sobre la respuesta inmune es de gran importancia. Por lo tanto, es necesario esclarecer si estos cambios constituyen efectos benéficos o perjudiciales en cuanto a las adaptaciones del hospedero frente a diversos agentes patógenos. El estudio de estos cambios inducidos por el estrés físico puede tener un impacto grande en la comprensión y prevención de algunas enfermedades que involucran la respuesta del sistema inmune como las alergias, las infecciones, las inmunodeficiencias y el cáncer. En este artículo se presenta una revisión actualizada de la información existente al respecto, con el propósito de aportar elementos que ayuden a comprender este fenómeno biológico, así como sus implicaciones para la salud humana. Se han estudiado varios parámetros de la respuesta inmune durante el ejercicio físico, entre ellos su relación con la respuesta hormonal al estrés y el comportamiento de las diferentes hormonas de acuerdo con la intensidad de aquél. También se han evaluado los cambios en las poblaciones de células sanguíneas (linfocitos, monocitos y neutrófilos) así como el comportamiento de las citoquinas y la síntesis de inmunoglobulinas específicas. Todo esto ha permitido establecer una relación entre los sistemas inmune y neuroendocrino, la cual explicaría en gran medida los diferentes cambios que ocurren durante la actividad física en la respuesta y la adaptación inmunes, así como las diferencias de acuerdo con la intensidad y la frecuencia del estrés físico

It has been demonstrated that physical exercise, carried out at diverse intensities, modulates the function of different human body systems, and that it plays a major role in the immune response. Therefore, it is necessary to find out if these changes have benefic or harmful effects on the host adaptation against several pathogenic agents. The study of these physical-stress-induced changes might have a great impact on the comprehension and prevention of some diseases that involve activation of the immune system such as allergies, infections, immunodeficiencies and cancer. This article presents a review of current information concerning this area, with the purpose of providing concepts to help readers understand this biological phenomena and their implications in human health. Several immune response parameters have been studied during physical exercise, including their relationship with the stress-induced hormonal response and the profile of different hormones according to the intensity of physical activity. Also, changes in blood cell populations (lymphocytes, monocytes and neutrophils) and the behavior of cytokines and the synthesis of specific immune globulins have been assessed. This knowledge has allowed to establish a relationship between the immune and neuroendocrine systems, which might explain the various changes in the immune response and the adaptation seen in physical activity, as well as the differences found at diverse exercise intensity and frequency levels

A randomized clinical trial of unfractioned heparin for treatment of sepsis (the HETRASE study): design and rationale [NCT00100308].

INTRODUCTION: Infection promotes coagulation via a large number of molecular and cellular mechanisms, and this procoagulant activity has boosted basic and clinical research using anticoagulant molecules as therapeutic tools in sepsis. Heparin, which is a naturally occurring proteoglycan that acts by reducing thrombin generation and fibrin formation, has not been rigorously tested in a randomized clinical trial. METHODS: Randomized, double-masked, placebo-controlled, single-center clinical trial. Patients are recruited through the emergency room at Hospital Universitario San Vicente de Paul. This is a 650-bed University Hospital in Medellín, Colombia and is a referral center for a region with approximately 3 million habitants. The recruitment process started on July 2005 and will finish on June 2007. Patients aged 18 years or older, males or females, hospitalized with clinically or microbiological confirmed sepsis, have been included. The interventions are unfractioned heparin in low dose continuous infusion (500 units per hour for 7 days) or placebo, additionally to the standard of care for sepsis patients in Colombia. RESULTS: Our primary aims are to estimate the effects of heparin on hospital length of stay and change from baseline Multiple Organ Dysfunction (MOD) score. Secondary objectives are to estimate the effects of heparin on 28-day all-cause mortality, and to estimate the possible effect modification on 28-day all-cause mortality, in subgroups defined by source and site of infection, and baseline values of APACHE II score, MOD score and D-dimer. CONCLUSION: The available literature in animal and human research, and the understanding of the molecular biology regarding inflammation and coagulation, supports a randomized clinical trial for the use of heparin in sepsis. Our study will provide appropriate power to detect differences in valid surrogate outcomes, and it will explore important preliminary data for efficacy regarding the clinical end-point of mortality.

Diketo acids derivatives as integrase inhibitors: the war against the acquired immunodeficiency syndrome.

Since the human immunodeficiency virus was identified as etiological agent of the acquired immunodeficiency syndrome, great advances have been accomplished in the therapeutic field leading to reduced morbidity and mortality among infected patients. However, the high mutation rate of the viral genome generates strains resistant to multiple drugs, pointing to the importance of finding new therapeutic targets. Among the HIV structural genes, the POL gene codes for three essential enzymes: reverse transcriptase, protease, and integrase; nineteen of the twenty drugs currently approved by the Food and Drug Administration to treat this viral infection, inhibit the reverse transcriptase and the protease. Although intense research has been carried out in this area during the last 10 years, HIV integrase inhibitors are not yet approved for clinical use; however the fact that presence of this enzyme is a sine qua non for a productive HIV life cycle joined to its unique properties makes it a promissory target for anti-HIV therapy. Many compounds have been claimed to inhibit integrase in vitro; however, few of them have proven to have antiviral activity and low cytotoxicity in cell systems. Diketoacid derivatives are the most promising integrase inhibitors so far reported. Initially discovered independently by Shionogi & Co. and the Merck Research Laboratories, these compounds are highly specific for the integrase with potent antiviral activity in vitro and in vivo, and low cytotoxicity in cell cultures. Some of these compounds have recently entered clinical trials. Due to the high relevance of integrase inhibitors, and specifically of diketoacid derivatives, we review the latest findings and patents in this important field of research.

Epidemiological assessment of mucocutaneous infections in patients with recurrent infection syndrome.

BACKGROUND: Recurrent infection syndrome (RIS) results from repeated interactions between hosts and environmental infectious agents and is considered normal (NRIS) because of its benign evolution and positive effects in the development of normal immune responses. Abnormal RIS (ARIS) is characterized by the unusually high frequency of severe infections, either as a result of anatomical or functional abnormalities or due to primary or secondary immunodeficiencies (PIDs and SIDs, respectively). Recurrent mucocutaneous infections (MCIs) can be manifestations of RIS or ARIS and could be more frequent in primary immunodeficiencies. Similarly, etiologic agents might vary from what is observed in the general population. METHODS: We carried out a descriptive study to determine the prevalence of aerobic bacterial and fungal mucocutaneous infections in 452 patients with recurrent infections, using clinical records to establish immunological status associated with the presence and characteristics of the infections. Microbiological analyses from mucocutaneous lesions were used to confirm the etiology. RESULTS: We found mucocutaneous infections in 50 patients for a total of 62 episodes (bacterial or fungal infections in 38 vs. 12 patients, respectively). Mucocutaneous infections were more frequent (21.8% vs. 9.1%; OR = 2.8) and recurrent (8.7% vs. 0.2%; P = 0.000) in primary immunodeficient patients. Furthermore, those with defects in phagocytic cells presented more mucocutaneous infections (56.2%) than patients with other primary immunodeficiencies (11.3%; OR = 10.1). CONCLUSIONS: Bacterial and fungal mucocutaneous infections are more frequent and severe in primary immunodeficient patients, particularly those with defective phagocytosis. Early and adequate assessment of the nature of mucocutaneous infections in ARIS should impact the ability of physicians to treat promptly, avoid complications and reduce the costs of medical assistance.

p40phox: the last NADPH oxidase subunit.

The phagocytic NADPH-oxidase is a multiprotein system activated during the inflammatory response to produce superoxide anion (O2-), which is the substrate for formation of additional reactive oxygen species (ROS). The importance of this system for innate immunity is established by chronic granulomatous disease (CGD), a primary immunodeficiency caused by defects in the NADPH oxidase. In this review, we present and discuss recent knowledge about p40phox, the last NADPH oxidase component to be identified. Furthermore, its interaction with cellular pathways outside of the NADPH oxidase is discussed. Described in this review is evidence that p40phox participates in NADPH oxidase dynamics within cells, what is known about its role in the oxidase, the possibility that p40phox participates in non-NADPH oxidase processes in phagocytic and non-phagocytic cells and whether p40phox could mediate a similar function in other NADPH oxidases. An improved understanding of p40phox should provide new insights about NADPH oxidase, the physiology of phagocytic cells and the innate immune system.

Presencia de Interleuquina 8 en fluido crevicular de pacientes con periodontitis agresiva / Presence of Interleukin 8 in crevicular fluid of patients with aggressive periodontitis

La periodontitis agresiva se asocia a la presencia de periodontopatógenos y a una respuesta alterada de los polimorfonucleares neutrófilos (PMN). La interleuquina 8 (IL-8) recluta y activa estas células en los sitios de infección. En la presente investigación se analizó la presencia de IL-8 en fluido crevicular de 17 pacientes con periodontitis agresiva y 11 individuos normales. En todos los pacientes y controles se realizó evaluación médica indicadora de salud sistémica, nivel de inserción (NI), índice de placa (IP), índice de sangría (SS) y volumen de fluido crevicular (VFC) con Periotron 8000. En el fluido crevicular se midió concentración y cantidad total de IL-8 con ELISA. El análisis estadístico no mostró diferencias significativas entre los pacientes y controles en relación con relación a edad 36,94 (D. E. 8,62) y 30,18 (D. E. 8,61) y a la higiene oral IP = 49,35 por ciento (D. E. 24,65) y 34,27 por ciento(D. E. 19,45) respectivamente. Los pacientes se diferenciaron de los controles en su pérdida de inserción NI (p = 0.000039), en el SS (p = 0,007) y en el VFC (p = 0,00001). Aunque la concentración de IL-8 en pacientes y controles no mostró diferencias 315,4 y 426,4 pg/mL respectivamente (p > 0,05), el contenido total de IL-8 sí (mediana 1844,06 y 229,87 pg respectivamente, (p = 0,0013). En definitiva se demuestra asociación entre periodontitis agresiva, NI, VFC y el contenido total de IL-8. Este estudio muestra la importancia de la IL-8, fundamental en la respuesta de los PMN en la periodontitis.

La interleuquina-8 como molécula clave en el periodonto / Interleukin 8 as key molecule in periodontum

Las periodontitis son el resultado de la interacción de microorganismos periodontopáticos y la respuesta inmune del individuo. Los polimorfonucleares neutrófilos (PMN) son la primera línea de defensa celular innata en tejidos periodontales y su funcionamiento es importante en la protección inicial contra las bacterias periodontopáticas. Las quimiocinas, en especial la interleuquina 8 (IL-8), son fundamentales para el reclutamiento y activación de los PMN en los tejidos periodontales. Las bacterias estimulan la producción de IL-8 en diferentes células derivadas de los tejidos periodontales in vitro y en pacientes con periodontitis. El estímulo bacteriano puede activar varios mecanismos de señalización intracelular, sin embargo, entre las bacterias periodontopáticas hay diferencias en el estímulo que induce la producción de esta citocina: Fusobacterium (Fn) sp, Actinobacillus actinomycetemcomitans (Aa), y algunos Treponemas siempre inducen su producción. Porphyromonas gingivalis (Pg) y Treponema denticola (Td) aunque estimulan producción, presentan mecanismos que pueden llevar a la degradación rápida de esta citocina. La demostración de proteasas de Pg y el hallazgo de anticuerpos contra la IL-8 pueden explicar las variaciones en los pacientes con periodontitis y probablemente en el funcionamiento de los PMN en diferentes periodontitis agresivas. En el presente artículo revisamos las respuestas de poblaciones celulares productoras de IL-8, en tejidos periodontales y fluido crevicular de pacientes con periodontitis y su papel como molécula clave en la defensa.

Papel de los adyuvantes en la modulación de la respuesta inmune / Role of adjuvant in the modulation of immune response

La inmunoprofilaxis es una herramienta valiosa en la prevención de las enfermedades infecciosas; ésta depende de la capacidad del sistema inmune para reconocer y desencadenar una respuesta efectora y de memoria ante los estímulos antigénicos usados como vacunas. Actualmente, existe la necesidad de desarrollar y mejorar las vacunas no replicativas ya existentes de manera que modulen e incrementen la efectividad de la respuesta inmune. Los adyuvantes constituyen una opción en el mejoramiento de este tipo de vacunas ya que incorporados en la formulación de éstas aumentan, aceleran o prolongan la calidad de la respuesta inmune a antígenos específicos. Los adyuvantes pueden ser clasificados de acuerdo a su mecanismo de acción en dos tipos: inmunoestimuladores y sistemas de liberación. Los adyuvantes inmunoestimuladores son derivados de patógenos(lipopolisacáridos, CpG) y su función es activar las células del sistema inmune innato. En contraste, los sistemas de liberación son partículas (emulsiones, micropartículas, ISCOMs) encargadas de entregar el antígeno asociado a una célula presentadora de antígeno. El descubrimiento y desarrollo de nuevos adyuvantes abre la posibilidad de implementar en un futuro vacunas terapéuticas y profilácticas contra el cáncer y enfermedades infecciosas agudas y crónicas que sean más eficaces y seguras para ser utilizadas en humanos y especies animales de importancia económica.

[Expression and activity of polymorphisms in the 67-kDa protein of the NADPH oxidase system]. / Expresión y actividad de posibles polimorfismos provenientes de individuos normales en la proteína de 67 kd del sistema NADPH oxidasa utilizando el sistema COSphox.

The NADPH oxidase system plays a central role in the antimicrobial activity of phagocytes. This system is initiated by the translocation of cytosolic proteins p67phox, p47phox and p40phox to be in close contact with membrane flavocytochrome b558. This event begins the electron transfer from cytosolic NADPH to molecular oxygen to produce superoxide anions. Herein, a functional analysis is presented of p67phox polymorphisms identified from healthy humans. Mutations were generated in the p67phox cDNA by site-directed mutagenesis and then transiently expressed in COS7 cells that also expressed gp91phox, p22phox, and p47phox from stable transgenes. The changes Va1166lle, Pro329Ser and His389Gln correspond to possible polymorphisms identified in healthy individuals revealed a functional activity similar to COSphox cells transiently transfected with WT p67phox; therefore, these modifications are not associated with genetic deficiencies in NADPH oxidase. In conclusion, the COSphox system represents an easily transfectable model for analysis of NADPH oxidase function in intact cells. The analysis of mutant derivatives of p67phox provides insight into molecular mechanisms by which this subunit regulates the NADPH oxidase.

Expresión y actividad de posibles polimorfismos provenientes de individuos normales en la proteína de 67 kd del sistema NADPH oxidasa utilizando el sistema COS phox / Expression and activity of polymorphisms in the 67-kDa protein of the NADPH oxidase system

El sistema NADPH oxidasa de las células fagocíticas cumple una función importante durante la respuesta antimicrobiana del organismo. La activación de este sistema está precedida por la translocación de las proteínas citosólicas p67 phox , p47 phox y p40 phox hacia la membrana para ponerse en contacto con el flavocitocromo b 558 , lo que induce la generación del anión superóxido, un precursor de agentes microbicidas oxidantes. El presente trabajo presenta un análisis funcional del sistema NADPH oxidasa basado en los hallazgos de polimorfismos encontrados en el gen de p67 phox de individuos sanos. Para esto se generaron mutaciones en el cADN que codifica la p67 phox y se expresaron en el sistema de células COS phox . Los datos obtenidos en el presente trabajo indican que los cambios Val 166 .Ile, Pro 329 .Ser y His 389 .Gln no generan alteraciones en el funcionamiento de la p67 phox cuando su función se analizó en el sistema transgénico basado en células COS-7. Por lo tanto, estos polimorfismos no generan ningún riesgo genético de producir deficiencias en la activación del sistema NADPH oxidasa. Además, se demuestra que el modelo de células COS phox representa un nuevo sistema celular, fácilmente transfectable que permite estudiar la función del sistema NADPH oxidasa de las células fagocíticas y sus particularidades genéticas. Finalmente, los hallazgos con estos polimorfismos nos permiten avanzar en el conocimiento sobre los mecanismos moleculares involucrados en la activación del sistema NADPH oxidasa células fagocíticas

Abnormal expression of CD54 in mixed reactions of mononuclear cells from hyper-IgE syndrome patients.

Hyper-IgE syndrome (HIES) is a rare multisystem disorder characterized by increased susceptibility to infections associated with heterogeneous immunologic and non-immunologic abnormalities. Most patients consistently exhibit defective antigen-induced-T cell activation, that could be partly due to altered costimulation involving accessory molecules; however, the expression of these molecules has never been documented in HIES. Therefore, we investigated the expression of CD11a, CD28, CD40, CD54, CD80, CD86, and CD154 in peripheral blood mononuclear cells from six patients and six healthy controls by flow cytometry after autologous and mixed allogeneic reactions. Only the allogeneic stimuli induced significant proliferative responses and interleukin 2 and interferon gamma production in both groups. Most accessory, molecules showed similar expression between patients and controls with the exception of CD54, being expressed at lower levels in HIES patients regardless of the type of stimulus used. Decreased expression of CD54 could partly explain the deficient T cell activation to specific recall antigens in HIES patients, and might be responsible for their higher susceptibility to infections with defined types of microorganisms.